SK286757B6 - 17-Methylene steroids, method for the production thereof and pharmaceutical compositions containing these compounds and the use of them - Google Patents

Abstract

Disclosed are 17-methylene steroids of formula (I), in which R4 is a halogen atom or a pseudohalogen, R10 is a hydrogen atom or a straight-chain or branched C1-4-alkyl group, R20 and R20a are, independently of one another, a hydrogen atom, a straight-chain or branched C1-4-alkyl or hydroxy-C1-4-alkyl group or one of the radicals R20 and R20a is a hydrogen atom, a straight-chain or branched C1-4-alkyl or hydroxy-C1-4-alkyl group, and the other radical is a halogen atom or a pseudohalogen, methods for the production thereof and pharmaceutical compositions containing these compounds. The inventive compounds have an active profile with a hybrid character of such that they act as inhibitors of the 5 alpha -reductase and, at the same time, as gestagens. The inventive compounds combined with other hormonal substances such as estrogen, testosterone or a potent androgen are suited as contraceptives for women and men.

Description

Technical field

The present invention relates to 17-methylene steroids, to a process for their preparation and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

The compounds of the invention have a hybrid effect profile in that they act as 5α-reductase inhibitors and at the same time as gestagens. They are therefore suitable for the treatment of diseases that occur in men and women in certain organs and tissues due to increased levels of androgens. In conjunction with other hormonal agents, such as estrogen, testosterone, and possibly a strong androgen, the compounds of the invention are useful as contraceptives for women and men.

In women, elevated levels of 5α-dihydroprogesterone may contribute to severe mental disorders in premenstrual syndrome. These disorders can also be favorably influenced by the inhibition of 5cc-reductase. The concomitant presence of gestagenic action leads to inhibition of gonadal function in male and female sex. This effect is desirable if the treatment is intended to achieve antifertile action or also inhibit hormonal secretion of the gonads. Since the inhibition of 5α-reductase in pregnant women carrying a male fetus may irreversibly interfere with the fetal development of the fetus, elimination of fertility accompanied by anti-androgen therapy is highly desirable. Possible indications are prostate disease, male type alopecia, acne and hirsutism. In adequately disposed women, difficulties in premenstrual syndrome can be alleviated.

It is therefore an object of the present invention to provide compounds which act as both 5α-reductase inhibitors and simultaneously as progestogens.

SUMMARY OF THE INVENTION

The solution to this objective is the 17-methylensteroids of formula (I)

(I) in which

R ⁴ is a hydrogen atom, a halogen atom or pseudohalogen,

R ¹⁰ represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 4 carbon atoms,

R ²⁰ and R ^20a independently of one another represent a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms or a hydroxyalkyl group containing 1 to 4 carbon atoms, or one of the radicals R ²⁰ and R ^20a represents a hydrogen atom, a straight or branched alkyl group 1-4 carbon atoms or 1-4C hydroxyalkyl and the other residue is halogen or pseudohalogen, with the exception of 4-chloro-17-methylene-4-androsten-3-one and 4-chloro-20T-fluoro 21-hydroxypregna-4,17 (20) -diene-3-one.

In addition to a hydrogen atom, R @ ⁴ can be a halogen atom such as a fluorine, chlorine, bromine or iodine atom or a pseudohalogen such as a cyanate, rhodanide, cyano or azide group, with a bromine atom and a cyano group being particularly preferred.

R ¹⁰ can be hydrogen or C 1 -C 4 straight or branched chain alkyl, examples of straight or branched C 1 -C 4 alkyl include methyl, ethyl, propyl, isopropyl , butyl, isobutyl and tert-butyl. Preferably, the symbol R ¹⁰ is H or methyl.

R ²⁰ and R ^20a may, independently of one another, denote a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms or a hydroxyalkyl group having 1 to 4 carbon atoms. In this case, R ²⁰ and R ^20a preferably represent, independently of one another, a hydrogen atom, a methyl group or a -CH ₂ OH group.

