HK1141535A

HK1141535A - 17β-CYANO-19-NOR-ANDROST-4-ENE DERIVATIVE, USE THEREOF AND MEDICAMENTS CONTAINING SAID DERIVATIVE

Info

Publication number: HK1141535A
Application number: HK10107995.8A
Authority: HK
Inventors: J‧库恩克; J‧许布纳; R‧博尔曼; T‧弗伦策尔; U‧克拉尔; F‧门格斯; S‧林; S‧博登; H-P‧穆恩; K‧普雷莱
Original assignee: 拜耳先灵医药股份有限公司
Priority date: 2007-06-12
Filing date: 2008-06-04
Publication date: 2010-11-12

Description

17 beta-cyano-19-nor-androst-4-ene derivatives, their use and medicaments containing them

The present invention relates to certain 17 beta-cyano-19-nor-androst-4-ene derivatives, their use and medicaments containing them and having a gestagenic effect, for example for the treatment of premenopausal, perimenopausal and postmenopausal symptoms as well as premenstrual symptoms.

From the literature, compounds with gestagenic, antimineralocorticoid, antiandrogenic or antiestrogenic action based on steroid structures are known, which are derived, for example, from 19-nor-androst-4-en-3-one or derivatives thereof (the number of steroid structures can be determined, for example, from Fresenius @3rd ed.1991“Organisch-chemische Nomenklatur”[Organic chemical nomenclature]pp.60ff).

Thus, WO 2006072467a1 describes the compound 6 β,7 β -15 β, 16 β -dimethylene-3-oxo-17-pregn-4-ene-21, 17 β -carbolactone (drospirenone) having a progestational effect, which has been used, for example, in oral contraceptives and in preparations for the treatment of postmenopausal symptoms. Drospirenone is included in contraceptives due to its relatively low affinity for the progestogen receptor and its relatively high ovulation-inhibiting dose, but the daily dose is relatively high at 3 mg. Furthermore, drospirenone appears to be important because, in addition to its progestational effect, it also has aldosterone antagonistic (antimineralocorticoid) and antiandrogenic effects. These two properties make drospirenone very similar in pharmacological profile to the natural progestin progesterone, however, unlike drospirenone, progesterone is not sufficiently orally bioavailable. In order to reduce the administration dose, 18-methyl-19-nor-17-pregn-4-ene-21, 17-carbolactone and pharmaceutical preparations containing this compound, which have a higher progestational potency than drospirenone, are further proposed in WO 2006072467A 1.

Further, for example, US-A3,705,179 discloses steroids having antiandrogenic activity and being suitable for the treatment of androgen related diseases.

In DE 2226552B 2, further 17-cyano-19-nor-androst-4-en-3-one compounds are described, which exhibit exogenous pseudoprogesterone, antiandrogen and antiestrogen effects.

The object of the present invention is to provide compounds which bind strongly to the progestagen receptor. Furthermore, the compounds should preferably also have antimineralocorticoid action.

The above objects are achieved by the novel 17 β -cyano-19-nor-androst-4-ene derivatives of claim 1, the use of the novel derivatives of claim 11 and the medicaments of claim 13 containing at least one of the novel derivatives. Advantageous embodiments of the invention are specified in the dependent claims.

Accordingly, the present invention relates to 17 beta-cyano-19-nor-androst-4-ene derivatives of the general formula 1

Wherein

Z is selected from O, two hydrogen atoms, NOR and NNHSO₂R, wherein R is hydrogen or C₁-C₄-an alkyl group,

R⁴is a hydrogen or a halogen, and the halogen,

further:

R^6a、R^6btogether forming a methylene or 1, 2-ethanediyl radical, or R^6aIs hydrogen, R^6bSelected from hydrogen, methyl and hydroxymethylene, and R⁷Selected from hydrogen, C₁-C₄Alkyl radical, C₂-C₃-an alkenyl group and a cyclopropyl group,

or:

R^6ais hydrogen, and R^6bAnd R⁷Together forming a methylene group or being absent in C⁶And C⁷A double bond is formed between the two groups,

R⁹、R¹⁰at C for hydrogen or not present⁹And C¹⁰A double bond is formed between the two groups,

R¹⁵、R¹⁶are hydrogen or together form a methylene group,

R¹⁷selected from hydrogen, C₁-C₄-an alkyl group and an allyl group,

wherein the substituent R⁴、R^6a、R^6b、R⁷、R¹⁵、R¹⁶And R¹⁷At least one of which is not hydrogen, or R^6bAnd R⁷Is absent and is in C⁶And C⁷A double bond is formed between the two groups,

and solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts thereof.

The numbering of the C ring system of the novel derivatives of general chemical formula 1 generally follows the numbering of the steroid ring system, as described, for example, in Fresenius, loc. Similarly, the radical numbering described in the claims corresponds to its bonding position on the derivative C ring system. For example, R⁴Radicals bound to C of novel derivatives⁴-a location.

For the radicals defining Z, NOR and NNHSO₂The R radicals are each bound with a double bond-NOR and-N-NH-SO₂R is bonded to the C-skeleton of the derivative via N, OR in NOR and NNHSO₂NHSO in R₂R may be in the cis or trans position.

In each case, C₁-C₄Alkyl is understood to mean a straight-chain or branched alkyl group, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Particularly preferred are especially the unbranched radicals methyl, ethyl and n-propyl. Furthermore, the alkyl group bonded to the 17 α position may be perfluorinated, so that in this case R¹⁷There may be further trifluoromethyl, pentafluoroethyl, n-heptafluoropropyl, iso-heptafluoropropyl, n-nonafluorobutyl, iso-nonafluorobutyl and tert-nonafluorobutyl.

C₂-C₃Alkenyl is preferably understood to mean vinyl or allyl.

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

Isomers are compounds having the same empirical formula, but different chemical structures. It is clear that all possible isomers and isomer mixtures (racemates) are also included, the position of the 17 β -cyano group in the novel derivatives being specified.

In general, structural isomers and stereoisomers are distinguished. The structural isomers have the same empirical formula but differ in the manner in which their atoms or groups of atoms are attached. The structural isomers include functional group isomers, positional isomers, tautomers, or valence isomers. In principle, stereoisomers have the same structure (conformation) and therefore also the same empirical formula, but differ in the spatial arrangement of their atoms. In general, configurational isomers and conformational isomers differ. Configurational isomers are stereoisomers which can only be converted into one another by cleavage of a bond. It includes enantiomers, diastereomers and E/Z (cis/trans) isomers. Enantiomers are stereoisomers that are in an image and mirror image relationship to each other and that have no plane of symmetry. All stereoisomers that are not enantiomers are designated as diastereomers. The E/Z (cis/trans) isomer about the double bond is a special case. Conformational isomers are stereoisomers that can be converted into each other by rotation of a single bond. For a description of the various isomeric forms see IUPAC rules section E (Pure appl. chem.45, 11-30 (1976)).

The novel derivatives of formula 1 also include the possible tautomeric forms and include the E or Z isomers or, if a chiral center is present, the racemates and enantiomers. Double bond isomers are also understood to be included therein.

The novel derivatives may also be present in the form of solvates, in particular hydrates, and accordingly the novel compounds contain polar solvents, in particular water, as structural elements of the crystal lattice of the novel compounds. The polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, hydrates, hemi-, (hemi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are also included.

The novel compounds or derivatives have been found to have a good progestational effect in vivo. Furthermore, certain interesting novel compounds act as mineralocorticoid receptor antagonists.

Preferably wherein Z is selected from O, NOH and NNHSO₂H toolNovel derivatives having the above chemical formula 1. Z is particularly preferably O.

Independent of the choice of Z, preference is given to novel derivatives of the abovementioned general chemical formula 1 in which the following variables occur alternately or at least in some cases simultaneously and are selected independently of one another:

particular preference is given to R¹⁵And R¹⁶Together form a methylene group, where both α -and β -methylene groups can be bonded at these positions.

More preferably R⁴Is hydrogen or chlorine.

More preferably R^6aAnd R^6bTogether form a1, 2-ethanediyl radical or are each hydrogen.

R⁷More preferably selected from hydrogen and methyl, wherein the methyl group may be either alpha-or beta-type.

More preferably R^6aAnd R⁷Together form a methylene group, wherein the methylene group may be either alpha-or beta-type.

R¹⁷More preferably selected from hydrogen and methyl.

And, R^6a、R^6b、R⁷、R¹⁵And R¹⁶The groups may be either alpha-or beta-type.

The novel 17 β -cyano-19-nor-androst-4-ene derivatives are particularly preferably selected from:

very particular preference is given to the 15 α, 16 α -and 15 β, 16 β -methylene derivatives from the above list.

Due to their progestational activity, the novel compounds of formula 1 may be used alone or in combination with estrogens in contraceptive medicaments.

The derivatives of the invention are therefore particularly suitable for the production of medicaments for oral contraception and for the treatment of premenopausal, perimenopausal and postmenopausal symptoms, including the use in formulations for Hormone Replacement Therapy (HRT).

Due to their good performance characteristics, the derivatives according to the invention are particularly highly suitable for the treatment of premenstrual symptoms such as headache, depression, water retention and mastalgia.

Particularly preferred is the use of the derivatives according to the invention for the production of a medicament having gestagenic and antimineralocorticoid action.

Preferably, humans are treated with the derivatives of the invention, but related mammalian species, such as dogs and cats, may also be treated.

When the derivatives of the invention are used as medicaments, they are used in combination with at least one suitable pharmaceutically acceptable non-hazardous additive, such as a carrier. The additive is suitable for e.g. parenteral administration, preferably oral administration. This is a problem with pharmaceutically suitable organic or inorganic inert additive materials, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils and polyalkylene glycols, and the like. The medicaments may be present in solid form, such as tablets, coated tablets, suppositories, capsules, or in liquid form, such as solutions, suspensions or emulsions. Optionally, it also contains excipients, such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. For parenteral administration, oily solutions, such as solutions in sesame, castor and cottonseed oil, are particularly suitable. To increase solubility, a solubilizing agent such as benzyl benzoate or benzyl alcohol may be added. The derivatives of the invention may also be included in transdermal systems, whereby they are administered transdermally. For oral administration, tablets, coated tablets, capsules, pills, suspensions or solutions are particularly suitable.

The dose of the derivative of the invention in the contraceptive formulation should be 0.01 to 10mg per day. The daily dose in the treatment of premenstrual symptoms is about 0.1 to 20 mg. The gestagenic derivatives of the invention are preferably administered orally in contraceptive formulations and medicaments for the treatment of premenstrual symptoms. The daily dose is preferably administered as a single dose.

