DE102007063499A1 - Steroid 17,17-lactol derivative, its use and the derivative containing drug - Google Patents

Abstract

The invention relates to 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, R15, R16a, R16b, R18, R22 and Z denote the in claim 1 have meanings, as well as their solvates, hydrates, stereoisomers and salts. The invention further relates to the use of these derivatives for the manufacture of a medicament for oral contraception and for the treatment of pre-, peri- and post-menopausal 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 This invention relates to steroid 17,17-lactol derivatives, their use and derivatives containing gestagenic drugs, For example, for the treatment of pre-, per- and postmenopausal as well as premenstrual symptoms.

From the literature compounds with gestagener, antimineralcortioider, antiandrogenic or antiestrogenic action based on a Steroidgerüstes are known, 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 3rd edition 1991 "Organic chemical nomenclature" p. 60 ff. refer to).

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 95/18621 A1 For example, steroids are compounds of which 6α, 9α-fluoro-11β, 17-dihydroxy-16α-methyl-pregna-1,4-dien-3-one-17-carboxylic acid is preferred for inhibiting angiogenesis in tumors and for ocular treatment Hypertension described.

In GB 1,193,951 A are steroids 13-C _2-4- alkyl-gonan compounds described with mineral corticosteroid, anesthetic or other steroid hormones usual activity.

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 steroid 17,17-lactol derivatives according to the invention according to claim 1, the use of the invention Derivatives according to claim 21 and at least one a medicament containing a derivative according to the invention solved according to claim 23. 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, C₂-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
F^6b ausgewählt ist aus der Gruppe, umfassend Wasserstoff, C₁-C₁₀-Alkyl, C₂-C₁₀-Alkenyl, C₂-C₁₀-Alkinyl,
ferner entweder:
R¹⁵ Wasserstoff ist und
R^16a, R^16b jeweils unabhängig voneinander ausgewählt sind aus der Gruppe, umfassend Wasserstoff und C₁-C₁₀-Alkyl, oder gemeinsam Methylen oder 1,2-Ethandiyl bilden
oder:
R¹⁵, R^16a ausgewählt sind aus der Gruppe, umfassend Wasserstoff und C₁-C₁₀-Alkyl, oder gemeinsam ein Sauerstoffatom bilden oder unter Bildung einer Doppelbindung zwischen C¹⁵ und C¹⁶ entfallen und
R^16b ausgewählt ist aus der Gruppe, umfassend Wasserstoff und C₁-C₁₀-Alkyl,
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 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,
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 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
F ^{6b is} selected from the group comprising hydrogen, C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl,
furthermore either:
R ^{15 is} hydrogen and
R ^16a , R ^{16b are} each independently selected from the group comprising hydrogen and C ₁ -C ₁₀ alkyl, or together form methylene or 1,2-ethanediyl
or:
R ¹⁵ , R ^{16a are} selected from the group comprising hydrogen and C ₁ -C ₁₀ alkyl, or together form an oxygen atom or omitted to form a double bond between C ¹⁵ and C ¹⁶ and
R ^{16b is} selected from the group comprising hydrogen and C ₁ -C ₁₀ -alkyl,
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 chemi Formulas I and Ia follow in a conventional manner the numbering of a steroid skeleton, for example described in Fresenius, loc. cit. The numbering of the radicals indicated in the claims corresponds in an analogous manner to their binding position on the C-skeleton of the derivatives, as far as R ⁴ , R ⁶ , R ⁷ , R ¹⁵ , R ¹⁶ 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 , R ⁷ , R ^16a and R ^16b are straight or branched chain alkyl groups having 1-10 carbon atoms, such as 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 ^16a , R ^16b , 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 -Arylgruppen (which in turn may be substituted by 1-3 halogen atoms) may be 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 ^6b 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 in turn may 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 which is 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 ^{15 is} hydrogen.

According to a further preferred embodiment of the invention, R ¹⁵ and R ^{16 a} together form oxygen or are omitted to form a double bond between C ¹⁵ and C ¹⁶ .

