The invention relates to novel 17β-substituted aza-androstane derivatives of formula

wherein carbon atoms 1 and 2 are joined by a single bond or by a double bond,

R. _! is hydrogen, methyl or ethyl,

R ₂ is hydrogen or lower alkyl,

R ₃ and R ₄ are each independently of the other hydrogen or lower alkyl, or together are

C ₂ -C ₆ alkylene,

X and Y are each independently of the other hydrogen or lower alkyl or together form a bond, and

R ₅ is hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted phenyl, halogen, cyano, formyl or free or functionally modified carboxy, and to salts of such compounds having salt-forming properties.

The invention relates also to processes for the preparation of the above-mentioned compounds as well as to pharmaceutical compositions comprising those compounds and to processes for the preparation thereof, and to the therapeutic use of those compounds and of pharmaceutical compositions comprising those compounds in warm-blooded animals, including humans.

Within the scope of this description, the definitions used hereinbefore and hereinafter have

preferably the following meanings:

The term "lower" used in connection with definitions of groups or compounds means that the corresponding groups or compounds contain up to and including 4 carbon atoms.

Lower alkyl is straight-chained or branched C ₁ -C ₄ alkyl and is, for example, n-propyl, n-butyl, isopropyl, tert-butyl and especially methyl and ethyl.

Substituents of substituted lower alkyl as the radical R ₅ are inter alia halogen, cyano, hydroxy, etherified or esterified hydroxy, carboxy or lower alkoxycarbonyl.

Halogen is, for example, fluorine, bromine and especially chlorine.

Etherified hydroxy is especially lower alkoxy, for example methoxy, ethoxy, propoxy or butoxy. Esterified hydroxy is especially hydroxy esterified by an inorganic or organic acid, especially halogen, also lower alkanoyloxy, for example acetyloxy or propionyloxy, or lower alkylsulfonyloxy, for example methylsulfonyloxy or ethylsulfonyloxy.

Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxy- carbonyl or butoxycarbonyl.

C ₂ -C ₆ alkylene is ethylene, trimethylene, tetramethylene, pentamethylene or hexamethyl- ene.

Phenyl as the radical R ₅ is unsubstituted or substituted by one, two or three substituents selected from the group consisting of halogen, cyano, carboxy and lower alkoxycarbonyl.

Functionally modified carboxy as the radical R ₅ is carboxy that is esterified or amidated or is present in salt form. Esterified carboxy is, for example, lower alkoxycarbonyl, especially ethoxycarbonyl and methoxycarbonyl. Amidated carboxy may be, for example, unsubstituted or N-lower alkylated carbamoyl.

The compounds according to the invention may also be in the form of salts, especially pharmaceutically acceptable salts, i.e. physiologically tolerable salts. Pharmaceutically unacceptable salts may also be used for isolation or purification purposes. Only pharma¬ ceutically acceptable salts are used therapeutically and those salts are therefore preferred.

For example, a compound having a free carboxy group may be in the form of a salt, preferably a physiologically tolerable salt, with a salt-forming basic component. Especially suitable are metal or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, especially tertiary monoamines and hetero- cyclic bases, for example triethylamine, tri(2-hydroxyethyl)amine, N-ethylpiperidine or N,N'-dimethylpiperazine.

The compounds of formula I have valuable pharmacological properties. They are, especially, potent inhibitors of the enzyme 5α-reductase which is responsible for the conversion of the androgen testosterone, which circulates predominantly in men, into 5α-dihydrotestosterone which has an even stronger action. 5α-dihydrotestosterone is found in increased concentrations in the prostate in cases of benign prostate hypertrophy, and it is therefore considered to be responsible for that hypertrophy. Inhibitors of 5α-reductase are therefore of great interest as therapeutic agents in the treatment of benign prostate hyperplasia and other 5α-dihydrotestosterone-dependent diseases such as Acne vulgaris, seborrhoea, female hirsutism, male hair loss, carcinoma of the prostate and the like. The inhibition of 5α-reductase can be studied, for example, in vitro using the microsome fraction of rat and/or human prostate tissue (T. Liang et al., Endocrin¬ ology 117, 571-579 (1985)). It has now been found that the compounds of formula I according to the invention have a strong inhibitory effect on the enzyme 5α-reductase.

