EP2238151A1

EP2238151A1 - 17-hydroxy-19-nor-21-carboxylic acid-steroid -lactone derivative, use thereof, and medicament containing the derivative

Info

Publication number: EP2238151A1
Application number: EP08868806A
Authority: EP
Inventors: Ulrich Klar; Joachim Kuhnke; Rolf Bohlmann; Jan HÜBNER; Sven Ring; Thomas Frenzel; Frederik Menges; Steffen Borden; Hans Peter Muhn; Katja Prelle
Original assignee: Bayer Schering Pharma AG
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2007-12-29
Filing date: 2008-12-23
Publication date: 2010-10-13
Also published as: IL206379A0; DOP2010000198A; CN101910190A; PA8809701A1; JP5600068B2; CA2710491A1; UY31584A1; CO6300845A2; WO2009083266A1; AU2008342910A1; JP2011507924A; BRPI0821922A2; CA2710491C; US20110021472A1; TW200940073A; US8937058B2; ECSP10010318A; KR20100102688A; AR069966A1; DE102007063503A1

Abstract

The invention relates to 17-hydroxy-19-nor-21-carboxylic acid-steroid γ-lactone derivatives with the chemical formula (I) wherein R4, R6a, R6b, R7, R15, R16a, R16b, R18 and Z have the designations given in claim 1, and to the solvates, hydrates, stereoisomers and salts thereof. The invention also relates to the use of said derivatives for producing a medicament for oral contraception and for the treatment of premenopausal, perimenopausal and postmenopausal troubles, and medicaments containing said derivatives. The derivatives according to the invention have a gestagen effect, and in preferred cases, also an anti-mineral corticoid and neutral to lightly androgenous effect.

Description

17-Hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative, its use and the derivative-containing drug

Description:

The invention relates to certain 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivatives, their use and the derivatives containing drugs with Gestagener effect, for example, for the treatment of pre-, peri- and postmenopausal and of premenstrual Complaints.

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 3rd edition 1991 "Organic chemical nomenclature" p. 60 ff.).

Thus, WO 2006072467 A1 discloses the progestin compound 6β, 7β, 15β, 16β-dimethylene-3-oxo-17-pregn-4-ene-21,17β-carbolactone (drospirenone), which is obtained, for example, in an oral contraceptive as well as a preparation used to treat postmenopausal complaints. 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 anti-androgenic 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. In order to reduce the dose to be administered, WO 2006072467 A1 further proposes an 18-methyl-19-nor-17-pregn-4-ene-21,17-carbolactone and also pharmaceutical preparations containing it which have a higher gestagen content Have potency as drospirenone. In addition, for example, US Pat. No. 3,705,179 discloses steroids which have antiandrogenic activity and are useful in the treatment of androgen related diseases.

Further, U.S. Patent No. 2,918,463 discloses 17-carboxyalkylated 17-hydroxy-19-nor-butrostene-3-ones, inter alia, 17α- (2-carboxyvinyl) -17β-hydroxy-19-nor-androst-4- en-3-on lactone. The compounds described are intended to block the action of desoxycorticosterone acetate on the content of sodium and potassium in the urine and at the same time have a salt-binding effect in a higher concentration. In addition, these compounds should also be effective against hypertension.

The object of the present invention is to provide compounds which have a strong binding to the gestagen receptor. In addition, the compounds should preferably also have an antimineralcorticoid effect as well as a neutral to slightly androgenic effect with regard to the androgen receptor. Another essential aim of the present invention is also to achieve a balanced effect profile with regard to the progestational effect on the antimineralcorticoid effect in such a way that the ratio of proteic to antimineralocorticoid action is lower than in the case of drospirenone.

This object is achieved by the inventive 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivatives according to claim 1, the use of the derivatives according to the invention according to claim 17 and a medicament according to claim 19 comprising at least one derivative according to the invention. Advantageous embodiments of the invention are specified in the subclaims.

Accordingly, the invention relates to a 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative having the following chemical formula I:

wherein

Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'and NNHSO ₂ R', wherein R ^{1 is} hydrogen, d-to-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 ₆ -alkyl, C ₂ -C ₁₀ -alkenyl and 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 ₂ -C ₁₀ -alkynyl,

or: R ^6a , R ⁷ together form an oxygen atom or methylene or omitted to form a double bond between C ⁶ and C ^7, and

₁₀ -alkyl, C ₂ -C ₁₀ alkenyl and C ₂ -C selected> 6b from the group comprising hydrogen, dC ₁₀ alkynyl,

furthermore either:

R ^{15 is} hydrogen and _R ⁱ ea _R ^i6b j j _ewe | _{s are} independently selected from the group comprising hydrogen and Ci-Ci _O alkyl, or together form methylene or 1, 2-ethanediyl

or:

R ¹⁵ , R ^16a together form an oxygen atom or form a double bond between C ¹⁵ and C ¹⁶ and R ^{16b is} hydrogen or C ₁ -C ₁₀ -alkyl,

R ^{18 is} hydrogen or d-Ca-alkyl,

and their solvates, hydrates, stereoisomers and salts,

with the proviso that 17α- (2-carboxyvinyl) -17β-hydroxy-19-nor-androst-4-en-3-one y-lactone (17β-hydroxy-19-nor-17α-pregna-4,20 ( Z) -diene-3-one-21-carboxylic acid γ-lactone) is excluded.

The numbering of the C-skeleton of the derivative according to the invention with the general chemical formula I usually follows the numbering of a steroid skeleton, for example described in Fresenius, loc. Cit. The numbering of the radicals indicated in the claims corresponds in an analogous manner to their binding position on the C-skeleton of the derivative 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 and in R ¹⁹ , R ²⁰ , R ^21a , R ^21b and R ²² in the general chemical formulas given below are straight-chain or branched C 1-10 carbonyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. Alkyl in R ¹⁸ is in particular methyl, ethyl, propyl or isopropyl understand. The alkyl groups R ¹ , R ^6a , R ^6b , R ⁷ , R ^16a , R ^16b and R ¹⁸ can also be perfluorinated or by 1-5 halogen atoms, hydroxy groups, C ₁ -C ₄ alkoxy groups, C ₆ -C ₁₂ aryl groups (den 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, pentynyl, 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, dC ₃ alkoxy groups, C ₆ -C ₁₂ aryl groups (which in turn may be substituted by 1-3 halogen atoms).

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 may be substituted by halogen, OH O-alkyl, CO ₂ H, CO ₂ -alkyl, NH _2, NO _2, N _3, CN, C ₁ -C ₀ - alkyl, C ₁ -C _O -acyl, dC ₁₀ acyloxy groups substituted.

