EP2167525A2 - 17ß-CYANO-19-ANDROST-4-ENE DERIVATIVE, USE THEREOF AND MEDICAMENTS CONTAINING SAID DERIVATIVE - Google Patents

Abstract

The 17ß-cyano-19-androst-4-ene derivatives of the present invention have gestagenic activity. They have the general chemical formula (1), in which Z is selected from the group comprising O, two hydrogen atoms, NOR and NNHSO2R, wherein R is hydrogen or C1-C4 alkyl, R1 and R2 independently of one another are hydrogen or methyl, or R1 and R2 together form methylene, or are omitted, whereby a double bond is formed between C1 and C2, R4 is hydrogen or halogen and in addition either: R6a, R6b together form methylene or 1,2 ethanediyl or R6a is hydrogen and R6b is selected from the group comprising hydrogen, methyl and hydroxymethylene, and R7 is selected from the group comprising hydrogen, C1-C4 alkyl, C2-C3 alkenyl and cyclopropyl, or: R6a is hydrogen and R6b and R7 together form methylene, or are omitted, whereby a double bond is formed between C6 and C7, or: R6a is methyl and R6b and R7 are omitted, whereby a double bond is formed between C6 and C7, R15 and R16 are hydrogen, or together form methylene and R17 is selected from the group comprising hydrogen, C1-C4- alkyl and aIIyI. The derivatives also comprise the solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts of the aforementioned substances, with the proviso that certain compounds are excluded.

Description

 17β-cyano-19-androst-4-ene derivative, its use and the derivative-containing drug

Description:

The invention relates to certain 17ß-cyano-19-androst-4-ene derivatives, their use and derivatives containing gestagenic drugs, for example, for the treatment of pre-, peri- and postmenopausal as well as premenstrual complaints.

The literature discloses compounds with gestagenic, antimineralcorticoid, anti-drogenic or antiestrogenic action based on a steroid skeleton which are derived, for example, from 19-androst-4-en-3-one or a derivative thereof (the numbering of the steroid skeleton is, for example, Fresenius / Görlitzer 3rd edition 1991 "Organic chemical nomenclature" p. 60 ff.).

Thus, WO 2006072467 A1 discloses the gestagenic compound 6β, 7β-15β, 16β-dimethylene-3-oxo-17-pregn-4-ene-21,17β-carbolactone (drospirenone), which is used, for example, in an oral contraceptive and a preparation used to treat postmenopausal symptoms. However, due to its relatively low affinity for the progestagen receptor and its comparatively high ovulation inhibitory dose, drospirenone is included in the contraceptive in the relatively high daily dose of 3 mg. In addition, drospirenone is characterized by the fact that it has aldosteronantagonist (antimineralcorticoid) and antiandrogenic effects in addition to gestagenic effects. These two properties make drospirenone in its pharmacological profile very similar to the progesterone progesterone, which unlike drospirenone, is not sufficiently orally bioavailable. In order to reduce the dose to be administered, WO 2006072467 A1 further proposes an 18-methyl-19-nor-17-pregn-4-ene-21,17-carbolactone and also pharmaceutical preparations containing it which have a higher progestational potency than Drospirenone.

In addition, for example, US Pat. No. 3,705,179 discloses steroids which have an antiandrogenic activity and are suitable for the treatment of diseases which occur in the Related to androgens. Among others, 17β-cyano-17α-methyl-androst-4-en-3-one derivatives are disclosed.

DE 22 26 552 B2 further describes 17-cyano-19-nor-androst-4-en-3-one compounds which exhibit progestomimetic, antiandrogenic and antiestrogenic effects of exogenous character.

The object of the present invention is to provide compounds which have a strong binding to the gestagen receptor. In addition, the compounds should preferably also have an antimineralcorticoid effect.

This object has been achieved by the 17β-cyano-19-androst-4-ene derivatives according to the invention as claimed in claim 1, the use of the derivatives according to the invention as claimed in claim 15 and a medicament according to claim 17 which contains at least one derivative according to the invention. Advantageous embodiments of the invention are specified in the subclaims.

Accordingly, the present invention relates to a 17β-cyano-19-androst-4-ene derivative having the general chemical formula 1

(1)

in which Z is selected from the group comprising O, two hydrogen atoms, NOR and NNHSO ₂ R, wherein R is hydrogen or C 1 -C ₄ -alkyl,

R ¹ , R ^{2 are} independently hydrogen or methyl or

R ¹ and R ² together form methylene or omitted to form a double bond between C ¹ and C ² ,

R ^{4 is} hydrogen or halogen,

furthermore either:

R ^6a , R ^6b together form methylene or 1,2-ethanediyl or R ^{6a is} hydrogen and R ^6b is selected from the group comprising hydrogen,

Methyl and hydroxymethylene, and R ^{7 is} selected from the group comprising hydrogen, C 1 -C ₄ -alkyl,

C ₂ -C ₃ alkenyl and cyclopropyl,

or:

R ^{6a is} hydrogen and R ^6b and R ⁷ together form methylene or omitted to form a double bond between C ⁶ and C ⁷

or:

R ^6a is methyl and R ^6b and R ⁷ are omitted to form a double bond between C ⁶ and C ^7,

R ¹⁵ , R ^{16 are} hydrogen or together form methylene, R ^{17 is} selected from the group comprising hydrogen, C 1 -C ₄ -alkyl and allyl,

and their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts,

with the proviso that compounds having the following general chemical formula A are excluded:

wherein X is hydrogen or methyl and the double bonds between C ¹ and C ² and between C ⁶ and C ^{7 are} optional double bonds and

with the further proviso that also 17β-cyano-androst-4-en-3-one is excluded.

The compounds of the general chemical formula A excluded from the present invention are the following compounds:

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The numbering of the C-skeleton of the derivative according to the invention with the general chemical formula 1 follows in a conventional manner the numbering of a steroid skeleton, for example described in Fresenius, loc. Cit. The numbering of the radicals indicated in the claims corresponds in an analogous manner to their binding position on the C-skeleton of the derivative. Thus, for example, the radical R ⁴ binds to the C ⁴ position of the derivative according to the invention. With regard to the groups defined for Z, the groups NOR and NNHSO2R each have a double bond via N to the C skeleton of the derivative according to = NOR or = N-NH-SO ₂ R. OR in NOR and NHSO ₂ R in NNHSO ₂ R can be syn or anti-static.

C 1 -C ₄ -alkyl is in each case to be understood as meaning a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, especially the unbranched radicals. Particularly preferred are methyl, ethyl and n-propyl. In addition, alkyl radicals attached in the 17α-position may be perfluorinated, so that in this case R ^{17 may} also be trifluoromethyl, pentafluoroethyl, n-heptafluoropropyl, isoheptafluoropropyl, n-nonafluorobutyl, iso-nonafluorobutyl and tert-nonafluorobutyl.

C ₂ -C ₃ -alkenyl is preferably vinyl or allyl.

Halogen is in each case fluorine, chlorine, bromine or iodine.

Isomers are to be understood as meaning chemical compounds having the same empirical formula but differing chemical structure. All possible isomers and mixtures of isomers (racemates) are expressly included, the 17β-cyano position being specified in the derivative according to the invention.

In general, constitutional isomers and stereoisomers are distinguished. Constitutional isomers have the same molecular formula, but differ in how their atoms or atomic groups are linked. These include functional isomers, positional isomers, tautomers or valence isomers. Stereoisomers basically have the same structure (constitution) and thus also the same molecular formula, but differ in the spatial arrangement of the atoms. In general, configuration isomers and conformational isomers are distinguished. Configuration isomers are stereoisomers that can only be converted into each other by bond breaking. These include enantiomers, diastereomers and E / Z (ice / trans) isomers. Enantiomers are stereoisomers that behave in the same way as image and mirror image and have no plane of symmetry. All stereoisomers, which are not enantiomers are called diastereomers. A special case is E / Z (ice / trans) isomers of double bonds. Conformational isomers are stereoisomers that can be converted into each other by the rotation of single bonds. For the delimitation of the Isomehe species from each other see also the IUPAC rules, Section E (Pure Appl. Chem. 45, 11-30 (1976)).

The derivatives of general chemical formula 1 according to the invention also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, also the racemates and enantiomers. These are also to be understood as meaning double bond isomers.

The derivatives according to the invention can also be present in the form of solvates, in particular of hydrates, the compounds according to the invention accordingly containing polar solvents, in particular of water, as structural element of the crystal lattice of the compounds according to the invention. The polar solvent, in particular water, may be present in a stoichiometric or even unstoichiometric ratio. In the case of stoichiometric solvates, hydrates, we also speak of hemi, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates.

It has been found that the compounds or derivatives according to the invention have a good gestagenic action in vivo. In addition, some interesting compounds of the invention act as antagonists to the mineralocorticoid receptor.

Preference is given to derivatives according to the invention having the aforementioned general chemical formula 1, in which Z is selected from the group comprising O, NOH and NNHSO ₂ H. Z is more preferably O.

Independently of the selection of Z, preference is furthermore given to derivatives according to the invention having the aforementioned general chemical formula 1, in which the following variants occur alternatively or at least partly together and are selected independently of one another: Above all, preferably R ¹⁵ and R ¹⁶ together form methylene, where both an α-terminal and a β-methylene group may be bonded in these positions.

Furthermore, preferably R ¹ and R ^{2 are} each hydrogen or together form methylene, more preferably α-methylene. More preferably, R ^{1 is} α-methyl.

Further, R ^{4 is} preferably hydrogen or chlorine.

Furthermore, R ^6a and R ^6b preferably together form 1, 2-ethanediyl or are each hydrogen.

Further, R ^{7 is} preferably selected from the group comprising hydrogen and methyl, where the methyl group may be both α-α and β-β.

In addition, R ^6b and R ⁷ preferably together form methylene, where the methylene group may be both α-α and β-β.

Further, R ^{17 is} preferably selected from the group comprising hydrogen and methyl.

Furthermore, the radicals R ^6a , R ^6b , R ⁷ , R ¹⁵ and R ^{16 may be} both α- and ß-constantly.

Particularly preferred are the 17β-cyano-19-nor-androst-4-ene derivatives of the invention selected from the group comprising:

Most preferred are the 15α, 16α and 15β, 16β-methylene derivatives in the list above. Because of their progestational efficacy, the novel compounds of general chemical formula 1 can be used alone or in combination with estrogens in contraceptive medicines.

The derivatives according to the invention are therefore particularly suitable for the preparation of a medicament for oral contraception and for the treatment of pre-, peri- and post-menopausal complaints, including the use in preparations for hormone replacement therapy (HRT).

Because of their favorable profile of action derivatives of the invention are also particularly well suited for the treatment of premenstrual disorders, such as headache, depressive moods, water retention and mastodyne.

Particularly preferred is the use of the derivatives according to the invention for the production of a medicament with gestagenic and antimineralcorticoid effect.

Treatment with the derivatives of the invention preferably takes place on humans, but can also be carried out on related mammalian species, such as, for example, dogs and cats.

For use of the derivatives according to the invention as medicaments, these are combined with at least one suitable pharmaceutically acceptable additive, for example a carrier. The additive is suitable, for example, for parenteral, preferably oral, administration. These are pharmaceutically suitable organic or inorganic inert adjunct materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The medicaments can be in solid form, for example as Tablets, dragees, suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions. If appropriate, they also contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for varying the osmotic pressure or buffers. Oily solutions, for example solutions in sesame oil, castor oil and cottonseed oil, are particularly suitable for parenteral administration. To increase the solubility, solubilizers, such as benzyl benzoate or benzyl alcohol, may be added. It is also possible to incorporate the derivatives of the invention into a transdermal system and thus to apply them transdermally. For oral administration in particular tablets, dragees, capsules, pills, suspensions or solutions in question.

The dosage of the derivatives according to the invention in contraceptive preparations should be 0.01 to 10 mg per day. The daily dose for the treatment of premenstrual disorders is about 0.1 to 20 mg. The gestagenic derivatives according to the invention are preferably administered orally in contraceptive preparations and in the medicaments for the treatment of premenstrual symptoms. The daily dose was preferably administered once.

