DE2449327C2 - 7α-hydroxy-estradiols, processes for their preparation and medicaments containing them - Google Patents

Description

OR ₂

ίο

worm

Ri

R2 and
R ₄

a hydrogen atom, an acyl group having 1-15 carbon atoms or a Cyclopentyl group and a hydrogen atom or an acyi group with 1-15 carbon atoms and an ethynyl or chloroethinyl group

mean ^
2.17a-Athynyl-13,5 (10) -estratrien-3 Yes, l 7ß-triol.

3. Medicaments based on a compound according to claim 1 or Z

4. Process for the preparation of 7a-hydroxyestradiols of the general formula I.

OR,

R ₁ O

OR ₂

in which R ₁ , R ₂ , R3 and R _{4 have} the meaning given above, characterized in that a 7a-hydroxy-oestratrien-17-one of the general formula II

OR ₂

The invention relates to m-hydroxy-estradiols general formula I according to claim 1.

Acyy residues come from physiologically compatible organic carboxylic acids with 1-15 Carbon atoms in question, those of the aliphatic, cycloaliphatic, aromatic or aromatic-aliphatic Belong to series.

Examples of these are the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, Isobutleric acid, valeric acid, isovalcric 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, benzoic acid.

The compounds according to the invention have a favorable associated pharmacological activity on. Because of their strong vaginotropic and weak uterotropic effects, they are preferred for treatment Suitable for postmenopausal women. So they can be used to treat estrogen deficiency symptoms are used in which a centrally controlled effect on the uterus can be avoided but an effect on the vagina is desired. The compounds of the invention are also useful as intermediates in the manufacture of pharmacologically valuable steroids.

The favorable estrogenic dissociation can be seen, for example, in the sialic acid test on mice detect both oral and subeutane application.

Thus, the compounds according to the invention, such as ™ in Table 1 a; n example of 17 «-älhinyl-1,3,5 (10) -östra-

triene-3.7 <x, 17ß- triol is shown to have a dissociation quotient. which far exceeds that of the standard substances estradiol and 17 «-ethynyl-estradiol.

Table 1 link Eye value ReI. Effectiveness of dissociation

| mg) quotient

ρ. ο. vaginotropic uterotropic ρ. ο.

Estradiol

17ar-ethynyl-estradiol

17ar-ethynyl-1,3,5 (10) -estratriene-

3,7a, 17> triol

0.05-0.1

0.01

0.03

9.1

0.898

10.9 0.099

0.9 9.1

The sialic acid test is carried out as follows:

The mice are ovariectomized. From the 10th day after the castratation, the animals are given the substance to be tested once for 3 days. On the 4th day, the animals are sacrificed. Vagina and uterus appear immediately. excised and weighed into a test tube for hydrolysis. The sialic acid is determined according to Svennerholm [Biochem. Biophys. Acta 24 (1957) 604]. 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 set in relation and result in the degree of dissociation Q. For the standard compound estradiol, Q = 1. Compounds with Q> 1 are relatively vaginotropic, with Q < 1 are relatively uterotropic.

The threshold values given in Table 1 were -in the usual AIIen-Doisy test on rats determined.

The invention also relates to medicaments which 7a-Hydroxy-estradiols of the general formula I as Contain active ingredient.

The production of the pharmaceutical specialties takes place in the usual way, by combining the active ingredients with the carrier substances customary in galenic pharmacy. Diluents, flavor corrections, etc. in the desired application form, such as tablets, Dragees, capsules, solutions, etc., transferred The active ingredient concentration in the drugs formulated in this way depends on the form of application. Thus a tablet preferably contains 0.01 to 10 mg; Solutions for parenteral application contain 0.1 to 20 mg / ml solution.

The dosage of the medicament according to the invention can vary with the form of administration and the change the selected connection. In addition, it can vary according to the person being treated change. In general, the compounds according to the invention are administered in a concentration that Can produce effective results without any adverse or harmful side effects cause; for example, they will be administered at a dose level ranging from about 0.02 mg to approximately 20 mg, although changes may be made under certain circumstances so that a dose level of more than 20 mg. for example up to 50 mg is used. However, one will Dosage levels ranging from about 0.05 mg to about 5 mg are preferably used.

The invention also relates to a process for the preparation of the 7 <x -hydroxy-estadiols of the general type Formula I.

pentylgriippe and
Ri and R3 are a hydrogen atom or an acyl group

with 1-15 carbon atoms and
R _{4 is} an ethynyl or chloroethyl group

mean, characterized in that a 7a-hydroxy-oestratrien-17-one is used in a manner known per se general formula II

R ₁ O

0)

OR ₂

a hydrogen atom, an acyl group mil 1-15 carbon atoms or a cvcloworin Ri and R2 have the meaning given above, Ethinylated or chloroetherylated in the 17 <x position and optionally, depending on the ultimately desired meaning of Ri, R2 and R3 in the end product 3-CycIopejityläther. Or acyl groups cleave or the free 3 ^ hydroxyl group in the 3-cyclopentyl ether transferred and / or esterified free hydroxyl groups

The ethynylation or chloroethinylation can be carried out by known methods using an organometallic compound, such as, for example, with alkynylmagnesium halide, such as ethynylmagnesium bromide, or with alkali metal acetylide, such as potassium acety-Hd. The organometallic compound used as the ethynylating agent can also be formed in situ and made to react with the 17-kelon of the formula II. So you can, for example, to react with organometallic ethynyl compounds on the ketone in a suitable solvent acetylene or chloroacetylene and an alkali metal, preferably in the presence of a tert. Alcohol or ammonia, if necessary act under increased pressure.

