13-Alpha-alkyl gonanes, their preparation and pharmaceutical compositions containing them.

0001The invention relates to new 13α-alkylgonanes of the general formula I, a process for their preparation, pharmaceutical preparations containing these compounds and the new 13-episteroids of the general formula III as intermediates.

0002The compounds of the general formula I have a strong affinity for the gestagen receptor without having self-gestagen activity. They are competitive antagonists of progesterone (anti-progestogens) and are suitable for triggering abortions because they displace the progesterone required for maintaining pregnancy from the receptor. The compounds are therefore valuable and interesting with regard to their use for postcoital (pc) fertility control.

0003Corresponding compounds in the tarran series have already been described as antigestagenic compounds in Fertility and Sterility 40 (1982), page 253.

0004The previously known structure-activity relationships for competitive progesterone antagonists indicated that a 1,3-diaxial arrangement of 11β-aryl radical and 13ß-alkyl group is absolutely necessary for the development of antigestagenic activity. All the more surprising is the strong and selective antagonistic effect of the 13α-alkylgonane type I, which has a completely different molecular topography compared to the Estran series.

0005To characterize the antigestagenic activity of the compounds according to the invention, the abortive activity was investigated in an early phase post nidationem (Experiment I) and in an advanced phase post nidationem (Experiment II).

0006The 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 (= d 1 pc).

0007The animals were treated with the substance or solvent to be tested in each case after the blastocysts had been nidated from d 5 pc to d 7 pc (Experiment I) or d 13 pc to d 15 pc (Experiment II). The animals were sacrificed on d 9 pc and d 17 pc and the uteri were examined for implants and absorption sites. Photos of all uteri were taken. The absence of implants was considered an abortion.

0008The following were examined as antigestagens:<ul id="ul0001" list-style="none"><li>A: 11ß- (4-Dimethylaminophenyl) -17ß-hydroxy-17α-propinyl-4,9-estradien-3-one (reference substance).</li><li>B: 11β- (4-dimethylaminophenyl) -17ß-hydroxy-17α- (3-hydroxy-propyi) -13a-methyl-4,9-gonadien-3-one (according to the invention).</li><li>C: 11β- (4-Dimethylaminophenyl) -17α-hydroxy-17ß- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one (according to the invention).</li></ul>

0009The 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 subcutaneous (sc).<tables id="tabl0001" num="0001"><img file="EP0129499A2_D0001.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0129499A2_D0002.tif" /></tables>

0010The compounds B and C according to the invention have a fully abortive effect in the early pregnancy rat in doses = 1.0 mg / d (abortion rate: 4/4). In contrast, reference substance A shows maximum abortion-inducing (anti-gestagenic) effects only at doses of = 3.0 mg / d (Table 1).

0011In an advanced phase of pregnancy (d 13 - 15 pc), the percentage of complete abortions with 3-day sc administration of 3.0 mg / d for B is 35.4%, for C 52.3% and for the comparison substance A 3, 5% (Table 2).

0012The 13a-alkylgonanes of the general formula I can be used in the form of pharmaceutical preparations. The preparations are prepared by galenical methods known per se by mixing with organic or inorganic inert carrier material which is suitable for enteral, percutaneous or parenteral administration.

0013The dosage of the active compounds according to the invention in humans is about 10 to 1000 mg per day.

0014Alkyl groups in R¹ and R¹¹ of the general formula I should contain 1 to 4 carbon atoms, the methyl and ethyl groups being preferred. The group

0015<chemistry id="chem0001" num="0001"><img file="EP0129499A2_D0003.tif" /></chemistry>also stands for a saturated 5- or 6-membered ring which, in addition to C atoms and N, can also contain a further heteroatom such as O, N or S, examples which may be mentioned are the pyrrolidino, piperidino, piperazino, morpholino and oxa - and thiazolidinos and thiadiazolidinoring.

0016Under<chemistry id="chem0002" num="0002"><img file="EP0129499A2_D0004.tif" /></chemistry>should also the corresponding tertiary

0017N-oxides are understood, such as dimethylamino-N-oxide, pyrrolidino, piperidino, piperazino, etc. N-oxide.

