11-Beta-aryl-4-estrene, method for its production and its use as a medicine.

The present invention relates to 11β-aryl-4-estrenes of the general formula I.<chemistry id="chem0001" num="0001"><img file="EP0404283A2_D0001.tif" /></chemistry> wherein X for an oxygen atom, the hydroxyimino grouping&gt; N∼OH or two hydrogen atoms, R¹ represents a hydrogen atom or a methyl group, R² represents a hydroxy group, a C₁-C₁₀ alkoxy or C₁-C₁₀ acyloxy group, R³ for a hydrogen atom, the grouping - (CH₂)_nCH₂Z, where n is 0, 1, 2, 3, 4 or 5, Z is a hydrogen atom, the cyano group or the radical -OR⁵ with R⁵ = H, C₁-C₁₀-alkyl or C₁-C₁₀-acyl, the grouping - ( CH₂)_mC≡CY, where m is 0, 1 or 2 and Y is a hydrogen, fluorine, chlorine, bromine or iodine atom, a C₁-C₁₀ hydroxyalkyl, C₁-C₁₀ alkoxyalkyl, C₁-C₁₀ acyloxyalkyl radical , the grouping - (CH₂)_p-CH = CH- (CH₂)_kCH₂R⁶, where p is 0 or 1 and k is 0, 1 or 2 and R⁶ is a hydrogen atom, a hydroxyl group, a C₁-C₄ alkoxy or C₁-C₄ acyloxy radical, or R² and R³ together for a radical of the formula<chemistry id="chem0002" num="0002"><img file="EP0404283A2_D0002.tif" /></chemistry> R⁴ for a hydrogen atom, a cyano group, a chlorine, fluorine, bromine, iodine atom, for a trialkylsilyl, trialkylstannyl group, for a straight-chain or branched, saturated or unsaturated C₁-C₈ alkyl, acyl or alkoxyalkyl radical, for an amino group<chemistry id="chem0003" num="0003"><img file="EP0404283A2_D0003.tif" /></chemistry> in which R⁷ and R⁸ independently represent a hydrogen atom or a C₁-C₄ alkyl group, or for a corresponding amine oxide<chemistry id="chem0004" num="0004"><img file="EP0404283A2_D0004.tif" /></chemistry> or for the groupings -OR⁹ or -S (O)_iR⁹ with i = 0, 1 or 2, in which R⁹ is a hydrogen atom, a methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl or a 2-dimethylaminoethyl group, or for a heteroaryl radical of the formula Iα<chemistry id="chem0005" num="0005"><img file="EP0404283A2_D0005.tif" /></chemistry> in which A is a nitrogen, oxygen or sulfur atom, -BDE- the sequence of elements -CCC-, -NCC- or -CNC- and R¹⁰ a hydrogen atom, a cyano group, a chlorine, fluorine, bromine, iodine atom, a trialkylsilyl -, Trialkylstannylgruppe, a straight-chain or branched, saturated or unsaturated C₁-C₈ alkyl, acyl or alkoxyalkyl radical, for an amino group<chemistry id="chem0006" num="0006"><img file="EP0404283A2_D0006.tif" /></chemistry> in which R⁷ and R⁸ independently represent a hydrogen atom or a C₁-C₄ alkyl group, or a corresponding amine oxide<chemistry id="chem0007" num="0007"><img file="EP0404283A2_D0007.tif" /></chemistry> or the grouping -OR⁹ or -S (O)_iR⁹ with i = 0, 1 or 2, in which R⁹ represents a hydrogen atom, a methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl or a 2-dimethylaminoethyl group, symbolize, or for a heteroaryl radical of the formula Iβ<chemistry id="chem0008" num="0008"><img file="EP0404283A2_D0008.tif" /></chemistry> in which A is a nitrogen atom and -BDE- the sequence of elements -CCC-, -NCC-, -CNC- or -CCN- mean and R¹ bedeuten has the meaning already given, or for a phenyl radical of the formula Iγ<chemistry id="chem0009" num="0009"><img file="EP0404283A2_D0009.tif" /></chemistry> where R¹⁰ has the meaning already given, stand, as well as their pharmacologically acceptable addition salts with acids, processes for their preparation, pharmaceutical preparations containing these compounds, their use for the production of medicaments and the new intermediates required for this.

The invention particularly relates to compounds in which X represents an oxygen atom.

The alkoxy, acyloxy, alkyl, acyl and hydroxyalkyl groups contained in R², R³, R⁵ and Y of the general formula I should each contain 1 to 10 and the alkoxyalkyl or acyloxyalkyl groups in Y contain 2 to 10 carbon atoms. The preferred groups of the alkoxy groups are the methoxy, ethoxy, propoxy and isopropoxy groups, the formyl (oxy), acetyl (oxy) and propionyl (oxy) groups come from the acyl (oxy) groups special meaning too.

In the case of the alkyl groups, the methyl, ethyl, propyl, isopropyl and tert-butyl group are to be mentioned in particular, and of the hydroxyalkyl groups the corresponding radicals which are substituted in any position by a hydroxyl group are preferred.

0, 1, 2 and 3 are particularly suitable for n; if Z = CN, a cyanomethyl group (n = 0) is particularly preferred. In addition to the groups already mentioned, Y can preferably also be a hydrogen, chlorine or bromine atom.

Of the alkenyl residues in R³, the propenyl and butenyl groups, which may be in the E or Z configuration, are preferred, that is, when R³ is - (CH₂)_p-CH = CH- (CH₂)_k-CH₂-R⁶, then k should preferably be 0 or 1 and p = 0. Among the alkoxy or acyloxy groups mentioned for R⁶, which can be either straight-chain or branched, the methoxy, ethoxy, propoxy, isopropoxy or formyloxy, acetyloxy and propionyloxy groups are particularly preferred.

Of the C₁-C₈-alkyl and alkoxyalkyl radicals which can represent R⁴, these are primarily the methyl, ethyl, propyl, isopropyl, cyclopentyl and cyclohexyl radical or the alkoxymethyl or 1- or 2- Alkoxyethyl groups with said alkyl radicals; of the C₁-C₈ acyl radicals for R⁴ is particularly intended for the acetyl, propionyl and isobutylryl radical.

R⁴ stands for the amino group<chemistry id="chem0010" num="0010"><img file="EP0404283A2_D0010.tif" /></chemistry> R⁷ and R⁸ preferably each represent a methyl radical, but the ethyl radical is also of particular importance, in which case either both radicals on the nitrogen atom represent an ethyl radical or one represents a methyl radical and one represents an ethyl radical. For the substituent R⁹, the methyl, ethyl and 2- (dimethylamino) ethyl group are particularly noteworthy.

Of the heteroaryl radicals possible according to formula Iα, the 3-thienyl, 3-furyl and 3-pyrrolyl radical are preferably with R¹ mit in the meaning of a cyano, methoxy or dimethylamino group.

Suitable heteroaryl radicals of the formula Iβ are, in particular, the 3- or 4-pyridyl, the 5-pyrimidinyl, 4-pyridazinyl or pyrazinyl radical. The phenyl radical of the formula Iγ has, in particular, the cyano, methoxy or dimethylamino group as the substituent R¹⁰, these substituents again preferably being in the p-position of the phenyl ring.

The compounds mentioned below are particularly preferred according to the invention: 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- (4-acetylphenyl) -17β-hydroxy-4-estren-3-one; 11β- (4-acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one; 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one; 11β- [4- (3-furyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- [4- (3-furyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one; 11β- [4- (5-pyrimidinyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- [4- (5-pyrimidinyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one; 11β- [4- (3-pyridyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- [4- (3-pyridyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one 11β- [4- (4-cyanophenyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- [4- (4-cyanophenyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one; 11β- (4-vinylphenyl) -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one; 11β- (4-vinylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- [4- (1-hydroxyethyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one; 11β- [4- (1-hydroxyethyl) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one; 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α-methoxymethyl) -4-estren-3-one; 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α-cyanomethyl) -4-estren-3-one; (11β, 17β) -4 ′, 5′-dihydro-11- [4- (dimethylamino) phenyl] spiro [estr-4-en-17.2 ′ (3′H) furan] -3-one; (11β, 17β) -3 ′, 4′-dihydro-11- [4- (dimethylamino) phenyl] spiro (estr-4-en-17,2′ (5′H) furan] -3,5-dione ; (11β, 17β) -11- [4- (dimethylamino) phenyl] spiro [estr-4-en-17.2 ′ (5′H) furan] -3-one; 11β- [4- (Dimethylamino) phenyl] -17α- (1-propynyl) -4-estren-17β-ol 17β-Hydroxy-3-oxo-11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (<i>E</i>) -17β-Hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (<i>Z.</i>) -17β-Hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile 17β-Hydroxy-17α- (2-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one 17β-Hydroxy-17α- (methoxymethyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one 11β- (4-ethylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (<i>Z.</i>) -11β- (4-ethylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (<i>Z.</i>) -11β- [4- (2-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one 11β- (4-ethenylphenyl) -17β-hydroxy-17α-methyl-4-estren-3-one (<i>Z.</i>) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -11β- (4-methylphenyl) -4-estren-3-one (11β, 17β) -11- [4- (5-pyrimidinyl) phenyl] spiro [estr-4-en-17.2 ′ (3′H) furan] -3-one.

The compounds of the general formula I are competitive antagonists of progesterone (antigestagens). In addition to a Δ⁴Δagen-3-oxo-chromophore, all steroidal antigestagens that have become known until recently have a preferably substituted 11β-phenyl residue (A. Belanger, D. Philibert and G. Teutsch, Steroids<u style="single">37</u>, 2742 (1981); D. Philibert, T. Ojasoo and JP Raynand, Endocrinology<u style="single">10</u>, 1850 (1977), EP-A 057 115; G. Teutsch, T. Ojasoo and JP Raynand, J. Steroid Biochem, 31, 549 (1988)).

Recently, antigestagens of steroidal origin have also been bound, in which a methylene bridge between the 9-C atom and one of the ortho-C atoms of the 11β-aryl ring has been substituted for the 9,10-double bond (EP-A 0283428). Obviously, the introduction of the 11β-aryl residue causes the transition from gestagen to antigestagenic activity. However, it has so far not been possible to produce an antigestagen closest to the progesterone, so to speak "the antiprogesterone", which would not have a 9,10-double bond but would have a "free" 10β-substituent, eg a hydrogen atom, in addition to an 11β-aryl radical. Attempts to isomerize 11β- [4- (substituent) aryl] -17β-hydroxy-5 (10) -estren-3-one into the corresponding compound with a 4 (5) double bond by brief treatment with dilute mineral acids, conditions , among which a double bond shift in the 11-unsubstituted row from the 5 (10) - to the 4 (5) -position occurs easily (G. Neef, G. Sauer and R. Wiechert, Tet. Let., <u style="single">24</u>, 5205 (1983)). However, conditions have now been set under which it is surprisingly possible to shift the 5 (10) double bond to the 4 (5) position. Treatment of compounds of general formula II<chemistry id="chem0011" num="0011"><img file="EP0404283A2_D0011.tif" /></chemistry> wherein R¹ and R⁴ have the meaning given in formula I, A for a β-hydroxy group or the radical R² and B for an α hydrogen atom, an α radical R³ or A and B together represent a keto oxygen atom, with acid in an inert solvent with heating leads to compounds of general formula Ia<chemistry id="chem0012" num="0012"><img file="EP0404283A2_D0012.tif" /></chemistry> wherein R¹, A and B have the meaning given in formula II and R^4′ has the same meaning as R⁴ in formula I, with the proviso that R⁴ is stable under the drastic reaction conditions mentioned.

The isomerization is preferably heated to a temperature between 80 and 120 ° C. in an inert solvent such as toluene. The reaction time is at least 45 minutes, but may be 24 hours or more if necessary. Both mineral and organic acids are suitable as acids; of the latter, p-toluenesulfonic acid is preferred.

The compounds of the general formula Ia can already be an end compound of the general formula I if the substituents R⁴, A and B in the starting compound of the general formula II are those substituents which withstand the drastic reaction conditions required for the isomerization. In particular, free hydroxyl groups on a tertiary carbon atom are eliminated under these reaction conditions.