Further, the one of the radicals R ²⁰ and R ^{20 a} hydrogen, a straight or branched alkyl of 1 to 4 carbon atoms or hydroxyalkyl of 1 to 4 carbon atoms and the other radical represents a halogen such as F, Cl, Br or I , or a pseudohalogen such as a cyanate, rhodanide, cyano or azide group. Additional examples of straight or branched, alkyl groups containing 1 to 4 carbon atoms include the groups for the symbol R ^10th Straight or branched hydroxyalkyl groups having 1 to 4 carbon atoms are derived from the above-mentioned straight-chain or branched alkyl groups having 1 to 4 carbon atoms, wherein one or more hydrogen atoms are replaced by hydroxy groups.

In this case, preferably one of the radicals R ^{20 and} R ²⁰¹ is a hydrogen atom or a methyl group and the other one a halogen atom, preferably a fluorine atom, particularly preferably a chlorine or bromine atom, or a pseudohalogen, preferably an azide or rodanide group, particularly preferably cyano.

In the case of R ²⁰ and R ^20a , examples of straight or branched alkyl groups having 1 to 4 carbon atoms are those given for R ¹⁰ . Straight or branched hydroxyalkyl groups containing 1 to 4 carbon atoms are derived from these alkyl groups containing 1 to 4 carbon atoms, wherein one or more hydrogen atoms are replaced by hydroxy groups, in particular - (CH ₂ ) _n -OH, where n is 1 to 4.

The following compounds are most preferred:

(1) E-17-chloromethylene-4-chloro-estr-4-en-3-one, (2) E'-17-cyanomethylene-4-chloro-estr-4-en-3-one, (3) Z-17-cyano-methylene-4-chloro-estr-4-en-3-one; (4) Z-20-cyano-4-chloro-19-norpregna-4,17 (20) -dien-3-one , (5) Ζ-4-chloro-19-norpregna-4,17 (20) -dien-3-one, (6) η-4-chloro-19-norpregna-4,17 (20) -dien-3 (7) E-17-bromomethylene-4-chloro-estr-4-en-3-one; (8) Z-20-chloro-19-norpregna-4,17 (20) -dien-3- (9) Z-4,20-dichloro-19-norpregna-4,17 (20) -dien-3-one; (10) Z-20-bromo-4-chloro-19-norpregna-4; 17 (20) -dien-3-one, (11) E-17-chloromethylene-4-cyano-androst-4-en-3-one, (12) E-17-chloromethylene-4-chloro-androst-4 -en-3-one, (1 S) -21-hydroxy-4-chloro-19-norpregna-4,17 (2 S) -dien-3-one and (14) 2 -21-hydroxy-4-chloro -19-nor-pregna-4,17 (20) -diene-3-one.

The present invention further provides pharmaceutical compositions comprising at least one 17-methylene steroid of formula (I) as an active ingredient, optionally containing suitable excipients and carriers, and the use of these compounds for the preparation of a medicament, in particular for the aforementioned indications.

The amount of compound of formula (I) administered is within a wide range and may include any effective amount. Depending on the condition to be treated and the route of administration, the amount of compound administered may be 0.01 pg / kg to 10 mg / kg body weight, preferably 0.04 pg / kg to 1 mg / kg body weight per day.

In humans, this corresponds to a dose of from 0.8 pg to 800 mg, preferably 3.2 pg to 80 mg per day.

The dosage unit of the invention contains 1.6 µg to 200 mg of one or more compounds of formula (I).

The compounds of the invention are suitable for the preparation of pharmaceutical compositions and preparations. The pharmaceutical compositions or medicaments contain as active ingredient one or more compounds according to the invention, optionally in admixture with other pharmacologically or pharmaceutically active substances. The preparation of the medicament is carried out in a known manner, using known and customary pharmaceutical excipients as well as various conventional carriers and diluents.