0018The in R^IV and R^V contained alkyl and alkanoyl groups should each have 1 to 4 carbon atoms, methyl, ethyl and acetyl, propionyl being preferred.

0019The new 13a-alkylgonanes of the general formula I are prepared according to the invention by the process according to claim 13.

0020By irradiation with ultraviolet light, the 13β-alkyl steroids of the general formula II are converted into the 13-episteroids (13a-alkyl steroids) of the general formula III in good yield.

0021The good yield of conversion product is surprising. It has long been known that 17-oxosteroids of the normal series can be converted into the 13-episteroids by UV radiation (A. Butenandt et al., Ber. Deutsch. Chem. Ges. 74, 1308 (1941)); however, mixtures of starting material and epimerized compound were always obtained, the irradiation times were several hours and the yields were extremely low. Hence the search for an alternative, chemical access to the ₁₃-Epi series still up to date, as a recent work by Barton et al., JCS Perkin I, 2163 (1977) shows. However, this alternative is not suitable for the production of type I compounds. It has been found that the irradiation of compounds of type II takes a much more favorable course under certain conditions than in the series 11-unsubstituted 17-oxosteroids. The average irradiation times are now only 10 - 30 minutes, and the yields of 13-episteroid are between 60 - 80%. The radiation products can optionally be reacted further without chromatographic purification. The essential prerequisite for a good result is the correct choice of solvent, the concentration of the substrate to be irradiated and the exact adherence to the irradiation time. These parameters must be determined separately for each new substrate.

0022The irradiation is carried out with the full light of a high pressure mercury lamp in the quartz glass apparatus. The temperature of the reaction solutions is set to about 25 ° C., the concentration of the solutions is 0.1-1.0 percent by weight. Tetrahydrofuran and dioxane are preferably used as solvents, but non-polar aprotic solvents such as hexane, cyclohexane, benzene, toluene and mixtures thereof can also be used. The irradiation time is about 10-50 minutes.

0023The 13-episteroids III obtained in this way are converted into the end compound of the general formula I by the usual methods by nucleophilic addition to the 17-ketone and subsequent reactions. The nucleophilic addition to III generally proceeds to form both possible isomeric forms at C-17, which, however, are easily separable by chromatography or fractional crystallization. In many cases, both isomers are pharmacologically active, although there may be differences in potency.

0024The nucleophilic addition of acetylene (ethyne) or propyne takes place with the aid of the residue -C = CH or -C≡C-CH₃ releasing agent. Examples of such agents are alkali metal acetylides, such as, for example, potassium and lithium acetylide or methyl acetylide.

0025The organometallic compound can also be formed in situ and reacted with the 17-ketone of the formula III. 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.

0026The 17-ethynyl-17-hydroxy compounds can be hydrated in alcoholic solution under mercury salt catalysis to give the 17-acetyl-17-hydroxy compounds (Chem. Ber. 111 (1973) 3086-3093).

00273-hydroxypropane or 3-hydroxypropene in the 17-position is introduced by reacting the 17-ketone with metalated derivatives of propargyl alcohol, for example with 1-lithium-3-tetrahydropyran-2'-yloxypropin-1 17- (3-hydroxy-1-propynyl) -17-hydroxy compounds, which are then hydrogenated to the 17- (3-hydroxypropyl or 3-hydroxypropenyl) -17-hydroxy compounds. The hydrogenation must be carried out under conditions which only ensure attack on the CC triple bond without saturating the tetrasubstituted 9 (10) double bond. This can be achieved, for example, by hydrogenation in solution at room temperature and normal pressure_- agents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with the addition of precious metal catalysts such as platinum or palladium.

0028The introduction of the homologous hydroxyalkane and hydroxyalkene groups of the general formula -CH = CH- (CH2) nOH or -CH₂-CH₂- (CH₂)_nOH is carried out in a corresponding manner with homologues of propargyl alcohol.

0029The 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). Examples of deactivated noble metal catalysts are 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate. The hydrogenation is stopped after the absorption of one equivalent of hydrogen.

