DE102007063498A1 - 15,16-methylene-steroid-17,17-lactol derivative, its use and the derivative-containing drug - Google Patents

Abstract

The invention relates to 15,16-methylene-steroid-17,17-lactol derivatives having the general chemical formula I and their tautomeric forms having the general chemical formula Ia, wherein R4, R6a, R6b, R7, R18, R22 and Z den the in claim 1 have meanings, as well as their solvates, hydrates, stereoisomers and salts. The invention also relates to the use of these derivatives for the manufacture of a medicament for oral contraception and for the treatment of pre-, peri and postmenopausal complaints as well as medicaments containing such derivatives. The derivatives according to the invention have a gestagenic and in addition, in a preferred case, an antimineralcorticoid and neutral to mildly androgenic action. $ F1

Description

The Invention relates to 15,16-methylene-steroid-17,17-lactol derivatives, their use and the derivatives containing drugs with gestagenic effect, for example for the treatment of pre-, peri- and postmenopausal as well as premenstrual symptoms.

The literature discloses compounds with gestagenic, antimineralcorticoid, antiandrogenic or antiestrogenic action based on a steroid skeleton which are derived, for example, from 19-nor-androst-4-en-3-one or a derivative thereof (the numbering of the steroid skeleton is, for example Fresenius / Görlitzer 3.Aufl. 1991 "Organic Chemistry Nomenclature" p. 60 ff.).

So revealed WO 2006072467 A1 the progestogenic compound 6β, 7β-15β, 16β-dimethylene-3-oxo-17-pregna-4-ene-21,17β-carbolactone (drospirenone), which is used, for example, in an oral contraceptive and a preparation for the treatment of postmenopausal disorders has been. 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 also characterized by its aldosterone antagonist (antimineralcorticoid) and antiandrogenic effects in addition to the gestagenic effect. These two properties make drospirenone in its pharmacological profile very similar to the progesterone progesterone, which unlike drospirenone, is not sufficiently orally bioavailable. To reduce the dose to be administered, in WO 2006/072467 A1 further proposed an 18-methyl-19-nor-17-pregn-4-ene-21,17-carbolactone and pharmaceutical preparations containing them, which have a higher progestational potency than drospirenone.

In addition, for example, discloses US-A 3,705,179 Steroids which have antiandrogenic activity and are useful in the treatment of androgen related diseases.

In WO 93/13122 A1 3-Methylsulfonylhydrazono- and 3-Oxyimino-steroids are disclosed with a 15,16-methylene group and their use as antiandrogens.

The The object of the present invention is to provide compounds to make that have a strong bond to the progesterone receptor feature. In addition, the compounds are preferred also an antimineralcorticoid effect as well as with regard to have the androgen receptor neutral to mild androgenic effect. Another essential objective of the present invention is also in it, a balanced impact profile with regard to gestagenen Effect to achieve antimineralcorticoid effect such that the ratio of gestagen to antimineralcorticoid Effect is less than with drospirenone.

These The object is achieved by the 15,16-methylene-steroid-17,17-lactol derivatives according to the invention according to claim 1, the use of the invention Derivatives according to claim 14 and at least one Medicament containing derivative according to the invention solved according to claim 16. advantageous Embodiments of the invention are in the subclaims specified.

sowie deren tautomere Formen mit der allgemeinen chemischen Formel Ia,

worin
Z ausgewählt ist aus der Gruppe, umfassend Sauerstoff, zwei Wasserstoffatome, NOR' oder NNHSO₂R', worin R' Wasserstoff, C₁-C₁₀-Alkyl, Aryl oder C₇-C₂₀-Aralkyl ist,
R⁴ ausgewählt ist aus der Gruppe, umfassend Wasserstoff und Halogen, ferner entweder:
R^6a, R^6b jeweils unabhängig voneinander ausgewählt sind aus der Gruppe, umfassend Wasserstoff, C₁-C₁₀-Alkyl, C₁-C₁₀-Alkenyl, C₂-C₁₀-Alkinyl, oder gemeinsam Methylen oder 1,2-Ethandiyl bilden und
R⁷ ausgewählt ist aus der Gruppe, umfassend Wasserstoff, C₁-C₁₀-Alkyl, C₃-C₆-Cycloalkyl, C₂-C₁₀-Alkenyl und C₂-C₁₀-Alkinyl,
oder:
R^6a, R⁷ gemeinsam ein Sauerstoffatom oder eine Methylengruppe bilden oder unter Bildung einer Doppelbindung zwischen C⁶ und C⁷ entfallen und
R^6b ausgewählt ist aus der Gruppe, umfassend Wasserstoff, C₁-C₁₀-Alkyl, C₁-C₁₀-Alkenyl, C₂-C₁₀-Alkinyl,
R¹⁸ ausgewählt ist aus der Gruppe, umfassend Wasserstoff und C₁-C₃-Alkyl,
R²² ausgewählt ist aus der Gruppe, umfassend Wasserstoff, C₁-C₆-Alkyl, Aryl, C₇-C₂₀-Aralkyl,
sowie deren Solvate, Hydrate, Stereoisomere und Salze.The present invention accordingly relates to 15,16-methylene-steroid-17,17-lactol derivatives having the general chemical formula I,

and their tautomeric forms with the general chemical formula Ia,

wherein
Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'or NNHSO ₂ R', wherein R 'is hydrogen, C ₁ -C ₁₀ -alkyl, aryl or C ₇ -C ₂₀ -aralkyl,
R ^{4 is} selected from the group comprising hydrogen and halogen, and further either
R ^6a , R ^{6b are} each independently selected from the group comprising hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, or together methylene or 1,2-ethanediyl form and
R ^{7 is} selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₁₀ -alkenyl and C ₂ -C ₁₀ -alkynyl,
or:
R ^6a , R ⁷ together form an oxygen atom or a methylene group or omitted to form a double bond between C ⁶ and C ^7, and
R ^{6b is} selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₁ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl,
R ^{18 is} selected from the group comprising hydrogen and C ₁ -C ₃ -alkyl,
R ^{22 is} selected from the group comprising hydrogen, C ₁ -C ₆ -alkyl, aryl, C ₇ -C ₂₀ -aralkyl,
as well as their solvates, hydrates, stereoisomers and salts.

The numbering of the C-skeleton of the derivatives according to the invention with the general chemical formulas I and Ia 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 C. Backbone of the derivatives as far as R ⁴ , R ⁶ , R ⁷ and R ^{18 are} concerned. 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 NNHSO ₂ R' each have a double bond via N to the C skeleton of the derivative according to = NOR 'or = NNH-SO ₂ R'. OR 'in NOR' and NHSO ₂ R 'in NNHSO ₂ R' can be syn- or antistatic.

Alkyl in R ', R ^6a , R ^6b and R ⁷ are straight or branched chain alkyl groups of 1-10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, decyl. Alkyl in R ¹⁸ is in particular methyl, ethyl, propyl or isopropyl and R ^{22 is} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl. The alkyl groups R ', R ^6a , R ^6b , R ⁷ , R ¹⁸ and R ²² may further be perfluorinated or by 1-5 halogen atoms, hydroxy groups, C ₁ -C ₄ alkoxy groups, C ₆ -C ₁₂ aryl groups (which in turn 1-3 halogen atoms may be substituted) substituted. In particular, alkyl may therefore also be hydroxymethylene (HO-CH ₂ ), hydroxyethylene (HO-C ₂ H ₄ ), hydroxypropylene (HO-C ₃ H ₆ ) and hydroxybutylene (HO-C ₄ H ₈ ) and their isomers.

Alkenyl in R ^6a , R ^6b and R ⁷ are straight or branched chain alkenyl groups having 2-10 carbon atoms, such as vinyl, propenyl, butenyl, pentenyl, isobutenyl, isopentenyl.

Alkynyl in R ^6a , R ^6b and R ⁷ are straight or branched chain alkynyl groups having 2-10 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, isobutinyl, isopentinyl.

The alkenyl and alkynyl groups R ^6a , R ^6a and R ⁷ may be substituted by 1-5 halogen atoms, hydroxy groups, C ₁ -C ₃ alkoxy groups, C ₆ -C ₁₂ aryl groups (which may in turn be substituted by 1-3 halogen atoms) be.

Cycloalkyl in R ⁷ is to be understood as meaning cycloalkyl groups having 3-6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups R ⁷ can be substituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, NH ₂ , NO ₂ , N ₃ , CN, C ₁ -C ₁₀ -alkyl, C ₁ -C ₁₀ -acyl, C ₁ -C ₁₀ acyloxy groups substituted.

