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

Descriptive Memory

The present invention relates to novel 13α-alkylgonanes of general formula I, a process for their preparation, pharmaceutical compositions containing them and novel 13-episteroids of general formula III which constitute novel intermediate compounds.

The compounds of general formula I have a strong affinity for the gestagen receptor without their own gestagenic activity. They are competitive progesterone antagonists (anti-gestagens) and are suitable for provoking abortion as they displace from the progesterone receptor necessary to maintain pregnancy. Therefore, these compounds are valuable and interesting from the point of view of their use in postcoital (pc) fertility control.

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Corresponding compounds in the stranger series have already been described in Fertility and Sterility 40 (1982), p. 253, as compounds with antigestogenic activity.

The structure-activity relationships hitherto known for competitive progesterone antagonists pointed to the imperative need for a 1,3-diaxial arrangement of the 11β-aryl radical and 13/3-alkyl group for the development of antigestagenic activity. This is why the strong and salective antagonistic activity of 130 (type I-alkylgonanes) having a completely different molecular topography compared to the stranger series is so surprising.

For characterization of the antistagenic activity of compounds referred to in the present invention, the abortifacient effect was analyzed at an early post nidationem stage (Experiment I) and an advanced post nidationem stage (Experiment II),

The assays were performed on rat females weighing about 200 g. After mating, early pregnancy was confirmed by detection of sperm in vaginal collection. The day of sperm detection represents 1®. day of pregnancy (= d 1 pc ·).

The animals were treated with their test substance or solvent after the blastocysts from dpc to dpc (Experiment I) and dp13c to dpc15 (Experiment II). At d 9 bp and 17 bc, respectively, the animals were slaughtered and the ions examined for implantation and resorption points. Photographs were taken of all the Oters. The absence of implantations was classified as abortion.

The following were tested as anti-gestagen:

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A: 11β- (4-dimethylaminophenyl) -17β-hydroxy-170β-propynyl-4.9 '

-estradien-3-one (Reference Substance).

Bs 11 / 7- (4-dimethylaminophenyl) -17β-hydroxy-1? of- (3-hydroxypropyl) -13 O-methyl-4,9-gonadien-3-one (according to the present invention).

C 11-11 - (4-dimethylamino phenyl) -17 ° 6-hydroxy 1-17 [4- (3-hydroxypropyl) -3- (3-methyl-4,9-gonadien-3-one) (according to the present invention ) ·

Test substances were dissolved in a mixture of benzyl benzoate and castor oil (1: 4 ratio). Vehicle volume per unit dose was 0.2 ml. The treatment was done subcutaneously (if).

Table 1 (Experiment I)

Abortive effect at an early stage of pregnancy in rats.

D 5 pc to d 7 pc treatment, autopsy on d 9 pc

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<td>Dose Compound mg / animal / day if</td><td>Proportion of abortions n abortions / n total</td><td> (%)</td>

<td> 30,0</td><td> 4/4</td><td> (100)</td>

<td> 10,0</td><td> -</td><td> -</td>

<td>A 3.0</td><td> 4/4</td><td> (100)</td>

<td> 1,0</td><td> 2/4</td><td> ( 50)</td>

<td> 0,3</td><td> 0/4</td><td> ( 0)</td>

<td> 0,1</td><td> 0/4</td><td> ( 0)</td>

<td> 10,0</td><td> 4/4</td><td> (100)</td>

<td> 3,0</td><td> 4/4</td><td> (100)</td>

<td>B 1.0</td><td> 4/4</td><td> (100)</td>

<td> 0,3</td><td> 0/4</td><td> ( 0)</td>

<td> 0,1</td><td> 0/4</td><td> ( 0)</td>

<td> 10,0</td><td> 4/4</td><td> (100)</td>

<td> 3,0</td><td> 4/4</td><td> (100)</td>

<td>C 1.0</td><td> 4/4</td><td> (100)</td>

<td> 0,3</td><td> 0/4</td><td> ( 0)</td>

<td> 0,1</td><td> 0/4</td><td> ( 0)</td>

<td>Solvent Used</td><td></td><td></td>

<td>as a control: -</td><td> 0/4</td><td> ( 0)</td>

0.2 ml benzyl benzoate + castor oil (1: 4) n = 4 mice / group

- 4 Table 2 (Experiment II)

Abortive effect on an advanced fasB of pregnancy in rats.