0030The 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 (J. Am. Chem. Soc. 7₇ (1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1971) 6560), with diisobutylaluminium hydride and methyl lithium (J. Am. Chem. Soc. 89 (1967) 5085 ) and especially 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.

0031If end products of formula I are desired with R³/ R⁴ in importance<chemistry id="chem0003" num="0003"><img file="EP0129499A2_D0005.tif" /></chemistry>the 17- (3-hydroxypropyl) 17-hydroxy compounds are oxidized in a manner known per se. The conditions for the oxidation depend on the nature of the substituent R.¹ in formula I. Is R¹ For example, a dialkylamino group, chromic acid reagents are unsuitable for oxidation since they primarily attack the dialkylamino group. In these cases, oxidizing agents such as silver carbonate / Celite (Fetizon reagent; M. Fetizon and M. Golfier, Comp. Rend. 267 (1963) 900) or platinum / oxygen (H. Muxfeldt et al., Angewandte Chemie International, Int. Ed. 1 (1962) 157) are used. Is R¹ on the other hand an alkoxy group, oxidizing agents such as Jones' reagent, chromic acid pyridine, pyridinium dichromate or pyridinium chlorochromate can also be used.

0032The 17-cyanomethyl side chain is built up in a manner known per se from the 17-ketone of the general formula III, for example via the 17-spiroepoxide and cleavage of the spiroepoxide with HCN according to Z. Chem. 18 (1978) 259-260.

0033The Introduction of the Cyanalkane Side Chain - (CH₂)_n-CH₂^C.N with n = 1 - 3 occurs, for example, by adding ^Li- (^C.H₂)_n-CH₂CN to the 17-ketone.

0034The 17-hydroxyacetyl side chain is also introduced by methods known per se, for example by the method described in J. Org. Chem. 47 (1982), 2993-2995.

0035Free hydroxyl groups in the 17-position can be esterified or etherified in a manner known per se.

0036After the reaction (nucleophilic addition) of the 17-ketone, the compounds of the formula III are treated with acid or an acidic ion exchanger for elimination of water with formation of the 4 (5) double bond and for simultaneous cleavage and removal of any further protective groups which can be removed with acid.

0037The acidic treatment is carried out in a manner known per se by containing the compound of the formula III, which contains a 3-ketal group and a 5a-hydroxy group and an optionally O-protected 17- (3-hydroxypropyl) group, in a water-miscible manner Solvents, such as aqueous methanol, ethanol or acetone, dissolve and catalytic amounts of mineral or sulfonic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid or an organic acid, such as acetic acid, until the water is split off and protective groups are removed. The reaction, which takes place at temperatures from 0 to 100 C, can also be carried out with an acidic ion exchanger. The course of the reaction can be followed using analytical methods, for example samples taken by thin-layer chromatography.

0038In addition to the compounds described in Examples 1 to 7, the following compounds are preferred:<ul id="ul0002" list-style="none"><li>11β- (4-Dimethylaminophenyl) -17α- (3-hydroxypropyl) -17ß-hydroxy-13a-methyl-4,9-gonadien-3-one N-oxide.</li><li>17α-ethynyl-17β-hydroxy-13α-methyl-11ß- (4-piperidino-phenyl) -4,9-gonadien-3-one.</li><li>17β-ethynyl-17α-hydroxy-13α-methyl-11ß- (4-piperidino-phenyl) -4,9-gonadien-3-one.</li><li>11β- / 4- (2-dimethylaminoethoxy) phenyl1 / -17α-hydroxy-17ß- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one.</li><li>11β- (4-ethoxyphenyl) -17α-hydroxy-17ß- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one.</li><li>11β- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-17ß-n-propyl-4,9-gonadien-3-one.</li><li>nß- (4-Dimethylaminophenyl) -17a-hydroxy-17ß- (3-methoxypropyl) -13α-methyl-4,9-gonadien-3-one.</li><li>11β- (4-Dimethylaminophenyl) -17ß- (ethoxymethyl) -17a-hydroxy-13a-methyl-4,9-gonadien-3-one.</li><li>17β- (3-acetoxy-1Z-propenyl) -11ß- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-4,9-gonadien-3-one.</li><li>11β- (4-Dimethylaminophenyl) -17α-hydroxy-17β- (3-methoxy-1Z-propenyl) -13a-methyl-4,9-gonadien-3-one.</li><li>17β-chloroethynyl-11ß- (4-dimethylaminophenyl) -17a-hydroxy-13a-methyl-4,9-gonadien-3-one.</li><li>17β- (2-cyan) ethyl-11ß- (4-dimethylaminophenyl) -17a-hydroxy-13a-methyl-4,9-gonadien-3-one.</li><li>17α, 21-bis-acetoxy-11β- (4-dimethylaminophenyl) -13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione.</li><li>11β- (4-dimethylaminophenyl) -21-methoxy-13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione.</li><li>3- / 11β- (4-dimethylaminophenyl) -17a-hydroxy-13a-methyl-3-oxo-4,9-gonadien-17β-yl] propionic acid lactone.</li></ul>