Aryl in R 'and R ²² is to be understood as meaning substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, for example phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, NH ₂ , NO ₂ , N ₃ , CN, C ₁ -C ₁₀ -alkyl, C ₁ -C ₁₀ -acyl, C ₁ -C ₁₀ acyloxy groups may be substituted. As far as otherwise aryl is mentioned as a substituent on alkyl, alkenyl or alkynyl, it is in particular aryl groups having 6-12 ring carbon atoms.

Aralkyl in R 'and R ²² is to be understood as meaning aralkyl groups which may contain up to 14 carbon atoms, preferably 6 to 10 C atoms, in the ring and 1 to 8, preferably 1 to 4, carbon atoms in the alkyl chain. Suitable aralkyl radicals are, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. The rings may be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, NO ₂ , N ₃ , CN, C ₁ -C ₂₀ -alkyl, C ₁ -C ₂₀ -acyl, C ₁ -C ₂₀ acyloxy groups substituted.

So far Alkoxy (O-alkyl) is mentioned as a substituent on alkyl, they are alkoxy groups with 1-4 carbon atoms, and, as far as alkoxy is mentioned as a substituent on alkenyl and alkynyl are, are alkoxy groups having 1-3 carbon atoms. Alkoxy may in particular be methoxy, ethoxy and propoxy.

So far Acyl (CO-alkyl) as a substituent on cycloalkyl and aryl mentioned is, are acyl groups with 1-10 carbon atoms, and, as far as acyl is mentioned as a substituent on aralkyl, they are acyl groups with 1-20 carbon atoms. acyl may be in particular formyl, acetyl, propionyl and butyryl.

So far Acyloxy (O-CO-alkyl) as a substituent on cycloalkyl and aryl mentioned is, are acyloxy groups having 1-10 carbon atoms, and, as far as acyloxy is mentioned as a substituent on aralkyl are, are acyloxy groups having 1-20 carbon atoms. Acyloxy may in particular formyloxy, acetyloxy, propionyloxy and Butyryloxy be.

halogen is fluorine, chlorine or bromine. Among these, chlorine is preferred.

According to a preferred embodiment of the invention Z is selected from the group comprising oxygen, NOR 'and NNHSO ₂ R'.

According to one preferred embodiment of the invention Z stands for Oxygen.

In a further preferred embodiment of the invention, R ^{4 is} hydrogen or chlorine.

According to a further preferred embodiment of the invention, R ^6a , R ^6b together form 1,2-ethanediyl or are each hydrogen.

In a further preferred embodiment of the invention, R ^{7 is} selected from the group comprising hydrogen, methyl, ethyl and vinyl.

According to a further preferred embodiment of the invention, R ^6a and R ⁷ together form methylene.

According to a further preferred embodiment of the invention, R ^6a and R ⁷ are eliminated to form a double bond between C ⁶ and C ⁷ .

In a further preferred embodiment of the invention, R ^{18 is} hydrogen or methyl.

In a further preferred embodiment of the invention, R ^{22 is} hydrogen.

According to a further preferred embodiment of the invention, R ^{22 is} selected from the group comprising methyl, ethyl and isopropyl.

Preference is given to compounds having the general chemical formula I or the general chemical formula Ia, in which
Z is oxygen or a group NOR ', in which R' is hydrogen, C ₁ -C ₆ -alkyl, aryl or C ₇ -C ₁₂ -aralkyl,
R ^{4 is} hydrogen or halogen, and either:
R ^6a , R ^{6b are} each independently selected from the group comprising hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, or together methylene or 1,2-ethanediyl form and
R ^{7 is} hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl,
or:
R ^6a , R ⁷ together form methylene or omitted to form a double bond between C ⁶ and C ⁷ and
R ^{6b is} selected from the group comprising hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl and C ₂ -C ₆ -alkynyl,
R ^{18 is} hydrogen or C ₁ -C ₂ -alkyl,
R ^{22 is} hydrogen, C ₁ -C ₃ alkyl or C ₇ -C ₁₂ aralkyl.

Particularly preferred are compounds having the general chemical formula I or the general chemical formula Ia, wherein
Z is oxygen or a group NOR ', where R' is hydrogen or C ₁ -C ₃ -alkyl,
R ^{4 is} hydrogen,
and either:
R ^6a , R ^{6b are} each independently hydrogen, C ₁ -C ₃ alkyl or C ₂ -C ₄ alkenyl or together form methylene or 1,2-ethanediyl and
R ^{7 is} hydrogen, C ₁ -C ₄ -alkyl, C ₃ -C ₄ -cycloalkyl or C ₂ -C ₄ -alkenyl,
or:
R ^6a , R ⁷ together form methylene or omitted to form a double bond between C ⁶ and C ⁷ and
R ^{6b is} selected from the group comprising hydrogen, C ₁ -C ₃ -alkyl and C ₂ -C ₄ -alkenyl,
R ^{18 is} hydrogen or methyl,
R ^{22 is} hydrogen or C ₁ -C ₃ alkyl.

Herewith Be explicit all possible stereoisomers and mixtures of isomers, including racemates, of the compounds with the general chemical formulas I and Ia expressly included. Each of said substituents on the steroid backbone can be in both an α and a β position available. In addition, the substituents can also on the steroid backbone, which contain a double bond and in which the double bond on each carbon atom is at least carries a substituent which is not hydrogen, both E- and Z-configured exist. At two adjacent Carbon atoms of the skeleton bound groups, for example an oxygen atom, methylene or 1,2-ethanediyl either in the α, α position or in the β, β position bound.

Expressly Also included are all crystal modifications of the compound with the general chemical formulas I and Ia.

Also explicitly included are derivatives according to the invention in the form of solvates, in particular of hydrates, the compounds according to the invention accordingly being polar solvents, in particular of water, as a structural element of the crystal lattice of the compounds of the invention. The polar solvent, especially 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.

is contain an acidic function, are as salts the physiological compatible salts of organic and inorganic bases suitable, such as the readily soluble alkali metal and alkaline earth salts, and the salts of N-methyl-glucamine, D-methyl-glucamine, Ethyl glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, Sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropanediol, Sovak base, 1-amino-2,3,4-butanetriol. Is a basic function contained, the physiologically acceptable salts are more organic and inorganic acids, such as hydrochloric acid, Sulfuric acid, phosphoric acid, citric acid, Tartaric acid and a.

It it was found that the compounds of the invention or derivatives have a good gestagene effect. Furthermore interact some interesting inventive Compounds with the mineralocorticoid receptor and are able to to convey an antagonistic effect. Furthermore, the inventive Compounds with respect to the androgen receptor a neutral up mildly androgenic effect on. Another property of the vast majority Number of connections is that the bonds of this Compounds to the progesterone receptor and the mineralocorticoid receptor are balanced relative to each other, in such a way that at to them the relationship of the ability to bind to Progesterone receptor for binding ability to mineral corticoid receptor less than with drospirenone. Thus, the antimineralcorticoide Effect of these compounds for a given Gestagener effect less as with drospirenone. If the dosage of a given invention Compound determined on the basis of its gestagenic effect, is the antimineralcorticoid effect of this compound in this Dosage thus lower than with drospirenone.

The below-mentioned compounds provided with the respective structural formulas numbered 1-80 and the tautomeric forms derivable therefrom are preferred in the present invention. Here, R in compounds Nos. 1-40 denotes hydrogen (H) and in compounds Nos. 41-80 methyl (CH ₃ ). The structural formulas denote the respective lactols, while the chemical names represent the tautomeric forms with opened Lactolring.

by virtue of their gestagenen effectiveness, the new compounds with the general chemical formulas I and Ia alone or in combination be used with estrogen in medicines for contraception.

The Therefore, derivatives of the invention are particularly suitable for the manufacture of a medicament for oral contraception and for the treatment of pre-, peri- and postmenopausal complaints, including use in preparations for the hormone replacement therapy (HRT).

Because of their favorable effect profile are the invention Derivatives also particularly well suited for treatment premenstrual symptoms, such as headache, depressive Upsets, water retention and mastodynia.

Especially preferred is the use of the invention Derivatives for the preparation of a medicament with gestagen, preferably also antimineralcorticoider and neutral to slightly androgenic Effect.