Suitable such carriers and excipients are, for example, those offered or referred to in the following literature as pharmaceutical, cosmetic and allied excipients: Ullmans Encyklopädie der technischen Chcmie, Vol. 4 (1953), p. 1 to 39; Joumal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918 et seq., H.V. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und Angrenzende Gebiete; Pharm. Ind., Notebook 2, 1961, p. 72 et seq. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und Angrenzende Gebiete, Cantor KG. Aulendorf in Wurttemberg 1971

The compounds may be administered orally or parenterally, for example, intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted into tissue.

For oral administration, capsules, pills, tablets, dragees, etc. are contemplated. Dosage units may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier such as starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.

For parenteral administration, the active compounds may be dissolved or suspended in a physiologically acceptable diluent. Very often oils are used as diluents with or without the addition of a co-solvent, a surfactant, a suspension aid or an emulsifier. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds may also be used in the form of a depot injection or implant preparation, which may be formulated so as to provide sustained release of the active ingredient.

Implants may contain, for example, biodegradable polymers or synthetic silicone, such as silicone rubber, as inert materials. In addition, the active compounds can be incorporated, for example, in a patch for percutaneous administration.

For the preparation of intravaginal (e.g. vaginal rings) or intrauterine (e.g. pessaries, spirals, intrauterine systems (IUS), Mirena®) systems with active compounds of formula (I) for topical administration, various polymers such as silicone polymers are suitable, ethylene vinyl acetate, polyethylene or polypropylene.

In order to achieve better bioavailability of the active compounds, the compounds can also be prepared as cyclodextrinclatrates. To this end, the compounds are modified by α-, β- or γ-cyclodextrin or derivatives thereof (PCT / EP95 / 02656).

According to the invention, the compounds of the formula I can also be encapsulated by liposomes.

The compounds can be used as an oral as well as parenteral dose for the following indications.

The compounds of the invention have a hybrid effect profile. They are 5cc-reductase inhibitors and, in addition, act as gestagens. Therefore, they are suitable for the treatment of diseases that occur in men and women in certain organs and tissues due to increased levels of androgens, such as in women, elevated levels of 5α-dihydroprogesterone may contribute to severe mental disorders in premenstrual syndrome. These can be favorably influenced by the inhibition of 5cc-reductase.

The concomitant presence of gestagenic action on the compounds of the invention results in inhibition of gonadal function in male and female sex. This effect is desirable if the treatment is intended to achieve antifertile action or also inhibit hormonal secretion of the gonads. This is often the case with prostate disease (benign prostatic hyperplasia). Possible indications are, in addition to prostate disease, contraception in both sexes, male type alopecia, acne and hirsutism. In conjunction with other hormonal agents, such as estrogen, testosterone, and possibly potent androgen, the compounds of the invention are useful as contraceptives for women and men, respectively. In the latter case, the action of testosterone in the prostate will be attenuated by the inhibition of 5α-reductase, while the gestagenic activity will potentiate the action in the male gonade, i.e. the inhibition of spermatogenesis.

When used in female contraception, the compounds of the invention may be used alone or in conjunction with estrogen. In principle, all estrogenically active compounds are suitable as estrogens. Estrogens that can be used are, for example, ethynyl estradiol, 17β-estradiol, as well as its esters such as estradiol-3-benzoate, estradiol-17-valerate, -cypionate, -undecylate, -enanthate and / or other estradiol esters (US -A-2,611,773, US-A-2,990,414, US-A-2,054,271, US-A-2,225,419 and US-A-2,156,599) and conjugated estrogens. Estradiol, ethynyl estradiol and estrone-3-sulfamates such as estrone-N, N-dimethylsulfamate, estrone-N, N-diethylsulfamate, ethinylestradiol-3-N, N-dimethylsulfamate, ethynyl estradrole-3-N, N-diethylsulfamate, ethynyl estradiol. -3-N, N-tetramethylene sulphamate, estrone sulphamate, estradiol-3-sulphamate, estradiol-3-N, N-dimethylsulphamate, estradiol-3-N, N-drethylsulphamate, ethynyl estradiol-3-sulphamate, all of which provide prodrugs corresponding to 3- hydroxyl compounds (W. Elger et al., J. Steroid Biochem. Molec. Biol., Vol. 55, No. 3/4, 395-403, 1995; DE 44 29 398 A1 and DE 44 29 397 A1) are possible. according to the invention also used.

