DE3504421A1 - 11 beta -Phenylgonanes, the preparation thereof and pharmaceutical products containing these - Google Patents

Abstract

13-Alkyl-11 beta -phenylgonanes of the general formula I <IMAGE> in which A and B together are an oxygen atom, a CH2 group or a second bond between carbon atoms 9 and 10, X is an oxygen atom or the hydroxyimino group N-OH, n is the number 0 or 1, R1 is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R2 is an alpha or beta methyl or ethyl radical and R3 and R4 have various meanings are described. The 11 beta -phenylgonanes have antiprogestogenic and antiglucocorticoid effects.

Description

New 11ß-Phenvl-Gonans, their manufacture

and pharmaceutical preparations containing them the The invention relates to new 11ß-phenyl-gonans, processes for their preparation and these Pharmaceutical preparations containing compounds according to the claims.

11.ß-phenyl steroids are already known. For example 11ß-Aryl-17a-propynyl- and -ethynyl-4,9 (10) -estradienes in the European patent application 82400025.1 (Publication No. 0 057 115) and US Patent 4,386,085, 11β-Phenyl-17α- (3-hydroxypropyl) 4.9 (10) estradiene in European patent application 84101721.3 (Publication No. 0 116 974), 11ß-phenyl-17a- (3-hydroxyprop-1-enyl) -4,9 (10) -estradienes in the European Patent application 84730147.0 and 17ß-Hydroxy-17a- (3-hydroxypropyl) -b or. 17α-Hydroxy-17β- (hydroxypropyl) -13α-methyl-4,9-gonane described in European patent application 8i730062.1. Own these connections a strong affinity for the progestin receptor without possessing gestagenic activity of its own. They are competitive antagonists of progesterone (anti-progestins) and are used for Triggering abortions is suitable as it helps to maintain the pregnancy displace the required progesterone from the receptor. They are therefore valuable and interesting in terms of their use in post-coital fertility control.

They can also be used against hormonal irregularities, e.g. for menstrual induction and used to induce labor.

The in European patent applications 84101721.3 and 84730147.0 listed compounds in addition to their antigestagens properties nor antimineralcorticoid effects.

The first mentioned 11ß-aryl-17-propynyl- and -ethyne ~ 1-4,9 (10) -estradienes on the other hand have an antiglucocorticoid activity and can therefore also be used as Medicines for the therapy of corticoid-induced disorders (glaucoma) and for combating them of side effects1 that occur with long-term treatment with glucocorticoids (Cushing's syndrome). They therefore also allow for super secretion disorders attributable to glucocorticoids, especially obesity, arteriosclerosis, Combat osteoporosis, diabetes and insomnia.

However, it has so far not succeeded to a desirable extent, a Dissociation between antigestagens and antiglucocorticoid effects in these Connections to achieve (G. Teutsch in "Adrenal Steroid Antagonism, Walter de Gruyter Berlin-New Kork, 1984, p. 43).

It has now been found that the new compounds of the general Formula I surprisingly not only very good antigestagens and antiglucocorticoids Effects show, but that a separation of the two effects can also be observed in them is.

The abortive effect was used to characterize the antigestagens effect certainly.

The experiments were carried out on female rats weighing approx. 200 g carried out. After mating, the onset of pregnancy was confirmed by evidence secured by sperm in vaginal swabs. The day of the sperm detection applies as day 1 of pregnancy (= dl p.c.).

The treatment of the animals with the respective substance to be tested or the solvent took place after the nidation of the blastocysts from d5 p.c. to d7 p.c.

At d9 p.c. the animals were sacrificed and the uteri on implants and Examined absorption sites. Photographs were taken of all uteri. That The absence of implants was classified as an abortion.

The test substances were in a benzyl benzoate-castor oil mixture (Ratio 1 + 9) solved. The vehicle volume per single dose was 0.2 ml Treatment was subcutaneous (s.c.).

The superiority of the compounds according to the invention is said to be achieved by comparing the biological properties of the compound according to the invention 11β- (4-acetylphenyl) -17β-hydroxy-17a- (1-propynyl) -4,9-estradien-3-one (A), that described in EP 82400025.1 described 11ß- (4-dimethylaminophenyl) -17ß-hydroxy-17a- (propyn-1-yl) -4,9 (10) -estradien-3-one RU 38486 (B), the 11ß- (4 -Dimethylaminophenyl) -17β-hydroxy-17a- (3-hydroxypropyl) -4,9 (10) -estradien-3-one (C), the 11β- (4-dimethylaminophenyl) -17β-hydroxy-17a described in EP 84730147.0 - (3-hydroxyprop-1 (Z) -enyl) -4,9 (10) -estradien-3-one (D) and the 11ß- (4-dimethylaminophenyl) -17ß-hydroxy-17a- ( 3-hydroxypropyl) -13a-methyl-4,9-gonadien-3-one (E) and 11β- (4-dimethylaminophenyl) -17ahydroxy-17β- (3-hydroxypropyl) -1 3a-methyl-4,9-gonadiene -3-on (F) are shown: Table 1 Abortion test in the pregnant rat Dose abortion rate Substance mg / animal / day n-abortion-positive / n total sc 3.0 4/4 A 1.0 4/4 0.3 4/4 10.0 4/4 3.0 4/4 B 1.0 2/4 0.3 0/4 10.0 4/4 3.0 4/4 C 1.0 0/4 10.0 4/4 3.0 4/4 D 1.0 4/4 0.3 0/4 10.0 4/4 3.0 4/4 E 1.0 4/4 0.3 0/4 10.0 4/4 3.0 4/4 F 1.0 4/4 0.3 0/4 From Table 1 it can be seen that only compound A according to the invention is fully abortive at a dose of 0.3 mg, ie it is more effective by a factor of 3-10 than the compounds of the prior art.