In a further preferred embodiment of the invention R ^{16a is} hydrogen and R ^{16b is} methyl.

In a further preferred embodiment of the invention R ^{16a is} hydrogen and R ^{16b is} methyl.

In a further preferred embodiment of the invention, R ^16a and R ^{16b are} hydrogen.

According to a further preferred embodiment of the invention, R ^16a and R ^16b together form methylene.

According to a further preferred embodiment of the invention, R ^16a and R ^16b together form 1,2-ethanediyl.

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 ₅ alkenyl or C ₂ -C ₆ alkynyl, or together methylene or 1,2-ethanediyl form and
R ^{7 is} hydrogen, C ₁ -C ₅ -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,
furthermore either:
R ^{15 is} hydrogen and
R ^16a , R ^{16b are} each independently of the other hydrogen or C ₁ -C ₆ -alkyl or together form methylene or 1,2-ethanediyl,
or:
R ¹⁵ , R ^{16a are} hydrogen or C ₁ -C ₆ alkyl or omitted to form a double bond between C ¹⁵ and C ^16, and
R ^{16b is} hydrogen or C ₁ -C ₆ -alkyl,
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,
furthermore either:
R ^{15 is} hydrogen and
R ^16a , R ^{16b are} hydrogen or together form methylene or 1,2-ethanediyl
or:
R ¹⁵ , R ^{16a are} hydrogen or omitted to form a double bond between C ¹⁵ and C ^16, and
R ^{16b is} hydrogen,
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.

Expressly also included are derivatives of the invention in the form of solvates, in particular of hydrates, the inventive Compounds accordingly polar solvents, in particular of water, as a structural element of the crystal lattice containing the compounds of the invention. The polar solvent, especially water, can be used in a stoichiometric or unstoichiometric ratio available. For stoichiometric solvates, hydrates speaks also 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 has been found that the compounds or derivatives according to the invention have a good gestagenic activity. In addition, some interesting compounds of the invention interact with the mineralocorticoid receptor and are capable of mediating antagonist activity. Further, the compounds of the present invention have a neutral to slightly androgenic effect on the androgen receptor kung up. Another property of the majority of the compounds is that the linkages of these compounds to the progesterone receptor and to the mineralocorticoid receptor are relatively balanced, such that the ratio of their ability to bind to the progesterone receptor to bind to the mineralocorticoid receptor is lower than that of drospirenone , Thus, the antimineralcorticoid activity of these compounds is less with given gestagenic effect than with drospirenone. If the dosage of a given compound according to the invention is determined on the basis of its gestagenic action, the antimineralcorticoid effect of this compound is thus lower at this dosage than in drospirenone.

The below-mentioned compounds provided with the respective structural formulas numbered 1-90 and the tautomeric forms derivable therefrom are preferred in the present invention. Here, R in compounds Nos. 1-46 denotes hydrogen (H) and in compounds Nos. 47-90 methyl (CH ₃ ).

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-, per- 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 included In addition, they contain excipients, such as preservatives, stabilizers, Wetting agents or emulsifiers, salts for modifying the osmotic pressure or buffer. For parenteral administration are especially 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 the derivatives of the invention in a transdermal Incorporate system and apply it transdermally. For oral administration is especially tablets, dragees, capsules, Pills, suspensions or solutions in question.

The Dosing of the derivatives according to the invention in contraceptive preparations should be 0.01 to 10 mg per day. The daily dose during treatment Premenstrual discomfort is around 0.1 to 20 mg. The gestagenic derivatives of the invention are disclosed in Contraceptive preparations and in the medicines for Treatment of premenstrual complaints preferably orally applied. The daily dose is preferably once administered.