When used in male contraceptives, the compounds of the invention may be used alone or in conjunction with testosterone or a strong androgen, examples of the strong androgen being the following compounds.

Tables 1 and 2 below show activity data against 5α-reductase type 2 in genital skin homogenates and in vivo gestagenic activity data.

Table 1

Activity against 5α-reductase type 2 in genital skin homogenates under optimized conditions at pH 5.5 (IC ₅₀ (nmol)).

Progesterone Receptor (PR) Binding in Uterine Cytosol, Rabbit, Sensitized Indicator: 3H-ORG 2058/0 to 4 ° C incubation conditions; 16 h

Reference substance: progesterone = 100%

Table 2: In vivo data on gestagenic activity

Mouse pregnancy test after s.c. application

compound Dosage mg / animal / day s.c. Pregnancy rate H . lA ' 1.0 5/5 0.1 0/5 (1) I C1

The data presented in Tables 1 and 2 demonstrate the activity profile of the hybrid nature of the compounds of the present invention which act as 5α-reductase inhibitors and as progestogens.

The compounds of the invention further represent intermediates for the synthesis of other pharmacologically highly active steroid products.

The 17-methylene steroids of formula (I) according to the invention can be obtained from compounds of formula (II) and formula (V)

They are obtained by treating a compound of formula (II) in an aprotic solvent, preferably pyridine or triethylamine, with an acid chloride, preferably thionyl chloride or phosphorus oxychloride, to give a compound of formula (III)

it is subjected to an epoxidation in a known manner with H ₂ O ₂ / NaOH in an alcohol, preferably methanol or ethanol, the resulting 4,5-epoxide is opened with a nucleophile such as a halide (hydrogen chloride) or pseudohalogenide in a dipolar aprotic solvent, preferably DMSO or DMPU , dioxane or acetone, to a halogen- or pseudohalohydrin, and this is then dehydrated by catalytic treatment with a mineral acid, carboxylic acid or sulfonic acid such as hydrochloric acid, oxalic acid or p-toluenesulfonic acid in a protic or aprotic solvent such as methanol or acetone, to the compound of formula (IV)

in which

R ⁴ represents a halogen atom or a pseudohalogen, wherein

R ¹⁰ takes the meanings given above and

R ²⁰ represents a C 1 -C 4 alkyl group or a C 1 -C 4 hydroxyalkyl group, a halogen atom or a pseudohalogen.

Further, the 17-methylene steroids of formula (I) may be obtained by treating a compound of formula (V) in an aprotic solvent, preferably pyridine or triethylamine, with an acid chloride, preferably thionyl chloride or phosphorus oxychloride, to form a compound of formula (VI)

it is subjected to an epoxidation in a known manner with H ₂ O ₂ / NaOH in an alcohol, preferably methanol or ethanol, the resulting 4,5-epoxide is opened with a nucleophile such as a halide (hydrogen chloride) or pseudohalogenide in a dipolar aprotic solvent, preferably DMSO or DMPU , dioxane or acetone, to a halogen- or pseudohalohydrin, and this is then dehydrated by catalytic treatment with a mineral acid, carboxylic acid or sulfonic acid such as hydrochloric acid, oxalic acid or p-toluenesulfonic acid in a protic or aprotic solvent such as methanol or acetone, to a compound of formula (VII) (VII)

Other 17-methylene steroids of formula (III) and (VI) of formula (I) may be obtained by

in a known manner (M. Haase-Held, M. Mattfis and J. Mann, I. Chem. Soc. Perkin Trans. 1, 2999, 1992) by means of NaIO ₄ / KMnO ₄ in alcohol, preferably Zerc-BuOH to 3, 5-seco-keto acid, which is converted to an unsaturated lactone by Ac ₂ O / AcCl and is converted to a compound of formula (VIII) and (IX) by n-BuLi / CH ₃ CN in a dipolar aprotic solvent such as THF