The gestagenic and estrogenic active ingredient components are preferably administered orally together in contraceptive preparations. The daily dose was preferably administered once.

Suitable estrogens are synthetic estrogens, preferably ethinylestradiol, but also mestranol.

The estrogen was administered in a daily amount equivalent to that of 0.01 to 0.04 mg of ethinylestradiol.

As estrogens in the medicaments for the treatment of pre-, peri- and postmenopausal complaints as well as for hormone replacement therapy, primarily natural estrogens are used, in particular the estradiol or its esters, for example estradiol valerate, or else conjugated estrogens (CEEs = Conjugated Equine Estrogens).

Insofar as the preparation of the starting compounds is not described here, these are known to the person skilled in the art or can be prepared analogously to known compounds or processes described herein. The isomer mixtures can be separated by customary methods, such as, for example, crystallization, chromatography or salt formation, into the enantiomers, E / Z isomers or epimers. The derivatives of general chemical formula 1 according to the invention are prepared as described below.

Suitable starting materials for the 17β-cyanoandrost-4-en-3-one derivatives described herein are various steroidal starting materials, such as androst-4-ene-3,17-dione (see, for example, J. Am. Chem. Soc , 3727 (1965)), or the partially reduced analogs, such as testosterone or prasterone.

Suitable starting materials which carry a 15α, 16α or also 15β, 16β-methylene group are likewise known from the literature (for example 15α, 16α-methylene-androst-5-en-17-one-3β-ol, see Chem. Ber. 106, 888 (1973); the corresponding Δ4-3,17-dione, see DE-A 21 09 555 (1972) The 15β, 16β-methylene-androst-4-ene-3,17-dione is in Izv. Nauk SSSR Ser. Khim., 8, 1893 (1985) and Chem., 107, 128-134 (1974); the corresponding Δ5-3 alcohol in Ängew Chem., 94 (9), 718 (1982) It is self-evident that in the descriptions of the synthetic transformations it has always been assumed that any other functional groups present on the steroid skeleton are suitably protected.

The introduction of a nitrile in position 17 (C ¹⁷ ) of the steroid skeleton can be done in many ways. Both single-stage and multi-stage variants are considered here. Preference is given here to methods which ultimately mean the replacement of an oxygen function by cyanide. Many possible process variants are described in Science of Synthesis Houben-Weyl Methods of Molecular Transformations Category 3 Volume 19 pp. 197-213 (2004 Georg Thieme Verlag Stuttgart, New York) and in Houben-Weyl Methods of Organic Chemistry Volume E5 Part 2 P. 1318-1527 (1985 Georg Thieme Verlag Stuttgart, New York).

As a one-step process, for example, offers the direct reductive exchange of a carbonyl oxygen atom against a cyano group. For this purpose, a 17-ketosteroid with tosylmethyl isocyanide in suitable solvents, such as dimethoxyethane, dimethyl sulfoxide, ethers, alcohols or else mixtures thereof, using suitable bases, such as alkali metal alkoxides, alkali metal hydrides, potassium hexamethyldisilazide, or alkali metal amides, such as lithium diisopropylamide, in a temperature range of 0 ⁰ C to 100 ⁰ C implemented. If desired, 17-epimer mixtures can be separated by chromatography, fractional crystallization or by a combination of these methods.

The SN ₂ -like exchange of a suitable leaving group at position 17, such as a halide (preferably iodine or bromine), or even a sulfonic acid ester of a 17-alcohol against cyanide comes into consideration. As cyanide sources, inorganic cyanides such as lithium, sodium and potassium cyanide are preferably used.

The following may be mentioned as examples of multistage variants of the nitrile introduction: a 17-ketone was converted into the corresponding 17-exomethylene compound by means of a Wittig olefination, which after hydroboration and oxidation to the aldehyde can be converted to the corresponding 17-carbaldehyde oxime. Dehydration of the oxime then leads to 17-nitrile.

The introduction of the nitrile can be carried out either at the beginning of a synthesis sequence or at any later time, provided that any further functional groups present are suitably protected.

The 17-cyano compounds may optionally be alkylated, resulting in stereochemically uniform 17β-cyano-17α-substituted derivatives. For this purpose, the 17-cyanosteroid was deprotonated in a suitable solvent, such as ethers, for example tetrahydrofuran. Here, various bases may be used, for example, an alkali amide such as lithium diisopropylamide. After addition of an alkylating agent, such as an alkyl or alkenyl halide, and work-up, the 17β-cyano-17α-substituted derivatives are then obtained.

By way of example, the further synthetic procedure is explained with reference to the following synthesis scheme, in which the already described compound 2 (Bull. Soc. Chim., Fr., 1835 (1976), US-A 3,705,179 (1971)) is listed as starting material: Scheme 1

The introduction of a 1, 2-double bond in the compound 2 then leads to 3. Here come, among other dehydrating agents, selenium dioxide (J. Org. Chem. 21, 239 (1956)) or 2,3-dichloro-5,6-dicyanobenzoquinone (Steroids 35 (5), 481 (1980)). A 1,4 addition to the 1-methyl derivative 4 can be carried out, for example, with trimethylaluminum with addition of trimethylsilyl chloride and copper bromide in suitable solvents (Angewandte 105 (9), 1429 (1993)).

The introduction of a 6,7-double bond takes place via bromination of the 3,5-dienol ether 5 and subsequent hydrogen bromide cleavage (see, for example, J. Fried, JA Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, pp. 265-374 ).

The introduction of a substituent R ⁴ can, for example, starting from a compound of formula 2, by epoxidation of the 4,5-double bond with hydrogen peroxide under alkaline conditions and reaction of the resulting epoxides in a suitable solvent with acids having the general chemical formula HR ⁴ , wherein R ^{4 may be} a halogen atom or a pseudohalogen, or by reacting with catalytic amounts of mineral acid and optionally the resulting 4 Bromine compounds having the general chemical formula 1 (wherein R ⁴ = bromine) with 2,2-difluoro-2- (fluorosulfonyl) acetic acid methyl ester in dimethylformamide in the presence of copper (l) iodide.

The dienol ether bromination of compound 5 can be carried out, for example, analogously to the procedure of Steroids 1, 233 (1963). The Bromwasserstoffabspaltung succeeds by heating the 6-bromine compound with basic reagents, such as LiBr or Li ₂ CO ₃ , in aprotic solvents, such as dimethylformamide, at temperatures from 50 ⁰ C to 120 ⁰ C or by the 6-bromo compounds in a solvent, such as collidine or lutidine, are heated to compound 6.

Compound 7 is prepared by methenylation of the 6,7-double bond by known methods, e.g. with dimethylsulfoxonium methylide (see, for example, DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291,029, J. Am. Chem. Soc., 84, 867 (1962)) into a Compound 8 converted to give a mixture of α- and ß-isomers, for example can be separated into the individual isomers by chromatography.

Compounds of type 7 can be obtained as described in the examples or analogously to these instructions using analogous to the reagents described there.

The synthesis of the spirocyclic compound 12 is based on 2, which was first converted into a 3-amino-3,5-diene-dehydrate 9. By reaction with formalin in alcoholic solution, the 6-hydroxymethylene Dehvat 10 was obtained. After conversion of the hydroxy group into a leaving group, such as a mesylate, tosylate (compound 11) or benzoate, compound 13 can be prepared by reaction with th-methylsulfoxonium iodide using bases such as alkali metal hydroxides, alkali alcoholates, in suitable solvents such as dimethylsulfoxide , represent. To introduce a 6-methylene group, compound 10 can be dehydrated with, for example, hydrochloric acid in dioxane / water. It is also possible to produce 6-methylene from 11 (see DE-A 34 02 3291, EP-A 0 150 157, US-A 4,584,288, J. Med. Chem., 34, 2464 (1991)).

Another way to prepare 6-methylene compounds is to directly react the 4 (5) unsaturated 3-ketones, such as compound 2, with acetals of formaldehyde in the presence of sodium acetate with e.g. Phosphorus oxychloride or phosphorus pentachloride in suitable solvents such as chloroform (see, e.g., K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).

The 6-methylene compounds can be used to prepare compounds of general formula 1 in which R ^6a is methyl and R ^6b and R ⁷ are omitted to form a double bond between C ⁶ and C ^7, is used.

For this one can e.g. a method described in Tetrahedron 21, 1619 (1965), in which isomerization of the double bond by heating the 6-methylene compounds in ethanol with 5% palladium-carbon catalyst, which has been pretreated either with hydrogen or by heating with a small amount of cyclohexene , is achieved. The isomerization can also be carried out with a non-pretreated catalyst, if a small amount of cyclohexene was added to the reaction mixture. The occurrence of small amounts of hydrogenated products can be prevented by adding an excess of sodium acetate.

However, the 6-methyl-4,6-dien-3-one derivatives can also be prepared directly (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb, Ann. 712 (1983)).

Compounds in which R ^{6b represents} an α-methyl function can be prepared from the 6-methylene compounds by hydrogenation under suitable conditions. The best results (selective hydrogenation of the exo-methylene function) are achieved by transfer hydrogenation (J. Chem. Soc. 3578 (1954)). If the 6-methylene derivatives are heated in a suitable solvent, such as, for example, ethanol, in the presence of a hydride donor, for example cyclohexene, very good yields are obtained to 6α-methyl derivatives. Small amounts of 6β-methyl compound can be acidically isolated (Tetrahedron 1619 (1965)).

The targeted representation of 6ß-methyl compounds is possible. For this purpose, the 4-en-3-ones, such as compound 2, for example, with ethylene glycol, trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid, eg p-toluenesulfonic acid, converted to the corresponding 3-ketals. During this ketalization, the double bond isomerizes to position 5 (C ⁵ ). Selective epoxidation of this 5-double bond is achieved, for example, by using organic peracids, for example m-chloroperbenzoic acid, in suitable solvents, such as dichloromethane. Alternatively, the epoxidation can also be carried out with hydrogen peroxide in the presence of, for example, hexachloroacetone or 3-nitrotrifluoroacetophenone. The formed 5,6α-epoxides can then be opened axially using appropriate alkylmagnesium halides or alkyllithium compounds. This gives 5α-hydroxy-6β-alkyl compounds. The cleavage of the 3-keto protective group can be carried out by treatment under mild acidic conditions (acetic acid or 4N hydrochloric acid at 0 ^° C.) to obtain the 5α-hydroxy function. Basic elimination of the 5α-hydroxy function with, for example, dilute aqueous sodium hydroxide gives the 3-keto-4-ene compounds having a β-position 6-alkyl group. Alternatively, ketal cleavage under more severe conditions (aqueous hydrochloric acid or other strong acid) yields the corresponding 6α-alkyl compounds.

The compounds obtained with the general chemical formula I, in which Z is an oxygen atom, can be converted by reaction with hydroxylamine hydrochloride in the presence of a tertiary amine at temperatures between -20 and + 40 ⁰ C in their corresponding oximes (general chemical formula I with Z in the meaning of NOH, where the hydroxy group can be syn or antistatic). Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyhdin, 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1, 5-diazabicyclo [5.4.0] undec-5-ene (DBU), pyridine being preferred. This is analogous to that described in WO-A 98/24801 for the preparation of corresponding 3-oxyimino-Dehvate the drospirenone. The removal of the 3-oxo group for the preparation of a final product having the general chemical formula 1 with Z meaning two hydrogen atoms can be carried out, for example, by reductive cleavage of a thioketal of the 3-keto compound according to the instructions given in DE-A 28 05 490.

The following examples serve to explain the invention in more detail:

The compounds according to the invention are surprisingly distinguished by strong gestagenic activity and are highly active in the pregnancy maintenance test in the rat after subcutaneous administration.

Carrying out the pregnancy maintenance test on the rat:

In gravid rats, the removal of corpora lutea or castration induces an abortion. The exogenous supply of progestins (gestagens) in combination with a suitable dose of estrogen succeeds in maintaining pregnancy. The pregnancy maintenance test on ovariectomized rats serves to determine the peripheral gestagenic activity of a compound.

