DK166729B1 - 13ALFA METHYL AND 13ALFA ETHYLGONANES AND PROCEDURES FOR PREPARING THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM - Google Patents

Description

X

DK 166729 B1

The present invention relates to novel 13α-methyl and 13α-ethylgonanes which are characterized by having the general formula I as claimed in claim 1, a process for their preparation and pharmaceutical compositions containing these compounds.

The compounds of general formula I have a strong affinity for the progestagen receptor without even having progestogenic effect.

They are competitive antagonists for progesterone (anti-gestations) and are suitable for triggering abortions as they displace the progesterone required by the receptor to maintain pregnancy. The compounds are therefore valuable and interesting for their use in postcoital (p.c.) fertility control.

15

Similar compounds in the eastern range have already been described as anti-gestagent active compounds, "Fertility and Sterility" 40 (1983), pages 253 - 257.

The known relationships between structure and action for competitive progesterone antagonists suggest that a 1,3-di-axial device of the 11/3-aryl residue and the 130-alkyl group is imperative to exert anti-progestogenic action. Even more surprising is the strong and selective antagonistic effect of the 13α-alkylgonans of Formula I, which has a completely different molecular topography compared to the estranges.

To detect the antigenic effect of the compounds 30 of the invention, the abortive effect was investigated in an early phase post-nidation (trial I) and in an advanced phase post-nidation (trial II).

The experiments were performed with female rats weighing approx. 200 g. 35 After mating, the onset of pregnancy was secured by detection of sperm in vaginal outgrowths. The day of sperm count is valid as day 1 of pregnancy (= d 1 p.c.).

2 DK 166729 B1

The treatment of the animals with the substance to be examined or the solvent occurred after nidation of the blastocysts from d 5 p.c. to d 7 p.c. (Experiment I) respectively d 13 5 p.c. to d 15 p.c. (Experiment II). On d 9 p.c. d 17 p.c, respectively. the animals were killed and the uterus examined for implants and resorption sites. Photos were taken of all the uteri. Missing implants were rated as abortion.

10

As anti-progestogens were investigated: A. 11 (3- (4-dimethylaminophenyl) -173-hydroxy-17a-propinyl-4,9-estradien-3-one (comparative substance).

B. 11 (3- (4-Dimethylaminophenyl) -17β-hydroxy-17α- (3-hydroxy-propyl) -13α-methyl-4,9-gonadien-3-one (according to the invention).

C. 11 (3- (4-Dimethylaminophenyl) -17α-hydroxy-173- (3-hydroxy-propyl) -13α-methyl-4,9-gonadien-3-one (according to the invention).

D. lip- (4-dimethylannophenyl) -17α-hydroxy-170- (3-hydroxy-1 (Z) -propenyl) -13α-methyl-4,9-gonadien-3-one (according to the invention).

The test substances were dissolved in a mixture of benzyl benzoate 25 and castor oil (ratio 1: 4). Carrier volume per single dose was 0.2 ml. The treatment was done subcutaneously (s.c.).

TABLE 1 (Experiment I).

30

Abortive effect at an early stage of pregnancy in rats.

Treatment from d 5 p.c. to d 7 p.c., autopsy d 9 p.c.

35 3 DK 166729 B1

Dose, Abortion Rate

Compound mg / animal / day s.c. n abortion / n total% A. 30.0 4/4 100 10.0 '-' 3/0 4/4 100 10 IrO 2/4 50 0.3 0/4 0 0.1 0/4 0 B. 10.0 4/4 100 3.0 4/4 100 15 1.0 4/4 100 0.3 0/4 0 0.1 0/4 0 C. 10.0 4/4 100 20 3.0 ^ 4 / 4 100 1.0 4/4 100 0.3 0/4 0 0.1 '0/4 0 D. 1.0 4/4 100 25 0.3 1/4 25

Solvent as control: 0.2 ml benzyl benzoate + castor oil (1: 4) - 0/4 0

3Q

n = 4 rats / group.

TABLE 2 (Experiment II).

35

Abortive effect in an advanced stage of pregnancy in rats.

Treatment with 3.0 mg / d. s.c., anti-gestagen (AG) from d 13 p.c. to d 15 p.c., autopsy d 17 p.c.

5 4 DK 166729 B1% complete abortions = empty nidation sites.