(VIII)

Compounds of formula (III) and (IV) can also be obtained by carbonylolefinization according to Wittig, Homer, Peterson.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Z-4,20-Dichloro-19-nor-pregna-4,17 (20) -diene-3-one

A) Ζ-20-Chloro-19-norpregna-4,17 (20) -dien-3-one

9.74 mmol (3.28 g) of (20) R-chloro-19-norpregn-4-en-3-one-17-ol are dissolved in 34 ml of pyridine. With gentle cooling, 12.66 mmol (0.92 ml) of thionyl chloride are added dropwise with stirring. After stirring for about 1 hour under argon, the reaction solution is poured into ice-cold water adjusted to pH 3-4 with hydrochloric acid. The precipitated product is extracted with methylene chloride, the combined, washed neutral extracts are dried over sodium sulfate and isolated. . The solid obtained is purified by flash chromatography on silica gel (eluent: toluene / ethyl acetate 95/5) and optionally recrystallization from methanol. 0.6 g of solid product is obtained.

Mp = 138-141 ° C; [a] _D ²⁰ = + 104 ° (CHC1 _3).

B) Z-20-Chloro-44Y-epoxy-19-norpregn-17 (20) -en-3-one

2.80 mmol (894 mg) of Z-20-chloro-19-norpregna-4,17 (20) -dien-3-one are dissolved in a mixture of 9 ml of methanol and

7.3 ml of methylene chloride and cooled to 0 ° C. Subsequently, 6.31 mmol (0.63 ml) of hydrogen peroxide (30%) and 1.26 mmol (0.3 ml) of sodium hydroxide (c = 4 mol / l) were added dropwise to the cooled solution under stirring under argon. ). After completion of the dropwise addition, the temperature is slowly raised to room temperature. After a reaction time of about 1.5 hours, the mixture is poured onto ice water and then extracted with methylene chloride. The combined extracts are dried over sodium sulfate and isolated. 926 mg of a pale yellow solid is obtained.

C) Z-4,20-Dichloro-19-norpregna-4,17 (20) -dien-3-one

2.71 mmol (896 mg) of Z-20-chloro-4,5,5-epoxy-19-norpregn-17 (20) -en-3-one are dissolved in 25 ml of 1,3-dimethyl-tetrahydro-2 (1). Of H-pyrimidinone (DMPU) and 26.54 mmol (2.2 ml) of hydrochloric acid (37%) are slowly added dropwise. After stirring for 1 hour under argon, the reaction solution is poured onto an ice-cold, aqueous sodium bicarbonate solution, The precipitate is filtered off with suction and finally dried in a desiccator with potassium hydroxide by flash chromatography on silica gel (eluent: toluene / ethyl acetate = 99/1) followed by recrystallization from methanol / acetone to give 353 mg of solid product.

Mp = 182-185 ° C; [a] _D ²⁰ = + 137 ° (CHC1 _3).

Example 2

Z-20-Bromo-4-chloro-19-nor-pregna-4,17 (20) -diene-3-one

A) Z-20-Bromo-19-norpregna-4,17 (20) -dien-3-one

9.7 mmol (3.7 g) of (2 R) -bromo-19-norpregn-4-en-3-one-17-ol are dissolved in 39 ml of pyridine. While cooling, thionyl chloride (12.61 mmol, 0.91 ml) was added dropwise with stirring. After stirring under protective atmosphere (argon) for about 1 hour, the reaction solution is poured into ice-cold water adjusted to pH 3-4 with hydrochloric acid. The precipitated product is extracted with methylene chloride, the combined neutral washed extracts are dried over sodium sulfate and isolated. . The resulting yellow foam was purified by flash chromatography on silica gel (eluent: n-hexane / ethyl acetate 95/5) and optionally recrystallized from methanol / acetone. 536 mg of a pale yellow solid are obtained.