Rats were mated overnight during Proestrus. The mating was controlled on the morning of the following day by the assessment of a vaginal smear. The presence of sperm was assessed as day 1 of an incipient pregnancy. On day 8 of pregnancy the animals were ovariectomized under ether anesthesia. Treatment with test compound and exogenous estrogen (estrone, 5 μg / kg / day) was performed subcutaneously once a day from day 8 to day 15 or day 21 of pregnancy. The first application on day 8 was performed two hours before castration. Intact control animals received vehicle only.

Evaluation:

At the end of the experiment (day 15 or day 21) the animals were sacrificed under CO 2 atmosphere and live fetuses (beating heart fetuses) and implantation sites (early resorptions and dead fetuses including autolysis and atrophic placentas) in both uterine horns. On day 22 fetuses could also be examined for malformations. In uteri without fetuses or implantation sites, the number of nidation sites was determined by staining with 10% ammonium sulfide solution. The pregnancy maintenance rate was calculated as the quotient of the number of live fetuses and the total number of nidation sites (both resorbed and dead fetuses and nidation sites). For certain test substances, the pregnancy-preserving doses (ED50) given in Table 1 were determined. For drospirenone, this value is 3.5 mg / kg / day.

The derivatives of general chemical formula 1 according to the invention have a very strong gestagenic activity. It has also been found that the derivatives of the invention show in vitro antimineralcorticoid activity. They should therefore have in vivo potassium retiring, natriuretic (antimeralcorticoid) effect. These properties were determined by the test described below:

For culture of the cells used for the assay, DMEM (Dulbecco's Modified Eagle Medium: 4500 mg / ml glucose, PAA, # E15-009) with 10% FCS (Biochrom, S0115, Lot # 615B), 4 mM L-glutamine was used as a culture medium , 1% penicillin / streptomycin, 1 mg / ml G418 and 0.5 μg / ml puromycin.

Reporter cell lines were grown at a density of 4x10 4 cells per well in white, 96-well opaque tissue culture plates (PerkinElmer, # P12-106-017) and in 6% DCC-FCS (charcoal treated serum, for removal in serum contained interfering components). The compounds to be tested were added eight hours later and the cells were incubated with the compounds for 16 hours. The experiments were carried out in triplicate. At the end of the incubation, the effector-containing medium was removed and replaced with lysis buffer. After luciferase assay substrate (Proega, # E1501) was added, the 96-well plates were then placed in a microplate luminometer (Pherastar, BMG labtech) and the luminescence was measured. The IC50 values were determined using a Software for calculating dose-response relationships evaluated. Table 1 shows experimental results:

Table 1

The following examples of the synthesis of preferred invention serve to further illustrate the invention. The novel intermediates disclosed in the individual synthesis examples are essential to the invention, as are the 17β-cyano-19-androst-4-ene derivatives according to the invention.

Many of the reactions described below lead to Epimerengemischen. As a rule, the chromatographic separation of these mixtures is carried out by preparative HPLC under the following conditions: Separations were carried out on a chiral normal phase, Chiralpak AD-H 5μ generally being used as the stationary phase. Usually, it was eluted with a mixture of hexane and ethanol. In some cases, however, other eluent mixtures, such as mixtures of methanol and ethanol, were used: Example 1 :

17-cyano-15SS, 16ss-methylene-androst-4-en-3-one

Ia)

3-methoxy-15SS, 16ss-methylene-androst-3 (4), 5 (6) -diene-17-one

50 g of 15β, 16β-methylene-androst-4-ene-3,17-dione were dissolved in 1 L of methanol and 175 ml of trimethyl orthoformate. With stirring at 25 ° C, 250 mg of p-toluenesulfonic acid was added. After a short time, the product failed. The mixture was stirred at 25 ° C. for 1 hour and at -5 ° C. for 1 hour. It was neutralized with pyridine, filtered off with suction to give 3-methoxy-15β, 16β-methylene-androst-3 (4), 5 (6) -dien-17-one (48 g).

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

3.54 (s, 0-CH _3), 5.12 (m, 4-H), 5.25 (m, 6-H).

MS (Cl +) m / z (rel intensity) = 312 (100); corresponds to C _2I H ₂₈ O ₂ .

I b) 17β-cyano-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene

To a solution of 25 g of 15β, 16β-methylene-3-methoxy-androstane-3 (4), 5 (6) -diene-17-one and 45 g of potassium tert-butoxide in 1 l of dimethoxyethane and 300 ml of tert-butoxide. Butanol was added under ice-cooling slowly over a period of 1, 5 hours, the solution of 23.43 g TOSMIC ^® in 140 ml of dimethoxyethane and then allowed to stir for 3 hours at room temperature. The reaction mixture was poured onto ice-cold, half-saturated sodium chloride solution, the precipitated product filtered off with suction, washed with water and dried overnight in a vacuum oven (50 ⁰ C, 200 mbar). 17β-Cyano-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene (23.7 g) were obtained as beige crystals.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.42 [m, 15'-H (β)], 2.73 [d, J = 4.5 Hz, 17 -H (α)], 5.14 (br.s, 4-H), 5.27 (m, 6-H). MS (Cl +) m / z (rel intensity) = 324 (100), 341 (85); corresponds to C ₂₂ H ₂₉ NO. Ic) 17β-cyano-15β, 16β-methylene-androst-4-en-3-one

To a solution of 700 mg of 17β-cyano-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene in 10 ml of methanol at room temperature was added 5 ml of sulfuric acid (8% by weight). given and left under stirring at this temperature for 2 hours. After stopping the reaction with saturated bicarbonate solution was extracted with dichloromethane, washed with H ₂ O and saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. As a result, 17β-cyano-15β, 16β-methylene-androst-4-en-3-one (599 mg) crystallized out.

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.44 [m, 15'-H (β)], 2.74 [d, J = 4.5 Hz, 17 -H (α)], 5.44 (brs s, 4-H). MS (El +) m / z (rel intensity) = 309 (50); corresponds to C21 _H27 NO.

Example 2: 17β-Cyano-6β-hydroxymethyl-15β-16β-methylene-androst-4-en-3-one

9.5 g of 17β-cyano-15β, 16β-methylene-androst-4-en-3-one were taken up in 60 ml of methanol, admixed with 4.8 ml of pyrrolidine and heated at reflux for 1 hour. After cooling, the product was filtered off with suction, washed with a little cold methanol and pulled dry. The crystals (11 g) were dissolved in 135 ml of toluene and 235 ml of ethanol. 11.5 ml of 30% formaldehyde solution was added. After stirring for 2 hours at room temperature, it was evaporated to dryness and chromatographed on silica gel. 17β-cyano-6β-hydroxymethyl-15β, 16β-methylene-anhydrous-4-en-3-one (4.7 g) was obtained.

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

0.47 [m, 15'-H (β)], 2.76 [d, J = 4.5 Hz, 17-H (α)], AB signal (δ _A = 3.68, δ _B = 3.80, J _AB

= 10.5 Hz additionally split by JH (A), 6-H = 7.4 Hz, JH (B), 6-H = 10.5 Hz) 5.84 (s,

4-H).

MS (El +) m / z (rel intensity) = 339 (37); corresponds to C ₂₂ H ₂₉ NO ₂ . Example 3:

17β-cyano-6,6-ethylene-15β, 16β-methylene-androst-4-en-3-one 3a) 17β-cyano-15β, 16β-methylene-6β-tosyloxymethyl-androst-4-en-3-one

2.93 g of toluenesulfonic acid chloride were added in one portion to a solution of 1.74 g of 17β-cyano-6β-hydroxymethyl-15β, 16β-methylene-anest-4-en-3-one in 20 ml of pyridine Stir for 6 hours at room temperature. Thereafter, the reaction mixture was poured into ice-cold 1 N hydrochloric acid, the precipitated crude product was filtered off with suction and redissolved in ethyl acetate. After washing twice each time with water, saturated bicarbonate solution and saturated sodium chloride solution, and drying the organic phase with sodium sulfate, after concentration to dryness, 17β-cyano-15β, 16β-methylene-6β-tosyloxy-methyl-androst-4 were obtained -en-3-on, which was used immediately in the next stage.

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.46 [m, 15'-H (β)], AB signal (δ _A = 3.95, δ _B = 4.20, J _AB = 9.5 Hz additionally split by J _H (A), 6-H = 7.0 Hz, J _{H (} B), 6-H = 9.5 Hz) 5.72 (s, 4-H).

3b) 17β-cyano-6,6-ethylene-15β, 16β-methylene-androst-4-en-3-one

To a solution of 6.02 g of trimethylsulfoxonium iodide in 50 ml of dry DMSO, 913 mg of sodium hydride were added portionwise at room temperature and, after completion of the addition, allowed to stir for 1 hour at room temperature. Subsequently, the solution of 3.13 g of 17β-cyano-15β, 16β-methylene-6β-tosyloxymethyl-anstros-4-en-3-one was added to the YNd formed and stirred for 6 hours at room temperature. After stopping the reaction by adding 350 ml of water, extracting twice with 150 ml of ethyl acetate, washing the organic phase with water and saturated brine, and drying over sodium sulfate, the organic phase was treated with activated carbon at room temperature for 15 minutes. After filtration through a pad of Celite ^® crystallized 17-cyano-6,6-ethylene-15SS, 16ss-methylene-androst-4-en-3-one upon concentration of the organic phase from (K1 503 mg, 379 mg K2). ¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.38-0.53 [m, (3H) spiroethylene], 0.88 [m, (1 H) spiroethylene], 2.75 [d, J = 4.5Hz, 17H (α)], 5.65 (s, 4-H). MS (El +) m / z (rel intensity) = 335 (100); corresponds to C ₂₃ H ₂₉ NO.

Example 4: 17β-Cyano-6-exo-methylene-15β, 16β-methylene-androst-4-en-3-one

To a solution of 1 g of 17β-cyano-6β-hydroxymethyl-15β, 16β-methylene-androst-4-en-3-one in 10 ml of dioxane was added at room temperature 1 ml of 6 N hydrochloric acid and left at this temperature for 2 hours. The reaction mixture was then added to 250 ml of ice-cold, half-saturated bicarbonate solution and extracted twice with 150 ml of ethyl acetate. After treatment, the combined organic phases with sodium sulfate and activated carbon, was filtered through a Celite ^® layer and evaporated to dryness. Flash chromatography on silica gel [hexane / ethyl acetate (0-25%)] afforded 17β-cyano-6-exo-methylene-15β, 16β-methylene-androst-4-en-3-one (399 mg).

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.48 [m, 15'-H (β)], 2.77 [d, J = 4.7 Hz, 17 -H (α)], 5.02 and 5.12 (dd → t, each J = 2.0 Hz, = CH ₂ ), 5.94 (d, J = 0.6 Hz, 4-H). MS (El +) m / z (rel intensity) = 321 (96); corresponds to C ₂₂ H ₂₇ NO.

Example 5: 17β-Cyano-6α-methyl-15β, 16β-methylene-androst-4-en-3-one

To a solution of 330 mg of 17β-cyano-6-exo-methylene-15β, 16β-methylene-androst-4-en-3-one in 40 ml of toluene and 10 ml of ethanol was added under argon atmosphere 300 mg Wilkinson's catalyst and hydrogenated for 3 hours and under normal hydrogen pressure by means of shaking apparatus. After the catalyst had been separated by flash chromatography on silica gel [hexane / ethyl acetate (0-50%)], the mixture of 6-epimers in the ratio 17β-cyano-6β-methyl-15β, 16β-methyl-androstane 4-en-3-one: 17β-cyano-6α-methyl-15β, 16β-methylene-androst-4-ene-3 on = 2.5: 1. Acid epimerization in dichloromethane with catalytic amounts of p-toluene sulfonic acid and flash chromatography on silica gel [hexane / ethyl acetate (0-50%)] afforded pure 17β-cyano-6α-methyl- 15β, 16β-methylene-androst-4-en-3-one (39 mg).

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.46 [m, 15'-H (β)], 1, 12 (d, J = 6.3 Hz, 6 -CH ₃ ), 2.75 [d, J = 4.6 Hz, 17-H (α)], 5.82 (d, J = 1, 3 Hz, 4-H). MS (El +) m / z (rel intensity) = 324 (95), 341 (55); corresponds to C ₂₂ H ₂₉ NO.