To characterize the antiglucocorticoid effect, the influence of the substances according to the invention determined on the tyrosine aminotransferase. That Test system is based on a measurement of the activity of the liver enzyme tyrosine aminotransferase (TAT) in cultures of RHC (Rat Hepatoma Cells) cells. The enzyme catalyzes the first step in the metabolism of tyrosine and is both in the liver as well as inducible in hepatoma cells by glucocorticoids. The activity is in Easily measurable crude extracts (Granner and Tomkins, (1970) Meth. Enzymol. 15, 633).

The enzyme converts the amino group from tyrosine to 2-oxoglutaric acid. This produces glutamic acid and p-hydroxyphenyl pvruvate. In an alkaline solution the more stable p-hydroxybenzaldehyde is formed from p-hydroxyphenylpyruvate, its Absorbance is measured at 331 nm. The TAT activity in RHC cells shows a dose-dependent induction with cortisol (max. act. at 10-6M) or dexamethasone (max. Current at 10-7M). The activity can be increased by a factor of 4 - 6 above the basal value stimulate. Simultaneous treatment with corticoid and antiglucocorticoid results to a decrease in TAT activity.

Compound A according to the invention shows 30 ° of activity in this test of RU 38.486 (B), a substance that is to be regarded as a standard (7th Int. Congress of Endocrinology July 1-7, 1984, Quebec City, Canada; Excerpta Eledica, Amsterdam-Oxford-Princeton).

Since compound (A) is 10 times more antigestagenic than RU 38,486 (B) is effective, this results in a clear dissociation of the antiglucocorticoids and antigestagens properties.

A further example according to the invention is 11β- / 6- (anti-hydroxyiminomethyl) -phenyl7-17β-hydroNy-17- (1-propynyl) -4,9-estradien-3-one anti-oxime (G) listed; this compound shows an antiglucocorticoid comparable to RU 38.486 (B) Effect. In the anti-gestagen test, however, it is at least 10 times less effective than RU 38.486 (B).

In the gestagen receptor binding test, the affinity of the invention Connections to the progestin receptor investigated. The displacement is measured of the agonist by the antagonist.

One uses cytosol from Eaninchenuterushomogenat, which the receptor molecule - contains a protein. This binds with high affinity and low capacity Progesterone.

If these receptors with 3H-progesterone in the presence of the test, unlabeled substance will be loaded, so it depends on the concentration and from the binding affinity of the compound to be investigated, how strong 3H-progesterone is is displaced by the receptor. After separation of the receptor-bound progesterone of the non-bound one can determine the binding in percent and this value against Plot the logarithm of the molar concentration of the test substance. You get characteristic dose-dependent displacement curves and can now change the concentration determine the test substance that is required to complete the reference substance to be displaced by the receptor. The competition factor K as a measure of the strength of the bond is defined as the ratio of the concentration of the test substance to the concentration the reference substance (Progesterone), in which both connect one show equal displacement of H-progesterone from the progesterone receptor complex, so that a low K value indicates high binding strength (high affinity): Table 2 Gestagen receptor binding test rabbit uterus compound K (gestagen) A 1.0 B 2.9 H 1.5 The table shows that the examples mentioned according to the invention Compounds A and 11β- (4-Formylphenyl) -17β-hydroxy-17a- (1-propynyl) -4,9-estradien-3-one (H) are about 3 or 2 times more effective in the gestagen receptor binding test than the connection RU 38.486 (B), which is to be regarded as the standard.

The invention also relates to pharmaceutical preparations containing the compounds of the general formula I.

The pharmacologically active compounds according to the invention of the general Formula I can be made pharmaceutical according to known galenical methods Preparations processed for enteral, percutaneous or parenteral application will.

The dosage of the compounds according to the invention is in humans at about 1 to 100 mg per day.

Those contained in R1, R3, R4, R5, R6 and R7 of the general formula 1 Alkyl or acyl groups should each contain 1 to 4 carbon atoms, where the methyl and ethyl or. the formyl, acetyl and propionyl groups are preferred.

Of the alkenyl radicals, the propenyl group is in the E or Z configuration may be present, preferably, i.

if R4 is -CH =CH- (CH2) k-CH2-R6, then k should preferably be zero mean.

The new 13-alkyl-11ß-phenylgonanes of the general formula I are produced according to the invention by the method according to claim 21.

Starting from the compounds of general formula II is used for Elimination of water with formation of the 4 (5) double bond and at the same time Removal of existing protective groups with acid or an acidic ion exchanger treated. The acidic treatment is carried out in a manner known per se by the Compound of the formula II, which contains at least two protecting groups, in one with Water-miscible solvents, such as aqueous methanol, ethanol or acetone, dissolve and on the solution catalytic amounts of mineral or sulfonic acid, such as hydrochloric acid, Sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid, or a Organic acid, such as acetic acid, is allowed to act until water is split off and protecting groups are removed. The implementation, which takes place at temperatures from 0 to 100 ° C can also be done with an acidic ion exchanger. Of the The course of the reaction can be carried out using analytical methods, for example thin-layer chromatography samples taken can be tracked.

Those included in the general formula II of K, K R and R4, 3 '4' Protecting groups are easy in an acidic environment detachable groups, such as the ethylenedioxyketal, ethylenedithioketal, 2,2-dimethyltrimethylenedioxyketal, H-hydroxyimino, nethoxyimino, tetrahydropyranyl, methoxymethyl or ethoxytnethyl group.