In contraceptive preparations, the progestational active ingredient and the estrogenic active ingredient are preferably administered orally together. The daily dose is preferably administered as a single dose.

Possible estrogens are synthetic estrogens, preferably ethinyl estradiol or mestranol.

The estrogen is administered in a daily dose corresponding to 0.01 to 0.04mg of ethinyl estradiol.

Of course, estrogens are used mainly as estrogens in drugs used for the treatment of premenopausal, perimenopausal and postmenopausal symptoms and for hormone replacement therapy, in particular estradiol or its esters, such as estradiol valerate or conjugated estrogens (CEEs ═ conjugated equine estrogens).

If the preparation of the starting compounds is not described herein, it is known to those skilled in the art or can be prepared according to methods analogous to those described for the known compounds or herein. The isomer mixture can be separated into enantiomers, E/Z isomers or epimers by a usual method such as crystallization, chromatography or salt formation.

The derivative of the present invention having the chemical formula 1 is prepared according to the following method.

Suitable starting materials for the 17 β -cyano-19-nor-androst-4-en-3-one derivatives described herein are various steroid starting materials, such as 19-nor-androst-4-ene-3, 17-dione, or partially reduced analogs.

Microbiologically, for example, 15 α -hydroxy-19-nor-androst-4-ene-3, 17-dione is available, which opens up the route to 15 β, 16 β -methyleneated 17-cyano steroids, for which see the examples in the experimental section. Likewise, 15 α, 16 α -methyleneated precursors suitable for the synthesis of the corresponding 17-cyano steroids are known, for example 17 β -hydroxy-15 α, 16 α -methylene-19-nor-androst-4-en-3-one in DE-A2207421 (1973). The acquisition of 17 beta-cyano-19-nor-androst-4-en-3-one is described in DE-A2226552.

It will be apparent to those skilled in the art that in the description of synthetic transformations, other functional groups optionally present on the steroid ring system are always protected in a suitable form.

The 17 (C) position of the steroid ring system can be achieved in various ways¹⁷) The nitrile is introduced above. Both single-stage methods and multi-stage variants are possible here. Preference is given here to a process in which the oxygen function is finally replaced by cyanide. In the Science of Synthesis Houben-Weyl Methods of molecular transformations Category 3Volume 19pp.197-213(2004Georg Thieme Verlag Stuttgart, New York) and Houben-Weyl Methoden der organischen chemistry [ Houben-Weyl Methods of organic chemistry]Volume E5Part 2pp.1318-1527(1985Georg Thieme Verlag Stuttgart, New York)Many possible process variants.

A single stage process is shown as such, for example, as a direct reduction replacement of the carbonyl oxygen atom by a cyano group. To this end, 17-ketosteroids are reacted with tosylmethyl isocyanide in a suitable solvent such as dimethoxyethane, dimethyl sulfoxide, ether, alcohol or mixtures thereof, using a suitable base such as an alkali metal alkoxide, alkali metal hydride, potassium hexamethyldisilazide or an alkali metal amide such as lithium diisopropylamide, at a temperature in the range of 0 ℃ to 100 ℃. Mixtures of the 17-epimers which may be formed may be separated by chromatography, fractional crystallization or by a combination of the two.

SN can also be carried out by cyanide on a suitable leaving group in position 17, such as a halide, preferably iodine or bromine, or a sulfate of 17-alcohol₂-type substitution. Inorganic cyanides such as lithium cyanide, sodium cyanide and potassium cyanide are preferred as the cyanide source used.

The following may be mentioned as examples of multistage variants in which the nitrile is introduced: 17-ketones are converted to the corresponding 17-exocyclic methylene compounds by Witting olefination, which can react to form the corresponding 17-carboxaldehyde oximes after hydroboration and oxidation to form aldehydes. The oxime is then dehydrated to form 17-carbonitrile.

The introduction of the nitrile can be carried out either at the beginning of the synthesis sequence or at any desired point in time thereafter, provided that the other functional groups which may be present are protected in a suitable manner.

Optionally, the 17-cyano compound may be alkylated to produce stereochemically homogeneous 17 β -cyano-17 α -substituted derivatives. To this end, the 17-cyano steroid is deprotonated in a suitable solvent such as an ether (e.g., tetrahydrofuran). Different bases can be used here, for example alkali metal amides such as lithium diisopropylamide. After addition of an alkylating agent such as a haloalkane or haloalkene and after work-up, the 17 β -cyano-17 α -substituted derivative is obtained.

By way of example, the further synthetic procedure is illustrated by means of the following synthetic route, the already described compound 2 (DE-A2226552 (1972)) being mentioned as starting material:

route 1

The introduction of the 6, 7-double bond is effected by bromination of the 3, 5-dienol ether 5 and subsequent elimination of hydrogen bromide (see, for example, J.Fried, J.A.Edwards, Organic Reactions in Steroid chemistry, von Nostrand and Reinhold Company 1972, pp.265-374).

Substituent R⁴The introduction can be effected, for example, by starting from a compound of the formula 2, epoxidizing its 4, 5-double bond with hydrogen peroxide under basic conditions and reacting the resulting epoxide with a compound of the general formula H-R in a suitable solvent⁴Wherein R is⁴May be a halogen atom or a pseudohalogen, or with a catalytic amount of an inorganic acid, and optionally reacting the resulting compound of formula 1 (wherein R is⁴Bromine) is reacted with methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate in dimethylformamide in the presence of copper (I) iodide.

Bromination of the dienol ether of compound 5 can be carried out, for example, according to a procedure similar to Steroids 1, 233 (1963). Can be prepared by reacting a 6-bromo compound with a compound such as LiBr or Li₂CO₃Is heated together in an aprotic solvent such as dimethylformamide at a temperature of 50 to 120 c to eliminate hydrogen bromide, or by heating the 6-bromo compound in a solvent such as collidine or lutidine to give compound 6.

Compound 7 is converted to compound 8 by the methylation of the 6, 7-double bond according to known methods, for example using dimethylsulfoxonium ylide (see, for example, DE-A1183500, DE-A2922500, EP-A0019690, U.S. Pat. No. 3, 4,291,029; J.Am.chem.Soc.84, 867(1962)), to give a mixture of alpha-and beta-isomers, which can be separated, for example, by chromatography to give the individual isomers.

The compound of type 7 can be obtained according to the methods described in the examples or analogous thereto, using analogous reagents to those described therein.

The synthesis of spiro compound 12 starts from compound 2, which is first converted to 3-amino-3, 5-diene derivative 9. Compound 9 is reacted with formalin in an alcoholic solution to give 6-hydroxymethylene derivative 10. After conversion of the hydroxyl group to a leaving group, e.g., mesylate, tosylate (compound 11) or benzoate, compound 13 can be prepared by reaction with trimethyl sulfoxide iodide in a suitable solvent such as dimethyl sulfoxide using a base such as an alkali metal hydroxide or alkali metal alkoxide.

To introduce the 6-methylene group, compound 10 can be dehydrated using, for example, hydrochloric acid in dioxane/water. 6-methylene can also be prepared from compound 11 (cf. DE-A34023291, EP-A0150157, U.S. Pat. No. 4,584,288; J.Med.chem.34, 2464 (1991)).

Another possibility for preparing 6-methylene compounds consists in reacting 4(5) unsaturated 3-ketones, for example compound 2, with acetals of formaldehyde in the presence of sodium acetate, using, for example, phosphorus oxychloride or phosphorus pentachloride, in suitable solvents such as chloroform (see, for example, k. annex, h. hofmeister, h. laurent and r. wiechert, Synthesis 34 (1982)).

The 6-methylene compound can be used for preparing a compound having the chemical formula 1, wherein R^6aIs methyl, and R^6bAnd R⁷Is absent and is in C⁶And C⁷Form a double bond therebetween.

To this end, for example, the process described in Tetrahedron 21, 1619(1965) can be employed, in which isomerization of the double bonds is effected by heating the 6-methylene compounds in ethanol with 5% palladium-carbon catalyst, the catalyst being pretreated with hydrogen or by heating with small amounts of cyclohexene. If a small amount of cyclohexene is added to the reaction mixture, this isomerization can also be achieved by using a catalyst which has not been pretreated. The presence of small amounts of hydrogenation products can be prevented by adding an excess of sodium acetate.

However, 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)).

Wherein R is^6bThe compounds which are alpha-methyl functional groups can be prepared by hydrogenation of 6-methylene compounds under appropriate conditions. The best results (selective hydrogenation of exocyclic methylene function) were achieved by transfer hydrogenation (j. chem. soc.3578 (1954)). If the 6-methylene derivative is heated in a suitable solvent such as ethanol in the presence of a hydride donor such as cyclohexene, a very high yield of the 6 α -methyl derivative is obtained. Small amounts of 6 β -methyl compounds can be isomerized by acid (Tetrahedron1619 (1965)).

6 beta-methyl compounds can also be selectively prepared. To this end, a 4-en-2-one, such as compound 2, is reacted with, for example, ethylene glycol or trimethyl orthoformate in methylene chloride in the presence of a catalytic amount of an acid, such as p-toluenesulfonic acid, to form the corresponding 3-ketal. In this ketalization process, the 5-position (C)⁵) The double bond on (a) isomerizes. The 5-double bond can be selectively epoxidized using, for example, an organic peracid such as m-chloroperoxybenzoic acid in a suitable solvent such as methylene chloride. In addition, the epoxidation can also be carried out using hydrogen peroxide in the presence of, for example, hexachloroacetone or 3-nitrotrichloroacetophenone. The 5, 6 α -epoxide can then be axially opened with the appropriate alkylmagnesium halide or alkyllithium compound. Thereby obtaining the 5 alpha-hydroxy-6 beta-alkyl compound. Cleavage of the 3-keto protecting group can be achieved by treatment under mild acidic conditions (0 ℃ C. acetic acid or 4N hydrochloric acid) to give a 5 α -hydroxy function. Dissolving in water using, for example, dilute sodium hydroxideThe 5 alpha-hydroxyl functional group is subjected to alkaline elimination to obtain the 3-keto-4-alkene compound containing the beta-6-alkyl group. In addition, ketal cleavage under more severe conditions (aqueous hydrochloric acid or other strong acid) gives the corresponding 6 α -alkyl compounds.