Example 6: 17β-Cyano-15β, 16β-methylene-androsta-4,6-dien-3-one

A suspension of 3.4 g of 17.beta.-cyano-3-methoxy-15SS, 16ss-methylene-androst-3 (4), 5 (6) -diene in 100 ml of 1-methyl-2-pyrrolidone was treated sequentially at 0 ⁰ C treated with 4 ml of a 10% sodium acetate solution and at this temperature with 1, 6 g of 1, 3-dibromo-5,5-dimethylhydantoin in portions, stirred for 0.5 hours at 0 ⁰ C (ice bath), with 1, 5 g lithium bromide and 1, 3 g of lithium carbonate, and stirred for 3.5 hours at 100 ⁰ C bath temperature. The mixture was then stirred into ice-water / common salt and the precipitate was filtered off. 17β-Cyano-15β, 16β-methyl-androsta-4,6-dien-3-one (2.42 g) was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.53 [m, 15'-H (β)], 2.78 [d, J = 4.5 Hz, 17 -H (α)], 5.70 (s, 4-H), 6.18 (dd, J = 2.8 Hz, J = 9.8 Hz, 5-H *), 6.33 (dd, J = 2.1 Hz, J = 9.8 Hz, 6-H *), * = assignment interchangeable.

Example 7:

6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-4-en-3-one and

6α, 7α-15SS, 16ss-bismethylene-17-cyano-androst-4-en-3-one

468 mg of sodium hydride were added in portions to a solution of 3.09 g of trimethylsulfoxonium iodide in 25 ml of dry dimethyl sulfoxide at room temperature and stirred at room temperature for 1 hour after completion of the addition. Subsequently The solution of 1.0 g of 17β-cyano-15β, 16β-methylene-androsta-4,6-dien-3-one was added to the formed YNd and stirred at room temperature for 6 hours. After stopping the reaction by adding 150 ml of ammonium chloride solution, extracting twice with 75 ml of ethyl acetate, washing the organic phase with water and saturated brine, and drying over sodium sulfate, the organic phase was concentrated to dryness. Flash chromatography twice on silica gel [hexane / ethyl acetate (0-50%)] afforded as a more nonpolar fraction 6α, 7α-15β, 16β-bismethylene-17β-cyano-androst-4-en-3-one (59 mg) and as well more polar fraction 6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-4-en-3-one (67 mg).

Fraction 1: 6α, 7α-15β, 16β-bismethylene-17β-cvano-androst-4-en-3-one: 1 H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.53 0.63 0.87 and 0.98 [4 xm, Ge 1 H) cyclopropyl], 2.80 [d, J = 4.3 Hz, 17-H (α)], 6.01 (s, 4- H). MS (Cl +) m / z (rel intensity) = 322 (100), 339 (33); corresponds to C ₂₂ H ₂₇ NO.

Fraction 2: 6β7β-15β,16β-bismethylene-17β-cvano-androst-4-en-3-one: 1 H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.57 and 0.92 [2 xm, Ge 1 H) cyclopropyl], 2.84 [d, J = 4.3 Hz, 17-H (α)], 6.07 (s, 4-H). MS (El +) m / z (rel intensity) = 322 (100), 339 (33); corresponds to C ₂₂ H ₂₇ NO.

Example 7 - Variant 2:

6ß, 7.beta.-15SS, 16ss-bismethylene-17-cyano-androst-4-en-3-one

7 variant 2-a)

6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17β-cyano-androstane and 6β, 7β-

15SS, 16fl-bismethylene-3.beta.-5ß-bishydroxy-17α-cyano-androstan

6β, 7β-15β, 16β-bismethylene-3β, 5β-dihydroxy-androstane-17-one (Angew. Chemie 1982, 94, 718-719) was reacted analogously to the method given in Example 1b. Chromatography on silica gel with a mixture of hexane and ethyl acetate gave 6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17β-cyano-andros-tane and 6β, 7β-15β, 16β-bismethylene-3β-5β -bishydroxy-17α-cyano-androstan. Gβ, Zβ, δβ, β, β-bisnithethanes, ββ, β-bis-hydroxy, Zβ-cvano-androstane: 1 H-NMR (D6-DMSO): 0.41 (m, 2H), 0.61 (Hn ₁ IH), 0.73 (5.3H), 0.83 (s, 3H) _; wide, 1 H), 3.79 (s wide, 1 H), 4.31 (s wide, 1 H), 4.79 (s wide, 1 H)

6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17α-cvano-androstane: 1 H-NMR (D6-DMSO): 0.41 (m, 2H), 0.61 (m, 1H), 0.73 (s, 3H), 0.80 (s, 3H), 3.05 (s wide, 1H)

7 variant 2-b)

6ß, 7.beta.-15SS, 16ss-bismethylene-17-cyano-androst-4-en-3-one

6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17β-cyano-androstane was reacted analogously to the procedure given in Example 3Oe. 6ß, 7ß-15ß, 16ß-

Bismethylene-17-cyano-androst-4-en-3-one.

The NMR data are identical to those given in Example 7.

Example 8: 17β-Cyano-7α-methyl-15β, 16β-methylene-androst-4-en-3-one

To a solution of 1.0 g of 17β-cyano-15β, 16β-methylene-androstan-4,6-dien-3-one in 50 ml of tetrahydrofuran was added 67 mg of cuprous chloride at room temperature and stirred for 10 minutes before was cooled to -15 ⁰ C, mixed with 450 mg of aluminum chloride, stirred for 30 minutes at this temperature, with 4.5 ml of methyl magnesium bromide solution (3 M in tetrahydrofuran) was added dropwise, and stirred at -15 ° C for one hour. For workup, the reaction mixture was treated at -15 ° C with 30 ml of 2 M hydrochloric acid, stirred for 0.5 hours at room temperature, added to water, extracted three times with ethyl acetate, dried over sodium sulfate, concentrated in vacuo, and on silica gel with hexane / ethyl acetate (0-50%) chromatographed. 17β-Cyano-7α-methyl-15β, 16β-methylene-androst-4-en-3-one (149 mg) was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.45 [m, 15'-H (β)], 0.88 (d, J = 7.1 Hz, 7 -Me), 1, 08 and 1, 21 [2 xs, each (3H), 2 x Me], 2.75 [d, J = 4.6 Hz, 17-H (α)], 5.76 ( s, 4-H). MS (Cl +) m / z (rel intensity) = 324 (100), 341 (55); corresponds to C ₂₂ H ₂₉ NO. Example 9:

17-cyano-17α-methyl-15SS, 16ss-methylene-androst-4-en-3-one

9a)

-dien 17-Cyano-3-methoxy-17α-methyl-15SS, 16ss-methylene-androstan-3 (4), 5 (6)

At -78 ° C, to a solution of 8 g of 17-cyano-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene was added a cold, fresh solution of lithium diisopropylamide (LDA) previously prepared from 12.1 ml of diisopropylamine and 54.1 ml of n-BuLi (1 6 M in hexane) was prepared in 82 ml of tetrahydrofuran at 0 ⁰ C, and the mixture is left for 1 hour at -78 ° C. Before the subsequent addition of 6.9 ml of methyl iodide was wieter cooled to -90 ⁰ C. Upon complete addition, the reaction mixture was allowed to warm slowly to room temperature overnight. The reaction was stopped by the addition of saturated ammonium chloride solution, extracted with ethyl acetate, washed with water and saturated sodium chloride solution. Drying of the organic phase with sodium sulfate, evaporation to dryness and flash chromatography on silica gel [hexane / ethyl acetate (0-30%)] afforded 17β-cyano-3-methoxy-17α-methyl-15β, 16β-methylene-androstane-3 (cf. 4), 5 (6) -dies (6.5 g).

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.40 [m, 15'-H (β)], 1, 01 (s, Me), 1, 15 (s , Me), 1, 38 (s, Me), 3.58 (s, 0-CH _3), 5.15 (m, 4-H), 5.27 (m, 6-H). MS (Cl +) m / z (rel intensity) = 355 (100), 338 (53); corresponds to C ₂₃ H ₃₁ NO.

9b) 17β-cyano-17α-methyl-15β, 16β-methylene-androst-4-en-3-one

385 mg of 17β-cyano-3-methoxy-17α-methyl-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene were obtained by crystallization from ethyl acetate 17β-cyano by the method of Example 1c -17α-methyl-15β, 16β-methylene-androst-4-en-3-one (285 mg).

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.43 [m, 15'-H (β)], 1, 16; 1, 21 and 1, 38 [3 xs, each (3H), 3 x Me], 5.75 (d, J = 1, 1 Hz, 4-H). MS (Cl +) m / z (rel intensity) = 324 (38), 341 (100); corresponds to C ₂₂ H ₂₉ NO. Example 10:

17α-allyl-17-cyano-15SS, 16ss-methylene-androst-4-en-3-one

10a)

-diene 17α-allyl-17-cyano-3-methoxy-15SS, 16ss-methylene-androstan-3 (4), 5 (6)

According to the method of Example 9a was obtained from 1 g of 17-cyano-3-methoxy-15ß, 16ß-methylene-androstane-3 (4), 5 (6) -diene with allyl bromide as the alkylating agent after flash chromatography 17α-allyl -17β-cyano-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene (358 mg).

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.41 [m, 15'-H (β)], 3.58 (s, O-CH ₃ ), 5, 15 (m, 4-H), 5.25 [m, (3H), 6-H, and = CH ₂ ], 6.05 [m, (1H), -CH =].

10b)

17α-allyl-17-cyano-15SS, 16ss-methylene-androst-4-en-3-one

300 mg of 17α-allyl-17β-cyano-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene were obtained according to the method of Example 1c after flash chromatography of 17α- Allyl-17β-cyano-15β, 16β-methylene-androst-4-en-3-one (210 mg).

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

0.45 [m, 15'-H (β)], 5.18-5.30 [m, (2H), = CH ₂ ], 5.76 (d, J = 1.7 Hz, 4-H ), 6.03 [m,

(1H) ₁ -CH =].

MS (Cl +) m / z (rel intensity) = 350 (100), 367 (68); corresponds to C ₂₄ H ₃₁ NO.

Example 11: 17β-Cyano-6β-hydroxymethyl-17α-methyl-15β, 16β-methylene-androst-4-en-3-one

The method of Example 2 was obtained from 5.90 g of 17β-cyano-17α-methyl-15β, 16β-methylene-androst-4-en-3-one after crystallization from ethyl acetate and flash chromatography of the mother liquors on silica gel [hexane / Ethyl acetate (0-50%)] 17β-cyano-6β-hydroxymethyl-17α-methyl-15β, 16β-methylene-androst-4-en-3-one (2.22 g). ¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.50 [m, 15'-H (β)], 1, 21; 1, 27 and 1, 43 [3 xs, each (3H), 3 x Me], AB signal (δ _A = 3.73, δβ = 3.85, JAB approx. 10.0 Hz wide signals, additionally split by JH (A), 6-H = 7.5 Hz, J _{H (B), 6} - _H approx. 10.0 Hz), 5.89 (s, 4-H). MS (Cl +) m / z (rel intensity) = 341 (100), 354 (35), 371 (22); corresponds to C ₂₃ H _3I NO ₂ .

Example 12:

17-cyano-15α, 16α-methylene-androst-4-en-3-one

12a)

-en 17-cyano-3ß-hydroxy-15α, 16α-methylene-androst-5 (6)

24.2 g of 3β-acetoxy-15α, 16α-methylene-androst-5 (6) -ene were obtained by flash chromatography on silica gel [hexane / ethyl acetate (0-50%) by the method of Example 1b]. ] and fractional crystallization from ethyl acetate 17β-cyano-3β-hydroxy-15α, 16α-methylene-androst-5 (6) -ene (3.2 g) and also 17α-cyano-3β-hydroxy-15α, 16α-methylene-androst -5 (6) -en (3.6 g).

17-Cvano-3.beta.-Hydroxy-15α, 16α-methylene-androst-5 (6) -en:

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

0.54 [m, (2H), cyclopropyl], 0.90 [m, (1H), cyclopropyl], 1, 03 and 1, 17 [2xS, each

(3H), 2x Me], 3.52 (m, 3-H), 5.37 (m, 6-H).

MS (El +) m / z (rel intensity) = 311 (88); corresponds to C _2i H ₂₉ NO.