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 estrogens, 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-, per- 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 # 6156), 4mM L-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 evaluated using dose-response relationship calculation software. 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 (1310 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 having the general chemical formula I, starting from compounds having the general chemical formula 1a (Scheme 2) or 1b (Scheme 3), are prepared according to the methods given in Scheme 1, wherein R ⁴ , R ^6a , R ^6b R ⁷ , R ¹⁵ , R ¹⁸ , R ²² and Z have the meanings given above and in which
R ⁶ , R ⁷ together form oxygen or methylene in 8b,
R ^16a , R ^16b together form methylene in 32a and 40a,
32b and 40b together form 1,2-ethanediyl,
in 32c and 40c are each independently of the other hydrogen or C ₁ -C ₁₀ -alkyl,
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, is 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.

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 5, 8a, 10 or 12 via bromination of the respective 3,5-dienol ethers 4, 7, 9 or 11 and subsequent hydrogen bromide cleavage (see eg J. Fried, JA Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, pp. 265-374 ).

The dienol ether bromination of compounds 4, 7, 9 or 11 can be carried out, for example, analogously to the procedure of Steroids 1, 233 (1963). The hydrogen bromide cleavage to form the compounds of general chemical formula 5, 8a, 10 or 12 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 R ⁴ can, for example, starting from a compound having one of the general chemical formulas 3, 5, 6, 8a, 8b or 10 by epoxidation of the 4,5-double bond with hydrogen peroxide under alkaline conditions and reaction of the resulting epoxides in a suitable solvent with acids having the general chemical formula HR ⁴ , 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- (fluorosulfonyl) 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 3, 5, 6, 8a, 8b or 10, 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 5 or 12 is prepared by methenylation of the 6,7-double bond by known methods, for example with dimethylsulfoxonium methylide (see, for example DE-A 11 83 500 . DE-A 29 22 500 . EP-A 0 019 690 . US-A 4,291,029 ; J. Am. Chem. Soc. 84, 867 (1962) ) into a compound 8b or 13 (R ⁶ , R ⁷ together form a methylene group) to give a mixture of α- and β-isomers, which can be separated, for example by chromatography in the individual isomers.

links Type 8b or 13 can, as described in the examples or analogously to these regulations, using analogous to the reagents described there are obtained.

The synthesis of the spirocyclic compound 10 (R ^6a , R ^6b together form 1,2-ethanediyl) starts from the compounds 3 or 6, which are first transformed into a 3-amino-3,5-diene derivative 7 (X = NR ^21a R ^21b ). By reaction with formalin in alcoholic solution, the 6-hydroxymethylene derivative 8a (R ⁶ = hydroxymethylene) is obtained. After conversion of the hydroxy group into a leaving group, such as a mesylate, tosylate or benzoate, compound 10 may be prepared by reaction with tri methylsulfoxonium iodide using bases such as alkali metal hydroxides, alkali alcoholates, in suitable solvents such as dimethylsulfoxide.

To introduce a 6-methylene group, compound 8a (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 10 (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 10 is the direct reaction of 4 (5) unsaturated 3-ketones, such as compound 8a (R ⁶ = hydrogen), with acetals of formaldehyde in the presence of sodium acetate with, for example, phosphorus oxychloride or phosphorus pentachloride in suitable solvents, such as chloroform (see, e.g. K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982) ).

The 6-methylene compounds can be used to prepare compounds of general chemical formula 10 in which R ^6a is methyl and R ^6b and R ⁷ together form an additional bond.

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

Alternatively, compound 9 (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 10 in which R ^{6b represents} an α-methyl function can be prepared under suitable conditions from the 6-methylene compounds (10: R ^6a , R ^6b together 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 10 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 8a, 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 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 6 is carried out by 1,6-addition of a corresponding organometallic Compound to the precursor with the general chemical formula 5 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 compounds 3, 5, 6, 8a, 8b, 10, 11 or 12 in which Z is an oxygen atom can be converted by reaction with hydroxylamine hydrochloride alkyloxyamine hydrochlorides or sulfonylhydrazines in the presence of a tertiary amine at temperatures from -20 ° C to +40 ° C are converted into their corresponding E / Z-configured oximes or sulfonylhydrazones (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-biazabicyclo [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 3-keto compound on a suitable precursor, such as compounds with one of the general chemical formulas 3, 5, 6, 8a, 8b, 10, 11 or 12, are removed.