Treatment with 3.0 mg / d s and anti-gestation (AG) from d 13 pc to d 15 pc ·, autopsy at d 17 pc

% of complete abortions = empty nesting points

100 % (10)

Control □ ae () NS. of mice

35,4 (6)

52,3 % (6)

3,5 (6)

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THE

Compounds B and C according to the present invention have a fully abortifacient action in rats in early pregnancy at doses of> 1.0 mg / d (proportion of abortions> 4/4). In

<img file="PT78732B_D0005.tif" />

In contrast, reference substance A only shows maximal abortifacient action (antigestagenic) at doses of 3.0 mg / d (Table 1).

At an advanced stage of pregnancy (d 13 - d 15 ch), the percentage of complete miscarriages at a dose of 3.0 mg / d for 3 days is 35.4% for substance B, 52.3%. for substance C and 3.5% for reference substance A (Table 2).

The 13 (alkylalkanes of formula I) may be used in the form of the pharmaceutical compositions The preparation of the compositions is by known processes by mixing with an inert or organic inert carrier suitable for enteral, percutaneous or parenteral application.

The dosage of active ingredients according to the present invention is about 10 to 1000 mg per day for humans.

The alkyl groups in R s and R of formula I should contain 1 to 4 carbon atoms, with methyl and ethyl groups being preferred. The group 11 also represents a penta or hexagonal saturated nucleus which, in addition to C and N atoms, may also contain a heteroatom such as O, N or 5, with examples of pyrolidine, piperidino, piperazine, morpholine, oxa to thiazolidine, as well as thiadiazolidine.

By Ν 'must also be understood the corres ·

I .II

<img file="PT78732B_D0006.tif" />

pending tertiary N-oxides such as dimstylamino N-oxide, pyrrolidine N-oxide, piperidino, piperazine, etc.

The alkyl and alkanoyl groups in R1 and R3 should have 1 to 4 carbon atoms respectively, with methyl, ethyl and acetyl being propionyl being preferred.

In accordance with the present invention, the novel 130f-alkylgonanes of general formula I are prepared by the process indicated in claim 1.

The 13Î ± -alkyl steroids of general formula II are transformed in good yield into the 13-episteroid (1304-alkylesteroid) of general formula III by ultraviolet light irradiation.

Born yield on the product of processing is amazing. In fact, it has long been known that 17-oxosteroids of the normal series are converted to 13-episteroids by UV irradiation (A. Buteriandt et al., Ber. Deutsche Chem, Ges. 74, (1941), 1308), however, mixtures of starting substance and epimerized compound were always obtained, the irradiation periods lasted for several hours and the yields were extraordinarily low. Accordingly, the demand for alternative chemical access to the 13-epi series remains current, as shown by recent work by Barton et al., JC5. Perkin I, 2163 (1977). However, this alternative is not suitable for the preparation of type I compounds. It has been found that the irradiation of type II compounds under certain conditions is substantially more favorable than in the 11-unsubstituted 17-oxosteroid series. Thus, sac irradiation times averaged only 10-30 minutes and yields on 13-episteroids range from 60 to 80%. Irradiation products may optionally be used in other reactions without purification.

- 7 il

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chronatographic. Essential conditions for a good result are the choice of solvent chart, the concentration of the substrate to be irradiated and the accurate maintenance of the irradiation time.