17α-cvano-3β-hydroxy-15α, 16α-methylene-androst-5 (6) -en: 1 H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.78 [m, ( 1 H), cyclopropyl], 0.89-0.99 [m, (2H), cyclopropyl], 1, 02 and 1, 08 [2x, each (3H), 2x Me], 2.79 [d , J = 7.7 Hz, 17-H (β)], 3.54 (m, 3-H), 5.38 (m, 6-H). MS (El +) m / z (relative intensity) = 311 (18); corresponds to C ₂₁ H ₂₉ NO. 12b) 17β-cyano-15α, 16α-methylene-androst-4-en-3-one

To the solution of 3.2 g of 17β-cyano-3β-hydroxy-15a, 16a-methylene-androst-5 (6) -en in 80 ml of 2-butanone 2.10 g of aluminum tri-isopropylate were added in one portion and Heated to boiling for 15 hours. Then the reaction was stopped by adding saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate. After concentration, the flash chromatography on silica gel [hexane / ethyl acetate (0-50%)] afforded 17β-cyano-15α, 16α-methylene-androst-4-en-3-one (3.0 g).

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

0.55 [m, (2H), cyclopropyl], 0.81-0.97 [m, (3H)], 1, 21 [s, (6H), 2 x Me], 5.74 (br , 4-

H).

MS (Cl +) m / z (rel intensity) = 310 (100), 327 (23); corresponds to C ₂ iH ₂₇ NO.

Example 13: 17β-Cyano-6β-hydroxymethyl-15α, 16α-methylene-androst-4-en-3-one

The procedure of Example 2 was used to obtain from 3.0 g of 17β-cyano-15α, 16α-methylene-androst-4-en-3-one after flash chromatography on silica gel [hexane / ethyl acetate (0-50%)] 17β -Cyano-6β-hydroxymethyl-15α, 16α-methylene-androst-4-en-3-one (850 mg).

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.56 [m, (2H), cyclopropyl], 0.91 [m, (1H), cyclopropyl], 1, 22 [s, (6H), 2 x Me], AB signal (δ _A = 3.68, δ _B = 3.77, strongly broadened signals), 5.83 (s, 4-H). MS (Cl +) m / z (rel intensity) = 340 (100), 357 (51); corresponds to C ₂₂ H ₂₉ NO ₂ . Example 14:

17β-cyano-15α, 16α-methylene-6β-tosyloxymethyl-androst-4-en-3-one and 17β-cyano-6-exo-methylene-15α, 16α-methylene-androst-4-en-3-one

By the method of Example 3a was obtained from 700 mg of 17β-cyano-6β-hydroxymethyl-15α, 16α-methylene-androst-4-en-3-one after flash chromatography on silica gel [hexane / ethyl acetate (0-50 %)] 17β-cyano-15α, 16α-methylene-6β-tosyloxy-methyl-androst-4-en-3-one (880 mg) and in its precursor as minor component 17β-cyano-6-exo-methylene-15α, 16α-methylene-androst-4-en-3-one (22 mg).

Fraction 1: 17β-covano-6-exo-methylene-15α, 16α-methylene-androst-4-en-3-one: 1 H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0 , 64 [m, (2H), cyclopropyl], 1, 09 [m, (1H), cyclopropyl], 1, 16 and 1, 25 [2x, each (3H), 2x Me], 5.04 and 5.15 (dd → t, each J = 1.9 Hz, = CH ₂ ), 5.97 (s, 4-H).

MS (Cl +) m / z (rel intensity) = 322 (100), 339 (28); corresponds to C ₂₂ H ₂₇ NO.

Fraction 2: 17β-cvano-15α, 16α-methylene-6β-tosyloxymethyl-androst-4-en-3-one: ¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0, 56 [m, (2H), cyclopropyl], 0.91 [m, (1H), cyclopropyl], 1, 13 and 1, 22 [2 xs, each (3H), 2 x Me], 2.50 [ s, (3H), C ₆ H ₄ -CH ₃ ], AB signal (δ _A = 3.95, δ _B = 4.29, J _AB = 9.7 Hz additionally split by JH (A), 6- H = 6.2 Hz, JH (B), 6-H = 9.7 Hz) 5.77 (s, 4-H), AA'BB 'signal [δ _A = 7.40, δ _B = 7 , 82, each (2H), C ₆ H ₄ ]. MS (Cl +) m / z (rel intensity) = 494 (5), 511 (15); corresponds to C ₂₉ H ₃₅ NO ₄ S.

Example 15: 17β-Cyano-6,6-ethylene-15α, 16α-methylene-androst-4-en-3-one

860 mg of 17β-cyano-15α, 16α-methylene-6β-tosyloxymethyl-androst-4-en-3-one were obtained by flash chromatography on silica gel [hexane / ethyl acetate (0-50%) by the method of Example 3b]. ] 17β-cyano-6,6-ethylene-15α, 16α-methylene-anhydrous-4-en-3-one (265 mg). ¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.45-0.63 [m, (4H) spiroethylene and cyclopropyl], 0.88 [m, (1 H) spiroethylene ], 1, 02 [m, (1H), cyclopropyl], 1, 28 and 1, 32 [2 xs, each (3H), 2 x Me], 5.69 (s, 4-H). MS (El +) m / z (rel intensity) = 335 (88); corresponds to C ₂₃ H ₂₉ NO.

Example 16:

17β-cyano-17α-methyl-15α, 16α-methylene-androst-4-en-3-one 16a) 17α-cyano-15α, 16α-methylene-3β-triisopropylsilyoxy-androst-5 (6) s

To a solution of 3.6 g of 17α-cyano-3β-hydroxy-15α, 16α-methylene-androst-5 (6) - ene, 1, 7 g of imidazole and 141 mg of dimethylaminopyridine in 20 ml of dimethylformamide (DMF) was at 0 ⁰ C was slowly added the solution of 5.44 ml Triisopropylsilychlorid in 2.5 ml of tetrahydrofuran. It was then allowed to warm to room temperature overnight, poured onto saturated bicarbonate solution and extracted with ethyl acetate. The organic phase was washed 5 times with water and finally with saturated sodium chloride solution and concentrated to dryness. The crude product 17α-cyano-15α, 16α-methylene-3β-triisopropylsilyoxy-androst-5 (6) -ene (7.3 g) was used directly in the subsequent step.

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.78 [m, (1 H), cyclopropyl], 0.88-0.99 [m, (2H), cyclopropyl ], 1, 02 and 1, 08 [2 xs, each (3H), 2 x Me, overlaid by δ = 1, 05, br. s, (18H), TiPS-Me], 2.79 [d, J = 7.1 Hz, 17-H (β)], 3.56 (m, 3-H), 5.33 (d, J = 4.8 Hz, 6-H). MS (El +) m / z (rel intensity) = 468 (12); corresponds to C ₃₀ H ₄₉ NOSi.

16b)

17β-cyano-17α-methyl-15α, 16α-methylene-3β-triisopropylsilyoxy-androst-5 (6) - ene in admixture with

17α-Cyano-17β-methyl-15α, 16α-methylene-3β-triisopropylsilyoxy-androst-5 (6) - ene

By the method of Example 9a was obtained from 5.29 g 17α-cyano-15α, 16α-methylene-3ß-isopropylsilyoxy-androst-5 (6) -en with Me-I as alkylating agent after In flash chromatography, the mixture of the 17-epimers of 17-cyano-17-methyl-15α, 16α-methylene-3β-triisopropylsilyoxy-androst-5 (6) -ens (3.65 g).

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

0.60-0.72 [m, (1H), cyclopropyl], 1, 05, [br. s, (18H), TiPS-Me], 3.54 (m, 3-H), 5.33 (m,

6-H).

MS (Cl +) m / z (rel intensity) = 499 (55); corresponds to C ₃ iH ₅ iNOSi.

16c)

17β-cyano-3β-hydroxy-17α-methyl-15α, 16α-methylene-androst-5 (6) -enes in admixture with 17α-cyano-3β-hydroxy-17β-methyl-15α, 16α-methylene-androst-5 (6) -en

To a solution of 3.6 g of the 17-epimers of 17-cyano-17-methyl-15α, 16α-methyl-3β-triisopropylsilyoxy-androst-5 (6) -ens in 5 ml of tetrahydrofuran were at room temperature Add 9 ml of tetrabutylammonium fluoride (TBAF) (1 M in tetrahydrofuran) and allow to stir for 4 hours. After stopping the reaction by addition of saturated bicarbonate solution, extraction with ethyl acetate, washing the organic phase with water and saturated sodium chloride solution, drying with sodium sulfate and concentration to dryness, the subsequent flash chromatography provided the 17-epimer mixture of 17-cyano-3β-hydroxy-17-methyl-15α, 16α-methylene-androst-5 (6) -ens (1, 9 g).

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.74 [m, (1 H), cyclopropyl], 3.57 (m, 3-H), 5.42 ( m, 6-H).

16d) 17β-cyano-17α-methyl-15α, 16α-methylene-androst-4-en-3-one

By the method of Example 12b was obtained from 1, 9 g of the 17-epimers of 17-cyano-3ß-hydroxy-17-methyl-15α, 16α-methylene-androst-5 (6) -ens after preparative HPLC chromatography 17ß -Cyano-17α-methyl-15α, 16α-methylene-androst-4-en-3-one (335 mg). ¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.69 [m, (2H), cyclopropyl], 0.82 [m, (1H), cyclopropyl], 0, 96 [m, (1H), cyclopropyl], 1, 14; 1, 21 and 1, 33 [3 xs, each (3H), 3 x Me], 5.74 (s, 4-H). MS (El +) m / z (rel intensity) = 323 (100); corresponds to C ₂₂ H ₂₉ NO.

Example 17:

17β-cyano-15α, 16α-methylene-androsta-4,6-dien-3-one 17a)

17β-cyano-3-methoxy-15α, 16α-methylene-androst-3 (4), 5 (6) -dien-17-one in admixture with 17α-cyano-3-methoxy-15α, 16α-methylene-androst 3 (4), 5 (6) -diene-17-one

The 17-epimer of 17-cyano-15α, 16α-methylene-androst-4-en-3-one was obtained from 7 g of the 17-epimer of the 17-cyano group after work-up by the method of Example 1a. 3-methoxy-15α, 16α-methylene-androst-3 (4), 5 (6) -diene (7.6 g), which were used directly in the next step.

17b) 17β-cyano-15α, 16α-methylene-androsta-4,6-dien-3-one

By the method of Example 6 was obtained from 7.6 g of the 17-epimers of 17-cyano-3-methoxy-15α, 16α-methylene-androst-3 (4), 5 (6) -diene by preparative HPLC chromatography Part of the crude product obtained 17β-cyano-15α, 16α-methylene-androsta-4,6-dien-3-one (48 mg)

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.66 [m, (1 H), cyclopropyl], 0.78 [m, (1 H), cyclopropyl], 1 , 19 and 1, 32 [2 xs, each (3H), 2 x Me], 5.74 (s, 4-H), 6.21 (dd, J = 2.8 Hz, J = 9.8 Hz , 5-H *), 6.34 (dd, J = 1, 9 Hz, J = 10.0 Hz, 6-H *), * = assignment interchangeable. MS (El +) m / z (rel intensity) = 307 (26); corresponds to C _2i H ₂₅ NO. Example 18: 17β-Cyano-7α-methyl-15α, 16α-methylene-androst-4-en-3-one

Using the method of Example 8, from 17.5 g of 17-cyano-15α, 16α-methylene-androsta-4,6-dien-3-one obtained from 2.2 g of preparative HPLC chromatography 17ß-cyano- 7α-methyl-15α, 16α-methylene-androst-4-en-3-one (257 mg).

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.58 [m, (1 H), cyclopropyl], 0.69 [m, (1 H), cyclopropyl], 0 , 86 (d, J = 7.2 Hz, 6-Me), 1, 25 and 1, 26 [2 xs, each (3H), 2 x Me], 5.79 (s, 4-H). MS (El +) m / z (rel intensity) = 323 (100); corresponds to C ₂₂ H ₂₉ NO.