The Formation of spirolactols to compounds with one of the general chemical formulas 3 or 8b, starting from the corresponding 1,7-hydroxypropenyl compounds 2 or 13, by oxidation. When Oxidation processes are, for example, the oxidation according to Swern, the oxidation with N-methylmorpholine N-oxide and catalytic amounts to tetrabutylammonium perruthenate or the oxidation with manganese dioxide called.

Scheme 1

The compounds of general chemical formula 1a are prepared by the methods given in Scheme 2, wherein
R ¹⁵ and R ^{18 have} the meanings given above, and
R ^16a , R ^16b together form methylene in 32a,
32b together form 1,2-ethanediyl,
each 32c independently of one another is hydrogen, C ₁ -C ₁₀ -alkyl
and
R ₂₀ is C ₁ -C ₂₀ alkyl.

The compounds 30 to 1a in Scheme 2 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 .

Scheme 2

The compounds of general chemical formula 1b are prepared according to the procedures given in Scheme 3, wherein
R ¹⁵ and R ^{18 have} the meanings given above, and
R ^16a , R ^16b in 40a together form methylene,
in 40b together form 1,2-ethanediyl and
in 40c each independently of one another are hydrogen, C ₁ -C ₁₀ -alkyl,
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, is where
R ^{19 is} a C ₁ -C ₂₀ -alkyl radical.

The compounds 38 to 1b in Scheme 3 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 .

Scheme 3

The The following examples serve for further explanation of the invention, without these on the examples given narrow:

Example 1 (17-Spirolactolization with Braunstein):

17β-Hydroxy-18-methyl-19-no-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol

The solution of 500 mg of the compound described in Example 1a in 25 ml of dichloromethane was added in portions with a maximum of 3.5 g of manganese dioxide and stirred for about 1 hour at 23 ° C. The solution was filtered through Celite, and after concentration and chromatography, 302 mg of the title compound were isolated.
¹ H-NMR (CDCl ₃ ): δ = 0.71-0.93 (2H), 0.94-1.14 (5H), 1.18-1.94 (11H), 2.03-2, 55 (8H), 5.62-6.15 (4H) ppm.

Example 1a (3-ketal cleavage):

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

The solution of 367 mg of the compound shown in Example 1b in 30 ml of acetone was treated with 1.51 ml of 4 N hydrochloric acid and stirred for 30 minutes at 23 ° C. The solution was poured into saturated sodium bicarbonate solution, 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. Isolated wur the 269 mg of the title compound.

Example 1b (Lindlar hydrogenation):

-en (3'-hydroxypropene-1'-yl) -3,3-dimethoxy-17β-hydroxyestra-5 (10) - 17α (Z)

The Solution of 3.94 g of the compound prepared according to Example 1c in 90 ml of tetrahydrofuran was added 5.35 ml of pyridine, 560 mg of palladium on barium sulfate and in one atmosphere of hydrogen hydrogenated. The mixture was filtered through Celite, and after concentration and chromatography, 3.04 g of the title compound were obtained isolated.

Example 1c (hydroxypropyne addition):

-en 17α- (3'-hydroxypropine-1'-yl) -3,3-dimethoxy-17β-hydroxyestra-5 (10)

The Solution of 92.7 ml of 2-propyn-1-ol in 1.4 l of tetrahydrofuran was at -60 ° C with 1.13 L of a 2.5 molar solution butyllithium in hexane. After 30 minutes, the solution became of 100 g of 3,3-dimethoxy-estra-5 (10) -en-17-one in 0.8 l of tetrahydrofuran added dropwise, allowed to warm to 23 ° C and still Stirred for 16 hours. The mixture was poured into water, 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. 72.9 g of the title compound were isolated.