example 1

0039<ul id="ul0003" list-style="none"><li>a) A solution of 2.0 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-9 (10) -estren-17- on (F. 143 - 145 ° C) in 300 ml absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25 ° C with a high pressure mercury lamp (Philips HPK 125, immersion lamp, quartz glass reactor). The solvent is then distilled off in vacuo and the residue is chromatographed on aluminum oxide (Merck, neutral, stage III) with hexane / ethyl acetate. 1.46 g of 11β- (4-dimethylaminophenyl) -3.3- (2,2-dimethylpropane-1,3-dioxy) -5α-hydroxy-13α-methyl-9 (10) -gon-17 are obtained -on as a colorless oil.</li><li>b) Absolute THF (248 ml) is saturated with acetylene at 5 ° C. by introducing it for 30 minutes. Then 51 ml of a 15% solution of n-butyllithium in hexane are slowly added dropwise and the mixture is stirred for a further 15 minutes while cooling with ice water. A solution of 2.7 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-13a-methyl-9-gonen-17-one in 40 ml of absolute THF is then added dropwise to the suspension of the lithium acetylide within 15 minutes and the mixture is stirred for a further 2 hours at room temperature. For working up, pour into ice water and extract with ethyl acetate. The crude product thus obtained (2.85 g) is used in the next step without further purification.</li><li>c) 2.8 g of the crude product obtained under b) are suspended in 29 ml of 70% aqueous acetic acid and stirred at 50 ° C. for 3 hours. After cooling, the mixture is diluted with about 100 ml of water and made up by adding concentrated aqueous NH₃Solution with a pH of 10.5. After extraction with ethyl acetate, an oily isomer mixture is obtained, which is separated by column chromatography on silica gel with hexane / ethyl acetate. In the elution order you get:<ul id="ul0004" list-style="none"><li>1. 530 mg 11ß- (4-dimethylaminophenyl) -17a-ethinyl-17ß-hydroxy-13a-methyl-4,9-gonadien-3-one with a melting point of 120 - 123 ° C (ethyl acetate / diisopropyl ether) and</li><li>2nd 1.33 g of 11β- (4-dimethylaminophenyl) -17ß-ethinyl-17α-hydroxy-13α-mettiyl-4,9-gonadien-3-one with a melting point of 201-204 ° C (ethyl acetate).</li></ul></li></ul>

0040Analogously to b) and c), methylacetylene instead of acetylene gives:<ul id="ul0005" list-style="none"><li>1. 11ß- (4-Dimethylaminophenyl) -17ß-hydroxy-13a-methyl-17a-propinyl-4,9-gonadien-3-one as an oil.</li><li>2nd 11ß- (4-Dimethylaminophenyl) -17a-hydroxy-13a-methyl-17ß-propinyl-4,9-gonadien-3-one as an oil.</li></ul>

