WO1994022897A1

WO1994022897A1 - 17β-SUBSTITUTED ANDROSTA-3,5-DIENE DERIVATIVES

Info

Publication number: WO1994022897A1
Application number: PCT/EP1994/000830
Authority: WO
Inventors: Michel Biollaz
Original assignee: Ciba-Geigy Ag
Priority date: 1993-04-02
Filing date: 1994-03-16
Publication date: 1994-10-13
Also published as: AU6427094A

Abstract

17β-Substituted androstane derivatives of formula (I) wherein R1 is tetrazolyl, free carboxy or functionally modified carboxy, R2 is hydrogen or lower alkyl, R3 and R4 are each independently of the other hydrogen or lower alkyl or together are C2-C6 alkylene, X and Y are each independently of the other hydrogen or lower alkyl or together form a bond, and R5 is hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted phenyl, halogen, cyano, formyl or free or functionally modified carboxy, and salts thereof, are inhibitors of 5α-reductase and can be used in the therapeutic treatment of the human and animal body.

Description

17β-substituted androsta-3.5-diene derivatives

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

wherein

Rj is tetrazolyl or free or functionally modified carboxy,

R₂ is hydrogen or lower alkyl,

R₃ and R₄ are each independently of the other hydrogen or lower alkyl or together are

C₂-C₆alkylene,

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

R₅ 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.

Functionally modified carboxy is carboxy that is esterified or amidated or is present in salt form. Esterified carboxy is, for example, lower alkoxycarbonyl, especially butoxy- carbonyl, propoxycarbonyl, ethoxycarbonyl and methoxycarbonyl. Amidated carboxy is carbamoyl, which may be unsubstituted or substituted. Substituted carbamoyl is especially lower alkyl- or aryl-carbamoyl.

Lower alkylcarbamoyl is lower alkyl- or di-lower alkyl-carbamoyl, for example methyl- carbamoyl or dimethylcarbamoyl.

Arylcarbamoyl is, for example, diphenylcarbamoyl or especially phenylcarbamoyl, the phenyl radical being unsubstituted or substituted. Substituents of substituted phenyl are inter alia free or etherified hydroxy, for example lower alkoxy, free or functionally modified carboxy, sulfo or lower alkoxycarbonyl. Preference is given to lower alkoxy, especially n-propoxy or n-butoxy, which may be unsubstituted or substituted by halogen or by free or functionally modified carboxy.

Functionally modified carboxy includes carboxy protected by a protecting group, the protecting groups used in peptide chemistry generally being used. Such a protecting group is readily removable, i.e. without undesired secondary reactions taking place, for example by solvolysis or under physiological conditions. Protecting groups of that type are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and also in "The Peptides", Vol. I, Schrϋder and LUbke, Academic Press, London, New York, 1965, and in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.

Lower alkyl is straight-chained or branched C₁-C 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 R₅ 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.

C₂-C₆alkylene is ethylene, trimethylene, tetramethylene, pentamethylene or hexamethyl- ene.

Phenyl as the radical R₅ is unsubstituted or substituted by one, two or three substituents selected from the group consisting of halogen, cyano, carboxy and lower alkoxycarbonyl.

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 ammoma 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 fractions 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 thera¬ peutic 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.

Special mention should be made of compounds of formula I wherein R_! is tetrazolyl or free or functionally modified carboxy, especially esterified carboxy or unsubstituted or N-substituted amidated carboxy, R₂ is lower alkyl or preferably hydrogen,

R₃ and R₄ 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 R₅ is hydrogen, lower alkyl, which may be unsubstituted or substituted, especially hydroxy-substituted, or is free or functionally modified carboxy, especially lower alkoxy¬ carbonyl.