However, it can make sense in any case to introduce the substituents R² and R³ on the C-17 atom or to build R⁴ in the 4-position of the 11β-phenyl radical only after the isomerization. Depending on the substituents R², R³ and R⁴ ultimately desired in the compound of the general formula I after the isomerization, either<ul id="ul0001" list-style="none"><li>a) in the compound of general formula Ia, if A is a β-hydroxy group and B is an α-hydrogen atom, if desired the 17-hydroxy group is oxidized to the 17-keto group and</li><li>b) the 3-keto function is converted into a dithioketal, all other keto groups which may be present are also ketalized or else first b) and then a) and then</li><li>c) in the event that R^4′ in the 3-thioketalized compound stands for a methoxy or a hydroxy group and R⁴ in the ultimately desired compound of the general formula I should not stand for a methoxy or hydroxy group, the hydroxy compound, optionally after cleavage of the methoxy compound, into a corresponding perfluoroalkylsulfonic acid compound in which -alkyl- represents a C₁-C₄alkyl radical, transferred and from this either directly by reaction with an appropriately substituted tin (trialkyl) compound R⁴^'- Sn (alkyl) ₃ or with an appropriately substituted boron compound R⁴ --BL₂ (L = hydroxy or alkyl), in which R^4˝ is identical to R⁴ of the general formula I or represents a tautomeric precursor of R⁴ and alkyl is a C₁-C₄ alkyl radical or indirectly via a 4-position of the 11β-phenyl residue with a tin (trialkyl) residue (alkyl = C₁-C₄) substituted compound which was obtained by reacting the perfluoroalkylsulfonate compound with Sn₂alkyl₆, and further treatment of the 11β- (4-trialkylstannyl) phenyl -Connection with a connection R^4˝-Y, where R^4˝ is identical to R⁴ of the general formula I or represents a tautomeric precursor of R⁴ and Y is a leaving group, preferably a halogen atom and in particular a bromine atom, in the presence of a transition metal catalyst a compound of the general formula III<chemistry id="chem0013" num="0013"><img file="EP0404283A2_D0013.tif" /></chemistry> wherein Z represents a keto group protected in the form of a dithioketal, and</li><li>d) then, if R² and R³ in the ultimately desired compound of general formula I are not intended to represent a hydroxyl group or a hydrogen atom or R² and R³ together are not intended to represent a keto oxygen atom, the desired substituents R² on the C-17 atom of the steroid skeleton and R³ introduced by methods known per se or first d) and then c) is executed, Splitting off protective groups, alkylating free hydroxyl groups if desired or are acylated and, if desired, the 3-keto group is converted into a 3-hydroxyimino group&gt; N∼OH or the 3-keto group into the dihydro compound using hydroxylamine hydrochloride, and a pharmaceutically acceptable addition salt is optionally prepared with an acid.</li></ul>

Process steps a), b), c) and d) are carried out according to methods known per se. The oxidation a) of the hydroxy group to the keto group can be carried out, for example, according to Oppenauer or with chromic acid reagents (Jones' reagent) or chromic acid pyridine. The protecting group for the 3-keto function is preferably the ethane-1,2-diyl-bis (thio) group, which is obtained by reacting the 3-keto compound with ethane-1,2-dithiol in the presence of, for example p-Toluenesulfonic acid can be introduced at the steroid 3-C atom. Optionally, the oxidation and then the protective group introduction or first the protective group introduction and then the oxidation can be carried out. The reaction step c) serves to build up the substituent R⁴ or R^4′ in the p-position on the 11β-phenyl ring. This procedure is necessary if R⁴ represents such a substituent that does not withstand the drastic isomerization conditions, for example an allyl or vinyl radical.

The starting point for this structure is the 11β- (4-hydroxyphenyl) compound which can be obtained from the corresponding methoxy compound by ether cleavage, for example using sodium methanethiolate in a solvent such as dimethylformamide.

By reacting the hydroxy compound with a perfluoro (C₁-C₄) alkylsulfonic anhydride or halide in the presence of a base such as pyridine or 4- (dimethylamino) pyridine, the corresponding 11β- [4- (perfluoroalkylsulfonyloxy) phenyl] compound (PJ Stang, M. Hanack and LR Subramanian, <u style="single">Synthesis</u> 85, (1982)). In the subsequent coupling of the 11β-aryl compound with R^4˝ -Sn (alkyl) ₃ or R^4˝-BL₂ is either carried out in such a way that in a transition metal-catalyzed reaction (preferably Pd⁰) the perfluoroalkyl sulfonate leaving group is displaced with essentially almost simultaneous substitution by the desired substituent or its precursor (aryl couplings with tin compounds: JE McMurry and S. Mohanraj, Tetrahedron Letters, <u style="single">24</u>, No. 27, pp. 2723-2726, 1983; X. Lu and J. Zhu, Communications, pp. 726-727, 1987; Q. -Y. Chen and Z.-Y. Yang, tetrahedron letters<u style="single">27</u>, No. 10, pp. 1171-1174, 1986; S. Cacchi, PG Ciattini, E. Morera and G. Ortar, Tetrahedron Letters,<u style="single">27</u>, No. 33, pp. 3931-3934, 1986; AM Echavarren and JK Stille, J. Am. Chem. Soc. 1987, 109, pp. 5478-5486; with boron compounds: Synthesis 936 (1984), Chem.Pharm.Bull.<u style="single">33</u>, 4755-4763 (1985); J.Org.Chem.<u style="single">49</u>, 5237-5243 (1984); Bull.Chem.Soc.Jpn.<u style="single">61</u>, 3008-3010ß (1988) or an appropriate tri-organylstannyl, preferably tri-n-alkylstannyl compound is prepared from the perfluoroalkyl sulfonate compound as an intermediate and transition metal catalyst [JK Stille, Angew. Chem. 98 (1986), pp. 504-519]. This is then carried out in a one-pot reaction with a halogen, preferably bromine or iodine substituted carbocyclic or heterocyclic aromatic [Y. Yamamoto, Y. Azuma, H. Mitoh, Communications, pp. 564-565, 1986; TJ Bailey, Tetrahedron Letters, <u style="single">27</u>, No. 37, pp. 4407-4410, 1986], which can optionally carry further substituents, implemented; the 11β-phenyl radical then has the desired or a precursor of the desired substitution. Numerous such reactions with steroids, in which a trifluoromethanesulfonate group is in the 4-position of an 11β-phenyl ring, are described in EP-A-0283428. Free hydroxy groups can be alkylated or acylated in a manner known per se. Dialkylamines can be converted into the desired N-oxides using suitable oxidizing agents (eg hydrogen peroxide or peracids) [see eg Contacts (Darmstadt) 1986.3, p.12].

Compounds with a dialkylamine substituent on the 11β-phenyl ring can by reaction with cyanogen bromide in aprotic solvents such as dioxane, benzene or toluene at elevated temperature (amine degradation according to Braun) analogous to those in, for example, Org. Reactions <u style="single">7</u>, 198 (1953), KW Bentley, Techniques of Organic Chemistry <u style="single">11</u>, 773 (1963) and Houben-Weyl, 5/4, 151 (1960) instructions given in good yield can be converted into the corresponding (N-cyano-N-alkylaminoaryl) derivatives.

Depending on the meaning you want from<chemistry id="chem0014" num="0014"><img file="EP0404283A2_D0014.tif" /></chemistry> in the end product in a manner known per se to the corresponding dialkylamine compounds (for example with diisobutylaluminum hydride in toluene to the N-formyl-N-alkylaminophenyl intermediates and then with lithium aluminum hydride) or NHN-alkyl compounds (for example with lithium aluminum hydride or with lithium in liquid ammonia). If desired, the latter are then acylated in a manner known from the literature and, if appropriate, subsequently reduced in a known manner to, for example, lithium aluminum hydride to give the new dialkylamine derivative (see DE 36 23 038).

Finally, in process step d) the substituents R² and R³ which are ultimately desired on the 17-C atom are introduced, provided that this is not a methoxy or hydroxyl group already contained as R² from the outset, or a hydrogen atom as R³ or one together from R² and R³ is keto oxygen atom formed. This introduction follows analogous methods known from the literature (for example J. Fried, JA Edwards, "Organic Reactions in Steroid Chemistry," Van Nostrand Reinhold Company, 1972, Vol. 1 and 2; "Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, Vol. 1-2) by nucleophilic addition to the C-17 ketone.

The introduction of the substituent -C≡CY as R³, where Y has the meaning given above, is carried out with the aid of a metalated compound of the general formula MC≡CY`, in which Y` is an alkyne protecting group, such as trimethylsilyl or tert.- Butyldimethylsilyl.

The organometallic compound can also be formed in situ and reacted with the 17-ketone. For example, acetylene and an alkali metal, especially potassium, sodium or lithium, can be allowed to act on the 17-ketone in a suitable solvent in the presence of an alcohol or in the presence of ammonia. The alkali metal can also act in the form of, for example, methyl or butyllithium. Dialkyl ethers, tetrahydrofuran, dioxane, benzene and toluene are particularly suitable as solvents.

The introduction of 3-hydroxypropin, propene or -propane in the 17-position takes place by reacting the 17-ketone with the dianion of the propargyl alcohol (3-hydroxypropin), for example the dipotassium salt of the propargyl alcohol generated in situ, to give the 17α- (3-hydroxyprop-1-ynyl) -17β-hydroxy derivative or with metalated derivatives of 3-hydroxypropine, for example with 1-lithium-3- (tetrahydropyran-2'-yloxy) prop-1-in-1-id, for 17- [3- (tetrahydropyran-2'-yloxy ) -prop-1-ynyl] -17β-hydroxy derivative, which subsequently leads to the 17- (3-hydroxypropyl or Hydroxypropenyl) 17β-hydroxy compounds can be hydrogenated. This can be achieved, for example, by hydrogenation at room temperature and normal pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with the addition of noble metal catalysts such as platinum or palladium.

Homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups are introduced in a corresponding manner with homologues of propargyl alcohol.

The compound with the Z-configured double bond in the hydroxypropenyl group is formed by hydrogenating the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, JA Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, page 134; and HO House: Modern Synthetic Reactions 1972, page 19). For example, 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate are suitable as deactivated noble metal catalysts. The hydrogenation is stopped after the absorption of one equivalent of hydrogen.

The connection with the E-configured double bond in the hydroxypropenyl group is formed by reducing the acetylenic triple bond in a manner known per se. A whole series of methods for converting alkynes to trans-olefins are described in the literature, for example reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63 (1941) 216), with sodium amide in liquid ammonia (J Chem. Soc. 1955, 3558), with lithium in low molecular weight amines (JA Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1972) 6560), with diisobutylaluminum hydride and methyl lithium (J. Am. Chem. Soc. 89 (1967) 5085) and in particular with lithium aluminum hydride / alcoholate (J. Am. Chem. Soc. 89 (1967) 4245). Another possibility is the reduction of the triple bond with chromium (II) sulfate in the presence of water or dimethylformamide in a weakly acidic medium (J. Am. Chem. Soc. 86 (1964) 4358) and generally the reduction by the action of transition metal compounds with a change in the oxidation state.

The hydroxyalkenes can also be introduced directly by adding a corresponding metalated hydroxyalkenyl compound, such as, for example, 1-lithium-3- (tetrahydropyran-2'-yloxy) prop-1 (E) -en (J. Org. Chem. <u style="single">40</u> 2265) or 1Lithium-3- (tetrahydropyran-2′-yloxy) prop-1 (Z) -en (synthesis <u style="single">1981</u>, 999) Homologues can also be introduced in this way.

The introduction of 3-hydroxypropane in the 17-position can also be carried out directly by reacting the 17-ketone with metalated derivatives of 3-halopropanols - the hydroxyl group in the metalation step as an alcoholate (tetrahedron letters <u style="single">1978</u>, 3013) or as a protected function (J. Org. Chem. <u style="single">37</u>, 1947) - to the 17- (3-hydroxypropyl) -17β-hydroxy compound or to the compound protected at the terminal hydroxyl group. The protective groups include, for example, the ethoxyethyl, tetrahydropyranyl and methoxymethyl groups. If end products of formula I are desired with R² / R³ in the meaning of<chemistry id="chem0015" num="0015"><img file="EP0404283A2_D0015.tif" /></chemistry> the 17- (3-hydroxypropyl) or 17- (4-hydroxybutyl) compound is oxidized in a manner known per se, for example using Jones' reagent, manganese dioxide, pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine or the fetizone reagent Silver carbonate / Celite (Compt. Rend. 267 [1968] 900).

The representation of end products of formula I with R² / R³ in the meaning of<chemistry id="chem0016" num="0016"><img file="EP0404283A2_D0016.tif" /></chemistry> is carried out by the ring closure reaction of the corresponding 17- (3-hydroxyprop-1- (Z) -enyl- or 17- (4-hydroxybut-1- (Z) -enyl-17-β-hydroxy-educt. Hydrogenation of the unsaturated 5- or 6-ring spiroethers on the palladium / activated carbon contact leads to the saturated spiroethers.