0041d) A suspension of 1.02 g of mercury oxide (HgO, red) in 20 ml of water is stirred for 30 minutes at 60 ° C. after the addition of 0.87 ml of concentrated sulfuric acid. 9 ml of this mercury salt solution are added to a solution of 3.25 g of 11β- (4-dimethylaminophenyl) -17β-ethynyl-17α-hydroxy-13α-methyl-4,9-gonadien-3-one in 32 ml of glacial acetic acid. The mixture is then stirred at 60 ° C. for 2 hours. For working up, the cooled reaction solution is poured into ice water and made up by adding concentrated aqueous NH₃Solution a pH of 10.5 and extracted with ethyl acetate. The oily crude product thus obtained is crystallized from methylene chloride / diisopropyl ether. 2.37 g of 11β- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione with a melting point of 224-225 ° C. are obtained.

0042e) A suspension of 2.3 g of 11β- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione in 58 ml of toluene is added after the addition of 11.6 ml of acetic anhydride and 5.8 g of 4-dimethylaminopyridine were stirred at 25 ° C. for 20 hours. Then pour into saturated NAHCO₃Solution and extracted with ethyl acetate. The crude product is chromatographed on 200 g of silica gel with hexane / ethyl acetate. After crystallization of the main fraction from hexane / ethyl acetate, 1.71 g of 17α-acetoxy-11β- (4-dimethylaminophenyl) -13a-methyl-18,19-dinor-4,9-pregnadien-3,20-dione with a melting point of 194 are obtained - 195 ° C.

Example 2

0043<ul id="ul0006" list-style="none"><li>a) A solution of 1.8 g of 11β- (4-diethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5α-hydroxy-9-estren-17-one (F 223-226 ° C. in 300 ml of THF is irradiated for 26 minutes under the conditions of Example 1 a). After chromatography of the crude product, 1.58 g of 11β- (4-diethylaminophenyl) 13α- (2,2-dimethyl-propane-1,3-dioxy) -5α-hydroxy-13α-methyl-9-gonen-17-one is obtained as a colorless oil.</li><li>b) From 3.94 g of 3-tetrahydropyran-2'-yloxy-1-propyne in 85 ml of abs. THF and 23.1 ml of a 15% solution of n-butyllithium in hexane are used to prepare the organolithium compound at 0 ° C. A solution of 3.53 g of the product described under 2a) in 71 ml of abs is then added dropwise. THF and stir for 4 hours at room temperature. The reaction solution is then in ice water. poured and extracted with ethyl acetate. The crude product (3.85 g) 11β- (4-diethylaminophenyl) -3,3- (2,2-dimethylpropan-1,3-dioxy) -13α-methyl-17α- [3- (tetrahydropyran-2-yloxy) -1-propynyl] -9-gonen-5α, 17β-diol and 11ß- (4-diethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -13α-methyl-17β- [3- (tetrahydropyran-2-yloxy) -1-propynyl7-9-gonen-5a, 17a-diol is used for the hydrogenation without further purification.</li><li>c) 3.85 g of the crude product obtained under 2 b) are hydrogenated in 95 ml of ethanol after addition of 400 mg of 10% palladium-carbon at room temperature and normal pressure. After taking up 191 ml of hydrogen, the catalyst is filtered off and the mixture is concentrated.</li><li>d) The hydrogenation crude product obtained under 2 c) (3.85 g) is stirred in 30 ml of 70% acetic acid at 60 ° C. for 2 hours. After cooling, the procedure is as in 1 c) and the mixture of isomers obtained is chromatographed.</li></ul>

0044In the elution order you get:<ul id="ul0007" list-style="none"><li>1. 410 mg of 11β- (4-diethylaminophenyl) -17a- (3-hydroxypropyl) -17ß-hydroxy-13a-methyl-4,9-gonadien-3-one as a yellowish oil. UV (methanol): ε₂₆₆ = 19080, ε₃₀₉ = 19110^.</li><li>2nd 1.39 g of 11β- (4-diethylaminophenyl) -17ß- (3-hydroxypropyl) -17a-hydroxy-13a-methyl-4,9-gonadien-3-one as a solid foam.</li></ul>