A Treatment with the derivatives of the invention prefers to humans, but can also be related to Mammalian species, such as dogs and cats, be performed.

to Use of the derivatives according to the invention as Medicines will treat these with at least one suitable pharmaceutical harmless additive, for example carrier, combined. The additive is for example for the parenteral, preferably oral, application suitable. It deals 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 drugs can be in solid form, for example as tablets, dragees, Suppositories, capsules, or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain excipients, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffer. For the parenteral administration are in particular oily solutions, such as solutions in sesame oil, castor oil and cottonseed oil, suitable. To increase the Solubility can solubilizers, such as benzyl benzoate or benzyl alcohol. It is also possible to use the invention Incorporate derivatives into a transdermal system and use them to apply transdermally. Come for oral administration especially 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 is preferably administered once.

The gestagen and estrogenic drug components are in contraceptive preparations preferably applied together orally. The daily dose is preferably administered once.

When Estrogens are synthetic estrogens, preferably ethinyl estradiol, but also mestranol, as well as natural esterogens, including Phytoestrogens, into consideration.

The Estrogen is administered in a daily amount the pharmacological effect of 0.01 to 0.04 mg ethinylestradiol equivalent.

When Estrogens in the medicinal products for the treatment of pre-, peri- and postmenopausal complaints as well as for hormone replacement therapy First and foremost, natural estrogens are used all the estradiol, but also the esters of estradiol, for example Estradiol valerate, or conjugated estrogens (CEEs = Conjugated Equine estrogens).

The gestagen, antimineralcorticoids and androgens or antiandrogens Effect of the compounds of the invention was with the investigated the following methods:

1. Progesterone receptor binding test:

Using cytosol from progesterone receptor-expressing insect cells (Hi5), competitive binding ability to the progesterone receptor was assessed by the ability to displace ³ H-progesterone as a reference from the receptor. If a compound has an affinity corresponding to progesterone, this corresponds to the competition factor (KF) of 1. KF values greater than 1 are characterized by a lower, KF values less than 1 by a higher affinity for the progesterone receptor.

2. Mineralocorticoid Receptor Binding Test:

The test was carried out analogously to 1., with the following modifications: Cytosol was used from mineralocorticoid receptor-expressing insect cells (Hi5), the reference substance was ³ H-aldosterone.

3. Androgen Receptor Binding Test:

The test was carried out analogously to 1., with the following modifications: Cytosol was used from androgen receptor-expressing insect cells (Hi5), the reference substance was ³ H-testosterone.

The Results of the binding tests and the ratio of the competition factors KF (PR) and KR (MR) are given in Table 1, for comparison Receptor binding values also of drospirenone as reference substance A are indicated.

4. Determination of Gestagenen effect using of transactivation tests:

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

Reporter cell lines (CHO K1 cells stably transfected with a fusion protein from the PR ligand binding domain and a Gal4 transactivation domain as well as a reporter construct containing the luciferase under the control of a Gal4 responsive promoter) were grown at a density of 4 x 10 ⁴ cells per well Well grown in white, 96-well opaque tissue culture plates (PerkinElmer, # P12-106-017) and maintained in culture medium with 3% DCC-FCS (charcoal treated serum, for removal of interfering components contained in the serum). 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 (Promega, # E1501) was added, the 96-well plates were then inserted into a microplate luminometer (Pherastar, BMG labtech) and luminescence was measured. The IC ₅₀ values were used software for calculating dose-response relationships. Table 2 shows experimental results and comparative results of drospirenone as reference substance A.

5. Determination of antimineralocorticoid Effect of using transactivation tests:

The Determination of the antimineralocorticoid activity of the test substances was carried out analogously to the transactivation tests described above.

The following Modifications were made: here were reporter cell lines for use (MDCK cells) containing the human mineralocorticoid receptor and transiently contain a reporter construct that Luciferase under the control of a steroid hormone responsive promoter contains.

to Cultivation of the cells used for the assay was as culture medium DMEM EARLE'S MEM (PAA, Cat .: E15-025) provided with 1000 penicillin / 0.1 mg / ml streptomycin (PAA, Cat: P11-010), 4 mM L-glutamine (PAA, Cat: M11-004) and fetal calf serum (BIO Witthaker, Cat: DE14-801F).

to Determination of antimineralocorticoid efficacy was given to the cells 1 nM aldosterone (SIGMA A-6628, Lot 22H4033) added to a near-maximum To achieve stimulation of the reporter gene. An inhibition of the effect showed a mineralcorticoid-antagonistic effect of the substances (Table 2, corresponding values for drospirenone for comparison) (A)).

6. Determination of androgenic / antiandrogenic Effect of using transactivation tests:

The Determination of the androgenic / antiandrogenic effect of the test substances was carried out analogously to the transactivation tests described above.

The following Modifications were made: here were reporter cell lines for use (PC3 cells) expressing the androgen receptor, and a reporter construct, the luciferase under the control of a contains steroid hormone-responsive promoter.

to Cultivation of the cells used for the assay was as culture medium RPMI medium without phenol red (PAA, # E15-49), provided with 1000 penicillin / 0.1 mg / ml streptomycin (PAA, Cat: P11-010), 4 mM L-glutamine (PAA, Cat: M11-004) and fetal calf serum (BIO Witthaker, Cat: DE14-801F).

to Determination of antiandrogenic activity was 0.05 for the cells nM R1881 added to a near-maximal stimulation of the reporter gene to reach. An inhibition of the effect showed an androgen-antagonistic Effect of substances (Table 2; Values for drospirenone (A)).

So far the preparation of the starting compounds is not described here are, these are known in the art or analogous to known compounds or methods described herein. The isomer mixtures can by conventional methods, such as Crystallization, chromatography or salt formation, in the individual Connections are separated. The preparation of the salts takes place in the usual way, by giving a solution of the compounds with the general chemical formulas I and Ia with the equivalent Amount or an excess of a base or acid, which is optionally in solution, added, if necessary separates the precipitate or in the usual way the solution worked up.

Compounds of general chemical formula I are prepared starting from compounds of general chemical formula 1 (Scheme 2) according to the procedures given in Scheme 1, wherein R ⁴ , R ^6a , R ^6b , R ⁷ , R ¹⁸ , R ²² and Z have the meanings given above and in which
R ⁶ , R ⁷ in 5 and 6 together form oxygen or methylene,
U is an oxygen atom, two alkoxy groups OR ¹⁹ , a C ₂ -C ₁₀ -alkylene-α, ω-dioxy group, which may be straight-chain or branched, where R ^{19 is} a C ₁ -C ₂₀ -alkyl radical,
R ^{20 is} a C ₁ -C ₂₀ -alkyl radical,
X is an NR ^21a R ^21b group or an alkoxy group OR ²³ ,
R ^21a , R ^{21b are} each independently of one another hydrogen, C ₁ -C ₁₀ -alkyl or together form a C ₄ -C ₁₀ -α, ω-alkylene group, which may be straight-chain or branched,
R ^{23 is} a C ₁ -C ₂₀ alkyl radical.

The compounds 2 and 3 in Scheme 1 each carry a double bond between C ⁵ and C ⁶ or between C ⁵ and C ¹⁰ and another double bond between C ² and C ³ or between C ³ and C ⁴ .

The compounds 7 to 9 in Scheme 1 each carry a double bond between C ⁴ and C ⁵ or between C ⁵ and C ⁶ or between C ⁵ and C ¹⁰ .

For It is obvious to the person skilled in the art that in the descriptions the synthetic transformations are always presupposed that optionally present on the steroid skeleton other functional Groups are protected in appropriate form.

The introduction of a 6,7-double bond to form compounds having the general chemical formulas 4, 13 or 18 takes place via bromination of the respective 3,5-dienol ethers 3, 12 or 17 and subsequent hydrogen bromide removal (see, for example, US Pat. J. Fried, JA Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, pp. 265-374 ).

The dienol ether bromination of compounds 3, 12 or 17 can be carried out, for example, analogously to the procedure of Steroids 1, 233 (1963). The hydrogen bromide cleavage to form the compounds of the general chemical formulas 4, 13 or 18 is achieved by heating the 6-bromo compound with basic reagents, such as LiBr or Li ₂ CO ₃ in aprotic solvents, such as dimethylformamide, at temperatures of 50-120 ° C. or by heating the 6-bromo compounds in a solvent such as collidine or lutidine.