The methods commonly used in steroid chemistry can be used for the esterification. There the hydroxyl groups in the 3-, 7- and 17-positions are different Have reactivity, the hydroxyl groups can be esterified in stages. Depending on your choice of the reaction conditions, one arrives at the 3-mono-, 3,7-di- or 3,7,17-triacyl compounds. the Acylation in the 3- and 7-position is preferably carried out with pyridine / acid anhydride or pyridine / acid halide Room temperature. Acylation will be lower at

^{If the} temperature is terminated after about 3 to 1 hour, the 3-monoacyl compound is obtained, but if the acylation is continued over several hours, the 3,7-diacyl compound is formed. To esterify the 170-hydroxy group in 3,7-diesters, for example, acid anhydrides are allowed to act on the steroid 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 triacylate. The triicyials can be obtained by gentle partial saponification the 3-hydroxy group are released.

The etherification with the cyclopentyl radical in the 3-position is preferably with a Cyclopenlylhaloge-

not in the presence of a weak base such as potassium carbonate. Sodium carbonate etc .. carried out in alcoholic solution at boiling temperature

Compounds made in 3-Si'jllung can

then esterified in .7-position and! 7-position will.

example 1

By suspending 3.7 g of potassium terL-butylate acetylene is passed in 20 ml of absolute tetrahydrofuran (THF) at -10 ° C. for an hour. To the resulting pasty mass is added dropwise with stirring the solution of 500 mg 3Ja-dihydroxy-13.5 (10) -östratrien-17-one, in 45 ml of absolute THF dissolved at - 10 ° C, leads a acetylene is added for a further hour and the mixture is subsequently stirred for 2 hours. For work-up, the mixture 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 raw product (630 mg) is recrystallized from acetone / hexane over charcoal. 474 mg of 17a-ethynyl-1315 (10) -estratriene-3,7 <x, 17β-triol are obtained from melting point 230-232 ° C

Example 2

500 mg of 17a-ethinyi-13.5 (10) -östratrkn-3.7.x, 17jJ-triof are dissolved in 10 ml of pyridine, 0.5 ml of acetic anhydride is added and the mixture is stirred for 20 minutes while cooling with ice. The solution is then stirred into 100 ml of cooled 8% strength sulfuric acid and the precipitate formed neutral washed. After drying, it is recrystallized from ether / hexane and pure 3-acetoxy-17 <x-ethhinyM3.5 (10) -estratriene-7a, 170-diol from melting point 133-135 ° C

Example 3

The solution of 100 mg of 17 "-äthinyM3,5 (10) -estratrien-3,7", 17 /? - triol 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, with washed with saturated sodium chloride solution, dried and evaporated. 78 mg of 3.7%, 170-triacetoxy-17% - ethinyl-133 ( 10) estratria.

Example 4

To the solution of 150 mg of 17 "-Äthinyl-13.5 (10) -estr £ rien-3,7", 17 /? - triol j _n 3 ml of pyridine, 1 ml acetic anhydride and stirred for 16 hours at room temperature. The batch is evaporated to dryness with the addition of cyclohexane or CCU. The residue is dissolved in Pssigester and washed with water, after drying and evaporation 120 ntg of crude product is obtained, which is purified by layer chromatography. 10 mg of 3,7 "-diacetoxy-17" -ethinyl-13,5 (10) -estra trien-170-ol are obtained.

Example 5

200 mg of 17 "-etninyl-13,5 (10) -estra-trien-3,7", 170-triol 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. Then you give the approach in acetic ice water and extracted with methylene chloride. The organic phase is washed neutral, dried and evaporated. The crude product (150 mg) is purified by layer chromatography, man receives 110 mg IVV -ethynyl-O-cyclopentyloxy-IJ.SOO) -estratriene-7a.17ß-diol.

Example 6

The solution of 350 mg of 17a-ethynyl-3-cycIopentyloxy-13,5 (10) -estratriene-7a, 170-diol in 5 ml of ethyl acetate is added 1 ml of acetic anhydride and 1 drop ■ Perchloric acid (70%) added and stirred for 3 minutes at room temperature. Then 0.15 ml are added Add pyridine, wash with saturated sodium chloride solution, dry and evaporate. one receives 310 mg to 7o, l 7f? -Diacetoxy-l 7a-ethinyl-3-cyclopentyIoxy-13,5- (10) -estratriene.