Example 19: 17β-Cyano-androsta-4,6-dien-3-one

19a) 17β-cyano-3-ethoxy-androst-3,5-diene

17β-cyano-androst-4-en-3-one was reacted analogously to the procedure specified in Example 1a, with trimethyl orthoformate being exchanged for methyl orthoformate. 17β-Cyano-3-ethoxy-androst-3,5-diene was obtained.

¹ H-NMR (D6-DMSO): 0.81 (s, 3H), 0.86 (s, 3H), 1, 17 (t, 3H, J = 7.1 Hz, 3-O-CH2-CH3 ), 3.36 (m, 2H, 3-O-CH 2 -CH 3), 5.09 (m, 2H, H-4 and H-6)

19b) 17β-cyano-androsta-4,6-dien-3-one

17β-Cyano-3-ethoxy-androst-3,5-diene was reacted analogously to the instructions given in Example 6. 17β-cyano-androsta-4,6-dien-3-one was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 1, 02 (s, 3H), 1, 13 (s, 3H), 5.68 (s, 1 H, H- 4), 6.06 (s, 1H, 6H), 6.13 (s, 1H, 7H) Example 20: 17β-Cyano-7α-methyl-androst-4-en-3-one

17β-cyano-androsta-4,6-dien-3-one was reacted analogously to the procedure given in Example 8. 17β-Cyano-7α-methyl-androst-4-en-3-one was obtained

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.77 (d, 3H, 7-CH 3, J = 7.3 Hz)), 0.98 (5.3H), 1, 21 (s, 3H), 5.74 (s, 1H, H-4)

Example 21: 17β-Cyano-7α-ethyl-androst-4-en-3-one

17β-Cyano-androsta-4,6-dien-3-one was reacted analogously to the instructions given in Example 8, using ethylmagnesium bromide instead of the methylmagnesium bromide used there. 17β-Cyano-7α-ethyl-androst-4-en-3-one was obtained

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.88 (t, 3H, 7-CH 2 -CH 3, J = 7.3Hz)), 0.98 (s, 3H ), 1, 22 (s, 3H), 5.74 (s, 1H, H-4)

Example 22:

17β-Cyano-6α, 7α-methylene-androst-4-en-3-one and 17β-cyano-6β, 7β-methylene-androst-4-en-3-one

17β-cyano-androsta-4,6-dien-3-one was reacted analogously to the instructions given in Example 7. 17β-Cyano-6α, 7α-methylene-androst-4-en-3-one and 17β-cyano-6β, 7β-methylene-androst-4-en-3-one were obtained.

17-Cvano-6α, 7α-methylene-androst-4-en-3-one:

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

0.46 (m, 1H), 0.77 (m, 1H), 0.85 (m, 1H), 1, 01 (s, 3H), 1, 15 (s, 3H), 5, 95 (s, 1H, H-4) 17-Cvano-6ß, 7.beta.-methylene-androst-4-en-3-one:

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ =

0.79Cm ₁ IH), 0.95 (5.3H), 1, 09 (s, 3H), 6.01 (s, 1H, H-4)

Example 23: 17β-Cyano-6β-hydroxymethyl-androst-4-en-3-one

17β-Cyano-androst-4-en-3-one was reacted analogously to the instructions given in Example 2. 17β-cyano-6β-hydroxymethyl-androst-4-en-3-one was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.98 (s, 3H), 1, 21 (s, 3H), 3.68 (m, 2H, 6-CH 2 -OH), 5.82 (s, 1H, H-4)

Example 24: 17β-Cyano-6,6-ethylidene-androst-4-en-3-one

17β-Cyano-6β-hydroxymethyl-androst-4-en-3-one was reacted analogously to the examples given in Examples 3a and 3b, the intermediate tosylate being reacted further in crude form. 17β-cyano-6,6-ethylidene-androst-4-en-3-one was obtained.

¹ H NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.42 (m, 2H), 0.77 (m, 1H), 0.99 (s, 3H), 1 , 26 (s, 3H), 5.62 (s, 1H, H-4)

Example 25: 17β-Cyano-17α-methyl-androst-4-en-3-one

25a) 17-cyano-3,3-ethanediylbisoxy-androst-5-ene

5 g of the cyano compound were stirred in a mixture of 56 ml of dichloromethane, 14 ml of ethylene glycol, 37 ml of trimethyl orthoformate and 1.5 g of para-toluenesulfonic acid for two hours at room temperature. After addition of sodium hydrogen carbonate solution and ethyl acetate, the phases were separated and the organic phase was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated. The resulting 17β-cyano-3,3-ethanediylbisoxy-androst-5-ene was used without further purification.

25b) 17β-cyano-3,3-ethanediylbisoxy-17α-methyl-androst-5-ene

17β-Cyano-3,3-ethanediylbisoxy-androst-5-ene was reacted analogously to the method given in Example 9a. 17β-Cyano-3,3-ethanediylbisoxy-17α-methyl-androst-5-ene was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 1, 04 (s wide, 6H), 1, 28 (5,3H), 3,94 (m, 4H, ketal) , 5.34 (s, 1H, H-6)

25c) 17β-cyano-17α-methyl-androst-4-en-3-one

17β-Cyano-3,3-ethanediylbisoxy-17α-methyl-androst-5-ene were reacted analogously to the method given in Example 1c. 17β-Cyano-17α-methyl-androst-4-en-3-one was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 1, 09 (s, 3H), 1, 20 (s, 3H), 1, 28 (s, 3H), 5, 73 (s, 1H, H-4)

Example 26:

17β-Cyano-6β-hydroxymethyl-17α-methyl-androst-4-en-3-one

17β-Cyano-17α-methyl-androst-4-en-3-one were reacted analogously to the procedure given in Example 2. 17β-cyano-6β-hydroxymethyl-17α-methyl-androst-4-en-3-one was obtained.

¹ H-NMR (D6-DMSO): 1, 01 (s, 3H), 1, 15 (s, 3H), 1, 25 (s, 3H), 3.35 (m, 1H, 6-CH2- OH), 3.57 (m, 1H, 6-CH 2 -OH), 4.73 (t, 1H, J = 5.8Hz, 6-CH 2 -OH), 5.65 (s, 1H, H-4) Example 27: 17β-Cyano-6,6-ethanediyl-17α-methyl-androst-4-en-3-one

β-cyano-θβ-hydroxymethyl-α-methyl-androsM-en-S-on was reacted analogously to the instructions given in Examples 3a and 3b, the intermediate tosylate being reacted further in crude form. 17β-Cyano-6,6-ethanediyl-17α-methyl-androst-4-en-3-one was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.42 (m, 2H), 0.78Cm ₁ IH), 1, 10 (s, 3H), 1, 27 ( s, 3H), 1, 29 (s, 3H), 5.63 (s, 1H, H-4)

Example 28: 17α-Allyl-17β-cyano-androst-4-en-3-one

28a) 17β-cyano-17α-methyl-androst-4-en-3-one

17-Cyano-3,3-ethanediylbisoxy-androst-5-ene was reacted analogously to the method given in Example 9a, allyl bromide being used instead of the methyl iodide used there. 17α-Allyl-17β-cyano-3,3-ethanediylbisoxy-androst-5-ene was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 1, 10 (s, 3H), 1, 13 (s, 3H), 3.99 (m, 4H, ketal), 5.26 (m, 2H, -CH = CH 2), 5.39 (s, 1 H, H-6)), 5.97 (m, 1 H, -CH = CH 2)

28b) 17α-allyl-17β-cyano-androst-4-en-3-one

17α-Allyl-17β-cyano-3,3-ethanediylbisoxy-androst-5-ene was reacted analogously to the method given in Example 1c. 17α-Allyl-17β-cyano-androst-4-en-3-one was obtained. ¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.97Cm ₁ IH), 1, 17 (5.3H), 1, 25 (s, 3H), 5.25 ( m, 2H, -CH = CH 2), 5.79 (s, 1 H, 4-H), 5.96 (m, 1 H, -CH = CH 2)

Example 29:

17β-cyano-1α-methyl-androst-4-en-3-one 29a) 17β-cyano-androst-1,4-dien-3-one

2.5 g of 17β-cyano-androst-4-en-3-one and 2.7 g of dichlorodicyanobenzoquinone were boiled in 50 ml of dioxane for 3 hours. After cooling, it was diluted with dichloromethane and filtered. The filtrate was washed with sodium bicarbonate solution, water and saturated brine. After drying over sodium sulfate, filtration and concentration of the filtrate, it was chromatographed on silica gel with a hexane / ethyl acetate mixture. 17β-cyano-androst-1, 4-dien-3-one was obtained.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 1.00 (s, 3H), 1.25 (s, 3H), 6.07 (s, 1H, H- 4), 6.25 (s wide, 1H, H-2), 7.06 (s, 1H, H-1)

29b) 17β-cyano-1α-methyl-androst-4-en-3-one

0.6 g of 17β-cyano-androst-1, 4-dien-3-one warden in 6 ml of tetrahydrofuran in succession with 6 mg of copper (l) bromide, 1, 1 ml of trimethylaluminum and 0.31 ml of trimethylsilyl chloride added. After three hours' rest at room temperature, partitioned between water and ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel with a mixture of hexane / ethyl acetate gave 17β-cyano-1α-methyl-androst-4-en-3-one.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.94 (d, 3H, 1 -CH 3)), 0.98 (s, 3H), 1, 29 (s, 3H), 5.71 (s, 1H, H-4) Example 30:

6ß, 7.beta.-15SS, 16ss-bismethylene-17-cyano-17α-methlyl-androst-4-en-3-one

30a)

6β, 7β-15β, 16β-bismethylene-3β-tert-butyldimethylsilyloxy-5β-hydroxyandrostane-17-one

By the method of Example 16a, 16β-bismethylene-3β, 5β-dihydroxy-androstan-17-one (Angew. Chemie 1982, 94, 718-719) and tert-butyldimethylsilyl chloride as a silylating reagent after crystallization were obtained from 6β, 7β-15β 6β, 7β-15β, 16β-bismethylene-3β-tert-butyldimethylsilyloxy-5β-hydroxy-androstan-17-one.

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.08 and 0.11 [2 xs, each (3H), Si-Me], 4.13 (s, 3 H), 4.40 (s, 5-OH). MS (Cl +) m / z (relative intensity) = 445 (50), 462 (15); corresponds to C ₂₇ H ₄₄ NO ₃ Si.

30b) ββββ-ISβ, βββ-bismethylene-Sβ-tert-butyldimethylsilyloxy-β-cyano-S-hydroxy-androstan-17-one

6β, 7β-15β, 16β-bismethylene-3β-tert-butyldimethylsilyloxy-5β-hydroxy-androstan-17-one was reacted analogously to the method described in Example 1b. This gave 6β, 7β-15β, 16β-bismethylene-3β-tert-butyldimethylsilyloxy-17-cyano-5β-hydroxyandrostan-17-one as a mixture of the 17-epimeric nitriles, which was further processed without epimer separation.

¹ H-NMR (D6-DMSO): 0.02 (s, 3H), 0.04 (s, 3H), 0.40 (m, 2H), 0.60 (m, 1H), 0.74 (s, 3H), 0.82 (s wide, 12H), 2.36 (m, 2H), 2.97 (m, 1H), 4.01 (m, 1H)

30c) 6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17β-cyano-17α-methyl-androstane

6β, 7β-15β, 16β-bismethylene-3β-tert-butyldimethylsilyloxy-17-cyano-5β-hydroxyandrostan-17-one was synthesized analogously to the methods given in Examples 9a and 16c. implemented. There were obtained 6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17β-cyano-17α-methyl-androstane.

¹ H-NMR (D6-DMSO): 0.40 (m, 2H), 0.61 (Hn ₁ IH), 0.74 (5.3H), 0.93 (s, 3H), 1, 36 ( s, 3H), 1, 93 (m, 1H), 2.03 (m, 1H), 3.79 (m, 1H)

3Oe) 6β, 7β-15β, 16β-bismethylene-17β-cyano-17α-methyl-androst-4-en-3-one

310 mg of 6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17β-cyano-17α-methylandrostane were dissolved in 10 ml of acetone and added with 0.42 ml of Jones reagent. After 15 minutes, 0.4 ml of isopropanol was added to the batch. It was then partitioned between water and ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel with a mixture of hexane and ethyl acetate gave 6β, 7β-15β, 16β-bismethylene-17β-cyano-17α-methyl-androst-4-en-3-one.