The irradiation is made in full light of a high pressure mercury lamp in quartz glass apparatus. The temperature of the reaction solutions is adjusted to about 25 ° C, the concentration of the solutions is 0.1-1.0 wt%. Tetrahydrofuran and dioxane are preferably used as solvents, but nonpolar aprotic solvents such as hexane, cyclohexane, benzene, toluene and mixtures thereof may also be used. The irradiation time is approximately 10-50 minutes ·

The 13-episteroids of formula III thus obtained are converted to the final compounds of general formula I by standard procedures by nucleophilic addition to 17-ketone and subsequent reactions. Nucleophilic addition to the compound of formula III generally results from the formation of both possible C-17 isomeric forms, which are however easily separable by chromatography or fractional crystallization. In many cases both isomers are pharmacologically active, although there are also differences in the potency of their action. Nucleophilic addition of acetylene (atine) or brine is made with the aid of a -C = CH or -CsC-CHg radical releasing agent. Such agents are for example alkali metal acetylides, such as potassium lithium acetylide or methylacetylide.

The organometallic compound may also be formed in situ and reacted with the 17-ketone of formula II. Thus, acetylene or an alkali metal, in particular potassium, sodium or lithium, can be acted upon the 17-ketone in a

<img file="PT78732B_D0008.tif" />

appropriate solvent in the presence of an alcohol or in the presence of ammonia. Alkali metal should also be used in the form of, for example, lithium methyl or butyl. Particularly suitable as solvents are dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene.

The 17-ethynyl-17-hydroxy compounds may be hydrated in alcoholic solution under mercury salt catalysis by becoming the 17-acetyl-17-hydroxy compounds (Chem, Bar. 111 (197B), 3086-3093).

The introduction of 3-hydroxypropane or 3-hydroxypropene at position 17 is by reaction of 17-ketone with 'propargyl alcohol' metal derivatives, for example with 1-lithium-3-tetrahydropyran-2'-yloxy-propino-1 to give 17- (3-hydroxy-1-propynyl) -17-hydroxy compounds, which are then hydrogenated to give 17- (3-hydroxypropyl or 3-hydroxypropenyl) -17-hydroxy compounds. Hydrogenation must be carried out under conditions which exclusively assure the attack on the triple C * C bond without saturating the tetra-substituted 9 (10) double bond. 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.

The Z-bonded double bond compound in the hydroxypropenyl group is formed by hydrogenating the acatylenic triple bond with a deactivated noble metal catalyst (J, Fried, J, A. Edwards, Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, 134} and H.0 »Housei Modern Synthetic Reactions 1972, p. 19). Examples of 10% palladium on barium sulphate deactivated noble metal catalysts in the presence of a 5% palladium on amine or

<img file="PT78732B_D0009.tif" />

barium sulphate in the presence of a 5% amine or palladium on calcium carbonate with the addition of lead (II) acetate. Hydrogenation is stopped after incorporation of one equivalent of hydrogen.

The double bond compound of configuration E in the hydroxypropenyl group is formed by reducing the acetylenic triple bond by known process. A number of processes have been described in the literature for the transformation of alkynes to transolefins, 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 boron hydrides (J. Amer. Chem. Soc. 93 (1971) 3395 and 94 (1971) 656Q), with lithium diisobutylaluminum hydride (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 triple bonding with chromium (II) sulfate in the presence of water or dimethylformamide in slightly acidic medium (J. Am. Chem. Soc. 86 (1964) 4358), as well as the general reduction by the action of transition metal compounds, with alteration of the degree of oxidation.

In case 3 4 formula I where R / R is desired end products with the

<img file="PT78732B_D0010.tif" />

17- (3-hydroxypropyl) -17-hydroxy compounds are oxidized by known process. Oxidation conditions depend on the nature of the substituent R¹ in the formula Ί. To be¹ For example, a dialkylamino group are not suitable for oxidation

- 10 chromic acid as they primarily attack the dialkylamino group · In these cases oxidizing agents such as silver carbonate / celite (Fetizon reagent; M. Fetizon and H. Golfier, Corapt. Rend. 267 (1968)) 900) or platinum / oxygen (H. Muxfeldt et al., Angewandte Chemie, Int, Ed. 1 (1962) 157). If, on the contrary, R¹ is an alkoxy group, oxidizing agents such as Jones reagent, chromic acid pyridine, pyridine dichromate or pyridine chlorochromate may be used.