Aryl in R '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 are simple or more times by halogen, OH, O-alkyl, CO ₂ H, CO ₂ - alkyl, NH _2, NO _2, N _3, CN, d-do-alkyl, C ₁ -C ₀ -acyl, Ci-Cio-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 ⁷ is to be understood as meaning aralkyl groups which contain up to 14 carbon atoms, preferably 6 to 10 C atoms, in the ring and 1 to 8, preferably 1 to 8, in the alkyl chain 4, carbon atoms may contain. 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 -alkyl, CrCl ₂ -Acyloxy groups be substituted.

As far as alkoxy (O-alkyl) is mentioned as a substituent on alkyl, it concerns alkoxy groups with 1-4 carbon atoms, and, as far as Alkoxy is mentioned as substituent at alkenyl and Al kinyl, it concerns Alkoxygruppen with 1- 3 carbon atoms. Alkoxy may in particular be methoxy, ethoxy and propoxy.

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

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

Halogen is fluorine, chlorine or bromine.

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

According to a further preferred embodiment of the invention, Z is 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 , 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 , R ^16a account for forming a double bond between C ¹⁵ and C ^16, or R ¹⁵ , R ^16a together form an oxygen atom.

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 or 1,2-ethanediyl.

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

Preference is given to compounds having the chemical formula I in which

Z is oxygen, a group NOR ', wherein R ^{1 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 independently hydrogen, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -

Cβ alkynyl or together are methylene or 1, 2-ethanediyl form and R ⁷ is hydrogen, Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ - alkynyl .

or:

R ^6a, R ⁷ eliminated to form a double bond between C ⁶ and C ^7, or together form methylene, and R ^6b is selected from the group consisting of hydrogen, Ci-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 independently of one another are hydrogen or C ₁ -C ₆ -alkyl or together form methylene or 1,2-ethanediyl,

or:

R ^15, R ^16a omitted to form a double bond between C ¹⁵ and C ^16, and R ^16b is hydrogen or C _r C ₆ alkyl,

R ^{18 is} hydrogen, methyl or ethyl.

Particular preference is given to compounds of the formula I in which

Z is oxygen or a group NOR ', where R' is hydrogen or C ₁ -C ₃ -

Is alkyl, R ^{4 is} hydrogen, chlorine or bromine,

and either:

6a 6b

R, R independently of one another are 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 omitted to form a double bond between C ⁶ and C ⁷ or together form methylene and

R _r C ₃ alkyl or C ₂ -C ₄ alkenyl ^6b is hydrogen, C

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 omitted to form a double bond between C ¹⁵ and C ¹⁶ and R ^{16b is} hydrogen,

R ^{18 is} hydrogen or methyl.

Hereby expressly all possible stereoisomers and mixtures of isomers, including racemates, the compound having the general chemical formula I expressly included, wherein the position of the unsaturated γ-lactone ring in the derivative according to the invention may occur in two isomeric forms. Each of the abovementioned substituents on the steroid skeleton can be present both in an α and in a β position. In addition, the substituents on the steroid backbone that contain a double bond and in which the double bond on each carbon atom carries at least one non-hydrogen substituent may also be both E- and Z-configured. Groups bound to two adjacent carbon atoms of the skeleton, for example an oxygen atom, methylene or 1,2-ethanediyl, are bonded either in the α, α position or in the β, β position.

Also included are all crystal modifications of the compound with the general chemical formula I.

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 containing polar solvents, in particular of water, as structural element of the crystal lattice of the compounds according to the invention. The polar solvent, in particular Water, may be in a stoichiometric or 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.

If an acidic function is present, suitable salts are the physiologically tolerated salts of organic and inorganic bases, for example the readily soluble alkali metal and alkaline earth metal salts, and the salts of N-methylglucamine, D-methylglucamine, ethylglucamine , Lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxymethyl-aminomethane, aminopropanediol, Sovak's base, 1-amino-2,3,4-butanetriol. If a basic function is contained, the physiologically acceptable salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid and the like.

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. Furthermore, the compounds according to the invention have a neutral to mild androgenic effect with regard to the androgen receptor. Another property of the majority of the compounds is that the bonds 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 less than that of drospirenone , Thus, the antimineralcorticoi- de effect of these compounds is less given given Gestagener effect than 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 following compounds are particularly preferred according to the invention:

Because of their progestational efficacy, the novel compounds having the general chemical formula I can be used alone or in combination with estrogen in medicaments for contraception.

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

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

Particularly preferred is the use of the derivatives according to the invention for the preparation of a medicament with gestagenic, preferably also antiimineralcorticoider and neutral to mildly androgenic effect.

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

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

As administration routes, for example, an intravaginal or intrauterine administration may be considered. This can be achieved by physiologically acceptable solutions, e.g. an aqueous or oily solution with or without suitable solubilizers, dispersants or emulsifiers. Suitable oils include, for example, peanut oil, cottonseed oil, castor oil or sesame oil. The selection is by no means limited to this. For intravaginal or intrauterine administration, special systems such as an intravaginal system (eg, vaginal ring, VRS) or an intrauterine system (IUS) may be used, which may be an active substance of the present invention from a reservoir over an extended period of time (e.g. 1, 2, 3, 4 or 5 years).

® As an example of an intrauterine system, MIRENA is taken as a proxy.

This is a T-shaped, levonorgestrel-releasing intrauterine system of BAYER SCHERING PHARMA AG.

Furthermore, an application via an implanted depot system may consist of an inert carrier material, such as e.g. a biodegradable polymer or a synthetic silicone polymer. These depot systems release the drug in a controlled manner over an extended period of time (e.g., 3 months to 3 years) and are implanted subcutaneously.

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 above dosages refer to oral administration forms. When using a depot formulation, the equivalent dosage equivalent to the above-mentioned oral dosages is released continuously per day from the longer term depot systems described above. From a depot formulation, for example from an IUS, an amount of from 0.005 to 10 mg of a compound of general formula 1 is released daily.

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

Suitable estrogens are synthetic estrogens, preferably ethinylestradiol, but also mestranol, as well as natural estrogens, including phytoestrogens.

The estrogen is administered in a daily amount that corresponds to the pharmacological effect of 0.01 to 0.04 mg of ethinylestradiol. This amount refers to an oral administration form. If a different route of administration is chosen, a corresponding dosage amount equivalent to the above oral dosage should be used.

As estrogens in the drugs for the treatment of pre-, peri- and postmenopausal complaints as well as for hormone replacement therapy are primarily natural estrogens are used, especially the estradiol, but also the esters of estradiol, such as estradiol valerate, or conjugated estrogens (CEEs = Conjugated Equine Estrogens).