If a compound of the general formula II is used, the K1 contains a protected hydroxyl group, this is then with one of the oxidizing agents customary for the oxidation of allylic hydroxyl groups, e.g. Chromic acid, pyridine, pyridinium dichromate, pyridinium chlorochromate, manganese dioxide, silver carbonate on Celite, converted into the oxo function. Is preferred at temperatures between -20 oC and +40 OC carried out conversion with manganese dioxide.

The compounds of general formula I thus obtained with X in the If desired, the significance of an oxygen tonicity can be achieved by reaction with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between -20 and +40 oC in the Oxime (formula I with X meaning the hydroxyimino group N # OH, where the Hydroxy group can be syn- or anti-resistant) are transferred. Suitable tertiary Bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5-diazabicyclo / 0.3.07nonen-5 (DBN) and 1,5-diazabicyclo [5.4.0] undecen-5 (DBU), with pyridine being preferred.

If an esterification of compounds of general formula I, their If R3 and / or R4 contains a hydroxyl group, this acylation is carried out in a manner known per se, for example by reaction with the acid anhydride in pyridine at room temperature.

The preparation of the starting compounds of the general formula II starts, as described, for example, in European patent applications 84101721.3 and 82400025.1, from the epoxide of the general formula III where R2 is ß-.

The introduction of the 11β-phenyl radical with the formation of the # 9,10-5α-hydroxy structural element takes place either by Cu (I) -catalyzed Grignard reaction with the corresponding Arylmagnesiumhalogeniden (Tetrahedron Letters 1979, 2051) or by reaction with mixed organocuprates of the type R2 Cu (CN) Li2 (J. Amer. Chem. Soc. 103 (1981) 7672).

Access to the 13α-methyl or 13α-ethyl-rich (R2 is α-position) is achieved - as described, for example, in European patent application 84730062.1 - by irradiating intermediate products of the general formula IV with ultraviolet light.

The introduction of a 9,10-epoxy or -methylene group (A and B stand then together for an oxygen atom or a CH2 group) takes place at the stage of the L 9 '-5a, 1 7-dihydroxy 11 ß-phenyl intermediate according to known Methods by reaction with e.g. hydrogen peroxide, organic peracids, such as e.g. m-chloroperbenzoic acid or perphthalic acid, tert. Butyl hydroperoxide or with e.g. methylene iodide / zinc (Simmons-Smith).

The introduction of the substituents R3 and R4 takes place in accordance with the usual methods Process of building up the C1 7 side chain by nucleophilic addition to the 7-ketone and follow-up reactions ("Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, Vol. 1-12). While nucleophilic addition to the 17-ketone of the 13ß-alkyl series only adducts with the hydroxyl group in ß- and the incoming Group supplies in a-position to the five-membered ring, the addition proceeds to the corresponding one 13 Epi-17-ketone in general with the formation of both possible, isotropic forms at C-1-7, but easily accessible by chromatography or fractional crystallization are separable.

In many cases, both isomers are pharmacologically effective, though there may also be differences in the effectiveness.

The nucleophilic addition of HCrCX, in which X is hydrogen, alkyl with 1 - 4 carbon atoms or halogen means, takes place with the help of a compound of the general Formula MCCX, in which X has the meaning given above and AL is an alkali metal represents.

The organometallic compound can also be formed in situ and with the 17-ketone are reacted. For example, you can use the 17-ketone in a suitable solvent acetylene and an alkali metal, especially potassium, Sodium or lithium, in the presence of an alcohol or in the presence of ammonia let it act. The alkali metal can also be in Fortn of, for example, methyl or Butyllithium come into action. Particularly suitable solvents are dialkyl ethers, Tetrahydrofuran, dioxane, benzene and toluene are suitable.

To produce the 17-chloroethynyl compound, the organometallic Ohloroethynyl compound in situ from 1,2-dichloroethylene and an ethereal alkali metal solution, such as methyl or butyllithium solution, formed and with the 17-ketone implemented in solvents such as tetrahydrofuran or diethyl ether.

The 17-ethyl-17-hydroxy compounds can be broken down into alcoholic Solution under mercury salt catalysis hydrate to the 17-acetyl-17-hydroxy-compounds (Chem. Ber. 111 (1973) 3086-3093).

The introduction of 3-hydroxypropyne, -propene or -propane in the 17-position takes place by reacting the 17-ketone with metalated derivatives of propargyl alcohol, for example with 1-lithium-3-tetrahydropyran-2-loxy-propyne-1, to the 1 7- (3-hydroxy-1-propynyl) -1 7-hydroxy compounds, which then lead to the 17- (3-hydroxypropyl or 3-hydroxypropenyl) -17-hydroxy compounds can be hydrogenated.

The hydrogenation must be carried out under conditions that are exclusive ensure the attack on the C-C triple bond1 without the one that may be present tetrasubstituted 9 (10) double bond. This succeeds, for example, with the hydrogenation at room temperature and Normal pressure in solvents such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with added of precious metal catalysts such as platinum or palladium.

The introduction of the homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups takes place in a corresponding manner with homologues of propargyl alcohol.

The compound with the Z-configured double bond in the hydroxypropenyl group is formed by hydrogenating the acetylenic triple bond with a deactivated one Edelr.letallliatalysator (J. rried, J.A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, p. 134, and H.0. House: Modern Synthetic Reactions 1972, page 19). As deactivated noble metal catalysts, for example 10% palladium on hydrogen sulfate in the presence of an amine or 5 Vu palladium Calcium carbonate with the addition of lead (II) acetate is an option. The hydrogenation is after the uptake of one equivalent of hydrogen is canceled.

The compound with the E-configured double bond in the hydroxypropenyl group is formed by reducing the acetylenic triple bond in a known per se Way.