0045Analogously to b) to d), when 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-13a-methyl-9- is used gonen-17-one as starting material:<ul id="ul0008" list-style="none"><li>1.) -11β- (4-dimethylaminophenyl) -17β-hydroxy-17α- (3-hydroxy propyl) -13a-methyl-4,9-gonadien-3-one as an oil.</li><li>2.) 11β- (4-Dimethylaminophenyl) -17α-hydroxy-17β- (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one as 01.</li></ul>

Example 3

0046<ul id="ul0009" list-style="none"><li>a) A solution of 1.75 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5α-hydroxy-11β- (4-methoxyphenyl) -9-estren-17-one in 290 ml of dioxane is irradiated for 19 minutes under the conditions of Example 1 a). After chromatography, 1.45 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -5α-hydroxy-11β- (4-methoxyphenyl) -13α-methyl-9-gonen-17- on as a colorless oil.</li><li>b) To a suspension of lithium acetylide, prepared from a saturated solution of acetylene in 450 ml of THF and 130 ml of a 15% solution of n-butyllithium in hexane, a solution of 8.2 g of 3,3- (2, 2-Dimethyl-propan-1,3-dioxy) -5α-hydroxy-11β- (4-methoxyphenyl) -13α-methyl-9-gonen-17-one in 130 ml THF.</li></ul>

0047The mixture is then stirred for 3 hours at room temperature, then the reaction solution is poured into about 3 l of ice water and extracted with ethyl acetate. The crude product is chromatographed on aluminum oxide with hexane / ethyl acetate.

0048In the elution order you get:<ul id="ul0010" list-style="none"><li>1. 1.8 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -17a-ethinyl-11β- (4-methoxyphenyl) -13α-methyl-9-gonen-5a, 17ß-diol as colorless oil.</li><li>2nd 5.1 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -17β-ethynyl-11β- (4-methoxyphenyl) -13α-methyl-9-gonen-5a, 17a-diol as solid foam.</li></ul>

0049c) A solution of 3.28 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -17β-ethynyl-11β- (4-methoxyphenyl) -13α-methyl-9-gonen-5a , 17a-diol in 33 ml of 70% aqueous acetic acid is stirred at 60 ° C for 30 minutes. After cooling, pour into ice water, extract with methylene chloride, wash the MeCl₂-Extracts with saturated NAHCO₃Solution and constricts. Crystallization of the crude product from ethyl acetate gives 2.0 g of 17β-ethynyl-17a-hydroxy-11ß- (4-methoxyphenyl) -13a-methyl-4,9-gonadien-3-one from the melting point₁86 - ₁3₇ ° c.

Example 4

0050Irradiation of 1.84 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a-hydroxy-18-methyl-9-estrene-17 for 20 minutes -one in 280 ml of THF under the conditions of Example 1 a) leads to 1.36 g of 11β- (4-dimethylaminophenyl) -3.3- (2,2-dimethyl-propane-1,3-dioxy) -13a- ethyl 5a-hydroxy-9-gons_-17-one as foam.

00516.1 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropan-1,3-dioxy) -13a-ethyl-5a-hydroxy-9-gonen-17-one are under the conditions of Example 1 b) reacted with lithium acetylide and the crude product thus obtained split under the conditions of Example 1 c) with acetic acid. After chromatography and crystallization from ethyl acetate / diisopropyl ether, 3.2 g of 11ß- (4-dimethylaminophenyl) -17ß-ethinyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-one with a melting point of 197-198 ° C. are obtained ,<maths id="math0001" num=""><img file="EP0129499A2_D0006.tif" /></maths> + 450.4 ° (CHCl₃, c = 0.505).

0052Mercury-salt-catalyzed hydration analogous to Example 1 d) and subsequent acetylation analogous to Example 1 e) gives 11ß- (4-dimethylaminophenyl) -17ß-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadiene from 1.3 g -3-one after chromatographic purification 720 mg 17α-acetoxy-11β- (4-dimethylaminophenyl) -13α-ethyl-18,19-dinor-4,9-pregnadien-3,20-dione as a solid foam. <maths id="math0002" num=""><img file="EP0129499A2_D0007.tif" /></maths> + 290.8 ° (CHCl₃, c = 0.515).