The 17-cyanomethyl side chain is built up in a manner known per se from the 17-ketone, for example via the 17-spiroepoxide and cleavage of the spiroepoxide with HCN according to Z. Chem. <u style="single">18</u> (1978) 259-260.

The 17-hydroxyacetyl side chain is also introduced by methods known per se, for example by the methods described in J. Org. Chem. <u style="single">47</u> (1982), 2993-2995, Chem. Ber. <u style="single">113</u> (1984), 1184 and U.S. Patent 4,600,538. Free hydroxy groups can be alkylated or acylated in a manner known per se.

If necessary, the introduction of the substituents R² and R³ as described under d) can also be carried out first and then the substituent R⁴ can be built up according to c), depending on whether the process conditions of the second reaction step impair the substituents introduced first but built up.

Protective groups that are still present are split off using standard methods.

If desired, the compounds of general formula I with X in the meaning of an oxygen atom can be obtained by reaction with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between -20 and + 40 ° C. in the oximes (formula I with X in the meaning of the hydroxyimino grouping N OH , where the hydroxyl group can be syn- or anti-stable). Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU), with pyridine being preferred.

The removal of the 3-oxo group to an end product of the general formula I with X meaning 2 hydrogen atoms can be carried out, for example, by reductive cleavage of the thioketal according to the instructions given in DE-A-2805490.

The new compounds of general formula I and their addition salts with pharmaceutically acceptable acids are valuable pharmaceuticals. They have a strong affinity for the gestagen receptor and have surprisingly strong antigestagenic, antiglucocorticoid, antimineralcorticoide and antiandrogenic properties. These important biological effects can be used for medical purposes. Active substances of this type with pronounced antigestagenic activity are suitable for triggering abortions, since they displace the progesterone required to maintain pregnancy from the receptor. They are therefore valuable and interesting with regard to their use for postcoital fertility control. The new compounds can also be used to treat endometriosis. They can also be used against hormonal irregularities, for triggering menstruation and for induction of labor. They can also be used to treat hormone-dependent carcinomas.

The compounds of the general formula I according to the invention and their addition salts with pharmaceutically acceptable acids also have antiglucocorticoid activity and can therefore also be used as medicaments for the therapy of corticoid-induced disorders (glaucoma) and for combating side effects which occur during long-term treatment with glucocorticoids (Cushing Syndrome). They therefore also make it possible to combat the disorders due to supersecretion of the glucocorticoids, especially obesity, arteriosclerosis, hypertension, osteoporosis, diabetes and insomnia.

The compounds of general formula I and their addition salts with pharmaceutically acceptable acids with antiandrogenic activity can be used in the treatment of hypertrophy and prostate cancer. They also enable a specific therapy for symptoms of androgenization in women: the pathological hairiness in hirsutism, androgenetic alopecia and the increased sebum gland function in acne and seborrhea can be influenced favorably.

The invention thus also relates to medicaments based on the compounds of the general formula I and their addition salts with pharmaceutically acceptable acids, if appropriate together with the customary auxiliaries and carriers.

The compounds according to the invention and their salts can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragees, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.

The active ingredient (s) can be combined with the auxiliaries customary in galenics such as gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens^(R) or Myrj^(R), Magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifying agents, preservatives and flavoring agents for flavor correction (for example essential oils) are mixed. The invention thus also relates to pharmaceutical compositions which contain at least one compound according to the invention or one of its addition salts with pharmaceutically acceptable acids as the active ingredient. The hydrochlorides and the methanesulfonates are to be mentioned in particular as addition salts of the products according to the invention with acids. One dose unit contains about 1-100 mg of active ingredient (s). The dosage of the compounds according to the invention in humans is about 1-1000 mg per day.

The abortive effect was determined to identify the antigestagenic effect.

The experiments were carried out on female rats weighing approx. 200 g. After mating, the onset of pregnancy was confirmed by detection of sperm in vaginal smears. The day of the sperm detection is considered day 1 of pregnancy (= d1 pc).

The animals were treated with the substance to be tested or the solvent after the blastocysts were nidated from d5 pc to d7 pc. On d9 pc, the animals were sacrificed and the uteri were examined for implants and absorption sites. Photos of all uteri were taken. The absence of implants, pathological, hemorrhagic or otherwise abnormal nidation sites was considered an abortion.

The test substances were dissolved in a benzyl benzoate-castor oil mixture (ratio 1 + 4). The vehicle volume per single dose was 0.2 ml. The treatment was carried out subcutaneously.

The superiority of the compounds according to the invention is clearly demonstrated by comparing the abortive activity of the compounds A to E with the compound F described in European patent 0 057 115; the comparison compound F (= RU 486) differs from compound A only in the additional 9 (10) double bond.

The following were examined as antigestagens:

<ul id="ul0002" list-style="none"><li>A: 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one</li><li>B: (Z) -11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one</li><li>C: (Z) -11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one</li><li>D: (Z) -17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one</li><li>E: (Z) -4 ′ - [17β-hydroxy-17α- (3-hydroxy-1-propenyl) -3-oxo-4-estren-11β-yl] [1,1′-biphenyl] -4-carbonitrile</li><li>F: 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -4.9 (10) estradien-3-one</li></ul><tables id="tabl0001" num="0001"><table frame="all"><title>Table 1</title><tgroup cols="4" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="39.37mm" /><colspec colnum="2" colname="col2" colwidth="39.37mm" /><colspec colnum="3" colname="col3" colwidth="39.37mm" /><colspec colnum="4" colname="col4" colwidth="39.37mm" /><thead valign="top"><row><entry namest="col1" nameend="col4" align="center"><u style="single">Abortive test in the gravid rat treatment from d5 pc to d7 pc, autopsy on d9 pc</u></entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="center">connection</entry><entry namest="col2" nameend="col2" align="center">Dose mg / animal / day sc</entry><entry namest="col3" nameend="col3" align="center">Abortion rate n Abort / n Total</entry><entry namest="col4" nameend="col4" align="center">%</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" morerows="2" rowsep="1" align="left">A</entry><entry namest="col2" nameend="col2" align="char" char=",">3.0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">1.0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row rowsep="1"><entry namest="col2" nameend="col2" align="char" char=",">0.3</entry><entry namest="col3" nameend="col3" align="right">3/4</entry><entry namest="col4" nameend="col4" align="right">( 75)</entry></row><row><entry namest="col1" nameend="col1" morerows="2" rowsep="1" align="left">B</entry><entry namest="col2" nameend="col2" align="char" char=",">3,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">1,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row rowsep="1"><entry namest="col2" nameend="col2" align="char" char=",">0,3</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col1" nameend="col1" morerows="3" rowsep="1" align="left">C.</entry><entry namest="col2" nameend="col2" align="char" char=",">3,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">1,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">0,3</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row rowsep="1"><entry namest="col2" nameend="col2" align="char" char=",">0,1</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col1" nameend="col1" morerows="2" rowsep="1" align="left">D</entry><entry namest="col2" nameend="col2" align="char" char=",">3,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">1,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row rowsep="1"><entry namest="col2" nameend="col2" align="char" char=",">0,3</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col1" nameend="col1" morerows="3" rowsep="1" align="left">E</entry><entry namest="col2" nameend="col2" align="char" char=",">3,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">1,0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">0,3</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row rowsep="1"><entry namest="col2" nameend="col2" align="char" char=",">0,1</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col1" nameend="col1" morerows="2" rowsep="1" align="left">F</entry><entry namest="col2" nameend="col2" align="char" char=",">3.0</entry><entry namest="col3" nameend="col3" align="right">4/4</entry><entry namest="col4" nameend="col4" align="right">(100)</entry></row><row><entry namest="col2" nameend="col2" align="char" char=",">1.0</entry><entry namest="col3" nameend="col3" align="right">2/4</entry><entry namest="col4" nameend="col4" align="right">( 50)</entry></row><row rowsep="1"><entry namest="col2" nameend="col2" align="char" char=",">0,3</entry><entry namest="col3" nameend="col3" align="right">0/4</entry><entry namest="col4" nameend="col4" align="right">( 0)</entry></row></tbody></tgroup><tgroup cols="4" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="39.37mm" /><colspec colnum="2" colname="col2" colwidth="39.37mm" /><colspec colnum="3" colname="col3" colwidth="39.37mm" /><colspec colnum="4" colname="col4" colwidth="39.37mm" /><thead valign="top"><row><entry namest="col1" nameend="col4" align="center">Control solvent:</entry></row></thead><tbody valign="top"><row rowsep="1"><entry namest="col1" nameend="col1" align="left">0.2 ml benzyl benzoate + castor oil (1 + 4)</entry><entry namest="col2" nameend="col2" align="char" char=",">-</entry><entry namest="col3" nameend="col3" align="right">0/5</entry><entry namest="col4" nameend="col4" align="right">( 0)</entry></row><row rowsep="1"><entry namest="col1" nameend="col4" align="justify">n = 4 rats</entry></row></tbody></tgroup></table></tables>

Preparation of the required intermediates of general formula II

The preparation of the starting compound A, 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5α, 10α-epoxy-estr-9 (11) -en-17β-ol, required for all syntheses, is described in EP-A-0110434 or EP-A-0127864.

For R⁴ = -N (CH₃) ₂ is the representation of 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -5 (10) -estren-3-one (1M) as indicated a representative of a compound of general formula II.

By using a nucleophilic reagent other than propyne in synthesis step 1L, under conditions as specified in the description above, the other R 2 / R 3 radicals provided according to the invention can also be introduced.

Example 2 shows the preparation of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] 10β, 11β- (5-methoxy-o-phenylenethio) -estran-5α, 17β-diol. As described in Example 1, optionally using a nucleophilic reagent other than propyne in the analogous implementation of step 1L, compounds of the general formula II are obtained in which R^4′ represents a methoxy group.

Other starting products of general formula II can be prepared as shown in the reaction scheme below (the meanings of the substituents R¹, R², R³, R^4′ and R⁴ are identical to those of the general formulas):

The compounds D, E and L are compounds of the general formula II. The reaction step <u style="single">F</u> → <u style="single">I.</u> will with such connections <u style="single">F</u> in which R^4′ represents a hydroxy group. If necessary, this is introduced by cleavage of the corresponding methyl ether. The steps <u style="single">F</u>→ <u style="single">I.</u> such as <u style="single">I.</u> → <u style="single">K</u> are carried out analogously to the triflate formation carried out and described after the isomerization, with subsequent coupling in the 4-position of the 11β-aryl radical.<chemistry id="chem0017" num="0017"><img file="EP0404283A2_D0017.tif" /></chemistry>

Unless stated otherwise, the column chromatography purification steps in the examples below are carried out on silica gel with hexane / ethyl acetate, optionally with a mixture of increasing polarity.

EXAMPLE 1

Preparation of 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (1N)

A. 10β - [(3-aminophenyl) thio] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 9 (11) -estr-en-5α, 17β-diol (1A )

750 mg of 3-mercaptoaniline are dissolved in 5 ml of absolute THF, and 3.73 ml of a 1.6 molar n-butyllithium solution in hexane are added at -40 ° C. The cooling is removed and stirred for 30 minutes. Now 500 mg of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5α, 10α-epoxy-estr-9 (11) -en-17β-ol, dissolved in 4 ml of absolute THF added dropwise, the temperature being kept at 0 ° C. The mixture is then stirred at room temperature for 2 hours. The reaction mixture is mixed with 15 ml of saturated NH₄Cl solution and extracted with ethyl acetate, the organic phase washed with water and dried over Na₂SO₄, the solvent removed in vacuo. Column chromatography gives 484 mg<u style="single">1A</u> as foam.

B. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 10β - [(3- (formylamino) phenyl] thio) -9 (11) -estr-en-5α, 17β- diol (1B)

0.4 ml of acetic anhydride and 0.17 ml of formic acid are combined and stirred at room temperature under argon for 15 minutes. 1.0 g is added to this solution<u style="single">1A</u> dissolved in 5 ml pyridine pa and stirred at room temperature under argon for 2 hours. Then the reaction mixture is taken up in ethyl acetate, shaken with saturated NaHCO₃ solution until a pH of about 8 is reached, washed with water, dried over Na₂SO₄ and concentrated on a rotary evaporator. Yield after column chromatography: 935 mg <u style="single">1B</u>, Foam

C. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 10β - [[3- (methylamino) phenyl] thio] -9 (11) -estr-en-5α, 17β- diol (1C)

9.4 g <u style="single">1B</u> and 2.5 g of lithium aluminum hydride in 400 ml of THF abs. heated to reflux at 80 ° C under argon for 1 hour. Excess lithium aluminum hydride is then hydrolyzed with water, diluted with ethyl acetate, the org. Phase separated and washed with water, dried over Na₂SO₄ and the solvent removed on a rotary evaporator. Yield after column chromatography: 8.4 g <u style="single">1C</u>, Foam

D. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 10β - [[3- (N-formyl-N-methylamino) phenyl] thio] -9 (11) -estr- en-5α, 17D-diol (10)

Execution and processing as example 1B. Amounts used: 8.6 g <u style="single">1C</u>, 3.39 ml acetic anhydride, 1.4 ml formic acid, 45 ml pyridine pa Yield after column chromatography: 6.0 g <u style="single">1D</u>, Foam

E. 10β - [[3- (Dimethylamino) phenyl] thio] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 9 (11) -estr-en-5α, 17β- diol

(1E)

3.95 g 1D in 150 ml abs. Dissolved THF and treated at 0 ° C under argon with 1.46 ml of a 10 molar borane dimethyl sulfide complex solution in THF. The mixture is stirred at room temperature for 2.5 hours. The reaction mixture is slowly mixed with 4 ml of methanol at 0 ° C. and left to stand in the air overnight. Then it is diluted with H₂O and ethyl acetate. The organic phase is separated off, washed with H₂O, dried over Na₂SO₄ and concentrated in vacuo. Yield after column chromatography: 3.6 g <u style="single">1E</u>, Foam.

F. 10β - [[2-bromo-5- (dimethylamino) phenyl] thio] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 9 (11) -estr-en- 5α, 17β-diol (1F)

5 G <u style="single">1E</u> are dissolved in 200 ml of CCl₄, treated at 0 ° C with 1.65 g of N-bromosuccinimide and stirred at 0 ° C under argon for 2 hours. The reaction mixture is diluted with CH₂Cl₂ and mixed with saturated NaHCO₃ solution, the org. Phase washed with water and dried over Na₂SO₄ and the solvent removed on a rotary evaporator. Yield after column chromatography: 2.7 g <u style="single">1F</u>, Foam

G. 10β, 11β- [5- (dimethylamino) -o-phenylene thio] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] estran-5α, 17β-diol (1G)

1.7 g <u style="single">1F</u>, 1.15 ml of tri-n-butyltin hydride and 30 mg of azobisisobutyronitrile are stirred in 115 ml of toluene per year under argon and under reflux for 1 hour in the light of a 300W light bulb. Column chromatography gives 675 mg <u style="single">1G</u> as foam.

H. 11β- [4- (dimethylamino) -2- (methylthio) phenyl] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5 (10) -estrene-17β- ol (1H)

300 ml of liquid ammonia is condensed in a flask cooled to -70 ° C. A solution of 7.23 g<u style="single">1G</u> in 50 ml of absolute tetrahydrofuran is added dropwise at -70 ° C. 521 mg of lithium are added in portions, then the mixture is stirred for 3 hours under an inert gas at the same temperature. 1.5 ml of t-butanol are then added dropwise and the mixture is stirred for a further 2 hours. After adding 1.5 ml of iodomethane, the mixture is warmed to room temperature and diluted with water. The mixture is extracted with ethyl acetate. The organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. Column chromatography of the residue gives 4.34 g<u style="single">1H</u> as a white foam.

I. 11β- [4- (dimethylamino) phenyl] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5 (10) -estren-17β-ol (1I)

Four spatula tips of Raney nickel are washed five times with methanol and a solution of 4.30 g of 1H in 200 ml of methanol is added. The reaction mixture is stirred for 16 hours under protective gas at room temperature. The solution is decanted off, the residue is washed twice with methanol and three times with methylene chloride. The combined solutions are suctioned off through a frit and concentrated in vacuo. Column chromatography of the residue gives 2.35 g<u style="single">1I</u> as a white foam.

K. 11β- [4- (Dimethylamino) phenyl] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5 (10) -estren-17-one (1K)

A solution of 2.3 g <u style="single">1I</u>, 2.45 ml of cyclohexane and 350 mg of aluminum triisopropylate in 50 ml of toluene is boiled for 14 hours under a protective gas on a water separator. After cooling, the reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on aluminum oxide (neutral, stage III) with a mixture of hexane / ethyl acetate. 2.16 g are obtained<u style="single">1K</u> as a white foam.

L. 11β- [4- (Dimethylamino) phenyl] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 17α- (1-propynyl) -5 (10) -estrene-17β -ol (1L)

75 ml of absolute tetrahydrofuran are saturated by introducing propyne at 0 ° C for 1 hour. 16 ml of a 15% strength solution of butyllithium in hexane are then added dropwise at 0 ° C. and the mixture is stirred under an inert gas for one hour. After dropping a solution of 2.1 g<u style="single">1K</u> is stirred for 20 hours at room temperature. The reaction mixture is mixed with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on aluminum oxide (neutral, stage III) with a mixture of hexane / ethyl acetate. There will be 2.13 g<u style="single">1L</u> obtained as a white foam.

M. 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (1-propynyl) -5 (10) -estren-3-one (1M)

2.11 g <u style="single">1L</u> are dissolved in 100 ml of acetone, mixed with 17 ml of 4N aqueous hydrochloric acid and stirred under protective gas at room temperature for 30 minutes. The reaction solution is neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography of the residue gives 1.59 g<u style="single">1M</u> as a white foam.

N. 11β- [4- (dimethylamino) phenyl)] - 17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (1N)

509 mg of p-toluenesulfonic acid are heated to boiling in 95 ml of toluene under a protective gas. 1.05 g<u style="single">1M</u>dissolved in 5 ml of toluene are added quickly. The mixture is stirred at 110 ° C. for 45 minutes, then a few drops of triethylamine are added. After cooling, it is washed with sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 223 mg of the title compound<u style="single">1N</u> as a white foam.

1 H-NMR (CDCl₃) δ: 7.27 ppm (2H, d J = 8Hz, aromatic); 6.67 ppm (2H, d J = 8Hz, aromatic); 5.85 ppm (IH, broad s, H-4); 3.33 ppm (1H, broad dd J = 6.0Hz and J = 5.5Hz, H11) 2.94ppm (6H, s, H-NCH₃); 1.89ppm (3H, s, H-CH₃-C≡C-); 0.67ppm (3H, s, H-18). [α]<maths id="math0001" num=""><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>20</mtext></mrow><mrow><mtext>D</mtext></mrow></mfrac></mrow></math><img file="EP0404283A2_D0018.tif" /></maths>= 17.0 ° (CHCl₃; c = 0.505).

The connection

1I

can also be produced according to the following regulation:

To a solution of 2.5 g of 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-5 (10) -estren-3-one (preparation see Tet.Let <u style="single">24</u>, 5205 (1983)) in 18 ml of methylene chloride, 1.66 g of 2,2-dimethyl-1,3-propanediol, 0.87 ml of trimethoxymethane and 150 mg of p-toluenesulfonic acid are added. The reaction mixture is stirred under protective gas at room temperature for 14 hours, diluted with methylene chloride and washed with sodium bicarbonate solution. The aqueous phase is extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Column chromatography of the residue gives 2.32 g <u style="single">1I</u>.

EXAMPLE 2

Preparation of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 10β, 11β- (5-methoxy-o-phenylenethio) -estran-5α, 17β-diol (2B)

A. 10β - [(2-bromo-5-methoxyphenyl) thio] -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] 9 (11) -estr-en-5α, 17β- diol (2A)

The procedure and processing are carried out as described in Example 1A. Amounts used: 12.73 g of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5α, 10α-epoxy-estr-9 (11) -en-17β-ol in 100 ml abs . Tetrahydrofuran, 22.3 g 2-bromo-5-methoxythiophenol in 182 ml abs. Tetrahydrofuran, 40 ml 2.5 molar butyllithium solution in n-hexane. Column chromatography gives 17.99 g<u style="single">2A</u>, M.p .: 117-119 ° C.

B. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 10β, 11β- (5-methoxy-o-phenylene thio) -estran-5α, 17β-diol (2B)

Execution and processing are carried out as in Example 1G. Yield: 1.09 g <u style="single">2 B</u>, M.p .: 95-97 ° C.

EXAMPLE 3

Preparation of 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one (3E)

A. 11β- [4- (Dimethylamino) phenyl] -17β-hydroxy-4-estren-3-one (3A)

A solution of 2.7 g of 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-5 (10) -estren 3-one (preparation see Tet.Let. <u style="single">24</u>, 5205 (1983)) in 270 ml of methylene chloride is heated to boiling under an inert gas with 3.91 g of p-toluenesulfonic acid for a day, then a few drops of triethylamine are added. After cooling, it is washed with sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 1.85 g<u style="single">3A</u> as a white foam.

B. 11β- [4- (Dimethylamino) phenyl] -3,3- [1,2-ethanediylbis (thio)] - 4-estren-17β-ol (3B)

To a solution of 500 mg <u style="single">3A</u> 0.11 ml of 1,2-ethanedithiol and 3.62 mg of p-toluenesulfonic acid are added to 5 ml of glacial acetic acid. The reaction mixture is stirred for one hour at room temperature under a protective gas and then made basic with 2N aqueous sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 399 mg<u style="single">3B</u>.

C. 11β- [4- (dimethylamino) phenyl] -3,3- [1,2-ethanediylbis (thio)] - 4-estren-17-one (3C)

A solution of 390 mg <u style="single">3B</u>, 0.42 ml cyclohexanone and 76 mg aluminum triisopropylate in 10 ml toluene is boiled under a protective gas on a water separator for 30 hours . After cooling, the reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 330 mg<u style="single">3C</u> as a white foam.

D. 11β- [4- (dimethylamino) phenyl] -3,3- [1,2-ethanediylbis (thio)] - 17α- [3 - [(tetrahydro-2H-pyran-2-yl) oxyl] -1- propinyl] -4-estren-17β-ol (3D)

A solution of 0.89 ml of 2- (2-propynyloxy) tetrahydro-2H-pyran in 30 ml of tetrahydrofuran is mixed at 0 ° C. with a solution of 3.66 ml of a 15% solution of butyllithium in hexane and at 30 minutes 0 ° C stirred under protective gas. A solution of 280 mg is then made at the same temperature<u style="single">3C</u> added dropwise in 10 ml of tetrahydrofuran. The mixture is then stirred at 0 ° C for two hours. The reaction mixture is mixed with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 328 mg<u style="single">3D</u> as a white foam.

E. 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propynyl) -4-estren-3-one (3E)

300 mg <u style="single">3D</u> and 2.21 g of glyoxylic acid hydrate are dissolved in 18 ml of glacial acetic acid. The reaction mixture is stirred for 1.5 minutes under protective gas at room temperature, mixed with 2.1 ml of 4N aqueous hydrochloric acid and stirred for a further 10 minutes. Then it is neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 135 mg<u style="single">3E</u>. Crystallization from ethyl acetate / hexane leads to 112 mg of the named compound. Mp: 142-145 ° C; [α]<maths id="math0002" num=""><math display="inline"><mrow><mfrac linethickness="0"><mrow><mtext>20</mtext></mrow><mrow><mtext>D</mtext></mrow></mfrac></mrow></math><img file="EP0404283A2_D0019.tif" /></maths>= + 4.0 ° (CHCl₃; c = 1,000)

F. 11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1Z-propenyl) -4-estren-3-one (3F)

A solution of 78 mg <u style="single">3E</u> in 2 ml of ethanol and 2 ml of pyridine is hydrogenated for 3 hours in the presence of 13 mg of 10% Pd / BaSO₄ catalyst. The reaction mixture is suctioned off through Celite and washed with ethanol and methylene chloride. The filtrate is concentrated in vacuo. The residue is chromatographed on silica gel with a mixture of methylene chloride / methanol. There will be 63 mg<u style="single">3F</u> isolated as a white foam.

1 H-NMR (CD₂Cl₂) δ: 7.27 ppm (2H, d J = 9Hz, H-aromatic); 6.67 ppm (2H, d J = 9Hz, aromatic); 5.78 ppm (1H, broad s, H-4); 5.68 ppm (1H, ddd J = 12.5Hz and J = 5.0Hz and J = 4.5Hz, H-CH =); 5.63 ppm (1H, d J = 12.5 Hz, H-CH =); 4.32 ppm (1H, dd J = 13.0Hz and J = 5.0Hz); 3.28 ppm (1H, broad dd J = 6.0Hz and J = 5.0Hz, H-11); 2.92 ppm (6H, s, H-NCH₃); 0.71 ppm (3H, s, H-18).

