DE2449327A1 - 7-Hydroxy-17-alpha-hydrocarbyl-oestradiol derivs - prepd by 17-alkylating 7-hydroxy-oestrone derivs - Google Patents

Abstract

Oestradiol derivs. of formula (I) (where R1 is H, acyl, alkyl, cycloalkyl or an O-contg. satd. heterocyclic gp; R2 and R3 are H, acyl or an O-contg. satd. heterocyclic gp; and R4 is an opt. unsatd. lower hydrocarbon gp. which is unsatd. can be substd. by Cl; and OR2 can be in the alpha- or beta-posn) e.g. 17alpha-ethynyl-1,3,5(10)-oestratriene-3,7alpha,17beta-triol are new cpds. (I) are oestrogens with a favourably dissociated pharmacological action. they have a strong vaginotropic effect but a weak uterotropic effect and are therefore suitable for the treatment of oestrogen deficiency disorders (e.g. the postmenopausal syndrome in women) in which a centrally mediated effect on the uterus should be avoided but an effect on the vagina is desirable. (I) are also useful as inters. for other pharmacologically valuable steroids.

Description

7-Hydroxy-estradiols The invention relates to 7-hydroxy-estradiols of the general formula I wherein OR2 is in α or β position, R1 is a hydrogen atom, an acyl, alkyl, cycloalkyl or oxygen-containing saturated heterocyclic group, R2 and R3 are identical or different and a hydrogen atom, an acyl or oxygen-containing saturated heterocyclic group and R4 denote a saturated or unsaturated lower hydrocarbon radical, where the unsaturated hydrocarbon radical can also be substituted by chlorine.

The acyl radicals are those from physiologically acceptable acids in question. Preferred acids are organic carboxylic acids with 1-15 carbon atoms, those of the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These acids can also be saturated and / or polybasic and / or substituted in the usual way. As examples of the Substituents are alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms mentioned.

The following carboxylic acids may be mentioned as examples: formic acid, Acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, Caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, Lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethyl acetic acid, Diethyl acetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, Cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, mono-, di- and trichloroacetic acid, Aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, Lactic acid, succinic acid, adipic acid, beneoic acid, nicotinic acid, isonicotinic acid, Buran-2-carboxylic acid.

The alkyl radicals R1 are preferably lower alkyl radicals having 1-5 carbon atoms into consideration, which can be substituted or branched in the usual way. as Examples of the Substituents are halogen atoms or lower alkoxy groups called. The methyl and ethyl groups are particularly preferred.

Cycloalkyl groups include, for example, those with 3-8 carbons Substance atoms into consideration, of which the cyclopentyl group is preferred.

Such heterocyclic radicals can be used as saturated oxygen-containing radicals in question that differ from heterocycles with at least one oxygen atom in the ring derive and which are perhydrated in the oxygen atom-containing ring. Be mentioned the tetrahydrofuryl and the tetrahydropyranyl radical, of which the tetrahydropyranyl radical is preferred.

The hydrocarbon radicals R4 are alkyl, alkenyl or alkynyl groups with up to 5 carbon atoms, examples include the methyl, Ethyl, propyl, butyl, pentyl, vinyl, ethynyl, propynyl and butadiynyl radical. The unsaturated hydrocarbon radical can also be substituted by chlorine.

Preferred hydrocarbon radicals R4 are the xthinyl and chloroethinyl radicals.

The compounds according to the invention have a favorable dissociation pharmcological effectiveness. Because of the strongly vaginotropic and weakly uterotropic Effect, they are particularly suitable for the treatment of postmenopausal women.

So they can be used to treat estrogen deficiency symptoms in which a centrally controlled effect on the uterus is avoided but an effect on the vagina is desired. The compounds according to the invention are also pharmacologically more valuable as intermediates for manufacture Steroids useful.

The favorable estrogenic dissociation can be seen, for example, in the sialic acid test in the mouse both after oral and subcutaneous administration.

Thus, the compounds according to the invention, as shown in Table 1 on Example of 17α-ethynyl-1,3,5 (10) -estratriene-3,7α, 17β-triol shown is, a dissociation quotient that of the standard substances estradiol and 17a-ethynyl-estradiol far exceeds.