100 90 _ □ AG '10 gQ () number of rats 70 _ 60 15 52.3% 50 _ (6) 40 _ 35.4% 20 30 · - (6) 20 _ 0% 3.5% 25 10 - ( 10) (6) o J _ dZ3 i_ _

Kontrol AB C

30 35 DK 166729 B1 5

Compounds B and C of the invention act in early pregnant rat at doses = 1.0 mg / d completely abortively (abortion rate 4/4). In contrast, comparator A first exhibits maximal abortion-triggering (anti-progestagen) activity at 5 doses = 3.0 mg / d (Table 1).

In the one-stage phase of pregnancy (d 13 - 15 -p.c.), the percentage of complete abortions at 3 days s.c. administration of 3.0 mg / d for B 35.4%, for C 52.3% and for Comparative A 3.5% (Table 2).

The 13a-alkylgonans of general formula I may find use in the form of pharmaceutical preparations. The preparation of the compositions is carried out in known ways in the art of galenics by mixing with organic or inorganic inert carrier materials suitable for interal, percutaneous or parenteral application.

The dosage of the active substances according to the invention is for 20 people at approx. 10 - 1000 mg per day. day

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

25

^ rI

N also means the corresponding tertiary N-oxides, such as e.g. dimethylamino-N-oxide.

35 DK 166729 B1 6

The novel 13α-alkylgonans of the general formula I are prepared by the process according to the invention which is characterized by the characterizing part of claim 4.

By ultraviolet light irradiation, the 133-alkyl steroids of general formula II are converted in good yield to the 13-episteroids (13a-alkyl steroids) of the general formula III.

The good yield of conversion product is surprising. It has long been known that 17-oxosteroids of the normal range by UV irradiation can be converted to the 13 epistroids (A ^ Butanandt et al., Ber.Deutsch.Chem.Ges. 74, 1308 ( 1941)). However, mixtures of starting material and epimerized compound are always obtained; the irradiation time lasted several hours and the yields were extremely low.

Therefore, a search for an alternative chemical approach to the 13-epitope was still current, as shown by a recent work by Barton et al., J.C.S.Pérkin I, 2163 (1977). However, this alternative is not suitable for the preparation of compounds of formula I, since the compounds of the 13-epi series have a different backbone than the compounds of the invention and are not suitable for introducing a β-aryl group in the absence of a reactive center thereon. place. It has been found that, under certain conditions, the irradiation of compounds of formula II assumes a substantially more favorable course than in the series of 11-unsubstituted 17-oxosteroids. Thus, the average irradiation time is only 10 - 30 minutes and the yields of 13-episteroid are between 60 and 80%. The irradiation products may optionally be reacted without chromatographic purification. An essential prerequisite for a good result is the correct choice of solvent, the concentration of the substance to be irradiated, and the exact adherence to the duration of the irradiation. Different parameters need to be determined especially for each new substance.

35 7 DK 166729 B1

The irradiation is performed with the full light from a Hg high-pressure lamp in a quartz glass apparatus. The temperature of the reaction

5 Q

the solutions are set to approx. 25 C; the concentration of the solutions is 0.1 - 1.0% by weight. As the solvent, tetrahydrofuran and dxoxane are preferably used, but non-polar aprotic solvents such as hexane, cyclohexane, benzene, toluene and mixtures thereof can also be used. The duration of the radiation is approx. 10 - 50 minutes.

The 13-episteroids III thus obtained are converted by the usual methods of nucleophilic addition to the 17 ketone and sequential reactions to the final compound 15 of general formula I. The nucleophilic addition to III generally proceeds to form both possible isomeric forms at C -17, which however can be easily separated by chromatography or fractional crystallization. In all cases, both isomers are pharmacologically active, although there may be 20 differences in the potency of the effect.

The nucleophilic addition of acetylene (ethyne) or propyne is effected by an agent which gives the residue -C = CH or -C = C-CH_. Such agents are e.g. alkali metal acetylides, 3 such as e.g. potassium and lithium acetylide or methyl acetylide.

The metal-organic compound can also be formed in situ and reacted with the 17-ketone of formula III. Thus, e.g. allow acetylene and an alkali metal, especially potassium, sodium or lithium, in the presence of an alcohol or in the presence of ammonia, to act on the 17-ketone in a suitable solvent. The alkali metal can also act in the form of e.g. methyl or butyllithium. As a solvent, especially dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene are suitable.