Example 5

0053<ul id="ul0011" list-style="none"><li>a) By reacting 7.3 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5a-hydroxy-13a-methyl-9-gonen-17 -one with 10.7 g of 3-tetrahydropyran-2'-yloxy-1-propyne under the conditions of Example 2 b), after chromatography of the crude product on aluminum oxide with hexane / ethyl acetate, 4.83 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -13α-methyl-17β- [3- (tetrahydropyran-2-yloxy) -1-propynyl] -9-gonen-5a, 17a diol as a yellowish foam.</li><li>b) A solution of 2.2 g of the adduct obtained under a) in 67 ml of ethanol and 0.56 ml of triethylamine is hydrogenated after adding 210 mg of palladium on barium sulfate (10%) at room temperature and normal pressure. After 83.5 ml of hydrogen have been taken up, the catalyst is filtered off and concentrated. The crude hydrogenation product thus obtained is cleaved with 14 ml of 70% acetic acid under the conditions of Example 1 c). After crystallization from ethyl acetate / diisopropyl ether, 1.1 g of 11β- (4-dimethylaminophenyl) 17a-hydroxy-17ß- (3-hydroxy-1 (Z) -propenyl) -13α-methyl-4,9-gonadien-3- on from melting point 133 - 135 ° c.</li></ul>

Example 6

Preparation of 11β- (4-dimethylaminophenyl) -17β-ethynyl-16β-ethyl-17α-hydroxy-13α-methyl-4,9-gonadien-3-one

0054<ul id="ul0012" list-style="none"><li>a) A suspension of 29.3 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5 (10), 9 (11) -estradien-17-one and 28.6 g of bis -dimethylamino-tert-butoxymethane is stirred under argon at 160 ° C for 60 minutes. After cooling, the crude product is triturated with about 50 ml of ethyl acetate, filtered and the filter residue is recrystallized from ethyl acetate. This gives 27.6 g of 16-dimethylaminomethylene-3,3- (2,2-dimethyl-propane-1,3-dioxy) -5- (10), 9 (11) -estradiene-17- on from melting point 208 - 2₁₁ ° C.</li><li>b) A solution of 14.4 g of 16-dimethylaminomethylene-3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 (10), 9 (11) -estradien-17-one in 220 ml of toluene is added dropwise with ice-water cooling with 85 ml of a 5% solution of methyl lithium in diethyl ether. After the addition, the mixture is stirred at +5 to +10 ° C for 15 minutes, excess reagent is decomposed by carefully adding about 20 ml of water, the reaction solution is then poured into about 3 l of ice water and extracted with methylene chloride. The crude product is chromatographed on neutral aluminum oxide with hexane / ethyl acetate. After crystallization of the main fraction from ethyl acetate, 13.0 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -16 (E) -ethylidene-5 (10), 9 (11) -estradiene are obtained -17-one from melting point 121 -₁23 ° C.</li><li>c) To a solution of 9.4 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -16 (E) -ethylidene-5 (10), 9 (11) -estradiene-17 -one in 43 ml methylene chloride, 0.34 ml hexachloroacetone and 0.0₁ ml of pyridine is added dropwise to ice water cooling 4.3 ml of 30% hydrogen peroxide and then stirred at 25 ° C for 16 hours. For working up, the reaction solution is diluted with about 100 ml of methylene chloride, washed successively with 5% i^Ghe well₂S₂0₃Solution and water, the methylene chloride phase dries over Na₂SO₄ and constricts. The resulting 5,10-epoxy mixture is Al₂O₃, neutral, stage III, chromatographed with hexane / ethyl acetate. 4.7 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -5α, 10α-epoxy-16 (E) -ethyliden-9 (11) -estren-17-one with a melting point of 139 are obtained - 141 ° C (ethyl acetate / diisopropyl ether).</li><li>d) A solution of 8.2 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5α, 10α-epoxy-11 (E) -ethyliden-9 (11) -estren-17 -one in 400 ml of ethanol is hydrogenated after adding 930 mg of palladium-on-carbon (10%) at room temperature and normal pressure. After 510 ml of hydrogen have been taken up, the catalyst is filtered off and the mixture is concentrated in vacuo. 7.7 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5α, 10α-epoxy-11β-ethyl-9 (11) -estren-17-one are obtained as a colorless oil.</li><li>e) From 1.4 g of magnesium, 0.05 ml of methyl iodide and 17.9 g of 4-bromo-N, N-dimethylaniline in 150 ml of abs. THF is the organomagnesium compound. After adding 344 g of CuCl, the mixture is stirred at OC for 15 minutes and then a solution of 7.7 g of the product obtained under d) in 70 ml of abs is added dropwise. THF added. The mixture is then stirred at room temperature for 3.5 hours. For working up, the reaction solution is poured into a mixture of ice water and NH₃Solution and extracted with ethyl acetate. After chromatography of the crude product on aluminum oxide with hexane / ethyl acetate and crystallization of the main fraction from diisopropyl ether / ethyl acetate, 6.5 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) - 16β-ethyl-5α-hydroxy-9 (10) -estren-17-one with a melting point of 180-181 ° C.</li><li>f) A solution of 4.0 g of the product obtained under e) in 600 ml of dioxane is irradiated under the conditions of Example 1 a). After crystallization of the crude radiation product from diisopropyl ether, 1.74 g of 11β- (4-dimethylaminophenyl) -3.3- (2,2-dimethylpropane-1,3-dioxy) -16β-ethyl-5α-hydroxy-13α- methyl-9 (10) -gon-17-one, melting point 192-194 ° C.</li><li>g) Under the conditions of Example 1 b), 1.4 g of the product obtained under f) are reacted with lithium acetylide. After crystallization of the crude product from ethyl acetate / diisopropyl ether, 960 mg of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -17ß-ethynyl-16ß-ethyl-13a- methyl-9 (10) -gon-5a, 17a-diol melting point 132-134 ° C.</li><li>h) Under the conditions of Example 1 c), 760 mg of the product obtained under g) are reacted with 8 ml of 70% acetic acid. Crystallization of the crude product from hexane / diethyl ether gives 460 mg of 11β- (4-dimethylaminophenyl) -17ß-ethinyl-16ß-ethyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one with a melting point of 195-197 ° C .</li></ul>