The resulting compound of the formula 1, wherein Z is an oxygen atom, can be converted into its corresponding oxime by reacting with hydroxylamine hydrochloride in the presence of a tertiary amine at a temperature of-20 to +40 ℃ (in the formula 1 wherein Z represents NOH, the hydroxyl group may be cis or trans). Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N-dimethylaminopyridine, 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1, 5-diazabicyclo [5.4.0] undec-5-ene (DBU), preferably pyridine. This is similar to the preparation of the corresponding 3-oximino derivative of drospirenone described in WO-A98/24801.

In order to prepare the final product of the general chemical formula 1, in which Z represents two hydrogen atoms, the removal of the 3-oxo group can be achieved by subjecting the thioketal of the 3-keto compound to reductive cleavage, for example, according to the procedure described in DE-A2805490.

The following examples serve as a more detailed description of the invention:

the compounds of the invention are very distinctive due to their strong progestational activity and are highly active in the pregnancy maintenance test in rats after subcutaneous administration.

Implementation of the rat pregnancy maintenance test:

in pregnant rats, resection of the corpus luteum or ovariectomy surgery induces abortion. Maintenance of pregnancy is possible by exogenous co-administration of a progestin (progestin) and an appropriate dose of an estrogen. Pregnancy maintenance tests performed on ovariectomized rats were used to determine the peripheral gestagenic activity of the compounds.

Rats were paired overnight in the early phase of estrus. The matching was checked by evaluating vaginal smears the following morning. Here, the presence of sperm is assessed as the first day of the onset of pregnancy. On day 8 of pregnancy, animals were ovariectomized under ether anesthesia. The test compound and exogenous estrogen (estrone, 5 μ g/kg/day) were administered subcutaneously once a day for treatment from day 8 to day 15 or day 21 of pregnancy. The first dose was administered two hours prior to ovariectomy on day eight. Vehicle alone was given to intact control animals.

Evaluation:

at the end of the experiment (day 15 or day 21), the animals were exposed to CO₂Sacrificed in the environment and live fetuses (fetuses with heartbeats) and implantation sites (early resorbtion and dead fetuses, including autolyzed and atrophic placenta) were counted in two uterine horns. On day 22, the possibility of examining a misshapen fetus was higher. In the uterus without a fetus or implantation site, the number of implantation sites was determined by staining with a 10% strength ammonium sulfide solution. The pregnancy maintenance rate was calculated as the quotient of the number of live births and the total number of implantation sites (resorptive and dead births and implantation sites). For some of the test substances, pregnancy maintenance doses (ED50) described in table 1 were determined. For drospirenone, this value was 3.5 mg/kg/day.

The derivatives of the present invention having the chemical formula 1 have strong progestational activity. Furthermore, it was found that the derivatives of the invention exhibit an in vitro antimineralocorticoid effect. It should therefore have potassium-sparing natriuretic (antimineralocorticoid) activity in the body. These properties were determined by the following tests:

for culturing the cells used for the assay, DMEM (Dulbecco 'S modified Eagle' S medium: 4500mg/ml glucose; PAA, # E15-009) containing 10% FCS (Biochrom, S0115, batch #615B), 4mM L-glutamine, 1% penicillin/streptomycin, 1mg/ml G418 and 0.5. mu.g/ml puromycin was used.

Reporter cell line at 4X 10 per well⁴The density of individual cells was grown in white opaque tissue culture plates with 96 wells per plate (Perkinelmer, # P12-106-Interfering components contained in the serum). The compound used for the study was added after 8 days, and the cells were cultured in the compound for 16 hours. The experiment was performed in triplicate. At the end of the culture, the medium containing the effector is removed and replaced with lysis buffer. After adding luciferase assay substrate (promega, # E1501), the 96-well plate was placed in a microplate luminometer (Pherastar, BMG labtech) and luminescence was measured. The IC50 values were assessed using software for calculation of dose-activity relationships. The results are shown in Table 1:

compound (I)	MR antagonism IC50[ nM]	Mr antagonistic Activity [% maximum Effect]	ED50[ mg/kg/d s.c in PR body.]
compound (I)	MR antagonism IC50[ nM]	Mr antagonistic Activity [% maximum Effect]	ED50[ mg/kg/d s.c in PR body.]	17 beta-cyano-15 alpha, 16 alpha-methylene-19-nor-androst-4-en-3-one	16.0	93.01	0.8
17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one	29.0	96.00	0.8		16.0	93.01	0.8
	29.0	96.00	0.8	7 alpha, 17 alpha-bis-methyl-17 beta-cyano-19-Nor-androst-4-en-3-one	31.0	96.20	1.0
17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one	4.5	95.57	0.84		31.0	96.20	1.0
	4.5	95.57	0.84	17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one	440	106.4	1.9
17 beta-cyano-7 alpha-methyl-19-nor-androst-4-en-3-one	8.2	108.02	0.33		440	106.4	1.9
17 beta-cyano-7 alpha-methyl-19-nor-androst-4-en-3-one	8.2	108.02	0.33	17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one	15	108.51	3.3
17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one	190	114	2.1		15	108.51	3.3
	190	114	2.1	17 beta-cyano-7 alpha-methyl-15 beta,16 beta-methylene-19-nor-androst-4-en-3-one	8.3	108.4	0.11

17 beta-cyano-7 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one	10.3	110	2.9
	10.3	110	2.9	17 beta-cyano-17 alpha-ethyl-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one	90.17	160	0.22

The following examples of the synthesis of preferred compounds serve as further illustration of the invention. The novel intermediates disclosed in the various synthetic examples are important to the present invention, as are the 17 β -cyano-19-nor-androst-4-ene derivatives of the present invention.

Many of the reactions described below produce mixtures of epimers. Typically, these mixtures are chromatographed by preparative HPLC under the following conditions: the separation is carried out on the chiral normal phase, the stationary phase usually being Chiralpak AD-H5. mu.l. Typically, elution is performed using a mixture of hexane and ethanol. However, other eluent mixtures, such as methanol and ethanol mixtures, are used in some cases.

Example 1:

17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

1a.

15 alpha-acetoxy-19-nor-androst-4-ene-3, 17-dione

95g of 15 alpha-hydroxy-19-nor-androstenedione (described in DE-A2456068; 1976) were dissolved in 332ml of pyridine. After addition of 166ml of acetic anhydride, the solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into a mixture consisting of 10L of ice water, 109ml of concentrated sulfuric acid and 16ml of methanol. After stirring overnight, the precipitate was filtered off with suction and the filter residue was washed with 3 l of water. To obtain 15 alpha-acetoxyl-19-nor-androst-4-ene-3, 17-dione, and carrying out the next reaction without purifying the same.

1b.

15 alpha-acetoxy-3-methoxy-19-nor-androst-3, 5-dien-17-one

90.6g of the compound described in example 1a are suspended in 955ml of 2, 2-dimethoxypropane and treated with 10.3g of pyridine tosylate. The reaction mixture was heated to 100 ℃ for 6.5 hours and then stirred at room temperature overnight. After addition of 13.8ml of pyridine, it was partially concentrated under reduced pressure on a rotary evaporator and the remaining content of the flask was treated with 550ml of methanol. After stirring for one and a half hours at room temperature, the mixture is cooled to 0 ℃, filtered with suction and the filter cake is dried. Thereby obtaining the 15 alpha-acetoxyl group-3-methoxyl group-19-nor-androstane-3, 5-diene-17-ketone.

¹H-NMR(d6-DMSO)：0.87(s，3H，18-CH3)，1.98(s，3H，CH3-CO-)，3.46(s，3H，3-O-CH3)，5.10(m，1H，H-15)，5.18(s，1H，H-4)，5.21(m，1H，H-6)

1c.

15 beta, 16 beta-methylene-3-methoxy-19-nor-androsta-3, 5-dien-17-one

26.03g of trimethylsulfoxidide and 8.3g of powdered sodium hydroxide are stirred in 344ml of dimethyl sulfoxide for 30 minutes at a bath temperature of 50 ℃. The solution obtained is added dropwise within 5 minutes to a suspension of 33.4g of the compound described in example 1b in 110ml of dimethyl sulfoxide. After 20 minutes, the batch was transferred to a beaker and 500ml of water was slowly added dropwise with stirring. After the mixture was stirred for 20 minutes, it was suction filtered through a porous glass filter (frit), and the filter cake was dried. To obtain 15 beta, 16 beta-methylene-3-methoxyl-19-nor-androstane-3, 5-diene-17-ketone.

¹H-NMR(d6-DMSO)：0.91(s，3H，18-CH3)，3.51(s，3H，3-O-CH3)，5.26(s，1H，H-4)，5.33(m，1H，H-6)

1d.

17-cyano-15 beta, 16 beta-methylene-3-methoxy-19-nor-androsta-3, 5-diene

2.5g of the compound described in example 1c are initially added to a mixture of 40ml of 1, 2-dimethoxyethane and 25ml of tert-butanol. After addition of 4.7g of potassium tert-butoxide, 2.77g of tosylmethyl isocyanide (TOSMIC) are added and the mixture is stirred for 90 minutes. The batch was added to 10 times the amount of ice water, salt was added to saturation, and the mixture was filtered. The filter cake was taken up in ethyl acetate, the solution was washed with water and brine, dried over sodium sulfate and filtered, and the filtrate was concentrated. A mixture of 17 alpha-cyano and 17 beta-cyano-15 beta, 16 beta-methylene-3-methoxy-19-nor-androsta-3, 5-diene is obtained which is subjected to the next reaction without purification.

1e.

17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

2.8g of the crude isomer mixture described in example 1d are stirred for 3 hours in a mixture of 100ml of acetone and 10ml of 1 strength-equivalent HCl. After the reaction mixture was neutralized with a saturated sodium bicarbonate solution, it was extracted with ethyl acetate, and then the organic phase was washed with water and a saturated saline solution. After drying over sodium sulfate, it is filtered, the filtrate is concentrated and the residue is first chromatographed on silica gel with a gradient solvent of n-hexane and ethyl acetate. The product-containing fractions are then chromatographed again on silica gel using a mixture of n-hexane and ethyl acetate.

The fractions containing predominantly the desired product were combined, concentrated and recrystallized from a mixture of diisopropyl ether and acetone. Crystals of 17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one (crystallizate) were obtained. The mother liquor and the product-containing fractions remaining from chromatography are concentrated to provide a mixture of 17 α -cyano and 17 β -cyano-15 β, 16 β -methylene-19-nor-androst-4-en-3-one.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.46(m, 1H), 0.90(m, 1H), 1.04(m, 1H), 1.10(s, 3H, 18-CH3) 1.67(m, 1H), 1.86(m, 2H), 2.11(m, 2H), 2.55(m, 1H), 2.77(d width, 1H, J ═ 4.4Hz, 17-H)，5.86(s，1H，H-4)

Example 2

17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one

2a.