Table 1 Compound threshold value [mg] relative effectiveness dissociation vagino-utero-quotient po trop trop po Estradiol 0.05-0.1 1 1 1 17α-ethynyl estradiol 0.01 9.1 10.9 0.9 17α-ethynyl-1,3,5 (10) -estratria- 3.7α, 17β-triol 0.03 0.898 0.099 9.1 The sialic acid test is carried out as follows: The mice are ovariectomized. From the 10th day after the castration, the animals are given the substance to be tested po once a day for 3 days. On the 4th day, the animals are sacrificed. The vagina and uterus are dissected out immediately and weighed into a test tube for hydrolysis. The sialic acid is determined according to Svennerholm rSiochem. Biophys. Acta 24 (1957) 604J. The dose-dependent increase in the organ weights of the vagina and uterus as well as the decrease in the sialic acid content are determined, from which the relative potency of the substance to be tested compared to the standard substance estradiol is determined.

The relative efficacies are put in relation and result the degree of dissociation Q. For the standard compound is estradiol Q = 1. Connections with Q 1 are relatively vaginotropic, with Q <1 they are relatively uterotropic.

The threshold values given in Table 1 were determined using the standard Allen-Doisy test determined on rats.

The invention also relates to medicaments, the 7-hydroxyestradiols of the general formula I contain as active ingredient.

The production of the drug specialties takes place in the usual way Way, by mixing the active ingredients with those commonly used in galenic pharmacy Carriers, diluents, flavoring agents, etc. in the desired Application form, such as tablets, coated tablets, capsules, solutions, etc., transferred.

The active ingredient concentration in the pharmaceuticals formulated in this way is depending on the form of application. Thus, a tablet preferably contains from 0.01 to 10 mg; Solutions for parenteral administration contain 0.1 to 20 mg / ml solution.

The dosage of the medicament according to the invention can vary with the Change the form of administration and the respective selected connection. About that In addition, it can change according to the person being treated. Generally will the compounds according to the invention administered in a concentration which is effective Can produce results without causing any adverse or harmful Cause side effects; for example, they are administered at a dose level which ranges from about 0.02 mg to about 20 mg, although under certain circumstances Modifications can be made so that a dose level of more than 20 mg, for example up to 50 mg is used. However, a dose level will be in the range from about 0.05 mg to about 5 mg is preferably used.

The invention also relates to a process for the preparation of the 7-hydroxy-estradiols of the general formula I, which is characterized in that a) a 7-hydroxy-estrone of the general formula II in which R1 and R2 have the meaning given above, alkylated by methods known per se, if desired an unsaturated la-alkyl group hydrogenated and, depending on the ultimately desired meaning of R1, R2 and R3 in the end product, optionally splitting off ether or acyl groups and / or free hydroxyl groups etherified and / or esterified or b) for the preparation of 7a-OR2 compounds of the general formula I a 17a-R4-estradiol of the general formula III in which R1 and R4 have the meaning given above, fermented with a fungal culture of the genera Absidia, Aspergillus, Rhizopus, Pellicularia or Diplodia and, depending on the ultimately desired meaning of R1, -R2 and R3 in the end product, optionally etherified one or more hydroxyl groups and / or esterified.

The alkylation can by known methods with an organometallic Compound are carried out in which the means organic radical R4 H d in the it is an alkyl magnesium halide such as methyl magnesium bromide or aodide, an alkenyl magnesium and / oZer alkenyl zinc halide, such as vinyl magnesium bromide or allyl magnesium bromide, an alkynyl magnesium halide, such as ethynyl magnesium bromide, Propynyl magnesium bromide or propynyl zinc bromide, or an alkali metal acetylide, like potassium acetylide, can act.

The organometallic compound used as an alkylating agent can also be formed in situ and caused to react with the 17-eetone of the formula II will. For example, it is allowed to react with organometallic alkynyl compounds on the ketone in a suitable solvent an alkyne, chloroalkyne or alkadiyne and an alkali metal, preferably in the presence of a tert. Alcohol or ammonia, act under increased pressure if necessary.