Mp = 153-158 ° C; [a] _D ²⁰ = + 109 ° (CHC1 _3).

B) 20-20-η0ηι-4ξ, 5ξ-οροχ} - 19-norpregn-17 (20) -en-3-one

2.09 mmol (760 mg) of Z-20-bromo-19-norpregna-4,17 (20) -dien-3-one are dissolved in a mixture of 7.8 ml of methanol and

6.3 ml of methylene chloride and cooled to 0 ° C. Subsequently, 4.7 mmol (0.48 ml) of hydrogen peroxide (30%) and 0.94 mmol (0.24 ml) of sodium hydroxide (c = 4 mol / l) were added dropwise to the cooled solution under stirring under argon. ). After completion of the dropwise addition, the temperature is slowly raised to room temperature. After about 1 hour of reaction time, 50 ml of water are added to the mixture. A two-phase system is obtained which is extracted with methylene chloride. The combined neutral washed extracts are dried over sodium sulfate and isolated. The resulting yellow solid was purified by flash chromatography on silica gel (eluent: n-hexane / ethyl acetate 95/5). 680 mg of a white solid are obtained.

C) Z-20-Bromo-4-chloro-19-norpregna-4,17 (20) -dien-3-one

2.57 mmol (975 mg) of Z-20-bromo-4 ' -E-epoxy-19-norpregn-17 (20) -cn-3-one are dissolved in 25 ml of DMPU and 25.2 mmol (2, 09 ml) hydrochloric acid (37%). After stirring under argon for 1 hour, the reaction solution is poured onto an ice-cold, aqueous sodium bicarbonate solution, the precipitate is filtered off with suction and finally dried in a desiccator with potassium hydroxide. Flash chromatography on silica gel (eluent: toluene) followed by recrystallization from methanol / acetone gave 600 mg of white crystals.

Mp = 164-173 ° C; [α] _D ³⁰ = + 138 ° (CHCl ₃ ).

Example 3

E-17-Chloromethylene-4-chloro-estr-4-en-3-one

A) E-17-Chloromethylene-estr-4-en-3-one

18.27 mmol (5.9 g) of 17α-chloromethyl-17-hydroxy-estr-4-en-3-one are dissolved in 60 ml of pyridine. With gentle cooling, 21.9 mmol (1.56 mL) of thionyl chloride are added dropwise with stirring. After stirring under protective atmosphere (argon) for about 1 hour, the reaction solution is poured into ice-cold water adjusted to pH 3-4 with hydrochloric acid. The precipitated product is extracted with methylene chloride, the combined neutral washed extracts are dried over sodium sulfate and isolated. . The resulting solid was purified by flash chromatography on silica gel (eluent: n -hexane / ethyl acetate 85/15). 1.6 g of product are obtained after recrystallization from acetone.

Mp = 143-146 ° C; [a] _D ²⁰ = + 20 ° (CHC1 _3).

B) E-17-Chloromethylene-4-Y-epoxy-estran-3-one

3.93 mmol (1.2 g) of E-17-chloromethylene-estr-4-en-one are dissolved under argon in a mixture of 12 ml of methanol and 10 ml of methylene chloride and cooled to 0 ° C. Subsequently, 9.2 mmol (0.94 ml) of hydrogen peroxide (30%) and 1.65 mmol (0.24 ml) of sodium hydroxide (c = 4 mol / l) were added dropwise to the cooled solution. After completion of the dropwise addition, the temperature is slowly raised to room temperature. After about 1.5 hours of reaction time, the mixture was added to ice water and extracted with methylene chloride. The combined extracts are dried over sodium sulfate and isolated. 1.1 g of white, viscous foam are obtained.