EXAMPLE 4

Preparation of 11β- (4-acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (4K)

A. 17β-Hydroxy-11β- (4-hydroxyphenyl) -5 (10) -estren-3-one (4A)

To a solution of 5 g of 17β-hydroxy-11β- (4-methoxyphenyl) -5 (10) -estren-3-one (preparation see Tet.Let. <u style="single">24</u>, 5205 (1983)) in 50 ml abs. N, N-dimethylformamide are added to 3.27 g of sodium methanethiolate. The reaction mixture is stirred at 160 ° C. for 90 minutes. After cooling, it is diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 4.29 g<u style="single">4A</u> as a white foam.

B. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- (4-hydroxyphenyl) -5 (10) -estrene 17β-ol (4B)

A solution of 4.2 g <u style="single">4A</u>, 1.72 g of 2,2-dimethyl-1,3-propanediol, 1.5 ml of trimethoxymethane and 250 mg of p-toluenesulfonic acid in 40 ml of methylene chloride is stirred for 14 hours under protective gas at room temperature. Then saturated sodium bicarbonate solution is added. The aqueous phase is extracted with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. Column chromatography leads to 3.25 g<u style="single">4B</u> as a white foam.

C. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4 - [[(trifluoromethyl) sulfonyl] oxy] phenyl] -5 (10) -estrene 17β-ol ( 4C)

To a solution of 3.2 g <u style="single">4B</u> and 4.75 4- (dimethylamino) pyridine in 100 ml of methylene chloride, a solution of 1.86 ml of trifluoromethanesulfonic anhydride in 10 ml of methylene chloride is added dropwise at -78 ° C. under a protective gas. The reaction mixture is stirred at -78 ° C for 2 hours and then poured into saturated sodium bicarbonate solution. The aqueous phase is extracted with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 2.9 g <u style="single">4C</u> as a white foam.

D. 11β- (4-acetylphenyl) -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5 (10) -estren-17β-ol (4D)

A solution of 2.84 g <u style="single">4C</u> in 35 ml of N, N-dimethylformamide, 393 mg of lithium chloride are added and the mixture is stirred under protective gas at room temperature for 15 minutes. Then 277 mg of tetrakis (triphenylphosphine) palladium (0) and 1.7 ml (1-ethoxyethenyl) tributylstannane are added. The reaction mixture is stirred for 3 hours at 110 ° C., after cooling, diluted with 120 ml of ethyl acetate and suction filtered through Celite. The filtrate is washed four times with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 1.79 g<u style="single">4D</u>, white foam.

E. 11β- (4-acetylphenyl) -17β-hydroxy-5 (10) -estren-3-one (4E)

1.7 g <u style="single">4D</u> are dissolved in 100 ml of acetone, mixed with 5.4 ml of 4N aqueous hydrochloric acid and stirred for one hour under protective gas at room temperature. The reaction solution is neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 1.31 g<u style="single">4E</u>, white foam.

F. 11β- (4-acetylphenyl) -17β-hydroxy-4-estren-3-one (4F)

485 mg of p-toluenesulfonic acid are heated to 90 ° C. in 100 ml of toluene under a protective gas. 500 mg<u style="single">4E</u>dissolved in 5 ml of toluene are added quickly. The reaction mixture is stirred for one hour at 90 ° C. and, after cooling, saturated sodium bicarbonate solution is added. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate / hexane. 239 mg of the title compound are obtained<u style="single">4F</u> as a white foam. 1 H-NMR (CDCl₃) δ: 7.90 ppm (2H, d J = 8Hz, H-aromatic); 7.54 ppm (2H, d J = 8Hz, H aromatic); 5.87 ppm (1H, s, H-4); 3.61 ppm (1H, broad dd J = 9.0Hz and J = 7.5Hz, H-17); 3.42 ppm (1H, broad dd J = 6.0Hz and J = 5.5Hz, H-11); 2.61 ppm (3H, s, H-Ac); 0.52 ppm (3H, s, H-18).

G. 3,3- [1,2-ethanediylbis (thio)] - 11β- [4- (2-methyl-1,3-dithiolan-2-yl) phenyl] -4-estren-17β-ol (4G)

To a solution of 2.12 g <u style="single">4F</u> 0.90 ml of 1,2-ethanedithiol and 1.18 g are added to 40 ml of glacial acetic acid <i>p</i>-Toluenesulfonic acid given. The reaction mixture is stirred for five hours at room temperature under a protective gas and then made basic with 2 M aqueous sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The crude product is dissolved in 80 ml of methylene chloride and 160 ml of ethanol and refluxed with 1.49 g of solid potassium carbonate for six hours. The cooled solution is filtered and concentrated. Column chromatography gives 2.02 g<u style="single">4G</u> as a white foam.

H. 3,3- [1,2-ethanediylbis (thio)] - 11β- [4- (2-methyl-1,3-dithiolan-2-yl) phenyl] -4-estren-17-one (4H)

As under <u style="single">3C</u> are described from 1.95 g <u style="single">4G</u> with 2.42 ml cyclohexanone and 438 mg aluminum triisopropoxide in 35 ml toluene 1.81 g <u style="single">4H</u> manufactured. IR (KBr): 1740 cm⁻¹ (C = O).

I. 3,3- [1,2-ethanediylbis (thio)] - 11β- [4- (2-methyl-1,3-dithiolan-2-yl) phenyl] -17α- (1-propynyl) -4- estren-17β-ol (4I)

As under <u style="single">1L</u> are described from 763 mg <u style="single">4H</u> with 5.8 ml of a 15% solution of butyllithium in hexane in 50 ml of tetrahydrofuran saturated with propyne 779 mg <u style="single">4I</u> manufactured. IR (KBr): 2240 cm⁻¹ (C≡C).

K. 11β- (4-acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (4K)

1.28 g <i>N</i>Chlorosuccinimide and 1.83 g of silver (I) nitrate are placed in 50 ml of an acetonitrile / water mixture (8: 2). At room temperature, a solution of 700 mg<u style="single">4I</u> rapidly added dropwise in 3 ml of acetone and 2 ml of acetonitrile. After 15 minutes, saturated sodium sulfite solution, saturated sodium carbonate solution and saturated sodium chloride solution and methylene chloride are added in succession. The mixture is filtered through Celite, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 238 mg of the title compound<u style="single">4K</u> as a pale yellow foam. IR (KBr); 2235 cm⁻¹ (C≡C), 1678 cm⁻¹ (C = O), 1664 cm⁻¹ (C = O).

1 H-NMR (CDCl₃) δ: 7.90 ppm (2H, d J = 9 Hz, H-aromatic); 7.54 ppm (2H, d J = 9 Hz, H aromatic); 5.88 ppm (1H, broad s, H-4); 3.48 ppm (1H, broad dd J = 6.5 Hz and J = 6.0 Hz, H-11); 2.80 ppm (1H, m, H-10); 2.60 ppm (3H, s, H-Ac); 1.89 ppm (3H, s, H-CH₃-C≡C-); 0.59 ppm (3H, s, H-18).

EXAMPLE 5

Production of (<i>Z.</i>) -11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (5C)

A. 3,3- [1,2-ethanediylbis (thio)] - 11β- [4- (2-methyl-1,3-dithiolan-2-yl) phenyl] -17α- [3 - [(tetrahydro-2<i>H</i>-pyran-2-yl) oxy] -1-propynyl-4-estren-17β-ol (5A)

As under <u style="single">3D</u> be described from 1.0 g <u style="single">4H</u> with 2.74 ml of 2- (2-propynyloxy) tetrahydro-2<i>H</i>-pyran and 11.3 ml of a 15% solution of butyllithium in hexane in 120 ml of tetrahydrofuran 1.19 g <u style="single">5A</u> manufactured.

B. 11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propynyl) -4-estren-3-one (5B)

As under <u style="single">4K</u> 1.73 g are described <u style="single">5A</u> with 2.71 g <i>N</i>-Chlorsuccinimid and 3.87 g of silver (I) nitrate in 10 ml of acetone, 24 ml of water and 96 ml of acetonitrile. The crude product is with 127 mg of pyridinium<i>p</i>-toluenesulfonate in 15 ml of moist ethanol stirred at 60 ° C for two hours. The solution is evaporated to half the volume, diluted with ethyl acetate, washed with semi-saturated sodium chloride solution and with water, dried over sodium sulfate and concentrated in vacuo. Column chromatography gives 265 mg<u style="single">5B</u> as a pale yellow foam. IR (KBr): 2235 cm⁻¹ (C≡C), 1678 cm⁻¹ (C = O), 1665 cm⁻¹ (C = O).

1 H-NMR (CDCl₃) δ: 7.91 ppm (2H, d J = 9 Hz, H-aromatic); 7.54 ppm (2H, d J = 9 Hz, H aromatic); 5.88 ppm (1H, broad s, H-4); 4.37 ppm (2H, broad s, H-CH₂OH); 3.48 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.81 ppm (1H, m, H-10); 2.61 ppm (3H, s, H-Ac); 0.62 ppm (3H, s, H-18).

C. (<i>Z.</i>) -11β- (4-acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (5C)

As under <u style="single">3F</u> 245 mg are described <u style="single">5B</u> hydrogenated with 60 mg 10% Pd / BaSO₄ catalyst in 4 ml pyridine and 4 ml ethanol. After silica gel chromatography, 170 mg of the title compound<u style="single">5C</u> receive. Crystallization from methylene chloride / diisopropyl ether gives 146 mg<u style="single">5C</u> as light yellow crystals. Mp: 225-230 ° C; [α]_D²² = + 76.4 ° (CHCl₃; c = 0.500). IR (KBr): 1680 cm⁻¹ (C = O), 1665 cm⁻¹ (C = O).

EXAMPLE 6

Preparation of 11β- [4- (dimethylamino) phenyl] -17α- (1-propynyl) -4-estren-17β-ol (6C)

A. 11β- [4- (Dimethylamino) phenyl] -4-estren-17β-ol (6A)

120 ml of liquid ammonia is condensed into a flask cooled to -75 ° C. 91 mg of lithium are added. After 20 minutes a solution of 770 mg<u style="single">3B</u> added dropwise in 4 ml of tetrahydrofuran. 182 mg of lithium are added in portions, then the mixture is stirred at -75 ° C for two hours. 9 ml of ethanol are then added dropwise. The mixture is left to stand at room temperature overnight, then diluted with water. The mixture is extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography of the residue gives 350 mg<u style="single">6A</u> as a white foam.

1 H-NMR (CD₂Cl₂) δ: 7.27 ppm (2H, d J = 9 Hz, H-aromatic); 6.63 ppm (2H, d J = 9 Hz, H aromatic); 5.40 ppm (1H, broad s, H-4); 3.51 ppm (1H, broad dd J = 9 Hz and J = 6 Hz, H-17); 3.22 ppm (1H, broad dd J = 6 Hz and J = 5 Hz, H-11); 2.91 ppm (6H, s, H-NCH₃); 2.46 ppm (1H, m, H-10); 0.50 ppm (3H, s, H-18).

B. 11β- [4- (Dimethylamino) phenyl] -4-estren-17-one (6B)

As under <u style="single">3C</u> are described from 327 mg <u style="single">6A</u> with 400 µl cyclohexanone and 409 mg aluminum triisopropylate in 10 ml toluene 225 mg <u style="single">6B</u> manufactured. IR (KBr): 1740 cm⁻¹ (C = O).

1 H-NMR (CD₂Cl₂) δ: 7.28 ppm (2H, d J = 9 Hz, H-aromatic); 6.64 ppm (2H, d J = 9 Hz, H aromatic); 5.43 ppm (1H, broad s, H-4); ; 3.29 ppm (1H, broad dd J = 5.5 Hz and J = 5 Hz, H-11); 2.91 ppm (6H, s, H-NCH₃); 2.50 ppm (1H, m, H-10); 0.63 ppm (3H, s, H-18).

C. 11β- [4- (dimethylamino) phenyl] -17α- (1-propynyl) -4-estren-17β-ol (6C)

As under <u style="single">1L</u> are described from 215 mg <u style="single">6B</u> with 2.1 ml of a 15% solution of butyllithium in hexane in 20 ml of tetrahydrofuran saturated with propyne 207 mg <u style="single">6C</u> manufactured. Crystallization from pentane / ethyl acetate leads to 168 mg of the named compound. Mp: 187 ° C; [α]_D²² = -28.3 ° (CHCl₃; c = 0.505). IR (KBr): 2240 cm⁻¹ (C≡C).