The introduction of a substituent R4 can, for example, starting from a compound having one of the general chemical formulas 6, 11, 13, 14, 16 or 18 by epoxidation of the 4,5-double bond with hydrogen peroxide under alkaline conditions and reaction of the resulting epoxides in a suitable solvents with acids having the general chemical formula HR ⁴ , where R ^{4 may be} a halogen atom, preferably chlorine or bromine. Compounds in which R ^{4 has} the meaning of bromine can be reacted, for example, with 2,2-difluoro-2- (fluorosulphonyl) acetic acid methyl ester in dimethylformamide in the presence of copper (I) iodide to give compounds in which R ^{4 has} the meaning fluorine. Alternatively, halogen, starting from a compound having one of the general chemical formulas 6, 11, 13, 14, 16 or 18, by reaction with sulfuryl chloride or sulfuryl bromide in the presence of a suitable base, such as pyridine, with R ⁴ meaning chlorine or Bromine can be introduced directly.

Compound 4 is prepared by methenylation of the 6,7-double bond by known methods, for example with dimethylsulfoxonium methylide (see, eg, US Pat. 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) ) in a compound 5 (R ⁶ , R ⁷ together form a methylene group), whereby a mixture of α- and β-isomers is obtained, which can be separated, for example by chromatography in the individual isomers.

links Type 5 can, as described in the examples or analogous to these instructions, using analogous to the reagents described therein.

The synthesis of the spirocyclic compound 18 (R ^6a , R ^6b together form 1,2-ethanediyl) starts from the compounds 11 or 14, which are first transformed into a 3-amino-3,5-diene derivative 15 (X = NR ^21a R ^21b ). By reaction with formalin in alcoholic solution, the 6-hydroxymethylene derivative 16 (R ⁶ = hydroxymethylene) is obtained. After conversion of the hydroxy group to a leaving group such as a mesylate, tosylate or even benzoate, compound 18 may be prepared by reaction with trimethylsulfoxonium iodide using bases such as alkali metal hydroxides, alkali alcoholates in suitable solvents such as dimethylsulfoxide.

To introduce a 6-methylene group, compound 16 (R ⁶ = hydroxymethylene) can be dehydrated with, for example, hydrochloric acid in dioxane / water. Even after conversion of the hydroxy group into a leaving group, such as a mesylate, tosylate or benzoate, compound 18 (R ^6a , R ^6b together produce methylene) (see DE-A 34 02 329 . EP-A. 0 150 157 . US-A 4,584,288 ; J. Med. Chem. 34, 2464 (1991) ).

Another possibility for the preparation of 6-methylene compounds 18 is the direct reaction of 4 (5) unsaturated 3-ketones, such as compound 16 (R ⁶ = hydrogen), with acetals of formaldehyde in the presence of sodium acetate with, for example, phosphorus oxychloride or phosphorus pentachloride in ge suitable solvents, such as chloroform (see eg K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982) ).

The 6-methylene compounds can be used to prepare compounds of general chemical formula 18 in which R ^6a is methyl and R ^6b and R ⁷ together form an additional bond.

For this For example, one described in Tetrahedron 21, 1619 (1965) Apply method in which an isomerization of the double bond by heating the 6-methylene compounds in ethanol with 5% palladium-carbon catalyst, either with hydrogen or pretreated by heating with a small amount of cyclohexene was achieved. The isomerization can not work with one either pretreated catalyst, when added to the reaction mixture a small amount of cyclohexene is added. The occurrence lower Proportions of hydrogenated products can be made by adding an excess be prevented on sodium acetate.

Alternatively, compound 17 (X = OR ²³ ) can be used as a precursor. The direct preparation of 6-methyl-4,6-dien-3-one derivatives is described (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983) ).

Compounds 18 in which R ^{6b represents} an α-methyl function can be prepared under suitable conditions from the 6-methylene compounds (18: R ^6a , R ^6b together form methylene) by hydrogenation. 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 18 are heated in a suitable solvent, such as, for example, ethanol, in the presence of a hydride donor, for example cyclohexene, 6α-methyl derivatives are obtained in very good yields. Small amounts of 6β-methyl compound can be acid isomerized (Tetrahedron 1619 (1965)).

The targeted preparation of 6β-methyl compounds is possible. For this purpose, the 4-en-3-ones, such as compound 16, for example, with ethylene glycol, trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid, for example p-toluenesulfonic acid, converted to the corresponding 3-ketals. During this ketalization, the double bond isomerizes to position C ⁵ . Selective epoxidation of this 5-double bond is achieved, for example, by using organic peracids, for example of m-chloroperbenzoic acid, in a suitable solvent, such as dichloromethane. Alternatively, the epoxidation can also be carried out with What 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. In this way 5α-hydroxy-6β-alkyl compounds are obtained. The cleavage of the 3-keto protective group can be carried out by treatment under mild acid 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 (with aqueous hydrochloric acid or with another strong acid) yields the corresponding 6α-alkyl compounds.

The Introduction of a 7-alkyl, 7-alkenyl or 7-alkynyl group to form compounds having the general chemical formula 14 is carried out by 1,6-addition of a corresponding organometallic Compound to the precursor with the general chemical formula 13 under the action of copper salts. Preference is given to bivalent Metals, such as magnesium and zinc, as counterion are chlorine, bromine and Iodine preferred. Suitable copper salts are monovalent or divalent salts Copper compounds, such as copper chloride, copper bromide or copper acetate. The reaction is carried out in an inert solvent, such as tetrahydrofuran, diethyl ether or dichloromethane.

The resulting compounds 6, 11, 13, 14, 16, 18 or 20, in which Z is an oxygen atom, can be prepared by reaction with hydroxylamine hydrochloride, Alkyloxyaminhydrochlorchlorid or sulfonylhydrazines in the presence of a tertiary amine at temperatures between -20 and + 40 ° C in their corresponding E / Z-configured oximes or sulfonylhydrazones are converted (general formula I with Z in the meaning of NOR ', NNHSO ₂ R')). Examples of suitable tertiary bases are trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,5-diazabicyclo [5.4.0] undec-5- en (DBU), with pyridine being preferred. An analogous process is for example in WO 98/24801 A1 for the preparation of corresponding 3-oxyimino derivatives of drospirenone described.

For the preparation of a final product having the general chemical formula I with Z in the meaning of two hydrogen atoms, the 3-oxo group may, for example, according to the in DE-A 28 05 490 specified provision by reductive cleavage of a thioketal of the 3-keto compound on a suitable precursor, such as compounds with one of the general chemical formulas 6, 11, 13, 14, 16, 18 or 20 removed.

Schema 1 (Fortsetzung:

The formation of spirolactols into compounds having one of the general chemical formulas 3 or 8b takes place, starting from the corresponding 17-hydroxypropenyl compounds 2 or 13, by oxidation. Examples of oxidation processes which may be mentioned are the oxidation according to Swern, the oxidation with N-methylmorpholine N-oxide and catalytic amounts of tetrabutylammonium peruthenate or by oxidation with manganese dioxide. Scheme 1

Scheme 1 (continued)

The compound 1 in Scheme 2 carries in each case one double bond between C ⁵ and C ⁶ or between C ⁵ and C ¹⁰ and a further double bond between C ² and C ³ or between C ³ and C ⁴ . Scheme 2

The The following examples serve for further explanation the invention without these to the examples given narrow:

Example 1 (17-Spirolactolization with Braunstein):

17β-hydroxy-18-methyl-15β, 16β-methylene-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carbaldehyde γ-lactol

The solution of 3.07 g of the compound described in Example 1a in 140 ml of dichloromethane was added in portions with 6 g of manganese dioxide and stirred for about 15 hours at 23 ° C. The solution was filtered through Celite, and after concentration and chromatography, 1.63 g of the title compound was isolated.
¹ H-NMR (CDCl _3): δ = 0.50 (1H), 0.83 to 0.98 (1H), 0.90 + 0.98 (3H), 1.06 to 1.87 (10H) , 1.99 (1H), 2.19-2.59 (5.5H), 2.76 (0.5H), 5.80 (1H), 5.84 (1H), 6.00 (0, 5H), 6,12-6,18 (1,5H), 6,26 (1H), 6,48 (1H) ppm.