The compounds of formula I according to the invention are therefore suitable for the therapeutic treatment, in warm-blooded animals (humans and animals), of benign prostate hypertrophy and other diseases and conditions that respond favourably to a reduction in the physiological 5α-dihydrotestosterone level, such as carcinoma of the prostate, seborrhoea, Acne vulgaris, female hirsutism, male hair loss and the like. The novel compounds can be used as enterally, for example orally, topically or parenterally, adminis- trable 5α-reductase inhibitors, for example in the form of suitable pharmaceutical compositions.

The invention relates especially to compounds of formula I wherein carbon atoms 1 and 2 are joined by a single bond or by a double bond, Rj is ethyl or especially hydrogen or methyl, R ₂ is hydrogen or lower alkyl,

R ₃ and R ₄ are each independently of the other hydrogen or lower alkyl, especially methyl, X and Y are each independently of the other hydrogen or lower alkyl, and R ₅ is hydrogen, lower alkyl, which may be unsubstituted or substituted, especially hydroxy-substituted, or is free or functionally modified carboxy, especially lower alkoxy¬ carbonyl.

The invention relates likewise to compounds of formula I wherein carbon atoms 1 and 2 are joined by a single bond or by a double bond, Rj is ethyl or especially hydrogen or methyl, R ₂ is hydrogen or lower alkyl,

R ₃ and R ₄ are each independently of the other hydrogen or lower alkyl, especially methyl, X and Y together form a bond, and

R ₅ is hydrogen, lower alkyl, which may be unsubstituted or substituted, especially hydroxy-substituted, or is free or functionally modified carboxy, especially lower alkoxy¬ carbonyl.

The invention relates especially to compounds of formula I wherein carbon atoms 1 and 2 are joined by a single bond or by a double bond,

Rj and R ₂ are hydrogen,

R ₃ and R ₄ are each independently of the other hydrogen or lower alkyl, especially methyl,

X and Y are each independently of the other hydrogen or lower alkyl, and

R ₅ is hydrogen or lower alkyl, especially methyl, and to compounds of formula I wherein carbon atoms 1 and 2 are joined by a single bond or by a double bond,

Rj and R are hydrogen,

R ₃ and R are each independently of the other hydrogen or lower alkyl, especially methyl,

X and Y together form a bond, and

R ₅ is hydrogen or lower alkyl, especially methyl.

The invention relates preferably to the compounds of formula I described in the Examples.

The compounds of the present invention are obtained by processes known per se.

The compounds of formula I according to the invention are prepared, for example, as follows:

a compound of formula

wherein carbon atoms 1 and 2 are joined by a single bond or by a double bond, Rj is as defined for formula I, and Z is a carboxy group or a reactively activated carboxy group, is reacted with a compound of formula

wherein R ₂ , R ₃ , R ₄ , R ₅ , X and Y are as defined for formula I, and, if desired, a compound of formula I obtainable in accordance with the process is converted into a different compound of formula I.

The said process is an acylation reaction. An amine of formula (III) is acylated with a carboxylic acid or with a reactive derivative thereof to form an acid amide (carboxamide), it being possible for the carboxylic acid used as acylating agent also to be activated in the presence of the compound to be acylated (see, for example, Haslam, E., Tetrahedron 36, 2409-2433 (1980)).

Carboxylic acid derivatives that can be used as acylating agents are especially reactive activated esters or reactive anhydrides and also reactive cyclic amides.

Suitable activated esters are, for example, esters of the amidino type, such as N,N'-disubstituted amidino esters obtainable, for example, by treatment of the corres¬ ponding acid of formula II wherein Z is carboxy with a suitable N.N'-disubstituted carbo-

diimide, for example N,N'-dicyclohexylcarbodiimide (carbodiimide method); thioesters, especially 2-pyridylthio esters, formed, for example, by reacting the corresponding acid with triphenylphosphine and 2,2'-dithio-dipyridine (activated thioesters method); or N-hydroxy esters, for example amino esters or amido esters, obtainable, for example, by treatment of the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthal- imide or 1 -hydroxy benzotriazole, for example by the carbodiimide method. Preferred amino esters include benzotriazol-1-yl-oxy derivatives. The latter are formed, for example, by reacting the corresponding acid of formula π wherein Z is carboxy with a suitable benzotriazole derivative, especially benzotriazol-l-yl-oxy-tris(dimethylamino)- phosphonium hexafluorophosphate (Castro's reagent) or O-(lH-benzotriazol-l-yl)- N,N,N' ,N'-tetramethyluronium hexafluorophosphate.