The unsaturated 17a-alkyl radicals can be converted into the convert corresponding 17a-alkenyl or saturated 17a-alkyl steroids. This hydrogenation is known to be preferably carried out in such a way that one steroids with unsaturated Reacts 17a-alkyl radical with hydrogen in the presence of a hydrogenation catalyst. Palladium catalysts, for example, can be used as hydrogenation catalysts or Platinum oxide catalysts, optionally on supports, can be used.

7α-OH compounds of general formula I can also on obtained microbiologically from la-R4-estradiol of the general formula III will. The 7a-hydroxylation succeeds with fungal cultures of the genera Absidia, Aspergillus, Rhizopus, Pellicularia and Diplodia. Suitable strains are, for example, Absidia orchidis (ADCC 8990), Aspergillus luchuensis (CBS), Rhizopus nigricans (ATCC 6227b), Pellicularia filamentosa (ATCC 13 289), Diplodia natalensis (ATCC 9055), Rhizopus oryzae (ATCC 4858), Rhizopus kazanensis (ATCC 8998), Rhizopus cohuii (ATCC 8996), Rhizopus shanghaiensis (ATCC 10 329), Rhizopus stolonifer (ATCC 10 404), The carrying the fermentation takes place under the same conditions as with the known ones uses fermentative conversions of steroids with fungal cultures. Preferably will the fermentative hydroxylation of the compounds of general Formula III in submerged cultures of the abovementioned strains under aerobic conditions carried out. For this purpose, the fungal cultures are aerated in a nutrient medium, the carbohydrates, proteins and nutrient salts required for the growth of the mushrooms and contains growth substances. After cultivation is done, the cultures are set the substrate as an aqueous suspension or in a suitable solvent such as methanol, Ethanol, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide, dissolved too and fermented until the reaction has ended. The transformation of the substrate will be expediently by thin-layer chromatographic analysis of sample extracts tracked. As with all known microbiological conversions of steroids, this is how the optimal substrate concentration is also in the method according to the invention and the optimal fermentation time on the specific structure of the substrate and depends on the fermentation conditions themselves and must by means of the one skilled in the art common preliminary tests can be determined.

After fermentation, the fermentation products are in on known way. isolated. The isolation can be done, for example, in the way that the fermentation batches with a polar, water-insoluble solvent, such as ethyl acetate, butyl acetate or methyl isobutyl ketone, extracted, the Extracts concentrate and the crude products obtained in this way, optionally by chromatography and / or crystallization cleans.

Free hydroxyl groups can then be esterified or etherified. Esterified or etherified hydroxyl groups can be converted into the free hydroxyl groups will.

For the esterification, they usually come in steroid chemistry applied procedure in question. Since the hydroxyl groups are in the 3-, 7- and 17-positions have different reactivities, the hydroxyl groups may be gradual be esterified.

Depending on the choice of reaction conditions, one arrives at the 3-mono-, 3,7-di- or 3,7,17-triacyl compounds. The acylation takes place in the 3- and 7-positions preferably with pyridine / acid anhydride or pyridine / acid halide at room temperature. If the acylation is terminated after about 0.3 to 1 hour at a low temperature, if the 3-monoacyl compound is obtained, on the other hand, the acylation takes several hours continued, the 3,7-diacyl compound is formed.

For esterification of the 17β-hydroxy group in 3,7-diesters one leaves on the steroid, for example, acid anhydrides in the presence of strong acids such as p-toluenesulfonic acid or perchloric acid at room temperature or pyridine / acid anhydride in the heat.

These methods can also be used to remove the free trihydroxy compound to be converted directly into the triacrylate.

The triacylates can be obtained by gentle partial saponification the 3-hydroxy group are released.

The trihydroxy compound as well as the mono- and diesters can with dihydropyran in the presence of a strong acid, such as p-toluenesulfonic acid, into the corresponding Tetrahydropyranylether are transferred. From 3-monoacyl- or 3,7-diacyl-7,17- or

17-tetrahydropyranyl ethers can, through alkaline saponification, die 3- or 3,7-hydroxyl groups are released.

The cleavage of tetrahydropyranyl ethers takes place under mild conditions with the addition of acid, for example with oxalic acid in methylene chloride and methanol in the boiling heat.

The etherification with an alkyl or cycloalkyl radical in the 3-position is preferably with an appropriate halide in the presence of a weak Base such as potassium carbonate, sodium carbonate, etc.

carried out in alcoholic solution at boiling temperature.