Special mention should likewise be made of compounds of formula I wherein R_! is tetrazolyl or free or functionally modified carboxy, especially esterified carboxy or unsubstituted or N-substituted amidated carboxy, R₂ is lower alkyl or preferably hydrogen,

R₃ and R are each independently of the other hydrogen or lower alkyl, especially methyl, X and Y together form a bond, and

R₅ 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 R_j is free or esterified carboxy, for example ethoxycarbonyl and especially methoxy¬ carbonyl,

R₂ is lower alkyl or preferably hydrogen,

R₃ and R₄ 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 R₅ is hydrogen, lower alkyl, which may be unsubstituted or substituted, especially hydroxy-substituted, or is free or functionally modified carboxy, especially lower alkoxy¬ carbonyl, and to compounds of formula I wherein

R_] is free or esterified carboxy, for example ethoxycarbonyl and especially methoxy¬ carbonyl,

R is lower alkyl or preferably hydrogen,

R₃ and R₄ are each independently of the other hydrogen or lower alkyl, especially methyl, X and Y together form a bond, and

The invention relates especially to compounds of formula I wherein Rj is free or esterified carboxy, for example ethoxycarbonyl and especially methoxy¬ carbonyl, R₂ is hydrogen,

R₃ and R are each independently of the other hydrogen or preferably lower alkyl, especially methyl, X and Y are hydrogen, and R₅ is hydrogen or lower alkyl, especially methyl, and to compounds of formula I wherein

Rj is free or esterified carboxy, for example ethoxycarbonyl and especially methoxy¬ carbonyl, R₂ is hydrogen,

R₃ and R are each independently of the other hydrogen or preferably lower alkyl, especially methyl, X and Y together form a bond, and R₅ is hydrogen or lower alkyl, especially methyl.

Special preference is given to the compounds of formula I described in the Examples, and to salts, especially pharmaceutically acceptable salts, of such compounds having salt- forming groups.

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

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

(a) a compound of formula

wherein Rj is tetrazolyl or functionally modified carboxy, and Z is a carboxy group or a reactively activated carboxy group, is reacted with a compound of formula

wherein R₂, R₃, R₄, R₅, X and Y are as defined for formula I, or

(b) a compound of formula

wherein A is a suitable leaving group, and R₂, R₃, R₄, R₅, X and Y are as defined for formula I, is converted into a compound of formula

wherein R'_} is esterified or amidated carboxy, and, if desired, a compound of formula I obtainable in accordance with the process is converted into a different compound of formula I.

Process (a) is an acylation reaction. An amine of formula (HI) 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 l-hydroxybenzotriazole, 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' -dicyclohexylcarbodϋmide.

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 temper¬ ature 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 of 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(C₁-C₄)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-C₁-C₄alkylmorpholine, for example N-methylmorpholine, or a base of the pyridine type, for example pyridine or quinoline.

Process (b) is a carbonylation reaction which is carried out in a manner known er se (see, for example, EP 289 327 and Cacchi et al., Tetrahedron Letters 26, 1109-1112 (1985)). A suitable leaving group A in compounds of formula IV is, for example, halogen, for example chlorine or bromine, or a trihalosulfonyl group, especially the trifluoromethyl- sulfonyl group (triflate group). The reaction can, for example, be carried out by adding to a compound of formula IV a suitable base, for example a tertiary organic amine, such as trimethylamine or triethylamine, a phosphine, for example l,3-bis(diphenylphosphino)- propane or especially triphenylphosphine, a palladium(II) compound, for example palladium(II) chloride or preferably palladium(II) acetate, a lower alkanol, for example ethanol or methanol, or a suitable unsubstituted or N-monosubstituted amine, and subsequently passing carbon monoxide into the mixture.

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 R₂ is hydrogen and R_lt R₃, R₄, R₅, 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 Cι-C alkyl halide in an anhydrous inert solvent, for example DMF or THF, into compounds of formula I wherein R₂ is lower alkyl.

Alkynes of formula I wherein X and Y together form a bond and Rj, R₂, R₃, R and R₅ 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.

Compounds of formula I containing esterified carboxy can be converted into compounds having free carboxy, for example by hydrolysis with inorganic acids, such as hydrohalic acids or sulfuric acid, or with aqueous alkalis, preferably alkali metal hydroxides, such as lithium or sodium hydroxide.