Example 1a (dienone formation from dienol ether):

17α (Z) - (3'-hydroxypropene-1'-yl) -18-methyl-15β, 16β-methylene-17β-hydroxyestra-4,6-dien-3-one

The Solution of 10.4 g of the compound prepared according to Example 1b in 125 ml of dimethylformamide was added at 3 ° C with 1.03 g of sodium acetate, 10 ml of water and added in portions with a total of 4.23 g Dibromhydantoin. After 30 minutes, 3.91 g of lithium bromide, 3.42 g of lithium carbonate and mixed for 3 hours at a bath temperature of 100 ° C heated. The solution was poured into water and repeatedly extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and over Dried sodium sulfate. The after filtration and solvent removal The residue obtained was purified by chromatography. Isolated 6.35 g of the title compound.

Example 1b (Lindlar hydrogenation):

17α (Z) - (3'-hydroxypropene-1'-yl) -3-methoxy-18-methyl-15β, 16β-methylene-17β-hydroxyestra-3,5-diene

The Solution of 75 g of the compound prepared according to Example 1c in 1.5 l of tetrahydrofuran was reacted with 100 ml of pyridine, 5 g of palladium on barium sulfate and in one atmosphere of hydrogen hydrogenated. The solution was filtered through Celite, and after concentration, 75.7 g of the title compound were isolated, was further reacted without purification.

Example 1c (hydroxypropyne addition):

17α (Z) - (3'-hydroxypropyn-1'-yl) -3-methoxy-18-methyl-15β, 16β-methylene-17β-hydroxyestra-3,5-diene

The Solution of 83 ml of 2-propyn-1-ol in 1 liter of tetrahydrofuran at -78 ° C with 1 L of a 2.5 molar solution butyllithium in hexane. After 30 minutes, the solution became of 90 g of 3-methoxy-18-methyl-15β, 16β-methylene-estra-3,5-dien-17-one added dropwise in 0.5 l of tetrahydrofuran, heat to 23 ° C. left and stirred for 3 hours. The solution was in saturated, ice-cold ammonium chloride solution poured, extracted several times with ethyl acetate, the combined organic Extracts were washed with saturated sodium chloride solution washed and dried over sodium sulfate. The after filtration and solvent removed residue purified by crystallization. Isolated were 90.3 g of the title compound.

Example 2:

17β-Isopropoxy-18-methyl-15β, 16β-methylene-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carbaldehyde γ-lactol

The solution of 860 mg of the compound shown in Example 1 in 70 ml of isopropanol was treated with 62 mg of p-toluenesulfonic acid pyridinium salt and stirred at 75 ° C for 3 hours. The solution was concentrated, the residue was purified by chromatography, and 733 mg of the title compound was isolated.
¹ H-NMR (CD ₂ Cl ₂ ): δ = 0.42 (1H), 0.89 + 0.95 (3H), 0.86-0.97 (1H), 1.04-1.28 ( 8H), 1.16 + 1.21 (3H), 1.38-1.56 (3H), 1.64-1.85 (3H), 1.97 (1H), 2.17-2.49 (5H), 3.96 (1H), 5.67 + 5.71 (1H), 5.79 + 5.91 (1H), 6.09 (1H), 6.26 (1H), 6.49 (1H) ppm.

Example 3 (1,6-addition):

17β-hydroxy-7α, 18-dimethyl-15β, 16β-methylene-19-nor-17α-pregna-4,20 (2) -dien-3-one-21-carbaldehyde γ-lactol (A) and 17β-hydroxy-7β, 18-dimethyl-15β, 16β-methylene-19-nor-17α-pregna-4,20 (2) -dien-3-one-21-carbaldehyde γ-lactol (B)

To the cooled to -30 ° C suspension of 15 mg of copper (I) chloride in 3 ml of tetrahydrofuran was added dropwise 0.64 ml of a 3 molar solution of methylmagnesium chloride in tetrahydrofuran, and the solution was stirred for 10 minutes. The solution was cooled to -25 ° C and added dropwise to 300 mg of the compound shown in Example 2 in 12 ml of tetrahydrofuran. After 3 minutes, the solution was poured onto 1N hydrochloric acid, extracted several times with ethyl acetate, the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by chromatography. 108 mg of title compound A were isolated next to a still contaminated mixture containing portions of title compound B.
¹ H-NMR (CDCl ₃ ) of A: δ = 0.43 (1H), 0.82-1.34 (12H), 1.41-1.92 (7H), 2.00-2.11 ( 2H), 2.18-2.68 (6H), 5.79-6.20 (4H) ppm.

Example 4:

17β-Isopropoxy-7α, 18-dimethyl-15β, 16β-methylene-19-nor-17α-pregna-4,20 (2) -dien-3-one-21-carbaldehyde γ-lactol

In analogy to Example 2, 81 mg of the compound shown in Example 3 were reacted, and after work-up and purification 69 mg of the title compound were isolated.
¹ H NMR (CD ₂ Cl ₂ ): δ = 0.30-0.45 (1H), 0.79-1.32 (18H), 1.38-1.95 (8H), 2.04 ( 1H), 2.16-2.36 (4H), 2.45 + 2.56 (1H), 3.96 (1H), 5.66 + 5.69 (1H), 5.73-5.91 (2H), 6.08 + 6.12 (1H) ppm.

Example 5:

17β-hydroxy-18-methyl-15β, 16β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol

In analogy to Example 1, 250 mg of the compound prepared according to Example 5a were reacted, and after work-up and purification 123 mg of the title compound were isolated.
¹ H-NMR (CDCl _3): δ = 0.41 (1H), 0.80 to 1.36 (11H), 1.41 to 1.87 (7H), 2.03 to 2.69 (7H) , 5.69-6.26 (4H) ppm.

Example 5a:

17α (Z) - (3'-hydroxypropene-1'-yl) -18-methyl-15β, 16β-methylene-17β-hydroxyestra-4-en-3-one

The Suspension of 5.0 g of the compound prepared according to Example 1b in 30 ml of acetone and 30 ml of water was washed with 50 ml of a saturated aqueous solution of oxalic acid, 30 ml of methanol and 50 ml of tetrahydrofuran were added, and 5 Stirred at 23 ° C for hours. The solution was in saturated sodium bicarbonate solution poured, extracted repeatedly with ethyl acetate, the combined or ganic Extracts were washed with saturated sodium chloride solution washed and dried over sodium sulfate. The after filtration and solvent removed residue purified by chromatography. Isolated 4.26 g of the title compound.

Example 6:

17β-Isopropoxy-18-methyl-15β, 16β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol

In analogy to Example 2, 90 mg of the compound shown in Example 5 were reacted, and after work-up and purification, 65 mg of the title compound were isolated.
¹ H-NMR (CD ₂ Cl ₂ ): δ = 0.34 (1H), 0.78-1.32 (16H), 1.39-1.86 (7H), 2.01-2.42 ( 6H), 2.53 (1H), 3.96 (1H), 5.65 + 5.69 (1H), 5.78 + 5.90 (2H), 6.10 (1H) ppm.

Example 7:

17β-hydroxy-15α, 16α-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol

In analogy to Example 1, 58 mg of the compound prepared according to Example 7a were reacted, and after work-up and purification 28 mg of the title compound were isolated.
¹ H-NMR (CDCl _3): δ = 0.59 to 0.84 (3H), 0.95 to 1.85 (14H), 2.09 to 2.61 (7H), 5.78 to 6, 22 (4H) ppm.

Example 7a (3-ketal cleavage):

17α (Z) - (3'-hydroxypropene-1'-yl) -15α, 16α-methylene-17β-hydroxyestra-4-en-3-one

The Solution of 300 mg of the compounds prepared according to Example 7b in 15 ml of acetone was added 0.83 ml of a 4 N hydrochloric acid and stirred for 1 hour at 23 ° C. The solution was in saturated sodium bicarbonate solution poured, extracted several times with ethyl acetate, the combined organic Extracts were washed with saturated sodium chloride solution washed and dried over sodium sulfate. The after filtration and solvent removed residue purified by chromatography. Isolated 135 mg of the title compound.

Example 7b:

17α (Z) - (3'-hydroxypropene-1'-yl) -15α, 16α-methylene-17β-hydroxyestra-5-en-3-one 3-ethylene ketal and 17α (Z) - (3'-hydroxypropen-1'-yl) -15α, 16α-methylene-17β-hydroxyestra-5 (10) -en-3-one-3-ethylene ketal

In By analogy with Example 1b, 300 mg of that shown in Example 7c Compounds reacted, and after work-up, 300 mg of Title compounds isolated, which were further reacted without purification.