The 17-ethynyl-17-hydroxy compounds can be hydrated in alcoholic solution under mercury salt catalysis to the 17-acetyl-17-hydroxy compounds (Chem.Ber. 111 (1978) 3086-3093).

The introduction of 3-hydroxypropane and 3-hydroxypropene at the 17-position, respectively, is effected by reaction of the 17-ketone with 5 metallized propargylal carbon derivatives, e.g. with 1-1 in the thium-3-tetrahydropyran-21-yl oxy-propyn-1, to the 17- (3-hydroxy-1-propynyl) -17-hydroxy compounds which are then hydrogenated to 17- (3) -hydroxypropyl- and 3-hydroxypropenyl) -17-hydroxy compound, respectively. The hydrogenation must be carried out under conditions which exclusively attack the C-C triple bond without saturating the tetrasubstituted 9 (10) double bond. This succeeds e.g. by hydrogenation at room temperature and normal pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or vinegar ester, with the addition of noble metal catalysts such as platinum or palladium.

The compound with the Z-configured double bond in the hydroxy-propenyl group is formed by hydrogenation of the acetylenic triple double bond with a deactivated noble metal catalyst (J.

Fried, J.A. Edwards: "Organic Reactions in Steroid Chemistry",

Van Nostrand Reinhold Company 1972, page 134, and H.O.House: "Modern Synthetic Reactions" 1972, page 19). As deactivated precious metal catalyst, e.g. may be 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 taking up an equivalent hydrogen.

The compound with the E-configured double bond in the hydroxypropenyl group is formed by reduction of the acetylenic triple bond in a manner known per se. In the literature, a variety of methods for converting alkines to trans-olefins, e.g. 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 amines (J. 77 (1955) 3378), with boranes 9 DK 166729 B1 (J.Am.Chem.Soc. 93 (1971) 3395 and 94 (1971) 6560), with diisobutyl aluminum hydride and methyl lithium (J .Am.Chem.Soc. 89 5 (1967) 5085) and especially with lithium aluminum hydride / alcoholate (J.Am.Chem.Soc. 89 (1967) 4245). A further possibility is the reduction of the triple bond with chromium (II) sulfate in the presence of water or dimethylformamide in a weakly acidic environment (J.Am.Chem.Soc. 86 (1964) 4358) as well as the general reduction by the effect of transition metal compounds during shifts. of the oxidation step.

If end products of formula I are desired where R 3 and R 4 together with the carbon atom to which they are attached, the group means Λ

177-207, the 17- (3-hydroxypropyl) -17-hydroxy compounds are oxidized in a manner known per se. The conditions of the oxidation depend on the nature of the substituent R1 of formula I. If R1 2g e.g. is a dialkylamino group, chromic acid reagents are not down to the oxidation as these primarily attack the dialkylamino group. In these cases, oxidizing agents such as silver carbonate / Celite (Fetizon reagent, M.Fetison & M.Golfier, compte rendu 267 (1968) 900) or platinum / oxygen (HiMuxfeldt et al., Angewandte Chemie, International Edition Gift 1 (1962) 157). On the other hand, if R 2 is an alkoxy group, oxidizing agents such as Jones reagent, chromic acid pyridine, pyridinium dichromate or pyridinium chlorochromate can also be used.

35

The uptake of the 17-cyanmethyl side chain takes place in a manner known per se from the 17-ketone of the general formula III, for example via the 17-spiro epoxide and cleavage of the spiro epoxide with HCN according to Z.Chem. 18 (1978) 259-260.

DK 166729 B1

Also, the introduction of the 17-hydroxyacetyl side chain takes place in ways known per se, e.g. in the manner described in J.Org.Chem.47 (19821 2993-2995.

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

Following reaction (nucleophilic addition) of the 17 ketone, the compounds of formula III for water cleavage form to form the 4 (5) double bond and for simultaneous ketal cleavage and removal of any other protecting groups present which can be cleaved with acid, treated with acid or an acidic ion exchanger.

The acid treatment is carried out in a manner known per se, by dissolving the compound of formula III containing a 3-ketal group and a 5a-hydroxy group and an optionally O-protected 17- (3-hydroxypropyl) group, in a water-miscible solvent, such as aqueous methanol, ethanol or acetone, and letting catalytic amounts of mineral or sulfonic acid such as hydrochloric, sulfuric, phosphoric, perchloric or p-toluenesulfonic, or an organic acid such as acetic acid 25 until water is split off and protection groups are removed. The reaction, which runs at temperatures from 0 to 100 ° C, can also be carried out with an acidic ion exchanger. The course of the turnover can be followed by analytical methods, e.g. by thin layer chromatography on samples taken. 30

The invention is further illustrated in the following examples.