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, EP 528485 and 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, pharmaceutically 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 preparation 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) absorption accelerators, for example quaternary ammonium compounds, g) surface-active compounds, 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 suppos¬ itory base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration there are especially suitable aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or aqueous injection suspensions comprising viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilisers. The active ingredient, if desired together with excipients, may also be in the form of a lyophil- isate and can be made into a solution before parenteral administration by the addition of suitable solvents.

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 ml of solution or 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 (m.p.) are uncorrected. The angle of rotation [α] is measured at a temperature of 20°.

Example 1 ; N-(2-Methvl-but-3-vn-2-yI)-3-ιnethoxvcarbonvl-androsta-3,5-diene- 17β-carboxamide

In the course of 6 minutes, at from 10 to 15°, 10 ml of thionyl chloride in 60 ml of chloro¬ form are added to a solution of 3.5 g (10 mmol) of 3-methoxycarbonyl-androsta- 3,5-diene-17β-carboxylic acid in 150 ml of chloroform (freshly filtered over basic aluminium oxide). The resulting solution is stirred at room temperature for 30 minutes. The reaction mixture is then concentrated to dryness under a high vacuum. The residue, which comprises 3-methoxycarbonyl-androsta-3,5-diene-17β-carboxylic acid chloride, is dissolved in 120 ml of chloroform and, in succession, in the course of 5 minutes, with stirring at 25°C, 0.25 ml of triethylamine and 8 ml of 2-methyl-but-3-yn-2-ylamine (2-amino-2-methyl-but-3-yne) in 60 ml of chloroform are added dropwise thereto. The reaction mixture is then stirred for 2 hours at room temperature, poured onto 200 ml of ice- water and extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried and concentrated under a water-jet vacuum. The residue is chromatographed on a column of silica gel. Elution with a mixture of toluene/- methanol (99:1) yields N-(2-methyl-but-3-yn-2-yl)-3-methoxycarbonyl-androsta- 3,5-diene-17β-carboxamide which, after crystallisation from methylene chloride/diiso- propyl ether, melts at 163-164°, [α]o = -126.4° (c = 0.459 in chloroform).

Example 2: N-(2-MethvI-but-3-en-2-vI)-3-methoxvcarbonvl-androsta-3.5-diene- 17β-carboxamide

1.5 g of benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, 0.6 ml of N-methylmorpholine and 2.1 ml of 2-methyl-but-3-en-2-ylamine are added to a suspension of 986 mg of 3-methoxycarbonyl-androsta-3,5-diene-17β-carboxylic acid in 6.0 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 then concentrated to dryness under a water-jet vacuum and under a high vacuum. The residue is chromatographed on a column of silica gel. Elution with a mixture of methylene chloride/methanol (99:1) and evapor¬ ation of the solvent yield amorphous N-(2-methyl-but-3-en-2-yl)-3-methoxycarbonyl- androsta-3,5-diene-17β-carboxamide, which melts at 65-76°.

ExamE e^ N-(2-Methyl-pent-3-yn-2-yI)-3-methoxycarbonyl-androsta-3,5-diene- 17β-carboxamide

Analogously to the process described in Example 1, the resulting 3-methoxycarbonyl- androsta-3,5-diene-17β-carboxylic acid chloride is reacted with 2-methyl-3-pentyn-2-yl- amine (R. D. Dillard et al., J. Org. Chem., 3_1, 122 (1966)) in chloroform and processed further to yield N-(2-methyl-pent-3-yn-2-yl)-3-methoxycarbonyl-androsta-3,5-diene- 17β-carboxamide. Exa ple 4; N-(2-Methyl-but-3-y n-2-yI)-3-carboxy-androsta-3,5-diene- 17β-carbox- amide