There are quite a number of conversion methods in the literature described from alkynes to trans-olefins, for example reduction with sodium in liquid Amtnöniak (J. Am. Rohem. Soc. 63 (1941) 216), with sodium amide in liquid Ammonia (J. Ghem. Soc. 1955, 3558), with lithium in low molecular weight amines (J. At the. Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1971) 6560), with diisobutylaluminum hydride and methyl lithium (J. Am. Chem. Soc. 89 (1967) 5035) and in particular with lithium aluminum hydride / alcoholate (J. At the. Chem. Soc. 89 (1967) 4245). Another option is to reduce the triple bond with chromium (II) sulfate in the presence of water or dimethylformamide in weakly acidic Milieu (J. Am. Chem. Soc. 86 (1964) 4358) and, in general, reduction by action of transition metal compounds with a change in the oxidation state.

If end products of the formula I are desired with R3 / R4 meaning the 17- (3-hydroxypropyl) compound is oxidized in a manner known per se, for example with Jones' reagent, manganese dioxide, pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine or the Fetizon reagent silver carbonate / Celite (Compt. rend. 267 ( 1968) 900).

To introduce grouping the 17-ketone is converted into the 17-nitrile compound with tosylmethyl isocyanide, the 17-acetyl compound is obtained from the 17-nitrile compound with methyllithium or methylmagnesium bromide, which after enolization with K-tert-butylate in tetrahydrofuran and reaction with methyl iodide, the desired grouping in 17 position delivers.

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

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

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

Example 1 17α-Ethynyl-11β- (4-formylphenyl) -17β-hydroxy-4,9 estradien-3-one A solution of 9.0 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- / R- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl7 -17-ethinS 9-estren-5a, 17ß-diol in 90 ml of 70% aqueous acetic acid is 30 minutes at 50 OC stirred. After cooling, it is poured into ice water, neutralized by adding of aqueous ammonia solution and extracted with dichloromethane. By crystallization of the crude product from ethyl acetate / diisopropyl ether, 5.3 g of 17α-ethynyl-11β- (4-formylphenyl) -17β-hydroxy-4,9-estradien-3-one are obtained from melting point 197-19800.

The production of the raw material takes place in the following way: a) A solution of 25 g of 4-bromobenzaldehyde in 250 ml of dichloromethane is gradually added Addition of 37.5 g of 2,2-dimethyl-propane-1,3-diol, 18.75 ml of trimethyl orthoformate and 20 mg of p-toluenesulfonic acid were stirred at room temperature for 24 hours.

For work-up, it is poured into saturated aqueous NaHOO3 solution and extracted with diethyl ether. Obtained after crystallization of the crude product from hexane 37.1 g of 4- (5,5-dimethyl-1,3-dioxan-2-yl) bromobenzene with a melting point of 62-64 ° C.

b) To a suspension of 4.5 g of magnesium shavings in 120 ml of absolute (abs.) Tetrahydrofuran (THF) is added at 25 ° C. first of all 0.05 ml of iodomethane and then a solution of 54 g of 4- (5,5-dimethyl-1,3-dioxan-2-yl) bromobenzene in 270 ml of abs. THF so added that the internal temperature does not exceed 45 oO.

After the magnesium has completely dissolved, cool to + 5 ° C and add 1.07 g of CuCl in portions to the reaction solution. The mixture is stirred for 15 minutes and then gives a solution of 25.4 g of 3, 3- (9,2-dimethyl-trimethylenedioxy) -5a at + 5 ° C, 1 Oa- epoxy-9 (11) -estren-17β-ol in 250 ml of abs. Add THF drop by drop. After The addition is stirred for a further 2 hours at room temperature, and the reaction solution is poured then into a mixture of ice water / aqueous ammonia solution and extracted with ethyl acetate. The oily crude product obtained in this way is treated with hexane / ethyl acetate on aluminum oxide (Merck, Stage III, neutral) chromatographed. After the main fraction has crystallized out Ethyl acetate / diisopropyl ether gives 33.8 g of 3,3- (2,2-dimethyltrimethylenedioxy) - [4- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl] -9-estren-5α , 17β-diol with a melting point of 218-220 00.

[α] D + 36.0 ° C (CH2Cl2, c = 0.505).

c) A suspension of 12.7 g of the product obtained under b), 74 ml of cyclohexanone, 7.1 g of aluminum isopropoxide and 494 ml of toluene is under for 4 hours Heated to reflux, about a third of the amount of solvent being distilled off leaves. After cooling, it is poured into ice water and the resulting emulsion is filtered over Celite, wash the filter residue thoroughly with ethyl acetate, separate the organic Phase of the filtrate off, dry this over Na2S04 and concentrate. After chromatography via Al203, neutral, stage III, with hexane / ethyl acetate and crystallization of the main fraction 9.6 g of 3,3- (2,2-dimethyltrimethylenedioxy) -11β- / 0- (5,5-dimethyl-1) are obtained from hexane / ethanol , 3-dioxan-2-yl) -phenyl7-50C-hydroxy-9-estren-1 7-one with a melting point of 209-21100.

/ -725 + 62.30 (CH2Cl2, c = 0.510).

d) Abs. THF (495 ml) is saturated with acetylene at 0 ° C. for 30 minutes. 100 ml of the above solution of n-butyllithium in hexane are then added dropwise and then a solution of 3.75 g of the ketone obtained under c) in 135 ml THF. The mixture is stirred for 3.5 hours at Ratun temperature, then poured into about 2 liters of ice water and extracted with ethyl acetate. The oily crude product obtained in this way (9.0 g) is without further purification used in the final stage.