Example 7c:

17α (Z) - (3'-hydroxypropine-1'-yl) -15α, 16α-methylene-17β-hydroxyestra-5-en-3-one 3-ethylene ketal and 17α (Z) - (3'-hydroxypropyne-1'-yl) -15α, 16α-methylene-17β-hydroxyestra-5 (10) -en-3-one-3-ethylene ketal

In By analogy with Example 1c, 278 mg of that shown in Example 7d Compounds reacted, and after work-up 347 mg of Title compounds isolated, which were further reacted without purification.

Example 7d (oxidation of 17-OH):

15α, 16α-methylene-estra-5-en-3,17-dione-3-ethylene ketal and 15α, 16α-methylene-estra-5 (10) -en-3,17-dione-3-ethylene ketal

The Solution of 1.06 g of the compounds prepared according to Example 1d in 32 ml of dichloromethane was molecular sieved with a spatula tip 4A, 700 mg N-methylmorpholino-N-oxide, 90 mg tetrabutylammonium peruthenate and stirred at 23 ° C for about 16 hours. The solution was concentrated and the residue became purified by chromatography. Isolated 878 mg of the title compounds.

Example 7e (3-enol ether to ethylene ketal):

15α, 16α-methylene-17α-hydroxyestra-5-en-3-one 3-ethylene ketal and 15α, 16α-methylene-17α-hydroxyestra-5 (10) -en-3-one-3-ethylene ketal

The Solution of 500 mg of the compound prepared according to Example 7f in 10 ml of tetrahydrofuran was washed with 10 ml of ethylene glycol, 4.4 mg of p-toluenesulfonic acid Hydrate and stirred at 23 ° C for 2 hours. The solution was made up in saturated sodium bicarbonate solution poured, extracted several times with ethyl acetate, the combined organic Extracts were washed with saturated sodium chloride solution washed and dried over sodium sulfate. The after filtration and solvent removed residue purified by chromatography. Isolated 359 mg of the title compound.

Example 7f (Birch):

3-methoxy-15α, 16α-methylene-17α-hydroxyestra-2,5 (10) -diene

597 ml of ammonia were at -75 ° C with 9.91 g of lithium and within 1 hour was the solution of 24.6 g of the compound according to Example 7g in 1.2 l of tetrahydrofuran dropwise. The mixture was treated with 720 ml of ethanol, after Allow to warm to -50 ° C for 1 hour and stirred for a further 2 hours. Subsequently was added with 600 ml of water, heated to 23 ° C. left, extracted several times with ethyl acetate, the combined organic Extracts were washed with saturated sodium chloride solution washed and dried over sodium sulfate. After filtration and solvent removed were 27.1 g of the title compound isolated, which was reacted further without purification.

Example 7g (Simmons Smith):

3-methoxy-15α, 16α-methylene-17α-hydroxyestra-1,3,5 (10) -triene

A Suspension of 1.5 g of copper (II) acetate in 900 ml of diethyl ether was added with 86.6 g of zinc dust and refluxed for 10 minutes heated. Subsequently, the suspension was 11.7 ml Diiodomethane was added and refluxed for a further 30 minutes heated. The solution of 37.6 g of the example shown in Example 7h Compound in 100 ml of tetrahydrofuran and in total A total of 40 ml of diiodomethane was added for 40 hours. The cooled mixture was filtered through celite, the Filtrate was washed with saturated sodium chloride solution washed and dried over sodium sulfate. The after filtration and solvent removed residue purified by recrystallization. Isolated 24.6 g of the title compound.

Example 7h (benzoate saponification):

3-methoxy-17α-hydroxyestra-1,3,5 (10), 15-tetraene

The Solution of 96.3 g of the compound prepared according to Example 7i in 1.1 l of methanol was added with 75.5 g of potassium carbonate and at Stirred at 50 ° C for 2 hours. The solution was concentrated, mixed with water, extracted several times with ethyl acetate, the combined organic extracts were washed with water and transferred Dried sodium sulfate. The after filtration and solvent removal The residue obtained was purified by recrystallization. Isolated 46 g of the title compound.

Example 7i (Mitsunobu):

4-nitro-benzoic acid 3-methoxy-estra-1,3,5 (10), 15-tetraen-17-yl ester

The solution of 43.9 g of 3-methoxy-17β-hydroxyestra-1,3,5 (10), 15-tetraene in 1.61 tetrahydrofuran was treated with 121 g of triphenylphosphine, 27.1 g of 4-nitrobenzoic acid, 30.9 ml Azodicarbonsäisiisopropylester and stirred at 23 ° C for 2 hours. The solution was added with saturated sodium chloride solution, extracted with ethyl acetate, the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was taken up in 1.2 l of acetone, admixed with 80 ml of a 30% strength hydrogen peroxide solution while cooling and, after cooling for 20 minutes, poured into 600 ml of a half-concentrated sodium thiosulfate solution. The mixture was extracted with ethyl acetate, the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by recrystallization. Isolated 52.5 g of the title compound.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 2006072467 A1 [0003]
• WO 2006/072467 A1 [0003]
• US 3705179 A [0004]
• WO 93/13122 A1 [0005]
• - DE 1183500 A [0074]
• - DE 2922500 A [0074]
• EP 0019690A [0074]
• - US 4291029 A [0074]
• - DE 3402329 A [0077]
• - EP 0150157 A [0077]
• - US 4584288 A [0077]
• WO 98/24801 A1 [0085]
• - DE 2805490 A [0086]

Cited non-patent literature

• - Fresenius / Görlitzer 3.Aufl. 1991 "Organic Chemical Nomenclature" p. 60 [0002]
• J. Fried, JA Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, pp. 265-374 [0071]
• - J. Am. Chem. Soc. 84, 867 (1962) [0074]
• - J. Med. Chem. 34, 2464 (1991) [0077]
• K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982) [0078]
• - K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983) [0081]
• J. Chem. Soc. 3578 (1954) [0082]

Claims (22)

15,16-Methylene-steroid-17,17-lactol derivative having the general chemical formula I.