Example 7

mg of 17α-ethynyl-13,5 (10) -estratriene-3,7ix, 17β-triol are dissolved in 10 ml of pyridine, 1 ml of butyric anhydride is added and the mixture is 60 minutes at room temperature touched. Then the solution is chilled in 100 ml 8 percent. Stirred in sulfuric acid and the precipitated Precipitate washed neutral, after drying it is recrystallized from ether / hexane and pure is obtained

3-butyryloxy-L7A-äthinyI-13. <LO) -estratriene-7a, l7 / ^ diol of melting point 130-131 ⁰ C.

Example 8

500 mg of 17α-ethynyl-13,5 (10) -estratriene-3,7oü 70-triol v-örden dissolved in 10 ml of pyridine, 3 ml of butyric anhydride added and stirred for 72 hours at room temperature. After that, the solution is cooled in 100 ml 8 percent Sulfuric acid stirred in and the precipitated

Precipitation washed neutral. For further purification, the product is passed over a silica gel column Chromatographs and recrystallized from ether / hexane. The pure 3,7a-DibutyryIoxy-I7iX-äthinyl-13.5 (I0) -östratrien-17jS-ol melts at 132.5-133 ° C.

Example 9

a) The suspension of 500 mg 3.7 "-dihydroxy-13,5 (10) -estratrien-17-one in 20 ml of benzene is dried azeotropically by concentration to 10-15 ml After cooling to room temperature, 1.1 ml of dihydropyran and 5.4 mg p-Toluoisulfonic acid (by distilling off a benzene solution watered in azeotropically) added and stirred for 2.5 hours at room temperature under nitrogen. After funeral implementation 1 drop of pyridine is added, the solution is washed with sodium hydrogen carbonate solution and Water neutral, dries and evaporates. 750 mg of SJa-bis-tetrahydropyranyloxy-133 (IO) -östratrien-17-onalsÖI are obtained.

b) 135 g of lithium and 75 ml of methyl iodide are used in 75 ml ether abs. made a solution of Lithiurr.methyl. 3.75 ml of dichloroethylene are added in 15 ml of absolute ether and allowed to stir for 13 hours at room temperature. To this solution of Lithium octiloroacetylene is added dropwise to b00 mg of 3,6a-bis-tetrahydropyranyloxy-13.5 ( 10) -östratrien-17-one in 30 ml of absolute tetrahydrofuran, stir for 1 hour at room temperature and 1 hour at reflux temperature. Then it is cooled down 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 3,7ix-bis-tetrahydropyranyloxy-17a-ch! Oril'.hiny are obtained I-13,5 (10) -estratria-17 /? - ol.

c) The solution of 200 mg of 3,7 "-Bis-tetra-hydropyranyloxy-17" -chloroäthinyl-1,3,5 ( 10) -estratrien-170-ol, 500 me oxalic acid in 10 ml methanol, 5 ml methyl

lene chloride and 5 ml of water are heated to boiling for 1 hour. Then it is diluted with ethyl acetate and neutral with saturated sodium chloride solution washed. After drying and evaporation, b) 150 mg of 17A-chloroethinyl-i.3.5 (10) -estratriene-> are obtained 3.7λ.Ι7 / ΜγϊοΙ.

Example 10

a) The solution of 250 mg of 3.7a-dihydroxy-1.J.5 (IO) -östratrien-17-one in 1 ml of dimethyl sulfoxide is ι ο 250 mg of sodium hydride (50% suspension in paraffin oil) are added with cooling and stirring and Stirred for 30 minutes at room temperature under nitrogen. Then 0.57 ml of cyloctyl bromide is added and stir for a further 1.5 hours at room temperature temperature under nitrogen. Thereafter, the batch is poured into acetic ice water, filtered and the Precipitation taken up in ethyl acetate. After neutral washing. Drying and evaporation obtained a crude product which is purified by column chromatography. 200 mg of 3-cycloppnium-oxy-7-hydroxy-1,3,5 (IO) -östratrien-17-one are obtained. Athynylation is carried out by passing through a suspension of 1.5 g of potassium butoxide in 10 ml of absolute THF in acetylene for 1 hour. To the resulting pulpy mass one drips the Solution of 200 mg of S-cyclopentyloxy ^ a-hydroxy-1.3.5 (IO) -estratrien-17-one in 20 ml of absolute THF at -10 ° C with stirring, passes for 1 hour Acetylene and stirred for 1/2 hour. For work-up, the approach is given in acetic acid Ice water, extracted with ethyl acetate, and the organic phase was washed neutral with sodium chloride solution. After drying, evaporation and chromatographic purification, 110mg Ι7λ-

Ethynyl-3-cyclopentyloxy-1,3.5 (10) -estratriene-7.1.170-diol.

Claims (1)

Patent claims: 1. 7a-Hydroxy-ostradiols of the general formula R ₁ O where Ri and R »have the meaning given above, ethynylated or chloroethinylated in 17 & -S division and optionally, depending on the ultimately desired meaning of Ri, R2 and. R _s in the end product which cleaves 3-cyciopentyl ether or acyl groups or converts the free 3-hydroxyl group into 3-cyclopentyl ether and / or esterifies free hydroxyl groups.