¹ H-NMR (D6-DMSO): 0.41 (m, 1H), 0.85 (m, 1H), 0.99 (s, 3H), 1, 02 (s, 3H), 1, 31 (s, 3H), 5.86 (s, 1H, 4H)

Example 31:

17α-allyl-6ß, 7.beta.-15SS, 16ss-bismethylene-17-cyano-androst-4-en-3-one

31 a)

17α-allyl-6ß, 7.beta.-15SS, 16fl-bismethylene-3.beta.-5ß-bishydroxy-17-cyano-androstan

6β, 7β-15β, 16β-bismethylene-3β-tert-butyldimethylsilyloxy-17-cyano-5β-hydroxyandrostan-17-one was reacted analogously to the methods given in Examples 9a (replacement of the methyl iodide used for allyl bromide) and 16c , 17α-Allyl-6β, 7β-15β, 16β-bismethylene-3β-5β-bis-hydroxy-17β-cyano-androstane were obtained.

¹ H-NMR (D6-DMSO): 0.40 (m, 2H), 0.61 (m, 1H), 0.74 (s, 3H), 0.96 (s, 3H), 2.02 (m, 2H), 3.79 (m, 1H), 4.78 (m, 1H), 5.19 (s, 1H), 5.24 (m, 1H), 5.94 ( m, 1H) 31 b) 17α-Allyl-6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-4-en-3-one

17α-Allyl-6β, 7β-15β, 16β-bisnethylene-3β-5β-bis-hydroxy-17β-cyano-androstane was reacted analogously to the method given in Example 3Oe. 17α-Allyl-6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-4-en-3-one were obtained.

¹ H-NMR (D6-DMSO): 0.43 cm ₁ IH), 0.86 cm ₁ IH), 1, 02 (5.3H), 1, 03 (s, 3H), 5.20 (171.1 H , -CH = CH 2), 5.24 (171.1 H, -CH = CH 2), 5.87 (s, 1 H, 4-H), 5.94 (m, 1 H, -CH = CH 2)

Example 32: 17β-Cyano-6-methyl-15β, 16β-methylene-androsta-4,6-dien-3-one

To a solution of 100 mg of 17β-cyano-6-exo-methylene-15β, 16β-methylene-androst-4-en-3-one in 10 ml of ethanol is added 25 mg of Pd-C (10%, water wet) and heated to boiling. The solution of 0.5 ml of cyclohexene in 2 ml of ethanol is then slowly added dropwise over 1 hour, and the mixture is refluxed for a further 7 hours. After cooling the reaction mixture, filtering off the catalyst and concentration, 17β-cyano-6-methyl-15β, 16β-methylene-androsta-4,6-dien-3-one (25 mg) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.53 [m, (1 H) cyclopropyl], 2.78 [d, J = 4.5 Hz, 17-H (α)], 5.89 and 6.18 [2 xs, (1 H each), 4-H and 7-H].

MS (Cl +) m / z (rel intensity) = 322 (100), 339 (50); corresponds to C ₂₂ H ₂₇ NO.

Example 33: 4-Chloro-17β-cyano-15β, 16β-methylene-androst-4-en-3-one

700 mg of 17-cyano-15SS be 16ss-methylene-androst-4-en-3-one dissolved in 8 ml of pyridine and cooled to 0 ⁰ C. After addition of 0.32 ml of sulfuryl chloride is stirred for 1.5 hours at this temperature. After addition of saturated aqueous sodium bicarbonate solution, water and ethyl acetate, the phases are separated and the organic phase washed with water and saturated aqueous sodium chloride solution. After drying the organic phase over Nathumsulfat and filtration is concentrated and the product recrystallized from ethyl acetate. 4-Chloro-17β-cyano-15β, 16β-methylene-androst-4-en-3-one (211 mg) is obtained.

¹ H-NMR (300 MHz, CDCl 3 TMS as internal standard, selected signals): δ = 0.47 [m, (1 H) cyclopropyl], 2.75 [d, J = 4.5 Hz, 17 H ( α)], 3.33 (ddd, J ₁ = 15.3 Hz, J ₂ = 4.5 Hz, J ₃ = 2.6 Hz).

Example 34: 17β-Cyano-3-hydroxyimino-15β, 16β-methylene-androst-4-ene

700 mg of 17β-cyano-15β, 16β-methylene-androst-4-en-3-one are dissolved in 5 ml of pyridine and admixed with 211 mg of hydroxylamine hydrochloride. After stirring for one hour at 125 ° C bath temperature, the mixture is partitioned between water and ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Column chromatography afforded 17β-cyano-3-hydroxyimino-15β, 16β-methylene-androst-4-en-3-one as an E / Z mixture of the oximes (157 mg).

¹ H-NMR (300 MHz, CDCl 3 TMS as internal standard, selected signals): δ = 0.43 [m, (1H) cyclopropyl], 2.73 [d, J = 4.5 Hz, 17H ( α)], 3.05 (m, 5-H ₁ ), 5.79 (m, 4-H).

MS (Cl +) m / z (rel intensity) = 325 (100), 342 (76); C _{2 is} IH ₂₈ N ₂ O.

Example 35: 17β-Cyano-6-exo-methylene-17α-methyl-15β, 16β-methylene-androst-4-en-3-one

130 mg of 17β-cyano-6β-hydroxymethyl-17α-methyl-15β, 16β-methylene-androst-4-en-3-one are obtained by the method of Example 4 after chromatography on silica gel 17β-cyano-6-exo methylene-17α-methyl-15β, 16β-methylene-androst-4-en-3-one (86 mg). 17β-Covano-6-exo-n-ethylene-17α-ethyl-15β, 16β-n-ethylene-androst-4-en-3-one 1H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0 , 47 [m, (1H), cyclopropyl], 1, 12, 1, 16 and 1, 39 [3xs, Ge 3H), 3x Me], 5,02 and 5,12 [2 xt, J = 2 Hz, (1 H each), = CH ₂ ], 5.93 (br. S, 4-H).

Example 36: 17β-Cyano-17α-methyl-15β, 16β-methylene-androsta-4,6-dien-3-one

17.7 g of 17β-cyano-3-methoxy-17α-methyl-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene are obtained according to the method of Example 6 from 17β-cyano- 17α-methyl-15β, 16β-methylene-androsta-4,6-dien-3-one (5.84 g).

¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.52 [m, (1 H), cyclopropyl], 1, 14, 1, 21 and 1, 39 [3 × s, Ge 3H), 3 x Me], 5.70 (s, 4-H), 6.18 (dd, J ₁ = 9.8 Hz, J ₂ = 2.8 Hz, 6-H), 6.33 (dd, J ₁ = 9.6 Hz, J ₂ = 1.8 Hz, 7-H).

MS (Cl +) m / z (rel intensity) = 322 (100), 339 (32); corresponds to C ₂₂ H ₂₇ NO ₂ .

Example 37:

6β, 7β-15β, 16β-bismethylene-17β-cyano-17α-methyl-androst-4-en-3-one as well

6α, 7α-15SS, 16ss-bismethylene-17-cyano-17α-methyl-androst-4-en-3-one

According to the method of Example 7 is obtained from 3.0 g of 17β-cyano-17α-methyl-15ß, 16ß-methylene-androsta-4,6-dien-3-one after HPLC separation of the crude product on silica gel as a non-polar fraction 6α , 7α-15β, 16β-bismethylene-17β-cyano-17α-methyl-androst-4-en-3-one (475 mg) and as polar fraction 6β, 7β-15β, 16β-bismethylene-17β-cyano-17α- methyl-androst-4-en-3-one (1.2 g).

Fraction 1: 6α, 7α-15β, 16β-bismethylene-17β-cvano-17α-methyl-androst-4-en-3-one: ¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.46, 0.57, 0.80 and 0.93 [4 xm, (1 H each), 4 x cyclopropyl], 1, 15, 1, 20 and 1, 39 [3 xs, (each 3H ), 3 x Me], 5.96 (s, 4-H). Fraction 2: 6β, 7β-15β, 16β-bismethylene-17β-cvano-17a-methyl-androst-4-en-3-one ¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.50 and 0.87 [2 xm, Ge 1 H), 2 x cyclopropyl], 1, 10, 1, 14 and 1, 41 [3 xs, (3H each), 3 x Me], 6.02 (s, 4-H).

MS (Cl +) m / z (rel intensity) = 336 (100), 353 (28); corresponds to C ₂₃ H ₂₉ NO.

Example 38:

17β-cyano-17α-ethyl-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene and also 17β-cyano-17α-ethyl-15β, 16β-methylene-androst-4- en-3-one

The method of Example 9a) gives 18.0 g of 17β-cyano-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene and the use of ethyl iodide instead of methyl iodide after crystallization 17β-cyano-17α-ethyl-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene (6.85 g) and after flash chromatography of the mother liquor 17β-cyano-17α- ethyl-15β, 16β-methylene-androst-4-en-3-one (338 mg).

17β-Cvano-17α-ethyl-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene: 1 H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.42 [m, (1H), cyclopropyl], 1, 00, and 1, 17 [2 xs, (each 3H), 2 x Me], 1, 21 (t, J = 7.1 Hz , CH ₂ -CH ₃ ), 3.58 [s, (3H), OMe], 5.14 (m, 4-H), 5.26 (m, 6-H).

MS (Cl +) m / z (rel intensity) = 352 (90), 369 (100); corresponds to C ₂₄ H ₃₃ NO.

17β-Cvano-17α-ethyl-15β, 16β-methylene-androst-4-en-3-one: 1 H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.45 [m, (1H), cyclopropyl], 1, 19 and 1, 21 [2 xs, (each 3H), 2 x Me; superimposed on 1.23 (t, J≥6.4 Hz, CH ₂ -CH ₃ )], 5.75 (s, 4-H).

MS (Cl +) m / z (rel intensity) = 338 (100), 355 (59); corresponds to C ₂₃ H ₃₁ NO. Example 39:

17β-Cyano-17α-ethyl-15β, 16β-methylene-androsta-4,6-dien-3-one

According to the method of Example 6, 6.0 g of 17β-cyano-17α-ethyl-3-methoxy-15β, 16β-methylene-androstane-3 (4), 5 (6) -diene are obtained after crystallization and subsequent flash reaction. Chromatography of the mother liquor 17β-cyano-17α-ethyl-15β, 16β-methylene-androsta-4,6-dien-3-one (4.87 g).

¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.59 [m, (1H), cyclopropyl], 1, 18 and 1, 29 [2 xs, (3H each) , 2 times Me; superimposed on 1.27 (t, J = 7.4 Hz, CH ₂ -CHs)], 5.75 (s, 4-H), 6.22 (dd, J ₁ = 9.8 Hz, J ₂ = 2.8 Hz, 6-H), 6.38 (dd, J ₁ = 9.6 Hz, J ₂ = 1.9 Hz, 7-H).

MS (Cl +) m / z (rel intensity) = 336 (100), 353 (43); corresponds to C ₂₃ H ₂₉ NO.

Example 40:

6β, 7β-15β, 16β-bismethylene-17β-cyano-17α-ethyl-androst-4-en-3-one as well

6α, 7α-15SS, 16ss-bismethylene-17-cyano-17α-ethyl-androst-4-en-3-one

By the method of Example 7 is obtained from 2.5 g of 17β-cyano-17α-ethyl-15ß, 16ß-methylene-androsta-4,6-dien-3-one by HPLC separation of the crude product on silica gel as a nonpolar fraction 6α , 7α-15β, 16β-bismethylene-17β-cyano-17α-ethyl-androst-4-en-3-one (290 mg) and as the polar fraction 6β, 7β-15β, 16β-bis-methylene-17β-cyano-17α- ethyl-androst-4-en-3-one (670 mg).

Fraction 1: 6α, 7α-15β, 16β-bismethylene-17β-cvano-17α-ethyl-androst-4-en-3-one: ¹ H-NMR (300 MHz, CDCI ₃ TMS as internal standard, selected signals): δ = 0.48, 0.53, 0.80 and 0.93 [4 xm, (each 1 H), 4 x cyclopropyl], 1, 16 and 1, 23 [2 xs, (each 3H), 2 x me; superimposed on 1.22 (t, J = 6.3 Hz, CH ₂ -CH ₃ )], 5.96 (s, 4-H).

