NO161499B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE 11BETA-ARYL ESTRADIENTS. - Google Patents

Description

The present invention relates to an analogue process for the production of therapeutically active 10-aryl-estradienes of general formula I

wherein R^" denotes wherein R<1> and R<11> denote hydrogen, alkyl of 1 to 4 carbon atoms or alkanoyl of 1 to 8 carbon atoms, or where R<1> and R<11> together with N denote a piperidine- or pyrrolidine ring, as well as the corresponding acid addition salts, or where R and R together with N can denote an optionally methyl-substituted pyrrole ring, -OR111 in which R<111> denotes hydrogen, methyl, ethyl or propyl,

-SRIV in which RIV denotes hydrogen, methyl, ethyl or propyl,

"R 3 denotes a hydrogen atom or an alkanoyl group of 1 to 8 carbon atoms, and

wherein R 4 denotes alkyl with 1 to 4 carbon atoms in the a- or 3-position, and R^ denotes an E- or Z-configured alkylidene group, and the C20/C2^ double bond exhibits a Z- or E-configuration.

113-aryl steroids are previously known. Thus, for example, lip-aryl-17a-propynyl- and -ethynyl-4,9(10)-

oestradium described in European patent application 82400025.1 (publication no. 0057115) and US patent 4,386,085 as compounds with antigestagen and antiglucocorticoid properties.

It has now been found that the new compounds of general

formula I exhibits antigestagen and antimineralcorticoid effects. A simultaneous occurrence of the antigestagen and antimineralcorticoid effect for a substance has not previously been described. Surprisingly, both effects of the new compounds also occur when administered orally in a comparable potency as compounds according to the state of the art, whereby the antigestagen effect is most pronounced with some of the new compounds, but the antimineralcorticoid effect is most prominent for others. The new compounds of general formula I are thus applicable to the treatment of disease states in which hyperaldosteronism is involved. The antiglucocorticoid effect found in the compounds according to the state of the art does not occur with the new compounds.

For characterization of the glucocorticoid, resp. antiglucocorticoid effect, the influence of the new compounds on DNS synthesis in mouse lymphoma cells was determined. prin-

the sip is based on the glucocorticoid sensitivity of T-lymphocytes. This sensitivity is retained in the lymphoma strain S 49.1 which originates from these T-lymphocytes and can be easily quantitatively determined by incorporation of <3>H-thymidine. After addition of cortisol to the cultures, the cells exhibit a dose-dependent hem-

ning of the DNS synthesis (see fig. 1), whereby a 50% inhibition effect is achieved with approx. 10M cortisol. In order for the potential agonistic and antagonistic effect of the test substance to be seen, the cells were simultaneously treated with 10~^ M cortisol and suitable amounts of the test substance

(cortisol and the test substance were dissolved in ethanol. The final concentration of ethanol in the mixture was 1%. Only ethanol was added to the control samples).

The known antiglucocorticoid B, the 116-(4-dimethylaminophenyl)-173-hydroxy-17a-(propyn-1-yl)-4,9(10)-estradien-3-one described in European patent application 82 400 025.1, exhibited a dose-dependent reversal of the cortisol inhibitory effect, and an equimolar concentration is sufficient to neutralize the effect of 10 M cortisol (see Fig. 2). The new compound A, 116-(4-dimethylaminophenyl)-176-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one, on the other hand, did not show any appreciable antigluco -corticoid effect (see fig. 2). Compound B alone as an addition to the cultures produced no agonistic (corticoid-like) effect (see Fig. 1). Compound A had a weak intrinsic effect which, admittedly, constituted only 1% of the effect of cortisol (see Fig. 2).

To determine the antimineralcorticoid effect of the new compounds, the antialdosterone test was used. In this test, adrenalectomized fluocortolone- and fluocortolone-capronate-treated, fasting Wistar rats were treated with 1.0 - 2.0 - 4.0 mg of test substance per animals. The test substance was administered orally as a crystal suspension in NaCl/Myrj 53. One hour after administration, the animals received an intravenous maintenance infusion of physiological saline solution with an addition of 0.15 µg/ug aldosterone per animals per hour. From the third to the tenth hour, Na and K salt excretion was measured every hour, and the Na/K quotient as well as the log Na (100)/K quotient were determined.

It turned out that the antimineralcorticoid effect of the new compounds was of the same order of magnitude as that of spironolactone.

Compared to the compounds according to the state of the art, the new compounds exhibit stronger antigestagen action and not antiglucocorticoid action, but antimineralcorticoid action.

The treatment of certain forms of aldosteronism/hypertonia, edema and other aldosterone-related diseases

is the main field of application of the compounds of general formula I.

The pharmacologically active new compounds of general formula I can be prepared according to known methods in the galenic field into pharmaceutical preparations for oral or parenteral administration.

The dosage of the new compounds is in humans at 10 to 1000 mg per day.

The new 113-aryl esters contain in the 17a position of the steroid skeleton in a 3-hydroxy- or alkanoyloxyprop-1-enyl side chain with Z- or E-configured double bond.

Acyl is to be understood as carboxylic acid residues with 1 to 8 carbon atoms. Preferred are alkanoyl groups such as the acetyl, propionyl, butyryl, pentanoyl, hexanoyl and heptanoyl groups.

The dimethylamino and formylamino residues are the preferred groups for R..

1 4

The substituent denoted by R in formula I is an alkyl residue with 1 to 4 carbon atoms, preferably the methyl or ethyl residue, and R<5> denotes an alkylidene residue, preferably the ethylidene residue.

The analog method according to the invention is characterized by the fact that in a compound of general formula II

wherein A is equal to C<=>C-CH2OR or CH=CH-CH2OR and R<1> and

have the meanings specified for formula I,

Z denotes an ethylene or 2,2-dimethyltrimethylene group, and R denotes a hydrogen atom or an organic group that can easily be split off in an acidic environment or hydrogenolytically,

in the presence of a deactivated noble metal catalyst, the acetylenic triple bond hydrogenates to the Z-configured C2c/C21~ double bond, or that the acetylenic triple bond is reduced in a manner known per se to the E-configured C2c/<C>21~ double bond, and

that then, under the influence of dilute acid, a pyridinium salt of a strong acid or an acidic ion exchanger, cleavage of the 3-ketal protection, removal of any acid-cleavable protecting group R, and water splitting to form 4,9(10 )-dien-3-one system,

and optionally that a free 22-hydroxy group is then acylated.

In the first step, hydrogenation the triple bond (II) in the 17a-(3-oxygenated-1-propynyl) compound is reduced to the Z- or E-configured double bond (III).

The compound with the Z-configured double bond is formed by hydrogenation of the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, J. A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, p. 134, and H. 0. House: Modern Synthetic Reactions 1972, p. 19). For example, 10% palladium on barium sulphate in the presence of an amine, or 5% palladium on calcium carbonate with the addition of lead(II) acetate can be used as a deactivated noble metal catalyst. The hydrogenation is interrupted after the uptake of an equivalent of hydrogen.

The compound with E-configured double bond is formed

by reduction of the acetylenic triple bond in a manner known per se. A number of methods for converting alkynes to trans-olefins are described in the literature, for example reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63> (1941) 216), with sodium amide in liquid ammonia (J. Chem . Soc. 1955, 3558), with lithium in low molecular weight amines (J. Am. Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1971) 6560), with diiso-butyl aluminum hydride and methyllithium (J. Am. Chem. Soc. £[9

(1967) 5085) and in particular with lithium aluminum hydride/alcoholate (J. Am. Chem. Soc. 89 (1967) 4245).

A further possibility is 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. 8£ (1964) 4358), as well as general reduction under the influence of transition metal- compounds during alternation of the oxidation step.

For water elimination during formation of the 4,9(10)-dien-3-one system and simultaneous ketal cleavage and removal of any hydroxy protecting group R present in the 22-position, the 17a-oxypropenyl-170-hydroxy compound of general formula III is then treated with acid, a pyridinium salt or an acidic ion exchanger.

The in general formula II or III by R characterized hydroxy protecting group is a group which is easily cleavable in an acidic environment or which can be easily cleaved hydrogenolytically, such as e.g. methoxymethyl, ethoxymethyl, tetrahydropyranyl or benzyl.

The acid treatment takes place in a manner known per se by dissolving the compound of formula III, which contains a 3-ketal group and a 5a-hydroxy group and an optionally O-protected 17a-(3-hydroxypropenyl) group, in a water-miscible solution agent such as aqueous methanol, ethanol or acetone, which is treated with catalytic amounts of mineral or sulphonic acid such as hydrochloric, sulfuric, phosphoric, perchloric or p-toluenesulphonic acid or an organic acid such as acetic acid, until water is split off and the protecting group is removed. The reaction, which takes place at temperatures of from 0 to 100°C, can be carried out with a particularly high yield with a pyridinium salt such as pyridinium tosylate or an acidic ion exchanger. The course of the turnover is followed with analytical methods, for example by thin-layer chromatography on samples taken.