Synthesis of the 17-cyanomethyl side chain is by a known process from 17-ketone of general formula III, for example by 17-spiroepoxide and cleavage of spiroapoxide with HCN, according to Z. Chem. 18 (1878), 259-260.

Also introduction of the 17-hydroxystyl side chain is by known procedures, for example according to the procedure described in J. Org. Chem. 47 (1982), 2993-2995.

Free hydroxy groups at position 17 may be esterified or etherified by known process.

After reaction (nucleophilic addition) of 17-ketone, the compounds of formula III are treated with acid or an acid ion exchanger to remove water with formation of the double bond 4 (5) and to simultaneously dissociate the metal. and removing any protecting groups which may be present, which may be dissociable with acid.

Acid treatment is by known procedure by dissolving the compound of formula III which contains a 3-ketal group and a 5-hydroxy group and an optionally 0-protected 17- (3-hydroxypropyl) group in a water miscible solvent as

<img file="PT78732B_D0011.tif" />

aqueous methanol, ethanol or acetone, and allowing catalytic quantities of mineral or sulfonic acid to act on the solution, such as hydrochloric, sulfuric, phosphoric, perchloric or toluene-p-sulfonic acid, or an organic acid such as acid until the water and SBrem protecting groups are removed. The reaction, which takes place at temperatures from 0 to 100²C, may also be carried out with an acid ion exchanger, the course of the reaction may be monitored by analytical methods, for example by thin layer chromatography of collected samples.

Example 1

a) A solution of 2.0 g of 11,9- (4-dimethylaminophenyl) -3,3 (2,2-dimethyl-propan-1,3-dioxy) -5-0-hydroxy-9 (10) -estren-17-one (F. 143-145²c) in 300 ml of absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25Â ° 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, grade III) with hexane / ethyl acetate. 1.46 g of 11- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -5'-hydroxy-13 ° / -methyl-9 (10 ) -ganen-17-one as a colorless oil.

b) Absolute THF (248 ml) is saturated at 5 ° C²C per May of acetylene adduction in 30 min. Then 51 ml of a 15% lithium n-butyl solution in hexane are slowly added dropwise and stirred for a further 15 minutes while chilled by ice water. A solution of 2.7 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -benzamide is then added dropwise within 15 minutes. 5 The Î ± -hydroxy-13 of methyl-9-gonen-17-one in 40 ml of absolute tHF is suspended in the lithium acetylide suspension and stirred for a few hours at room temperature. For processing, it is poured into ice water and extracted with ethyl acetate.

The crude product thus obtained (2.85 g) is used for the next step without further purification.

(c) 2.8 g of the crude product obtained in (b) is suspended in 29 ml of 70% aqueous acetic acid and stirred for 3 hours at 50 ° C.^sC. After cooling, dilute with about 100 ml of water and adjust the pH to 10.5 by adding concentrated aqueous NH 3 solution. After extraction with ethyl acetate, an oily isomer mixture is obtained which is separated by column chromatography over silica gel with hexane / ethyl acetate. Obtained following elution

1. 1130- (4-dimethylaminophenyl) -17-6-ethynyl-17Î ± -hydroxy-139-methyl-4,9-gonadien-3-one m.p. 120-30Â ° C (ethyl acetate / diisopropyl ether}, and

2 · 1.33 g of ll / 3^>- (4-dimethylaminophenyl) -17_/^^>-methyl-17α-hydroxy-13α-methyl-4,9-gonadien-3-one m.p. 201-204 ° C (ethyl acetate).

Analogously ab) and c) but using methylacetylene instead of acetylene, we obtain:

1. 13_t[Α- (4-dimethylaminophenyl) -17α-hydroxy-13β'-methyl-17α-propynyl-4,9-gonadien-3-one instead of oil form.