Example 2 11β- (4-Formylphenyl) -17β-hydroxy-17α- (1-propionyl) -4,9-estradien-3-one 20.1 g dimethyl-1,3-dioxan-2yl) -phenyl] -17α- (1-propionyl) -9-estren-5 ", 17β-diol are stirred in 83 ml of 70% aqueous acetic acid for 30 minutes at 60 oO and under the conditions of Example 1 worked up. After crystallization of the crude product from methylene chloride / diisopropyl ether, 10.6 g of the title compound with a melting point are obtained 207 - 208 00.

The raw material is produced in the following ways: Par. THF (1040 ml) is saturated with methyl acetylene by passing it in at 0 0O for 30 minutes. 84.4 ml of a 15% solution of n-butyllithium are then added dropwise at 0 to +5 oO added, stirred after addition for 15 minutes and then a solution of 19.4 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2yl ) -phenyl] -5α-hydroxy-9-estren-17-one (see Example 1 c)) added dropwise. You rip another 60 minutes at room temperature, pour into ice water and extracted with ethyl acetate. The raw product (20.1) g) is used in the final stage without further purification.

Example 3 1β- (4-ormylphenyl) -17-hydroxy-13a-methyl-17β- (1-propynyl) -4,9-gonadien-3-one Under the conditions of Example 1, 1.1 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β1 [4- (5,5-dimethyl-1,3-dioxan-2yl) -phenyl] -13α are used -17ß- (1-propionyl) -9-gonen-5α, 17α-diol with 15 ml of 70% acetic acid at 60 oC.

After chromatography of the crude product on silica gel with hexane / ethyl acetate 530 mg of the title compound are obtained amorphous.

[α] D + 437.8 (CHCl3, c = 0.5).

The production of the raw material takes place in the following way: a) A solution of 4.0 g of the ketone obtained under 1 c) in 600 ml of dioxane is in a quartz glass immersion apparatus 35 for 5 minutes at 25 oO with a high-pressure mercury lamp (Philips HPK 125) irradiated. The solvent is then in a water jet vacuum removed and the oily residue on Al2O3 (Merck, neutral, stage III) with hexane / ethyl acetate chromatographed. Crystallization of the main fraction from diisopropyl ether results 2.05 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β1 [4- (5,5-dimethyl-1,3-dioxan-2yl) -phenyl] -5α-hydroxy-13α-methyl-9 -gonen-17-on of melting point 135-187 ° C.

[α] D + 27.3 ° (CH2O12, c = 0.53).

b) Under the conditions of Example 2 a) 1.9 g of the under a) resulting ketones reacted with methylacetylene. After chromatography of the crude product on Al2O3 with hexane / ethyl acetate and crystallization of the main fraction from CH2Cl2 / ethyl acetate 1.22 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl] -13α-methyl-17β- are obtained (1-propynyl) -9-gonen-5α, 17α-diol with a melting point of 240 - 243 ° C.

/ a7D25 +35.20 (CH2Cl2, c = 0.5).

Example 4 11β- (3-Formylphenyl) -17β-hydroxy-17α- (1-propionyl) -4.9 estradien-3-one 2.7 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [3- (5,5 dimethyl-1,3-dioxan-2-yl) -phenyl] -17β- (1-propionyl) -9-estren-5a, 17EJ-diol are cleaved under the conditions of Example 1 with 30 ml of 70% acetic acid.

After crystallization of the crude product thus obtained from dichloromethane / acetone 1.15 g of the title compound of, melting point 260-26200 are obtained.

[α] D-3 -60.2 (pyridine, c = 0.35).

The production of the raw material takes place in the following way: a) From 31.7 ml of 3-bromobenzaldehyde, 75 g of 2,2-dimethyl-propane-1,3-diol, 37.6 ml of trimethyl orthoformate and 50 mg of p-toluenesulfonic acid in 500 ml of dichloromethane are obtained under the conditions of Example 1 a) after crystallization from hexane, 73.0 g of 3- (5,5-dimethyl-1,3-dioxan-2-yl) methyl-bromobenzene from melting point 42 - 43 b) From 15.0 g of 3,3- (3,2-dimethyl-trimethylenedioxy) -5α, 10α-epoxy-9 (11) -estren-17β-ol, 62.2 g of the ketal obtained under a), 4.82 g of magnesium, 0.08 ml of iodomethane and 1.02 g CuCl in 420 ml THF are obtained under the conditions of example 1 b) according to chromatography over Al2O3 with hexane / ethyl acetate 19.6 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [3- (3,5-dimethyl-1,3-dioxan-2-yl) -phenyl] - 9-estren-5α, 17β-diol as a colorless oil.

c) Oppenauer oxidation of the product obtained under b) (18.0 g), 10.3 g of aluminum isopropoxide, 112 ml of cyclohexanone, 560 ml of toluene under the conditions of Example 1 c) results after crystallization of the crude product from diisopropyl ether 13.8 pounds of the 17-ketone with a melting point of 195-1970.

[α] D +51.2 (CH2CL2, c = 0.5).

d) Under the conditions of Example 2 a) 2.5 g of the under c) the ketone obtained reacted with the lithium derivative of methylacetylene. The raw product (2.7 g) is used in the final stage without further purification.

Example 5 11 β- (3-Formylphenyl) -1 7a-hydroxy-1 3a-niethyl-1 7ß- (1 propynyl) -4, 9-gonadien-3-one By acid hydrolysis of 1.0 g of 3, 3- (2,2-dimethyl-trimethylenedioxy) -11ß- [3- (5,5-dimethyl- 1,3-dioxan-2-yl) -phenyl] -13α-methyl-17β- (1-propionyl) -9-gonen-5α, 17α-diol analogously to Example 1, the crude product is obtained after chromatography on silica gel Hexane / acetone 56o mg of the title compound amorphous.