The acylation of the 22-hydroxy group takes place in a manner known per se, for example by reaction with an acid anhydride in pyridine at room temperature.

Preparation of the starting compounds of general formula II is illustrated by the following reaction scheme:

Oxiran (1) according to European patent application no. 82 400 025.1 (publication no. 0057115) is reacted with metallized derivatives of propargyl alcohol, e.g. with 1-lithium-3-tetrahydro-pyran-2'-yloxypropyn-1, to the 17α-[3-oxygenated-1-propynyl]-17α-hydroxy compounds (2). Introduction of the 113-aryl residue to (II) occurs either by Cu(I)-catalyzed Grignard reaction with the corresponding arylmagnesium halides (Tetrahedron Letters 1979, 2051) or by reaction with mixed organocuprates of the type R2Cu(CN)Li2 (J. Am. Chem. Soc. 103 (1981) 7672). Finally, according to EP 57115, the ketone (3) can be reacted with free propargyl alcohol in the presence of bases such as potassium ethylate, potassium t-butylate or butyllithium (BuLi) to (II).

In the following, the preparation of certain starting compounds of general formula II is illustrated: la) To a solution of 35.7 g of 3-tetrahydropyran-2-yloxy-1-propyne in -760 ml of absolute tetrahydrofuran, 208 ml of a 15 % solution of n-butyllithium in hexane. After the addition, the reaction mixture was stirred for a further 15 minutes at +5 to +10°C and then a solution of 23.7 g of 3,3-(2,2-dimethyl-propane-1,3-dioxy)-5a was added dropwise ,10α-oxido-9(11)-estren-17-one in 470 ml of absolute THF. The reaction mixture was stirred for 20 minutes at 25°C, after which it was poured over for approx. 5 1 ice water and extracted with vinegar. The acetic ester extract was dried over sodium sulfate/active carbon and evaporated in vacuo.

After filtration over aluminum oxide with hexane/acetic ester as eluent, 29.3 g of 3,3-(2,2-dimethyl-propane-1,3-dioxy)-5a,10a-oxido-17a-[3-(tetrahydropyran) were obtained -2-yloxy)-1-propynyl]-9(11)-estren-173-ol as a colorless oil.

b) A suspension of 5.28 g of magnesium (shavings) in 275 ml of absolute THF was successively added with 0.05 ml of methyl iodide and

a solution of 50.27 g of 4-bromodimethylaniline in 245 ml of absolute THF. The reaction mixture was stirred under an argon atmosphere until the magnesium was completely dissolved whereby the internal temperature did not exceed 50°C. The reaction mixture was

then cooled to +5°C, the Grignard solution was added with 1.12 g of CuCl and stirred for 15 minutes at +5 - +10°C. In addition to this, a solution of 29.3 g of the product obtained in a) in 275 ml of absolute THF was added dropwise, and the mixture was stirred for 5 hours at room temperature. The reaction solution was then poured into 4 l of ice water and extracted with acetic acid. Chromatography of the impure product thus obtained over aluminum oxide with hexane/acetic ester gave 32.6 g of lip-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-17a-[3-( tetrahydropyran-2-yloxy)-1-propynyl]-9(10)-estrene-5α,173-diol as a yellowish oil.

2a) 22.6 g 3,3-(2,2-dimethylpropan-1,3-dioxy)-18-methyl-5a,10a-oxido-9(11)-estren-17-one (m.p. 156-158 °C) was reacted as described in la) with 1-lithio-3-(tetrahydropyran-2-yloxy)-propyn-1 to form 25.4 g of 3,3-(2,2-dimethylpropane-1,3- dioxy)-18-methyl-5α,10α-oxido-17α-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9(11)-estren-170-ol as a colorless oil.

b) To a suspension of 4.3 g magnesium (shavings) in 40 ml absolute THF was added dropwise at 25°C first 0.1 ml

methyl iodide and then a solution of 40 g of p-dimethylamino-ethoxy-phenyl bromide (prepared according to D. Lednicer et al.,

J. Med. Chem. 8, 52 (1964)) in 200 ml of absolute THF. The reaction mixture was stirred at a bath temperature of a maximum of 70°C until the magnesium was completely dissolved. After cooling to 0°C, 820 mg of CuCl was added and the mixture was stirred for 20 minutes at 0°C. Then a solution of 15/9 g of the product obtained under a) in 120 ml of absolute THF was added dropwise. The reaction mixture was stirred for 16 hours at 25°C, poured into ice water and extracted with acetic acid. Chromatography over alumina (neutral, III) with hexane/acetic ester gave 17.1 g of lip-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-18-methyl-17a-[ 3-(tetrahydropyran-2-yloxy)-1-propynyl]-9(10)-estrene-5α,17β-diol as a yellowish oil.

3) From 2.4 g of magnesium in 120 ml of absolute THF and 11.6 ml of 4-bromoanisole, a Grignard reagent was prepared as described under lb) and 260 mg of CuCl was added. A solution of 6.4 g of the adduct prepared under la) in 80 ml of absolute THF was added dropwise at 0°C. The reaction solution was stirred for 4 hours at 25°C and was worked up as described under lb). 7.15 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-113-(4-methoxyphenyl)-17a-[3-tetrahydropyran-2-yloxy)-1-propynyl]- 9(10)-estrene-5α,173-diol as an oily product. 4a) From 6.7 g of propargyl-tetrahydropyranyl ethers in 100 ml of THF and 40 ml of n-butyllithium (15% in hexane) the lithium-organic compound was prepared under the conditions described in la) and was reacted with 4.63 g 3,3-(2,2-dimethylpropan-1,3-dioxy)-16α-methyl-5α,10α-oxido-9(11)-ε stren-17-one. After chromatography, 4.22 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-16|3-methyl-5a,10a-oxido-17a-[3-(tetrahydropyran-2-yloxy) were obtained )-prop-l-ynyl]-9(11)-estren-173-ol as crystalline isomeric mixture with m.p. 156-166°C. b) From 1.23 g magnesium shavings in 100 ml absolute THF, 11.48 g 4-dimethylaminophenyl bromide in 50 ml absolute THF, 0.03 ml methyl iodide and 230 mg CuCl, a Grignard reagent was prepared under the conditions described in lb ) which was reacted with 3.55 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-163-methyl-5a,10a-oxido-17a-(3-tetrahydropyran-2-yloxy-prop- 1-ynyl)-9(11)-estren-17B-ol. After chromatography, 3.56 g of 11|3-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropan-1,3-dioxy-160-methyl-17a-L3-(tetrahydropyran-2-yloxy) were obtained )-prop-l-ynyl]-9(10)-estrene-5a,173-diol as an oily isomeric mixture. 5) To a suspension of 1.02 g of magnesium shavings and 0.05 ml of methyl iodide in 25 ml of absolute tetrahydrofuran was added dropwise a solution of 10.5 g of 4-(2,5-dimethylpyrrol-1-yl)-bromobenzene (prepared according to J. Chem. Soc. 1951, 3155) in 40 ml of absolute tetrahydrofuran in such a way that the temperature during the course of the reaction did not exceed 45°C. After dissolving the magnesium, the reaction mixture was cooled to 0°C, 210 mg of CuCl was added, stirred for 15 minutes at 0°C and then a solution of 4.00 g of 3,3-(2,2-dimethyl-propane) was added dropwise -1,3-dioxy)-5α,10α-oxido-17α-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]-9(11)-estren-17β-ol in 50 ml of absolute tetrahydrofuran. The reaction mixture was then stirred overnight at room temperature, poured into ice water and extracted with acetic acid. Chromatography on Al 2 O 3 (neutral, III) with hexane/acetic ester gave 4.42 g of 3,3-(2,2-dimethyl-propane-1,3-dioxy)-lip-[4-(2 ,5-dimethylpyrrol-1-yl)-phenyl]-17α-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]-9(10)-estrene-5α,17β-diol as pale yellow solid foam . 6) 1.46 g of magnesium shavings and 0.05 ml of methyl iodide were introduced into 15 ml of absolute tetrahydrofuran. Then a solution of 14.5 g of N-(4-bromophenyl)-piperidine (prepared according to J. Am. Chem. Soc. 75, 5280 (1953)) in 100 ml of absolute tetrahydrofuran was added dropwise in such a way that the temperature below the reaction time did not exceed 45°C. After dissolving the magnesium, the reaction mixture was cooled to 0°C, 450 mg of CuCl was added, stirred for 15 minutes at 0°C and finally a solution of 6.0 g of 3,3-(2,2-dimethylpropane- 1,3-dioxy)-5α,10α-oxido-17α-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]-9(11)-estren-173-ol in 50 ml of absolute tetrahydrofuran. The reaction mixture was then stirred at room temperature overnight, poured into ice water and extracted with acetic acid. Chromatography on Al 2 O 2 (neutral, III) with hexane/acetic ester gave 7.0 g of 3,3-(2,2-dimethyl-propane-1,3-dioxy)-lip-(4-piperidinophenyl) )-17α-[3-(tetrahydro-pyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5α,17β-diol as a colorless solid foam. 7) 2.16 g of magnesium shavings and 0.05 ml of methyl iodide were introduced into 15 ml of absolute tetrahydrofuran. Then a solution of 13.5 g of N-(4-bromophenyl)-pyrrolidine (prepared according to J. Am. Chem. Soc. 75./ 5280 (1953)) in 150 ml of absolute tetrahydrofuran was added dropwise in such a way that the temperature on the reaction mixture during the course of the reaction was not exceeded

45°C. After dissolution of the magnesium, the reaction mix-

none cooled to 0°C, added 4 50 mg of CuCl/ stirred for 15 minutes at 0°C and finally a solution of 6.0 g of 3,3-(2,2-dimethylpropane-1,3-dioxy) was added dropwise )-5α,10α-oxido-17α-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]-9(11)-estren-17f}-ol in 70 ml of absolute tetrahydrofuran. The reaction mixture was then stirred overnight at room temperature, poured into ice water and extracted with acetic acid. By chromatography on A^O^

(neutral, III) with hexane/acetic ester, 7.0 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-113-[4-(pyrrolidin-1-yl)-phenyl]- 17α-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5α,17α-diol as a colorless solid foam.