17 beta-cyano-15 beta, 16 beta-methylene-3-methoxy-19-nor-androsta-3, 5-diene

9g of 17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one (see example 1e) were dissolved in 92ml of methanol and treated with 83ml of methyl orthoformate. After addition of 53mg of p-toluenesulfonic acid, the mixture was stirred at 15 ℃. A precipitate formed. After addition of 0.8ml pyridine at 0 ℃ the mixture was cooled to-10 ℃ and stirred for 30 minutes. After decompression and concentration, 17 beta-cyano-15 beta, 16 beta-methylene-3-methoxyl-19-nor-androstane-3, 5-diene is obtained, and the next reaction is carried out without purifying the diene.

2b.

17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one

A suspension of 3.4g of 17 β -cyano-15 β, 16 β -methylene-3-methoxy-19-nor-androsta-3, 5-diene in 100ml of 1-methyl-2-pyrrolidone was treated at 0 ℃ with 4ml of a 10% strength sodium acetate solution and at this temperature further treated partly with 1.6g of 1, 3-dibromo-5, 5-dimethylhydantoin, stirred for 0.5 h at 0 ℃ (ice bath), treated with 1.5g of lithium bromide and 1.3g of lithium carbonate and stirred for 3.5 h at a bath temperature of 100 ℃. Subsequently, the mixture was stirred in ice water/salt and the precipitate was filtered. To obtain 17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androstane-4, 6-diene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.54(m, 1H, cyclopropyl), 1.10(m, 1H, cyclopropyl), 1.12(s, 3H, 18-CH3)，2.80(d，1H，J＝4.4，H-17)，5.81(s，1H，H-4)，6.27(m，1H，H-6)，6.41(m，1H，H-7)

Example 3

17 beta-cyano-15 beta, 16 beta-methylene-7 alpha-methyl-19-nor-androst-4-en-3-one and 17 beta-cyano-15 beta, 16 beta-methylene-7 beta-methyl-19-nor-androst-4-en-3-one

67mg of copper (I) chloride were added at room temperature to a solution of 1.0g of 17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one in 50ml of tetrahydrofuran and the mixture was stirred for 10 minutes, then cooled to-15 ℃ and treated with 450mg of aluminum chloride, stirred at this temperature for 30 minutes, treated dropwise with 4.5ml of methylmagnesium bromide solution (3M in tetrahydrofuran) and stirred at-15 ℃ for 1 hour. As work-up, the reaction mixture is treated with 30ml of 2M hydrochloric acid at-15 ℃, stirred at room temperature for 0.5 h, added to water, extracted three times with ethyl acetate, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel with hexane/ethyl acetate. 17 beta-cyano-7 alpha-methyl-18 a-homo-19-nor-androst-4-en-3-one as part I and 17 beta-cyano-15 beta, 16 beta-methylene-7 beta-methyl-19-nor-androst-4-en-3-one as part II are obtained.

17 β -cyano-15 β, 16 β -methylene-7 α -methyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.45(m, 1H, cyclopropyl), 0.88(d, 3H, J is 6.97, 7-CH3) 1.03(m, 1H, cyclopropyl), 1.10(s, 3H, 18-CH3)，5.86(s，1H，H-4)

17 β -cyano-15 β, 16 β -methylene-7 β -methyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.53(m, 1H, cyclopropyl), 1.01(m, 1H, cyclopropyl), 1.10(s, 3H, 18-CH3)，1.21(d，3H，J＝6.22，7-CH3)，5.83(s，1H，H-4)

Example 4

17 beta-cyano-7 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

Chromatographic separation using ethylmagnesium bromide in diethyl ether instead of methylmagnesium bromide according to the procedure of example 3 gave 17 β -cyano-7 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-7 β -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 β -cyano-7 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.46(m, 1H, cyclopropyl), 0.92(m, 3H, 7-CH3-CH2), 1.03(m, 1H, cyclopropyl), 1.10(s, 3H, 18-CH3)，5.87(s，1H，H-4)

17 β -cyano-7 β -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.54(m, 1H, cyclopropyl), 0.95(m, 3H, 7-CH3-CH2), 1.02(m, 1H, cyclopropyl), 1.11(s, 3H, 18-CH3)，5.84(s，1H，H-4)

Example 5

17 beta-cyano-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

Chromatographic separation using vinylmagnesium bromide instead of methylmagnesium bromide according to the procedure of example 3 gave 17 β -cyano-7 α -vinyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-7 β -vinyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 β -cyano-7 α -vinyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.51(m, 1H, cyclopropyl), 1.08(m, 1H, cyclopropyl), 1.14(s)，3H，18-CH3)，5.22(m，2H，CH2＝CH)，5.88(m，1H，CH2＝CH)，5.92(s，1H，H-4)

17 β -cyano-7 β -vinyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.42(m, 1H, cyclopropyl), 0.95(m, 1H, cyclopropyl), 1.10(s, 3H, 18-CH3)，5.05(m，2H，CH2＝CH)，5.86(s，1H，H-4)，5.88(m，1H，CH2＝CH)

Example 6

17 beta-cyano-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

Chromatographic separation using cyclopropyl magnesium bromide instead of methyl magnesium bromide according to the procedure of example 3 gave 17 β -cyano-7 α -cyclopropyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-7 β -cyclopropyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 β -cyano-7 α -cyclopropyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ ═ 0.05(m, 1H, cyclopropyl), 0.26(m, 1H, cyclopropyl), 0.47(m, 3H, cyclopropyl), 1.08(s, 3H, 18-CH3)，5.90(s，1H，H-4)

17 β -cyano-7 β -cyclopropyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.29(m, 2H, cyclopropyl), 0.47(m, 1H, cyclopropyl), 0.60(m, 2H, cyclopropyl)) 0.78(m, 1H, cyclopropyl), 0.97(m, 3H, cyclopropyl), 1.12(s, 3H, 18-CH3)，5.81(s，1H，H-4)

Example 7

17 beta-cyano-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

3g of 17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one (see example 1e) are placed in 16ml of methanol, treated with 1.6ml of pyrrolidine and heated to reflux for 1 hour. After cooling, the precipitate is filtered off with suction, washed with a little cold methanol and dried by suction. The crystals were dissolved in 30ml of benzene and 60ml of ethanol and 3.1ml of a 30% strength formaldehyde solution were added. After stirring at room temperature for 2 hours, the mixture was concentrated to dryness and chromatographed on silica gel. To obtain 17 beta-cyano-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ 1.09(s, 3H, 18-CH3) 0.43-1.06(m, 2H, cyclopropyl), 3.74(m, 2H,CH2OH)，5.94(s，1H，H-4)

example 8

17 beta-cyano-6, 6-ethylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

8a.

17 beta-cyano-15 beta, 16 beta-methylene-6 beta-tosyloxymethyl-19-nor-androst-4-en-3-one

2.93g of p-toluenesulfonyl chloride are added in one portion to a solution of 1.74g of 17 β -cyano-6 β -hydroxymethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one in 20ml of pyridine and stirred at room temperature for 6 hours. After this time, the reaction mixture was poured into ice-cold 1N HCl, and the precipitated crude product was filtered off with suction and dissolved again in ethyl acetate. The organic phase was washed twice with water, saturated bicarbonate solution and saturated salt solution, respectively, dried over sodium sulfate and concentrated to dryness to give 17 β -cyano-15 β, 16 β -methylene-6 β -tosyloxymethyl-19-nor-androst-4-en-3-one, which was subjected to the next reaction without purification.

8b.

450mg of sodium hydride are added in portions to a solution of 3g of trimethylsulfoxonium iodide in 50ml of anhydrous DMSO at room temperature, and after the addition is complete, the mixture is stirred at room temperature for 1 hour. Subsequently, a solution of 1.5g of 17 β -cyano-15 β, 16 β -methylene-6 β -toluenesulfonyloxymethyl-19-nor-androst-4-en-3-one was added to the formed ylide and the mixture was stirred at room temperature for 6 hours. After the reaction was terminated by adding 350ml of water, extraction was performed twice with 150ml of ethyl acetate, the organic phase was washed with water and a saturated saline solution and dried over sodium sulfate, and the organic phase was concentrated to obtain 17 β -cyano-6, 6-ethylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.39-1.02(m, 6H, 6, 6-ethylene/cyclopropyl), 1.11(s, 3H, 18-CH3)，5.70(s，1H，H-4)

Example 9

17 beta-cyano-6 beta, 7 beta-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

714mg of sodium hydride (60% strength in paraffin) are added in portions to a solution of 3.93g of trimethylsulfoxonium iodide in 38ml of anhydrous dimethyl sulfoxide at room temperature, and after the addition is complete, the mixture is stirred at room temperature for 1 hour. Subsequently, 2.0g of 17 β -cyano-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one in dimethyl sulfoxide were added to the formed ylide and the mixture was stirred at room temperature for 6 hours. After the reaction was terminated by adding 150ml of ammonium chloride solution, it was extracted twice with 75ml of ethyl acetate, and the organic phase was washed with water and a saturated saline solution and dried over sodium sulfate, and concentrated to dryness. Flash chromatography on silica gel using hexane/ethyl acetate and subsequent HPLC separation on a chiral normal phase stationary phase using hexane and ethanol as eluent gave 17 β -cyano-6 β,7 β -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as fraction I and 17 β -cyano-6 α,7 α -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as fraction II.

17 β -cyano-6 β,7 β -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.46-0.62(2xm, 2H, cyclopropyl), 1.06(s, 3H, 18-CH3)，2.79(d，1H，J＝4.14，H-17)，6.12(s，1H，H-4)

17 β -cyano-6 α,7 α -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.49, 0.77, 0.83, 0.98(4x m, 4H, cyclopropyl), 1.11(s, 3H, 18-CH3)，2.77(d，1H，J＝4.40，H-17)，6.05(s，1H，H-4)

Example 10

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

10a.