[α] 25 D + 326 ° (CHCl2, c = 0.525).

The raw material is produced in the following ways: a) A solution of 3.5 g is irradiated under the conditions of Example 3 a) of the ketone obtained under Example 4 c) in 525 ml of dioxane. By chromatography of the crude I product on Al2O3 with hexane / ethyl acetate and crystallization of the main fraction 1.97 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [3- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl] -5α- are obtained from diisopropyl ether hydroxy-13α-methyl-9-gonen-1 7-one with a melting point of 209-211 ° C.

αD + 27 ° (CH2Cl2, c = 0.525).

b) By reacting the product obtained under a) (i, 8 g) with methylacetylene under the conditions of Example 2 a) is obtained after chromatography and crystallization from ethyl acetate / diisopropyl ether 1.12 g of 3,3- (2,2-dimethyltrimethylenedioxy) -11β- [3- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl] -13α-methyl- 17β- (1-propynyl) -9-gonen-5α, 17α-diol of melting point 167-170 ° C.

α D +35.2 (CH2Cl2, c = 0.525).

Example 6 11β- (4-Acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -4,9-estradiene- 3-one by reacting 2.36 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [4- {1,1- (2,2-dimethyltrimethylenedioxy) -ethyl} -phenyl] -5α- hydroxy-9-estren-17-one with riethylacetylen ullter the conditions of Example 2 a) and then Acetic acid hydrolysis of the crude product under the conditions of Example 1 is obtained 1.14 g of the title compound with a melting point of 151-154 00 (from hexane / acetone).

α 25 D + 117.1 ° (CHCl3, c = 0.525).

The production of the raw material takes place in the following way: a) From 50.0 g of 4-bronacetophenone, 75 g of 2,2-dimethylpropane-1,3-diol, 37.6 ml of trimethyl orthoformate and 30 mg of p-toluenesulfonic acid in 500 ml of dichloromethane are obtained under the conditions of Examples 1 a) and 4 a) after chromatography of the crude product on Al2O3 with hexane / ethyl acetate 73 g of the ketal as a colorless oil.

b) From 14.1 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -5α, 10α-epoxy-9 (11) -estren-17β-ol, 4.12 g of magnesium, 55.92 g of the bromoketal obtained under a), 0.05 ml of iodomethane and 874 mg of CuCl in a total of 390 ml of THF are obtained under the conditions of the example 1 b) after chromatography, 14.6 g of adduct as a colorless oil.

c) By Oppenauer oxidation analogously to Example 1 c) is obtained from 12.8 g of the Grignard product obtained under b) after crystallization of the crude product from ethyl acetate / diisopropyl ether 11.5 g of the 17-ketone with a melting point of 211-215 ° C.

Example 7 11β- (4-Acethylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4, 9-gonadieii-3-one By irradiating 4.0 g of that obtained under Example 6 c) Ketones under the conditions of Example 3 a), reaction of the product thus obtained with methyl acetylene under the conditions of Example 2 a) and subsequent elimination of acetic acid analogously to 1, 1.09 g of 11β- (4-acethylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one are obtained, amorphous.

αD25 + 420.1 ° (CHCl3, c = 0.525).

Example 8 17β-Hydroxy-11β- [4- (3-oxo-1 (E) -propenyl) -phenyl] -17α- (1-propynyl) -4,9-estradien-3-one A solution of 750 mg of 17β-hydroxy-11β- [4- (3-hydroxy-1- (E) -propenyl) -phenyl] -17α- (1-propynyl) -4,9-estradien-3-one in 20 nil dichloromethane is added after adding 4.0 g of manganese dioxide for 15 minutes at room temperature touched. It is then filtered over the side and the filtrate is concentrated. You get 620 mg 17-Hydro, iy-11ß- / 0- (3-oxo-1 (E) propenyl) -phenyl7-17-a- (1-propynyl) -4,9-estradien-3-one, amorphous.

αD25 + 218.60 (CHCl3, c = 0.5).

The production of the raw material takes place in the following way: a) To a solution of 20.0 g of 4-bromobenzaldehyde in 300 ml of abs. THF is added in drops -10 oO 81 ml of a 1.6 molar solution of vinyl magnesium bromide in THE. After adding The mixture is stirred for 60 minutes at 0 ° C., poured into ice water and extracted with ethyl acetate. After chromatography on Al 203 with hexane / ethyl acetate, 18.6 g of 4- (1-hydroxy-2-propenyl) bromobenzene are obtained as a colorless oil, b) The product obtained under a) (18.6 g) is in 100 ml THF dissolved and after adding 25 ml of dihydropyran and 0.02 ml of POCl3 for 3 hours Room temperature stirred.

Then it is poured into saturated NaHCO 3 solution and extracted 3 with diethyl ether. Chromatography of the crude product on Al2O3 with hexane / ethyl acetate gives 19.2 5 4- [3- (tetrahydropyran-2-yloxy) -1 (E) -propenyl] -bromobenzene as colorless Oil.

c) From 920 mg of magnesium in 15 ml of abs. THF, 0.05 ml iodomethane and 13.0 g of the bromide obtained under b) in 50 ml of THF, a Grignard reagent is prepared and after adding 193 mg of CuCl with 5.0 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -5α, 10α-epoxy-9 (11) -estrene-17β-oil in 50 ml TH? under the conditions of the example 1 b) implemented; however, the response time is 24 hours. After chromatographic Purification of the crude product gives 4.5 g of the adduct as yellowish oil.

d) Analogously by Oppenauer oxidation of the adduct obtained under c) Example 1 c) is obtained from 3.3 g of starting material after chromatography on Al Al 2 O 3 with hexane / ethyl acetate 2.94 g of the 17-ketone as an oil.

e) Reaction of the ketone obtained under d) (2.9 g) with methyl acetylene under the conditions of Example 2 a) and acidic cleavage of the crude product thus obtained under the conditions of Example 1 gives 960 mg of 17β-hydroxy-11β- [4- (3-hydroxy-1 (E) -propenyl) -phenyl] -17α- (1-propynyl) -4, 9-estradien-3-one as a firm foam.