8) A solution of 2.4 g of 113-(4-dimethylaminophenyl)-3,3-ethylenedioxy-5a-hydroxy-9-estren-17-one (European Patent Application Publication No. 57 115 (82)) in 36 ml anhydrous tetrahydrofuran was added at 0°C with 9.35 g of potassium ethylate. A solution of 3.6 ml of propargyl alcohol in 3.6 ml of tetrahydrofuran was added dropwise over the course of 20 minutes, and the reaction mixture was stirred for 2 hours at room temperature under argon. The reaction solution was cooled to 0°C and 8 ml of ice-cold 30% sulfuric acid was added to a weakly acidic reaction. During the addition, the internal temperature of the flask was not allowed to exceed 20°C. Finally, the solution was neutralized with sodium bicarbonate solution and poured into water. The reaction mixture was extracted three times with ethyl acetate, the extract was washed neutral, dried over sodium sulfate and evaporated in vacuo to dryness. The impure product was chromatographed on

300 g silica gel with a methylene chloride-acetone gradient (0-25% acetone).

Yield: 1.4 g of 113-(4-dimethylaminophenyl)-3,3-ethylenedioxy-17a-(3-hydroxy-1-propynyl)-9-estrene-5a,173-diol with m.p. 130-132°C. [ a]^ 5 = -44°.

Example 1

113-(4-dimethylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one

a) A solution of 2.23 g (3.5 mmol) 3,3-(2,2-dimethyl-propane-1,3-dioxy)-113-(4-dimethylaminophenyl)-17a-[3-(tetra -hydropyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5a,173-diol in 100 ml of ethanol and 2 ml of triethylamine was hydrogenated with the addition of 200 mg of Pd/BaSO^ (10%) at room temperature and normal pressure. After absorption of 80 ml of hydrogen, the hydrogenation was interrupted, the catalyst was filtered off, the solution was evaporated and the residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 1.50 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-113-(4-dimethylaminophenyl)-17a-[3-(tetrahydropyran-2-yloxy)-prop-1 ( Z)-enyl]-9 (10)-iso-stren-5a, 173-diol as a colorless foam.

b) 1.1 g (1.7 mmol) of the product obtained under a) was stirred in 10 ml of 70% acetic acid overnight at room temperature

and under argon. Then the reaction mixture was stirred for 1 hour at 50°C to complete the reaction. For the work-up, the reaction mixture was poured over a mixture of 25 g ice/10 ml concentrated ammonia water and extracted with acetic acid.

After drying over Na^SO^, the solution was evaporated and chromatographed on silica gel with n-hexane/acetic acid. There was obtained - 0.42 g of 113-(4-dimethylaminophenyl)-173~hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one as lemon yellow, solid foam.

[αJD (CHCl 3 ) = +203.5°

Example 2

II3-(4-dimethylaminophenyl)-173~hydroxy-17a-(3-hydroxyprop-1(E)-enyl)-4,9(10)-estradien-3-one

a) To a solution of 4.0 g (6.3 mmol) 3,3-(2,2-dimethyl-propane-1,3-dioxy)-II3-(4-dimethylaminophenyl)-17a-[3-( tetra-hydropyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5α,173-diol in 100 ml absolute tetrahydrofuran was under argon portionwise

added 4.8 g (60.13 mol) lithium aluminum hydride. The reaction mixture was then stirred for 2 hours at room temperature and then for 1 hour at 50°C. Under ice cooling, 4.8 ml of water, 4.8 ml of 4 N NaOH and 14.4 ml of water were then added dropwise. The precipitate formed was slurried with a water/acetic acid mixture, separated over a frit and washed thoroughly with vinegar. The acetate phase was dried with Na 2 SO 2 , evaporated and chromatographed with n-hexane/acetate on Al 2 O 2 (III, neutral). 1.05 g of 3,3-(2,2-dimethyl-propan-1,3-dioxy)-113-(4-dimethylaminophenyl-17a-(3-hydroxyprop-1(E)-enyl)-9 was obtained (10)-estrene-5α,173-diol as a colorless foam.

b) 1.0 g (1.8 mmol) of the product obtained under a) was stirred in 30 ml of 70% acetic acid overnight at room temperature

and under argon. The reaction solution was poured onto a mixture of 25 g ice/10 ml concentrated ammonia water and was extracted with acetic acid. After drying over Na^O^, the solution was evaporated and chromatographed on silica gel with n-hexane/acetic acid. 0.59 g of 113-(4-dimethylaminophenyl)-173-hydroxy-17a-(3-hydroxyprop-1(E)-enyl)-4,9(10)-estradien-3-one was obtained as lemon yellow, solid foam.

La]D (CHCl 3 ) = +157.3°

Example 3

173-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-II3-(4-methylamino-phenyl)-4,9(10)-estradien-3-one

a) A solution of 2.6 g of the product prepared according to example la) in 100 ml of methylene chloride was added

of 3.55 g brownstone (MnO2) stirred for 6 hours at room temperature. After filtration, the solution was washed with methylene chloride, evaporated and chromatographed with n-hexane/acetic ester on Al-^O^

(III, neutral). In addition to 1.3 g of starting material, 0.86 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-113-(4-methylaminophenyl)-173-[3-(tetrahydropyran-2) was obtained -yloxy)-prop-1(Z)-

enyl]-9 (10)-estrene-5a, 17|3-diol as a colorless solid foam.

b) 0.86 g of the product obtained under a) was stirred in 8.6 ml of 70% acetic acid overnight at room temperature and under

argon. The reaction mixture was then stirred for 1.5 hours at 50°C to complete the reaction. The mixture was then poured into water and brought to pH 10 with concentrated ammonia water. The reaction solution was extracted with methylene chloride, washed neutral with water, dried over Na 2 SO 4 , evaporated, and the residue chromatographed with n-hexane/acetic ester on Al 2 O 3 (III, neutral). 0.25 g of 17(3-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-110-(4-methylaminophenyl)-4,9(10)-estradien-3-one was obtained as lemon yellow , solid foam.

<1>H-NMR (CDCl 3 ): <f = 6.98; 6.52 (dd, 4H, aromatic C-H,

J = 8 Hz), 5.7-5.6 (m, 2H, -CH=CH-,

J. = 12.5 Hz), 5.74 (s, 1H, H-4),

cis

4.4-4.2 (m, 2H, -CH2OH), 2.80 (s, 3H,

-NCH3), 0.62 (s, 3H, CH3)

Alternative manufacturing

Preparation of p-bromo-N-methyl-N-trimethylsilylaniline

To 20 g of p-bromo-N-methylaniline in 50 ml of absolute tetrahydrofuran, a lithium diisopropylamide solution prepared from 12.12 g of diisopropylamine in 100 ml of absolute tetrahydrofuran and 68 ml of 1.6 m n-butyllithium/n- hexane at a temperature of -50°C, whereby a colorless precipitate was formed. After further stirring for 1 hour at -20°C, 11.6 g (= 13.5 ml) of trimethylsilyl chloride was added dropwise, whereby the precipitate was again dissolved. The reaction solution was stirred for 16 hours at room temperature. The lithium chloride formed during the reaction was separated, the filtrate was evaporated, and the residue was distilled in a water jet vacuum. 2.3.9 g of p-bromo-N-methyl-N-trimethylsilylaniline with boiling point (16 torr) 131-135°C were obtained.

a) To a suspension of 2.25 g of magnesium in 20 ml of absolute tetrahydrofuran and 0.1 ml of methyl iodide, 23.9 g of p-bromo-N-methyl-N-trimethylsilylaniline in 10 ml of tetrahydrofuran were added dropwise under argon. A slight exothermic reaction was observed and the mixture was stirred for a further 4 hours at +50°C to effect a complete dissolution of the magnesium. The reaction mixture was then cooled to +5°C, and 1 g of copper chloride was added. After further stirring for 15 minutes, 10 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5a,10a-epoxy-17a-[3-(tetrahydropyran-2-yloxy)-prop- 1-y nyl]-9 (11)-estren-17(3-ol in 50 ml of absolute tetrahydrofuran. The reaction mixture was stirred for 20 hours at room temperature. For the work-up, the mixture was poured into 100 g of ice/10 ml of saturated ammonium chloride solution and extracted with ethyl acetate .

