DE102011004899A1 - New 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl-derivatives are progesterone receptor antagonists useful to treat and prevent e.g. uterine fibroids, endometriosis, heavy menstrual bleeding and meningioma - Google Patents

Abstract

17-Hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl-derivatives (I) and their salts, solvates, solvate of the salts or subsequently all crystal modifications are new. 17-Hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl-derivatives of formula (I) and their salts, solvates, solvate of the salts or subsequently all crystal modifications are new. Either R 1>, R 2>6-10 membered aryl, 5-10-membered heteroaryl, 1-6C-arylalkyl or 1-6C-heteroarylalkyl (all optionally mono-, di-or poly-substituted by halo (F, Cl, Br, I), -OH, -O-alkyl, -C(O)OH, -C(O)Oalkyl, -C(O)NH 2, -C(O)NHalkyl, -C(O)Ndialkyl, -C(O)NHaryl, -C(O)NHheteroaryl, -NH 2, -NH(1-10C-alkyl), -N(1-10C-alkyl) 2(preferably -N(CH 3) 2), -NHC(O)alkyl, -NO 2, -N 3, -CN, -1-10C-alkyl, 1-10C-perfluoro-alkyl, -1-10C-acyl, 1-10C-acyloxy, -SO 2NH 2or -SO 2NHalkyl of -SO 2Ndialkyl), H or optionally dimethylamine-substituted 1-10C-alkyl; or R 1>R 2>3-10 membered ring (optionally substituted on carbon by alkyl, carboxyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylalkyl, heteroarylalkyl or aminoalkyl, or optionally substituted on N by alkyl, alkanoyl, carboxyl, alkoxycarbonyl, phenyl, phenylalkyl, pyridinyl, pyrimidinyl, pyrazinyl, sulfonyl, benzoyl, alkylsulfonyl, arylsulfonyl, aminocarbonyl, aminocarbonylalkyl, arylalkyl, heterocycloalkyl, heteroarylalkyl or aminoalkyl, where the ring optionally contains N, O or S, optionally oxidized to sulfoxide or sulfone, and an aryl group is optionally fused on the 3-10-membered ring); either R 3>, R 4>H; or R 3>R 4>a methyl bridge; X : O, NOR 5>or NHSO 2R 5>; and R 5>H, 1-10C-alkyl or aryl. An independent claim is included for a medicament comprising (I) optionally in combination with further active agents. [Image] ACTIVITY : Gynecological; Cytostatic; Contraceptive. MECHANISM OF ACTION : Progesterone receptor antagonist. The progesterone receptor A antagonistic activity of (I) was tested using SK-N-MC cells. The results showed that tert-butyl-4-{4-[(11beta ,17beta )-17-hydroxy-3-oxo-17-(pentafluoroethyl)estr-4-en-11-yl]benzyl}piperazin-1-carboxylate exhibited an IC 50value of 0.014 nM.

Description

The invention relates to 17-hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-aryl derivatives of the formula I having progesterone antagonizing action and a process for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular uterine fibroids (fibroids, uterine leiomyomas), endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancers and menopausal complaints or for fertility control and emergency contraception.

These compounds are valuable pharmaceutical agents. They may be used, inter alia, for the preparation of pharmaceutical preparations for the treatment of uterine fibroids or endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancers and disorders associated with menopause or for fertility control and emergency contraception. For the treatment of uterine fibroids and endometriosis, the inventive. Compounds can also be administered sequentially in combination with progestins. In such a regimen, the compounds of the present invention could be given over a period of 1-6 months, followed by a treatment break or a sequential treatment with a progestogen over a period of 2-6 weeks or followed by treatment with an oral contraceptive (OC). Combinations) over the same period.

The efficacy of the compounds of the invention as a progesterone receptor antagonist has been demonstrated in vitro in transactivation assays.

Compounds with antagonistic action on the progesterone receptor (competitive progesterone receptor antagonists) are first known in 1982 ( RU 486 ; EP 57115 ) and since then numerous have been described. Progesterone receptor antagonists with fluorinated 17α-side chain have been identified in WO 98/34947 and Fuhrmann et al., J. Med. Chem. 43, 5010-5016 (2000) released.

As a 4-substituent on the 11β-phenyl ring, the dimethylamino functionality has been chosen in various clinical and preclinical progesterone receptor antagonists (eg mifepristone, onapristone, ulipristal, proellex). Advantages of the basic nitrogen atom include, for example, increased solubility, especially in acidic aqueous medium. As has been described several times, compounds with an aromatic NH ₂ group are liberated by metabolic degradation of one or both methyl groups on the nitrogen atom. These aniline metabolites can have potential side effects. Onapristone is a progesterone receptor antagonist with a dimethylamino functionality that has been in clinical trials. In some patients, abnormalities were observed in liver function tests, which eventually led to the cessation of clinical trials. Increased transaminase activities have also been described for mifepristone, the only progesterone receptor antagonist on the market which also carries a dimethylamino group at the 4-position of the 11β-phenyl radical. For both compounds, onapristone and mifepristone, compounds with partial or complete demethylation as major metabolites were found. It has recently been published that treatment with Proellex in higher doses also leads to an induction of liver enzymes.

The object of the present invention is to provide highly potent competitive progesterone receptor antagonists which have the advantages of a basic nitrogen atom in the 4-position of the 11β-phenyl radical but can not form free anilines as metabolites and thus provide alternative treatment options for gynecological diseases.

This problem has been solved by introducing a methylene group between the amino group and the 11β-phenyl radical. The compounds of the general claim 1 are therefore particularly suitable for achieving this object. While some of the compounds mentioned in claim 1 show a slightly reduced antagonistic potency at the progesterone receptor compared to the analogous anilines, it has surprisingly been found that the incorporation of carbonyl functions or sulfonyl functions at a certain distance from the 11β position of the steroid skeleton results in a marked increase in the antagonist Potency leads.

worin
R¹ und R²
gleich oder verschieden sind und für
Wasserstoff,
einen gegebenenfalls Dimethylamin-substituierten C₁-C₁₀-Alkylrest,
einen gegebenenfalls ein-, zwei- oder mehrfach mit Halogen (-F, -Cl, -Br, -I), -OH, -O-Alkyl, -C(O)OH, -C(O)OAlkyl, -C(O)NH₂, -C(O)NHAlkyl, -C(O)NDialkyl, -C(O)NHAryl, -C(O)NHHeteroaryl, -NH₂, -NH(C₁-C₁₀-Alkyl), -N(C₁-C₁₀-Alkyl)₂, insbesondere -N(CH₃)₂, -NHC(O)Alkyl, -NO₂, -N₃, -CN, -C₁-C₁₀-Alkyl, -C₁-C₁₀-Perfluor-Alkyl, -C₁-C₁₀-Acyl, -C₁-C₁₀-Acyloxy, -SO₂NH₂, -SO₂NHAlkyl oder -SO₂NDialkyl substituierten 6-10-gliedrigen Arylrest,
einen gegebenenfalls ein-, zwei- oder mehrfach mit den oben genannten Substituenten des 6-10-gliedrigen Arylrests substituierten 5-10-gliedrigen Heteroarylrest,
einen am Arylring gegebenenfalls ein-, zwei- oder mehrfach mit den oben genannten Substituenten des 6-10-gliedrigen Arylrests substituierten C₁-C₆-Arylalkylrest oder
einen am Heteroarylring gegebenenfalls ein-, zwei- oder mehrfach mit den oben genannten Substituenten des 6-10-gliedrigen Arylrests substituierten C₁-C₆-Heteroarylalkylrest stehen
oder aber
R¹ und R²
gemeinsam Bestandteil eines gegebenenfalls am Kohlenstoff Alkyl-, Carboxyl-, Alkoxycarbonyl-, Alkylcarbonyl-, Aminocarbonyl-, Arylalkyl-, Heteroarylalkyl-, Aminoalkyl-substituierten bzw. am Stickstoff Alkyl-, Alkanoyl-, Carboxyl-, Alkoxycarbonyl-, Phenyl-, Phenylalkyl-, Pyridinyl-, Pyrimidinyl-, Pyrazinyl-, Sulfonyl-, Benzoyl-, Alkylsulfonyl-, Arylsulfonyl-, Aminocarbonyl-, Aminocarbonylalkyl, Arylalkyl-, Heterocyclylakyl-, Heteroarylalkyl- und Aminoalkyl-substituierten 3-10-gliedrigen Ringes sind, der gegebenenfalls Stickstoff-, Sauerstoff- oder Schwefelatome, die gegebenenfalls zum Sulfoxid oder Sulfon oxidiert sein können enthält, wobei an den 3-10-gliedrigen Ring gegebenenfalls ein Aromat ankondensiert sein kann,
R³ und R⁴ entweder für je ein Wasserstoffatom stehen oder gemeinsam eine Methylenbrücke bilden
X für ein Sauerstoffatom oder, NOR⁵ oder NNHSO₂R⁵,
R⁵ ausgewählt ist aus der Gruppe, umfassend Wasserstoff, C₁-C₁₀-Alkyl, Aryl
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen.The present invention relates to 17-hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-aryl derivatives having the general chemical formula I:

wherein
R ¹ and R ²
are the same or different and for
Hydrogen,
an optionally dimethylamine-substituted C ₁ -C ₁₀ -alkyl radical,
optionally mono-, di- or polysubstituted by halogen (-F, -Cl, -Br, -I), -OH, -O-alkyl, -C (O) OH, -C (O) Oalkyl, -C ( O) NH ₂ , -C (O) NH alkyl, -C (O) N dialkyl, -C (O) NH aryl, -C (O) NH heteroaryl, -NH ₂ , -NH (C ₁ -C ₁₀ alkyl), N (C ₁ -C ₁₀ alkyl) ₂ , especially -N (CH ₃ ) ₂ , -NHC (O) alkyl, -NO ₂ , -N ₃ , -CN, -C ₁ -C ₁₀ alkyl, -C C ₁ -C ₁₀ perfluoroalkyl, C ₁ -C ₁₀ acyl, C ₁ -C ₁₀ acyloxy, -SO ₂ NH ₂ , -SO ₂ NHalkyl or -SO ₂ N dialkyl-substituted 6-10-membered aryl radical,
an optionally mono-, di- or polysubstituted with the abovementioned substituents of the 6-10-membered aryl radical, 5-10-membered heteroaryl radical,
a C ₁ -C ₆ -arylalkyl radical optionally substituted one, two or more times on the aryl ring with the abovementioned substituents of the 6-10-membered aryl radical or
a C ₁ -C ₆ -Heteroarylalkyl substituted on the heteroaryl optionally one, two or more times with the abovementioned substituents of the 6-10-membered aryl radical
or but
R ¹ and R ²
together form part of an optionally substituted on the carbon alkyl, carboxyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylalkyl, heteroarylalkyl, aminoalkyl-substituted or on the nitrogen alkyl, alkanoyl, carboxyl, alkoxycarbonyl, phenyl, phenylalkyl , Pyridinyl, pyrimidinyl, pyrazinyl, sulfonyl, benzoyl, alkylsulfonyl, arylsulfonyl, aminocarbonyl, aminocarbonylalkyl, arylalkyl, heterocyclylakyl, heteroarylalkyl and aminoalkyl substituted 3-10 membered ring, optionally Nitrogen, oxygen or sulfur atoms, which may optionally be oxidized to the sulfoxide or sulfone, may optionally be fused to the 3-10-membered ring, an aromatic,
R ³ and R ^{4 are} either each a hydrogen atom or together form a methylene bridge
X is an oxygen atom or, NOR ⁵ or NNHSO ₂ R ⁵ ,
R ^{5 is} selected from the group comprising hydrogen, C ₁ -C ₁₀ alkyl, aryl
and their salts, solvates or solvates of the salts, including all crystal modifications.

Depending on their structure, the compounds of the general formula I according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures including the racemates. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

Each of said substituents on the steroid backbone may be present in both an α and a β position.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention comprise - if a basic function is included - salts with inorganic or organic acids, in particular of mineral acids, carboxylic acids and sulfonic acids, eg. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds of the invention include, when containing an acidic function, alkali metal salts, alkaline earth metal salts or ammonium salts, such as may be obtained by reaction with corresponding inorganic or organic bases. By way of example and by way of preference, mention may be made of alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and preferably ethylamine , Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methyl-glucamine, D-methyl-glucamine, ethyl glucamine, 1,6-hexadiamine, glucosamine, N-methylglycine, 2-amino-1,3-propanediol, tris-hydroxy-methylaminomethane and 1-amino-2,3,4-butanetriol.

Solvates in the context of the invention are those forms of the compounds according to the invention which, in the solid or liquid state, show adduct formation with solvent molecules. The solvent may be present in a stoichiometric or unstoichiometric ratio. Stoichiometric solvates are also known as hemi, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates. Hydrates are a special form of solvates that coordinate with water.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" encompasses compounds which, during their residence time in the body, are converted into compounds according to the invention, for example by enzymatic or hydrolytic processes.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl is a straight-chain or branched-chain alkyl group having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl hexyl, Heptyl, octyl, nonyl and decyl.

The alkyl radical may optionally be C ₁ -C ₄ -dialkylamine, in particular dimethylamine-substituted.

Aryl is a mono- to tricyclic aromatic, substituted or unsubstituted carbocyclic radical such as phenyl or naphthyl.

The aryl radical may be monosubstituted, disubstituted or polysubstituted by halogen (-F, -Cl, -Br, -I), -OH, -O-alkyl, -CO ₂ H, -CO ₂ -alkyl, -C (O) NH ₂ , -C (O) NH alkyl, -C (O) N dialkyl, -C (O) NH aryl, -C (O) NH heteroaryl, -NH ₂ , -NH (C ₁ -C ₁₀ alkyl), -N ( C ₁ -C ₁₀ -alkyl) ₂ , especially -N (CH ₃ ) ₂ , -NHC (O) -alkyl, -NO ₂ , -N ₃ , -CN, -C ₁ -C ₁₀ -alkyl, -C ₁ - C ₁₀ perfluoroalkyl, C ₁ -C ₁₀ acyl, C ₁ -C ₁₀ acyloxy, -SO ₂ NH ₂ or -SO ₂ NH alkyl, -SO ₂ NDialkyl be substituted.

Heteroaryl is an aromatic, mono- or bicyclic radical having usually 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, for example and preferably benzofuranyl, benzothiophenyl , Quinolinyl, furyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, oxazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, pyrazolyl, isoxazolyl, pyrazinyl, quinolyl or tetrazolyl.

The heteroaryl radical may be monosubstituted, disubstituted or polysubstituted by halogen (-F, -Cl, -Br, -I), -OH, -O-alkyl, -CO ₂ H, -CO ₂ -alkyl, -C (O) NH ₂ , -C (O) NHalkyl, -C (O) N dialkyl, -C (O) NHaryl, -C (O) NH heteroaryl, -NH ₂ , -NH (C ₁ -C ₁₀ alkyl), -N ( C ₁ -C ₁₀ -alkyl) ₂ , especially -N (CH ₃ ) ₂ , -NHC (O) -alkyl, -NO ₂ , -N ₃ , -CN, -C ₁ -C ₁₀ -alkyl, -C ₁ - C ₁₀ perfluoroalkyl, C ₁ -C ₁₀ acyl, C ₁ -C ₁₀ acyloxy, -SO ₂ NH ₂ or -SO ₂ NHalkyl, -SO ₂ NDialkyl be substituted.

Arylalkyl represents arylalkyl groups which may contain up to 14 carbon atoms, preferably 6-10 carbon atoms in the ring, and 1-8, preferably 1-4, carbon atoms in the alkyl chain. Suitable arylalkyl radicals are, for example, benzyl, phenylethyl, naphthylmethyl or naphthylethyl.

