DE3144049A1 - 16 beta -Methyl-8 alpha -oestradiols, process for their preparation and pharmaceutical products containing these - Google Patents

Abstract

16 beta -Methyl-8 alpha -oestradiols of the general formula I <IMAGE> in which R<1> and R<2> are identical or different and are hydrogen, acetyl, propionyl, butyryl or benzoyl. The compounds of the general formula I are steroid hormones with antioestrogenic activity and with a good dissociation between antioestrogenic and oestrogenic effects. They are suitable, for example, for the treatment of oestrogen-dependent tumours.

Description

16ß-methyl-8α-estradiols,

Process for their preparation and pharmaceutical products containing them preparations The invention relates to 16β-methyl-8 "-estradiols, processes for their production and pharmaceutical preparations containing them according to the claims 1 to 7.

The compounds of general formula I have valuable pharmacological properties Properties. The compounds are, for example, antiestrogenic steroid hormones with better dissociation between antiestrogenic and estrogenic effects than in the case of the known antiestrogen 17 "-ethynyl-11" -methoxy-1,3,5 (10) -estratriene-3,17β-diol (Chimica Therapeutica 13 (1978) 313).

Estrogenic and anti-estrogenic effects can for example in the uterus growth test to be determined. The uterus of rodents responds to potent estrogens with growth.

Effective anti-estrogens are able to stimulate estrogen-induced uterine growth to inhibit. The test is carried out as follows: Female infantile mice are obtained the test substance either alone (estrogenic effect) or at the same time as 0.03 yg estradiol (anti-estrogenic effect). The substances are in castor oil / benzyl benzoate applied subcutaneously.

It is applied once a day for 3 days. A control group receives only 0.03 μg of estradiol (E2), another control group remains untreated. On the 4th day, the animals are sacrificed, the uteri are dissected out and weighed empty. The percentage inhibition (anti-oestrogenic effect) or stimulation (oestrogenic Effect) of uterine growth, based on the control treated with estradiol (E2), determined. The uterus weight of the untreated control group (base value) is from deducted from the corresponding weight of the E2 control.

The individual dosage groups are based on the control value obtained in this way also obtained after deduction of the base value. The following table also shows the threshold dose indicated. This is the smallest dose at which the uterus will grow stimulated by 20% (estrogen effect = E) or inhibited (anti-estrogen effect = AE) will.

Anti-estrogen and estrogen-effective threshold doses are then ins Ratio set and result in the AE / E quotient O The smaller the quotient, the more anti-estrogenic is the effect of the test substance in relation to its Self-estrogenicity.

From the table it can be seen that the quotient AE / E for the inventive Compound 16β-Nethyl-8a-oestra-1,3,5 (10) -triene-3,17B-diol at 0.7 and for the comparison substance 17α-ethynyl-11α-methoxy-1,3,5 (10) -estratriene-3,17β-diol is 3.3.

Estrogenic and anti-oestrogenic effects of 16ß-methyl-8a-estra-1,3,5 (10) -triene-3,17ß-diol and 17α-ethynyl-11α-methoxyestradiol in the uterine growth test in infantile Mice ANTIESTROGENIC EFFECT (AE) dose, s.c.

µg / animal / day mg% µg / animal / day 16β-Me-8α-E + E 2 0.1 3 63.0 + 6.0 11 1 3 59.6 # 3.7 18 10 3 51.1 # 1.1 34 100 3 43S9 + 1.2 47 17α-ethynyl-11α-MeO-E2 + E2 0.3 4 61.4 # 3.8 15 3 4 47.5 # 1.4 4o 0.5 30 4 33i9 + 3.3 65 control 4 14.5 # 1.3 (100) E2 control 4 69.9 # 9.0 (0) ESTROGENIC EFFECTS (E) dose, s.c. n uterine weight Stimula threshold dose n µg / animal / day mg tion% µg / animal / day 16ß-Me-8α-E2 1 4 15.4 + 2.2 3 10 4 42.7 + 2.6 74 1.8 100 4 44.2 + 1.7 78 control 4 14.3 # 1.4 (o) E2 control 4 52.7 + 5.0 (100) 17α-ethynyl-11α-MeO-E2 OS1 13 13.2 # 0.7 9 0.3 5 25.9 # 0.9 42 0.15 1 13 34.7 # 2.0 64 Control 13 9.5 # 0.7 (100) E2 control 14 49.0 # 2.4 (O) Continuation of table: AE / E quotient 16β-Me-8a-E2 0t7 17α-ethynyl-11α-MeO-E2 3.3 Because of the favorable ratio of antagonistic to agonistic estrogenic effect the compounds according to the invention can be used for the treatment of estrogen-dependent tumors, for example, breast cancer or prostatic hyperplasia can be used.