The organic phases were washed neutral with water and dried over sodium sulfate. The evaporated residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 10.7 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-113-(4-methylaminophenyl)-17a-13-(tetrahydropyran-2-yloxy)-prop-1-ynyl were obtained ] -9(10)-estrene-5α,173-diol as a colorless solid foam.

b) 10.7 g of the compound obtained in a) was hydrogenated in 250 ml of absolute ethanol and 9.6 ml of triethylamine in the presence of

0.96 g palladium/BaSO 4 (10%) under normal conditions. After absorption of 300 ml of hydrogen, the hydrogenation was interrupted, the catalyst was filtered off, the solution was evaporated, and the residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/10-70% acetate. 6.3 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-II3-(4-methylaminophenyl)-17a-[3-(tetrahydropyran-2-yloxy)-prop-1( Z)-enyl]-9(10)-estrene-5α,173-diol as a colorless solid foam.

<1>H-NMR (CDCl 3 ): δ = 6.98; 6.52 ppm (dd, 4H, arom. C-H, 90 MHz,

J = 8 Hz), 5.7-5.6 (m, 2H, -CH=CH-,

J. = 12.5 Hz)

cis

c) 4.25 g of the product obtained in b) was dissolved in 100 ml of 70% acetic acid, and the solution was stirred for 1 hour at 50°C.

The mixture was then stirred into 100 g ice/100 ml concentrated aqueous ammonia solution and extracted with ethyl acetate. The organic phases were washed neutral with water and dried over sodium sulfate. After evaporation, the residue was chromatographed on silica gel with an n-hexane/acetic ester mixture. 1.86 g of 173-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-113-(4-methylaminophenyl)-4,9(10)-estradien-3-one were obtained as lemon yellow, solid foam.

[αJD (CHCl 3 ) = +196.2°

Example 4

113-(4-aminophenyl)-173~hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one

a) To a suspension of 2.64 g of magnesium and 0.05 ml of methyl iodide in 20 ml of absolute tetrahydrofuran was added under argon

a solution of 18.5 g of N,N-bis-ltrimethylsilylJ-4-bromoaniline (J. Org. Chem. 40, 1090 (1975)) in 50 ml of absolute tetrahydrofuran in such a way that the temperature during the course of the reaction did not exceed 45°C . After complete dissolution of the magnesium, the reaction mixture was cooled to 0°C, 500 mg of CuCl was added and stirred for 15 minutes at 0°C. Then a solution of 6.0 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5α,10α-epoxy-17α-13-(tetrahydropyran-2-yloxy)-prop-1-ynyl ]-9(11)-estren-173-ol in 80 ml of absolute tetrahydrofuran was added dropwise, and the reaction mixture was stirred for 16 hours at room temperature. For the work-up, the reaction mixture was poured into aqueous ammonia solution and extracted with acetic acid. After drying the organic phase over ^£30^, this was filtered, evaporated, and the residue was stirred for 4 hours at 50 C under argon in 200 ml of 20% ethanolic potassium hydroxide solution. The reaction mixture was then stirred into an ice/water mixture and extracted with acetic acid. The organic phase was washed neutral with water and dried over Na 2 SO 4 . After evaporation, the residue was chromatographed on Al 2 O 3 (III, neutral) with hexane/acetate. 5.27 g of 113"(4-aminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-17a-[3-(tetrahydropyran-2-yloxy)-prop-1- ynyll -9(10)-estrene-5a,173-diol as a colorless solid foam.

b) 3.8 g of the product obtained in a) was hydrogenated in 100 ml of ethanol and 3.6 ml of triethylamine with the addition of

360 mg palladium/BaSO 4 (10%); under normal conditions. After

absorption of 141 ml of hydrogen, the hydrogenation was stopped, the catalyst was filtered off, the solution was evaporated, and the residue was chromatographed with n-hexane/acetic ester on Al2O3

(III, neutral). 2.98 g of 113-(4-aminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-17a-[3-(tetrahydropyran-2-yloxy)-prop-1( Z)-enyl J-9(10)-estrene-5α,173-diol as a colorless solid foam.

c) 2.97 g of the product obtained in b) was stirred in 50 ml of 70% acetic acid overnight at room temperature and under argon.

For the work-up, the reaction mixture was poured into 50 g of ice/50 ml of concentrated ammonia water and was extracted with acetic acid. After drying over Na 2 SO 4 , the solution was evaporated, and the residue was chromatographed on silica gel with n-hexane/acetic ester. 1.57 g of 113-(4-aminophenyl)-173-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one were obtained as lemon yellow, solid foam.

[o]D (CHCl 3 ) = +185.7°

Example 5

113-(4-dimethylaminophenyl)-173-hydroxy-17a-(3-hydroxyprop-1( Z)-enyl)- 163- methyl- 4, 9( 10)- estradiene- 3- one

a) 2.67 g (4.1 mmol) 3,3-(2,2-dimethylpropane-1,3-dioxy)-113-(4-dimethylaminophenyl)-163-methyl-17a-[3-(tetrahydropyran- 2-yloxy)-prop-l-ynylJ-9(10)-estrene-5α,173-diol was hydrogenated in 100 ml ethanol with the addition of 2.3 ml triethylamine and 2 35 mg Pd/BaSO 4 (10%) at room temperature and under normal pressure. After absorption of 100 ml of hydrogen, the catalyst was filtered off, the solution was evaporated and the residue chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 1.9 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-113-(4-dimethylaminophenyl)-163-methyl-17a-[3-(tetrahydropyran-2-yloxy)- prop-1(Z)-enyl]-9(10)-estrene-5α,173-diol as a colorless solid foam. b) 1.9 g (2.9 mmol) of the product obtained in a) was stirred in 40 ml of 70% acetic acid overnight at room temperature and under argon. For the work-up, the reaction mixture was poured into 40 g of ice/40 ml of concentrated ammonia water and extracted with acetic acid. After drying over Na-^SO^, the solution was evaporated, and the residue was chromatographed on silica gel with n-hexane/acetic ester. 0.92 g of lip-(4-dimethylaminophenyl)-173-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-163-methyl-4,9(10)-estradien-3-one were obtained as lemon yellow, solid foam. [a] (CHC13) = +210.8° Example 6 113-(4-dimethylaminophenyl)-173~hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-16a-methyl-4,9( 10 )- estradiene-3-one a) 700 mg (1.08 mmol) 3,3-(2,2-dimethylpropane-1,3-dioxy)-113-(4-dimethylaminophenyl)-16a-methyl-17a-[ 3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5α,173-diol was hydrogenated in 100 ml of ethanol with the addition of 0.6 2 ml of triethylamine and 6 2 mg of Pd/ BaSO^ (10%) at room temperature and under normal pressure. After absorption of 24 ml of hydrogen, the catalyst was filtered off, the solution was evaporated, and the residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 525 mg of 3,3-(2,2-dimethylpropan-1,3-dioxy)-113-(4-dimethylaminophenyl)-16a-methyl-17a-[3-(tetrahydropyran-2-yloxy)-prop- 1(Z)-enyl]-9(10)-estrene-5α,173-diol as colorless solid foam.

b) 500 mg (0.77 mmol) of the product obtained in a) was

stirred in 20 ml of 70% acetic acid overnight at room temperature and

under argon. For the work-up, the reaction mixture was poured onto 20 g of ice/20 ml of concentrated ammonia water and was extracted with acetic acid. After drying over Na 2 SO 4 , the solution was evaporated, and the residue was chromatographed on silica gel with n-hexane/acetic ester. 289 mg of 113-(4-dimethylaminophenyl)-173-hydroxy-17ct-(3-hydroxyprop-1(Z)-enyl)-16a-

methyl-4,9(10)-estradien-3-one as a lemon yellow solid foam.

[α]D (CHCl 3 ) = +194.6°

Example 7

17β-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-lip-[4-(piperidin-1-yl)-phenyl]-4,9(10)-estradien-3-one

a) 5.3 g (7.9 mmol) 3,3-(2,2-dimethylpropane-1,3-dioxy)-lip-[4-(piperidin-1-yl)-phenyl]-17a-[3 -(tetrahydropyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5α,170-diol was hydrogenated in 220 ml of ethanol with the addition of 4.5 ml of triethylamine and 450 mg of Pd/BaSO^ ( 10%) at room temperature and under normal pressure. After absorption of 180 ml of hydrogen, the catalyst was filtered off, the solution was evaporated, and the residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 3.41 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-lip-[4-(piperidin-1-yl)-phenyl]-17a-[3-(tetrahydropyran- 2-yloxy)-prop-1(Z)-enyl]-9(10)-estrene-5α,17β-diol as a colorless solid foam.

b) 3.37 g (5 mmol) of the product obtained in a) was stirred in 60 ml of 70% acetic acid overnight at room temperature and under

argon. The mixture was then stirred for 1 hour at 50°C. For the work-up, the reaction mixture was poured onto 60 g of ice/60 ml of concentrated ammonia water and extracted with acetic acid. After drying over Na,,SO 4 , the solution was evaporated, and the residue was chromatographed on silica gel with n-hexane/acetic ester. 1.75 g of 17β-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl) was obtained -lip-[4-(piperidin-1-yl)-phenyl]-4,9(10)-estradien-3-one as lemon yellow solid foam.