The aryl part of the arylalkyl radical may be monosubstituted, disubstituted or polysubstituted by halogen (-F, -Cl, -Br, -I), -OH, -O-alkyl, -CO ₂ H, -CO ₂ -alkyl, -C ( O) NH ₂ , -C (O) NH alkyl, -C (O) N dialkyl, -C (O) NH aryl, -C (O) NH heteroaryl, -NH ₂ , -NH (C ₁ -C ₁₀ alkyl), N (C ₁ -C ₁₀ alkyl) ₂ , especially -N (CH ₃ ) ₂ , -NHC (O) alkyl, -NO ₂ , -N ₃ , -CN, -C ₁ -C ₁₀ alkyl, -C ₁ -C ₁₀ perfluoroalkyl, -C ₁ -C ₁₀ acyl, -C ₁ -C ₁₀ acyloxy, -SO ₂ NH ₂ or -SO ₂ NHalkyl, -SO ₂ NDialkyl be substituted.

Heteroarylalkyl represents heteroarylalkyl groups, where heteroaryl has the meaning defined above and which may contain 1-8, preferably 1-4, carbon atoms in the alkyl chain. Suitable heteroarylalkyl radicals are, for example, furylmethyl, thienylethyl or pyridylpropyl.

The heteroaryl moiety of the heteroarylalkyl group may be monosubstituted, disubstituted or polysubstituted by halogen (-F, -Cl, -Br, -I), -OH, -O-alkyl, -CO ₂ H, -CO ₂ -alkyl, -C ( O) NH ₂ , -C (O) NH alkyl, -C (O) N dialkyl, -C (O) NH aryl, -C (O) NH heteroaryl, -NH ₂ , -NH (C ₁ -C ₁₀ alkyl), N (C ₁ -C ₁₀ alkyl) ₂ , especially -N (CH ₃ ) ₂ , -NHC (O) alkyl, -NO ₂ , -N ₃ , -CN, -C ₁ -C ₁₀ alkyl, -C ₁ -C ₁₀ perfluoroalkyl, -C ₁ -C ₁₀ acyl, -C ₁ -C ₁₀ acyloxy, -SO ₂ NH ₂ or -SO ₂ NHalkyl, -SO ₂ NDialkyl be substituted.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

For compounds in which R ¹ and R ² together form part of an optionally substituted ring, this ring may be 3-10-membered and bear, in addition to the nitrogen atom present, only carbon atoms or up to 2 further heteroatoms. As further heteroatoms are particularly, optionally substituted nitrogen, oxygen, optionally oxidized sulfur mentioned. Suitable substituents on the carbon are alkyl groups, carboxyl groups, alkylcarboxyl groups, alkylcarbonyl groups, aminocarbonyl groups, arylalkyl groups, heteroarylalkyl groups, aminoalkyl groups. Suitable substituents on the nitrogen are in particular alkyl groups, alkanoyl groups, alkylcarboxyl groups, carboxyl groups, phenyl groups, phenylalkyl groups, pyridinyls, pyrimidinyls, pyrazinyls, sulfonyl groups, benzoyl groups, alkyl- or arylsulfonyl, aminocarbonyl, arylalkyl, heteroarylalkyl and aminoalkyl. Sulfur atoms in the ring can be oxidized to the sulfoxide or sulfone. Optionally, an aromatic may be fused to the 3-10 membered ring.

Rings which are formed jointly by R ¹ and R ² are in particular piperidines, piperazines, morpholines, diazepanes, thiomorpholines, dioxothiomorpholines, tetrahydropyrroles.

Heterocyclyl in the context of the invention is a non-aromatic mono- or bicyclic ring system having at least one heteroatom or a hetero group. As heteroatoms nitrogen atoms, oxygen atoms and / or sulfur atoms may occur. Hetero groups can be -S (O) -, -S (O) ₂ -.

Heterocyclylalkyl represents heterocyclylalkyl groups, where heterocyclyl has the meaning defined above and which may contain 1-6, preferably 1-4, carbon atoms in the alkyl chain. Suitable heterocyclylalkyl radicals are, for example, pyrrolidinoethyl.

A monocyclic heterocyclyl ring according to the present invention may have 3 to 8, preferably 5 to 8, more preferably 5 or 6 ring atoms. Examples of monocyclic heterocyclyl radicals having 5 ring atoms are: pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl and tetrahydrofuranyl. Examples of monocyclic heterocyclyl radicals having 6 ring atoms are: piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl and thiomorpholinyl.

A bicyclic heterocyclyl group according to the present invention may have 5 to 12, preferably 8 to 10, ring atoms. Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S. Particularly preferred are morpholinyl, piperidinyl and pyrolidinyl.

The radical definitions given in detail in the respective combinations or preferred combinations of radicals are also replaced, irrespective of the particular combinations of the radicals indicated, by radical definitions of other combinations.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

• – (1S,3aS,3bS,9aS,14bS,14cR,15aS)-12-[(Dimethylamino)methyl]-1-hydroxy-15a-methyl-1-(pentafluorethyl)-1,2,3,3a,3b,4,5,8,9,10,14b,14c,15,15a-tetradecahydro-7H-benzo[n]indeno[4,5,6-de]anthracen-7-on (Bsp. 1)
• – tert-Butyl-4-{[(1S,3aS,3bS,9aS,14bS,14cR,15aS)-1-hydroxy-15a-methyl-7-oxo-1-(pentafluorethyl)-1,2,3,3a,3b,5,7,8,9,10,14b,14c,15,15a-tetradecahydro-4H-benzo[n]indeno[4,5,6-de]anthracen-12-yl]methyl}piperazin-1-carboxylat (Bsp. 2)
• – (1S,3aS,3bS,9aS,14bS,14cR,15aS)-1-Hydroxy-15a-methyl-1-(pentafluorethyl)-12-(piperazin-1-ylmethyl)-1,2,3,3a,3b,4,5,8,9,10,14b,14c,15,15a-tetradecahydro-7H-benzo[n]indeno[4,5,6-de]anthracen-7-on (Bsp. 3)
• – (1S,3aS,3bS,9aS,14bS,14cR,15aS)-12-[(4-Acetylpiperazin-1-yl)methyl]-1-hydroxy-15a-methyl-1-(pentafluorethyl)-1,2,3,3a,3b,4,5,8,9,10,14b,14c,15,15a-tetradecahydro-7H-benzo[n]indeno[4,5,6-de]anthracen-7-on (Bsp. 4)
• – (11β,17β)-11-{4-[(Dimethylamino)methyl]phenyl}-17-hydroxy-17-(pentafluorethyl)estr-4-en-3-on (Bsp. 5)
• – tert-Butyl-4-{4-[(11β,17β)-17-hydroxy-3-oxo-17-(pentafluorethyl)estr-4-en-11-yl]benzyl}piperazin-1-carboxylat (Bsp. 6)
• – (11β,17β)-17-Hydroxy-17-(pentafluorethyl)-11-[4-(piperazin-1-ylmethyl)phenyl]estr-4-en-3-on (Bsp. 7)
• – (11β,17β)-11-{4-[(4-Acetylpiperazin-1-yl)methyl]phenyl}-17-hydroxy-17-(pentafluorethyl)estr-4-en-3-on (Bsp. 8)

Also preferred are the compounds:

• - (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -12 - [(dimethylamino) methyl] -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -1,2,3,3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracen-7-one (Ex. 1)
• Tert -Butyl 4 - {[(1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -1-hydroxy-15a-methyl-7-oxo-1- (pentafluoroethyl) -1,2,3,3a , 3b, 5,7,8,9,10,14b, 14c, 15,15a-tetradecahydro-4H-benzo [n] indeno [4,5,6-de] anthracene-12-yl] methyl} piperazin-1 carboxylate (Ex. 2)
• - (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -12- (piperazin-1-ylmethyl) -1,2,3,3a, 3b , 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracen-7-one (Ex. 3)
• - (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -12 - [(4-acetylpiperazin-1-yl) methyl] -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -1,2, 3,3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracen-7-one (ex. 4)
• - (11β, 17β) -11- {4 - [(dimethylamino) methyl] phenyl} -17-hydroxy-17- (pentafluoroethyl) estr-4-en-3-one (Ex. 5)
• Tert -Butyl 4- {4 - [(11β, 17β) -17-hydroxy-3-oxo-17- (pentafluoroethyl) estr-4-en-11-yl] benzyl} piperazine-1-carboxylate (Ex. 6)
• - (11β, 17β) -17-hydroxy-17- (pentafluoroethyl) -11- [4- (piperazin-1-ylmethyl) phenyl] estr-4-en-3-one (Ex. 7)
• - (11β, 17β) -11- {4 - [(4-acetylpiperazin-1-yl) methyl] phenyl} -17-hydroxy-17- (pentafluoroethyl) estr-4-en-3-one (Ex 8)