EXAMPLE 7

Production of (<i>Z.</i>) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (7I)

A. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4- (3-pyridinyl) phenyl] -5 (10) -estren-17β-ol (7A) and

B. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- (4-ethylphenyl) -5 (10) -estren-17β-ol (7B)

Under a protective gas, a solution of 2.71 g <u style="single">4C</u> 747 mg of diethyl (3-pyridinyl) borane (Aldrich), 392 mg of lithium chloride, 6 ml of 2 M sodium carbonate solution and 267 mg of tetrakis (triphenylphosphine) palladium (0) were added to 40 ml of toluene and 18 ml of ethanol. The mixture is heated to 95 ° C. for two hours and, after cooling, is taken up in ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography, 1.94 g<u style="single">7A</u> and 171 mg <u style="single">7B</u> receive.

C. 17β-hydroxy-11β- [4- (3-pyridinyl) phenyl] -5 (10) -estren-3-one (7C)

As under <u style="single">4E</u> are described from 1.9 g <u style="single">7A</u> with 7 ml of 4 M aqueous hydrochloric acid in 150 ml of acetone, 1.07 g <u style="single">7C</u> manufactured.

D. 17β-hydroxy-11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (7D)

1.06 g <u style="single">7C</u> are dissolved in 20 ml of chloroform under a protective gas of 944 mg <i>p</i>-Toluenesulfonic acid added and heated under reflux for three hours. The cooled solution is mixed with a few drops of triethylamine, diluted with methylene chloride, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. Silica gel chromatography gives 644 mg<u style="single">7D</u>. IR (KBr): 1667 cm⁻¹ (C = O).

1 H-NMR (CDCl₃) δ: 8.87 ppm (1H, broad d J = 2 Hz, H-Py2); 8.58 ppm (1H, broad dd J = 5.0 Hz and J = 2 Hz, H-Py6); 7.89 ppm (1H, ddd J = 8 Hz and J = 2 Hz and J = 2 Hz, H-Py4); 7.54 ppm (4H, m, H aromatic); 7.37 ppm (1H, broad dd J = 8 Hz and J = 5.0 Hz, H-Py5); 5.88 ppm (1H, broad s, H-4); 3.61 ppm (1H, broad dd J = 9.0 Hz and J = 7.0 Hz, H-17); 3.40 ppm (1H, broad dd J-6.0 Hz and J = 5.0 Hz, H-11); 2.86 ppm (1H, m, H-10); 0.58 ppm (3H, s, H-18).

E. 3,3- [1,2-ethanediylbis (thio)] - 11β- [4- (3-pyridinyl) phenyl] -4-estren-17β-ol (7E)

As under <u style="single">4G</u> are described from 629 mg <u style="single">7D</u> with 123 ul 1,2-ethanedithiol and 419 mg <i>p</i>-Toluenesulfonic acid in 6 ml glacial acetic acid and with 203 mg potassium carbonate in 8 ml methylene chloride and 45 ml methanol 569 mg <u style="single">7E</u> manufactured.

F. 3,3- [1,2-ethanediylbis (thio)] - 11β- [4- (3-pyridinyl) phenyl] -4-estren-17-one (7F)

As under <u style="single">3C</u> are described from 550 mg <u style="single">7E</u> with 510 µl cyclohexanone and 100 mg aluminum triisopropylate in 17 ml toluene 460 mg <u style="single">7F</u> manufactured. IR (KBr): 1736 cm -1 (C = O).

G. 3,3- [1,2-ethanediylbis (thio)] - 11β- [4- (3-pyridinyl) phenyl-17α- [3 - [(tetrahydro-2<i>H</i>-pyran-2-yl) oxy] -1-propynyl] -4-estren-17β-ol (7G)

As under <u style="single">3D</u> are described from 442 mg <u style="single">7F</u> with 1.30 ml of 2- (2-propynyloxy) tetrahydro-2<i>H</i>-pyran and 5.36 ml of a 15% solution of butyllithium in hexane in 70 ml of tetrahydrofuran 460 mg <u style="single">7G</u> manufactured.

H. 17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (7H)

As under <u style="single">3E</u> are described from 453 mg <u style="single">7G</u> with 3.27 g of glyoxylic acid and 2.98 ml of 4 M aqueous hydrochloric acid in 8 ml of acetone and 8 ml of glacial acetic acid 234 mg <u style="single">7H</u> manufactured.

1 H-NMR (CDCl₃) δ: 8.88 ppm (1H, broad d J = 2 Hz, H-Py2); 8.59 ppm (1H, broad dd J = 4.5 Hz and J = 2 Hz, H-Py6); 7.90 ppm (1H, ddd J = 8 Hz and J = 2 Hz and J = 2 Hz, H-Py4); 7.53 ppm (4H, m, H aromatic); 7.38 ppm (1H, broad dd J = 8 Hz and J = 45, Hz, H-Py5); 5.89 ppm (1H, broad s, H-4); 4.38 ppm (2H, m, H-CH₂OH); 3.48 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.88 ppm (1H, m, H-10); 0.68 ppm (3H, s, H-18).

I. (<i>Z.</i>) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (7I)

As under <u style="single">3F</u> 225 mg are described <u style="single">7H</u> hydrogenated with 45 mg of 10% Pd / BaSO₄ catalyst in 2 ml of pyridine and 4 ml of ethanol. After silica gel chromatography, 160 mg of the title compound<u style="single">7I</u> receive. IR (KBr): 1663 cm⁻¹ (C = O).

1 H-NMR (CDCl₃) δ: 8.88 ppm (1H, broad d J = 2 Hz, H-Py2); 8.59 ppm (1H, broad dd J = 4.5 Hz and J = 2 Hz, H-Py6); 7.91 ppm (1H, ddd J = 8 Hz and J = 2 Hz and J = 2 Hz, H-Py4); 7.52 ppm (4H, m, H aromatic); 7.40 ppm (1H, broad dd J = 8 Hz and J = 4.5 Hz, H-Py5); 5.88 ppm (1H, broad s, H-4); 5.72 ppm (1H, ddd J = 11.5 Hz and J = 5.5 Hz and J = 5.5 Hz, H-CH =); 5.65 ppm (1H, broad d J = 11.5 Hz, H-CH =); 4.28 ppm (2H, m, H-CH₂OH); 3.42 ppm (1H, broad dd J = 6.0 Hz and J = 4.5 Hz, H-11); 2.87 ppm (1H, m, H-10); 0.73 ppm (3H, s, H-18).

EXAMPLE 8

Preparation of 17β-hydroxy-3-oxo-11β- [4- (3-pyridinyl) phenyl] -4-estren-17α-acetonitrile (8B)

A. 3,3- [1,2-ethanediylbis (thio)] - 17β-hydroxy-11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (8A)

13.7 ml of a 15% solution of butyllithium in hexane are added dropwise to a solution of 3.31 ml of diisopropylamine in 100 ml of tetrahydrofuran at -78 ° C. under protective gas. After 30 minutes, 1.13 ml of acetonitrile are added at the same temperature. 15 minutes later, a solution of 1.00 g is made at the same temperature<u style="single">7F</u> added dropwise in 90 ml of tetrahydrofuran and stirred for a further two hours. Saturated ammonium chloride solution is then added and the mixture is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 1.05 g<u style="single">8A</u>.

B. 17β-Hydroxy-3-oxo-11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (8B)

As under <u style="single">3E</u> are described from 1.04 g <u style="single">8A</u> with 7.51 g of glyoxylic acid and 6.85 ml of 4 M aqueous hydrochloric acid in 18 ml of acetone and 18 ml of glacial acetic acid 644 mg <u style="single">8B</u> manufactured. Crystallization from ethyl acetate / hexane gives 597 mg of the compound mentioned. Mp: 173-174 ° C; [α]_D²² = + 131.8 ° (CHCl₃; c = 0.500). IR (KBr): 2245 cm⁻¹ (C≡N), 1664 cm⁻¹ (C = O).

EXAMPLE 9

Production of (<i>E</i>) -17β-hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (9A) and

(<i>Z.</i>) -17β-Hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (9B)

A. (<i>E</i>) -17β-hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (9A) and

B. (<i>Z.</i>) -17β-Hydroxy-3- (hydroxyimino) -11β- [4- (3-pyridinyl) phenyl] -4-estrene-17α-acetonitrile (9B)

219 mg <u style="single">8B</u> are stirred for 90 minutes at 50 ° C. with 50 mg hydroxylammonium chloride in 5 ml pyridine under protective gas. The reaction mixture is taken up in water and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo. After column chromatography and crystallization from methylene chloride / diisopropyl ether, 97 mg are obtained<u style="single">9A</u> {Mp .: 227-229 ° C; [α]_D²² = + 192.4 ° (CHCl₃ / MeOH; c = 0.500); IR (KBr): 2250 cm⁻¹ (C≡N), 1635 cm⁻¹ (C = NOH)} and 61 mg<u style="single">9B</u> {Mp: 198-200 ° C; [α]_D²² = + 230.4 ° (CHCl₃; c = 0.500); IR (KBr): 2250 cm⁻¹ (C≡N), 1635 cm⁻¹ (C = NOH)}.

EXAMPLE 10

Preparation of 17β-hydroxy-17α- (2-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (10B)

A. 3,3- [1,2-ethanediylbis (thio)] - 17α- (2-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-17β-ol (10A)

414 mg of magnesium shavings in 5 ml of diethyl ether are placed under a protective gas. 150 µl of 3-bromo-1-propene and some crystals of iodine are added, then a solution of 2.00 g is slowly added<u style="single">7F</u> and 1.32 g of 3-bromo-1-propene in 40 ml of diethyl ether and 10 ml of tetrahydrofuran were added dropwise and the mixture was refluxed for three hours. For working up, saturated ammonium chloride solution is added and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 1.63 g<u style="single">10A</u>.

B. 17β-Hydroxy-17α- (2-propenyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (10B)

As under <u style="single">3E</u> are described from 1.44 g <u style="single">10A</u> with 10.35 g glyoxylic acid and 9.40 ml 4 M aqueous hydrochloric acid in 25 ml acetone and 25 ml glacial acetic acid 592 mg <u style="single">10B</u> manufactured. Crystallization from ethyl acetate / hexane gives 483 mg of the compound mentioned. Mp: 127-128 ° C; [α]_D²² = + 128.7 ° (CHCl₃; c = 0.470). IR (KBr): 1668 cm -1 (C = O).

EXAMPLE 11

Preparation of 17β-hydroxy-17α- (methoxymethyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (11C)

A. (11β, 17β) -3,3- [1,2-ethanediylbis (thio)] - 11- [4- (3-pyridinyl) phenyl] spiro [estr-4-en-17,2′-oxirane] (11A)

2.5 g <u style="single">7F</u> are mixed with 4.12 g trimethylsulfonium iodide and 2.75 g potassium<i>tert</i>-butylate in 100 ml of dimethylformamide under protective gas for 30 minutes at room temperature. Then water is added with ice bath cooling and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 866 mg<u style="single">11A</u>.

B. 3,3- [1,2-ethanediylbis (thio)] - 17α- (methoxymethyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-17β-ol (11B)

1.20 g of sodium are dissolved in 15 ml of methanol. A solution of 842 mg <u style="single">11A</u> in 20 ml of methanol is added dropwise. The reaction mixture is heated to boiling for five hours. Then the methanol is largely evaporated. The residue is taken up in water and extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 486 mg<u style="single">11B</u>.

C. 17β-Hydroxy-17α- (methoxymethyl) -11β- [4- (3-pyridinyl) phenyl] -4-estren-3-one (11C)

As under <u style="single">3E</u> are described from 470 mg <u style="single">11B</u> with 3.38 g of glyoxylic acid and 3.00 ml of 4 M aqueous hydrochloric acid in 8 ml of acetone and 8 ml of glacial acetic acid 252 mg <u style="single">11C</u> manufactured. Crystallization from ethyl acetate / hexane gives 204 mg of the compound mentioned. Mp: 145-146 ° C; [α]_D²² = + 120.8 ° (CHCl₃; c = 0.465). IR (KBr): 1665 cm⁻¹ (C = O).

EXAMPLE 12

Preparation of 11β- (4-ethylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (12F)

A. 11β- (4-ethylphenyl) -17β-hydroxy-5 (10) -estren-3-one (12A)

As under <u style="single">4E</u> are described from 863 mg <u style="single">7B</u> with 3 ml of 4 M aqueous hydrochloric acid in 70 ml of acetone 576 mg <u style="single">12A</u> manufactured.

B. 11β- (4-ethylphenyl) -17β-hydroxy-4-estren-3-one (12B)

As under <u style="single">7D</u> are described from 568 mg <u style="single">12A</u> with 500 mg <i>p</i>-Toluenesulfonic acid in 10 ml chloroform 443 mg <u style="single">12B</u> manufactured. IR (KBr): 1665 cm⁻¹ (C = O).