[<x]D (CHCl 3 ) = +209°

Example 8

17β-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-lip-[4-(pyrrolidin-1-yl)-phenyl]-4,9(10)-estradien-3-one

a) 4.36 g (6/6 mmol) 3,3-(2,2-dimethylpropane-1,3-dioxy)-lip-[4-(pyrrolidin-1-yl)-phenyl]-17a-[3 -(tetrahydropyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5a,17p-diol was hydrogenated in 200 ml of ethanol with the addition of 3.8 ml of triethylamine and 380 mg of Pd/BaSO 4 (10 %) at room temperature and under normal pressure. After absorption of 160 ml of hydrogen, the catalyst was filtered off, the solution was evaporated and the residue chromatographed on A^O^ (III, neutral) with n-hexane/acetic ester. 2.91 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-II3-[4-(pyrrolidin-1-yl)-phenyl]-17a-[3-(tetrahydropyran-2 -yloxy)-prop-1(Z)-enyl]-9(10)-estrene-5α,173-diol as a colorless solid foam.

b) 2.91 g (4.4 mmol) of the product obtained in a) was stirred in 50 ml of 70% acetic acid for 5 hours at 50°C. For the work-up, the reaction mixture was poured onto 50 g of ice/50 ml of concentrated ammonia water and extracted with acetic acid.

After drying over Na 2 SO 4 , the solution was evaporated, and the residue was chromatographed on silica gel with n-hexane/acetic ester. 1.66 g of 173-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-113-[4-(pyrrolidin-1-yl)-phenyl]-4,9(10)-estradiene were obtained -3-one as lemon yellow, solid foam.

[α]D (CHCl 3 ) = +214.1°

Example 9

113-[4-(2,5-dimethylpyrrol-1-yl)-phenyl]-173-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradiene-3- Wed

a) 1.4 g (2.1 mmol) 3,3-(2,2-dimethylpropan-1,3-dioxy)-113-[4-(2,5-dimethylpyrrol-1-yl)-phenyl]- 173-[3-(tetrahydro-pyran-2-yloxy)-prop-l-ynyl]-9(10)-estrene-5a,173-diol was hydrogenated in 60 ml of ethanol with the addition of 1.2 ml of triethylamine and 120 mg Pd/BaSO^ (10%) at room temperature and under normal pressure. After absorption of 48 ml of hydrogen, the catalyst was filtered off, the solution was evaporated, and the residue was chromatographed on Al 2 O.j (III, neutral) with n-hexane/acetic ester. 758 mg of 3,3-(2,2-dimethylpropane-1,3-dioxy)-II3-[4-(2,5-dimethylpyrrol-1-yl)-phenyl]-17a-[3-(tetrahydropyran) were obtained -2-yloxy)-pro-1(Z)-enyl]-9(10)-estrene-5α,173-diol as dye-

loose, solid foam.

b) 2.57 g (3.7 mmol) of the product obtained in a) was stirred in 50 ml of ethanol for 2 hours at room temperature and under argon

while adding 300 mg of p-toluenesulfonic acid monohydrate.

For processing, the mixture was poured into 50 ml of ice water/

5 ml of concentrated ammonia solution and was extracted with acetic acid. After drying over Na0SO4, the solution was evaporated, and the residue was chromatographed on silica gel with n-hexane/acetic ester. 0.85 g of lip-[4-(2,5-dimethylpyrrol-1-yl)-phenyl]-17|3-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4 were obtained, 9 (10) - oestradien-3-one as yellow solid foam. [a]D (CHC13) = +152.4° Example 10 110-(4-dimethylaminophenyl)-16(E)-ethylidene-173-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4 , 9(10)-estradien-3-one a) A suspension of 29.3 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5(10),9(11)-estradien- 17-one and 28.6 g of bis-dimethylamino-t-butoxymethane were stirred under argon for 60 minutes at 160°C. After cooling, the crude product was triturated with 50 ml of ethyl acetate, the mixture was filtered and the residue crystallized from ethyl acetate. 27.6 g of 16-dimethylaminomethylene-3,3-(2,2-dimethylpropan-1,3-dioxy)-5(10),9(11)-estradien-17-one with m.p. 208-211°C. b) A solution of 14.4 g of 16-dimethylaminomethylene-3,3-(2,2-dimethylpropan-1,3-dioxy)-5(10),9(11)-estradien-17-one in

220 ml of toluene was added dropwise under ice water cooling to 85 ml of a 5% solution of methyllithium in diethyl ether. After the addition, the mixture was stirred for 15 minutes at +5 to +10°C, the excess reagent was cleaved by careful addition of approx. 20 ml of water, the reaction solution was then poured over 13 l of ice water and extracted with methylene chloride. The impure product was chromatographed on neutral aluminum oxide with hexane/ethyl acetate. After crystallization of the main

the fraction from ethyl acetate, 13.0 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-16(E)-ethylidene-5(10),9(11)-estradiene-17 were obtained -on with m.p. 121-123°C.

c) To a solution of 9.4 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-16(E)-ethylidene-5(10),9(11)-estradien-17-one in 43 ml

methylene chloride, 0.34 ml of hexachloroacetone and 0.01 ml of pyridine were added dropwise under ice water cooling to 4.3 ml of 30% hydrogen peroxide, and the mixture was then stirred for 16 hours at 25°C. For the work-up, the reaction solution was diluted with 100 ml of methylene chloride, washed with 5% Na 2 S-jO 4 solution and water, the methylene chloride phase was dried over Na 2 SO 4 and then evaporated. The 5,10-epoxide mixture thus obtained was chromatographed on Al 2 O.j, (neutral, step III) with hexane/ethyl acetate. 4.7 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5a,10a-epoxy-16(E)-ethylidene-9(11)-estren-17-one with m.p. . 139-141°C (ethyl acetate/diisopropyl ether).

d) A solution of 1.95 g of 3-(tetrahydropyran-2-yloxy)-1-propyne in 41 ml of absolute tetrahydrofuran (THF) was at 0 to

+5°C added dropwise 11.3 ml of a 15% solution of n-butyllithium in hexane. A solution of 2.25 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5a,10a-epoxy-16(E)-ethylidene-9(11)-estrene-17 was then added dropwise -on, and the mixture was stirred for 60 minutes at room temperature. For the work-up, pour the reaction mixture completely into ice water and extract with ethyl acetate. The crude product was crystallized from diisopropyl ether. 2.8 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5α,10α-epoxy-16(E)-ethylidene-17α-[3-(tetrahydropyran-2-yloxy) were obtained -1-propynyl]-9(11)-estren-173-ol with m.p. 196-198°C.

e) To a suspension of 604 mg of magnesium in 10 ml of absolute THF, 0.05 ml of methyl iodide and a solution of 6.4 2 g of 4-bromo-dimethylaniline in 30 ml of absolute THF were successively added at room temperature so that the internal temperature did not exceeded 45°C. After complete dissolution of the magnesium, the reaction mixture was cooled to 0°C, 124 mg of CuCl was added

(solid) and was stirred for 15 min at 0°C. Then a solution of 3.5 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5a,10a-epoxy-16(E)-ethylidene-17a-[3-(tetrahydropyran-2- yloxy)-1-propynyl]-9(11)-estren-170-ol in 25 ml of absolute THF was added dropwise, and the mixture was stirred for 20 hours at 25°C. For work-up, the mixture was poured into aqueous NH 4 solution and extracted with ethyl acetate. The crude product was chromatographed on Al 2 O 3 with hexane/ethyl acetate. The main oily fraction (4.3 g) was used in the next step. f) A solution of 4.3 g of the 110-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-16(E)-ethylidene-17a-[ 3-(tetrahydropyran-2-yloxy)-1-propynyl]-9(10)-estrene-5α,170-diol in 300 ml of ethanol, and 7 ml of triethylamine was after addition of 500 mg of Pd/BaSO^ (10%) hydrogenated at room temperature and under normal pressure. After absorption of 140 ml of hydrogen, the hydrogenation was stopped, the catalyst was filtered off, and the solution was evaporated. 4.3 g of 110-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-16(E)-ethylidene-17a-[3-(tetrahydropyran-2- yloxy)-prop-1(Z)-enyl]-9(10)-estrene-5α,170-diol as a colorless oil. g) A solution of 3.63 g of the product obtained in f) in 17 ml of 70% aqueous acetic acid was stirred for 20 hours at room temperature and under argon. The mixture was then poured into ice water, the pH was adjusted to 10.5 by the addition of concentrated aqueous NH 4 solution and was extracted with ethyl acetate. The crude product was chromatographed on silica gel with hexane/ethyl acetate. The main fraction was crystallized from hexane/ethanol. 1.3 g of 110-(4-dimethylaminophenyl)-16(E)-ethylidene-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradiene- 3-on with m.p. 127-130°C (the compound crystallized with 1 mol of ethanol).