The radical definitions given in detail in the respective combinations or preferred combinations of radicals are also replaced, irrespective of the particular combinations of the radicals indicated, by radical definitions of other combinations.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

wobei
R³ und R⁴ entweder für je ein Wasserstoffatom oder eine gemeinsame Methylenbrücke
R⁶ für eine Gruppierung C_mF_m+1SO₃ oder ein Chlor-, Brom- oder Iodatom
R⁷ für eine gegebenenfalls geschützte Hydroxygruppe
R⁸ für ein Wasserstoffatom, eine C₂F₅-Gruppe stehen, oder
R⁷ und R⁸ gemeinsam einen doppelt gebundenen Sauerstoff darstellen
PG für eine Ketalschutzgruppe steht
m gleich 1–4 sein kannIt has been found that the compounds or derivatives according to the invention have a good progesterone-antagonizing action. Several clinical studies have found that treatment with progestin receptor antagonists (mifepristone, asoprisnil, proellex) can lead to significant shrinkage of uterine fibroids and a significant reduction in the symptoms associated with these uterine fibroids. It has also been shown in clinical studies that treatment with these progesterone receptor antagonists can also significantly reduce symptoms (especially pain) caused by endometriosis. Scheme 1a Preparation of compounds of general formula I:

in which
R ³ and R ^{4 are} either each a hydrogen atom or a common methylene bridge
R ^{6 represents} a group C _m F _{m + 1} SO ₃ or a chlorine, bromine or iodine atom
R ^{7 represents} an optionally protected hydroxy group
R ^{8 is} a hydrogen atom, a C ₂ F ₅ group, or
R ⁷ and R ⁸ together represent a double-bonded oxygen
PG stands for a ketal protecting group
m can be 1-4

An overview of the preparation of compounds of general formula I is shown in Scheme 1. Starting from compounds of the general formula 1, a vinyl group can be introduced via transition metal, preferably palladium, coupled reactions and thus compounds of the general formula 2 can be prepared. Compounds of general formula 1 in which R ³ and R ⁴ together form a methylene group, z. In WO 98/34947 and DE 4216003 described. Compounds in which R ³ and R ^{4 are} each a hydrogen, for example, from in Steroids 1994, p. 176-180 ; Tetrahedron 1995, pp. 5563-5572 or Ger. Open DE 40181676 be prepared compounds in a few stages. For this purpose, in some cases existing 5 (6) double bonds z. B. epoxidized and the epoxides formed then opened reductively.

The vinyl group introduced in the coupling reaction is then used to build up the carbaldehydes contained in the compounds of general formulas 3 and 4. For this purpose, the process known in the art is oxidized by decomposing the terminal carbon atom. For example, the reaction with sodium periodate in the presence of catalytic amounts of osmium tetroxide is suitable for this oxidation, but also methods using ozone.

The introduction of the 17α-Pentafluorethylseitenkette to the corresponding 17-keto compounds is carried out according to the in WO 98/34947 and in WO 2008/058767 described method. This side-chain introduction is carried out either before the carbaldehyde function is established on the 11β-phenyl ring or after the aminomethylene function has been established. Alternatively, however, the carbaldehyde functionality can also be temporarily protected, for example, as acetal, and then the pentafluoroethyl group can be added to C-17 in the presence of this protective group.

At a suitable stage then takes place the removal of the protective groups in the position 3 according to the methods known in the art. In the cleavage of the 3-ketal to the 3-keto group of the steroid skeleton an optionally present 5α-hydroxy group is eliminated, so that compounds of general formula 4 arise.

Starting from aldehydes of the general formula 4, the introduction takes place via reductive aminations. The amines used for this purpose can be primary or secondary and may carry protective groups.

Compounds of the general formula I can then be prepared from the compounds of the general formula 4. For this purpose, optionally existing protective groups are cleaved and the radicals on the Aminomethylenmgruppe modified if necessary. Oxidations or reductions, esterifications, saponifications, alkylation, acylations of free valences on the nitrogen and formations of sulfonamides may be mentioned as reactions of the radicals on the aminomethylene group.

Examples of ketal protecting or acetal protecting groups are the ethylenedioxy or 2,2-dimethylpropylene-1,2-dioxy group. For example, hydroxy groups are protected in the form of methoxymethyl, methoxyethyl, tetrahydropyranyl, benzyl, or silyl ethers.

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 equivalent amount or an excess of a base or acid, optionally in solution, optionally separating the precipitate or in the usual way the solution works up.

The resulting compounds of formula (I) are optionally reacted with the appropriate (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

The abovementioned general or preferred radical definitions apply both to the end products of the formula (I) and correspondingly to the starting materials or intermediates required in each case for the preparation.

The compounds of the invention show an unpredictable, valuable pharmacological, pharmacokinetic and pharmacodynamic profile of action.

They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

The pharmaceutical activity of the compounds according to the invention can be explained by their action as progesterone receptor antagonists, ie their antagonizing action on the progesterone receptor.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases based on hormone-dependent hyperproliferative processes, preferably of gynecological diseases, especially of uterine fibroids, endometriosis or hormone-dependent breast carcinomas.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of uterine fibroids, endometriosis and hormone-dependent breast carcinomas.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using 0.1-100 mg of the compounds of the invention per day and patient in the treatment of uterine fibroids or endometriosis and for the Contraceptive application or of 0.1-500 mg of the compounds of the invention per day and patient in tumor diseases (eg Menginiome or hormone-dependent tumors such as breast cancer) and in emergency contraception.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more further active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.

For the treatment of tumor diseases z. For example, the following drugs / classes of drugs can be administered either simultaneously or sequentially: SERMs, SERDs, antiestrogens, aromatase inhibitors, kinase inhibitors, angiogenesis inhibitors, and / or cytostatic agents.

For the treatment of uterine fibroids or endometriosis, the compounds according to the invention can be combined simultaneously or sequentially with gestagens or combinations of estrogens and gestagens.

In WO 96/15794 (Spicer et al., Balance Pharm. Inc.), WO 96/03130 (Stöckemann et al., Schering AG) and PCT / EP2009 / 003249 (Moller et al., Bayer Schering Pharma AG) are disclosed progesterone receptor antagonist / progestin regime. Well suited for the treatment of uterine fibroids and endometriosis are - optionally repeating - regimens in which the progesterone receptor antagonist is given over a period of two to four months, followed by the administration of the progestogen over a period of one to four weeks. Particularly suitable is the - optionally repeated - 84-day administration of the progesterone receptor antagonist followed by the 14-day administration of the gestagen.

For the treatment of menopausal symptoms associated with a simultaneous or sequential administration of the compounds of the invention z. B. with SERMs, SERDs and estrogens into consideration.

SERMs (Selective Estrogen Receptor Modulators) are those compounds that have tissue-selective either an antiestrogenic or estrogenic effect, for example, on the uterus the effect of Inhibit estrogen, but have a neutral or estrogen-like effect on the bone. Examples are clomifene, raloxifene, tamoxifen, torimifene, bazedoxifene, lasofoxifene and ormeloxifene.

Selective Estrogen Receptor Stabilizers (SERDs) are drugs that completely antagonize the estrogen receptor ('pure antiestrogens' with no estrogenic active component) and lead to degradation of the receptor (eg fulvestrant, ZK-703 and ZK-253 ( Hoffmann J et al., J Natl Cancer Inst 2004, 96: 210-218 ) as in WO 98/007740 . WO 99/33855 and WO 03/045972 described compounds.