Example 2 (lactol "etherification"):

18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one

The solution of 94 mg of the compound according to Example 1 in 5 ml of methanol was treated with 7 mg of p-toluenesulfonic acid pyridinium salt and stirred under reflux for 3 hours. The solution was concentrated, the residue was purified by chromatography, and 41 mg of the title compound was isolated
¹ H-NMR (CD ₂ Cl ₂ ): δ = 0.71-1.14 (7H), 1.18-1.91 (11H), 2.03-2.36 (6H), 2.46 ( 1H), 3.22 + 3.40 (3H), 5.59 (1H), 5.65 (1H), 5.75 (1H), 6.13 (1H) ppm.

Example 3:

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

In analogy to Example 1, 150 mg of the compound prepared according to Example 3a were reacted, and after work-up and purification 73 mg of the title compound were isolated.
¹ H-NMR (CDCl _3): δ = 0.04 to 0.52 (3H), 0.80-1.20 (7H), 1.20-1.90 (10H), 2.10 (1H) , 2.20-2.51 (5H), 5.55-5.88 (3H), 5.97-6.07 (1H) ppm.

Example 3a:

16,16 (1,2-ethanediyl) -17α (Z) - (3'-hydroxypropene-1'-yl) -17β-hydroxyestra-4-en-3-one

2.83 g of the compound prepared according to Example 3b were in analogy converted to Example 1a, and after work-up and purification were 1.64 g of the title compound isolated.

Example 3b:

-en (3'-hydroxypropene-1'-yl) -17β-hydroxyestra-5 (10) - 3,3-dimethoxy-16,16 (1,2-ethanediyl) -17α (Z)

2.98 g of the compound prepared according to Example 3c were in analogy reacted to Example 1b, and after work-up 2.84 g of Isolated title compound, which were reacted further without purification.

Example 3c:

-en (3'-hydroxypropyn-1'-yl) -17β-hydroxyestra-5 (10) - 3,3-dimethoxy-16,16 (1,2-ethanediyl) -17α (Z)

100 mg of the compound prepared according to Example 3d were in analogy reacted to Example 1c, and after work-up and purification were Isolated 116 mg of the title compound, which reacted further without purification were.

Example 3d (16,16-cyclopropanation from 16,16-methylene):

3,3-dimethoxy-16,16 (1,2-ethanediyl) estra-5 (10) -en-17-one

A Solution of 5.61 g Sulfoxoniumiodid in 100 ml of dimethyl sulfoxide was portionwiese at 23 ° C with 1.05 g of a 60% suspension of sodium hydride in white oil. The solution was stirred for a further 2 hours, then The solution was 2.1 g of that shown in Example 3e Added dropwise in 40 ml of dimethyl sulfoxide and another 16 hours long reacted. The mixture was poured into water, extracted several times with ethyl acetate, the combined organic Extracts were washed with saturated sodium chloride solution washed and dried over sodium sulfate. Isolated 2.52 g of the title compound, the remaining amounts of white oil contained and further reacted without additional purification has been.

Example 3e (16,16-methylene from silyl enol ether):

3,3-dimethoxy-16-methylene-estra-5 (10) -en-17-one

The Solution of 6.1 g of 3,3-dimethoxy-17-trimethylsilyloxy-estra-5 (10), 16-diene in 30 ml of tetrahydrofuran was added 10 ml of N, N, N ', N'-tetramethyldiamonomethane cooled, cooled to 3 ° C and with 10 ml of acetic anhydride added. The solution was warmed to 23 ° C and allowed to react for 2 days. The mixture was in saturated Na triumhydrogencarbonatlösung poured, several times with ethyl acetate extracted, the combined organic extracts were saturated with Sodium chloride solution and washed over sodium sulfate dried. The mixture was purified by chromatography on silica gel Purified, and isolated 1.6 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 95/18621 A1 [0005]
• GB 1193951 A [0006]
• - DE 1183500 A [0080]
• - DE 2922500 A [0080]
• EP 0019690A [0080]
• - US 4291029 A [0080]
• - DE 3402329 A [0083]
• - EP 0150157 A [0083]
• - US 4584288 A [0083]
• WO 98/24801 A1 [0091]
• - DE 2805490 A [0092]