The gestagenic, antimineralcorticoid and androgenic or antiandrogenic activity of the compounds according to the invention was investigated by 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. Has a Affinity corresponding to the progesterone affinity corresponds to the competition factor (KF) of 1. KF values greater than 1 are characterized by a lower, KF values smaller 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 reproduced in Table 1, with receptor binding values also being given for drospirenone as reference substance A for comparison.

4. Determination of the gestagenic effect by means of transactivation tests:

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

Reporter cell lines (CHO K1 cells stably transfected with a fusion protein from the PR ligand binding domain and a Gal4 transactivation domain and a reporter construct containing the luciferase under the control of a Gal4-responsive promoter) were grown at a density of 4x10 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 too investigating compounds 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 introduced into a microplate luminometer (Pherastar, BMG labtech) and the luminescence was measured. The IC ₅₀ values were evaluated using dose-response relationship calculation software. Table 2 shows test results and corresponding results of drospirenone as reference substance A for comparison.

5. Determination of the Antimineralocorticoid Effect by 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: Reporter cell lines (MDCK cells) expressing the human mineralocorticoid receptor and transiently containing a reporter construct containing luciferase under the control of a steroid hormone responsive promoter.

For cultivation of the cells used for the assay, DMEM EARLE ^'S MEM (PAA, Cat .: E15-025) was provided as culture medium with 100 U 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: DE 14-801 F).

To determine antimineralocorticoid activity, 1 nM aldosterone (SIGMA A-6628, lot 22H4033) was added to the cells to achieve almost maximal stimulation of the reporter gene. Inhibition of the effect indicated a mineralcorticoid-antagonistic effect of the substances (Table 2, corresponding values for drospirenone (A) for comparison).

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

Modifications were made using reporter cell lines (PC3 cells) expressing the androgen receptor and a reporter construct containing luciferase under the control of a steroid hormone responsive promoter.

For cultivation of the cells used for the assay, RPMI medium without phenol red (PAA, # E15-49) provided with 100 U 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 determine the antiandrogenic activity, 0.05 nM R1881 was added to the cells in order to achieve almost maximum stimulation of the reporter gene. Inhibition of the effect indicated an androgen-antagonistic action of the substances (Table 2, corresponding values for drospirenone (A) for comparison).

Insofar as the preparation of the starting compounds is not described here, these are known to the person skilled in the art or can be prepared analogously to known compounds or processes described herein. The isomer mixtures can be separated into the individual compounds by customary methods, such as, for example, crystallization, chromatography or salt formation. The preparation of the salts is carried out in a customary manner by adding a solution of the compound of the general formula I with the appropriate amount or an excess of a base or acid, which may be in solution, optionally separating the precipitate or in usually the solution works up.

The compounds of general chemical formula I are prepared starting from compounds having the general chemical formula 1a (Scheme 2) or 1b (Scheme 3), according to the methods given in Scheme 1, wherein R ⁴ , R ^6a , R ^6b , R ⁷ , R ¹⁵ , R ¹⁸ and Z have the meanings given above, with the proviso that R ⁶ , R ⁷ in the compound of the general chemical formula 8b together form oxygen or methylene, and in which R ^16a , R ^16b in the compounds having the general chemical formulas 32a and

40a together form methylene, in the compounds having the general chemical formulas 32b and 40b together form 1, 2-ethanediyl and in the compounds having the general chemical formulas 32c and

40c are independently hydrogen, C ₁ -C are ₀ -alkyl, U is an oxygen atom, two alkoxy groups OR ¹⁹ or a C ₂ -C ₀ alkylene-dioxy α.ω, which may be straight or branched, wherein R ¹⁹ is a C 1 -C 4 -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 ²² ,

R ^21a , R ^21b independently of one another are hydrogen, C 1 -C ₄ -alkyl or together form a C ₄ -C ₁₀ -α, ω-alkylene group which may be straight-chain or branched, and

R ^{22 is} a C ₁ -C ₂₀ alkyl radical.

It is obvious to the person skilled in the art that in the descriptions of the synthetic transformations it is always assumed that any other functional groups present on the steroid skeleton are suitably protected.

The introduction of a 6,7-double bond to form compounds having the general chemical formula 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 for example 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 accomplished 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 ° C. 120 ⁰ 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 methyl 2,2-difluoro-2- (fluorosulfonyl) acetate in dimethylformamide in the presence of copper (I) iodide to give compounds in which R ^{4 has} the meaning Has 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 processes, 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, US Pat. 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 the α- and β-isomers, which can be separated for example by chromatography in the individual isomers.

Compounds of type 8b or 13 can be obtained as described in the examples or analogously to these instructions, using analogous to the reagents described there.

The synthesis of the spirocyclic compound 10 (R ^6a , R ^6b together form 1,2-ethanediyl) is based on the compounds 3 or 6, which initially in 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 to a leaving group, such as mesylate, tosylate or benzoate, compound 10 can be prepared by reaction with trimethylsulfoxonium iodide using bases such as alkali 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, for example, 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 purpose, for example, one can use Tetrahedron 21, 1619 (1965) described 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 by heating with a small amount of cyclohexene was pretreated, can be achieved. 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 ²² ) 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 form methylene) by hydrogenation. The best results (selective hydrogenation of the exo-methylene function) are achieved by transfer hydrogenation (J. Chem. Soc. 3578 (1954)). When the 6-methylene derivatives 10 are heated in a suitable solvent such as ethanol in the presence of a hydride donor such as 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 representation of 6ß-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 protecting group can be carried out by treatment under mild acidic conditions (acetic acid or 4N hydrochloric acid at 0 ⁰ C) to give 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 other 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 having the general chemical formula 5 under the action of copper salts. Preferred are divalent metals such as magnesium and zinc; as counterions, chlorine, bromine and iodine are preferred. Suitable copper salts are monovalent or divalent copper compounds, such as, for example, 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 3, 5, 6, 8a, 8b, 10, 11 or 12, in which Z is an oxygen atom, by reaction with hydroxylamine hydrochloride, alkyloxyamine hydrochlorides or sulfonylhydrazines in the presence of a tertiary amine at temperatures of -20 ⁰ C. to +40 ⁰ C are converted into their corresponding E / Z-configured oximes or sulfonylhydrazone (general chemical formula I with Z in the meaning of NOR ¹ , NNHSO ₂ R ¹ )). 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 described, for example, in WO-A 98/24801 for the preparation of corresponding 3-oxyimino derivatives of drospirenone.

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, for example, according to the procedure given in DE-A 28 05 490 by reductive cleavage of a thioketal of 3-keto compound on a suitable precursor, such as for example, compounds with one of the general chemical formulas 3, 5, 6, 8a, 8b, 10, 11 or 12, are removed.