Connections etherified in the 3-position can then in the 7-position and 17-position esterified or reacted with dihydropyran.

Example 1 (microbiological 7a-hydroxylation) A 2 l Erlenmeyer flask, the 500 ml of a nutrient solution sterilized in an autoclave at 1200 C for 30 minutes 3% glucose, 1% corn steep, 0.2% NaN03, 0.1% KH2PO4, 0.2% K2HP04, 0.05% MgSO4, Containing 0.002% FeSO4 and 0.05% KCl is made with a lyophil culture from Diplodia natalensis (ATCC 9055) and 72 hours at 300 C on a rotary shaker shaken. With this preculture, a 20 l fermenter is then used, which is filled with 15 l of a at 12100 and 1.1 atm sterilized medium of the same composition as that Preculture is filled, inoculated. With the addition of Silicon SH as an antifoam agent is at 290 C with aeration (10 1 / min.), 0.7 atmospheric pressure and stirring (220 rpm.) Germinated for 24 hours. 1 liter of the culture broth is stored under sterile conditions in 14 1 of a nutrient medium of the same composition sterilized as above and grown under the same conditions. After 12 hours, a sterile-filtered A solution of 3 g of ethinyl estradiol in 100 ml of dimethyl sulfoxide was added.

The course of the conversion is carried out by thin layer chromatography Analysis of methyl isobutyl ketone extracts from fermenter samples followed. After complete Conversion (45 hours of contact time) the fermenter content is twice with 10 1 Stirring out methyl isobutyl ketone and the extract at a bath temperature of 500 ° C. in vacuo evaporated.

The residue is dissolved in methanol to remove the antifoam taken up, the silicone oil separated in a separating funnel, the solution then filtered through a fluted filter and again evaporated to dryness. The left behind The crude product is now dissolved in methylene chloride and purified over a silica gel column chromatographed by means of a solvent gradient methylene chloride-methylene chloride / acetone. After crystallization from ethyl acetate, the pure white 17α-ethynyl-1,3,5 (10) -estratriene-3,7α, 17β-triol melts at 234-235 ° C (decomposition). C20H24O3 (MW 312.4).

Example 2 500 mg of 17α-ethynyl-1,3,5 (10) -estratriene-3,7α, 17β-triol are dissolved in 10 ml of pyridine, 0.5 ml of acetic anhydride is added and taken for 20 minutes Ice cooling stirred. The solution is then cooled in 100 ml of 8% strength sulfuric acid stirred in and the precipitate which has separated out is washed neutral. After drying it is recrystallized from ether / hexane and pure 3-acetoxy-17a-ethinyl-1,3,5 (10) -estratriene-7a, 17ß-diol is obtained from melting point 133-1350C.

Example 3 The suspension of 3.7 g of potassium tert-butoxide in Acetylene is passed in at -100C for 1 hour at 20 ml of absolute tetrahydrofuran (THF). A solution of 500 mg is added dropwise to the resulting pulpy mass while stirring 3,7a-Dihydroxy-1,3,5 (10) -estratrien-17-one, dissolved in 45 ml of absolute THF, at -100C to, acetylene is passed in for a further hour and the mixture is stirred for a further 1/2 hour. For work-up if the batch is poured into acetic ice water (saturated with NaCl), the substance extracted with ethyl acetate and the organic phase washed neutral with sodium chloride solution. The crude product (630 mg) is recrystallized from acetone / hexane over charcoal. You get 474 mg of 17α-ethynyl-1,3,5 (10) -estratriene-3,7α, 17β-triol of melting point 230-2320C.

Example 4 The solution of 100 mg of 17a-xthynyl-1,3,5 (10) -estratriene-3,7a, 17ßtriol in 5 ml of ethyl acetate, 1 ml of acetic anhydride is added one after the other at room temperature and 1 drop of perchloric acid (70%) added. After 3 minutes, 1 drop of pyridine is added added, washed with saturated sodium chloride solution, dried and evaporated. 78 mg of 3,7 ”, 17β-triacetoxy-17α-ethinyl-1,3,5 (10) -estratriene are obtained.