Example 11

113-(4-dimethylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one

a) 110-(4-dimethylaminophenyl)-3,3-ethylenedioxy-17a-(3-hydroxyprop-1(Z)-enyl)-9-estrene-5a,170-diol

A solution of 500 mg of 110-(4-dimethylaminophenyl)-3,3-ethylenedioxy-17a-(3-hydroxy-1-propynyl)-9-estrene-5a,170-diol in 5 ml of ethanol was, after addition of 5 mg Lindlar catalyst (Pd/CaCO-j (5%) hydrogenated for 16 hours at room temperature and under normal pressure with the addition of Pb (0 acetyl)^)• The hydrogen uptake amounted to 22.7 ml. The reaction solution was filtered over Celite, washed with ethyl acetate, and the solution was evaporated to dryness in vacuo. The crude product was purified on 100 g of silica gel with a methylene chloride-acetone gradient (0-20% acetone). 420 mg of 110-(4-dimethylaminophenyl)-3,3-ethylenedioxy-17α-(3-hydroxyprop-1(Z)-enyl)-9-estrene-5α,170-diol were isolated as a colorless foam.

[a]J<5> = -13°.

b) 110-(4-dimethylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1 (Z)-enyl)-4,9(10)-estradien-3-one

A solution of 255 mg of 110-(4-dimethylaminophenyl)-3,3-ethylenedioxy-17a-(3-hydroxyprop-1(Z)-enyl)-9-estrene-5a,170-diol in 4 ml of ethanol was stirred with 15 mg of pyridinium tosylate for 15 minutes at 55°C bath temperature. After adding a few drops of pyridine, the solvent was evaporated in vacuo. The residue was chromatographed on 50 g silica gel with n-hexane/acetic ester. 210 mg of 110-(4-dimethylaminophenyl)-170-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one were isolated as a solid foam.

Example 12

17a-(3-acetoxyprop-1(Z)-enyl)-110-(4-dimethylaminophenyl)-170- hydroxy- 4, 9( 10 )- estradiene- 3- one

1.1 g of 110-(4-dimethylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one was stirred for 3 hours in 20 ml pyridine and 10 ml acetic anhydride at room temperature

trip and under protective gas. For the work-up, the reaction mixture was stirred into an ice/water mixture and extracted with acetic acid. The organic phase was washed with NaHCO 3 solution and water and dried over Na 2 SO 3 . After evaporation, the residue was chromatographed on silica gel with n-hexane/acetic ester. 1.15 g of 17α-(3-acetoxyprop-1(Z)-enyl)-HØ-(4-dimethyl-aminophenyl)-173-hydroxy-4,9(10)-estradien-3-one were obtained as a lemon-yellow, firm foam.

[o]D (CHCl 3 ) = +197°.

Example 13

173~hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-II3-(4-trimethyl-silylphenyl)- 4, 9( 10)- estradiene- 3- one

Preparation of p-bromotrimethylsilylbenzene

94.4 g of p-dibromobenzene was cooled in 400 ml of absolute ether to -20°C under argon. 255 ml of 15% butyllithium in hexane was added dropwise in such a way that the temperature did not exceed -10°C. The mixture was then stirred for a further 1 hour at room temperature. After a negative Gilman test [H. Gilman, J. Swiss, J. Amer. Chem. Soc. 6_2, 1847

(1940)], the mixture was cooled to -20°C and 46 ml of trimethylchlorosilane in 200 ml of absolute ether was added dropwise so that the temperature did not exceed -10°C. After the addition was complete, the reaction mixture was stirred for 16 hours at room temperature and for 1 hour under reflux. The precipitate formed was separated and washed thoroughly with ether. The filtrate obtained was evaporated and then distilled in a water jet vacuum. 65.52 g of p-bromotrimethylsilylbenzene with a boiling point (16 torr) of 103-110°C were obtained.

a) To a suspension of 4.86 g magnesium and 0.1 ml methyl iodide in 30 ml absolute tetrahydrofuran was added under argon

a solution of 45.84 g of p-bromotrimethylsilylbenzene in 50 ml of absolute tetrahydrofuran in such a way that the temperature during the course of the reaction did not exceed +45°C. After complete dissolution of the magnesium, the reaction mixture was cooled to

-20°C, added 2 g copper chloride and stirred for 15 minutes. There-

after, a solution of 19.49 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5α,10α-epoxy-17α-[3-(tetrahydropyran-2-yloxy)-prop-1- ynyl]-9 ( 11 )-estren-170-ol in 130 ml of absolute tetrahydrofuran added dropwise at -20°C. After finishing addition got. the reaction mixture warmed to room temperature and was stirred for an additional 2 hours. For the work-up, the reaction mixture was poured into 200 g ice/20 ml saturated ammonium chloride solution and was extracted with acetic acid. The organic phases were washed neutral with water and were dried over sodium sulfate. The evaporated residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 21.8 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-17a-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-110-(4- trimethylsilylphenyl)-9(10)-estrene-5a,170-diol as a colorless solid foam.

b) 2.2 g of the product obtained in a) was hydrogenated in 50 ml of ethanol and 2.2 ml of triethylamine under normal conditions

while adding 0.22 g of palladium/BaSO 4 (10%). After absorption of 74 ml of hydrogen, the hydrogenation was terminated, the catalyst was filtered off, the solution was evaporated, and the residue was chromatographed with n-hexane/acetic ester on Al 2 O 3 (III, neutral). 1.62 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-17a-[3-(tetrahydropyran-2-yloxy)-prop-1(Z)-enyl]-110- (4-trimethylsilylphenyl)-9(10)-estrene-5α,170-diol as a colorless solid foam.

<1>H-NMR (CDC13): 7.5-7.15 ppm (qu., 4H, arom. CH, JAB = 5 Hz)'

c) 5.98 g of the product obtained in b) was stirred in 50 ml of 70% acetic acid for 3 hours at 50°C. Because the preparation was

the reaction mixture poured into 50 g ice/50 ml concentrated aqueous ammonia solution and extracted with acetic acid. The organic phases were washed neutral with water and dried over sodium sulfate. The evaporated, impure product was chromatographed on silica gel with n-hexane/acetic ester. 3.08 g of 170-hydroxy-17α-(3-hydroxy-prop-1(Z)-enyl)-110-(4-

trimethylsilylphenyl)-4,9(10)-estradien-3-one as colorless crystals with m.p. 198-201°C.

[<xJD (CH 3 OH) = +189.3°

Example 14

170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-110-phenyl-4,9(10)-estradien-3-one

a) To a suspension of 2.43 g of magnesium and 0.015 ml of methyl iodide in 30 ml of absolute tetrahydrofuran was added under argon

added dropwise 15.7 g of bromobenzene in 70 ml of absolute tetrahydrofuran in such a way that the internal temperature did not exceed +45°C. After complete dissolution of the magnesium, 0.54 g of copper chloride was added to the reaction mixture at +5°C and stirred for 15 minutes. A solution of 18.4 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5a,10a-epoxy-17a-[3-(tetrahydropyran-2-yloxy)-prop was then added dropwise -1-ynyl]-9(11)-estren-170-ol in 100 ml of absolute tetrahydrofuran, and the mixture was stirred for 16 hours at room temperature.

For the work-up, the reaction mixture was poured into a mixture of 20 g ice/20 ml saturated ammonium chloride solution and was extracted with acetic acid. The organic phases were washed neutral with water and dried over sodium sulfate. The evaporated residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 21.1 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-110-phenyl-17a-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-9 were obtained (10)-Oestrene-5α,170-diol as a colorless solid foam.

b) 3 g of the product obtained in a) was hydrogenated in 150 ml of absolute ethanol and 3 ml of triethylamine under normal conditions and with the addition of 0.3 g of palladium/BaSO4 (10%). After absorption of 112 ml of hydrogen, the hydrogenation was terminated, the catalyst was filtered off, and the solution was evaporated. The residue was chromatographed on Al 2 O 3 (III, neutral) with n-hexane/acetic ester. 2.18 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-110-phenyl-17a-[3-(tetrahydropyran-2-yloxy)-prop-1(Z)-enyl were obtained ]-9(10)-estrene-5α,170-diol as color

loose, firm foam.

<1>H-NMR (CDC13): 7.13 ppm (s, 5H, arom. CH), 90 MHz

c) 2.18 g of the compound obtained in b) was dissolved in 50 ml of 70% acetic acid and stirred at room temperature for 24 hours.