The formation of spirolactones 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. Oxidation processes according to Jones, oxidation with potassium permanganate, for example in an aqueous system of tert-butanol and sodium dihydrogenphosphate, oxidation with sodium chlorite in aqueous tert-butanol, if appropriate in the presence of a chlorine scavenger, for example in the presence of 2-methyl-2-butene, or called by oxidation with manganese dioxide.

The compounds of general chemical formula 1a are prepared by the methods given in Scheme 2, wherein

R ¹⁵ and R ^{18 have} the abovementioned meanings and R ⁱ ea _R ^i6b _{jn 32a} together form methylene, in 32b together form 1, 2-ethanediyl and in 32c independently of one another hydrogen, C _r Ci ₀ alkyl and R ²⁰ Ci-Cao 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 .

The compounds of general chemical formula 1b are prepared according to the procedures given in Scheme 3, wherein R and R have the meanings given above, and

R 1 ^l 6 ^B A ^A, _D R 16b together form methylene 40a, 40b together in 1, 2-ethanediyl form and 40c are each independently 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 dC _Σ o-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 following examples serve to explain the invention in more detail, without limiting it to the examples given:

Example 1 (Dienone formation from dienol ether):

17β-hydroxy-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-lactone

The solution of 4.12 g of the compound described in Example 1a in 44.8 ml of N-methylpyrrolidone was treated at -10 ⁰ C with 448 mg of sodium acetate, 4.5 ml of water and in portions with a total of 1, 73 g Dibromhydantoin. After 30 minutes, 1.68 g of lithium bromide were added to 1.68 g of lithium carbonate, and the mixture was heated for 1 hour to a bath temperature of 100 ^° C. The mixture was poured onto a mixture of ice and sodium chloride solution and the precipitated product was suction filtered. 3.83 g of the title compound were isolated as crude product, which were directly reacted further or purified by recrystallization.

¹ H-NMR (CDCl ₃ ): δ = 1, 01-1, 17 (2H), 1, 12 (3H), 1, 33 (1H), 1, 46-1, 62 (3H), 1, 70 (1H), 1, 81 (1H), 1, 91-2.07 (2H), 2.22-2.41 (5H), 2.55 (1H), 5.80 (1H), 5 , 97 (1H), 6.17 (1H), 6.24 (1H), 7.42 (1H) ppm.

Example 1a (dienol ether formation): 17β-Hydroxy-3-methoxy-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

The solution of 6.02 g of the compound prepared according to Example 1 b was mixed in 68.7 ml of 2,2-dimethoxypropane with 695 mg of pyridinium p-toluenesulfonate and heated under reflux for 2 hours. The mixture 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 the product was dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by recrystallization. Isolated 4.12 g of the title compound.

Example 1 b (17-spirolactonization with manganese dioxide):

17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

The solution of 269 mg of the compound according to Example 1c in 21 ml of dichloromethane was admixed with 2.03 g of manganese dioxide and the mixture was stirred for about 5 hours at 23 ° C. It was then filtered through Celite and after concentration and chromatography, 211 mg of the title compound were isolated as a crystalline solid. 1 H-NMR (CDCl ₃ ): δ = 0.84 (1H), 0.97-1, 17 (2H), 1, 10 (3H), 1, 27 (1H), 1, 34-1, 67 (5H), 1, 78-1, 98 (4H), 2.11 (1H), 2.20-2.45 (5H), 2.50 (1H), 5.84 (1H) , 5.96 (1H), 7.43 (1H) ppm.

Example 1c (3-ketal cleavage):

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

To the solution of 367 mg of the compound shown in Example 1d in 30 ml of acetone was added 1.51 ml of 4N hydrochloric acid, and the mixture was stirred at 23 ^° C. for 30 minutes. It was then poured into saturated sodium bicarbonate solution, extracted several times with ethyl acetate, the combined organic extracts were washed with saturated sodium chloride solution, and the product was dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by chromatography. Isolated were 269 mg of the title compound.

Example 1d (Lindlar hydrogenation): 17α (Z) - (3'-hydroxypropen-1'-yl) -3,3-dimethoxy-17β-hydroxyestra-5 (10) -ene

The solution of 3.94 g of the compound according to Example 1e in 90 ml Tetrahy- drofuran was treated with 5.35 ml of pyridine, 560 mg of palladium on barium sulfate, and the mixture was hydrogenated in one atmosphere of hydrogen. The mixture was filtered through Celite, and after concentration and chromatography, 3.04 g of the title compound were isolated. Example 1e (hydroxypropyne addition):

17α- (3'-hydroxypropyne-1'-yl) -3,3-dimethoxy-17β-hydroxyestra-5 (10) -ene

The solution of 92.7 ml of 2-propyn-1-ol in 1, 4 I tetrahydrofuran was added at -60 ⁰ C with 1, 13 I of a 2.5 molar solution of butyllithium in hexane. After 30 minutes, the solution of 100 g of 3,3-dimethoxy-estra-5 (10) -en-17-one in 0.8 l of tetrahydrofuran was added dropwise, the mixture was warmed to 23 ° C and stirred for a further 16 hours. Then, the mixture was poured into water, extracted several times with ethyl acetate, and 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 crystallization. 72.9 g of the title compound were isolated.

Example 2 (1,6-addition):

17β-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β-methyl-19-nor -17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

To the cooled to -30 ⁰ C suspension of 4.6 mg of copper (I) chloride in 0.7 ml of tetrahydrofuran 193 ul of a 3 molar solution of methylmagnesium chloride in tetrahydrofuran were added dropwise, and it was stirred for 10 minutes , The solution was cooled to -25 ° C and added dropwise to 75 mg of the compound according to Example 1 in 2 ml of tetrahydrofuran. After 1 minute, was poured onto 1 N 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. 23.4 mg of the title compound A were isolated next to a still contaminated mixture containing portions of the title compound B.

¹ H-NMR (CDCl ₃ ) of A: δ = 0.85 (3H), 0.98-1, 38 (4H), 1, 15 (3H), 1, 45-2.46 (14H), 2 , 52 (1H), 5.89 (1H), 6.00 (1H), 7.50 (1H) ppm. Example 3:

17β-hydroxy-7α-ethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β-ethyl-19-nor -17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 2, 100 mg of the compound prepared according to Example 1 were reacted using ethylmagnesium chloride, and after working up and purification 19 mg of the title compound A were isolated in addition to a still contaminated mixture containing proportions of the title compound B. 1 H-NMR (CDCl ₃ ) of A: δ = 0.9 (3H), 0.94-1, 16 (3H), 1, 11 (3H), 1, 18-1, 37 (2H), 1, 44-1, 98 (9H), 2.06 (1H), 2.21-2.45 (5H), 2.58 (1H), 5.86 (1H), 5.96 (1H) , 7.45 (1H) ppm.