12 ml of a IN potassium hydroxide solution and 120 ml of water are added to a solution of 2.50 g of N-(2-methyl-but-3-yn-2-yl)-3-methoxycarbonyl-androsta-3,5-diene-17β-carbox- amide in 360 ml of dioxane. The reaction mixture is stirred for 3 days at room temperature and then diluted with 120 ml of water. The dioxane is then distilled off under a water-jet vacuum. The residue is mixed with 600 ml of methylene chloride and acidified with ice- cold 0.5N hydrochloric acid. The organic phase is then washed with saturated sodium chloride solution and dried over sodium sulfate. T e solvent is removed under a water-jet vacuum and the crystalline crude product is recrystallised once from methylene chloride/- methanol/diisopropyl ether. The N-(2-methyl-but-3-yn-2-yl)-3-carboxy-androsta- 3,5-diene-17β-carboxamide obtained after recrystallisation from methylene chloride/dϋso- propyl ether melts at 242-248°; [a]-~- = -133.9° (c = 0.493 in chloroform).

Example s: N-(2-Methyl-but-3-en-2-yI)-3-carboxy-androsta-3,5-diene-17β arbox- amide

Analogously to Example 4, N-(2-methyl-but-3-en-2-yl)-3-methoxycarbonyl-androsta- 3,5-diene-17β-carboxamide in dioxane is reacted with IN potassium hydroxide solution and processed further to yield N-(2-methyl-but-3-en-2-yl)-3-carboxy-androsta-3,5-diene- 17β-carboxamide, m.p. 214-218°; [α]o = -139.6° (c = 0.49 in chloroform).

Example 6: N-(2-Methyl-pent-3-yn-2-yl)-3-carboxy-androsta-3_tS-diene-17β-carbox- amide

In a manner analogous to that described in Example 4, N-(2-methyl-pent-3-yn-2-yl)- 3-methoxycarbonyl-androsta-3,5-diene-17β-carboxamide is hydrolysed with a IN potassium hydroxide solution and processed further to yield N-(2-methyl-pent-3-yn-2-yl)- 3-carboxy-androsta-3,5-diene-17β-carboxamide.

Example 7; N-(2-Methyl-but-3-yn-2-yl)-3-N-f2-(3-ethoxycarbonylpropyloxy)lphenyl- carbamoyl-androsta-3,5-diene-17β-carboxamide

With stirring in an argon atmosphere at room temperature, 0.6 ml of 1-chloro-l-dimethyl- amino-2-methyl-prop-l-ene is added to a suspension of 818 mg (2 mmol) of N-(2-methyl- but-3-yn-2-yl)-3-carboxy-androsta-3,5-diene-17β-carboxamide in 30 ml of chloroform (freshly filtered over basic aluminium oxide) and stirring is continued for two hours. The resulting clear solution, which comprises N-(2-methyl-but-3-yn-2-yl)-3-chloroformyl- androsta-3,5-diene-17β-carboxamide, is added dropwise in the course of 5 minutes with stirring at 4° to a solution of 1.2 g of 2-aminophenoxybutyric acid ethyl ester in 12 ml of chloroform. The reaction mixture is stirred for two hours at room temperature, then diluted with 30 ml of ice-water and extracted twice with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and concentrated by evapor¬ ation. Chromatography of the residue on silica gel with a hexane/acetone mixture (6:1) yields N-(2-methyl-but-3-yn-2-yl)-3-N-[2-(3-ethoxycarbonylpropyloxy)]phenyl- carbamoyl]-androsta-3,5-diene-17β-carboxamide.