αD25 + 142.4 ° (CHCl3, c = 0.5).

Example 9 To a solution of 4.07 g of 11β- (4-formylphenyl) -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one (See Example 2) in 60 ml of pyridine is added in portions with 3.65 while cooling with ice water g hydroxylamine hydrochloride. After the addition, stir for 30 minutes at +5 ° C, pour into a mixture of ice water / 0.5N hydrochloric acid and extracted with dichloromethane.

By fractional crystallization of the crude product (4.53 g) from ethyl acetate you get: a) 2.17 g 1 1β- [4- (anti-hydroxyiminomethyl) -phenyl] -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one anti-oxime with a melting point of 242-244 ° C.

b) 880 mg 11ß- [4- (anti-Hydroxyiminomethyl) -phenyl] -17ßhydroxy-17 «- ( 1 -pro3? In) 4, 9-estradien-3-on-syn-osim with a melting point of 248 - 251 ° C.

Example 10 1 1ß- (4-Formylphenyl) -1 7ß-hydroxy-1 7a- (3-hydroy-1 (Z) -propenvl) -4, 9-estradien-3-one Conversion of 5.71 g of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [4- (5,5-dimethyl-1,3-dioxane -2-yl) phenyl] -17α- [3- (tetra hydropyran-2-yloxy) -1 (Z) -propenyl] -9-estren-5α, 17β-diol with 70 ml of 70% Acetic acid under the conditions of the example gives after chromatographic purification 2.3 g of 11β- (4-formylphenyl) -17β-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one as solid foam.

+ 221.1 ° (CHCl3, c = 0.520).

The production of the raw material takes place in the following way: a) From 6, 35 g of 3- (tetrahydropyran-2-yloxy) -1-propyne in 115 parts of abs. THF and 31.6 ml of a 15% solution of n-butyllithium in hexane is put at 0 ° C. the organolithium Compound and add a solution of 5.1 g of the example below at 0 to +5 oC 1 c) obtained ketones in 70 ml of abs. THF. The mixture is then stirred for 3 hours at room temperature, then poured into ice water and extracted with ethyl acetate. The crude product is on neutral aluminum oxide chromatographed with hexane / ethyl acetate. as oily The main fraction is 7.2 g of 3,3- (2,2-dimethyltrimethylenedioxy) -11β- [5,5-dimethyl-1,3-dioxan-2-yl) phenyl] -17α- [3- (tetrahydropyran- 2-yloxy) -1-propynyl] -9-estren-5α, 17β-diol.

b) A solution of 5.75 g of the product obtained under a) in 75 ml TH is after the addition of 5 ml of pyridine and 560 mg of palladium / barium sulfate (10% Pd) hydrogenated at room temperature and normal pressure. After the hydrogen uptake has stopped the catalyst is filtered off and the filtrate is concentrated. 5.71 g of 3,3- (2,2-dimethyltrimethylendoixy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl] -17α- [3- ( tetrahydropyran-2-yloxy) -1 (Z) -propenyl] -9-estren-5a, 17β-diol than oil.

Example 11 11β- (4-For, ylphenyl) -17β-hydroxy-13α-methyl-17α- (1-propynyl) -4,9-golladien-3-one Under the conditions of Example 1, 420 mg of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) phenyl] - 13α-methyl-17α- (1-propynyl) -9-gonen-5α, 17β-diol with 6.5 ml of 70% acetic acid at 60,000. After chromatography of the crude product on silica gel with hexane / ethyl acetate, 10 mg of the title compound is obtained as yellowish 5 ch aum.

αD25 + 162.5 ° (CHCl3, c = 0.5).

The production of the starting material takes place in the following ways: The addition reaction with methylacetylene described under 3 b) gives after chromatography as a non-polar by-product 480 mg of 3,3- (2,2-dimethyl-trimethylenedioxy) -11β- [4- (5,5-dimethyl-1,3-dioxan-2-yl) -phenyl] -13α- methyl-17α- (1-propynyl) -9-gonen-5α, 17β-diol as a yellowish oil.

Claims (23)