Example 4:

17β-hydroxy-7α-vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β-vinyl-19-nor -17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 2, 700 mg of the compound prepared according to Example 1 were reacted using vinylmagnesium chloride, and after working up and purification, 46 mg of the title compound A were isolated in addition to a still contaminated mixture containing proportions of the title compound B.

¹ H-NMR (CD ₂ Cl ₂ ) of A: δ = 1.03 (1H), 1, 13 (3H), 1, 16-1, 36 (2H), 1, 42-1, 66 (4H 1, 76 (1H), 1, 84-1, 99 (3H), 2.10-2.68 (8H), 5.14 (1H), 5.18 (1H), 5, 74-5.87 (2H), 5.94 (1H), 7.47 (1H) ppm.

Example 5:

16,16- (1,2-Ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

400 mg of the compound according to Example 5a were reacted in analogy to Example 1 b, and after work-up and purification, 358 mg of the title compound were isolated. ¹ H NMR (CDCl ₃ ): δ = 0.11 (1H), 0.44 (1H) ₁ 0.54 (1H), 0.89 (1H), 1.03 (1H), 1.06 1.17 (2H), 1, 23 (3H), 1, 31 (1H), 1, 46-1, 63 (4H), 1, 72-1, 89 (4H), 2.12 (1H ), 2.22 to 2.34 (3H) ₁ 2.41 (1 H), 2.50 (1 H), 5.84 (1 H), 5.88 (1 H), 7.40 (1 H) ppm.

Example 5a:

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

2.83 g of the compound prepared according to Example 5b were reacted analogously to Example 1c, and after working up and purification, 1.64 g of the title compound were isolated.

Example 5b:

3,3-Dimethoxy-16,16- (1,2-ethanediyl) -17α (Z) - (3'-hydroxypropen-1'-yl) -17β-hydroxyestra-5 (10) -ene

2.98 g of the compound according to Example 5c were reacted in analogy to Example 1d, and after work-up, 2.84 g of the title compound were isolated, which were reacted further without purification.

Example 5c:

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

100 mg of the compound prepared according to Example 5d were reacted analogously to Example 1e, and after working up and purification, 116 mg of the title compound were isolated, which were reacted further without purification.

Example 5d (16,16 cycloropanation from 16-methylene): 3,3-Dimethoxy-i6,16- (1,2-ethanediyl) -estra-5 (10) -en-17-one

A solution of 5.61 g Sulfoxoniumiodid in 100 ml of dimethyl sulfoxide was added in portions at 23 ° C with 1.05 g of a 60% suspension of sodium hydride in white oil. The mixture was stirred for 2 hours, the solution of 2.1 g of the compound according to Example 5e in 40 ml of dimethyl sulfoxide was then added dropwise, and the Solution was allowed to react for an additional 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 and dried over sodium sulfate. Isolated 2.52 g of the title compound, which still contained residual amounts of white oil and which was further reacted without additional purification.

Example 5e (16,16-methylene from silyl enol ether): 3,3-dimethoxy-16-methylene-estra-5 (10) -en-17-one

To 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'-tetramethyldiaminomethane, to 3 Cooled ° C and treated with 10 ml of acetic anhydride. The mixture was warmed to 23 ° C and allowed to react for 2 days. Then it was poured into saturated sodium bicarbonate solution, extracted several times with ethyl acetate, and the combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The product was purified by chromatography on silica gel; 1.6 g of the title compound were isolated.

Example 6: 17β-Hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

10 g of the compound according to Example 6a were reacted in analogy to Example 1 b, and after work-up and purification, 9.3 g of the title compound were isolated. 1 H-NMR (CDCl ₃ ): δ = 0.77-0.90 (2H), 0.99 (3H), 1.02-1.18 (2H), 1.40-1.71 (6H), 1, 74-1, 99 (5H), 2.11 (1H), 2.20-2.44 (5H), 2.51 (1H), 5.84 (1H), 5.96 ( 1H), 7.44 (1H) ppm.

Example 6a:

17α (Z) - (3'-hydroxypropen-1'-yl) -18-methyl-17β-hydroxyestra-4-en-3-one

6.35 g of the compound prepared according to Example 6b were reacted analogously to Example 1c, and after work-up and purification, 3.02 g of the title compound were isolated. Example 6b:

17α (Z) - (3'-hydroxypropen-1'-yl) -3-methoxy-18-methyl-17β-hydroxyestra-2,5 (10) -diene

7.86 g of the compound according to Example 6c were reacted in analogy to Example 1d, and after work-up, 6.35 g of the title compound were isolated, which was further reacted without purification.

Example 6c:

17α (Z) - (3'-Hydroxypropyn-1'-yl) -3-methoxy-18-methyl-17β-hydroxyestra-2,5 (10) -diene

5.0 g of 3-methoxy-18-methyl-17β-hydroxyestra-2,5 (10) -dien-17-one were reacted in analogy to Example 1e, and after work-up, 7.86 g of the title compound were isolated Cleaning was further implemented.

Example 7:

17β-Hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-lactone

9.0 g of the compound according to Example 7a were reacted in analogy to Example 1, and after work-up and purification, 5.04 g of the title compound were isolated. ¹ H-NMR (CDCl ₃ ): δ = 0.93 (1H), 1, 6 (3H), 1, 16 (2H), 1, 50-1, 92 (7H) ₁ 1, 96-2, 10 (2H), 2.25-2.49 (5H), 2.59 (1H), 5.84 (1H) ₁ 6.03 (1H) ₁ 6.23 (1H), 6.29 (1H), 7.47 (1H) ppm.

Example 7a:

17β-Hydroxy-3-methoxy-18-methyl-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

10.0 g of the compound prepared according to Example 1 b were reacted in analogy to Example 1a, and after work-up, 10.9 g of the title compound were isolated, which was reacted further without purification.

Example 8:

17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β, 18-dimethyl 19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone (B) In analogy to Example 2, 200 mg of the compound prepared according to Example 7 were reacted using methylmagnesium chloride, and after working up and purification, 115 mg of the title compound A were isolated in addition to a still contaminated mixture containing proportions of the title compound B.

¹ H-NMR (CDCl ₃ ) of A: δ = 0.82 (4H), 1.00 (3H), 1.02-1.13 (2H), 1.49-1.61 (3H), 1 , 67 (2H), 1.71-1.81 (3H) ₁ 1.86 (1H), 1.95 (1H), 1.99-2.09 (2H), 2.22 to 2.45 ( 5H), 2.51 (1H), 5.85 (1H), 5.96 (1H), 7.45 (1H) ppm.