Example 5 To the solution of 150 mg of 17'-ethynyl-1,3,5 (10) -estratriene-3,7a, 17β-triol 1 ml of acetic anhydride is added to 3 ml of pyridine and the mixture is left at room temperature for 16 hours stand.

The batch becomes dry with the addition of cyclohexane or CC14 evaporated. The residue is dissolved in ethyl acetate and washed with water. After drying and evaporation, 120 mg of crude product are obtained, which is determined by layer chromatography is cleaned. 110 mg of 3,7-diacetoxyi7-ethinyl-1,3,5 (10) -estratrien-17β-ol are obtained.

Example 6 200 mg of 17α-ethynyl-1,3,5 (10) -estra-triene-3,7 «, 17ßtriol are dissolved in 3 ml of methanol and 1 ml of cyclopentyl bromide by heating, then gives 200 mg Potassium carbonate and heated to boiling under nitrogen for 12 hours. After that there one the approach in acetic acid ice water and extracted with methylene chloride. the organic phase is washed neutral, dried and evaporated. The raw product (150 mg) is purified by layer chromatography, 110 mg of 17α-ethynyl-3-cyclopentyloxy-1,3,5 (10) -estratriene-7 «, 17β-diol are obtained.

Example 7 The solution of 350 mg of 17'-ethynyl-3-cyclppentyloxy-1,3,5 (10) -estratriene-7a, 17β-diol in 5 ml of ethyl acetate is mixed with 1 ml of acetic anhydride and 1 drop of perchloric acid (70%) are added and the mixture is stirred at room temperature for 3 minutes. Then add 0.5 ml Pyridine too, washes with sat. Sodium chloride solution, dries and evaporates. Man receives 310 mg of 7a, 17ß-diacetoxy-17α-ethinyl-3-cyclopentyloxy-1,3,5 (10) -estratriene.

Example 8 Analogously to Example 3, 600 mg of 3,7β-dihydroxy-1,3,5 (10) -estratrien-17-one are obtained converted to 420 mg of 17α-ethynyl-1,3,5 (10) -estratriene-3,7β, 17β-triol, m.p. 2490C.

Example 9 Analogously to Example 4, 17α-ethynyl-1,3,5 (10) -estratriene-3,7β, 17β-triol acetylated to 3,7β, 17β-triacetoxy-17α-ethinyl-1,3,5 (10) -estratriene.

Example 10 Analogously to Example 5, 17α-ethynyl-1,3,5 (10) -estratriene-3,7β, 17β-triol acetylated to 3,7β-diacetoxy-17α-ethinyl-1,3,5 (10) -estratrien-17β-ol.

Example 11 Analogously to Example 6, 17α-ethynyl-1,3,5 (10) -estratriene-3,7β, 17β-triol etherified with cyclopentyl bromide to 17α-ethynyl-3-cyclopentyloxy-1,3,5 (10) -estratriene-7β, 17β-diol.

Example 12 Analogously to Example 7, 17α-ethynyl-3-cyclopentyloxy-1,3,5 (10) -estratriene-7β, 17β-diol acetylated to 7β, 17β-diacetoxy-17aethinyl-3-cyclopentyloxy-1,3,5 (10) -estratriene.

Example 13 500 mg of 17α-ethynyl-1,3,5 (10) -estratriene-3,7α, 17β-triol are dissolved in 10 ml of pyridine, 1 ml of butyric anhydride is added and 60 min.

stirred at room temperature. After that, the solution is cooled in 100 ml 8 percent Stir in sulfuric acid and wash the precipitate until neutral. After drying, it is recrystallized from ether / hexane and pure 3-butyryloxy-17α-ethinyl-1,3,5 (10) -estratriene-7a1I7β-diol is obtained from melting point 130-1310 C.

Example 14 500 mg of 17α-ethynyl-1,3,5 (10) -estratriene-3,7α, 17β-triol are dissolved in 10 ml of pyridine, 3 ml of butyric anhydride are added and 72 hours stirred at room temperature. Then the solution is chilled in 100 ml 8 percent. sulfuric acid stirred in and the precipitate which has separated out is washed neutral. For further purification the product is chromatographed on a silica gel column and from ether / hexane recrystallized. The pure 3,7a-dibutyryloxy-17a-ethinyl-1,3,5 (10) -estratrien-17β-ol melts at 132.5-133 ° C.