2. 11-5- (4-dimethylaminophenyl) -17 O-hydroxy-13 p -ethyl-17γ-propynyl-4,9-gonadien-3-one as an oil »

<img file="PT78732B_D0012.tif" />

(d) A suspension of 1,02 g of mercury oxide (HgO, red) is stirred in 20 ml of water after adding 0,87 ml of concentrated sulfuric acid for 30 minutes at 60 ° C.²Ç? 9 ml of this mercury salt solution is added to a solution of 3.25 g of ly2- (4-dimethylaminophenyl) -1T / S-ethynyl-17b / -hydroxy-13Î ± -methyl-4,9-gonadien -3-one in 32 ml glacial acetic acid. It is then stirred for 2 hours at 60 ° C.²C. For processing, the cooled reaction solution is poured into ice water, adjusted to pH 10.5 by the addition of concentrated aqueous NH4 solution and extracted with ethyl acetate. The oily crude product thus obtained is crystallized from methylene chloride / diisopropyl ether. 2.37 g of ll are obtained_l3- (4-dimethylaminophenyl) -17 ° t^/-hydroxy-13β-methyl-18,19-dinor-4,9-pregnadien-3,20-dione with melting point at 224-225 ° C.

e) A suspension of 2.3 g of 11β-dimethylaminophenyl) -17β-hydroxy-13β-methyl-18,19-dinor-4,9-pregnadien-3,20-dione is stirred in a suspension. 58 ml of toluene after addition of 11.6 ml of acetic anhydride and 5.8 g of 4-dimethylaminophenyl for hours at 25 ° C. It is then poured into saturated NaHCO3 solution and extracted with ethyl acetate. 0 The crude product is chromatographed on 200 g of silica gel with hexane / ethyl acetate. After crystallization of the main fraction in hexane / ethyl acetate gives 1.71 g of 17α-acetoxy-11,5- (4-dimethylaminophenyl). ) -13 O / -methyl-18,19-dinor-4,9-pregnadien-3,20-dione with melting point 194-195²Ç.

Example 2

a) A solution of 1.8 g of 1- [3- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropan-1,3-dioxy) -5-hydroxy-9-sstren-17-one (F. 223-2262C) in 300 ml of THF is irradiated for 26 minutes under the conditions described in Example 1a). After chroma14

PORTUGAL!

By means of the crude product, 1.58 g of 11- (4-diethylaminophenyl) -3,3- ( 2,2-dimethyl-propan-1,3-dioxy) -5'-2-hydroxyacetate are obtained. 13 &lt;Z-Methyl-9-gonen-17-one as a colorless oil.

b) From 3.94 g of 3-tstrahydropyran-2'-yloxy-1-propine in 85 ml of absolute THF and 23.1 ml of a 15% solution of n-butyl lithium in hexane forms the 0²C is the organolytic compound. Thereafter, a solution of 3.53 g of the product described in 2 a) in 71 ml of absolute THF is added dropwise and stirred for 4 hours at room temperature.

The reaction solution is then poured into ice water and extracted with ethyl acetate. Crude product (3.85 g), 11/3- (4-diethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -1306-methyl-17Î ± / [[3 - (tetrahydropyran-2-yloxy) -1-propynyl-7α-9-gonen-5β-diol and 11β- (4-diethylaminophenyl) -3,3- (2,2-dimethyl-propanyl) 1,3-dioxy) -13-methyl-1α-C 3- (tetrahydropyran-2-yloxy) -1-propynyl-7-9-gonen-5 ° 6,17-diol, is used for hydrogenation without further purification .

c) 3.85 g of the crude product obtained in 2 b) is hydrogenated in 95 ml of ethanol at room temperature and normal pressure after addition of 400 mg of 10% palladium-carbon. After 191 ml of hydrogen were incorporated, the catalyst was filtered off and evaporated.

d) The crude hydrogenation product obtained in 2 c) (3.85 g) is stirred in 30 ml 70% acetic acid for 2 hours at 60 ° C.²C. After cooling, work up as in 1 c) and chromatograph the obtained isomer mixture. The sequence of the elution gives:

1. 410 g of 11β- (4-diethylaminophenyl) -17%^z'- (3-hydroxypropyl) -17β-hydroxy-130α-methyl-4,9-gonadien-3-one as a yellowish oil.