and their tautomeric forms with the general chemical formula Ia,

wherein Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'or NNHSO ₂ R', wherein R 'is hydrogen, C ₁ -C ₁₀ alkyl, aryl or C ₇ -C ₂₀ aralkyl, R ^{4 is} selected from the group comprising hydrogen and halogen, furthermore either: R ^6a , R ^{6b are} each independently selected from the group comprising hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ Alkynyl, or together form methylene or 1,2-ethanediyl and R ^{7 is} selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₂ -C ₁₀ -alkenyl and C C ₂ -C ₁₀ -alkynyl, or: R ^6a , R ⁷ together form an oxygen atom or a methylene group or are omitted to form a double bond between C ⁶ and C ⁷ and R ^{6b is} selected from the group comprising hydrogen, C ₁ -C ₁₀ -Alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, R ^{18 is} selected from the group comprising hydrogen and C ₁ -C ₃ -alkyl, R ^{22 is} selected from de r group comprising hydrogen, C ₁ -C ₆ alkyl, aryl and C ₇ -C ₂₀ aralkyl, and their solvates, hydrates, stereoisomers and salts. A 15,16-methylene-steroid-17,17-lactol derivative according to claim 1, characterized in that Z is selected from the group comprising oxygen, NOR 'and NNHSO ₂ R'. 15,16-methylene-steroid-17,17-lactol derivative one of the preceding claims, characterized Z is oxygen. 15,16-Methylene-steroid-17,17-lactol derivative according to one of the preceding claims, characterized ge indicates that R ^{4 is} hydrogen or chlorine. 15,16-Methylene-steroid-17,17-lactol derivative according to one of the preceding claims, characterized in that R ^6a , R ^6b together form 1,2-ethanediyl or are each hydrogen. The 15,16-methylene-steroid-17,17-lactol derivative according to any one of the preceding claims, characterized in that R ^{7 is} selected from the group comprising hydrogen, methyl, ethyl and vinyl. A 15,16-methylene-steroid-17,17-lactol derivative according to any one of claims 1-4, characterized in that R ^6a and R ⁷ together form methylene. 15,16-methylene steroid-17,17-lactol derivative of any one of claims 1-4, characterized in that R ^6a and R ⁷ is omitted to form a double bond between C ⁶ and C. ⁷ 15,16-Methylene-steroid-17,17-lactol-derivative according to one of the preceding claims, characterized in that R ^{18 is} hydrogen or methyl. 15,16-Methylene-steroid-17,17-lactol derivative according to one of the preceding claims, characterized in that R ^{22 is} hydrogen. A 15,16-methylene-steroid-17,17-lactol derivative according to any one of the preceding claims, characterized in that R ^{22 is} selected from the group comprising methyl, ethyl and isopropyl. 15,16-Methylene-steroid-17,17-lactol-derivative according to one of the preceding claims, selected from the group - 17α- (3'-hydroxy-1'-propenyl) -15α, 16α-methylene-17β-3 ' -oxidoestra-4-en-3-one - 17α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-en-3-one - 7α-methyl- 15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-methyl-15α, 16α-methylene-17α- (3 '-hydroxy-1'-propenyl)-17β-3'-oxidoestra-4-en-3-one - 7α-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β- 3'-oxidoestra-4-en-3-one - 7β-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene-3 on-7α-ethyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-ethyl-15α, 16α-methylene -17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-ethyl-15β, 16β-methylene-17α- (3'-hydroxy-1 ' -propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-ethyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxide stra-4-en-3-one - 7α-vinyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β Vinyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-vinyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-vinyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 7β-cyclopropyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-cyclopropyl-15β, 16β-methylene-17α- (3'-hydroxy 1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6-methylene-15α, 16α-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3 ' -oxidoestra-4-en-3-one - 6-methylene-15β, 16β-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one 6α-hydroxymethylene-15α, 16α-methyls n-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β-hydroxymethylene-15α, 16α-methylene-7α- (3'-hydroxy-1 '-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α-hydroxymethylene-15β, 16β-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra 4-en-3-one - 6β-hydroxymethylene-15β, 16β-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6, 6- (1,2-ethanediyl) -15α, 16α-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6,6- 1,2-ethanediyl) -15β, 16β-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α, 7α; 15α, 16α- Bismethylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β, 7β; 15α, 16α-bismethylene-7α- (3'-hydroxy-1 '-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α, 7α, 15β, 16β-bismethylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra 4-en-3-one - 6β, 7β; 15β, 16β-bismethylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 17α- (3'-hydroxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoe stra-4,6-dien-3-one - 17α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4,6-dien-3-one - E / Z) -3- (hydroxyimino) -17α- (3'-hydroxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -17α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-methyl -15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene (E / Z) -3- (hydroxyimino) -7α-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -7β-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -7α-ethyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-ethyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α- ethyl 15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-ethyl-15β , 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-vinyl-15α, 16α- methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-vinyl-15α, 16α-methylene-17α - (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -7α-vinyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) - 3- (Hydroxyimino) -7β-vinyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- Hydroxyimino) -7α-cyclopropyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) - 7β-cyclopropyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-cyclopropyl -15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-cyclopropyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6-methylene-7α- (3 ') -hydroxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6-methylene-7α- (3'-hydroxy-) 1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene-7α- (3'-hydroxy-1'- propenyl) -15α, 16α-methylene-17β-3 ' oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β-hydroxymethylene-7α- (3'-hydroxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4 -en - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene-7α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -6β-hydroxymethylene-7α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E) Z) -3- (hydroxyimino) -6,6 (1,2-ethanediyl) -7α- (3'-hydroxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4- en - (E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -7α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β-3 ' -oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α, 15α, 16α-bismethylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra- 4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β, 15α, 16α-bismethylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α, 15β, 16β-bismethylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene (E. / Z) -3- (hydroxyimino) -6β, 7β; 15β, 16β 7-bismethylene- - (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -17α- (3'-hydroxy-1'-propenyl) - 15α, 16α-methylene-17β-3'-oxidoestra-4,6-diene - (E / Z) -3- (hydroxyimino) -17α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene -17β-3'-oxidoestra-4,6-diene - 17α- (3'-hydroxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4-ene-3 -one - 17α- (3'-hydroxy-1'-propenyl) -18-methyl-15β, 16β-methylene-17β-3'-oxidoestra-4-en-3-one - 7α, 18-dimethyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β, 18-dimethyl-15α, 16α-methylene-17α- (3 ') -hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α, 18-dimethyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) - 17β-3'-oxidoestra-4-en-3-one - 7β, 18-dimethyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4 en-3-one - 7α-ethyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β ethyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'- propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-ethyl-18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3 ' -oxidoestra-4-en-3-one - 7β-ethyl-18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 7α-vinyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-vinyl -18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-vinyl-18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-vinyl-18-methyl-15β, 16β-methylene-17α- 3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1 ' -propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-cyclopropyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3 '-oxidoestra-4-en-3-one - 7α-cyclopropyl-18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene -3-one - 7β-cyclopropyl-18-me ethyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6-methylene-18-methyl-15α, 16α-methylene -7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6-methylene-18-methyl-15β, 16β-methylene-7α- (3'- hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α-hydroxymethylene-18-methyl-15α, 16α-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one 6β-hydroxymethylene-18-methyl-15α, 16α-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α-hydroxymethylene-18- methyl-15β, 16β-methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β-hydroxymethylene-18-methyl-15β, 16β-methylene -7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6,6- (1,2-ethanediyl) -18-methyl-15α, 16α- methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6,6- (1,2-ethanediyl) -18-methyl-15β, 16β -methylene-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α, 7α, 15α, 16α-bismethylene-18-methyl-7α- (3 '-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β, 7β; 15α, 16α-bismethylene-18-methyl-7α- (3'-hydroxy-1'- propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α, 7α, 15β, 16β-bismethylene-18-methyl-7α- (3'-hydroxy-1'-propenyl) -17β-3 ' -oxidoestra-4-en-3-one - 6β, 7β; 15β, 16β-bismethylene-18-methyl-7α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 17α- (3'-hydroxy-1'-propenyl) -18- methyl-15α, 16α-methylene-17β-3'-oxidoestra-4,6-dien-3-one - 17α- (3'-hydroxy-1'-propenyl) -18-methyl-15β, 16β-methylene-17β 3'-oxidoestra-4,6-dien-3-one - (E / Z) -3- (hydroxyimino) -18-methyl-17α- (3'-hydroxy-1'-propenyl) -15α, 16α- methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -18-methyl-17α- (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β 3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α, 18-bismethyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β- 3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β, 18-bismethyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3 '-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α, 18-bismethyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3' -oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β, 18-bismethyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3 ' oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-ethyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3 ' -oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-ethyl 18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-ethyl -18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β- ethyl 18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α -vinyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) - 7β-vinyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) 7α-vinyl-18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino ) -7β-vinyl-18-methyl-15β, 16β-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- ( Hydroxyimino) -7α-cyclopropyl-18-methyl-15α, 16α-methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-cyclopropyl-18-methyl-15α, 16α-methylene -17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-cyclopropyl-18-methyl-15β, 16β- methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-cyclopropyl-18-methyl-15β, 16β -methylene-17α- (3'-hydroxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -18-methyl-6-methylene-7α- (3'-hydroxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -18-methyl-6-methylene-7α - (3'-hydroxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene-7α- (3 '-hydroxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β-hydroxymethylene-7α- 3'-hydroxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene-7α- (3'-hydroxy-1'-propenyl) -18-methyl-15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β-hydroxymethylene-7α - (3'-hydroxy-1 '-propenyl) -18-methyl-15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) - 7α- (3'-hydroxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6,6 - (1,2-ethanediyl) -7α- (3'-hydroxy-1'-propenyl) -18-methyl-15β, 16β-methyl- len-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α, 15α, 16α-bismethylene-18-methyl-7α- (3'-hydroxy-1'- propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β; 15α, 16α-bismethylene-18-methyl-7α- (3'-hydroxy-1 ' -propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α, 15β, 16β-bismethylene-18-methyl-7α- (3'-hydroxy-1 '-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β, 15β, 16β-bismethylene-18-methyl-7α- (3'-hydroxy) 1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -17α- (3'-hydroxy-1'-propenyl) -18-methyl-15α, 16α -methylene-17β-3'-oxidoestra-4,6-diene - (E / Z) -3- (hydroxyimino) -17α- (3'-hydroxy-1'-propenyl) -18-methyl-15β, 16β- methylene-17β-3'-oxidoestra-4,6-diene. 