Example 15 Analogously to Example 4, 17 [alpha] -thynyl-1,3,5 (10) -estratriene-3,7 [beta], 17 [beta] triol reacted with butyric anhydride to give 3,7ß-dibutyryloxy-17aethinyl-1,3,5 (10) -estratrien-i7ß-ol.

Example 16 Analogously to Example 13, 17α-ethynyl-1,3,5 (10) -estratriene-3,7β, 17β triol reacted with butyric anhydride to give 3-butyryloxy-17aethinyl-1,3,5 (10) -estratriene-7ß, 17ß-diol.

Example 17 a) The suspension of 500 mg of 3,7a-dihydroxy-1,3,5 (10) -estratrien-17-one in 20 ml of benzene is dried azeotropically by concentration to 10-15 ml. After cooling down 1.1 ml of dihydropyran and 5.4 mg of p-doluenesulfonic acid are successively brought to room temperature (dehydrated azeotropically by distilling off a benzene solution) added and Stirred for 2.5 hours at room temperature under nitrogen. After completion of the implementation 1 drop of pyridine is added and the solution is washed with sodium hydrogen carbonate solution and water neutral, dries and evaporates.

750 mg of 3,7α-bis-tetrahydropyranyloxy-1,3,5 (10) -estratrien-17-one are obtained than oil.

b) From 1.35 g of lithium and 7.9 ml of methyl iodide is abs in 75 ml of ether. made a solution of lithium methyl. 3.75 ml of dichloroethylene are added in 15 ml of absolute ether and allowed to stir for 1.5 hours at room temperature. To this A solution of lithium chloroacetylene is added dropwise to 600 mg of 3,7a-bis-tetrahydropyranyloxy-1,3,5 (10) -estratrien-17-one in 30 ml absolute Tetrahydrofuran, stirred for 1 hour at room temperature and 1 hour at reflux temperature. It is then cooled and decomposed while cooling with ice with saturated sodium chloride solution. The organic phase is washed neutral with water, dried and evaporated. 240 mg of 3,7a-bis-tetrahydropyranyloxy-17a-chloroethinyl-1s3, -5 (10) -estratrien-17B-ol are obtained.

Example 18 The solution of 200 mg of 3,7a-bis-tetra-hydropyranyloxy-17a-chloroethinyl-1,3,5 (10) -ö stratrien-17ß-ol, 500 mg of oxalic acid in 10 ml of methanol, 5 ml of methylene chloride and 5 ml of water is heated to boiling for 1 hour. Then it is diluted with ethyl acetate and washed neutral with saturated sodium chloride solution. After drying and evaporation 150 mg of 17a-chloroethinyl-1,3, 5 (10) -estratriene-3, 7a, 17ß-triol are obtained.

Example 19 a) The solution of 250 mg of 3,7a-dihydroxy-1,3,5 (10) -estratrien-17-one in 1 ml of dimethyl sulfoxide, while cooling and stirring, with 250 mg of sodium hydride (50% suspension in paraffin oil) and 30 minutes at room temperature under Nitrogen stirred. Then 0.57 ml of cyclopentyl bromide is added and stirring is continued 1.5 hours at room temperature under nitrogen.

The batch is then poured into ice-acid water and filtered and the precipitate is taken up in ethyl acetate 0 After washing neutral, drying and Evaporation gives a crude product which is purified by column chromatography will. 200 mg of 3-cyclopentyloxy-7α-hydroxy-1,3,5 (10) -estratrien-17-one are obtained.

b) For the ethynylation, a suspension of 1.5 g of potassium tert-butoxide is passed through acetylene in 10 ml of absolute THF for 1 hour. To the resulting pulpy The solution of 200 mg of 3-cyclopentyloxy-7α-hydroxy-1,3,5 (10) -estratrien-17-one is added dropwise to the mass in 20 ml of absolute THF at -10 ° C with stirring, acetylene is passed in for 1 hour and stirs for 1/2 hour.

For work-up, the batch is extracted into ice-acidic water and extracted with ethyl acetate and the organic phase was washed neutral with sodium chloride solution. After drying, evaporation and purification by chromatography, 110 mg of 17α-xthynyl-3-cyclopentyloxy-1,3,5 (10) -estratrien-7α, 17β-diol are obtained.