Claims (1.)) 13-Alkyl-11ß-phenyl-gonane of the general formula 1 wherein A and B together for an oxygen atom, a CH2 group or a second bond between the carbon atoms 9 and 10, X for an oxygen atom or the hydroxyimino group N # OH, n for the digits 0 or 1, R1 for a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R2 stands for an a- or ß-methyl or ethyl radical, where in the case of an a-methyl or ethyl radical R3 / R4 -OR5 / -C # CY 3 4 -C # CY / - OR5 -OR5 / - (CH2) m-CH2-R7 - (CH2) m-CH2-R7 / -OR5 -OR5 / -CH = CH- (CH2) k-CH2-R7 -CH = CH- (CH2) k- CH2-R7 / -OR5 and where in the case of a ß-methyl or ethyl radical R2 R3 / R4 -OR5 / -C # CY -OR5 / - (CH2) m-CH2-R7 -OR5 / -CH = CH- (CH2) k-CH2-R7 with R meaning a hydrogen atom 5 or acyl radical with 1 to 4 carbon atoms, Y meaning a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group with in each case 1 to 4 carbon atoms 10 alkyl or acyl radical, R6 in the meaning of a hydrogen atom, a hydroxyl group, an alkyl, 0-alkyl or 0-alkyl group each with 1 to 4 carbon atoms, m in the meaning O, 1, 2 or 3, R7 denotes a hydroxy or cyanide radical, an 0-alkyl or 0-acyl group each having 1 to 4 carbon atoms and k denotes O, 1 or 2, and the substituent of the 11ß-phenyl radical is 3- or 4 position. 2.) 17α-Ethynyl-11β- (4-formylphenyl) -17β-hydroxy-4,9-estradien-3-one. 3.) 11β- (4-Formylphenyl) -17β-hydroxy-17a- (1-propynyl) -4,9-estradien-3-one. 4.) 11β- (4-Formylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one. 5.) 11β- (3-Formylphenyl) -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one. 6.) 11β- (3-Formylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one. 7.) 11β- (4-Acetylphenyl) -17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one. 8.) 11β - ($ - Acetylphenyl) -17α-hydroxy-13α-methyl-17β- (1-propynyl) -4,9-gonadien-3-one. 9.) 11β- (4-Formylphenyl) -17β-hydroxy-17α- (3-hydroxypropyl) -4,9-estradien-3-one. 10.) 11β- (4-Formylphenyl) -17β-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one. 11.) 3- / 11β- (4-Formylphenyl) -17β-hydroxy-3-oxo-4,9-estradien-17α-yl] -propionic acid 1-actone. 12.) 17β-Hydroxy-11β- [4- (3-oxo-1 (E) -propenyl) -phenyl] 17α- (1-propynyl) -4,9-estradien-3-one. 13.) 11β- / E- (anti-hydroxyiminomethyl) -phenyl7-17β-hydroNy-17α- (1-propynyl) -4,9-estradien-3-one anti-oxime. 14.) 11β- / 6- (anti-hydroxyiminomethyl) -phenyl7-17β-hydroxy-17α- (1-propynyl) -4,9-estradien-3-one anti-oxime. 15.) 11β- (4-Acetylphenyl) -17β-hydroxy-17α- (3-hydroxy-1 (Z) -propenyl) -4,9-estradien-3-one. 16.) 11ß- (4-Acetylphenyl) -17α-hydroxy-17ß- (3-hydroxypropyl) 13a-methyl-4,9-gonadien-3-one. 17.) 11β- (4-Acetylphenyl) -17β-hydroxy-17α-methoxymethyl-4,9-estradien-3-one. 18.) 11β- (4-Formylphenyl) -17α-hydroxy-13β-methyl-18,19-Z) -dinor-4,9-pregnadiene-3,20-dione. 19.) 17α-Acetoxy-11β- (4-formylphenyl) -13α-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione. 20.) 11β- (4-Formylphenyl) -17β-hydroxy-13α-methyl-17α- (1-propynyl) -4,9-estradien-3-one. 21.) Process for the preparation of compounds of the general formula I. wherein A and B together for an oxygen atom, a CH2 group or a second bond between the carbon atoms 9 and 10, X for an oxygen atom or the Hydroxyimino group N - OH, n for the digits 0 or 1, R1 for a hydrogen atom or a Alkyl radical with 1 to 4 carbon atoms, R2 represents an a- or ß-methyl or ethyl radical, whereby in the case of an a-methyl or ethyl radical. R3 / R4 -OR5 / -C # CY -C # CY / -OR5 -OR5 / - (CH2) m-CH2-R7 - (CH2) m-CH2-R7 / -OR5 -OR5 / -CH = CH- (CH2) k-CH2-R7 -CH = CH- (CH2) k- CH2-R7 / -OR5 and where in the case of a ß-methyl or ethyl radical R2 R3 / R4 -OR5 / -C # CY -OR5 / - (CH2) m-CH2-R7 -OR5 / -CH = CH- (CH2) k-CH2-R7 where R stands for a hydrogen atom or acyl radical with 1 to 4 carbon atoms, Y stands for a hydrogen, chlorine, fluorine, iodine or bromine atom, an alkyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group with 1 to 4 each Carbon atoms in the alkyl or acyl radical, R6 in the meaning of a hydrogen atom, a hydroxyl group, an alkyl, O-alkyl or 0-acyl group each with 1 to 4 carbon atoms, m in the meaning 0, 1, 2 or 3, R denotes a hydroxy or cyanide radical, an O-alkyl or O-acyl group each having 1 to 4 carbon atoms and k denotes 0, 1 or 2, and the substituent of the 11ß-phenyl radical is 3- or 4-position, characterized in that a compound of the general formula II is obtained in a manner known per se wherein K denotes a keto group blocked in the form of the ketal, the thioketal, the oxime or the methyl oxime, A, B, R1, R2 and n have the abovementioned meaning and R3 has the same meaning as R3, with any hydroxyl groups present being protected and R4 has the same meaning as R4, with any hydroxyl or acyl groups present being protected and I, in addition to the meanings given above for K, also stands for a hydrogen atom and a protected hydroxyl group, the action of a dehydrating agent that also releases the protected Function (s) is capable of splitting off water with simultaneous formation of the 4 (5) double bond, oxidizes a hydroxyl group contained in K1 and, if desired, the hydroxyl groups present in R3 and R4 to form the product of the general formula I with X meaning a Esterified oxygen atom and, if desired, then with hydroxylamine hydrochloride in Gege Nwart of tertiary amines at temperatures between -20 and + 40 ° C. 22.) Pharmaceutical preparations, characterized by a content of compounds according to Claims 1 to 20. 23.) Use of compounds according to claims 1 to 20 for Manufacture of medicines.