Suitable acid anhydrides are especially mixed anhydrides of an acid of formula II wherein Z is carboxy, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides, which are obtained, for example, by treatment of the corresponding acid with oxalyl chloride, thionyl chloride or l-chloro-l-dimethylamino-2-methyl-prop-l-ene (acid chloride method).

Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole, obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole (imidazolide method).

As mentioned, derivatives of acids that are used as acylating agents can be formed in situ. For example, N-hydroxy esters can be formed in situ by reacting a mixture of the starting material to be acylated and the acid used as acylating agent in the presence of a suitable benzotriazole derivative, for example benzotriazol-l-yl-oxy-tris(dimethylamino)phos- phonium hexafluorophosphate. It is also possible for amino or amido esters of the acids used as acylating agents to be formed in situ in the presence of the starting material to be acylated by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbo- diimide, and an N-hydroxyamine, especially hydroxybenzotriazole, or an N-hydroxy- amide, for example N-hydroxysuccinimide, where appropriate in the presence of a suitable base, for example 4-dimethylaminopyridine. N,N'-disubstituted amidino esters are formed, for example, in situ by reacting the compound to be acylated with the acid used as

acylating agent in the presence of a suitable N,N-disubstituted carbodiimide, for example N,N' -dicyclohexylcarbodiimide.

The acylation can be carried out in a manner known per se, customarily at temperatures from the freezing point to the boiling point of the reaction mixture, such as in a tempera¬ ture range of from approximately -10 to approximately +150°C, preferably from room temperature (approx. +20°C) to approximately +70°C, for example in a closed reaction vessel and/or in the atmosphere pf an inert gas, for example nitrogen, in the presence of a suitable solvent, preferably an inert solvent, such as dimethylformamide (DMF), an ether, for example tetrahydrofuran (THF), or a halogenated, especially chlorinated, aliphatic hydrocarbon, for example chloroform or methylene chloride, and where appropriate in the presence of an acid-binding agent, for example a base. A suitable base is, for example, an amine, for example a tertiary amine, such as a tri(Cι-C ₄ )alkylamine, such as trimethyl- amine, triethylamine or ethyl diisopropylamine, or an arylalkylamine, for example N,N-dimethylaniline, or a cyclic tertiary amine, for example N-C ₁ -C ₄ alkylmorpholine, for example N-methylmorpholine, or a base of the pyridine type, for example pyridine or quinoline.

Compounds of formula I obtainable in accordance with the process can be converted in a manner known per se into different compounds of formula I.

For example, compounds of formula I wherein R _! and R ₂ are hydrogen and R ₃ , R ₄ , R ₅ , X and Y are as defined for formula I can be converted by reaction with a strong base, for example sodium hydride or sodium amide, and a C C ₂ alkyl halide in an anhydrous inert solvent, for example DMF or THF, into compounds of formula I wherein R _t and R ₂ are methyl or ethyl. Compounds of formula I wherein R ₂ is lower alkyl are obtained, for example, by reacting compounds of formula I wherein R _! is methyl or ethyl, R ₂ is hydrogen and R ₃ , R ₄ and R ₅ are as defined for formula I with a Cj- alkyl halide under suitable conditions.

1,2-Saturated compounds of formula I can be dehydrogenated in a manner known per se to form the corresponding 1,2-dehydro derivatives. Biological dehydrogenating methods can be used for that purpose; for example dehydrogenation using the microorganisms Coryne- bacterium simplex or Septomyxa affinis or the enzyme systems thereof, or treatment with selenium dioxide in an organic solvent, for example tert-butyl alcohol. The dehydrogen¬ ation is, however, preferably carried out using 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

(where appropriate in the presence of bis(trimethylsilyl) trifluoroacetamide, in which case O-trimethylsilylimidate is formed as intermediate) or using benzeneseleninic acid anhydride over a period of several hours, for example 6-24 hours, and, where appropriate, at room temperature or elevated temperature, for example boiling point, in organic solvents, for example aromatic hydrocarbons, such as benzene or xylene, lower aliphatic alcohols, such as ethanol, propanol or tert-butyl alcohol, lower aliphatic ketones, such as acetone or 2-butanone, aliphatic esters, such as ethyl acetate, or cyclic ethers, such as dioxane or tetrahydrofuran.