EXAMPLE 1.

A) A solution of 2.0 g of 11 / 3- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5α-hydroxy-9 (10) -ostren-17 -one (melting point 143 - 145 ° C) in 300 ml of absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25 ° C with a Hg high pressure lamp (Philips HPK 125, immersion lamp, quartz glass reactor). The solvent is then distilled off in vacuo and chromatographed on the residue over alumina (Merck, neutral, step III) with hexane / acetic ester. 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5α-hydroxy-13α-methyl-9 (10) -gonen-17 is obtained. -on like a colorless oil.

b) Absolute THF (248 ml) is saturated with acetylene at 5 ° C for 30 minutes. Then 51 ml of a 15% solution of n-butyllithium in hexane is slowly added dropwise and stirred for 15 minutes under cooling with ice water. A solution of 2.7 g of 118- (4-dimethylaminophenyl) -3,3 (2,2-dimethyl-1 κ propane-1,3-dioxy) -5α-hydroxy-13α-methyl-9-gonen-17 on in 40 ml of absolute THF is then added dropwise over 15 minutes to the suspension of the lithium acetylide and stirred for an additional 2 hours at room temperature. For processing, pour in ice water and extract with vinegar ester. The crude product thus obtained (2.85 g) is used in the following steps without further purification.

c) 2.8 g of the crude product obtained under b) is suspended in 29 ml of 70% aqueous acetic acid and stirred for 3 hours at 50 ° C.

25

After cooling, dilute with approx. 100 ml of water and adjust a pH of 10.5 by adding concentrated aqueous NH 2 solution. After extraction with vinegar ester, an oily mixture of isomers is obtained which is separated by column chromatography on silica gel with hexane / vinegar ester. There are obtained in elution order: 1) 530 mg of 118- (4-dimethylaminophenyl) -17a-eth; ynyl-178-hydroxy-13a-methyl-4,9-gonadien-3-one, m.p. 120-123 ° C (vinegar ester) (diisopropyl ether) and 2) 1.33 g of 118- (4-dimethylaminophenyl) -178-ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one, mp 201-204 ° C (acetic acid) .

12 DK 166729 B1

Analogously to b) and c), methyl acetylene is substituted for acetylene: 1) 11 / 5- (4-dimethylamino in nophenyl) -17 / 3-hydroxy-13a-methyl 1 -17a-5 -4,9-gonadien-3-one as an oil ([α] + = + 264.6 ° C + JCl 3, C = 0.51)) and -.

2) 11 / 3- (4-di with amine in nophenyl) -17a-hydroxy-13a-methyl-17/3-propynyl-4,9-gonadien-3-one with m.p. = 167-168 ° C.

d) A suspension of 1.02 g of mercury oxide (red, HgO) 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 brine solution is added to a solution of 3.25 g of 113- (4-dimethylaminophenyl) -173-ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one in 32 ml glacial vinegar. Then stir for 2 hours at 60 ° C. For work-up, the cooled reaction solution is poured into ice water, adjusted to a pH of 10.5 by adding concentrated aqueous NHg solution and extracted with ethyl acetate. The oily crude product thus obtained is crystallized by methylene chloride / diisopropyl ether. 2.37 g of 113- (4-dimethylaminopheriyl) -17α-hydroxy-13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione are obtained, mp 224-225 ° C.

e) A suspension of 2.3 g of 113- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione in 58 ml of toluene is added after addition of 11.6 ml of acetic anhydride and 5.8 g of 4-dimethylaminopyridine are stirred for 20 hours at 25 ° C. Then pour into saturated NaHCO 3 solution and extract with ethyl acetate. The crude product is chromatographed on 200 g of silica gel with hexane / ethyl acetate. After crystallization of the main fraction of hexane / ethyl acetate 1.71 g of 17α-acetoxy-113- (4-dimethylaminophenyl) -13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione is obtained with the melting point 194 - 195 ° C.