Cited non-patent literature

• - Fresenius / Görlitzer 3rd edition 1991 "Organic chemical nomenclature" p. 60 ff. [0002]
• J. Fried, JA Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, pp. 265-374 [0077]
• - J. Am. Chem. Soc. 84, 867 (1962) [0080]
• J. Med. Chem. 34, 2464 (1991) [0083]
• K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982) [0084]
• Tetrahedron 21, 1619 (1965) [0086]
• - K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983) [0087]
• J. Chem. Soc. 3578 (1954) [0088]
• Tetrahedron 1619 (1965 [0088]

Claims (29)

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 ₂ -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, further, either: R ^{15 is} hydrogen and R ^16a , R ^{16b are} each independently selected au s of the group comprising hydrogen and C ₁ -C ₁₀ -alkyl, or together form methylene or 1,2-ethanediyl or: R ¹⁵ , R ^{16a are} selected from the group comprising hydrogen and C ₁ -C ₁₀ -alkyl, or together form an oxygen atom or form a double bond between C ¹⁵ and C ¹⁶ and R ^{16b is} selected from the group comprising hydrogen and C ₁ -C ₁₀ -alkyl, 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 and C ₇ -C ₂₀ aralkyl, and the same Solvates, hydrates, stereoisomers and salts. 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'. Steroid 17,17-lactol derivative according to any one of the preceding Claims, characterized in that Z for Oxygen stands. Steroid 17,17-lactol derivative according to one of the preceding claims, characterized in that R ^{4 is} hydrogen or chlorine. 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. 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. Steroid 17,17-lactol derivative according to any one of claims 1-4, characterized in that R ^6a and R ⁷ together form 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 Steroid 17,17-lactol derivative according to any one of the preceding claims, characterized in that R ^{15 is} hydrogen. Steroid 17,17-lactol derivative according to one of the preceding claims, characterized in that R ¹⁵ form together with R ^16a oxygen or omitted to form a double bond between C ¹⁵ and C ¹⁶ . A steroid 17,17-lactol derivative according to any one of claims 1-9, characterized in that R ^{16a is} hydrogen and R ^{16b is} methyl. A steroid 17,17-lactol derivative according to any one of claims 1-9, characterized in that R ^{16a is} hydrogen and R ^{16b is} methyl. Steroid 17,17-lactol derivative according to any one of claims 1-9, characterized in that R ^16a and R ^{16b are} hydrogen. Steroid 17,17-lactol derivative according to any one of claims 1-9, characterized in that R ^16a and R ^16b together form methylene. Steroid 17,17-lactol derivative according to any one of claims 1-9, characterized in that R ^16a and R ^16b together form 1,2-ethanediyl. Steroid 17,17-lactol derivative according to one of the preceding claims, characterized in that R ^{18 is} hydrogen or methyl. Steroid 17,17-lactol derivative according to any one of the preceding claims, characterized in that R ^{22 is} hydrogen. 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. A steroid 17,17-lactol derivative according to any one of the preceding claims selected from the group comprising - 17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol 17β-hydroxy-7β-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7α-ethyl-19-nor-17α -pregna-4,20 (Z) -diene-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7β-ethyl-19-nor-17α-pregna-4,20 (Z) -diene-3 on-21-carbaldehyde γ-lactol - 17β-hydroxy-7α-vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7β -vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7α-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7β-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carbaldehyde γ Lactol - 17β-hydroxy-6-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-6α-hydroxymethylene-19-nor -17α-pregna-4,20 (Z) -diene-3-an-21-carbaldehyde γ-lactol-17β-hydroxy-6β-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -diene 3-on-21-carbaldehyde γ-lactol-6,6- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21 -carbaldehyde γ-lactol-17β-hydroxy-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-19-nor-17α-pregna-4,62,0 ( Z) -trien-3-one-21-carbaldehyde γ-lactol - 16,16- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -diene-3 -on-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3 - (Hydroxyimino) -17β-hydroxy-7β-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β -hydroxy-7α-ethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol- (E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-ethyl 19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-vinyl-19-nor-17α pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-vinyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (Hydroxyimino) -17β-hydroxy-6-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β- hydroxy-6α-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-6β-hydroxymethylene 19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -17β- hydroxy-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-6α, 