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-3-methoxy-19-nor-androsta-3, 5-diene

14.7ml of a 2M lithium diisopropylamide solution are added dropwise at-78 ℃ to a solution of 2.6g of 17 beta-cyano-15 beta, 16 beta-methylene-3-methoxy-19-nor-androst-3, 5-diene in 80ml of THF. The mixture was stirred at-78 ℃ for 1 hour, 2.35ml of methyl iodide was added, and then it was warmed to room temperature. 25ml of saturated ammonium chloride solution were added and the mixture was extracted three times with 100ml of ethyl acetate. The combined organic extracts were concentrated and crystallized from methanol. To obtain 17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-3-methoxyl-19-nor-androstane-3, 5-diene, which is immediately subjected to the next reaction.

10b.

2g of 17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-3-methoxy-19-nor-androst-3, 5-diene are placed in 50ml of methanol and treated with 3ml of 1N hydrochloric acid. After 1 hour, the mixture was neutralized with saturated sodium bicarbonate solution and concentrated in vacuo, and the product precipitated out. It is filtered off with suction, washed with water and recrystallized from ethyl acetate. To obtain 17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.42(m, 1H, cyclopropyl), 0.86(m, 1H, cyclopropyl), 1.06(m, 1H, cyclopropyl), 1.18(s, 3H, 18-CH3)，1.37(s，3H，17-CH3)，5.84(s，1H，H-4)

Example 11

17 beta-cyano-6 beta-hydroxymethyl-19-nor-androst-4-en-3-one

17 β -cyano-19-nor-androst-4-en-3-one was reacted according to a procedure analogous to that described in example 8. To obtain 17 beta-cyano-6 beta-hydroxymethyl-19-nor-androst-4-ene-3-one.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.97(s, 3H, 18-CH3)，3.66(m，2H，CH2OH)，5.91(s，1H，H-4)

Example 12

17 beta-cyano-6, 6-ethylene-19-nor-androst-4-en-3-one

17 β -cyano-6 β -hydroxymethyl-19-nor-androst-4-en-3-one was reacted according to a procedure analogous to that described in examples 8a and 8 b. Thereby obtaining the 17 beta-cyano-6, 6-ethylene-19-nor-androst-4-ene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.41(m, 1H), 0.54(m, 1H), 0.68(m, 1H), 1.01(s, 3H, 18-CH3) 2.45(s wide, 1H), 5.69(s, 1H, H-4)

Example 13

17 beta-cyano-19-nor-androsta-4, 6-dien-3-one

13a.

17 beta-cyano-3-methoxy-19-nor-androsta-3, 5-diene

17 β -cyano-19-nor-androst-4-en-3-one was reacted according to a method analogous to that described in step 2 a. To obtain 17 beta-cyano-3-methoxyl-19-nor-androstane-3, 5-diene.

¹H-NMR(d6-DMSO)：0.81(s，3H，18-CH3)，3.45(s，3H，OCH3) 5.19(s width, 2H, H-4 and H-6)

13b.

17 beta-cyano-19-nor-androsta-4, 6-dien-3-one

17 β -cyano-3-methoxy-19-nor-androst-3, 5-diene was reacted according to a method analogous to that described in step 2 b. To obtain 17 beta-cyano-19-nor-androstane-4, 6-diene-3-ketone.

¹H-NMR(d6-DMSO)：0.86(s，3H，18-CH3)，2.80(d，1H，J＝4.4，H-17)，5.69(s，1H，H-4)，6.18(m，1H，H-6)，6.24(m，1H，H-7)

Example 14

17 beta-cyano-6 beta, 7 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-6 alpha, 7 alpha-methylene-19-nor-androst-4-en-3-one

17 β -cyano-19-nor-androst-4, 6-dien-3-one was reacted according to a method analogous to that described in example 9. To obtain 17 beta-cyano-6 beta, 7 beta-methylene-19-nor-androst-4-ene-3-ketone and 17 beta-cyano-6 alpha, 7 alpha-methylene-19-nor-androst-4-ene-3-ketone.

17 β -cyano-6 β,7 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.52(m, 1H), 0.97(s, 3H, 18-CH3)，6.11(s，1H，H-4)

17 β -cyano-6 α,7 α -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.66(m, 1H), 0.78(m, 1H), 0.89(m, 1H), 1.01(s, 3H, 18-CH3)，6.03(s，1H，H-4)

Example 15

17 beta-cyano-7 alpha-methyl-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-methyl-19-nor-androst-4-en-3-one

17 β -cyano-19-nor-androst-4, 6-dien-3-one was reacted according to a method analogous to that described in example 3. To obtain 17 beta-cyano-7 alpha-methyl-19-nor-androst-4-ene-3-one and 17 beta-cyano-7 beta-methyl-19-nor-androst-4-ene-3-one.

17 β -cyano-7 α -methyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): delta 0.77(d, 3H, 7-CH3，J＝7Hz)，1.00(s，3H，18-CH3)，5.84(s，1H，H-4)

17 β -cyano-7 β -methyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.78(d, 3H, 7-CH3，J＝7Hz)，1.00(s，3H，18-CH3)，5.85(s，1H，H-4)

Example 16

17 beta-cyano-7 alpha-ethyl-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-ethyl-19-nor-androst-4-en-3-one

17 β -cyano-19-nor-androst-4, 6-dien-3-one was reacted according to a method analogous to that described in example 3 using ethylmagnesium bromide in diethyl ether instead of methylmagnesium bromide. To obtain 17 beta-cyano-7 alpha-ethyl-19-nor-androst-4-ene-3-one and 17 beta-cyano-7 beta-ethyl-19-nor-androst-4-ene-3-one.

17 β -cyano-7 α -ethyl-19-nor-androst-4-en-3-one:

¹H-NMR(d6-DMSO)：0.80(t，3H，7-CH2-CH3，J＝7.5Hz)，0.87(s，3H，18-CH3)，5.73(s，1H，H-4)

17 β -cyano-7 β -ethyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): delta 0.88(t, 3H, 7-CH2-CH3，J＝7.5Hz)，1.00(s，3H，18-CH3)，5.82(s，1H，H-4)

Example 17

17 beta-cyano-7 alpha-vinyl-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-vinyl-19-nor-androst-4-en-3-one

17 β -cyano-19-nor-androst-4, 6-dien-3-one the reaction was carried out according to a method analogous to that described in example 3, replacing methylmagnesium bromide with vinylmagnesium bromide. To obtain 17 beta-cyano-7 alpha-vinyl-19-nor-androst-4-ene-3-one and 17 beta-cyano-7 beta-vinyl-19-nor-androst-4-ene-3-one.

17 β -cyano-7 α -vinyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): delta 0.99(s, 3H, 18-CH3)，5.10(m，2H，CH2＝CH)，5.70(m，1H，CH2＝CH)，5.85(s，1H，H-4)

17 β -cyano-7 β -vinyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): delta 0.99(s, 3H, 18-CH3) 4.94(d wide, 1H, J ═ 10Hz,CH2CH), 5.04(d wide, 1H, J17 Hz,CH2＝CH)，5，71(m，1H，CH2＝CH)，5.84(s，1H，H-4)

example 18

17 beta-cyano-7 alpha-cyclopropyl-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-cyclopropyl-19-nor-androst-4-en-3-one

17 β -cyano-19-nor-androst-4, 6-dien-3-one was reacted according to a procedure analogous to that described in example 3 with cyclopropylmagnesium bromide instead of methylmagnesium bromide. To obtain 17 beta-cyano-7 alpha-cyclopropyl-19-nor-androst-4-ene-3-one and 17 beta-cyano-7 beta-cyclopropyl-19-nor-androst-4-ene-3-one.

17 β -cyano-7 α -cyclopropyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is-0.05 (m,1H, cyclopropyl), 0.27(m, 1H, cyclopropyl), 0.47(m, 3H, cyclopropyl), 1.00(s, 3H, 18-CH3)，5.88(s，1H，H-4)

17 β -cyano-7 β -cyclopropyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.13(m, 1H, cyclopropyl), 0.29(m, 1H, cyclopropyl), 0.58(m, 4H, cyclopropyl), 1.01(s, 3H, 18-CH3)，5.81(s，1H，H-4)

Example 19

17 alpha-allyl-17 beta-cyano-19-nor-androst-4-en-3-one

17 β -cyano-3-methoxy-19-nor-androst-3, 5-diene was reacted according to a method analogous to that described in examples 10a (using bromopropene instead of methyl iodide) and 10 b. To obtain 17 alpha-allyl-17 beta-cyano-19-nor-androst-4-ene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.85(m, 1H), 1.15(s, 3H, 18-CH3)，5.22(m，2H，-CH＝CH2)，5.84(s，1H，H-4)，5.92(m，1H，-CH＝CH2)

Example 20

17 beta-cyano-17 alpha-ethyl-19-nor-androst-4-en-3-one

17 β -cyano-3-methoxy-19-nor-androst-3, 5-diene the reaction was carried out according to a method analogous to that described in examples 10a (using iodoethane instead of iodomethane) and 10 b. To obtain 17 beta-cyano-17 alpha-ethyl-19-nor-androst-4-ene-3-ketone.

¹H-NMR(d6-DMSO)：0.97(t，3H，17-CH2-CH3)，1.00(s，3H，18-CH3)，5.69(m，1H，-CH＝CH2)

Example 21

17 beta-cyano-17 alpha-methyl-19-nor-androst-4-en-3-one

21a.

17 beta-cyano-17 alpha-methyl-3-methoxy-19-nor-androsta-3, 5-diene

17 β -cyano-3-methoxy-19-nor-androst-3, 5-diene was reacted according to a method analogous to that described in example 10 a. To obtain 17 beta-cyano-17 alpha-methyl-3-methoxyl-19-nor-androstane-3, 5-diene.

¹H-NMR(d6-DMSO)：0.93(s，3H)，1.20(s，3H)，3.45(s，3H，3-O-CH3) 5.19(m, 2H, H4 and H6)

21b.

17 beta-cyano-17 alpha-methyl-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-3-methoxy-19-nor-androst-3, 5-diene was reacted according to a method analogous to that described in example 10 b. To obtain 17 beta-cyano-17 alpha-methyl-19-nor-androst-4-ene-3-ketone.