Alkynes of formula I wherein X and Y together form a bond and Rj, R , R ₃ , R ₄ and R ₅ are as defined for formula I can be converted by reduction, especially with hydrogen in the presence of a poisoned transition metal catalyst, for example a Lindlar catalyst, into alkenes of formula I wherein X and Y are each hydrogen.

Salts of compounds of formula I having salt-forming groups can be prepared in a manner known per se. For example, salts of compounds of formula I having acid groups can be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of α-ethylcaproic acid, or with inorganic alkali metal or alkaline earth metal salts, for example sodium hydrogen carbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a slight excess of the salt-forming agent

Salts can be converted into the free compounds in customary manner, for example by treatment with suitable acids.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is interrupted at any stage, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example a salt thereof.

In the processes of the present invention starting materials that are known or that are obtainable by known methods are used (see, for example, G.H. Rasmusson et al., J. Med. Chem. 29, 2298-2315 (1986); A. Bhattacharya, J. Am. Chem. Soc. (JACS) 110, 3318 (1988); G.F. Hennion and E.G. Teach, J. Am. Chem. Soc. (JACS) 75, 1653-1654 (1953)), preferably those starting materials which result in the compounds described at the

beginning as being especially valuable.

The pharmaceutical compositions of the present invention comprising a compound of formula I can be used in the treatment of the above-mentioned indications, especially in the treatment of benign prostate hypertrophy. They comprise an effective amount of the active ingredient alone or in admixture with inorganic or organic, solid or liquid, pharma¬ ceutically acceptable carriers and, if desired, also other pharmacologically and/or therapeutically valuable compounds, for example aromatase inhibitors, and are suitable especially for enteral, for example oral or rectal, or parenteral, for example transdermal, administration or for topical application.

The present invention relates especially to pharmaceutical compositions comprising as active ingredient at least one compound of formula I according to the invention in the form of a sterile and/or isotonic aqueous solution, or alternatively in admixture with at least one solid or semi-solid carrier.

The present invention relates also to medicaments, and especially to medicaments in the form of unit dose forms comprising at least one of the compounds according to the invention alone or in admixture with one or more carriers, especially those in solid form.

The invention relates especially to medicaments in the form of tablets (including lozenges, granules and pastilles), dragέes, capsules, pills, ampoules, dry-filled vials or suppositories comprising the above-defined active ingredient alone or in admixture with one or more carriers.

Carriers for use in the pharmaceutical compositions (for example granules) for the prepar¬ ation of tablets, dragέes, capsules and pills are, for example, as follows:

a) customary pharmaceutical diluents, for example starch, sugars (such as lactose, glucose and saccharose), mannitol, sorbitol and silicic acid, b) binders, for example carboxymethylcellulose and other cellulose derivatives, alginic acid and its salts (such as sodium alginate), gelatin, and polyvinylpyrrolidone, c) humectants, for example glycerol, d) disintegrators, for example agar agar, calcium carbonate and sodium hydrogen carbonate, e) slow-release agents for retarding the uptake of the active ingredient, for example

paraffin, f) abso tion accelerators, for example quaternary ammonium compounds, g) surface-active agents, for example cetyl alcohol and glycerol monostearate, h) adsorbents, for example kaolin and bentonite, i) flow conditioners and lubricants, for example talcum, calcium stearate, magnesium stearate and solid polyethylene glycols.

The tablets, dragέes, capsules and pills comprising the above-mentioned pharmaceutical compositions according to the invention can be provided with the customary coatings and casing materials to which, if desired, colourings or pigments may be added, for example for identification purposes. The coatings may also be of a composition that allows retarded release of the active ingredient; suitable for that purpose are, for example, waxes and cellulose preparations, such as acetylcellulose phthalate, or hydroxypropylmethylcellulose phthalate.