Antiestrogens are compounds which completely antagonize the estrogen receptor, for example fulvestrant.

Aromatase inhibitors inhibit the enzyme aromatase and thus the aromatization of androgens in estrogens. These include u. a. Anastrozole, Letrozole, Exemestane, Vorozole, Formestane and Fadrozole.

Kinase inhibitors are enzymes that transfer a phosphate residue from ATP to other substrates, especially to hydroxy groups, e.g. Sorafenib (Nexavar) or Imatinib (Gleevec).

Angiogenesis inhibitors, z. B. Avastin, reduce or block the vascular supply and thus the circulation of a tumor.

Cytostatics, e.g. Cis-platin, Taxol, Taxotere are natural or synthetic substances that inhibit cell growth or cell division.

For the purposes of the present invention, progestins are understood to be either the natural progesterone itself or synthetic derivatives which, like the progesterone itself, bind to the progesterone receptor and inhibit ovulation in dosages which are above the ovulation inhibitor dose. Examples of the synthetic derivatives include drospirenone, gestodene, levonorgestrel, cyproterone acetate, desogestrel and 3-ketodesogestrel, norethisterone, norethisterone acetate and dienogest.

Combinations of progestogens and estrogens are the active ingredient combinations contained in the conventional oral contraceptives, for example, Yasmin, Femovan, Triquilar, Marvelon, YAZ, etc.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may suitably, such. As oral, intrauterine [är], intravaginal, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

Intrauterine [är] means in particular the application by means of IUS (intrauterine system) or IUD (intrauterine device). The intravaginal application may u. a. by IVR / VRS (intra vaginal ring / vaginal ring system).

Intrauterine or intravaginal application forms (cf., for example, US Pat. WO 01/47490 , in particular page 1, line 10 to page 5, line 13 and page 7, line 19 to page 58, line 6, or for vaginal rings: WO 06/010097 , in particular page 10, line 22 to page 14, line 28), the compounds according to the invention and nonsilicone and / or silicone polymers, in particular also siloxane-based elastomers (cf. WO 01/47490 , especially page 7, line 19 - page 15, line 15).

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. As tablets (uncoated or coated tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), rapidly disintegrating in the oral cavity tablets or films / wafers, films / lyophilisates, capsules (for example, Hart Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are z. Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, Pastes, foams, scattering powders, implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include u. a. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases, it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

The following examples serve to illustrate the invention without limiting it in any way.

Example 1:

(1S, 3aS, 3bS, 9a S, 14b S, 14Cr, 15aS) -12 - [(dimethylamino) methyl] -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -1,2,3,3a, 3b, 4 , 5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracene-7-one

a) (3aS, 3bS, 5aR, 9aS, 14bS, 14cR, 15aS) -5a-hydroxy-5 ', 5', 15a-trimethyl-12-vinyl-3,3a, 3b, 4,5,5a, 6, 8,9,10,14b, 14c, 15,15a-tetradecahydrospiro [benzo [n] indeno [4,5,6-de] anthracene-7,2 '- [1,3] dioxane] -1 (2H) - on

To a suspension of 2.5 g of 3aS, 3bS, 5aR, 9aS, 14bS, 14cR, 15aS) -5a-hydroxy-5 ', 5', 15a-trimethyl-1-oxo-1,2,3,3a, 3b , 4,5,5a, 6,8,9,10,14b, 14c, 15,15a-hexadecahydrospiro [benzo [n] indeno [4,5,6-de] anthracene-7,2 '- [1,3 ] dioxan] -12-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (see WO 98/34947 ; DE 4216003 ) in 25 ml of N, N-dimethylformamide was added 0.28 g of lithium chloride. The mixture was stirred for 15 minutes at 0 ° C and then added 0.38 g of palladium tetrakistriphenylphosphine and allowed to stir for a further 5 minutes. Subsequently, 1.559 g tributylvinyl tin were added and stirred at 110 ° C for 2.5 hours. Subsequently, the reaction mixture was diluted with saturated sodium bicarbonate solution. It was extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product obtained after concentration in vacuo was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate. 1.6 g of the title compound were obtained.
¹ H-NMR (300 MHz, CDCl3): δ = 7.37 (1H); 7.18 (1H); 7.07 (1H); 6.63 (1H); 5.68 (1H); 5.18 (1H); 4.45 (1H); 3,45-3,63 (4H); 3.18 (1H); 3.10 (1H); 2.62-2.80 (2H); 2.39 (1H); 1.00 (3H); 0.92 (3H); 0.38 (3H) ppm.

b) (1S, 3aS, 3bS, 5aR, 9aS, 14bS, 14cR, 15aS) -5 ', 5', 15a-trimethyl-1- (pentafluoroethyl) -12-vinyl-1,2,3,3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydrospiro [benzo [n] indeno [4,5,6-de] anthracene-7,2 '- [1,3] dioxan] -1 , 5 (6H) -diol

To a solution of 1.6 g of the compound described in Example 1a) in 20 ml of dichloromethane was added at -78 ° C, a solution of 12 g of condensed pentafluoroiodoethane in 10 ml of dichloromethane. To the reaction solution was slowly added 20 ml of a 1.5 molar solution of methyl lithium lithium bromide complex in diethyl ether at the same temperature. The mixture was then stirred for 2 hours, allowing the temperature of -78 ° C to -40 ° C come. Then, the reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. There was obtained 1.25 mg of the title compound.
¹ H-NMR (300 MHz, CDCl3): δ = 7.34 (1H); 7.18 (1H); 7.07 (1H); 6.63 (1H); 5.70 (1H); 5.19 (1H); 4.46 (1H); 3,45-3,65 (4H); 3.19 (1H); 3.10 (1H); 2.60-2.78 (2H); 2.37 (1H); 1.00 (3H); 0.93 (3H); 0.44 (3H) ppm.

c) (1S, 3aS, 3bS, 5aR, 9aS, 14bS, 14cR, 15aS) -1,5a-dihydroxy-5 ', 5', 15a-trimethyl-1- (pentafluoroethyl) -1,2,3,3a, 3b, 4,5,5a, 6,8,9,10,14b, 14c, 15,15a-hexadecahydrospiro [benzo [n] indeno [4,5,6-de] anthracene-7,2 '- [1, 3] dioxane] -12-carbaldehyde

A solution of 4 g of the compound described in Example 1b) in a mixture of 100 ml of tetrahydrofuran and 25 ml of water was treated with 1 ml of triethylamine and 3 ml of saturated sodium bicarbonate solution. Thereafter, 2.62 ml of a 0.04 molar solution of osmium tetroxide in tert-butanol and 2.23 g of sodium periodate were added. The mixture was stirred for 6 hours at 23 ° C and then added a further 2.62 ml of 0.04 molar solution of osmium tetroxide in tert-butanol and 2.23 g of sodium periodate. Thereafter, the mixture was stirred at 23 ° C for 18 hours. Subsequently, the reaction mixture was filtered. The residue was washed extensively with ethyl acetate. The combined organic phases were then washed with half-saturated sodium thiosulfate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate / dichloromethane. There was obtained 2.43 g of the title compound.
¹ H-NMR (400 MHz, CDCl3): δ = 9.93 (1H); 7.64 (1H); 7.58 (2H); 4.49 (1H); 3,48-3,63 (4H); 3.26 (1H); 3.18 (1H); 2.70-2.82 (2H); 2.39 (1H); 2.24 (1H); 1.00 (3H); 0.93 (3H); 0.39 (3H) ppm.

d) (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -1-hydroxy-15a-methyl-7-oxo-1- (pentafluoroethyl) -1,2,3,3a, 3b, 5,7, 8,9,10,14b, 14c, 15,15a-tetradecahydlo-4H-benzo [n] indeno [4,5,6-de] anthracene-12-carbaldehyde