7α-methylene-19- nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-6β, 7β-methylene-19-nor -17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-19-nor-17α-pregna-4,6,20 (Z) -triene-21-carbaldehyde γ-lactol-E / Z) -3- (hydroxyimino) -16,16- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4, 20 (Z) -diene-21-carbaldehyde γ-lactol-17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol 17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (2) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7β, 18-dimethyl-19- nor-17α-pregna-4,20 (Z) -diene-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna-4,20 ( Z) -diene-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7β-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21 -carbaldehyde γ-lactol-17β-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy 7β-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7α-cyclopropyl-18-methyl-19- nor-17α-p regna-4,20 (Z) -diene-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-7β-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene 3-on-21-carbaldehyde γ-lactol - 17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carbaldehyde γ-lactol - 17β-Hydroxy-18-methyl-6-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-6α-hydroxymethylene-18- methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna 4,20 (Z) -diene-3-one-21-carbaldehyde γ-lactol-6,6- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4, 20 (Z) -diene-3-one-21-carbaldehyde γ-lactol-17β-hydroxy-18-methyl-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -diene-3 -on-21-carbaldehyde γ-lactol - 17β-hydroxy-18-methyl-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ- Lactol - 17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carbaldehyde γ-lactol-16,16- (1,2-ethanediol l) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (Hydroxyimino) -17β-hydroxy-7β, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3 - (Hydroxyimino) -17β-hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- ( Hydroxyimino) -17β-hydroxy-7β-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β -hydroxy-7β-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β-hydroxy 7α-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol- (E / Z) -3- (hydroxyimino) -17β-hydroxy-7β -cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol - (E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl -19-nor-17 -pregna-4,6,20 (Z) -triene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-6-methylene-19-nor-17α -pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-6α-hydroxymethylene-18-methyl-19-nor-17α-pregna -4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna-4 , 20 (Z) -diene-21-carbaldehyde, γ-lactol (E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor -17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-6α, 7α-methylene-19-nor -17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-6β, 7β-methylene-19-nor -17α-pregna-4,20 (Z) -diene-21-carbaldehyde γ-lactol-E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4, 6,20 (Z) -triene-21-carbaldehyde γ-lactol (E / Z) -3- (hydroxyimino) -16,16- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19- nor-17α-pregna-4,2 0 (Z) -diene-21-carbaldehyde γ-lactol-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-methyl-17α- 3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-methyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra -4-en-3-one - 7α-ethyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7β-ethyl-17α- (3ξ '-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-vinyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra- 4-en-3-one - 7β-vinyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 7α-cyclopropyl-17α- (3ξ '-methoxy-1'-propenyl)-17β-3'-oxidoestra-4-en-3-one - 7β-cyclopropyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4 -en-3-one - 6-methylene-7α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α-hydroxymethylene-7α- (3ξ'- methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6β-hydroxymethylene-7α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4 en-3-one - 6,6- (1,2-ethanediyl) -7α- (3ξ'-methoxy-1 '-propenyl) -17β-3'-oxidoestra-4-en-3-one - 6α, 7α-methylene-7α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene 3-one - 6β, 7β-methylene-7α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-en-3-one - 17α-3ξ'-methoxy-1'- Propenyl) -17β-3'-oxidoestra-4,6-dien-3-one - 16,16- (1,2-ethanediyl) -17α- (3ξ'-methoxy-1'-propenyl) -17β-3 ' -oxidoestra-4-en-3-one - (E / Z) -3- (hydroxyimino) -17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene (E / Z) -3- (hydroxyimino) -7α-methyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-methyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-ethyl-17α- (3ξ '-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-ethyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-vinyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4 -en - (E / Z) -3- (hydroxyimino) -7β-vinyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene (E / Z) -3- (Hydroxyimino) -7α-cyclopropyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -7β-cyclopropyl-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6-methylene-17α - (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene-17α- (3ξ'-methoxy-1 ' -propenyl) -17β-3'-oxidoestra-4-ene (E / Z) -3- (Hydroxyimino) -6β-hydroxymethylene-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (Hydroxyimino) -6,6- (1,2-ethanediyl) -17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- ( Hydroxyimino) -6α, 7α-methylene-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β- methylene-17α- (3ξ'-methoxy-1'-propenyl) -17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -17α- (3ξ'-methoxy-1'- propenyl) -17β-3'-oxidoestra-4,6-diene - (E / Z) -3- (hydroxyimino) -16,16- (1,2-ethanediyl) -17α- (3ξ'-methoxy-1 ' -propenyl) -17β-3'-oxidoestra-4-ene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 7α, 18-Dimethyl-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 7β, 18-dimethyl-17α- (3ξ'-methoxy 1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 7α-ethyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -18- methyl-17β-3'-oxidoestra-4-en-3-one - 7β-ethyl-18-methyl-17α- (3ξ'-methoxy-1'-prop enyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 7α-vinyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β- 3'-oxidoestra-4-en-3-one - 7β-vinyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-ene 3-one - 7α-Cyclopropyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 7β-cyclopropyl-18 -methyl-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 6-methylene-17α- (3ξ'-methoxy-1 ' -propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 6α-hydroxymethylene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3 ' oxidoestra-4-en-3-one - 6β-hydroxymethylene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 6,6 - (1,2-ethanediyl) -17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 6α, 7α-methylene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 6β, 7β-methylene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - 17α - (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4,6-dien-3-one - 16,16- (1,2-ethanediyl) -17α- (3ξ '-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-en-3-one - (E / Z) -3- (hydroxyimino) -18-methyl-17α- (3ξ'-methoxy-1'-propenyl)-18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α, 18-dimethyl-17α- (3ξ'-methoxy- 1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β, 18-dimethyl-17α- (3ξ'-methoxy-1'- propenyl) -18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-ethyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl ) -18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-ethyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-vinyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl) - 18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-vinyl-18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -18 -methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7α-cyclopropyl-18-methyl-17α- 3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -7β-cyclopropyl-18-methyl-17α- (3ξ '-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6-methylene-17α- (3ξ'-methoxy-1 '-propenyl) -18-ethyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α-hydroxymethylene-17α- (3ξ'-methoxy-1'-propenyl) - 18-methyl-17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β-hydroxymethylene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β 3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -17α- (3ξ'-methoxy-1'-propenyl) -18- methyl 17β-3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6α, 7α-methylene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β 3'-oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -6β, 7β-methylene-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3 ' -oxidoestra-4-ene - (E / Z) -3- (hydroxyimino) -18-methyl-17α- (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4, 6-diene - (E / Z) -3- (hydroxyimino) -16,16- (1,2-ethanediyl) -17 - (3ξ'-methoxy-1'-propenyl) -18-methyl-17β-3'-oxidoestra-4-ene. Steroid 17,17-lactol derivative according to any one of the preceding Claims for oral contraception and treatment of Pre-, per- and postmenopausal complaints Use of steroid 17,17-lactol derivatives according to any one of claims 1-20 for the manufacture of a medicament for oral contraception and treatment of pre-, per- and postmenopausal complaints. Use according to claim 21, characterized that the drug is gestagenic, antimineralcorticoide and neutral until slightly androgenic effect. Medicament containing at least one steroid 17,17-lactol derivative according to any one of claims 1-20 and at least a suitable pharmaceutically acceptable additive. The pharmaceutical composition of claim 23, further containing at least one estrogen. Medicament according to Claim 24, characterized that the estrogen is ethinylestradiol. Medicament according to Claim 24, characterized the estrogen is estradiol valerate. Medicament according to Claim 24, characterized that the estrogen is a natural estrogen. Medicament according to Claim 27, characterized that the natural estrogen is estradiol. Medicament according to Claim 27, characterized that the natural estrogen is a conjugated estrogen is.