C) E-17-Chloromethylene-4-chloro-estr-4-en-3-one

3.42 mmol (1.1 g) of E-17-chloromethylene-4-epoxy-estran-3-one are dissolved in 26 ml of DMPU and 33 mmol (2.74 ml) of hydrochloric acid (37%) are slowly added dropwise. After 1 hour, the reaction solution is poured onto an ice-cold, aqueous sodium bicarbonate solution, the precipitate is filtered off with suction and finally dried in a desiccator with potassium hydroxide. Recrystallization from acetone gave 760 mg of white crystals. Mp = 182-194 ° C; [a] _D ²⁰ = + 63 ° (CHC1 _3).

Example 4

E-17-Bromomethylene-4-chloro-estr-4-en-3-one

A) E-17-Bromomethylene-estr-4-en-3-one

28.58 mmol (10.5 g) of 17α-bromomethyl-17-hydroxy-estr-4-en-3-one are dissolved in 90 ml of pyridine. With gentle cooling, 37.16 mmol (2.7 mL) of thionyl chloride are added dropwise with stirring. After stirring under protective atmosphere (argon) for about 1 hour, the reaction solution is poured into ice-cold water adjusted to pH 3-4 with hydrochloric acid. The yellow precipitated product is filtered off with suction and purified by flash chromatography on silica gel (eluent: (hexane)). ethyl acetate 85/15). 4.85 g of a slightly yellow colored solid are obtained. After recrystallization from acetone, 3.1 g of white crystals are obtained. Mp = 153-164 ° C; [a] _D ²⁰ = + 15 ° (CHC1 _3).

B)? -17-Bromomethylene-Y-epoxy-estran-3-one

2.86 mmol (1 g) of E-17-bromomethylene-estr-4-en-3-one were dissolved in a mixture of 10.5 ml of methanol and 8.5 ml of methylene chloride under protective atmosphere (argon) and cooled to 0 ° C. . Subsequently, 6.44 mmol (0.66 ml) of hydrogen peroxide (30%) and 1.26 mmol (0.32 ml) of sodium hydroxide (c = 4 mol / l) were added dropwise to the cooled solution. After completion of the dropwise addition, the temperature is slowly raised to room temperature. After about 1.5 hours of reaction time, the mixture was added to ice water. A two-phase system is obtained which is extracted with methylene chloride. The combined neutral washed extracts are dried over sodium sulfate and isolated. 891 mg of a white, viscous foam is obtained.

C) E-17-Bromomethylene-4-chloro-estr-4-en-3-one

2.38 mmol (about 870 mg) of β-17-bromomethylene-X-epoxy-estran-3-one are dissolved in 23 ml of DMPU under argon and slowly added dropwise with 23.33 mmol (1.93 ml) of hydrochloric acid. (37%). After 1 hour, the reaction solution is poured onto an ice-cold, aqueous sodium bicarbonate solution, the precipitate is filtered off with suction and finally dried in a desiccator with potassium hydroxide. Flash chromatography on silica gel (eluent: toluene / ethyl acetate 98/2) followed by recrystallization from acetone gave 552 mg of white crystals.

Mp = 169-176 ° C; [a] _D ²⁰ = + 45 ° (CHC1 _3).

PATENT CLAIMS

Claims (10)