UV (methanol):_2é6 = 19080, k₃₀₉ = s 19110

<img file="PT78732B_D0013.tif" />

2. 1.39 g of 11β- (4-diethylaminophenyl) -17-2- (3-hydroxypropyl) -176-6-hydroxy-13β-methyl-4,9-gonadien-3-one as a solid foam ·

Similarly to that described in b) to d) but using 11-9- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -5- (4-hydroxy) 13y^z-methyl-9-gonen-17-one as a starting substance, obtain

1. 11β- (4-dimethylaminophenyl) -17β-hydroxy-17β- (3-hydroxypropyl) -13 p-methyl-4,9-gonadien-3-one as an oil ·

2 · 11/3- (4-dimethylaminophenyl) -1,7'-hydroxy-17,9- (3-hydroxypropyl) -13O (^z-methyl-4,9-ganadien-3-one as an oil.

Example 3

a) A solution of 1.75 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 H -droxy-11,7- (4-methoxyphenyl) -9-estrogen 17-one in 290 ml dioxane is irradiated for 19 minutes under the conditions described in Example 1 a). After chromatography 1.45 g of 3_T3- (2,2-dimethyl-propan-1,3-diaxy) -5Î ± -hydroxy-1Î ± - (4-methoxyphenyl) -13CV-methyl-9-gonen-17-one as a colorless oil.

(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-butyl lithium in hexane is added dropwise. solution of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -50% -hydroxy-11,2 g₁- (4-Methoxyphenyl) -13 ° ('-methyl-9-gonen-17-one in THF (130 ml).) Then stir for 3 hours at room temperature, tb.

<img file="PT78732B_D0014.tif" />

The reaction solution is then taken up in about 3 l of ice water and extracted with ethyl acetate. The crude product is chromatographed on aluminum oxide with hexane / ethyl acetate. Following elution we obtain:

1. 1.8 g of 3,3- (2,2-dimethylpropan-1,3-dioxy) -173α-ethynyl-11β- (4-methoxyphenyl) -130r-methyl-9-gonen-506,17 / β-diol in colorless oil form.

2. 5.1 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -17./3-ethynyl-yl- (4-methoxyphenyl) -13c-methyl-9-gonenyl 5cT,

17/9-diol as a solid foam ·

c) A solution of 3.28 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -17Î ± -thynyl-lly9- (4-methoxyphenyl) -13 2r'-methyl-2-yl 9-gonen-5of, 17 &lt;X^/diol in 33 ml dB 70% aqueous acetic acid is stirred for 30 minutes at 60 ° C. After cooling, it is poured into ice water, extracted with methylene chloride, the MeCl2 extracts are washed with saturated NaHCO3 solution and evaporated. Crystallization of the crude product from ethyl acetate yields 2.0 g of 1 H, 4-ethynyl-1 H-hydroxy-11,9- (4-methoxyphenyl) -13 C'-methyl-4,9-gonadien. -3-one with melting point at 186-187 ° C^andÇ.

Example 4

Upon irradiation for 20 minutes of 1.84 g of 11- 3- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -50-hydroxy-18-methyl 9-estren-17-one in 280 ml of THF under the conditions described in Example 1 a) gives 1.36 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl) propan-1,3-dioxy) -1306-ethyl-506-hydroxy-9-gonen-17-one as a foam.

<img file="PT78732B_D0015.tif" />

6.1 g of ll are reacted_&lt;Β - (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -13 mp-ethyl-5 CB-hydroxy-9gonen-17-one with lithium acetylide under the conditions Example 1 (b) and the crude product thus obtained is dissociated with acetic acid under the conditions of Example 1 (c). After chromatography and crystallization from ethyl acetate / diisopropyl ether, 3.2 g of 11β- (4-dimethylaminophenyl) -1,7β-ethynyl-1H-ethyl-10β-hydroxy-4,9 are obtained. -gonadien-3-one m.p. 197-1982 ° C, + 450.42 (CHCl₃, c = 0.505).