Let ιυυ / ώντ u in 13 EXAMPLE 2.

a) A solution of 1.8 g of 113- (4-diethylaminophenyl) -3,3- (2,2-dimethylpropan-1,3-dioxy) -5α-hydroxy-9-estren-17-one (m.p. 226 ° C) in 300 ml of THF is irradiated for 26 minutes under the conditions described in Example 1 a). After chromatography of the crude product, 1.58 g of 118- (4-diethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5a-hydroxy-13a-methyl-9-gone are obtained. -17-on as a colorless oil.

b) Of 3.94 g of 3-tetrahydropyran-2'-yloxy-1-propine in 85 ml of X 5 absolute THF and 23.1 ml of a 15% solution of n-butyllithium in hexane, crude at 0 ° C makes the lithium organic connection. Then, a solution of 3.53 g of the product described under 2 (a) is dropped into 71 ml of absolute THF and stirred for 4 hours at room temperature. The reaction solution is then poured into ice water and extracted with vinegar ester. The crude product (3.85 g) 113- (4-diethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -13 α-methyl-17 α- [3- (tetrahydropyran-2 -yloxy) -1-propinyl] -9-gonen-5a, 173-diol, and 113- (4-diethylamino-phenyl) -3,3- (2-dimethylpropane-1,3-dioxy) -13 -Methyl-17β- [3- (tetrahydropyran-2-yloxy) -1-propinyl] -9-gonen-5α, 17α-diol is used for hydrogenation without further purification.

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

d) The hydrogenation product prepared under 2 (c) (3.85 g) is stirred in 30 ml of 70% acetic acid for 2 hours at 60 ° C. After cooling, work up as under 1 (c) and chromatograph the resulting isomer mixture. In elution order, one obtains: DK 166729 B1 14 1) 410 mg of 11 (3- (4-diethylaminophenyl) -17a- (3-hydroxypropyl) - 173-hydroxy-13a-methyl-4,9-gonadien-3-one yellow oil (UV (methanol): = 19080/6309 = 19110) and 2) 1.39 g of 113- (4-diethylaminophenyl) -178- (3-hydroxypropyl) -17α-hydroxy-13α-methyl 4, 9-gonadien-3-one as a solid foam.

Analogously to b) - d), 113- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5a-hydroxy-13a-methyl-9- gonen-17-one as starting material: 1) II3- (4-dimethylaminophenyl) -173-hydroxy-17a- (3-hydroxy-propyl) -13a-ethyl-4,9-gonadien-3-one as an oil and 2) 113- (4-Dimethylaminophenyl) -17 α-hydroxy-17 3- (3-hydroxy-propyl) -13α-ethyl-4,9-gonadien-3-one as an oil.

EXAMPLE 3.

a) A solution of 1,75 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -5a-hydroxy-113- (4-methoxyphenyl) -9-estren-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 3,3- (2,2-dimethylpropane-1,3-dioxy) -5a-hydroxy-113- (4-methoxyphenyl) -13a-methyl-9-gonen-17-one is obtained. 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-butyllithium in hexane, a solution of 8.2 g of 3.3- (2) is added. (2-Dimethylpropan-1,3-dioxy) -5α-hydroxy-113- (4-methoxyphenyl) -13α-methyl-9-gonen-17-one in 130 ml of THF. The mixture is stirred at room temperature for 3 hours, then the reaction solution is poured into ca. 31 ice water and extract with ethyl acetate. The crude product is chromatographed on alumina with hexane / ethyl acetate. In elution order: 1) 1.8 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -17a-ethynyl-118- (4-methoxyphenyl) -13a-methyl-9-gonen-5a are obtained. 17β-diol as a colorless oil and 2) 5.1 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -178-ethynyl-118- (4-methoxyphenyl) -13a-methyl 9-gonen-5a, 17a-diol as a solid foam.

c) A solution of 3.28 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -173-ethinyl-118- (4-methoxyphenyl) -13a-methyl-9-gonen-5a, 17a-diol in 33 ml of 70% aqueous acetic acid is stirred for 30 ml nuts at 60 ° C. After cooling, pour into ice water, extract with methylene chloride, wash the MeCl2 extract with saturated NaHCO 3 solution and evaporate. Crystallization of the crude product of ethyl acetate gives 2.0 g of 178-ethynyl-17a-hydroxy ~ 118 ~ 20 (4-methoxyphenyl) -13a-methyl-4,9-gonadien-3-one, melting at 186 DEG-187 DEG.