Mp = 169-176 ° C; [a] _D ²⁰ = + 45 ° (CHC1 _3). PATENT CLAIMS A compound of formula (I) wherein: R ⁴ is halogen or pseudohalogen, R ¹⁰ represents a hydrogen atom or a straight or branched chain alkyl group having 1 to 4 carbon atoms, R ²⁰ and R ^20a independently of one another represent a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms or a hydroxyalkyl group containing 1 to 4 carbon atoms or one of the symbols R ² and R ^20a represents a hydrogen atom, a straight or branched alkyl group (1-4C) or (1-4C) hydroxyalkyl and the second symbol represents a halogen atom or a pseudohalogen, with the exception of the compounds 4-chloro-17-methylene-4-androsten-3-one and 4-chloro-2 (? fluoro-21-hydroxypregna-4,17 (20) -diene-3-one. A 17-methylensteroid according to claim 1, wherein R ⁴ represents a chlorine or bromine atom, or a cyano group. The 17-methylensteroid of claim 1 or 2, wherein one of R ²⁰ and R ^20a is hydrogen or methyl and the other of fluorine, chlorine or bromine, azido, cyano or rhodano, or hydroxymethyl. The 17-methylensteroid of claim 1, 2 or 3, wherein R ¹⁰ represents a hydrogen atom or a methyl group. The 17-methylensteroid of claim 1 which is (1) E-17-chloromethylene-4-chloro-estr-4-en-3-one, (2)? -17-cyanomethylene-4-chloro-estr-4; -en-3-one, (3) Z-17-cyanomethylene-4-chloro-estr-4-en-3-one, (4) Z-17- (1 ') -cyanoethylidene-4-chloro-estr-4 -en-3-one, (5) Z-17-ethylidene-4-chloro-estr-4-en-3-one, (6) -17-ethylidene-4-chloro-estr-4-en-3 -one, (7) E-17-bromomethylene-4-chloro-estr-4-en-3-one, (8) Z-17-chloroethylidene-4-chloro-estr-4-en-3-one, ( (9) Z-17-bromomethylidene-4-chloro-estr-4-en-3-one; (10) E-17-chloromethylene-4-cyano-androst-4-en-3-one; (11) E- 17-chloromethylene-4-chloro-androst-4-en-3-one. (12) E '-17- (2') -hydroxyethylidene-4-chloro-estr-4-en-3-one; and (13) Z-17- (2 ') -hydroxyethylidene-4-chloro-estr-4. en-3-one. A process for the preparation of 17-methylenesteroids according to claim 1, wherein R ^20a represents a hydrogen atom, characterized in that a compound of formula (II) (H) is treated with an acid chloride in an aprotic solvent to form a 17-methylenesteroid of formula (III) ) with H ₂ O ₂ / NaOH, the 4,5-epoxide is obtained, which is then opened with a nucleophilic reagent derived from a halogen atom or a pseudohalogen in a dipolar aprotic solvent to form a halogen or pseudohalogen hydrine, and this is optionally dehydrates by means of a mineral acid, a carboxylic acid or a sulphonic acid, in a protic or aprotic solvent, to the compound 10 (IV), a compound of formula (IV) R ⁴ in which R ⁴ represents a halogen atom or a pseudohalogen, wherein R ¹⁰ is as defined in claim 1, and R ²⁰ represents a C 1 -C 4 alkyl group or a C 1 -C 4 hydroxyalkyl group, a halogen atom or a pseudohalogen. A process for the preparation of 17-methylenesteroids according to claim 1, characterized in that the compound of formula (V) (V) is treated with an acid chloride in an aprotic solvent to form a methylenesteroid of formula (VI) (VI) with H ₂ O ₂ / NaOH yields a 4,5-epoxide, which is then opened with a nucleophilic reagent derived from a halogen atom or a pseudohalogen in a dipolar aprotic solvent to form a halogen- or pseudohalogenic hydrine, which is optionally dehydrated with a mineral acid , a carboxylic acid or a sulfonic acid, in a protic or aprotic solvent, to a compound of formula (VII) wherein: R ⁴ is halogen or pseudohalogen, wherein (VII), R ¹⁰ is as defined in claim 1 a R ²⁰ is C 1 -C 4 alkyl or C 1 -C 4 hydroxyalkyl, and R ^20a represents a hydrogen atom, a halogen atom or a pseudohalogen. 5 Pharmaceutical compositions comprising at least one 17-methylene steroid according to claim 1, 2, 3, 4 or 5, optionally together with pharmaceutically acceptable excipients and carriers. A 17-methylensteroid according to any one of claims 1 to 5 for use as a therapeutic active ingredient. Use of compounds according to one of claims 1 to 5 for the preparation of a medicament for the treatment of prostate disease, 10 male-type alopecia, acne and hirsutism, for contraception in men and women and / or for inhibition of 5α-reductase.