To a solution of 2.4 g of the substance described in Example 1c) in 50 ml of acetone, 5 ml of 4 normal hydrochloric acid were added. The mixture was stirred for 18 hours at 23 ° C and then for a further 2.5 hours at 50 ° C. Subsequently, the reaction mixture was poured onto saturated sodium bicarbonate solution. It is extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. There were obtained 1.71 g of the title compound.
¹ H-NMR (400 MHz, CDCl3): δ = 9.95 (1H); 7.70 (1H); 7.62 (2H); 5.90 (1H); 3.44 (1H); 3.31 (1H); 2.81-2.91 (2H); 2.63 (1H); 0.45 (3H) ppm.

e) (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -12 - [(dimethylamino) methyl] -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -1,2,3,3a, 3b , 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracene-7-one

To a solution of 100 mg of the compound described under 1d) in 3 ml of dichloromethane was added 0.2 ml of a 2 molar solution of dimethylamine in tetrahydrofuran. The mixture was stirred for 15 minutes at 23 ° C and then added 84 mg of sodium triacetoxyborohydride. Then allowed to stir for 20 hours at 23 ° C. Thereafter, the reaction mixture was poured onto saturated sodium hydrogencarbonate aqueous solution. It was extracted several times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel. 44 mg of the title compound were obtained.
¹ H-NMR (400 MHz, CDCl3): δ = 7.35 (1H); 7.07 (1H); 7.01 (1H); 5.87 (1H); 3.32-3.41 (3H); 3.22 (1H); 2.81 (1H); 2.73 (1H); 2.60 (1H); 2.22 (6H); 0.45 (3H) ppm.

Example 2

tert-butyl 4 - {[(1S, 3aS, 3bS, 9a S, 14b S, 14Cr, 15aS) -1-hydroxy-15a-methyl-7-oxo-1- (pentafluoroethyl) -1,2,3,3a, 3b, 5,7,8,9,10,14b, 14c, 15,15a-tetradecahydro-4H-benzo [n] indeno [4,5,6-de] anthracene-12-yl] methyl} piperazin-1- carboxylate

Analogously to Example 1e), 324 mg of the title compound were prepared from 300 mg of the compound described under 1d), 165 mg of tert-butylpiperazine-1-carboxylate and 250 mg of sodium triacetoxyborohydride.
¹ H-NMR (300 MHz, CDCl3): δ = 7.34 (1H); 7,10 (1H); 7.00 (1H); 5.87 (1H); 3.30-3.52 (7H); 3.22 (2H); 2.53-2.87 (3H); 2.30-2.52 (4H); 1.46 (9H); 0.48 (3H) ppm.

Example 3

(1S, 3aS, 3bS, 9a S, 14b S, 14Cr, 15aS) -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -12- (piperazin-1-ylmethyl) -1,2,3,3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracene-7-one

To a solution of 295 mg of the compound described in Example 2 in 8 ml of dichloromethane was added 810 ul of trifluoroacetic acid. The mixture was stirred for 1.5 hours at 23 ° C and then poured the reaction mixture into saturated aqueous sodium bicarbonate solution. The mixture was then allowed to stir for a further 30 minutes and then extracted several times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel. 85 mg of the title compound were obtained.
¹ H-NMR (300 MHz, CDCl3): δ = 7.37 (1H); 7.08 (1H); 6.99 (1H); 5.87 (1H); 3.30-3.52 (3H); 3.22 (1H); 2.90-3.12 (3H); 0.95 (3H) ppm.

Example 4

(1S, 3aS, 3bS, 9a S, 14b S, 14Cr, 15aS) -12 - [(4-Acetyl-piperazin-1-yl) methyl] -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -1,2,3 , 3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracene-7-one

To a solution of 154 mg of the compound described in Example 3 in 5 ml of dichloromethane was added 75 ul of triethylamine. It was cooled to 0 ° C and added 25 ul of acetic anhydride. Then allowed to come to 23 ° C and stirred for 2.5 hours. Then, the reaction mixture was poured onto saturated sodium hydrogencarbonate aqueous solution. The mixture was stirred for a further 30 minutes and then extracted several times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel. 78 mg of the title compound were obtained.
¹ H-NMR (400 MHz, CDCl3): δ = 7.36 (1H); 7,10 (1H); 7.00 (1H); 5.88 (1H); 3.62 (2H); 3.40-3.54 (4H); 3.36 (1H); 2.81 (1H); 2.72 (1H); 2.61 (1H); 2.32-2.50 (6H); 2.10 (3H); 0.48 (3H) ppm.

Example 5

(11β, 17β) -11- {4 - [(dimethylamino) methyl] phenyl} -17-hydroxy-17- (pentafluoroethyl) estr-4-en-3-one

a) (4aR, 5aS, 6aR, 6bS, 9aS, 11S, 11aR, 11bR) -11- (4-methoxyphenyl) -9a-methyldodecahydrospiro [cyclopenta [1,2] phenanthro [8a, 9-b] oxirene-3, 2 '- [1.3] dioxolan] -9 (2H) -one

To a solution of 10 g (8R, 9S, 10R, 11S, 13S, 14S) -11- (4-methoxyphenyl) -13-methyl-1,4,7,8,9,10,11,12,13, 14,15,16-dodecahydrospiro [cyclopenta [a] phenanthrene-3,2 '- [1,3] dioxolane] -17 (2H) -one (see Steroids, 1994, p. 176-180; Tetrahedron, 1995, pp. 5563-5572 ; Ger. Open DE 40181676 ) in 100 ml of dichloromethane were added at 0 ° C 8 ml of saturated aqueous sodium bicarbonate solution, 2.6 g of 3'-nitro-2,2,2-trifluoroacetophenone and 9.7 ml of hydrogen peroxide (30%). It was allowed to stir for 6 days at 23 ° C. Thereafter, saturated aqueous sodium thiosulfate solution was added and stirred for a further 30 minutes. Subsequently, the reaction mixture was extracted several times with dichloromethane. The combined organic phases were washed with 2 molar sodium hydroxide solution, with water and with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel. This gave 7.59 g of the title compound.
¹ H NMR (300 MHz, CDCl3): δ = 7.23 (2H); 6.78 (2H); 3.75-4.03 (4H); 3.75 (3H); 3.24 (1H); 2.96 (1H); 0.60 (3H) ppm.

b) (5R, 8R, 9R, 10R, 11S, 13S, 14S, 17S) -11- (4-methoxyphenyl) -13-methyltetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '- [1,3] dioxolane] -5.17 (4H) -diol

To a solution of 8.19 g of the substance described in Example 5a) in 150 ml of ethanol was added 4.24 g of sodium borohydride. The mixture was refluxed for 3 hours, then allowed to cool to room temperature and then poured the reaction mixture into 1 liter of ice water. The mixture was stirred for 15 minutes and then extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The crude product (8.69 g) was used without further purification in the subsequent stage.
¹ H-NMR (300 MHz, CDCl3): δ = 7.28 (2H); 6.77 (2H); 3.82-4.03 (4H); 3.78 (3H); 3.58 (1H); 3.14 (1H); 0.46 (3H) ppm.

c) (5R, 8R, 9R, 10R, 11S, 13S, 14S, 17S) -11- (4-hydroxyphenyl) -13-methyltetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '- [1,3] dioxolane] -5.17 (4H) -diol

To a solution of 9.69 g of the compound described in Example 5b) in 100 ml of N, N-dimethylformamide was added 5 g of sodium methanethiolate. The mixture was stirred for 2 hours at 160 ° C. Subsequently, the hot reaction mixture was poured onto 1 liter of ice-cold saturated sodium chloride solution. The mixture was stirred for 16 hours and then sucked on a frit. The residue was dissolved in dichloromethane. The organic phase was washed several times with water, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by chromatography on silica gel followed by recrystallization from a mixture of dichloromethane and diisopropyl ether. This gave 5.11 g of the title compound.
¹ H NMR (300 MHz, CDCl3): δ = 7.23 (2H); 6.69 (2H); 4.91 (1H); 3,80-4,00 (4H); 3.58 (1H); 3.11 (1H); 0.44 (3H) ppm.

d) 4 - [(5R, 8R, 9R, 10R, 11S, 13S, 14S, 17S) -5,17-dihydroxy-13-methylhexadecahydrospiro [cyclopenta [a] phenanthrene-3,2 '- [1,3] dioxolane ] -11-yl] phenyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