The processing took place by introduction into 50 g ice/50 ml concentrated, aqueous ammonia solution and extraction with vinegar. After the organic phases had been washed neutral with water and dried over sodium sulfate, these were chromatographed after evaporation on silica gel with n-hexane/20-50% acetate. 0.43 g of 170-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-110-phenyl-4,9(10)-estradien-3-one were obtained as colorless crystals with mp, 245- 247°C.

[α]D (CHCl 3 ) = +148.1°

Example 15

110-(4-N-formyl-N-methylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one

3.15 g of the product obtained in 3a) was dissolved under argon in 60 ml of absolute tetrahydrofuran and, at a temperature of -20°C, 0.9 ml of acetic acid-formic anhydride was added dropwise under the exclusion of moisture. After a reaction time of 1 hour at room temperature, the solution was stirred into 60 g of ice/5 ml of concentrated, aqueous ammonia solution and extracted with acetic acid. The organic phase was washed neutral with water, dried over sodium sulfate and evaporated. The residue obtained was stirred with 100 ml of 70% acetic acid for 3 hours at 50°C. The solution was then poured into 100 g ice/100 ml concentrated aqueous ammonia solution and extracted with methylene chloride. The organic phases were washed neutral with water and dried over sodium sulfate, evaporated, and the residue was chromatographed on silica gel with methylene chloride/acetone. 1.84 g of 110-(4-N-formyl-N-methylaminophenyl)-170-hydroxy-17c-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3 were obtained -on.

[o]D (CH 3 OH) = +185.7°

Example 16

110-(4-N-acetyl-N-methylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one

3.15 g of the product obtained in 3a) was dissolved in 40 ml of absolute pyridine under argon. At +5°C, 0.41 ml of acetyl chloride was added dropwise to the solution in such a way that the temperature did not exceed +10°C. The reaction mixture was stirred for a further 1 hour at +5°C, then poured into 80 g ice/40 ml concentrated hydrochloric acid and extracted with methylene chloride. The organic phases were dried over sodium sulfate and evaporated, and the residue obtained was stirred in 100 ml of 70% acetic acid for 3 hours at 50°C. For the preparation, the solution was poured into 100 g of ice/100 ml of concentrated, aqueous ammonia solution and was extracted with methylene chloride. The organic phases were washed neutrally with water and dried over sodium sulfate. After evaporation, the residue was chromatographed on silica gel with methylene chloride/20-50% acetone. 1.8 g of 110-(4-N-acetyl-N-methylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3 were obtained -on.

[α]Q (CH 3 OH) = +156.4°

Example 17

110-(4-formylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one

1.2 g of the product obtained in 4b) was dissolved in 40 ml of absolute tetrahydrofuran and, at a temperature of -20°C and with the exclusion of moisture, 0.52 ml of acetic acid/formic anhydride was added. After a 30-minute reaction time, the solution was poured into 30 g of ice/5 ml of concentrated, aqueous ammonia solution and extracted with acetic acid. After drying over sodium sulfate, the crude product was dissolved in 50 ml of 70% acetic acid and stirred at 50°C for 3 hours to effect saponification. For the work-up, the reaction mixture was poured into 50 g of ice/50 ml of concentrated, aqueous ammonia solution and was extracted with methylene chloride. After drying over sodium sulfate, the solution was evaporated, and the residue was chromatographed on silica gel with methylene chloride/30-100% acetone. 0.6 2 g was obtained

110-(4-formylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one.

[α]D (CH 3 OH) = +193.7°

Example 18

1113-(4-acetylaminophenyl)-170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one

1.6 g of the product obtained in 4b) was dissolved in 40 ml of absolute pyridine under argon. At +5°C, 0.21 ml of acetyl chloride was added dropwise to the solution in such a way that the temperature did not exceed +10°C. After stirring for 4 hours at room temperature, the solution was introduced into 50 g of ice/40 ml of concentrated hydrochloric acid and extracted with methylene chloride. After drying over sodium sulfate, the impure product obtained was stirred with 70 ml of 70% acetic acid at 50°C for 3 hours. For the preparation, the solution was poured into 70 g of ice/70 ml of concentrated, aqueous ammonia solution and was extracted with methylene chloride. The organic phase was dried over sodium sulfate, evaporated, and the residue obtained was chromatographed on silica gel with methylene chloride/50-100% acetone. 0.97 g of 110-(4-acetylaminophenyl)-170-hydroxy-17α-(3-hydroxyprop-1(Z)-enyl)-4,9(10)-estradien-3-one was obtained.

[α] (CH 3 OH) = +196°

Example 19

110-(4-dimethylaminophenyl)-17aØ-hydroxy-17aa-(3-hydroxyprop-1( Z)-enyl)- D- homo- 4, 9, 16- estratriene- 3- one

a) A solution of 22.4 g of D-homo-4,9,16-estratriene-3,17a-dione in 225 ml of methylene chloride was successively added to 22.4 g

2,2-dimethylpropane-1,3-diol, 11.2 ml of ortho-formic acid trimethyl ester and 20 mg of p-toluenesulfonic acid. The reaction mixture was stirred for 2.5 hours at room temperature, diluted with 150 ml of methylene chloride, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated. The oily residue was chromatographed over Al 2 O 3 (neutral, III) with hexane/acetate. After recrystallization of the main fraction from diisopropyl ether, 19.1 g of 3,3-(2,2-dimethyl-

propan-1,3-dioxy)-D-homo-5(10),9(11)-16-estratrien-17a-one with m.p. 154-156°C.

b) To a solution of 19.1 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-D-homo-5(10),9(11)-16-estratrien-17a-one in 75 ml

methylene chloride, 0.6 ml hexachloroacetone and 0.1 ml pyridine were added dropwise under ice-water cooling to 7.6 ml 30% Ho02> The reaction mixture was stirred for 16 hours at room temperature, diluted with 100 ml methylene chloride, washed with 5% Na2S203 solution and evaporated . The thus obtained mixture of 5a,10a-epoxide and 53,100-epoxide was separated by chromatography on

A1203 with hexane/acetic acid. After crystallization from ethyl acetate/diisopropyl ether, 9.7 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5α,10α-epoxy-D-homo-9(11),16-estra- dien-17a-one with m.p. 188-191°C.

c) To a solution of 9.24 g of 3-(tetrahydropyran-2-yloxy)-1-propyne in 183 ml of absolute tetrahydrofuran at 0°C and below

protective gas was added dropwise to 53 ml of n-butyllithium/n-hexane (1.6 mol/l), and the mixture was stirred for 15 minutes. Then a solution of 9.1 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5α,10α-epoxy-D-homo-9(11),16-estradien-17α-one in 183 ml of absolute tetrahydrofuran was added dropwise, and the reaction mixture was stirred for 3 hours at 0°C. For the work-up, the reaction mixture was carefully added to ice/water and extracted with vinegar. The organic phases were washed with water, dried over sodium sulfate, added with active carbon, filtered over "Celite" and evaporated. 17.4 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-5a,10a-epoxy-17a3-hydroxy-17aa-[3-(tetrahydropyran-2-yloxy)-prop -1-ynyl]-D-homo-9(11),16-estradiene as a yellowish oil which was used in the next step without further purification.

d) To a suspension of 2.27 g of magnesium and 0.05 ml of methyl iodide in 42 ml of absolute tetrahydrofuran was added dropwise

a solution of 24.8 g of 4-bromo-N,N-dimethylaniline in 124 ml of absolute tetrahydrofuran in such a way that the temperature below

the course of the reaction did not exceed 45°C. To effect complete dissolution of the magnesium, the reaction mixture was stirred for a further 1 hour, after which it was cooled to 0°C, 480 mg of cuprous chloride was added and stirred for 15 minutes. Then a solution of 17.4 g of the impure product obtained in c) in 83 ml of absolute tetrahydrofuran was added dropwise,

and the reaction mixture was stirred for 5 hours at room temperature. For the work-up, the reaction mixture was poured into ice water, acetic acid was added, filtered over "Celite", and the filtrate was extracted with acetic acid. The organic phases were washed neutral with water, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on Al 2 O 3 (neutral, III) with hexane/acetic ester. 10.8 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-113-(4-dimethylaminophenyl)-17aa-[3-(tetrahydropyran-2-yloxy)-prop-1 were thus obtained -ynyl]-D-homo-9(10),16-estradien-5α,17α3~diol as pale yellow oil.