EXAMPLE 4.

Irradiation of 1.84 g of 118- (4-dimethylaminophenyl) - 3.3- (2,2-dimethylpropan-1,3-dioxy) -5α-hydroxy-18-methyl-9-estren-17-one in 280 ml of THF under the conditions of Example 1 a) leads to 1.36 g of 118- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -13a-ethyl-5α hydroxy-9-gonen-17-one as a foam.

6.1 g of II3- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -13a-ethyl-5a-hydroxy-9-gonen-17-one are obtained under the conditions of Example 1 b) reacted with lithium acetylide and the crude product thus obtained is cleaved with acetic acid under the conditions of Example 1 c). After chromatography and crystallization of ethyl acetate / diisopropyl ether, 3.2 g of 118- (4-dimethylaminophenyl) -178-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-one is obtained, m.p. - 198 ° C.

[A] p5 + 450.4 ° (CHCl3, c = 0.505).

Hydration catalyzed with mercury salt, analogous to Example 1 d) and subsequent acetylation analogous to Example 1 e) gives 1.3 g of 113- (4-dimethylaminophenyl) -173-ethinyl-13a-ethyl-17a-hydroxy 4,9-gonadien-3-one after chromatographic purification 720 mg of 17α-acetoxy-113- (4-dimethylaminophenyl) -13α-ethyl-18,19-dinor-4,9-pregnadiene-3,20-dione as a solid foam.

[a] q5 + 290.8 ° (CHCl3, c = 0.515).

EXAMPLE 5.

(a) By reaction of 7.3 g of 113- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5a-hydroxy-13a-methyl-9-gon-17 -one with 10.7 g of 3-tetrahydropyran-21-yloxy-1-propyne under the conditions of Example 2 b), after chromatography of the crude product pt alumina with hexane / ethyl acetate, 4.83 g of 113- (4-dimethylaminophenyl) -3 , 3- (2,2-Dimethylpropane-1,3-dioxy) -13a-methyl-173- [3- (tetrahydropyran-2-yloxy) -1-propynyl] -9-gonen-5a, 17a-diol as a yellow foam.

(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 hydrated at room temperature and normal pressure after addition of 210 mg of palladium on barium sulfate (10%). After uptake of 83.5 ml of hydrogen, the catalyst is filtered and evaporated. The resulting hydrogenation product is cleaved with 14 ml of 70% acetic acid under the conditions of Example 1 c). After crystallization of ethyl acetate / diisopropyl ether, 1.1 g of 113- (4-3 dimethylaminophenyl) -17 α-hydroxy-173- (3-hydroxy-1 (Z) -propenyl) - 13α-methyl-4.9- gonadien-3-one, mp 133-135 ° C.

EXAMPLE 6.

Preparation of 113- (4-dimethylaminophenyl) -173-ethynyl-163-ethyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one. a) A suspension of 29.3 g of 3,3- (2β-dimethylpropane-1β-dioxy) -5 (10), 9 (11) -estradien-17-one and 28f6 g of bis-dimethylamino tert -butoxymethane is stirred under argon for 60 minutes at 160 ° C. After cooling, the crude product is released with approx.

50 ml of ethyl acetate, filter and crystallize the residue of ethyl acetate. This gives 27.6 g of 16-dimethylaminomethylene-3,3- (2,2-dimethylpropan-1,3-dioxy) -5 (10), 9 (11) -estradien-17-one at the melting point 208 - 211 ° C.

b) A solution of 14.4 g of 16-diraethylaminomethylene-3,3- (2,2-dimethylpropan-1,3-dioxy) -5 (10), 9 (11) -estradien-17-one in 220 ml of toluene 85 ml of a 5% solution of methyl lithium in diethyl ether are added dropwise with cooling with ice water.