¹H-NMR(d6-DMSO)：0.97(s，3H)，1.19(s，3H)，5.69(s，1H，H-4)

Example 22

17 beta-cyano-6 beta-hydroxymethyl-17 alpha-methyl-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-19-nor-androst-4-en-3-one was reacted according to a procedure analogous to that described in example 8. To obtain 17 beta-cyano-6 beta-hydroxymethyl-17 alpha-methyl-19-nor-androst-4-ene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 1.09(s, 3H), 1.29(s, 3H), 3.68(m, 2H, 6-CH2-OH)，5.91(s，1H，H-4)

Example 23

17 beta-cyano-6, 6-ethylene-17 alpha-methyl-19-nor-androst-4-en-3-one

17 β -cyano-6 β -hydroxymethyl-17 α -methyl-19-nor-androst-4-en-3-one was reacted according to a procedure analogous to that described in examples 8a and 8 b. To obtain 17 beta-cyano-6, 6-ethylene-17 alpha-methyl-19-nor-androst-4-ene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.40(m, 1H), 0.54(m, 1H), 0.68(m, 1H), 0.94(m, 2H), 1.11(s, 3H), 1.29(s, 3H), 5.68(s, 1H, H-4)

Example 24

17 beta-cyano-17 alpha-methyl-19-nor-androsta-4, 6-dien-3-one

17 β -cyano-3-methoxy-19-nor-androst-3, 5-diene was reacted according to a method analogous to that described in example 2 b. To obtain 17 beta-cyano-17 alpha-methyl-19-nor-androstane-4, 6-diene-3-ketone.

¹H-NMR(d6-DMSO)：1.04(s，3H)，1.25(s，3H)，5.73(s，1H，H-4)，6.23(m，1H，H-6)，6.29(m，1H，H-7)

Example 25

17 beta-cyano-7 alpha, 17 alpha-dimethyl-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-19-nor-androst-4, 6-dien-3-one was reacted according to a method analogous to that described in example 3. To obtain 17 beta-cyano-7 alpha, 17 alpha-dimethyl-19-nor-androst-4-ene-3-ketone.

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): delta 0.78(d, 3H, J7 Hz, 7-CH3)，1.11(s，3H)，1.31(s，3H)，5.84(s，1H，H-4)

Example 26

17 beta-cyano-17 alpha-methyl-7 alpha-vinyl-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-methyl-7 beta-vinyl-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-19-nor-androst-4, 6-dien-3-one the reaction was carried out according to a method analogous to that described in example 3, replacing methylmagnesium bromide with vinylmagnesium bromide. To obtain 17 beta-cyano-17 alpha-methyl-7 alpha-vinyl-19-nor-androst-4-ene-3-one and 17 beta-cyano-17 alpha-methyl-7 beta-vinyl-19-nor-androst-4-ene-3-one.

17 β -cyano-17 α -methyl-7 α -vinyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ ═ 1.11(s, 3H), 1.24-1.31(m, 8H), 5.10(m, 2H, 7-CH ═CH2)，5.70(m，1H，7-CH＝CH2)，5.89(s，1H，H-4)

17 β -cyano-17 α -methyl-7 β -vinyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ 1.09(s, 3H), 1.26(s, 3H), 4.93(d width, 1H, J10 Hz, 7-CH ═ dCH2) 5.03(d width, 1H, J-17 Hz, 7-CH-17 Hz)CH2)，5.71(m，1H，7-CH＝CH2)，5.83(s，1H，H-4)

Example 27

17 beta-cyano-7 alpha-cyclopropyl-17 alpha-methyl-19-nor-androst-4-en-3-one and 17 beta-cyano-7 beta-cyclopropyl-17 alpha-methyl-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-19-nor-androst-4, 6-dien-3-one was reacted according to a procedure analogous to that described in example 3, with cyclopropylmagnesium bromide instead of methylmagnesium bromide. To obtain 17 beta-cyano-7 alpha-cyclopropyl-17 alpha-methyl-19-nor-androst-4-ene-3-one and 17 beta-cyano-7 beta-cyclopropyl-17 alpha-methyl-19-nor-androst-4-ene-3-one.

17 beta-cyano-7 alpha-cyclopropyl-17 alpha-methyl-19-nor-androst-4-ene-3-ketone:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ -0.05(m, 1H), 0.26(m, 1H), 0.39-0.58(m, 3H), 1.10(s, 3H), 1.32(s, 3H), 5.89(s, 1H, H-4)

17 β -cyano-7 β -cyclopropyl-17 α -methyl-19-nor-androst-4-en-3-one:

¹H-NMR(300MHz，CDCl₃TMS as internal standard, selection signal): δ is 0.12(m, 1H), 0.30(m, 1H), 0.59(m, 4H), 0.87(m, 1H), 1.12(s, 3H), 1.30(s, 3H), 5.81(s, 1H, H-4)

Example 28

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one

A suspension of 3.4g of 17 β -cyano-17 α -methyl-15 β, 16 β -methylene-3-methoxy-19-nor-androsta-3, 5-diene in 100ml of 1-methyl-2-pyrrolidone is treated at 0 ℃ with 4ml of 10% strength sodium acetate solution and at this temperature it is further treated partly in portions with 1.6g of 1, 3-dibromo-5, 5-dimethylhydantoin. Stirred at 0 deg.C (ice bath) for 0.5 hour, treated with 1.5g lithium bromide and 1.3g lithium carbonate, and stirred at a bath temperature of 100 deg.C for 3.5 hours. Subsequently, it was added to a mixture of ice water and salt solution with stirring, the precipitate was filtered and the filter cake was recrystallized in dimethoxyethane. To obtain 17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androstane-4, 6-diene-3-ketone.

17 β -cyano-17 α -methyl-15 β, 16 β -methylene-19-nor-androsta-4, 6-dien-3-one:

¹H-NMR(300MHz，CDCl₃as internal standard, signal selected): δ is 0.55(m, 1H, cyclopropyl) 1.18(m, 1H, cyclopropyl), 1.25(s, 3H, 18-CH3)，1.44(s，3H，17-CH3)，5.85(s，1H，H-4)，6.29(m，1H，H-6)，6.45(m，1H，H-7)

Example 29

17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

29a.

17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-3-methoxy-19-nor-androsta-3, 5-diene

17 β -cyano-15 β, 16 β -methylene-3-methoxy-19-nor-androst-3, 5-diene was reacted as described in example 10 a. In this case, iodoethane was used instead of iodomethane used in example 10. To obtain 17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-ketone.

29b.

The compound described in example 19a was reacted according to a procedure analogous to that described in example 10 b. To obtain 17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-ketone.

17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.46(m, 1H, cyclopropyl), 0.87(m, 1H, cyclopropyl), 1.08(m, 1H, cyclopropyl), 1.21(m, 7H, 18-CH3，17-CH2-CH3，Cyclopropyl), 5.86(s, 1H, H-4)

Example 30

17 beta-cyano-17 alpha-ethyl-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one the reaction was carried out analogously to example 7 to give 17 β -cyano-17 α -ethyl-6 β -hydroxymethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one.

17 beta-cyano-17 alpha-ethyl-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.46(m, 1H, cyclopropyl), 1.19(m, 6H, 17-CH2-CH3，18-CH3)，3.74(m，2H，CH2OH)，5.94(s，1H，H-4)

Example 31

17 beta-cyano-17 alpha-ethyl-6, 6-ethylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -ethyl-6 β -hydroxymethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one was reacted analogously to example 8 to give 17 β -cyano-17 α -ethyl-6, 6-ethylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one.

17 beta-cyano-17 alpha-ethyl-6, 6-ethylene-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.43(m, 2H, 6, 6-ethylene/cyclopropyl), 0.59, 0.79, 0.96, 1.08(4x m, 4H, 6, 6-ethylene), 1.22(m, 6H, 17-CH2-CH3，18-CH3)，5.70(s，1H，H-4)

Example 32

17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one

17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one was obtained from 17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-3-methoxy-19-nor-androst-3, 5-diene according to a procedure analogous to that described in example 2 b.

17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-norAndrosta-4, 6-dien-3-one:

¹H-NMR (CDCl 3): 0.53(m, 1H, cyclopropyl), 1.09-1,28(m, 9H, 18-CH3，17-CH2-CH3Cyclopropyl), 5.80(s, 1H, H-4), 6.25(m, 1H, H-6), 6.40(m, 1H, H-7)

Example 33

17 beta-cyano-17 alpha-ethyl-7 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-ethyl-7 beta-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one was reacted analogously to example 3 and, after chromatographic separation, gave 17 β -cyano-17 α -ethyl-7 α -methyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-17 α -ethyl-7 β -methyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 β -cyano-17 α -ethyl-7 α -methyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.45(m, 1H, cyclopropyl), 0.87(d, 3H, J ═ 7,34, 7-CH3)，1.23(m，6H，18-CH3，17-CH2-CH3)，5.86(s，1H，H-4)

17 β -cyano-17 α -ethyl-7 β -methyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.53(m, 1H, cyclopropyl), 1.22(m, 9H, 7-CH3，18-CH3，17-CH2-CH3)，5.82(s，1H，H-4)

Example 34

17 beta-cyano-17 alpha, 7 alpha-diethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha, 7 beta-diethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

From 17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one, 17 β -cyano-17 α,7 α -diethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-17 α,7 β -diethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II, 17 β -cyano-17 α,7 β -diethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one are obtained after chromatographic separation using ethyl magnesium bromide in diethyl ether instead of methyl magnesium bromide according to the method of example 3.

17 β -cyano-17 α,7 α -diethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.46(m, 1H, cyclopropyl), 0.92(t, 3H, J ═ 7.34, 7-CH2-CH3)，1.23(m，6H，18-CH3，17-CH2-CH3)，5.87(s，1H，H-4)

17 β -cyano-17 α,7 β -diethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.54(m, 1H, cyclopropyl), 0.94(t, 3H, J ═ 7.34, 7-CH2-CH3)，1.21(t，3H，J＝7.34，17-CH2-CH3)，1.24(s，3H，18-CH3)，5.84(s，1H，H-4)

Example 35

17 beta-cyano-17 alpha-ethyl-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-ethyl-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

Using vinylmagnesium bromide instead of methylmagnesium bromide, according to the procedure of example 3, after chromatographic separation, from 17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one 17 β -cyano-17 α -ethyl-7 α -vinyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one is obtained as part I and 17 β -cyano-17 α -ethyl-7 β -vinyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 beta-cyano-17 alpha-ethyl-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.46(m, 1H, cyclopropyl), 1.08(m, 1H, cyclopropyl), 1.22(m, 3H, CH2-CH3)，1.27(s，3H，18-CH3)，5.17(m，2H，CH2＝CH)，5.81(m，1H，CH2＝CH)，5.87(s，1H，H-4)

17 beta-cyano-17 alpha-ethyl-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.42(m, 1H, cyclopropyl), 0.99(m, 1H, cyclopropyl), 1.24(m, 6H, 18-CH3，CH2-CH3)，5.02(m，2H，CH2＝CH)，5.85(s，1H，H-4)，5.90(m，1H，CH2＝CH)

Example 36

17 beta-cyano-17 alpha-ethyl-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-ethyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

Cyclopropyl magnesium bromide was used instead of methyl magnesium bromide according to the method of example 3, after chromatographic separation, from 17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4, 6-dien-3-one 17 beta-cyano-17 alpha-ethyl-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one is obtained as part I and 17 beta-cyano-17 alpha-ethyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one as part II.