Those compositions can also be formulated as microcapsules.

There come into consideration as rectally administrable pharmaceutical compositions, for example, suppositories comprising a combination of the active ingredient and a supposi¬ tory base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

A composition for topical application may be, for example, in the form of a gel, an oily solution or suspension, or a fatty or, especially, emulsified ointment. The concentration of active ingredient is from approximately 0.1 to approximately 1.5 mg, preferably from 0.25 to 1.0 mg, in 10 g of gel.

An oily form of administration for topical application is obtained, for example, by suspending a compound according to the invention in an oil, if desired with the addition of swelling agents, such as aluminium stearate, and/or surface-active compounds (surfactants) having an HLB value of less than 10, such as fatty acid monoesters of polyols, for example glycerol monostearate, sorbitan monolaurate, sorbitan monostearate or sorbitan monooleate. A fatty ointment is obtained, for example, by suspending a compound according to the invention, or a salt thereof, in a spreadable fatty base, if desired with the addition of a surfactant having an HLB value of less than 10. An emulsified ointment is obtained by trituration of an aqueous solution of the compound

according to the invention in a soft spreadable base with the addition of a surfactant having an HLB value of less than 10. All those forms for topical application may also comprise preservatives. The concentration of active ingredient is from approximately 0.1 to approximately 1.5 mg, preferably from 0.25 to 1.0 mg, in approximately 10 g of base.

The pharmaceutical compositions according to the invention preferably comprise from approximately 0.1 to approximately 99.5 % by weight, especially from approximately 1 to approximately 90 % by weight, active ingredient

The invention relates also to a method of treating the above-mentioned pathological conditions, the compounds according to the invention being used preferably in the form of pharmaceutical compositions. The daily dose indicated for a body weight of 70 kg in the case of parenteral or enteral administration is from approximately 1 mg to approximately 100 mg.

The above-mentioned pharmaceutical compositions and medicaments according to the invention are manufactured using conventional manufacturing processes used in the pharmaceutical industry that are known per se, for example conventional mixing, granulating, tabletting, confectioning, dissolving and lyophilising processes. The processes are, if desired, carried out under aseptic conditions or an intermediate or a finished product is sterilised.

In the following Examples, which illustrate the invention without limiting the scope thereof, the temperatures are given in degrees Celsius. All melting points are uncorrected. The angle of rotation [α] _D is measured at a temperature of 20°.

Example 1 ; N-(Prop-l-en-3-yl)-3-oxo-4-aza-5α-androstane-17β-carboxami de

1.5 g of benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, 0.6 ml of N-methylmorpholine and 2.1 ml of allylamine are added to a suspension of 957 mg (3 mmol) of 4-aza-3-oxo-5α-androstane-17β-carboxylic acid in 6.6 ml of dimethylformamide and the reaction mixture is stirred for 2 hours at room temperature. The resulting solution is diluted with chloroform and washed in succession with sodium hydrogen carbonate solution, water and saturated sodium chloride solution. The organic phase is dried with sodium sulfate and concentrated to dryness under a water-jet vacuum and then under a high vacuum. The residue is chromatographed on a column of silica gel. Elution with a mixture of methylene chloride/methanol (98:2) yields N-(prop-l-en-3-yl)-

3-oxo-4-aza-5α-androstane-17β-carboxamide; m.p. 229-230°; [α] _D = +37.4° (c = 0.545 in chloroform).

Example 2; N-(2-Methvl-but-3-vn-2-yl)-3-oxo-4-aza-5α-androstane-17β-c arbox- amide

With stirring at room temperature in an argon atmosphere, 0.6 ml of 1-chloro-l-dimethyl- amino-2-methyl-prop-l-ene is added to a suspension of 638 mg (2 mmol) of 3-oxo-4-aza- 5α-androstane-17β-carboxylic acid in 36 ml of chloroform (freshly filtered over basic aluminium oxide) and stirring is continued for 2 hours. The resulting clear solution, which comprises 3-oxo-4-aza-5α-androstane-17β-carboxylic acid chloride, is added dropwise in the course of one hour with stirring at 4° to a solution of 1.6 ml of 2-methyl-but-3-yn-2-yl- amine (2-amino-2-methyl-but-3-yne) in 6 ml of chloroform. The reaction mixture is stirred for two hours at room temperature, then diluted with 10 ml of ice- water and extracted twice with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and concentrated by evaporation. Chromatography of the residue over silica gel with a mixture of methylene chloride/methanol (98:2) yields N-(2-methyl- but-3-yn-2-yl)-3-oxo-4-aza-5α-androstane- 17β-carboxamide; m.p. 282-291 °; [α] _D = +55.2° (c = 0.415 in chloroform).