By means of salt-catalyzed hydration of mercury according to Example 1 d) and subsequent acetylation according to Example 1 e), 1.3 g of 11β- (4-dimethylaminophenyl) is obtained. ~ 17 / ^ - ethinyl-13fl^z-ethyl-17A^z-hydroxy-4,9-gonadien-3-one and after chromatographic purification 720mg of 17β-acetoxy-11β- (4-dimethylaminophenyl) -130Î ± -ethyl-18,19-dinor-4,9-pregnadien -3.2O-dione as a solid foam, ♦ 290.82 (CHCl₃, c = 0.515).

Example 5

a) Reacting 7.3 g of 11- 3- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 K-hydroxy-13of'-methyl-9 -gonen-17-one with 10.7 g of 3-tetrahydropyran-2'-yloxy-1-propine under the conditions described in Example 2 b) is obtained after chromatography of the crude product on aluminum oxide with hexane / acetate 4.83 g of 13- (4-dimethylaminophanyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -13-methyl-17β-z? 3- (tetrahydropyran-2-yloxy) -1-propynyl 7-9-gonen-54t,

-diol in the form of yellowish foam.

<img file="PT78732B_D0016.tif" />

(b) A solution of 2,2 g of the addition product obtained in (a) is hydrogenated in 67 ml of ethanol and 0,56 ml of triethylamine at room temperature and normal pressure after the addition of 210 mg of palladium on barium sulphate. (10%). After incorporation of 83.5 ml of hydrogen, the catalyst is filtered off and evaporated. The hydrogenation product thus obtained is dissociated with 14 ml of 70% acetic acid under the conditions of Example 1 c). Crystallization from ethyl acetate / diisopropyl ether affords 1.1 g of 11/3- (4-dimethylaminophenyl) -17α-hydroxy-17/3- (3-hydroxy-1 (Z) -propenyl) - 13-methyl-4,9-gonadien-3-one melting point at 133-135 ° C.

Example 6

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

(a) A suspension of 29,3 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 (10), '9 (11) -estradien-17aone and 28, 6 g of bis-dimethylamino-butoxy tert-methane for 60 minutes at 160 ° C under argon atmosphere. After cooling, the crude product is triturated with about 50 ml of ethyl acetate, filtered and the filter residue is crystallized from ethyl acetate. This gives 27.6 g of 16-dimethyl-inomethylene-3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 (10), 9 (11) -estradien-17-one. melting point 208-2112 ° C.

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 with 85 ml of a 5% solution of methyl lithium in diethyl ether under ice water cooling. It is then stirred for 15 minutes at a temperature of +5 to +10 ° C.²C decomposes the

<img file="PT78732B_D0017.tif" />

surplus reagent 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 in ethyl acetate, 13.0 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -1-6 (E) -ethylider (10), 9 ( ll) -estradien-17-one with melting point at 121-123 ° C^sÇ,

(c) to a solution of 9,4 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -16 (E) -ethylidene-5 (10), 9 (11) -estradienyl 17-one in 43 ml of methylene chloride, 0.34 ml of hexachloroacetone and 0.01 ml of pyridine is added dropwise under ice water cooling 4.3 ml of 30% hydrogen peroxide while stirring in followed for 16 hours at 25 ° C. The reaction solution is diluted with methylene chloride (100 ml), washed successively with Ν325₂At 5% θ2 and water, the methylene chloride phase is dried over Na2 SO4 and evaporated. The thus obtained 5,10-epoxide mixture is chromatographed on neutral AlCl 2, grade III, with hexane / ethyl acetate. 4.7 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 (10,10-epoxy-1 H) -ethylidene-9 (11) -estren-17 are obtained. -one with melting point at 139-14 ° C (ethyl acetate / diisopropyl ether) ··

d) A solution of 8.2 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 (X, 10 -epoxy-16 (E) -ethylidene-9) is hydrogenated (8). 11) -estren-17-one in 400 ml ethanol at room temperature and normal pressure after addition of 930 mg palladium-carbon (10%) After 510 ml hydrogen was incorporated, the catalyst was filtered off and evaporate in vacuo to give 7.7 g of 3,3- (2,2-dimethyl-propan-1,3-dioxy) -5 O, 10α-X-epoxy-16,3-ethyl 9 (11) -estren-17-one under colorless oil forms.