Fraction 2: 6β, 7β-15β, 16β-bismethylene-17β-cvano-17α-ethyl-androst-4-en-3-one ¹ H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.50 and 0.86 [2 xm, (each 1 H), 2 x cyclopropyl], 1, 09 and 1, 15 [2 xs, Ge 3H), 2 x Me], 1, 22 (t, J = 7.3 Hz, CH ₂ -CHs), 6.00 (s, 4-H).

Example 41:

17β-cyano-17α-ethyl-7β-methyl-15β, 16β-methylene-androst-4-en-3-one and 17β-cyano-17α-ethyl-7α-methyl-15β, 16β-methylene-androst-4- en-3-one

According to the method of Example 8 is obtained from 1, 0 g 17ß-cyano-17α-ethyl-15ß, 16ß-methylene-androsta-4,6-dien-3-one after HPLC separation of the crude product on silica gel as non-polar fraction 17ß -Cyano-17α-ethyl-7α-methyl-15β, 16β-methylene-androst-4-en-3-one (165 mg) and as a polar fraction 17β-cyano-17α-ethyl-7β-methyl-15β, 16β- methylene-androst-4-en-3-one (292 mg).

17β-Cvano-17α-ethyl-7α-methyl-15β, 16β-methylene-androst-4-en-3-one 1H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.44 [m, (1H), cyclopropyl], 0.86 (d, J = 7.2Hz, 7-Me), 1, 08 [m, (1H), cyclopropyl], 1, 19 and 1, 21 [2 xs, (3H each), 2 x Me; superimposed on 1.22 (t, J = 7.4 Hz, CH ₂ -CHs)], 5.75 (s, 4-H).

17β-Cvano-17α-ethyl-7β-methyl-15β, 16β-methylene-androst-4-en-3-one 1H-NMR (300 MHz, CDCl ₃ TMS as internal standard, selected signals): δ = 0.53 and 1, 04 [2 xm, (1 H each), 2 x cyclopropyl], 1, 16 - 1, 26 (m, 7-Me, 2 x Me, and CH ₂ -CHs)], 5.73 (br s, 4-H).

Example 42: 17β-cyanoandrost-4-ene

Androst-4-en-17-one (see, for example, HeIv. Chim. Acta (45) 1962, 2575) is reacted analogously to the method given in Example 1b. After chromatography of the resulting crude product on silica gel with a mixture of ethyl acetate and n-hexane, the product-containing fractions are concentrated and rechromatographed by HPLC. Besides 17α-cyanoandrost-4-ene, 17β-cyanoandrost-4-ene is obtained. 17-Cvanoandrost-4-ene

¹ H-NMR (CDCI _3, TMS as internal standard, selected signals): δ = 0.94 [s, 3H, - CH _3], 1.04 [s, 3H, CH _3], 1.13 [m, 1H], 1.21 [m, 1H], 2.11 [m, 1H], 2.20 [m, 1H], 2.26 [m, 1H], 5.31 [s wide, 1H, 4- H]

Example 43: 4-chloro-17β-cyanoandrost-4-en-3-one

17β-Cyanoandrost-4-en-3-one are reacted and worked up analogously to the method given in Example 33. 4-Chloro-17β-cyanoandrost-4-en-3-one is obtained.

¹ H-NMR (CDCl 3 TMS as internal standard, selected signals): δ = 0.98 [s, 3H, CH _3], 1.24 [s, 3H, CH _3], 2.58 [m, 1H, 17 -H], 3.26 [ddd, J ₁ = 15.1 Hz, J ₂ = 4.0 Hz, J ₃ = 2.6 Hz]

Example 44 6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-1,4-dien-3-one

6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-4-en-3-one is reacted analogously to Example 29a to give 6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-1,4 -dien- 3-on.

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.55 (m, 1H), 1.10 (s, 3H), 1.14 (s, 3H), 2.81 (d, 1H, H-17) 6.18 (m, 1H , H-2), 6.33 (m, 1H, H-4), 6.85 (s, 1H, H-1)

Example 45

1α, 2α-6β, 7β-15β, 16β-trismethylene-17β-cyano-androst-4-en-3-one

6β, 7β-15β, 16β-bismethylene-17β-cyano-androst-1,4-dien-3-one is reacted analogously to Example 7 to give 1α, 2α-6β, 7β-15β, 16β-trismethylene-17β-cyano -androst-4-en-3-one

¹ H-NMR (300 MHz, CDCl ₃ ): δ = 0.52 (m, 1H), 0.74 (m, 1H), 0.82 (m, 1H), 1.07 (s, 3H), 1.14 (s, 3H), 2.81 (d, 1H, H-17), 5.86 (m, 1H, H-4)

Claims

claims

1. 17β-cyano-androst-4-ene-Dehvate having the general chemical formula 1

(1 )

in which

Z is selected from the group comprising O, two hydrogen atoms, NOR and NNHSO ₂ R, wherein R is hydrogen or C 1 -C ₄ -alkyl,

R ¹ , R ^{2 are} independently hydrogen or methyl or

R ¹ and R ² together form methylene or omitted to form a double bond between C ¹ and C ² ,

R ^{4 is} hydrogen or halogen,

furthermore either:

R ^6a , R ^6b together form methylene or 1,2-ethanediyl or R ^{6a is} hydrogen and R ^6b is selected from the group comprising hydrogen,

Methyl and hydroxymethylene, and R ^{7 is} selected from the group comprising hydrogen, C 1 -C ₄ -alkyl,

C2-C3 alkenyl and cyclopropyl, or:

R ^{6a is} hydrogen and R ^6b and R ⁷ together form methylene or omitted to form a double bond between C ⁶ and C ⁷

or:

R ^6a is methyl and R ^6b and R ⁷ are omitted to form a double bond between C ⁶ and C ^7,

R ¹⁵ , R ^{16 are} hydrogen or together form methylene, R ^{17 is} selected from the group comprising hydrogen, C 1 -C ₄ -alkyl and allyl,

and their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts,

with the proviso that compounds having the following general chemical formula A are excluded:

wherein X is hydrogen or methyl and the double bonds between C ¹ and C ² and between C ⁶ and C ^{7 are} optional double bonds and

with the further proviso that also 17β-cyano-androst-4-en-3-one is excluded.

2. 17ß-cyano-androst-4-ene derivative according to claim 1, characterized in that R ¹⁵ , R ¹⁶ together form methylene.

The 17β-cyano-androst-4-ene derivative according to claim 1, characterized in that Z is selected from the group comprising O, NOH and NNHSO 2 H.

4. 17ß-cyano-androst-4-ene derivative according to any one of the preceding claims, characterized in that Z is O.

5. 17ß-cyano-androst-4-ene derivative according to any one of the preceding claims, characterized in that R ¹ and R ^{2 are} each hydrogen or together form α-methylene.

6. 17ß-cyano-androst-4-en-derivative according to one of claims 1 to 3, characterized in that R ^{1 is} α-methyl.

7. 17ß-cyano-androst-4-ene derivative according to any one of the preceding claims, characterized in that R ^{4 is} hydrogen or chlorine.

8. 17ß-cyano-androst-4-ene derivative according to any one of the preceding claims, characterized in that R ^{6b is} methyl or hydroxymethyl.

9. 17β-cyano-androst-4-ene derivative according to one of the preceding claims, dadduurrcchh ggeekkeennnzzeieihnhnhnichhnneett ,, ddaassss RR ^66aa , RR ^66bb together form methylene or 1, 2-ethanediyl or are each hydrogen.

10. 17ß-cyano-androst-4-en-derivative according to any one of the preceding claims, characterized in that R ^{7 is} selected from the group comprising hydrogen, methyl and ethyl.

11. 17ß-cyano-androst-4-ene derivative according to any one of claims 1-6, characterized in that R ^6b , R ⁷ together form methylene.

12. 17ß-Cyano-androst-4-en-derivative according to any one of the preceding claims, characterized in that R ^{17 is} selected from the group comprising hydrogen, methyl and AlIIyI.

13. 17ß-cyano-androst-4-ene derivative according to any one of the preceding claims, characterized in that at least one of the substituents R ¹ , R ² , R ⁴ , R ^6a , R ^6b , R ⁷ , R ¹⁵ , R ¹⁶ and R ^{17 is} other than hydrogen.

14. 17ß-cyano-androst-4-ene derivative according to claim 1, selected from the group comprising

6ß, 7.beta.; 15SS, 16ss-bismethylene-17-cyano-17α-methyl-androst-4-en-3-one,

6ß, 7.beta.; 15SS, 16ss-bismethylene-17-cyano-androst-4-en-3-one,

17α-allyl-6ß, 7.beta.; 15SS, 16ss-bismethylene-17-cyano-androst-4-en-3-one,

17-cyano-androsta-4,6-dien-3-one,

17-Cyano-6α, 7α-methylene-androst-4-en-3-one,

17-cyano-6ß, 7.beta.-methylene-androst-4-en-3-one,

17-cyano-6,6-ethanediyl-androst-4-en-3-one,

17α-allyl-17-cyano-androst-4-en-3-one,

17β-cyano-1α-methyl-androst-4-en-3-one,

17β-cyano-androst-1, 4-dien-3-one,

17-cyano-7α-ethyl-androst-4-en-3-one,

17-cyano-15SS, 16ss-methylene-androst-4-en-3-one,

17-cyano-15α, 16α-methylene-androst-4-en-3-one,

17-cyano-6,6-ethanediyl-17α-methyl-androst-4-en-3-one,

17-cyano-17α-methyl-15SS, 16ss-methylene-androst-4-en-3-one,

17-cyano-6,6-ethanediyl-15SS, 16ss-methylene-androst-4-en-3-one,

17α-allyl-17-cyano-15SS, 16ss-methylene-androst-4-en-3-one,

17-cyano-6,6-exomethylene-15SS, 16ss-methylene-androst-4-en-3-one,

17-cyano-6,6-exomethylene-15α, 16α-methylene-androst-4-en-3-one,

17-cyano-6,6-ethanediyl-15α, 16α-methylene-androst-4-en-3-one,

17-cyano-15SS, 16ss-methylene-androsta-4,6-dien-3-one,

17-Cyano-6α-methyl-15SS, 16ss-methylene-androst-4-en-3-one,

17-cyano-17α-methyl-15α, 16α-methylene-androst-4-en-3-one,

6α, 7α; 15SS, 16ss-bismethylene-17-cyano-androst-4-en-3-one, , 16a-methylene-androsta-4,6-dien-3-one 17.beta.-cyano-15α

17-cyano-7α-methyl-15α, 16α-methylene-androst-4-en-3-one,

17-cyano-6,6-exomethylene-17α-methyl-15α, 16α-methylene-androst-4-en-3-one,

17-cyano-7α-methyl-androst-4-en-3-one,

17β-cyano-7α-methyl-15β, 16β-n-ethylene-androst-4-en-3-one and

17-Cyano-6-methyl-15SS, 16ss-methylene-androsta-4,6-dien-3-one.

15. Use of the 17ß-cyano-androst-4-ene derivative according to any one of claims 1 to 14 for the manufacture of a medicament for oral contraception and for the treatment of pre-, peri- and postmenopausal complaints.

16. Use according to claim 15, characterized in that the drug has gestagene and antimineralcorticoide effect.

17. A pharmaceutical composition containing at least one 17ß-cyano-androst-4-ene derivative according to any one of claims 1 to 14 and at least one suitable pharmaceutically acceptable additive.

18. A pharmaceutical composition according to claim 17, further comprising at least one estrogen.

19. Medicament according to claim 18, characterized in that the estrogen is ethinylestradiol.

20. Medicament according to claim 18, characterized in that the estrogen is a natural estrogen.

21. Medicament according to claim 20, characterized in that the natural estrogen is estradiol.

22. Medicament according to claim 20, characterized in that the natural estrogen is estradiol valerate.

3. Medicament according to claim 20, characterized in that the natural estrogen is a conjugated estrogen.