Example 9:

17β-Hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β-ethyl -18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 2, 200 mg of the compound prepared according to Example 7 were reacted using ethylmagnesium chloride, and after working up and purification, 91 mg of the title compound A were isolated in addition to a still contaminated mixture containing proportions of the title compound B. 1 H-NMR (CDCl ₃ ) of A: δ = 0.81 (1H), 0.90 (3H), 1.00 (3H), 1.02-1.11 (3H), 1.33 (1H) , 1.47-1.89 (10H), 1.94 (1H), 2.06 (1H), 2.22-2.44 (5H), 2.59 (1H), 5.85 (1H) , 5.96 (1H), 7.45 (1H) ppm.

Example 10:

17β-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β-vinyl -18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 2, 200 mg of the compound prepared according to Example 7 were reacted using vinylmagnesium chloride, and after working up and purification, 74 mg of the title compound A were isolated in addition to a still contaminated mixture containing proportions of the title compound B.

¹ H-NMR (CDCl ₃ ) of A: δ = 0.80 (1H), 1.00 (3H), 1.05 (1H), 1.15 (1H), 1.44-1.60 (4H ) ₁ 1.66 (2H) ₁ 1.73 to 1.95 (5H) ₁ 2.24 to 2.36 (3H), 2.41-2.48 (2H), 2.52-2.60 ( 2H), 5.11 (1H), 5.13 (1H) ₁ 5.74 (1H), 5.86 (1H), 5.95 (1H), 7.42 (1H) ppm. Example 11:

17β-Hydroxy-7α-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β-cyclopropyl -18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 2, 200 mg of the compound prepared according to Example 7 were reacted using cyclopropylmagnesium bromide, and after working up and purification 38 mg of the title compound A were isolated next to a still contaminated mixture containing proportions of the title compound B.

¹ H-NMR (CDCl ₃ ) of A: δ = -0.03 (1H), 0.31 (1H), 0.42-0.59 (3H), 0.85 (1H), 0 , 99 (3H), 1, 04 (1H), 1, 13 (1H), 1, 33 (1H), 1, 49-1, 68 (4H), 1, 74-2.00 (6H) , 2.11 (1H), 2.22-2.46 (5H), 2.51 (1H), 5.89 (1H), 5.97 (1H) 7.47 (1H) ppm ,

Example 12:

17β-Hydroxy-7α-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-7β-cyclopropyl-19-nor -17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 2, 300 mg of the compound prepared according to Example 1 were reacted using cyclopropylmagnesium chloride, and after working up and purification, 89 mg of the title compound A were isolated in addition to a still contaminated mixture containing portions of the title compound B. 1 H-NMR (CDCl ₃ ) of A: δ = -0.02 (1H), 0.31 (1H), 0.47 (1H), 0.5-0.57 (2H), 1, 04 (1H), 1, 10 (3H), 1, 13 (1H), 1, 24-1, 36 (2H), 1, 47-1, 59 (3H), 1, 74 (1H), 1, 80-1, 97 (4H), 2.11 (1H), 2.25-2.33 (3H) ₁ 2.38-2.45 (2H), 2.51 (1H), 5, 89 (1H), 5.97 (1H), 7.47 (1H) ppm.

Example 13 (4-chlorination):

4-Chloro-17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

The solution of 50 mg of the compound described in Example 6 in 0.5 ml of pyridine was added at 3 ° C with 20 ul of sufuryl chloride and stirred for 1, 5 hours at 3 ° C. The solution was poured into saturated sodium bicarbonate solution, several 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 chromatography. Isolated 14 mg of the title compound. 1 H-NMR (CDCl ₃ ): δ = 0.81-0.96 (2H), 0.99 (3H), 1, 02-1, 20 (2H), 1, 44 (1H), 1, 52 -1, 72 (5H), 1, 76-1, 86 (3H), 1, 91-2.00 (2H), 2.12 (1H), 2.21-2.45 (4H), 2 , 64 (1H), 3.38 (1H), 5.97 (1H), 7.43 (1H) ppm.

Example 14: 4-Chloro-17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

In analogy to Example 13, 100 mg of the compound according to Example 1 b were reacted, and after work-up and purification, 77.8 mg of the title compound were isolated. 1 H-NMR (CDCl ₃ ): δ = 0.84-1, 67 (10H), 1, 10 (3H), 1, 78-2.01 (4H), 2.11 (1H), 2.20 -2,47 (4H), 2,63 (1H), 5,96 (1H), 7,43 (1H) ppm.

Example 15 (6-hydroxymethyl introduction):

17β-Hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

The solution of 427 mg of the compound according to Example 15a in a mixture of 4 ml of toluene and 9 ml of ethanol was treated with 427 ul of a 37% aqueous formaldehyde solution and stirred for 6 hours at 23 ° C. The solution was concentrated and the residue was purified by chromatography. 23.4 mg of the title compound were isolated.

¹ H-NMR (CDCl ₃ ): δ = 0.78-0.91 (2H), 0.99 (3H), 1, 05 (1H), 1, 30-1, 85 (12H), 1, 90-1, 99 (2H) ₁ 2.17 to 2.48 (5H) ₁ 2.67 (1 H), 3.71 (2H), 5.93 (1 H), 5.96 (1H), 7.44 (1H) ppm. Example 15a (dienamine formation):

17β-Hydroxy-3-pyrrolidinyl-18-methyl-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

The solution of 500 mg of the compound prepared according to Example 1 b in 5 ml of methanol was mixed with 280 ul of pyrrolidine and heated under reflux for 2 hours. The mixture was cooled, the precipitate was filtered off with suction, rinsed with a little cold methanol, and 434 mg of the title compound were obtained, which were reacted further without additional purification.

Example 16 (6-spirocyclopropanation):

6,6- (1,2-Ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

235 mg of trimethylsulfoxonium iodide were dissolved in 1.7 ml of dimethyl sulfoxide, 43 mg of a 60% sodium hydride dispersion were added and the mixture was stirred for 2 hours at 23 ° C. Subsequently, the solution of 140 mg of the compound represented by Example 16a in... (?) Ml of dimethyl sulfoxide was added dropwise and the mixture was stirred for a further 2 hours at 23 ° C. The mixture was poured into water, extracted several times with ethyl acetate, the combined organic extracts were washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by chromatography. 38.2 mg of the title compound were isolated. 1 H-NMR (CDCl ₃ ): δ = 0.41 (1H), 0.56 (1H), 0.70 (1H) ₁ 0.82-1, 18 (4H), 1, 01 (3H ), 1, 26 (1H), 1, 38-1, 99 (11H), 2.13-2.47 (5H), 5.69 (1H), 5.96 (1H), 7 , 43 (1H) ppm.