Example 20 According to Example 19 a), 300 mg of 3,7β-dihydroxy-1,3,5 (10) -estratrien-17-one are obtained converted to 3-cyclopentyloxy-7β-hydroxy-1,3,5 (10) -estratrien-17-one. This connection becomes as in example 19 below b) described ethinylated to 17α-xthynyl-3-cyclopentyloxy-1.3.5 (10) -estratriene-7β, 17R-diol.

Claims (1)

Patent claims l.) 7-Hydroxy-estradiols of the general formula I. wherein OR2 is in α or β position, R1 is a hydrogen atom, an acyl, alkyl, cycloalkyl or oxygen-containing saturated heterocyclic group, R2 and R3 are identical or different and are a hydrogen atom, an acyl or oxygen-containing saturated heterocyclic group and R4 is a saturated or unsaturated lower hydrocarbon radical, it being possible for the unsaturated hydrocarbon radical to be substituted by chlorine. 2.) 17α-Ethynyl-1,3,5 (10) -estratriene-3,7α, 17β-triol. 3.) 3-Acetoxy-17α-ethinyl-1,3,5 (10) -estratriene-7α, 17β-diol. 4.) 3,7a, 17R-triacetoxy-17a-ethinyl-1,3,5 (10) estatriene. 5.) 3,7a-Diacetoxy-17a-ethinyl-1,3,5 (10) -estratrien-17β-ol. 6.) 17α-Ethynyl-3-cyclopentyloxy-1,3,5 (10) -estratriene-7α, 17β-diol. 7.) 7a, 17β-Diacetoxy-17a-ethinyl-3-cyclopentyloxy-1,3,5 (10) -estratriene. 8.) 17α-Ethynyl-1,3,5 (10) -estratriene-3,7β, 17β-triol. 9.) 3,7β, 17β-triacetoxy-17α-ethinyl-1,3,5 (10) -estratriene. 10.) 3,7β-Diacetoxy-17α-ethinyl-1,3,5 (10) -estratrien-17β-ol. 11.) 17α-Ethynyl-3-cyclopentyloxy-1,3,5 (10) -estratriene-7β, 17β-diol. 12.) 7β, 17β-Diacetoxy-17α-ethinyl-3-cyciopentyloxy-1,3,5 (10) -estratriene. 13.) 3-Butyryloxy-17a-ethinyl-1,3,5 (10) -estratriene-7a, 17β-diol. 14.) 3,7α-Dibutyryloxy-17α-ethinyl-1,3,5 (10) -estratrien-17β-ol. 15.) 3,7β-Dibutyryloxy-17α-ethinyl-1,3,5 (10) -estratrien-17β-ol. 16.) 3-Butyryloxy-17α-ethinyl-1,3,5 (10) -estratriene-7β, 17β-diol. 17.) 3,7a-Bis-tetrahydropyranyloxy-17a-chloroethinyl-1,3,5 (10) -estratrien-17β-ol. 18.) 17α-Chloräthinyl-1,3,5 (10) -estratriene-3,7α, 17β-triol. 19.) 17'-Ethynyl-3-cyclopentyloxy-1,3,5 (10) -estratriene-7β, 17β-diolO 20.) Medicines based on a compound according to claim 1-19. 21.) Process for the preparation of the 7-hydroxy-estradiols of the general formula I, characterized in that a) a 7-hydroxy-estrone of the general formula II in which R1 and R2 have the meaning given above, alkylated by methods known per se, if desired an unsaturated 17α-alkyl group hydrogenated and, depending on the ultimately desired meaning of R1, R2 and R3 in the end product, optionally splitting off ether or acyl groups and / or etherified and / or esterified free hydroxyl groups or b) for the preparation of 7α-OR2 compounds of the general formula I a 17a-R4-estradiol of the general formula III where R1 and R4 have the meaning given above, fermented with a fungal culture of the genera Absidia, Aspergillus, Rhizopus, Pellicularia or Diplodia and, depending on the ultimately combined meaning of R1, R2 and R3 in the end product, optionally etherified one or more hydroxyl groups and / or esterified.