17 beta-cyano-17 alpha-ethyl-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): -0.05(m, 1H, cyclopropyl)Base), 0.26(m, 1H, cyclopropyl), 0.42(m, 3H, cyclopropyl), 1.22(m, 6H, CH2-CH3，18-CH3)，5.90(s，1H，H-4)

17 beta-cyano-17 alpha-ethyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.25(m, 1H, cyclopropyl), 0.33(m, 1H, cyclopropyl), 0.47(m, 1H, cyclopropyl), 0.60(m, 2H, cyclopropyl), 1.06(m, 1H, cyclopropyl), 1.22(m, 3H, CH2-CH3)，1.27(s，3H，18-CH3)，5.81(s，1H，H-4)

Example 37

17 beta-cyano-17 alpha-ethyl-6 beta, 7 beta-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-ethyl-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one the reaction was carried out according to the procedure described in example 9 and, after chromatographic separation, 17 β -cyano-17 α -ethyl-6 β,7 β -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one was obtained as part I and 17 β -cyano-17 α -ethyl-6 α,7 α -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 beta-cyano-17 alpha-ethyl-6 beta, 7 beta-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR(CDCl₃): 0.49(m, 1H, cyclopropyl), 0.78(m, 2H, cyclopropyl), 0.96(m, 1H, cyclopropyl), 1.13(m, 1H, cyclopropyl), 1.23(m, 6H, CH2-CH3，18-CH3)，6.05(s，1H，H-4)

17 beta-cyano-17 alpha-ethyl-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR(CDCl₃): 0.52(m, 1H, cyclopropyl), 0.59(m, 1H, cyclopropyl), 0.97(m, 1H, cyclopropyl), 1.17(m, 1H, cyclopropyl), 1.18(s, 3H, 18-CH3)，1.23(m，3H，CH2-CH3)，6.12(s，1H，H-4)

Example 38

17 beta-cyano-17 alpha, 7 alpha-dimethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha, 7 beta-dimethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one was reacted analogously to example 3 and, after chromatographic separation, gave 17 β -cyano-17 α,7 α -dimethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-17 α,7 β -dimethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 β -cyano-17 α,7 β -dimethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.44(m, 1H, cyclopropyl), 0.88(d, 3H, J ═ 6.97Hz, 7-CH3) 1.08(m, 1H, cyclopropyl) 1.20(s, 3H, 18-CH3)，1.40(s，3H，17-CH3)，5.86(s，1H，H-4

¹H-NMR (CDCl 3): 0.51(m, 1H, cyclopropyl), 0.98(m, 1H, cyclopropyl), 1.06(m, 1H, cyclopropyl), 1.20(s, 3H, 18-CH3)，1.22(d，3H，J＝5.87Hz，7-CH3)，1.38(s，3H，17-CH3)，5.83(s，1H，H-4)

Example 39

17 beta-cyano-17 alpha-methyl-7 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-methyl-7 beta-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4, 6-dien-3-one the reaction was carried out according to the procedure of example 3 using ethylmagnesium bromide in diethyl ether instead of methylmagnesium bromide, and chromatographically separating to obtain 17 beta-cyano-17 alpha-methyl-7 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one as part I and 17 beta-cyano-17 alpha-methyl-7 beta-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one as part II.

17 β -cyano-17 α -methyl-7 α -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.45(m, 1H, cyclopropyl), 0.92(m, 3H, 7-CH3-CH2)，1.20(s，3H，18-CH3)，1.39(s，3H，17-CH3)，5.87(s，1H，H-4)

17 β -cyano-17 α -methyl-7 β -ethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR (CDCl 3): 0.52(m, 1H, cyclopropyl), 0.94(m, 3H, 7-CH2-CH3) 1.07(m, 1H, cyclopropyl), 1.21(s, 3H, 18-CH3)，1.38(s，3H，17-CH3)，5.84(s，1H，H-4)

Example 40

17 beta-cyano-17 alpha-methyl-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-methyl-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4, 6-dien-3-one the reaction was carried out according to the procedure of example 3 using vinylmagnesium bromide instead of methylmagnesium bromide, and chromatographically separating to obtain 17 beta-cyano-17 alpha-methyl-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-one as part I and 17 beta-cyano-17 alpha-methyl-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-one as part II.

17 beta-cyano-17 alpha-methyl-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.45(m, 1H, cyclopropyl), 1.09(m, 1H, cyclopropyl), 1.19(s, 3H, 18-CH3)，1.37(s，3H，17-CH3)，5.16(m，2H，CH2＝CH)，5.82(m，1H，CH2＝CH)，5.87(s，1H，H-4)

17 beta-cyano-17 alpha-methyl-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.40(m, 1H, cyclopropyl), 0.98(m, 2H, cyclopropyl), 1.20(s, 3H, 18-CH3)，1.36(s，3H，17-CH3)，5.03(m，2H，CH2＝CH)，5.85(s，1H，H-4)，5.90(m，1H，CH2＝CH)

EXAMPLE 41

17 beta-cyano-17 alpha-methyl-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-methyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4, 6-dien-3-one the reaction was carried out according to the procedure of example 3 using cyclopropylmagnesium bromide instead of methylmagnesium bromide, and chromatographically separating to obtain 17 beta-cyano-17 alpha-methyl-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one as part I and 17 beta-cyano-17 alpha-methyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one as part II.

17 beta-cyano-17 alpha-methyl-7 alpha-cyclopropyl-15 beta, 16Beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.05(m, 1H, cyclopropyl), 0.35(m, 1H, cyclopropyl), 0.41(m, 1H, cyclopropyl), 0.49(m, 1H, cyclopropyl), 0.59(m, 2H, cyclopropyl), 1.19(s, 3H, 18-CH3)，1.41(s，3H，17-CH3)，5.90(s，1H，H-4)

17 beta-cyano-17 alpha-methyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.25(m, 1H, cyclopropyl), 0.33(m, 1H, cyclopropyl), 0.45(m, 1H, cyclopropyl), 0.60(m, 2H, cyclopropyl), 0.79(m, 1H, cyclopropyl), 0.87(m, 1H, cyclopropyl), 0.94(m, 1H, cyclopropyl), 1.07(m, 1H, cyclopropyl), 1.22(s, 3H, 18-CH3)，1.39(s，3H，17-CH3)，5.82(s，1H，H-4)

Example 42

17 beta-cyano-17 alpha-methyl-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one was reacted according to a method analogous to that described in example 7. To obtain 17 beta-cyano-17 alpha-methyl-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-ketone.

17 beta-cyano-17 alpha-methyl-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.45(m, 1H, cyclopropyl), 1.08(m, 1H, cyclopropyl), 1.18(s, 3H, 18-CH3)，1.38(s，3H，17-CH3)，3.74(m，2H，CH2OH)，5.94(s，1H，H-4)

Example 43

17 beta-cyano-17 alpha-methyl-6, 6-ethylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-6 β -hydroxymethyl-15 β, 16 β -methylene-19-nor-androst-4-en-3-one was reacted according to a method analogous to that described in examples 8a and 8 b. To obtain 17 beta-cyano-17 alpha-methyl-6, 6-ethylidene-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3-ketone.

17 beta-cyano-17 alpha-methyl-6, 6-ethylene-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR (CDCl 3): 0.42-1.08(m, 6H, 6, 6-ethylene/cyclopropyl), 1.22(s, 3H, 18-CH3)，1.39(s，3H，17-CH3)，5.70(s，1H，H-4)

Example 44

17 beta-cyano-17 alpha-methyl-6 beta, 7 beta-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-methyl-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-15 β, 16 β -methylene-19-nor-androst-4, 6-dien-3-one was reacted according to a method analogous to that described in example 9 to give 17 β -cyano-17 α -methyl-6 β,7 β -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-17 α -methyl-6 α,7 α -methylene-15 β, 16 β -methylene-19-nor-androst-4-en-3-one as part II.

17 beta-cyano-17 alpha-methyl-6 beta, 7 beta methylene-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR(CDCl₃): 0.47(m, 1H, cyclopropyl), 0.80(m, 2H, cyclopropyl), 0.97(m, 1H, cyclopropyl), 1.13(m, 1H, cyclopropyl), 1.22(s, 3H, 18-CH3)，1.40(s，3H，17-CH3)，6.05(s，1H，H-4)

17 beta-cyano-17 alpha-methyl-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-ene-3- Ketone:

¹H-NMR(CDCl₃): 0.50(m, 1H, cyclopropyl), 0.59(m, 1H, cyclopropyl), 0.98(m, 1H, cyclopropyl), 1.16(s, 3H, 18-CH3)，1.41(s，3H，17-CH3)，6.12(s，1H，H-4)

Example 45

17 beta-cyano-17 alpha-methyl-6 beta, 7 beta-methylene-19-nor-androst-4-en-3-one and 17 beta-cyano-17 alpha-methyl-6 alpha, 7 alpha-methylene-19-nor-androst-4-en-3-one

17 β -cyano-17 α -methyl-19-nor-androst-4, 6-dien-3-one 17 β -cyano-17 α -methyl-6 α,7 α -methylene-19-nor-androst-4-en-3-one as part I and 17 β -cyano-17 α -methyl-6 β,7 β -methylene-19-nor-androst-4-en-3-one as part II were obtained by reaction according to the procedure described in example 9 and by chromatographic separation.

17 β -cyano-17 α -methyl-6 α,7 α -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(CDCl₃)：0.68(m，1H)，0.77(m，1H)，0.90(m，1H)，1.12(s，3H，CH₃)，1.32(s，3H，CH₃)，1.68(m，1H)，2.02(m，1H)，2.17(m，1H)，2.40(m，1H)，2.51(m，1H)，6.03(s，1H，H-4)

17 β -cyano-17 α -methyl-6 β,7 β -methylene-19-nor-androst-4-en-3-one:

¹H-NMR(CDCl₃)：0.52(m，1H)，0.93(m，1H)，1.08(s，3H，CH₃)，1.33(s，3H，CH₃)，1.95(m，1H)，2.37-2.48(m，2H)，6.11(s，1H，H-4)

example 46

4-chloro-17 beta-cyano-17 alpha-ethyl-19-nor-androst-4-en-3-one

100mg of 17 beta-cyano-17 alpha-ethyl-19-nor-androst-4-en-3-one are dissolved in 1.1ml of pyridine and cooled to 0 ℃. After addition of 42. mu.l of sulfonyl chloride, the mixture was subsequently stirred at 0 ℃ for 1.5 hours.