After the addition, stir for 15 minutes at +5 - + 10 ° C, decompose excess reagent by gently adding approx. 20 ml of water, then pour the reaction solution gene for approx. 3 1

c O

ice water and extract with methylene chloride. The crude product is chromatographed on neutral alumina with hexane / ethyl acetate. After crystallization of the main fraction of ethyl acetate, 13.0 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -16 (E) -ethylidene-5 (10), 9 (11) -estradiene-17 are obtained. -one with the melting point 121 - 123 ° C.

v U

c) To a solution of 9.4 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -16 (E) -ethylidene-5 (10), 9 (11) -estradien-17-one in 43 ml of methylene chloride, 0.34 ml of hexachloroacetone and 0.01 ml of pyridine, while cooling with ice water, 4.3 ml of 30% hydrogen peroxide are added dropwise and then stirred for 16 hours at 25 ° C. with approx. 100 ml of methylene chloride, wash sequentially with 5% Na 2 S 2 O 2 solution and water, dry the methylene chloride phase over ^ 230 ^ and evaporate. The thus obtained 5,10-epoxide mixture is chromatographed on neutral A₂O ^ / Step III, with hexane / ethyl acetate. 4.7 g of 3,3- (2,2-dimethyl-propane-1,3-dioxy) -5a, 10a-epoxy-16 (E) -ethylidene-9 (11) -ostren-17-one are obtained. mp 139-141 ° C (ethyl acetate / diisopropyl ether).

d) A solution of 8.2 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -10a, 10a-epoxy-16 (E) -ethylidene-9 (11) -ostrene-17- on 400 ml of ethanol is hydrogenated after addition of 930 mg of palladium carbon (10%) at room temperature and normal pressure. After uptake of 510 ml of hydrogen is filtered from the catalyst and evaporated in vacuo. 7.7 g of 3,3- (2,2-dimethylpropane-1,3-dioxy) -5a, 10a-epoxy-16f3-ethyl-9 (11) -ostren-17-one are obtained as a colorless oil.

e) Of the 20 g of magnesium, 0.05 ml of methyl iodide and 17.9 g of 4-bromo-Ν, Ν-dimethylaniline in 150 ml of absolute THF, the 20 magnesium organic compound is prepared. After the addition of 344 g of CuCl, stir for 15 minutes at 0 ° C and then add dropwise a solution of 7.7 g of the product prepared under (d) in 70 ml of absolute THF. Then stir for 3 1/2 hours at room temperature. For work up, the reaction solution is poured into a mixture of ice water and NH 2 solution and extracted with ethyl acetate. After chromatography of the crude product on alumina with hexane / ethyl acetate and crystallization of the main fraction of diisopropyl ether / ethyl acetate, 6.5 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3) are obtained. -dioxy) -16β-ethyl-5α-hydroxy-9 (10) -ester-17-one, mp 180-181 ° C.

f) A solution of 4.0 g of the product prepared under e) in 600 ml of dioxane is irradiated under the conditions of Example 1 a). After crystallization of the irradiation crude product of diisopropyl ether, 1.74 g of 11β- (4-dimethylamino-phenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -16 | 3-ethyl-5-o-19 is obtained. 5 hydroxy-13cc-methyl-9 (10) -gonen-17-one, mp 192 -194 ° C.

g) Under the conditions of Example 1 (b), 1.4 g of the product prepared under (f) is reacted with lithium acetylide. After crystallization of the crude product of ethyl acetate / diisopropyl ether, 960 mg of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethyl-propane-1,3-dioxy) -178-ethinyl-168-ethyl-13a are obtained. -methyl-9 (10) - gonen-5a, 17a-diol, mp 132-134 ° C.

(h) Under the conditions of Example 1 (c), 760 mg of the product prepared under (g) is reacted with 8 ml of 70 S acetic acid.

Crystallization of the crude product of hexane / diethyl ether gives 460 mg of 11β- (4-dimethylaminophenyl) -178-ethinyl-163-ethyl-17α-hydroxy-13α-methyl-4,9-gonadien-3-one, m.p. ° C.

EXAMPLE 7.

Preparation of 17β-cyanomethyl-113- (4-dimethylaminophenyl) - 17α-hydroxy-13α-methyl-4,9-gonadien-3-one.

A) A suspension of 5.0 g of 11β- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5α-hydroxy-13α-methyl-9 (10) -gone -17-one and 4.74 g of trimethylsulfonium iodide in 60 ml of dimethyl formamide are added under cooling with ice-water, portionwise 2.63 g of potassium tert-butylate. 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 first oily crude product of ethyl acetate / diisopropyl ether is crystallized to give 4.2 g of 11 (3- (4-dimethylaminophenyl) -3,3-35 (2,2-dimethylpropane-1,3-dioxy) ) -5a-hydroxy-13a-methyl-9 (10) - gonen-17a-spiro-1 ', 2'-oxyran, m.p. 234-26 ° C.