Example 7

Preparation of 17ß-cyanomethyl-liss- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-4,9-gonadien-3-one

0055<ul id="ul0013" list-style="none"><li>a) A suspension of 5.0 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -5α-hydroxy-13α-methyl-9 (10) - gonen-17-one and 4.74 g of trimethylsulfonium iodide in 60 ml of dimethylformamide are mixed in portions with 2.63 g of potassium tert-butoxide with ice-water cooling. The mixture is stirred for 4 hours at 25 ° C, then poured into ice water and extracted with ethyl acetate. After removal of the solvent, the initially oily crude product is crystallized from ethyl acetate / diisopropyl ether, and 4.2 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) are obtained in this way. -5α-hydroxy-13α-methyl-9 (10) -gon-17α-spiro-1 ', 2'-oxirane with a melting point of 234-236 ° C.</li><li>b) 2.0 g of the spiro-oxirane obtained in a) are dissolved in 84 ml of ethanol and, after the addition of 4.6 g of potassium cyanide, heated under reflux for 4 hours. The cooled solution is saturated in NaHCO₃-Poured solution and extracted with ethyl acetate. The crude product obtained after the concentration is taken up in 26 ml of 70% acetic acid without further purification and stirred at 60 ° C. for 60 minutes. After cooling, it is poured into ice water, adjusted to pH 10.5 by adding NH3 solution and extracted with methylene chloride. After chromatography of the crude product on silica gel with hexane / acetone and crystallization of the main fraction from ethanol, 1.4 g of 17β-cyanomethyl-11β- (4-dimethylaminophenyl) -17α-hydroxy-11α-methyl-4,9-gonadien-3- on from melting point 135 - 137 ° C.</li></ul>