Example 3: N-(Prop-l-yn-3-vl)-3-oxo-4-aza-5α-androst-l-ene-17β-carbox amide

In the course of 6 minutes at from 10 to 15°, 1 ml of thionyl chloride in 6 ml of chloroform is added to a suspension of 319 mg (1 mmol) of 3-oxo-4-aza-5α-androst-l-ene-17β-carb- oxylic acid (J. Am. Chem. Soc.110 3318 (1988)) in 15 ml of chloroform (freshly filtered over basic aluminium oxide). The resulting solution is stirred for 1 hour at room temperature. The reaction mixture is then concentrated to dryness under a high vacuum. The residue, which comprises 3-oxo-4-aza-5α-androst-l-ene-17β-acid chloride, is suspended in 12 ml of chloroform, and in succession, with stirring at 25°C, 0.2 ml of triethylamine and 0.8 ml of propargylamine in 6 ml of chloroform are added dropwise thereto. The reaction mixture is stirred at room temperature for 30 minutes, then poured onto 40 ml of ice-water and extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution and dried and then concentrated under a water-jet vacuum. The residue is chromatographed on a column of silica gel. Elution with a mixture of methylene chloride methanol (98:2) yields N-(prop-l-yn-3-yl)-3-oxo- 4-aza-5α-androst-l-ene-17β-carboxamide which, after crystallisation from methylene chloride/diisopropyl ether, melts at 246-249°; [α] _D = -14° (c = 0.50 in chloroform).

Example 4: N-(2-Methyl-but-3-yn-2-yl)-3-oxo-4-aza-5 -androst-l-ene-17β-carbox- amide

384 mg (1 mmol) of N-(2-methyl-but-3-yn-2-yl)-3-oxo-4-aza-5α-androstane-17β-c arbox- amide, 1.4 ml of N,O-bis(trimethylsilyl) trifluoroacetamide and 238 mg of 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone are suspended in 8 ml of dioxane. Under argon, the suspension is first stirred for 4 hours at 25° and then heated under reflux for 16 hours. The dark-red solution formed during the reaction is then concentrated to half. For working up, the residue is diluted with 30 ml of methylene chloride and washed in succession with 1 % sodium bisulfite solution and saturated sodium chloride solution. The aqueous phases are then extracted with methylene chloride and the combined organic phases are dried over sodium sulfate and concentrated by evaporation. The resulting crude product is chromato- graphed over silica gel. Elution with a mixture of methylene chloride/acetone (4:1) yields N-(2-methyl-but-3-yn-2-yl)-3-oxo-4-aza-5α-androst-l-ene- 17β-carboxamide which, after crystallisation from methylene chloride/diisopropyl ether, melts at 238-242°; [α] _D = +3.3° (c = 0.457 in chloroform).

Example 5: N-(2-Methyl-but-3-en-2-yl)-3-oxo-4-aza-5α-androstane-17β-c arbox- amide

1152 mg (3 mmol) of N-(2-methyl-but-3-yn-2-yl)-3-oxo-4-aza-5α-androstane-17β-c arbox- amide are dissolved in 20 ml of tetrahydrofuran. 0.12 g of Lindlar catalyst is added to the reaction solution which is then shaken with hydrogen at 23° until the calculated amount of hydrogen (3 mmol) has been taken up and the hydrogenation has virtually ceased. The catalyst is filtered off and the solvent is evaporated off under a water-jet vacuum. Chromatography of the residue on silica gel and recrystallisation from methylene chloride/diisopropyl ether yield pure N-(2-methyl-but-3-en-2-yl)-3-oxo-4-aza- 5α-androstane-17β-carboxamide having a melting point of 229-241°; [α] = +37.4° (c = 0.545 in chloroform).