1 H-NMR (CDCl₃ + Py-<i>d₅</i>) δ: 7.31 ppm (2H, d J = 9 Hz, H-aromatic); 7.10 ppm (2H, d J = 9 Hz, H aromatic); 5.84 ppm (1H, broad s, H-4); 3.59 ppm (1H, broad dd J = 9.0 Hz and J = 7.5 Hz, H-17); 3.33 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 2.62 ppm (2H, q J = 7.5 Hz, H-Et); 1.23 ppm (2H, t J = 7.5 Hz, H-Et); 0.55 ppm (3H, s, H-18).

C. 3,3- [1,2-ethanediylbis (thio)] - 11β- (4-ethylphenyl) -4-estren-17β-ol (12C)

As under <u style="single">4G</u> are described from 433 mg <u style="single">12B</u> with 85 ul 1,2-ethanedithiol and 285 mg <i>p</i>-Toluenesulfonic acid in 5 ml glacial acetic acid and with 140 mg potassium carbonate in 6 ml methylene chloride and 30 ml methanol 399 mg <u style="single">12C</u> manufactured.

D. 3,3- [1,2-ethanediylbis (thio)] - 11β- (4-ethylphenyl) -4-estren-17-one (12D)

As under <u style="single">3C</u> can be described from 390 mg <u style="single">12C</u> with 360 ul cyclohexanone and 70 mg aluminum triisopropylate in 15 ml toluene 347 mg <u style="single">12D</u> manufactured. IR (KBr): 1740 cm⁻¹ (C = O).

E. 3,3- [1,2-ethanediylbis (thio)] - 11β- (4-ethylphenyl) -17α- (1-propynyl) -4-estren-17β-ol (12E)

As under <u style="single">1L</u> be described from 100 mg <u style="single">12D</u> with 800 µl of a 15% solution of butyllithium in hexane in 10 ml of tetrahydrofuran saturated with propyne 99 mg <u style="single">12E</u> manufactured. IR (KBr): 2235 cm⁻¹ (C≡C).

F. 11β- (4-ethylphenyl) -17β-hydroxy-17α- (1-propynyl) -4-estren-3-one (12F)

As under <u style="single">3E</u> are described from 89 mg <u style="single">12E</u> with 64 mg glyoxylic acid and 600 µl 4 M aqueous hydrochloric acid in 2 ml acetone and 2 ml glacial acetic acid after crystallization from methylene chloride / hexane 34 mg <u style="single">12F</u> manufactured. Mp: 195-196 ° C; [α]_D²² = -17.9 ° (CHCl₃; c = 0.485). IR (KBr): 2240 cm⁻¹ (C≡C), 1655 cm⁻¹ (C = O).

EXAMPLE 13

Production of (<i>Z.</i>) -11β- (4-ethylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (13C)

A. 3,3- [1,2-ethanediylbis (thio)] - 11β- (4-ethylphenyl) - 17α- [3 - [(tetrahydro-2<i>H</i>-pyran-2-yl) oxy] -1-propynyl] -4-estren-17β-ol (13A)

As under <u style="single">3D</u> are described from 235 mg <u style="single">12D</u> with 0.70 ml of 2- (2-propynyloxy) tetrahydro-2<i>H</i>-pyran and 2.90 ml of a 15% solution of butyllithium in hexane in 40 ml of tetrahydrofuran 241 mg <u style="single">13A</u> manufactured.

B. 11β- (4-ethylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propynyl) -4-estren-3-one (13B)

As under <u style="single">3E</u> are described from 230 mg <u style="single">13A</u> with 1.60 g glyoxylic acid and 1.50 ml 4 M aqueous hydrochloric acid in 5 ml acetone and 5 ml glacial acetic acid 124 mg <u style="single">13B</u> manufactured. IR (KBr): 2230 cm⁻¹ (C≡C), 1660 cm⁻¹ (C = O).

C. (Z) -11β- (4-ethylphenyl) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (13C)

As under <u style="single">3F</u> 115 mg are described <u style="single">13B</u> hydrogenated with 25 mg 10% Pd / BaSO₄ catalyst in 1 ml pyridine and 4 ml ethanol. After silica gel chromatography and crystallization from methylene chloride / hexane, 76 mg of the title compound<u style="single">13C</u> receive. Mp 98-101 ° C; [α]_D²² = + 76.6 ° (CHCl₃; c = 0.500). IR (KBr): 1665 cm⁻¹ (C = O).

EXAMPLE 14

Production of (<i>Z.</i>) -11β- [4- (3-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (14D)

A. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4- (3-furanyl) phenyl] -5 (10) -estren-17β-ol (14A)

Under protective gas become a solution of 3.50 g <u style="single">4C</u> in 25 ml dioxane and 0.46 ml pyridine 6.43 g (3-furanyl) tributylstannane (for preparation see Synthesis <b>1985</b>, 898), 510 mg lithium chloride, and 693 mg tetrakis (triphenylphosphine) palladium (0). The mixture is heated to boiling for two hours, taken up in ethyl acetate after cooling and filtered through Celite. The organic phase is dried over sodium sulfate and concentrated in vacuo. After column chromatography, 2.79 g<u style="single">14A</u> receive.

B. 11β- [4- (3-furanyl) phenyl] -17β-hydroxy-4-estren-3-one (14B)

From 2.70 g <u style="single">14A</u> are analogous to the regulations <u style="single">4E</u> and <u style="single">7D</u> by ketal hydrolysis and isomerization 1.03 g of the compound <u style="single">14B</u> manufactured.

1 H NMR (CDCl₃) δ: 7.74 ppm (1H, dd J = 1.3 Hz and J = 0.8 Hz, H-Fu2); 7.48 ppm (1H, dd J = 1.8 Hz and J = 1.3 Hz, H-Fu5); 7.42 ppm (4H, m, H aromatic); 6.71 ppm (1H, dd J = 1.8 Hz and J = 0.8 Hz, H-Fu4); 5.87 ppm (1H, broad s, H-4); 3.60 ppm (1H, dd J = 9.0 Hz and J = 7.0 Hz, H-17); 3.36 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 0.57 ppm (3H, s, H-18).

C. 11β- [4- (3-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propynyl) -4-estren-3-one (14C)

From 1.00 g <u style="single">14B</u> are analogous to the regulations <u style="single">4G</u>, <u style="single">3C</u>, <u style="single">3D</u> and <u style="single">3E</u> 358 mg of the compound <u style="single">14C</u> manufactured. IR (KBr): 2230 cm⁻¹ (C≡C), 1660 cm⁻¹ (C = O).

D. (Z) -11β- [4- (3-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (14D)

As under <u style="single">3F</u> 344 mg are described <u style="single">14C</u> hydrogenated with 70 mg 10% Pd / BaSO₄ catalyst in 3 ml pyridine and 6 ml ethanol. After silica gel chromatography and crystallization from ethyl acetate / hexane, 180 mg of the title compound<u style="single">14D</u> receive. Mp: 164-166 ° C; [α]_D²² = + 99.0 ° (CHCl₃; c = 0.200). IR (KBr): 1662 cm⁻¹ (C = O).

EXAMPLE 15

Production of (<i>Z.</i>) -11β- [4- (2-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (15D)

A. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4- (2-furanyl) phenyl] -5 (10) -estren-17β-ol (15A)

Under protective gas become a solution of 4.00 g <u style="single">4C</u> in 65 ml of toluene and 25 ml of ethanol 1.52 g (2-furanyl) boronic acid (preparation see J. Heterocycl. Chem. <b>1975</b>, 195), 580 mg lithium chloride, 8.5 ml 2 M sodium carbonate solution and 340 mg tetrakis (triphenylphosphine) palladium (0). The mixture is heated to boiling for four hours and, after cooling, is taken up in ethyl acetate. The organic phase is washed with 1 M sodium hydroxide solution and with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography, 2.57 g<u style="single">15A</u> receive.

B. 11β- [4- (2-furanyl) phenyl] -17β-hydroxy-4-estren-3-one (15B)

From 2.52 g <u style="single">15A</u> are analogous to the regulations <u style="single">4E</u> and <u style="single">7D</u> by ketal hydrolysis and isomerization 1.10 g of the compound <u style="single">15B</u> manufactured. IR (KBr): 1664 cm⁻¹ (C = O).

1 H-NMR (CDCl₃ + Py-<i>d₅</i>) δ: 7.60 ppm (2H, d J = 9 Hz, H-aromatic); 7.47 ppm (1H, dd J = 1.8 Hz and J = 0.8 Hz, H-Fu5); 7.44 ppm (2H, d J = 9 Hz, H aromatic); 6.62 ppm (1H, dd J = 3.5 Hz and J = 1.8 Hz, H-Fu3); 6.48 ppm (1H, dd J = 3.5 Hz and J = 0.8 Hz, H-Fu4); 5.85 ppm (1H, broad s, H-4); 3.61 ppm (1H, dd J = 9.0 Hz and J = 7.0 Hz, H-17); 3.38 ppm (1H, broad dd J = 5.5 Hz and J = 5.0 Hz, H-11); 2.84 ppm (1H, m, H-10); 0.56 ppm (3H, s, H-18).

C. 11β- [4- (2-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propynyl) -4-estren-3-one (15C)

From 1.07 g <u style="single">15B</u> are analogous to the regulations <u style="single">4G</u>, <u style="single">3C</u>, <u style="single">3D</u> and <u style="single">3E</u> 313 mg of the compound <u style="single">15C</u> manufactured. IR (KBr): 2235 cm⁻¹ (C≡C), 1665 cm⁻¹ (C = O).

D. (<i>Z.</i>) -11β- [4- (2-furanyl) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -4-estren-3-one (15D)

As under <u style="single">3F</u> 299 mg are described <u style="single">15C</u> hydrogenated with 61 mg of 10% Pd / BaSO₄ catalyst in 3 ml of pyridine and 5 ml of ethanol. After silica gel chromatography and crystallization from ethyl acetate / hexane, 205 mg of the title compound<u style="single">15D</u> receive. Mp: 148-149 ° C; [α]_D²² = + 126.5 ° (CHCl₃; c = 0.350). IR (KBr): 1660 cm⁻¹ (C = O).

EXAMPLE 16

Production of (<i>Z.</i>) -4 ′ - [17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -3-oxo-4-estren-11β-yl] [1,1′-biphenyl] -4-carbonitrile (16D)

A. 4 ′ - [3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 17β-hydroxy-5 (10) -estren-11β-yl] [1,1′-biphenyl] -4-carbonitrile (16A)

A solution of 5.00 g <u style="single">4C</u> in 170 ml of dioxane is stirred with 1.09 g of lithium chloride for 15 minutes at room temperature under a protective gas. 13 ml hexabutylditin and 494 mg tetrakis (triphenylphosphine) palladium (0) are added. The reaction mixture is heated to boiling for two hours. Then 15.6 g of 4-bromobenzonitrile are added and the mixture is heated to boiling for a further 24 hours. After cooling, it is filtered through Celite, washed with ethyl acetate and concentrated in vacuo. After column chromatography 3.16 g are obtained <u style="single">16A</u>.

B. 4 ′ - [17β-Hydroxy-3-oxo-4-estren-11β-yl] [1,1′-biphenyl] -4-carbonitrile (16B)

From 3.10 g <u style="single">16A</u> are analogous to the regulations <u style="single">4E</u> and <u style="single">7D</u> by ketal hydrolysis and isomerization 1.36 g of the compound <u style="single">16B</u> manufactured. IR (KBr): 2233 cm⁻¹ (C≡N); 1660 cm⁻¹ (C = O).

1 H-NMR (CDCl₃ + Py-<i>d₅</i>) δ: 7.73 ppm (2H, d J = 9 Hz, H-aromatic); 7.70 ppm (2H, d J = 9 Hz, H aromatic); 7.53 ppm (4H, m, H aromatic); 5.87 ppm (1H, broad s, H-4); 3.60 ppm (1H, dd J = 9.0 Hz and J = 7.5 Hz, H-17); 3.43 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 0.57 ppm (3H, s, H-18).

C. 4 ′ - [17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -3-oxo-4-estren-11β-yl] [1,1′-biphenyl] -4-carbonitrile (16C)

From 1.32 g <u style="single">16B</u> are analogous to the regulations <u style="single">4G</u>, <u style="single">3C</u>, <u style="single">3D</u> and <u style="single">3E</u> 405 mg of the compound <u style="single">16C</u> manufactured. IR (KBr): 2230 cm⁻¹ (C≡N and C≡C); 1658 cm⁻¹ (C = O).