Claims (4)

After chromatography of the crude product on silica gel with hexane / acetone and crystallization of the major fraction of ethanol, 1.4 g of 173-cyanmethyl-113- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-4,9-gonadiene is obtained. -3-one, mp 135-137 ° C. 15 Patent claims. 1. 13a-methyl1 and 13a-ethylgonans of the general formula I 2 3 Y / - \ I R. Wherein R 1 is -N-R 1, where R 1 and R 11 are hydrogen or R 1 35 alkyl of 1-4 carbon atoms, or -R 11 1, where R 11 is methyl, ethyl or propyl, R 2 is a hydrogen atom or a methyl group, R 3 is - (CH 2) n-CH 2 OH, where n = 0-4 or -CH = CH- (CH 2) n-OH, where n = 1-4, -C = CX, where X means hydrogen or alkyl 5 with 1-4 carbon atoms, - (CH 2) n-CH 2 CN where n = 0 - 3, or -C-CH, II · 30 R 4 is hydroxy or alkanoyloxy of 1-4 carbon atoms, or R 3 and R 4 together with it carbon atom to which they are attached means the group 0 Λ is Jn - and where R3 is in the α position and R4 is in the E position, or R3 is in the E position and R4 is in the a position relative to the steroid separator. 2q is facilitated and r5 is a hydrogen atom or an iso-alkyl group having 1-4 carbon atoms. Compound according to claim 1, characterized in that it is selected from H 5 - (4-dimethylaminophenyl) -17a-ethynyl-17/5-hydroxy-13o-methyl-4,9-gonadien-3-one, 113- ( 4-dimethylaminophenyl) -17 / 3-ethynyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one, 113- (4-dimethylaminophenyl) -17 3-hydroxy-13 α-methyl -17 α-propynyl-4,9-gonadien-3-one, 35,13- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-173-propynyl-4,9-gonadien-3-one , 113- (dimethylaminophenyl) -17oc-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione, DK-166729 B1 17a-acetoxy-110- (4-dimethyl aminophenyl) -13a -methyl-18,19-di-nor-4,9-pregnadiene-3,20-dione, 11β- (4-diethyl aminophenyl) -17a- (3-hydroxypropyl) -170-hydroxy-13a-methyl 4,9-gonadien-3-one, 113 '(4-dimethylaminophenyl) -170-hydroxy-17a (3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one, 1 ° 110- (4 -dimethylaminophenyl) -17α-hydroxy-170- (3-hydroxypropyl) -13α-methyl 1-4,9-gonadien-3-one, 17β-ethynyl-17α-hydroxy-110- (4-methoxyphenyl) -1α -methyl-4,9-gonadien-3 -one, 110- (4-dimethylaminophenyl) -170-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-one, 17 α-acetoxy-110- (4-dimethylaminophenyl) -13 α- ethyl 18,19-dinor-4,9-pregnadiene-3,20-dione, 110- (4-dimethylaminophenyl) -17α-hydroxy-17β- (3β-hydroxy-1 (Z) -propenyl) -13α- methyl 4,9-gonadien-3-one, 25-fluoro- (4-dimethylaminophenyl) -17o-ethynyl-16o-ethyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one, and 170- cyanmethyl-110- (4-dimethylaminophenyl) -17α-hydroxy-13α-methyl-4,9-gonadien-3-one. 30 Pharmaceutical compositions, characterized in that they contain a compound according to claims 1-2. A process for the preparation of 13α-methyl or 13α-ethylgonanes of the general formula I wherein R, R, R, R and R are as defined in claim 1. meaning a radiation of a compound of the general formula II H J_1 (111 20 "OH wherein R 1, R 2 and R $ have the meaning given above and Z is an ethylene or 2,2-dimethylpropylene group, red ultraviolet light in the form of the full light from an Hg high-pressure lamp in a quartz glass apparatus, keeping the temperature of the solution of the compound of formula II at about 25 ° C and the concentration of the solution being 0.1-1.0 wt%, and at 30 ways known per se by nucleophilic addition to the 17-ketone, cleavage of the 3-ketal protection and water-cleavage from the 4,5-position convert the 13-episteroid produced by UV irradiation of the general formula III \ R2 H ^ J i (III) 10 OH wherein R 1, R 2, R 5 and z have the meaning given above for the compounds of general formula I. 15 20 25 30 35