Example 6; N-(Prop-l-yn-3-vl)-3-oxo-4-aza-5α-androstane-17β-carboxami de

In a manner analogous to that described in Example 2, the resulting 3-oxo-4-aza- 5α-androstane-17β-carboxylic acid chloride is reacted with propargylamine in chloroform and processed further to yield N-(prop-l-yn-3-yl)-3-oxo-4-aza-5α-androstane-17β-carbox- amide; m.p. 221-223°; [α] _D = +38.5° (c = 0.50 in chloroform).

Example 7: N-(2-Methyl-but-3-en-2-yl)-3-oxo-4-aza-5α-androst-l-ene-17Î ²- carboxamide

Analogously to Example 4, N-(2-methyl-but-3-en-2-yl)-3-oxo-4-aza-5α-androstane- 17β-carboxamide is reacted with N,O-bis(trimethylsilyl) trifluoroacetamide and 2,3-dicyano-5,6-chlorobenzoquinone and processed further to yield N-(2-methyl-but- 3-en-2-yl)-3-oxo-4-aza-5α-androst-l-ene-17β-carboxamide, m.p. 262-263°; [α] _D = +2.4° (c = 0.50 in chloroform).

Example 8: N-(2-Methvl-but-3-vn-2-vl)-3-oxo-4-aza-5α-androst-l-ene-17Î ²-carbox- amide

In a manner analogous to that described in Example 3, the resulting 3-oxo-4-aza- 5α-androst-l-ene-17β-acid chloride is reacted with 2-methyl-but-3-yn-2-ylamine in chloroform and processed further to yield N-(2-methyl-but-3-yn-2-yl)-3-oxo-4-aza-5α- androst-l-ene-17β-carboxamide, m.p. 238-240°.

Example 9: N-(Prop-l-en-3-yl)-3-oxo-4-aza-5α-androst-l-ene-17β-carbox amide

Analogously to the process described in Example 3, the resulting 3-oxo-4-aza- 5α-androst-l-ene-17β-carboxylic acid chloride is reacted with allylamine in chloroform and processed further to yield N-(prop-l-en-3-yl)-3-oxo-4-aza-5α-androst-l-ene- 17β-carboxamide; m.p. 240-241°; [α] _D = -17.1° (c = 0.420 in chloroform).

Example 10: N-(2-Methyl-pent-3-yn-2-yl)-3-oxo-4-aza-5α-androst-l-ene-17 β- carboxamide

Analogously to the process described in Example 3, the resulting 3-oxo-4-aza- 5α-androst-l-ene-17β-carboxylic acid chloride is reacted with 2-methyl-pent-3-yn-2-yl- amine (R. D. Dillard et al., J. Org. Chem., 31., 122 (1966)) in chloroform and processed further to yield N-(2-methyl-pent-3-yn-2-yl)-3-oxo-4-aza-5α-androst-l-ene-17 β-carbox- amide; m.p. 232-235°, [α] _D = -2.4° (c = 0.50 in chloroform).

Example 11 : N-(5-Hvdroxy-2,5-dimethvl-hex-3-yn-2-yl)-3-oxo-4-aza-5α-and rost- l-ene-17β-carboxamide

Analogously to the process described in Example 3, the resulting 3-oxo-4-aza- 5α-androst-l-ene-17β-carboxylic acid chloride is reacted with 2,5-dimethyl-5-amino-3- hexyn-2-ol (CF.Hennion et al., J.Org.Chem., 21, 791 (1956)) in chloroform and processed further to yield N-(5-hydroxy-2,5-dimethyl-hex-3-yn-2-yl)-3-oxo-4-aza-5α-and rost- l-ene-17β-carboxamide.

Example 12: N-(4-Ethoxycarbonγl-2-methyl-but-3-yn-2-yl)-3-oxo-4-aza-5α -androst- l-ene-17β-carboxamide

Analogously to the process described in Example 3, the resulting 3-oxo-4-aza- 5α-androst-l-ene-17β-carboxylic acid chloride is reacted with 4-amino-4-methyl-2-pent- inoic acid ethyl ester (EP 0 133407) in chloroform and processed further to yield N-(4-ethoxycarbonyl-2-methyl-but-3-yn-2-yl)-3-oxo-4-aza-5α- androst-l-ene-17β-carbox- amide.