Example 16a (6-tosyloxymethyl formation):

17β-Hydroxy-6β- (p-tolylsulfonyloxymethyl) -18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone

The solution of 400 mg of the compound prepared according to Example 15 in 15 ml of dichloromethane was admixed with 1.5 ml of triethylamine, 514 mg of p-toluenesulfonyl chloride and stirred at 23 ° C. for 15 hours. The mixture was poured into saturated sodium carbonate solution, extracted several times with ethyl acetate, and the combined organic extracts were extracted. washed with water and saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of the solvent was purified by chromatography. 145 mg of the title compound were isolated.

Example 17:

17β-hydroxy-6β-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

In analogy to Example 15, 517 mg of the compound shown in Example 17a were reacted düng, and after work-up and purification, 156 mg of the title compound were isolated.

¹ H-NMR (CDCl ₃ ): δ = 0.84 (1H), 0.97-1, 12 (2H), 1, 09 (3H), 1, 20-2.36 (15H), 2, 44 (1H), 2.66 (1H), 3.70 (2H), 5.93 (1H), 5.96 (1H), 7.43 (1H) ppm.

Example 17a:

17β-Hydroxy-3-pyrrolidinyl-19-nor-17α-pregna-3,5,20 (Z) -triene-21-carboxylic acid γ-lactone

In analogy to Example 15a, 840 mg of the compound prepared according to Example 1b were reacted, and after work-up and purification, 524 mg of the title compound were isolated.

Example 18:

6,6- (1,2-Ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-

lactone

In analogy to Example 16, 80 mg of the compound prepared according to Example 18a were reacted, and after work-up and purification 26 mg of the title compound were isolated. 1 H-NMR (CDCl ₃ ): δ = 0.42 (1H), 0.55 (1H) ₁ 0.70 (1H), 0.86-1, 10 (3H), 1, 12 (3H ) ₁ 1, 21-1, 97 (11H), 2.15-2.46 (5H), 5.69 (1H), 5.96 (1H), 7.43 (1H) ppm. 17β-Hydroxy-6β- (p-tolylsulfonyloxymethyl) -19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

In analogy to Example 16a, 540 mg of the compound prepared according to Example 17 were reacted, and after work-up and purification 80 mg of the title compound were isolated.

Example 19 (Corey Cyclopropanation): 17β-Hydroxy-18-methyl-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone ( A) and 17β-hydroxy-18-methyl-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 16, 1.5 g of the compound prepared according to Example 7 were reacted, and after work-up and purification, 188 mg of the title compound A and 430 mg of the title compound B were isolated.

¹ H-NMR (CDCl ₃ ) of A: δ = 0.58 (1H), 0.82-1, 07 (3H), 1, 02 (3H), 1, 24-1, 38 (2H), 1, 43-2, 09

(12H), 2.16-2.52 (4H), ₁ 6.02 (1H), 6.16 (1H), 7.50 (1H) ppm.

¹ H NMR (CDCl ₃ ) of B: δ = 0.71-1, 09 (5H), 1, 03 (3H), 1, 37-1, 53 (2H), 1, 56-2.46 ( 14H), 2.55 (1H), 6.01 (1H), 6.08 (1H), 7.52 (1H) ppm.

Example 20:

17β-Hydroxy-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone (A) and 17β-hydroxy-6α, 7α-methylene 19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone (B)

In analogy to Example 16, 1.28 g of the compound shown in Example 1 were reacted, and after work-up and purification, 66 mg of the title compound A and 112 mg of the title compound B were isolated. 1 H-NMR (CDCl ₃ ) of A: δ = 0.58 (1H), 0.89-1, 58 (9H), 1, 12 (3H), 1, 68-2.11 (6H), 2 , 22 (1H), 2.29-2.52 (3H), 6.02 (1H), 6.15 (1H), 7.50 (1H) ppm. ¹ H-NMR (CDCl ₃ ) of B: δ = 0.73 (1H), 0.81 (1H), 0.96 (1H), 1, 06 (1H), 1, 17 (3H), 1, 19 (1H), 1, 37-2.12 (11H), 2.19 (1H), 2.27-2.42 (2H), 2.55 (1H), 6.01 (1 H), 6.08 (1H), 7.51 (1H) ppm

Example 21

Inert, intrauterine implantable depot systems of a biodegradable polymer or a synthetic silicone polymer, consisting of a drug-containing core in appropriate polymer-drug mixing ratio, surrounded by a desired daily release rate ensuring polymer membrane are spent in the uterine lumen of rats. The female animals are castrated beforehand and pretreated with estradiol for three days. Implants of varying length (5-20 mm) and a limited diameter (1.1 to 2 mm) remain in the rat uterus for 4 to 14 days to reduce the local and systemic gestagenic effects of the released drug by different parameters in different tissues - search. The following parameters are determined: 1) gestagen local effect on uterus based on uterine weight, histologically detectable epithelial height, and expression of progestogen-regulated marker genes (e.g., IGFBP-1); 2) gestagenic systemic effect on mamma by expression of gestagen-regulated marker genes (e.g., Rank L), 3) gestagenic pituitary systemic action by LH level (lowering of estrogen-induced elevated LH level).

The compounds of the present invention show a significant gestagenic effect in the uterus which is comparable to a corresponding treatment with a levonorin.

® gestrel containing depot system such as MIRENA is.

Claims

claims:

1. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative having the following chemical formula I:

wherein

Z is selected from the group comprising oxygen, two hydrogen atoms, NOR 'and 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 6 ^b a ^a, o R6 'b Ci-C are each independently selected from the group comprising hydrogen, _C10 alkyl, C ₂ -C ₁₀ alkenyl and C ₂ -C ₁₀ alkynyl, or together form methylene or 1 To form 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 ₂ -C ₁₀ -alkynyl,

or:

R ^6a , R ⁷ together form an oxygen atom or 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 ₀ -alkyl,

C ₂ -C ₁₀ alkenyl and C ₂ -C ₀ alkynyl;

further, either: R ^{15 is} hydrogen and

_R ^iβa _R ^i6b j _ewe j | _s are independently selected from the group comprising hydrogen form and CRCI _O alkyl, or together form methylene or 1, 2-ethanediyl

or:

R ^15, R ^16a together form an oxygen atom or eliminated to form a double bond between C ¹⁵ and C ^16, and R ^16b is hydrogen or C _r C ₁₀ alkyl,

R ^{18 is} hydrogen or C _r C ₃ -alkyl,

and their solvates, hydrates, stereoisomers and salts,

with the proviso that 17α- (2-carboxyvinyl) -17β-hydroxy-19-nor-androst-4-en-3-one γ-lactone is excluded.

2. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to claim 1, characterized in that Z is selected from the group comprising oxygen, NOR 'and NNHSO ₂ R'.

3. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to claim 1, characterized in that Z is oxygen.

4. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of the preceding claims, characterized in that R ^{4 is} hydrogen or chlorine.

5. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of the preceding claims, characterized in that R ^6a , R ^6b together form 1, 2-ethanediyl or are each hydrogen.

6. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone 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.

7. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to one of claims 1 - 4, characterized in that R ^6a , R ⁷ together form methylene.

8. 17-hydroxy-19-nor-21-carboxylic acid γ-lactone steroid derivative to any 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

9. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of the preceding claims, characterized in that R ^{15 is} hydrogen.

10. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1-8, characterized in that R ¹⁵ , R ^16a to form a double bond between C ¹⁵ and C ¹⁶ omitted or together form an oxygen atom.

11. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1-9, characterized in that R ^{16a is} hydrogen and R ^{16b is} methyl.

12. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1-9, characterized in that R ^16a and R ^{16b are} hydrogen.

13. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1-9, characterized in that R ^16a and R ^16b together form methylene or 1, 2-ethanediyl.

14. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of the preceding claims, characterized in that R ^{18 is} hydrogen or methyl.

15. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of the preceding claims, selected from the group comprising

17β-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-

Lactone 17β-hydroxy-7β-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-

lactone

17β-hydroxy-7α-ethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-

lactone

17β-Hydroxy-7β-ethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-hydroxy-7α-vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-

lactone

17β-Hydroxy-7β-vinyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-

Lactone 17β-hydroxy-7α-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-7β-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-6-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-6α-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-6β-hydroxymethylene-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone 6,6- (1,2-ethanediyl) -ββ-hydroxy 19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-hydroxy-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone

17β-hydroxy-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

16,16- (1,2-Ethanediyl) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone (E / Z) -3- (hydroxyimino) -17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-7α-methyl-19-nor-17α-pregna-4,20 (Z) -diene

21 -carboxylic acid γ-lactone (E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-methyl-19-nor-17α-pregna-4,20 (Z) -diene

21 -carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-7α-ethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-ethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-7α-vinyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-7β-vinyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone (E / Z) -3 - (Hydroxyimino) -17β-hydroxy-7α-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-7β-cyclopropyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-6-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-6α-hydroxymethylene-19-nor-17α-pregna

4, 20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-6ß-hydroxymethylene-19-nor-17α-pregna

4,20 (Z) -diene-21-carboxylic acid γ-lactone (E / Z) -3- (hydroxyimino) -6,6- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna -

4, 20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17β-hydroxy-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-19-nor-17α-pregna-4,6 _l 20 (Z) -triene-21-carboxylic acid γ-lactone (E / Z) -3- (hydroxyimino) -16,16- (1,2-ethanediyl) -17β-hydroxy-19-nor-17α-pregna

4, 20 (Z) -diene-21-carboxylic acid γ-lactone

17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-

Lactone 17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-7β, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-7β-ethyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone 17β-hydroxy-7β-vinyl-18-methyl -19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-7α-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-7β-cyclopropyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -trien-3-one-21-carboxylic acid γ-

lactone

17β-hydroxy-18-methyl-6-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone 17β-hydroxy-6α-hydroxymethylene-18-methyl 19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone

17β-Hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone

17β-hydroxy-18-methyl-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone 17β-Hydroxy-18-methyl-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

Lactone 16,16- (1,2-Ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-3-one-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene

21 -carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17β-hydroxy-7α, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-7β, 18-dimethyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-7α-ethyl-18-methyl-19-nor-17α-pregna

4, 20 (Z) -diene-21-carboxylic acid γ-lactone (E / Z) -3- (hydroxyimino) -17β-hydroxy-7β-ethyl-18-methyl-19-nor-17α-pregna

4, 20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-7α-vinyl-18-methyl-19-nor-17α-pregna

4, 20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-7β-vinyl-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-7α-cyclopropyl-18-methyl-19-nor-17α-pregna

4, 20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-7.beta.-cyclopropyl-18-methyl-19-nor-17α-pregna

4,20 (Z) -diene-21-carboxylic acid γ-lactone (E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z ) -triene

21 -carboxylic acid γ-lactone

(E / Z) -3- (hydroxyimino) -17ß-hydroxy-18-methyl-6-methylene-19-nor-17α-pregna

4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-6α-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-6β-hydroxymethylene-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone (E / Z) -3- (Hydroxyimino) -6,6- (1, 2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -diene-21 -carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17β-hydroxy-18-methyl-6α, 7α-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone ( E / Z) -3- (hydroxyimino) -17β-hydroxy-18-methyl-6β, 7β-methylene-19-nor-17α-pregna-4,20 (Z) -diene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -17γ-hydroxy-18-methyl-19-nor-17α-pregna-4,6,20 (Z) -triene-21-carboxylic acid γ-lactone

(E / Z) -3- (Hydroxyimino) -16,16- (1,2-ethanediyl) -17β-hydroxy-18-methyl-19-nor-17D-pregna-4,20 (Z) -diene-21 -carboxylic acid γ-lactone

4-chloro-7β-hydroxy-18-methyl-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone

4-Chloro-17β-hydroxy-19-nor-17α-pregna-4,20 (Z) -dien-3-one-21-carboxylic acid γ-lactone.

16. 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of the preceding claims for oral contraception and for the treatment of pre-, peri- and postmenopausal complaints.

17. Use of the 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1-16 for the manufacture of a medicament for oral contraception and for the treatment of pre-, peri- and postmenopausal complaints.

18. Use according to claim 17, characterized in that the drug has gestagene, antimineralcorticoide and neutral to mild androgenic effect.

19. A pharmaceutical composition containing at least one 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1-16 and at least one suitable pharmaceutically acceptable carrier.

20. Medicament according to claim 19, further comprising at least one estrogen.

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

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

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

24. Medicament according to claim 23, characterized in that the natural estrogen is estradiol.

25. Medicament according to claim 23, characterized in that the natural estrogen is a conjugated estrogen.

26. Use of the 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1 to 14 for the manufacture of a medicament for intrauterine use.

27. Use according to claim 26 for the preparation of an intrauterine system (IUS).

28. A pharmaceutical composition comprising at least one 17-hydroxy-19-nor-21-carboxylic acid steroid γ-lactone derivative according to any one of claims 1 to 14 and at least one suitable pharmaceutically acceptable carrier, characterized in that it is prepared for intrauterine use ,

29. Medicament according to claim 28, characterized in that it is an intrauterine system.