e) 10.8 g of the product obtained in d) was hydrogenated in 182 ml of tetrahydrofuran and 5.3 ml of pyridine under normal conditions and with the addition of 1.1 g of palladium/BaSO 4 (10%). After uptake of 410 ml of hydrogen, the hydrogenation was terminated, the hydrogenation mixture was filtered over "Celite" and evaporated. The impure product thus obtained was then taken up in 55 ml of 70% acetic acid and was stirred for 1 hour at 60°C under protective gas. For the work-up, the reaction mixture was poured into ice water after cooling, was adjusted to pH 10-11 by the careful addition of concentrated, aqueous ammonia solution and was extracted with acetic acid. The acetic ester phases were washed neutral with water, dried over sodium sulfate, filtered and evaporated. From the residue, 5.1 g of 113-(4-dimethylaminophenyl)-17a3~hydroxy-17aa-(3-hydroxyprop-1(Z)-enyl)-D-homo-4 was obtained by chromatography on silica gel with hexane/acetic ester. 9,16-Estratrien-3-one as a lemon yellow solid foam. UV (CH 3 OH) : = 205 nm (36,800), 259 nm (17,400), 304 nm (21,500). Example 20 170-hydroxy-17a-(3-hydroxyprop-1 (Z)-enyl)-110-(4-methoxyphenyl)-4,9(10)-østradien-3-one a) To a suspension of 970 mg magnesium and 0.01 ml of methyl iodide in 10 ml of absolute tetrahydrofuran was added dropwise under argon to a solution of 7.46 g (5 ml) of p-bromoanisole in 5 ml of absolute tetrahydrofuran in such a way that the temperature during the course of the reaction did not exceed 45°C. After complete dissolution of the magnesium, the solution was cooled to 0°C, and 400 mg of cupric (I) chloride was added. The reaction mixture was stirred for 15 minutes at 0°C and then a solution of 3.9 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5a,10a-epoxy-17a-[3 -(tetrahydropyran-2-yloxy)-prop-1-ynyl]-9(11)-estren-170-ol in 20 ml of absolute tetrahydrofuran. After the addition was complete, the reaction mixture was stirred at room temperature overnight. For the work-up, the reaction mixture was poured into 40 g of ice/10 ml of concentrated ammonium chloride solution and was extracted with acetic acid. The organic phases were washed with water and dried with sodium sulfate. Then the solution was filtered, evaporated> and the residue was chromatographed on Al 2 O 2 (III, neutral) with n-hexane/acetic ester. 4.1 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-110-(4-methoxyphenyl)-17a-[3-(tetrahydropyran-2-yloxy)-prop-1- ynyl]-9(10)-estrene-5α,170-diol as a colorless solid foam. b) 4.1 g of the product obtained in a) was hydrogenated in 50 ml of ethanol and 4 ml of pyridine under normal conditions in the presence of 400 mg of palladium/BaSO4 (10%). After absorption of 150 ml of hydrogen, the hydrogenation was interrupted, the catalyst was filtered off, and the residue was chromatographed on Al.03 (III, neutral) with n-hexane/acetic ester. 3.6 g of 3,3-(2,2-dimethyl-propan-1,3-dioxy)-110-(4-methoxyphenyl)-17a-[3-(tetrahydro-pyran-2-yloxy)- prop-1(Z)-enyl]-9(10)-estrene-5α,170-diol as a colorless solid foam. <1>H-NMR (CDCl 3 ) : = 7.05; 6.75 ppm (dd, 4H, arom. CH, J=8 Hz) 90 MHz 5.8-5.5 (m, 2H, -CH=CH-, Jcig = 12 Hz) 3.75 (s, 3H , -0CH3) c) 3.5 g of the product obtained in b) was stirred in 50 ml of 70% acetic acid and under protective gas for 2 hours at 50°C.

For the work-up, the reaction mixture was stirred into 50 g of ice/50 ml of concentrated aqueous ammonia gas and was extracted with methylene chloride. The organic phases were washed neutral with water, dried over sodium sulfate, filtered and evaporated. By chromatography of the residue on silica gel with n-hexane/acetic ester, 2.2 g of 170-hydroxy-17a-(3-hydroxyprop-1 (Z)-enyl)-11(3-(4-methoxyphenyl)-4 , 9 (10) -ø stradien-3-one as light yellow, solid foam.

-"-H-NMR (CDCl 3 ) : = 7.03; 6.75 ppm (dd, 4H, arom. CH, J = 8 Hz) 5.8-5.6 (m, 2H, -CH=CH- , Jcis = 12.5 Hz)

3.77 (s, 3H, -OHCH3)

[α]D (CHCl 3 ) = +178°

Example 21

170-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-113-(4-methyl-mercaptophenyl)-4,9(10)-estradien-3-one

a) To a suspension of 486 mg magnesium and 0.01 ml methyl iodide in 10 ml absolute tetrahydrofuran was under argon

added dropwise 4.06 g of 4-bromothioanisole in 10 ml of absolute tetrahydrofuran in such a way that the temperature during the course of the reaction did not exceed 45°C. After complete dissolution of the magnesium, the reaction mixture was cooled to 0°C, and 100 mg of cupric (I) chloride was added. After a further 15 minutes of stirring, a solution of 3.68 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-5a,10a-epoxy-17a-[3-(tetrahydropyran-2-yloxy) was added dropwise )-prop-1-ynyl]-9(11)-estren-173-ol in 20 ml of absolute tetrahydrofuran, and the reaction mixture was stirred overnight at room temperature. For the work-up, the reaction mixture was poured into 40 g of ice/40 ml of concentrated ammonium chloride solution and was extracted with acetic acid. The organic phases were washed neutral with water, dried over sodium sulfate, filtered, evaporated, and the residue was chromatographed on Al 2 O 2 (III, neutral) with n-hexane/ethyl acetate. 3.41 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-113-(4-methylmercaptophenyl)-17a-[3-(tetrahydropyran-2-yloxy)-prop-1 were thus obtained -ynyl]-9(10)-estrene-5α,173-diol as a colorless solid foam.

b) 3.41 g of the product obtained in a) was hydrogenated in 50 ml of ethanol and 4 ml of pyridine under normal conditions in the presence

of 350 mg palladium/BaSO4 (10%). After absorption of 125 ml of hydrogen, the hydrogenation was interrupted, the catalyst was filtered off, and the residue was chromatographed on AlO03 (III, neutral) with n-hexane/acetic ester. 3.04 g of 3,3-(2,2-dimethylpropan-1,3-dioxy)-113-(4-methylmercapto-phenyl)-17a-[3-(tetrahydropyran-2-yloxy)-prop- 1(Z)-enyl]-9(10)-estrene-5α,173-diol as a colorless solid foam.

<1>H-NMR (CDC13): S = 7.05 ppm (s, 4H, arom. CH), 90 MHz 5.75-5.5 (m, 2H, -CH=CH-, Jc±s = 12 Hz)

2.36 (s, 3H, ~SCH3)

c) 2.9 g of the product obtained in b) was stirred in 40 ml of 70% acetic acid and under protective gas for 2 hours at 50°C.

For the work-up, the reaction mixture was poured into 40 g of ice/40 ml of concentrated, aqueous ammonia solution and extracted with methylene chloride. The organic phases were washed neutral with water, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed with n-hexane/acetic ester on silica gel. 1.58 g of 173-hydroxy-17a-(3-hydroxyprop-1(Z)-enyl)-113-(4-methylmercaptophenyl)-4,9(10)-estradien-3-one were thus obtained as pale yellow, solid foam.

<1>H-NMR (CDC13): = 7.03 ppm (s, 4H, arom. CH)

5.8-5.5 (m, 2H, -CH=CH-, Jc±s<=><1>2 Hz)

2.35 (s, 3H, -SCH3)

Claims (2)

1. Analogy method for the preparation of therapeutic active llg-aryl-estradienes of general formula I in which R^" denotes in which R<1> and R<11> denote hydrogen, alkyl of 1 to 4 carbon atoms or alkanoyl of 1 to 8 car bon atoms, or where R1 and R11 together with N denote one piperidine or pyrrolidine ring, as well as the corresponding ones acid addition salts, or where R<1> and R<11> together with N can pray draw an optionally methyl-substituted pyrrole ring, -OR11"1" in which R"*"11 denotes hydrogen, methyl, ethyl or propyl, -SR<IV> in which RIV denotes hydrogen, methyl, ethyl or propyl, "R 3 denotes a hydrogen atom or an alkanoyl group with 1 more 8 carbon atoms, and wherein R 4 denotes alkyl with 1 to 4 carbon atoms in a or Ø position, and R^ denotes an E or Z configured alkylidene group, and the C20/C21 double bond out shows a Z or E configuration, characterized in that in a compound of general formula II wherein A is equal to C<=>C-CH2OR or CH=CH-CH2OR and R<1> and have the meanings given for formula I, Z denotes an ethylene or 2,2-dimethyltrimethylene group, and R denotes a hydrogen atom or an organic group that is easily cleavable in an acidic environment or hydrogenolytically, in the presence of a deactivated noble metal catalyst, the acetylenic triple bond hydrogenates to the Z-configured <^ 20^ C2l~ double bond, or that the acetylenic triple bond is reduced in a manner known per se to the E-configured C2o/C21~ double bond, and that then, under the influence of dilute acid, a pyridinium salt of a strong acid or an acidic ion exchanger, cleavage of the 3-ketal protection, removal of any acid-cleavable protecting group R, and water splitting to form 4,9(10 )-dien-3-one system, and optionally that a free 22-hydroxy group is then acylated. 2. Process according to claim 1 for the production of IIP-(4-dimethylaminophenyl)-173-hydroxy-17a-(3-hydroxyprop-1 (Z)-enyl-4,9(10)-estradien-3-one, characterized by the fact that corresponding starting material is used.