D. (<i>Z.</i>) -4 ′ - [17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -3-oxo-4-estren-11β-yl] [1,1′-biphenyl] -4-carbonitrile (16D)

As under <u style="single">3F</u> 386 mg are described <u style="single">16C</u> hydrogenated with 77 mg of 10% Pd / BaSO₄ catalyst in 4 ml of pyridine and 6 ml of ethanol. After silica gel chromatography and crystallization from ethyl acetate / hexane, 242 mg of the title compound<u style="single">16D</u> receive. Mp: 259-260 ° C; [α]_D²² = + 135.2 ° (CHCl₃; c = 0.510). IR (KBr): 2230 cm⁻¹ (C≡N); 1664 cm⁻¹ (C = O).

EXAMPLE 17

Preparation of 11β- (4-ethenylphenyl) -17β-hydroxy-17α-methyl-4-estren-3-one (17E)

A. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- (4-ethenylphenyl) -5 (10) -estren-17β-ol (17A)

Under protective gas become a solution of 4.00 g <u style="single">4C</u> 2.40 ml of ethenyltributylstannane, 554 mg of lithium chloride, and 378 mg of tetrakis (triphenylphosphine) palladium (0) were added to 50 ml of dimethylformamide. The mixture is heated to 110 ° C. for 150 minutes, taken up in ethyl acetate after cooling and filtered through Celite. The filtrate is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography, 3.11 g<u style="single">17A</u> receive.

B. 11β- (4-ethenylphenyl) -17β-hydroxy-4-estren-3-one (17B)

From 3.08 g <u style="single">17A</u> are analogous to the regulations <u style="single">4E</u> and <u style="single">7D</u> by ketal hydrolysis and isomerization 1.09 g of the compound <u style="single">17B</u> manufactured. IR (KBr): 1663 cm⁻¹ (C = O).

C. 3,3- [1,2-ethanediylbis (thio)] - 11β- (4-ethenylphenyl) -4-estren-17-one (17C)

From 1.06 g <u style="single">17B</u>are analogous to the regulations <u style="single">4G</u> and <u style="single">3C</u> by thioketalization and oxidation 805 mg of the compound <u style="single">17C</u> manufactured. IR (KBr): 1736 cm -1 (C = O).

D. 3,3- [1,2-ethanediylbis (thio)] - 11β- (4-ethenylphenyl) -17α-methyl-4-estren-17β-ol (17D)

At 0 ° C to a solution of 780 mg <u style="single">17C</u> 11.9 ml of a 1.6 M solution of methyl lithium in diethyl ether were added dropwise in 20 ml of tetrahydrofuran under protective gas. The reaction mixture is stirred for 30 minutes and then poured into saturated ammonium chloride solution. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo. After column chromatography, 629 mg<u style="single">17D</u> receive.

E. 11β- (4-ethenylphenyl) -17β-hydroxy-17α-methyl-4-estren-3-one (17E)

As under <u style="single">3E</u> are described from 605 mg <u style="single">17D</u> with 4.23 g of glyoxylic acid and 3.70 ml of 4 M aqueous hydrochloric acid in 10 ml of acetone and 10 ml of glacial acetic acid, 216 mg of the title compound <u style="single">17E</u> manufactured. [α]_D²² = + 151.8 ° (CHCl₃; c = 0.505). IR (KBr): 1666 cm⁻¹ (C = O).

1 H-NMR (CDCl₃) δ: 7.39 ppm (2H, d J = 9.0 Hz, H-aromatic); 7.33 ppm (2H, d J = 9.0 Hz, H aromatic); 6.70 ppm (1H, dd J-17.0 Hz and J-10.5 Hz, H-vinyl); 5.86 ppm (1H, broad s, H-4); 5.73 ppm (1H, d J = 17.0 Hz, H-vinyl); 5.22 ppm (1H, d J = 10.5 Hz, H-vinyl); 3.39 ppm (1H, broad dd J = 9.5 Hz and J = 4.5 Hz, H-11); 2.87 ppm (1H, m, H-10); 1.22 ppm (3H, s, H-CH₃); 0.66 ppm (3H, s, H-18).

EXAMPLE 18

Production of (<i>Z.</i>) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -11β- (4-methnylphenyl) -4-estren-3-one (18D)

A. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- (4-methylphenyl) -5 (10) -estren-17β-ol (18A)

27.8 ml of a 1.6 M solution of methyl lithium in diethyl ether are added dropwise to a suspension of 2.10 g of copper (I) cyanide in 40 ml of diethyl ether and 10 ml of tetrahydrofuran at -78 ° C. under protective gas. The reaction solution is warmed to -20 ° C and cooled again to -78 ° C after 15 minutes. At this temperature a solution of 4.00 g<u style="single">4C</u> added dropwise in 25 ml of diethyl ether. The reaction mixture is slowly warmed to -20 ° C. and stirred at this temperature for two days. For working up, saturated ammonium chloride solution is added and extracted with ethyl acetate. The organic phase is washed with water and with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 1.65 g<u style="single">18A</u>.

B. 17β-Hydroxy-11β- (4-methylphenyl) -4-estren-3-one (18B)

From 1.61 g <u style="single">18A</u> are analogous to the regulations <u style="single">4E</u> and <u style="single">7D</u> by ketal hydrolysis and isomerization 920 mg of the compound <u style="single">18B</u> manufactured. IR (KBr): 1662 cm⁻¹ (C = O).

C. 17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -11β- (4-methylphenyl) -4-estren-3-one (18C)

From 895 mg <u style="single">18B</u> are analogous to the regulations <u style="single">4G</u>, <u style="single">3C</u>, <u style="single">3D</u> and <u style="single">3E</u> 294 mg of the compound <u style="single">18C</u> manufactured. [α]_D²² = -26.6 ° (CHCl₃; c = 0.500). IR (KBr): 2230 cm⁻¹ (C≡C), 1659 cm⁻¹ (C = O).

1 H-NMR (CDCl₃) δ: 7.29 ppm (2H, d J = 8.0 Hz, H-aromatic); 7.09 ppm (2H, d J = 8.0 Hz, H aromatic); 5.86 ppm (1H, broad s, H-4); 4.37 ppm (2H, m, H-CH₂OH); 3.39 ppm (1H, broad dd J = 6.5 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 2.32 ppm (3H, s, H-CH₃); 0.76 ppm (3H, s, H-18).

D. (<i>Z.</i>) -17β-hydroxy-17α- (3-hydroxy-1-propenyl) -11β- (4-methylphenyl) -4-estren-3-one (18D)

As under <u style="single">3F</u> 265 mg are described <u style="single">18C</u> hydrogenated with 53 mg of 10% Pd / BaSO₄ catalyst in 3 ml of pyridine and 6 ml of ethanol. After silica gel chromatography, 193 mg of the title compound<u style="single">18D</u> receive. [α]_D²² = + 75.8 ° (CHCl₃; c = 0.510). IR (KBr): 1664 cm⁻¹ (C = O).

1 H-NMR (CDCl₃) δ: 7.29 ppm (2H, d J = 8.0 Hz, H-aromatic); 7.09 ppm (2H, d J = 8.0 Hz, H aromatic); 5.85 ppm (1H, broad s, H-4); 5.71 ppm (1H, ddd J = 12.0 Hz and J = 5.5 Hz and J = 5.5 Hz, H-CH =); 5.62 ppm (1H, broad d J = 12.0 Hz, H-CH =); 4.24 ppm (2H, m, H-CH₂OH); 3.33 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.84 ppm (1H, m, H-10); 2.32 ppm (3H, s, H-CH₃); 0.71 ppm (3H, s, H-18).

Production of (<i>Z.</i>) -17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19D)

A. 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 11β- [4- (5-pyrimidinyl) phenyl] -5 (10) -estren-17β-ol (19A)

A solution of 4.40 g <u style="single">4C</u> in 300 ml of dioxane is stirred with 1.35 g of lithium chloride for 15 minutes at room temperature under a protective gas. 8.3 ml of hexabutylditin and 735 mg of tetrakis (triphenylphosphine) palladium (0) are added. The reaction mixture is heated to 100 ° C. for 90 minutes. Then 2.3 g of 5-bromopyrimidine are added and the mixture is heated to boiling for a further 7 hours. After cooling, it is filtered through Celite, washed with ethyl acetate and concentrated in vacuo. After column chromatography, 2.37 g are obtained<u style="single">19A</u>.

B. 17β-Hydroxy-11β-11β- [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19B)

From 2.31 g <u style="single">19A</u> are analogous to the regulations <u style="single">4E</u> and <u style="single">7D</u> by ketal hydrolysis and isomerization 991 mg of the compound <u style="single">19B</u> manufactured. IR (KBr): 1660 cm⁻¹ (C = O).

1 H-NMR (CDCl₃ + Py-<i>d₅</i>) δ: 9.19 ppm (1H, broad s, H-Py2); 8.99 ppm (2H, broad s, H-Py4 and Py6); 7.60 ppm (2H, d J = 9 Hz, H aromatic); 7.53 ppm (2H, d J = 9 Hz, H aromatic); 5.87 ppm (1H, broad s, H-4); 3.60 ppm (1H, dd J = 8.5 Hz and J = 7.0 Hz, H-17); 3.43 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.84 ppm (1H, m, H-10); 0.57 ppm (3H, s, H-18).

C. 17β-Hydroxy-17α- (3-hydroxy-1-propynyl) -11β- [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19C)

From 955 mg <u style="single">19B</u> are analogous to the regulations <u style="single">4G</u>, <u style="single">3C</u>, <u style="single">3D</u> and <u style="single">3E</u> 203 mg of the compound <u style="single">19C</u> manufactured. IR (KBr): 2235 cm⁻¹ (C≡C), 1665 cm⁻¹ (C = O).

D. (<i>Z.</i>) -17β-Hydroxy-17α- (3-hydroxy-1-propenyl) -11β- [4- (5-pyrimidinyl) phenyl] -4-estren-3-one (19D)

As under <u style="single">3F</u> 187 mg are described <u style="single">19C</u> hydrogenated with 37 mg of 10% Pd / BaSO₄ catalyst in 2 ml of pyridine and 4 ml of ethanol. After silica gel chromatography, 112 mg of the title compound<u style="single">19D</u> receive. IR (KBr): 1664 cm⁻¹ (C = O).

1 H NMR (CDCl₃) δ: 9.20 ppm (1H, broad s, H-Py2); 8.98 ppm (2H, broad s, H-Py4 and Py6); 7.59 ppm (2H, d J = 9 Hz, H aromatic); 7.52 ppm (2H, d J = 9 Hz, H aromatic); 5.88 ppm (1H, broad s, H-4); 5.72 ppm (1H, ddd J = 11.5 Hz and J = 5.5 Hz and J = 5.5 Hz, H-CH =); 5.65 ppm (1H, broad d J = 11.5 Hz, H-CH =); 4.29 ppm (1H, broad dd J = 14 Hz and J = 5.5 Hz, H-CH₂OH); 4.26 ppm (1H, broad dd J = 14 Hz and J = 5.5 Hz, H-CH₂OH); 3.44 ppm (1H, broad dd J = 6.0 Hz and J = 5.0 Hz, H-11); 2.85 ppm (1H, m, H-10); 0.72 ppm (3H, s, H-18).

EXAMPLE 20

Preparation of (11β, 17β) -11- [4- (5-pyrimidinyl) phenyl] spiro [estr-4-en-17,2′ (3′H) -furan] -3-one (20A)

A. (11β, 17β) -11- [4- (5-pyrimidinyl) phenyl] spiro [estr-4-en-17,2 ′ (3′H) -furan] -3-one (20A)

320 mg of the under <u style="single">19D</u> Compound described are at 0 ° C with 400 mg <i>p</i>-Toluene sulfonic acid chloride and 1 ml triethylamine combined. The reaction mixture is stirred for twelve hours at room temperature and then mixed with saturated sodium bicarbonate solution and extracted with methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography provides 140 mg<u style="single">20A</u>.

1 H NMR (CDCl₃) δ: 9.20 ppm (1H, broad s, H-Py2); 8.98 ppm (2H, broad s, H-Py4 and Py6); 7.57 ppm (2H, d J = 9 Hz, H aromatic); 7.52 ppm (2H, d J = 9 Hz, H aromatic); 5.88 ppm (1H, broad s, H-4); 5.86 ppm (1H, m, H-CH =); 5.81 ppm (1H, m, H-CH =); 4.52 ppm (1H, broad d J = 14 Hz, H-CH₂OC); 4.49 ppm (1H, broad d J = 14 Hz, H-CH₂OC); 3.39 ppm (1H, broad dd J = 9.0 Hz and J = 4.0 Hz, H-11); 2.84 ppm (1H, m, H-10); 0.71 ppm (3H, s, H-18).