<img file="PT78732B_D0018.tif" />

e) The organomagnetic compound is prepared 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 absolute THF. After addition of 344 g of CuCl, stir for 15 minutes at 0 ° C and then add a solution of 7.7 g of the product obtained in d) dropwise in 70 ml of absolute THF *. for 3.5 hours at room temperature. For processing, the reaction solution is poured into a mixture of ice water and NH 4 'solution and extracted with ethyl acetate. Chromatography of the crude product in aluminum oxide with hexane / ethyl acetate and crystallization of the main fraction in diisopropyl ether / ethyl acetate affords 6.5 g of 11.1.₍3- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -1,6-β-ethyl-5'-hydroxy-9 (10) -ran-17- melting point at 1BD-1B1^sÇ.

f) A solution of 4.0 g of the product obtained in e) in 600 ml of dioxane is irradiated under the conditions of Example 1 a). Crystallization of the crude product from the irradiation in diisopropyl ether gives 1.74 g of 11- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -16. -ethyl-β-hydroxy-13 β [^z-methyl-9 (10) -gonen-17-one m.p. 192-1945 ° C.

g) 1.4 g of the product obtained in f) are reacted with lithium acetylide under the conditions of Example 1 b). After crystallization of the crude product from ethyl acetate / diisopropyl ether, 960 mg of lly # - (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -1H-4 are obtained. Ethylethyl-16β-ethyl-1BA '-me111-9 (10) -90080-520 (.174-diol melting point at 132-1342 ° C.

(h) 760 mg of the product obtained in g) is reacted with 8 ml of

<img file="PT78732B_D0019.tif" />

70% acetic acid under the conditions of Example 1 c). Crystallization of the crude product hexane / diethyl ether yields 460 mg of 11β- (4-dimethylaminophenyl) -17β-ethynyl-16β-ethyl-17 ° (-hydroxy-13β-methyl-4). 9-gonadien-3-one melting point 195-197^sÇ.

Example 7

Preparation of 1 H -cyanomethyl-1 H [4 H -4-dimethylaminophenyl) -17 H -hydroxy-13 O (methyl-4,9-gonadien-3-one

a) A suspension of 5.0 g of 1- [4- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propan-1,3-dioxy) -5β-hydroxy-13β-methyl] -9 (10) -gonen-17-one and 4.74 g of trimethylsulfonium iodide in 60 ml of dimethylformamide, portionwise and under chilled water, with 2.63 g of potassium tertiary butylate. Stir for 4 hours at 25 ° C, then pour into ice water and extract with ethyl acetate. After removal of the solvent, the oily crude product is crystallized from ethyl acetate / diisopropyl ether to give 4.2 g of 11- 3- (4-dimethylaminophanyl) -3,3- (2,2-dimethyl). -propan-1,3-dioxy) -5 K-hydroxy-13A^z-methyl-9 (10) -gonen-17^(?6-spiro-1,2 ', 2'-oxirane melting at 234-236 ° C.

(b) 2.0 g of the spiro-oxirane obtained in (a) are dissolved and, after the addition of 4.6 g of potassium cyanide, is heated at reflux temperature for 2 hours. The cooled solution is poured into saturated NaHCO3 solution and extracted with ethyl acetate. 0 The crude product obtained after evaporation is incorporated without further purification in 26 ml of 70% acidic acid and stirred for 60 minutes at 60 ° C. After cooling, it is poured into ice water, the pH adjusted to 10.5 by addition of NHg solution and extract with chloride

- 22 ds methylene. Chromatography of the crude product on silica gel with hexane / acetone and crystallization of the main moiety in ethanol affords 1.4 g of t-N (N-rianouj-β-yl-β-dimethylaminophenyl) -17A6-hydroxy-13 powder. methyl-4,9-gonadien-3-one melting at 135-1372 ° C.