Example 8: N-(2-Methyl-but-3"Vn-2-yl)-3-N-f2-(3-carboxvpropvloxy)-phenvl- carbamoyl]-androsta-3,5-diene-17β-carboxamide

1 ml of a 10 % aqueous potassium hydroxide solution is added to a solution of 614 mg (1 mmol) of N-(2-methyl-but-3-yn-2-yl)-3-N-[2-(3-ethoxycarbonylpropyloxy)phenyl- carbamoyl]-androsta-3,5-diene-17β-carboxamide in 5 ml of dioxane and the reaction mixture is stirred for 20 hours at room temperature in an argon atmosphere. The reaction mixture is diluted with 10 ml of water and the dioxane is then distilled off under a water- jet vacuum. The residue is acidified with ice-cold IN hydrochloric acid. The precipitate is suction-filtered, washed with water, dried and recrystallised once from methylene chloride/methanol/diisopropyl ether to yield N-(2-methyl-but-3-yn-2-yl)- 3-N-[2-(3-carboxypropyloxy)phenylcarbamoyl]-androsta-3,5-diene-17β-carboxamide.

Example 9: Tablets comprising 10 mg of active ingredient, for example N-(2-methyl- but-3-yn-2-yl)-3-carboxy-androsta-3,5-diene-17β-carboxamide or another compound of Examples 1 to 8, 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 10: Tablets comprising 1 mg of active ingredient, for example N-(2-methyl- but-3-yn-2-yl)-3-carboxy-androsta-3,5-diene-17β-carboxamide or another compound of Examples 1 to 8, 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.

Claims

What is claimed is:

1. A compound of formula

wherein

Ri is tetrazolyl, free carboxy or functionally modified carboxy,

R₂ is hydrogen or lower alkyl,

C -C₆alkylene,

R₅ is hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted phenyl, halogen, cyano, formyl or free or functionally modified carboxy, or a salt of such a compound having salt-forming properties.

2. A compound of formula I according to claim 1, wherein

Rj is free or esterified carboxy,

R₂ is lower alkyl or hydrogen,

R₃ and R₄ are each independently of the other hydrogen or lower alkyl,

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

R₅ is hydrogen, lower alkyl, which may be unsubstituted or substituted, or is free or functionally modified carboxy.

3. A compound of formula I according to claim 1, wherein

R_! is free or esterified carboxy,

R₂ is lower alkyl or hydrogen,

R₃ and R₄ are each independently of the other hydrogen or lower alkyl, X and Y together form a bond, and

4. A compound of formula I according to claim 1, wherein Rj is free or esterified carboxy,

R₂ is hydrogen,

R and R₄ are each independently of the other hydrogen or lower alkyl,

X and Y are hydrogen, and

R₅ is hydrogen or lower alkyl.

5. A compound of formula I according to claim 1, wherein Rj is free or esterified carboxy,

R₂ is hydrogen,

R₃ and R₄ are each independently of the other hydrogen or lower alkyl,

X and Y together form a bond, and

R₅ is hydrogen or lower alkyl.

6. A pharmaceutical composition comprising a compound of formula I according to claim 1.

7. The use of a compound of formula I according to claim 1 in a method for the thera¬ peutic treatment of the human or animal body.

8. The use of a compound of formula I according to claim 1 in the preparation of a pharmaceutical composition.

9. A process for the preparation of a compound of formula I according to claim 1, which comprises

(a) reacting a compound of formula

wherein R_j is functionally modified carboxy and Z is a carboxy group or a reactively activated carboxy group, with a compound of formula

wherein R₂, R₃, R₄, R₅, X and Y are as defined for formula I, or

(b) converting a compound of formula

wherein A is a suitable leaving group, and R₂, R₃, R₄, R₅, X and Y are as defined in claim 1, into a compound of formula

wherein R'j is esterified or amidated carboxy, and, if desired, a compound of formula I obtainable in accordance with the process is converted into a different compound of formula I.

10. N-(2-Methyl-but-3-yn-2-yl)-3-carboxy-androsta-3,5-diene-17β-carboxamide or a salt thereof according to claim 1.

11. N-(2-Methyl-but-3-en-2-yl)-3-carboxy-androsta-3,5-diene-17β-carboxamide or a salt thereof according to claim 1.

12. N-(2-Methyl-pent-3-yn-2-yl)-3-carboxy-androsta-3,5-diene-17β-carboxamide or a salt thereof according to claim 1.