2.1 ml of a 2.5 molar solution of butyllithium in hexane were added at -15 ° C. to a solution of 1.5 g of the compound described under Example 5c) in 30 ml of tetrahydrofuran. The mixture was stirred for 30 minutes and then added a solution of 1.27 g of nonofluoro-1-butanesulfonsäurechlorid in 20 ml of tetrahydrofuran. The mixture was then stirred at 0 ° C for 2 hours. Thereafter, the reaction mixture was poured onto a mixture of 400 ml of saturated sodium bicarbonate solution and 10 ml of 2 molar sodium hydroxide solution. The mixture was stirred for 30 minutes and then extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel. This gave 1.45 g of the title compound.
¹ H-NMR (300 MHz, CDCl3): δ = 7.47 (2H); 7.17 (2H); 3.82-4.00 (4H); 3.58 (1H); 3.20 (1H); 0.40 (3H) ppm.

e) 4 - [(5R; 8R, 9R, 10R, 11S, 13S, 14S) -5-hydroxy-13-methyl-17-oxohexadecahydrospiro [cyclopenta [a] phenanthrene-3,2 '- [1,3] dioxolane ] -11-yl] phenyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

To a mixture of 40 ml of dichloromethane and 14 ml of pyridine was added at 0 ° C 4.2 g of chromium trioxide. Stirring was continued for 15 minutes with vigorous stirring at 0 ° C., a solution of 5 g of the compound described under Example 5d) in 20 ml of dichloromethane. Thereafter, the mixture was stirred at 0 ° C for 1.5 hours. Then the reaction solution was decanted off. The residue was washed with dichloromethane. The combined organic phases were washed twice with 2 molar sodium hydroxide solution and once with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel. 4.65 g of the title compound were obtained.
¹ H-NMR (400 MHz, CDCl3): δ = 7.47 (2H); 7.18 (2H); 3.84-4.02 (4H); 3.27 (1H); 0.52 (3H) ppm.

f) (5R, 8R, 9R, 10R, 11S, 13S, 14S) -5-hydroxy-13-methyl-11- (4-vinylphenyl) tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2 '- [1,3 ] dioxolan] -17 (2H) -one

Analogously to the process described under Example 1a), from 4.65 g of the compound described under Example 5e), 560 mg of lithium chloride, 758 mg of palladium tetrakistriphenylphosphine and 3.12 g of tributylvinyltin in N, N-dimethylformamide, after purification, 2.51 g of the title compound receive.
¹ H-NMR (300 MHz, CDCl3): δ = 7.27-7.42 (4H); 6.68 (1H); 5.71 (1H); 5.21 (1H); 3,80-4,00 (4H); 3.21 (1H); 0.59 (3H) ppm.

g) (5R, 8R, 9R, 10R, 11S, 13S, 14S, 17S) -13-methyl-17- (pentafluoroethyl) -11- (4-vinylphenyl) tetradecahydrospiro [cyclopenta [a] phenanthrene-3,2'- [1,3] dioxolane] -5.17 (4H) -diol

Analogously to the process described under Example 1b), from 2.51 g of the compound described under Example 5f), 13.5 ml of condensed pentafluoroethyl iodide and 41.8 ml of a 2.2 molar solution of methyl lithium lithium bromide complex in diethyl ether by reaction in dichloromethane, after purification, 2.02 g of the title compound.
¹ H-NMR (300 MHz, CDCl3): δ = 7.25-7.41 (4H); 6.68 (1H); 5.71 (1H); 5.20 (1H); 3,80-4,00 (4H); 3.26 (1H); 0.61 (3H) ppm.

h) 4 - [(5R, 8R, 9R, 10R, 11S, 13S, 14S, 17S) -5,17-dihydroxy-13-methyl-17- (pentafluoroethyl) hexadecahydrospiro [cyclopenta [a] phenanthrene-3,2 ' - [1,3] dioxolan] -11-yl] benzaldehyde

In analogy to Example 1c), from 1.46 g of the compound described under Example 5g), 1.97 ml of a 0.04 molar solution of osmium tetroxide in tert-butanol, 2.53 g of sodium periodate, 0.4 ml of triethylamine, 1 , 3 ml of saturated sodium bicarbonate solution in a mixture of 52 ml of tetrahydrofuran and 21 ml of water after purification by column chromatography on silica gel 1.33 g of the title compound.
¹ H-NMR (300 MHz, CDCl3): δ = 9.96 (1H); 7.78 (2H); 7.60 (2H); 3.80-4.10 (4H); 3.34 (1H); 2.40 (2H); 2.18 (1H); 0.59 (3H) ppm.

i) 4 - [(11β, 17β) -17-hydroxy-3-oxo-17- (pentafluoroethyl) estr-4-en-11-yl] benzaldehyde

In analogy to Example 1d), 523 mg of the title compound were obtained from 1 g of the compound described under Example 5h) and 2.24 ml of 4N hydrochloric acid in acetone after purification by column chromatography on silica gel.
¹ H-NMR (300 MHz, CDCl3): δ = 10.00 (1H); 7.80 (2H); 7.62 (2H); 5.89 (1H); 3.56 (1H); 2.87 (1H); 0.67 (3H) ppm.

k) (11β, 17β) -11- {4 - [(dimethylamino) methyl] phenyl} -17-hydroxy-17- (pentafluoroethyl) estr-4-en-3-one

In analogy to Example 1e), from 100 mg of the compound described under Example 5i), 200 μl of a 2 molar solution of dimethylamine in tetrahydrofuran and 85 mg of sodium triacetoxyborohydride in 4 ml of dichloromethane, after purification by column chromatography on silica gel, 46 mg of the title compound were obtained.
¹ H-NMR (300 MHz, CDCl3): δ = 7.37 (2H); 7.19 (2H); 5.88 (1H); 3.27-3.50 (3H); 2.89 (1H); 2.21 (6H); 0.67 (3H) ppm.

Example 6

tert-butyl 4- {4 - [(11β, 17β) -17-hydroxy-3-oxo-17- (pentafluoroethyl) estr-4-en-11-yl] benzyl} piperazine-1-carboxylate

In analogy to Example 2), 208 mg of the title compound were obtained from 250 mg of the compound described under Example 5i), 141 mg of tert-butylpiperazine-1-carboxylate and 214 mg of sodium triacetoxyborohydride in dichloromethane after purification by column chromatography on silica gel.
¹ H-NMR (400 MHz, CDCl3): δ = 7.37 (2H); 7.20 (2H); 5.86 (1H); 3.35-3.52 (6H); 2.89 (1H); 2.53 (1H); 2.37 (4H); 1.43 (9H); 0.68 (3H) ppm.

Example 7

(11β, 17β) -17-hydroxy-17- (pentafluoroethyl) -11- [4- (piperazin-1-ylmethyl) phenyl] estr-4-en-3-one

In analogy to Example 3), 162 mg of the title compound were obtained from 200 mg of the compound described under Example 6) and 578 μl of trifluoroacetic acid in dichloromethane after purification by column chromatography on silica gel.
¹ H-NMR (300 MHz, CDCl3): δ = 7.34 (2H); 7.21 (2H); 5.86 (1H); 3.33-3.57 (3H); 2.73-2.98 (6H); 2.54 (1H); 0.64 (3H) ppm.

Example 8

(11β, 17β) -11- {4 - [(4-Acetyl-piperazin-1-yl) methyl] phenyl} -17-hydroxy-17- (pentafluoroethyl) estr-4-en-3-one

In analogy to Example 4), 142 mg of the compound described under Example 7), 24 μl of acetic anhydride and 70 μl of triethylamine in dichloromethane were obtained after purification by column chromatography on silica gel 146 mg of the title compound.
¹ H-NMR (37.37 (2H); 7.20 (2H); 5.86 (1H); 3.61 (2H); 3.38-3.52 (5H); 2.90 (1H) 2.56 (1H), 2.39 (2H), 2.06 (3H), 0.68 (3H) ppm.