After mixing with saturated aqueous sodium bicarbonate, water and ethyl acetate, the phases were separated and the organic phase was washed with water and saturated aqueous sodium chloride. After the organic phase was dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was chromatographed on silica gel using a mixture of ethyl acetate and n-hexane to give 4-chloro-17 β -cyano-17 α -ethyl-19-nor-androst-4-en-3-one.

4-chloro-17 β -cyano-17 α -ethyl-19-nor-androst-4-en-3-one:

¹H-NMR(d6-DMSO)：0.97(t，3H，J＝7.3，-CH₂-CH ₃)，1.00(s，3H，-CH ₃)，1.99(m，1H)，2.08-2.22(m，2H)，3.10(m，1H)

example 47

17 beta-cyano-3-hydroxyimino-17 alpha-ethyl-19-nor-androst-4-en-3-one

100mg of 17 beta-cyano-17 alpha-ethyl-19-nor-androst-4-en-3-one was dissolved in 1ml of pyridine and mixed with 34.5mg of hydroxylamine hydrochloride. After stirring for 1 hour at a bath temperature of 125 ℃, the batch was partitioned between water and ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate was concentrated. After chromatographic separation on silica gel using a mixture of ethyl acetate and n-hexane, the eluate containing the product is concentrated and recrystallized from a mixture of acetone and diisopropyl ether to give 17 β -cyano-3-hydroxyimino-17 α -ethyl-19-nor-androst-4-en-3-one as E/Z mixture of the oximes.

17 beta-cyano-3-hydroxyimino-17 α -ethyl-19-nor-androst-4-en-3-one:

¹H-NMR(d6-DMSO)：0.41(m，1H)，0.96(t，3H，J＝7.3，-CH₂-CH ₃)，0.99(s，3H，-CH ₃) 2.82 and 2.98 (each m, common 1H), 5.76 and 6.36 (each s, common 1H, H-4)

Example 48

17 beta-cyano-19-nor-androsta-4, 9-dien-3-one

48a.

17 beta-cyano-3, 3-dimethoxyestra-5 (10) -ene

75g of 3, 3-dimethoxyestra-5 (10) -en-17-one are reacted in analogy to the procedure described in example 1 d. The crude product was taken up in a mixture of diisopropyl ether and hexane, the residue was filtered off and the filtrate was concentrated. The evaporation residue was crystallized from diisopropyl ether to give 17 β -cyano-3, 3-dimethoxyestra-5 (10) -ene.

17 β -cyano-3, 3-dimethoxyestra-5 (10) -ene:

¹H-NMR(d6-DMSO)：0.84(s，3H，17-CH₃)，1.46(m，1H)，1.70(m，1H)，2.57(m，1H)，3.07(s，3H，3-OCH ₃)，3.10(s，3H，3-OCH ₃)

48b.

17 beta-cyanoestra-5 (10) -en-3-one

3g of 17 β -cyano-3, 3-dimethoxyestra-5 (10) -ene are suspended in a mixture of 24ml of dichloromethane and 70ml of tert-butanol. After addition of 28ml of water and 0.11ml of 60% perchloric acid, the batch is stirred until complete reaction, mixed with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate was evaporated to dryness, leaving 17 β -cyanoestr-5 (10) -en-3-one, which was subjected to the next reaction without purification.

48c.

17 beta-cyano-19-nor-androsta-4, 9-dien-3-one

2.4g of 17 β -cyanoestr-5 (10) -en-3-one were mixed with 35ml of pyridine and 3.2g of pyridinium tribromide. The mixture was stirred at room temperature for 1 hour and then at 50 ℃ for 4 hours. After cooling, 40ml of ice-cold 6N aqueous hydrochloric acid solution were added and the mixture was extracted with ethyl acetate. The organic phase is washed with 1N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over sodium sulfate and filtered, and the residue of evaporation of the filtrate is purified by chromatography on silica gel with a mixture of ethyl acetate and N-hexane to give 17 β -cyano-19-nor-androst-4, 9-dien-3-one.

17 β -cyano-19-nor-androsta-4, 9-dien-3-one:

¹H-NMR(d6-DMSO)：0.94(s，3H，17-CH₃)，1.09-1.22(m，2H)，1.25-1.41(m，2H)，1.69(m，1H)，2.59(m，1H)，2.75-2.90(m，2H)，5.56(s，1H，H-4)

Claims

1.17 beta-cyano-19-nor-androst-4-ene derivatives of the general formula 1,

wherein

R⁴is a hydrogen or a halogen, and the halogen,

further:

or:

R¹⁵、R¹⁶are hydrogen or together form a methylene group,

R¹⁷selected from hydrogen, C₁-C₄-an alkyl group and an allyl group,

2. The 17 β -cyano-19-nor-androst-4-ene derivative of claim 1 wherein R is¹⁵And R¹⁶Together form a methylene group.

3. 17 β -cyano-19-nor-androst-4-ene derivatives as claimed in any of the preceding claims, characterized in that Z is selected from O, NOH and NNHSO₂H。

4. 17 β -cyano-19-nor-androst-4-ene derivative according to any of the preceding claims, characterized in that Z represents O.

5. 17 β -cyano-19-nor-androst-4-ene derivatives as claimed in any of the preceding claims wherein R is⁴Is hydrogen or chlorine.

6. 17 β -cyano-19-nor-androst-4-ene derivatives as claimed in any of the preceding claims wherein R is^6a、R^6bTogether form a1, 2-ethanediyl radical or are each hydrogen.

7. 17 β -cyano-19-nor-androst-4-ene derivatives as claimed in any of the preceding claims wherein R is⁷Selected from hydrogen and methyl.

8. 17 β -cyano-19-nor-androst-4-ene derivatives as claimed in any of claims 1 to 6 wherein R is^6bAnd R⁷Together form a methylene group.

9. 17 β -cyano-19-nor-androst-4-ene derivatives as claimed in any of the preceding claims wherein R is¹⁷Selected from hydrogen and methyl.

10. The 17 β -cyano-19-nor-androst-4-ene derivative of claim 1 selected from the group consisting of:

17 beta-cyano-6 beta-hydroxymethylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-19-nor-androst-4-en-3-one,

17 alpha-allyl-17 beta-cyano-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-19-nor-androst-4-en-3-one,

17 beta-cyano-6, 6-ethanediyl-19-nor-androst-4-en-3-one,

17 beta-cyano-6 beta, 7 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-6 alpha, 7 alpha-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-6 beta-hydroxymethylene-19-nor-androst-4-en-3-one,

17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-6, 6-ethanediyl-17 alpha-methyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-ethyl-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-6 alpha, 7 alpha-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-6 beta, 7 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-ethyl-19-nor-androst-4-en-3-one,

17 beta-cyano-19-nor-androsta-4, 6-dien-3-one,

17 beta-cyano-17 alpha-methyl-19-nor-androsta-4, 6-dien-3-one,

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

7 alpha, 17 alpha-dimethyl-17 beta-cyano-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-methyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-methyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-vinyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-vinyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-cyclopropyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-cyclopropyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-cyclopropyl-17 alpha-methyl-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-cyclopropyl-17 alpha-methyl-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 alpha-vinyl-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 beta-vinyl-19-nor-androst-4-en-3-one,

17 beta-cyano-15 beta, 16 beta-methylene-19-nor-androst-4, 6-dien-3-one,

17 beta-cyano-15 beta, 16 beta-methylene-6 beta-hydroxymethylene-19-nor-androst-4-en-3-one,

17 alpha-ethyl-17 beta-cyano-15 beta, 16 beta-methylene-6 beta-hydroxymethyl-19-nor-androst-4-en-3-one,

17 beta-cyano-6 beta, 7 beta-15 beta, 16 beta-dimethylene-19-nor-androst-4-en-3-one,

17 beta-cyano-6 alpha, 7 alpha-15 beta, 16 beta-dimethylene-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-7 beta-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-7 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androsta-4, 6-dien-3-one,

17 beta-cyano-17 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4, 6-dien-3-one,

17 beta-cyano-15 beta, 16 beta-methylene-7 beta-vinyl-19-nor-androst-4-ene-3-one,

17 beta-cyano-15 beta, 16 beta-methylene-7 alpha-vinyl-19-nor-androst-4-en-3-one,

17 beta-cyano-6, 6-ethanediyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-15 alpha, 16 alpha-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha, 7 alpha-dimethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha, 7 beta-dimethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 alpha-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 beta-ethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-6 beta-hydroxymethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-6, 6-ethylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-6 beta, 7 beta-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-methyl-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-7 alpha-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-7 beta-methyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha, 7 alpha-diethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha, 7 beta-diethyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-7 alpha-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-7 beta-vinyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-7 alpha-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-7 beta-cyclopropyl-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-6, 6-ethylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-6 beta, 7 beta-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one,

17 beta-cyano-17 alpha-ethyl-6 alpha, 7 alpha-methylene-15 beta, 16 beta-methylene-19-nor-androst-4-en-3-one.

11. Use of a 17 β -cyano-19-nor-androst-4-ene derivative according to any one of claims 1-10 for the manufacture of a medicament for oral contraception and for the treatment of premenopausal, perimenopausal and postmenopausal symptoms.

12. Use according to claim 11, characterized in that the medicament has progestational and antimineralocorticoid effects.

13. A medicament containing at least one 17 β -cyano-19-nor-androst-4-ene derivative according to any one of claims 1-10 and at least one suitable pharmaceutically harmless additive.

14. The medicament of claim 13, further comprising at least one estrogen.

15. A medicament according to claim 14, characterised in that the oestrogen is ethinyl oestradiol.

16. Medicament according to claim 14, characterized in that the estrogen is a natural estrogen.

17. The medicament according to claim 16, characterized in that said natural estrogen is estradiol.

18. The medicament according to claim 16, characterized in that said natural estrogen is estradiol valerate.

19. The medicament according to claim 16, characterized in that said natural estrogen is conjugated estrogen.