Example 13: N-(2-Methvl-but-3-vn-2-vl)-4-methyl-3-oxo-4-aza-5α-androsta ne- 17β-carboxamide

Analogously to the process described in Example 2, N-(2-methyl-but-3-yn-2-yl)- 4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide is prepared from 4-methyl-3-oxo- 4-aza-5α-androstane-17β-carboxylic acid (J. Med. Chem. 27, 1690 (1984)) and 2-methyl- but-3-yn-2-ylamine.

Example 14: N-(2-Methyl-but-3-yn-2-yl)-4-methyl-3-oxo-4-aza-5α-androst- l-ene- 17β-carboxamide

Analogously to the process described in Example 3, N-(2-methyl-but-3-yn-2-yl)- 4-methyl-3-oxo-4-aza-5α-androst-l-ene-17β-carboxamide is obtained from 4-methyl- 3-oxo-4-aza-5α-androst-l-ene-17β-carboxylic acid (J. Med. Chem. 29, 2298 (1986)) and 2-methyl-but-3-yn-2-ylamine.

Example 15: N-(2-Methyl-but-3-en-2-yl)-4-methyl-3-oxo-4-aza-Sα-androsta ne- 17β-carboxamide

In a manner analogous to that described in Example 5, N-(2-methyl-but-3-yn-2-yl)- 4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxamide is hydrogenated and processed further to yield N-(2-methyl-but-3-en-2-yl)-4-methyl-3-oxo-4-aza-5α-androsta ne- 17β-carboxamide.

Example 16: N-(2-Methyl-but-3-en-2-yl)-4-methyl-3-oxo-4-aza-5α-androst- l-ene- 17β-carboxamide

Analogously to Example 5, N-(2-methyl-but-3-yn-2-yl)-4-methyl-3-oxo-4-aza-5α- androst-l-ene-17β-carboxamide is converted into N-(2-methyl-but-3-en-2-yl)-4-methyl- 3-oxo-4-aza-5α-androst- 1 -ene- 17 β-carboxamide.

Example 17: Tablets comprising 10 mg of active ingredient, for example N-(2-methyl- but-3-yn-2-yl)-3-oxo-4-aza-5α-androst-l-ene-17β-carboxamid e or another compound of Examples 1 to 16, are prepared as follows:

Composition for 5000 tablets active ingredient, very finely ground 50.0 g saccharose 79.0 g gum arabic 4.75 g sorbitol 3.75 g talcum 2.5 g magnesium stearate 4.9 g mineral oil 0.1 g carboxymethylcellulose

(sodium salt) 5.0 g

Preparation: The active ingredient is mixed with the powdered saccharose and the gum arabic, sieved and granulated using an approximately 35 % aqueous sorbitol solution. The granules are passed through a sieve, dried and sieved again and then intimately mixed with the remaining excipients (the talcum, the magnesium stearate, the mineral oil and the sodium salt of carboxymethylcellulose). The mixture is compressed in customary manner to form 10 mg tablets.

Example 18: Tablets comprising 1 mg of active ingredient, for example N-(2-methyl- but-3-yn-2-yl)-3-oxo-4-aza-5α-androst-l-ene-17β-carboxamid e or another compound of Examples 1 to 16, are prepared as follows:

Composition for 50000 tablets active ingredient very finely ground 50.0 g saccharose 79.0 g gum arabic 4.75 g sorbitol 3.75 g talcum 2.5 g magnesium stearate 4.9 g mineral oil 0.1 g

carboxymethylcellulose

(sodium salt) 5.0 g

Preparation: The active ingredient is mixed with the powdered saccharose and the gum arabic, sieved and granulated using an approximately 35 % aqueous sorbitol solution. The granules are passed through a sieve, dried and sieved again and then intimately mixed with the remaining excipients (the talcum, the magnesium stearate, the mineral oil and the sodium salt of carboxymethylcellulose). The mixture is compressed in customary manner to form 1 mg tablets.