Progesterone Receptor Antagonist Activity in Stable Transfectants of Human Neuroblastoma Cells (SK-N-MC Cells) with the Human Progesterone A or Progesterone B Receptor and an MN-LUC Reporter Construct

SK-N-MC cells (human neuroblastoma cells) stably transfected with plasmids containing human progesterone receptor B (pRChPR-B-neo) or human progesterone receptor A (pRChPR-A-neo) and a reporter construct (pMMTV -LUC) were incubated for 24 hours either in the absence (negative control) or in the presence of increasing amounts of the respective test compound (0.01 nmol / l, 0.1 nmol / l, 1 nmol / l, 10 nmol / l, 100 nmol / l and 1 pmol / l) to determine agonist activity. As a positive control of reporter gene induction, the cells were treated with the synthetic progestin Promegeston (0.01 nmol / l, 0.1 nmol / l, 1 nmol / l, 10 nmol / l, 100 nmol / l and 1 pmol / l). To determine the antagonistic activity, the cells were incubated with 0.1 nmol / l promegestone and additionally with increasing amounts of the respective test compound (0.01 nmol / l, 0.1 nmol / l, 1 nmol / l, 10 nmol / l, 100 nmol / l and 1 pmol / l). The activity of the reporter gene LUC (LUC = luciferase) was determined in the cell lysates and measured as RLU (relative light units). All measured values are given as% effectiveness and as EC ₅₀ or IC ₅₀ concentrations.

a) agonistic activity:

None of the compounds mentioned shows an agonistic activity.

b) antagonistic activity:

All the compounds mentioned show a 100% antagonistic activity.

The antagonistic potency of the compounds is summarized in Table 1. Table 1: Antagonist potency of the compounds Ex. PR-A IC ₅₀ [nM] PR-B IC ₅₀ [nM] Ex. PR-A IC ₅₀ [nM] PR-B IC ₅₀ [nM] 1 37.2 72.5 5 2.59 0.46 2 0.46 1.2 6 0,014 0.08 3 31 21.4 7 0.96 0.30 4 0.59 0.85 8th 0.12 0.10

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• RU 486 [0004]
• EP 57115 [0004]
• WO 98/34947 [0004, 0040, 0042, 0085]
• DE 4216003 [0040, 0085]
• DE 40181676 [0040, 0093]
• WO 2008/058767 [0042]
• WO 96/15794 [0062]
• WO 96/03130 [0062]
• EP 2009/003249 [0062]
• WO 98/007740 [0065]
• WO 99/33855 [0065]
• WO 03/045972 [0065]
• WO 01/47490 [0075, 0075]
• WO 06/010097 [0075]

Cited non-patent literature

• Fuhrmann et al., J. Med. Chem. 43, 5010-5016 (2000) [0004]
• Steroids 1994, p. 176-180 [0040]
• Tetrahedron 1995, pp. 5563-5572 [0040]
• Hoffmann J et al., J Natl Cancer Inst 2004, 96: 210-218 [0065]
• Steroids, 1994, p. 176-180; Tetrahedron, 1995, pp. 5563-5572 [0093]

Claims (5)

Compound of formula I

wherein R ¹ and R ^{2 are the} same or different and are hydrogen, an optionally dimethylamine-substituted C ₁ -C ₁₀ alkyl radical, an optionally mono-, di- or polysubstituted by halogen (-F, -Cl, -Br, -I ), -OH, -O-alkyl, -C (O) OH, -C (O) O alkyl, -C (O) NH ₂ , -C (O) NH alkyl, -C (O) N dialkyl, -C (O ) NHAryl, -C (O) NH-heteroaryl, -NH ₂ , -NH (C ₁ -C ₁₀ -alkyl), -N (C ₁ -C ₁₀ -alkyl) ₂ , especially -N (CH ₃ ) ₂ , -NHC (O) alkyl, -NO ₂ , -N ₃ , -CN, -C ₁ -C ₁₀ alkyl, -C ₁ -C ₁₀ perfluoroalkyl, -C ₁ -C ₁₀ acyl, -C ₁ -C ₁₀ -acyloxy, -SO ₂ NH ₂ , -SO ₂ NHalkyl or -SO ₂ NDialkyl substituted 6-10-membered aryl radical, a 5 optionally substituted one, two or more times with the above-mentioned substituents of the 6-10-membered aryl group -10-membered heteroaryl radical, one on the aryl ring optionally mono-, di- or polysubstituted with the abovementioned substituents of the 6-10-membered aryl radical substituted C ₁ -C ₆ arylalkyl or one on heteroaryl optionally one, two or C ₁ -C ₆ -heteroarylalkyl radical substituted several times by the abovementioned substituents of the 6-10-membered aryl radical, or else R ¹ and R ² together form part of an optionally on the carbon alkyl, carboxyl-alkoxycarbonyl, alkylcarbonyl, aminocarbonyl radical , Arylalkyl, heteroarylalkyl, aminoalkyl-substituted or on the nitrogen, alkyl, alkanoyl, carboxyl, alkoxycarbonyl, phenyl, phenylalkyl, pyridinyl, pyrimidinyl, pyrazinyl, sulfonyl, benzoyl, alkylsulfonyl, Arylsulfonyl, aminocarbonyl, aminocarbonylalkyl, arylalkyl, heterocyclylakyl, heteroarylalkyl and aminoalkyl substituted 3-10 membered ring optionally containing nitrogen, oxygen or sulfur atoms which may optionally be oxidized to the sulfoxide or sulfone, wherein optionally an aromatic can be fused to the 3-10-membered ring, R ³ and R ^{4 are} either each a hydrogen atom or together form a methylene bridge X is a sour toffatom or, NOR ⁵ or NNHSO ₂ R ⁵ , R ^{5 is} selected from the group comprising hydrogen, C ₁ -C ₁₀ alkyl, aryl and their salts, solvates or solvates of the salts, including all crystal modifications. The compounds according to claim 1: (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -12 - [(dimethylamino) methyl] -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -1,2,3 , 3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracen-7-one (Ex ) tert -Butyl - [[(1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -1-hydroxy-15a-methyl-7-oxo-1- (pentafluoroethyl) -1,2,3,3a, 3b , 5,7,8,9,10,14b, 14c, 15,15a-tetradecahydro-4H-benzo [n] indeno [4,5,6-de] anthracene-12-yl] methyl} piperazine-1-carboxylate (Ex. 2) (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -12- (piperazin-1-ylmethyl) -1,2,3 , 3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracen-7-one (Example 3 ) (1S, 3aS, 3bS, 9aS, 14bS, 14cR, 15aS) -12 - [(4-acetylpiperazin-1-yl) methyl] -1-hydroxy-15a-methyl-1- (pentafluoroethyl) -1,2, 3,3a, 3b, 4,5,8,9,10,14b, 14c, 15,15a-tetradecahydro-7H-benzo [n] indeno [4,5,6-de] anthracen-7-one (ex. 4) (11β, 17β) -11- {4 - [(dimethylamino) methyl] phenyl} -17-hydroxy-17- (pentafluoroethyl) estr-4-en-3-one (Ex. 5) tert -Butyl 4- {4 - [(11β, 17β) -17-hydroxy-3-oxo-17- (pentafluoroethyl) estr-4-en-11-yl] benzyl} piperazine-1-carboxylate (Ex. 6 ) (11β, 17β) -17-hydroxy-17- (pentafluoroethyl) -11- [4- (piperazin-1-ylmethyl) phenyl] estr-4-en-3-one (Ex. 7) (11β, 17β) -11- {4 - [(4-acetylpiperazin-1-yl) methyl] phenyl} -17-hydroxy-17- (pentafluoroethyl) estr-4-one-3-one (Ex 8) A compound according to any one of claims 1-2 for the treatment and prophylaxis of uterine fibroids, endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast cancers and disorders associated with menopause or for fertility control and emergency contraception. A medicament containing a compound as defined in one of claims 1 or 2, optionally in combination with another active ingredient. A medicament according to claim 4 for the treatment and prophylaxis of uterine fibroids, endometriosis, severe menstrual bleeding, meningiomas, hormone-dependent breast carcinomas and menopausal-related disorders or for fertility control and emergency contraception.