17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-en-3-one - 17α- (3'-methoxy-1'-propenyl) - 15β, 16β-methylene-17β-3'-oxidoestra-4-en-3-one - 7α-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3 ' oxidoestra-4-en-3-one - 7β-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α -Methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-ethyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-ethyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 7α-ethyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-ethyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-vinyl-15α, 16α-methylene-17α- (3'-methoxy 1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-vinyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-vinyl-15β, 16β-methylene-17α - (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-vinyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl ) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4 en-3-one - 7β-cyclopropyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl-15β , 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-cyclopropyl-15β, 16β-methylene-17α- (3'- methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6-methylene-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3 '-oxidoestra-4-en-3-one - 6-methylene-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one 6α-hydroxymethylene-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β-hydroxymethylene-15α, 16α-methylene 17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α-hydroxymethylene-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β-hydroxymethylene-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 6,6- (1,2-ethanediyl) -15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene-3 on - 6,6- (1,2-ethanediyl) -15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α , 7α, 15α, 16α-bismethylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β, 7β, 15α, 16α-bismethylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α, 7α, 15β, 16β-bismethylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β, 7β, 15β, 16β-bismethylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4,6-dien-3-one - 17α- (3'-methoxy) 1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4,6-diene 3-one - (E / Z) -3- (hydroxyimino) -17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene (E / Z) -3- (hydroxyimino) -17α- (3'-methoxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- ( Hydroxyimino) -7α-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) - 7β-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-methyl -15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-ethyl-15α, 16α-methylene -17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-ethyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-ethyl-15β, 16β-methylene-17α- (3 '). -methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxy imino) -7β-ethyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) - 7α-vinyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-vinyl -15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-vinyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-vinyl-15β, 16β-methylene -17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-cyclopropyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoest ra-4-ene - E / Z) -3- (hydroxyimino) -7β-cyclopropyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4 en - (E / Z) -3- (Hydroxyimino) -7α-cyclopropyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - ( E / Z) -3- (hydroxyimino) -7β-cyclopropyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene (E / Z ) -3- (Hydroxyimino) -6-methylene-17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3 - (Hydroxyimino) -6-methylene-17α- (3'-methoxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino ) -6α-hydroxymethylene-17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β -hydroxymethylene-17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene 17α- (3'-methoxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β-hydroxymethylene-17α- 3'-methoxy 1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6,6- (1,2-) ethanediyl) -17α- (3'-methoxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α; 15α, 16α-bismethylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β; 15α, 16α bismethylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α, 15β, 16β-bismethylene 17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β, 15β, 16β-bismethylene-17α- 3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4,6-diene - (E / Z) -3- (hydroxyimino) -17α- (3'-methoxy-1'-propenyl) -15β, 16β-methylene-17β 3'-oxidoestra-4,6-diene - 17α- (3'-methoxy-1'-propenyl) -18-methyl-15α, 16 α-methylene-17β-3'-oxidoestra-4-en-3-one - 17α- (3'-methoxy-1'-propenyl) -18-methyl-15β, 16β-methylene-17β-3'-oxidoestra- 4-en-3-one - 7α, 18-dimethyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β , 18-dimethyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α, 18-dimethyl-15β, 16β- methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β, 18-dimethyl-15β, 16β-methylene-17α- (3'-methoxy 1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-ethyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) - 17β-3'-oxidoestra-4-en-3-one - 7β-ethyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra- 4-en-3-one - 7α-ethyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one 7β-ethyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-vinyl-18- methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-prop enyl) -17β-3'-oxidoestra-4-en-3-one - 7β-vinyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3 ' -oxidoestra-4-en-3-one - 7α-vinyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 7β-vinyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl -18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-cyclopropyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl-18-methyl-15β, 16β-methylene-17α- 3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-cyclopropyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1 ' -propenyl) -17β-3'-oxidoestra-4-en-3-one - 6-methylene-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3 '-oxidoestra-4-en-3-one - 6-methylene-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 6α-hydroxymethyl en-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β-hydroxymethylene-18-methyl-15α , 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α-hydroxymethylene-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β-hydroxymethylene-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1 '-propenyl) -17β-3'-oxidoestra-4-one-3-one - 6,6- (1,2-ethanediyl) -18-methyl-15α, 16α-methylene-17α- (3'-methoxy) 1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6,6- (1,2-ethanediyl) -18-methyl-15β, 16β-methylene-17α- (3'-methoxy 1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α, 7α, 15α, 16α-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) - 17β-3'-oxidoestra-4-en-3-one - 6β, 7β, 15α, 16α-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra- 4-en-3-one - 6α, 7α, 15α, 16α-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β, 7β, 15β, 16β-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 17α- (3'- methoxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4,6-dien-3-one - 17α- (3'-methoxy-1'-propenyl) -18 -methyl-15β, 16β-methylene-17β-3'-oxidoestra-4,6-dien-3-one - (E / Z) -3- (hydroxyimino) -18-methyl-17α- (3'-methoxy) 1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -18-methyl-17α- (3'-methoxy-1'- propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α, 18-bismethyl-15α, 16α-methylene-17α- (3'-) methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β, 18-bismethyl-15α, 16α-methylene-17α- (3'-methoxy 1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α, 18-bismethyl-15β, 16β-methylene-17α- (3'-methoxy) 1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β, 18-bismethyl-15β, 16β-methylene-17α- (3'-methoxy-1 '-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydr oxyimino) -7α-ethyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -7β-ethyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3 - (Hydroxyimino) -7α-ethyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) - 3- (Hydroxyimino) -7β-ethyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -7α-vinyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z ) -3- (Hydroxyimino) -7β-vinyl-18-methyl-15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -7α-vinyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene (E. / Z) -3- (hydroxyimino) -7β-vinyl-18-methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - ( e / Z) -3- (hydroxyimino) -7α-cyclopropyl-18-methyl-15α , 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-cyclopropyl-18-methyl- 15α, 16α-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-cyclopropyl-18-methyl -15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-cyclopropyl-18- methyl-15β, 16β-methylene-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -18-methyl-6 -methylene-17α- (3'-methoxy-1'-propenyl) -15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -18-methyl- 6-methylene-17α- (3'-methoxy-1'-propenyl) -15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene -17α- (3'-methoxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β- hydroxymethylene-17α- (3'-methoxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α -hydroxymethylen-17α - (3'-methoxy-1'-propenyl) -18-methyl-15β, 16β-methylene-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β-hydroxymethylene 17α- (3'-methoxy-1'-propenyl) -18-methyl-15β, 16β-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6,6 - (1,2-ethanediyl) -17α- (3'-methoxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4-ene - (E / Z) - 3- (hydroxyimino) -6,6-(1,2-ethanediyl) -17α- (3'-methoxy-1'-propenyl) -18-methyl-15β, 16β-methylene-17β-3'-oxidoestra-4 (E / Z) -3- (hydroxyimino) -6α, 7α, 15α, 16α-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra- 4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β; 15α, 16α-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) -17β-3'-oxidoestra 4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α, 15β, 16β-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) -17β-3 ' oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β, 15β, 16β-bismethylene-18-methyl-17α- (3'-methoxy-1'-propenyl) -17β-3 ' -oxidoes tra-4-ene - (E / Z) -3- (hydroxyimino) -17α- (3'-methoxy-1'-propenyl) -18-methyl-15α, 16α-methylene-17β-3'-oxidoestra-4 , 6-diene - (E / Z) -3- (hydroxyimino) -17α- (3'-methoxy-1'-propenyl) -18-methyl-15β, 16β-methylene-17β-3'-oxidoestra-4, 6-dien 15,16-methylene-steroid-17,17-lactol derivative one of the preceding claims for oral contraception and for the treatment of pre-, peri- and postmenopausal Complaints. Use of the 15,16-methylene-steroid 17,1,17-lactol derivatives according to any one of claims 1-13 for the preparation a drug for oral contraception and treatment of pre-, peri- and postmenopausal complaints. Use according to claim 14, characterized that the drug is gestagenic, antimineralcorticoide and neutral until slightly androgenic effect. Medicament containing at least one 15,16-methylene-steroid-17,17-lactol derivative according to any one of claims 1-13 and at least a suitable pharmaceutically acceptable additive. The pharmaceutical composition of claim 16, further containing at least one estrogen. Medicament according to Claim 17, characterized that the estrogen is ethinylestradiol. Medicament according to Claim 17, characterized the estrogen is estradiol valerate. Medicament according to Claim 17, characterized that the estrogen is a natural estrogen. Medicament according to Claim 20, characterized that the natural estrogen is estradiol. Medicament according to Claim 20, characterized that the natural estrogen is a conjugated estrogen is.