The invention therefore also relates to pharmaceutical preparations marked by a content of a compound of the general formula 1.

The production of the pharmaceutical preparations takes place in the usual way Way, by mixing the active ingredients with those commonly used in galenic pharmacy Carriers, diluents, flavor corrections, 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 depends on the Application form. Thus, a tablet preferably contains 5 to 20 mg; Solutions for parenteral administration preferably contain 10 to 50 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 any adverse or harmful side effects to cause; so they are administered, for example, at a dose level that im Range is from about 5 mg to 50 mg, although changes may be made can be made so that a dose level greater than 50 mg, for example up to 100 mg, is used.

The compounds of general formula I are prepared according to claim 7 in a manner known per se, characterized in that in 3-methoxy-16ß-methyl-8a-estra-1 13.5 <10) -triene 17-one reduces the 17-keto group, which cleaves the 3-methyl ether and optionally esterifying the hydroxyl groups in the 3- and / or 17-position.

The 17-keto group is reduced by reaction with hydrogen donors (Bydride donors) in suitable solvents. Come as hydrogen donors In particular, complex metal hydrides, such as sodium borohydride in Methanol, ethanol or i-propanol or lithium aluminum hydrides in tetrahydrofuran or dioxane or diisobutylaluminum hydride in toluene.

The ether cleavage is carried out according to known methodsO For example The cleavage with HBr / glacial acetic acid at 20 to 100 ° C., with boron tribromide, may be mentioned in a non-polar, aprotic solvent such as methylene chloride, pentane, hexane, Benzene, toluene, at -20 to +50 ° C or with diisobutylaluminum hydride in hexane and Toluene at boiling point O The latter method can also be used to reduce the 17-keto group and at the same time cleave the 3-methoxy group.

The free hydroxyl groups in the 3- and 17-positions can then be esterified.

A partial esterification of the 3-hydroxyl group succeeds, for example under phase transfer conditions with the acid chlorides at room temperature or below initial ice cooling. The steroid to be esterified is dissolved in an organic solvent, such as toluene, tetrahydrofuran, dioxane, dichloromethane, diethyl ether, submitted with powdered sodium hydroxide was added and the acid chloride was added dropwise with stirring. The esterification can also be carried out in the presence of catalytic amounts of a tetraalkylammonium salt, especially from Tetrabutylammonium hydrogen sulfate will. For partial esterification of the 3-hydroxy group with acetic acid, 16ß-methyl-8-estra-1 13,5 (10) -triene-3117ß-diol also with acetic anhydride and lead (II) acetate in dimethylformamide or dimethylacetamide at temperatures of 30-80 ° C.

The esterification in the 3- and 17-positions is preferably carried out with the corresponding acid anhydride or halide in the presence of a tertiary organic Base, such as pyridine, collidine, dimethylaminopyridine, triethylamine etc. 1 at temperatures between 0 and 120 OC.

For the preparation of compounds partially esterified in the 17-position of the general formula I, the 3-hydroxy group is protected before the esterification, for example by forming the 3-benzyl ether or the 3-dimethyl-tert.-butylsilyl ether. After introducing the ester residue in the 17-position in a manner known per se, for example with pyridine / acid anhydride, the protective group in the 3-position is split off again. The benzyl ether is cleaved, for example, by hydrogenation in the presence of palladium on charcoal at room temperature. The silyl ether is left to cleave on the steroid a fluoride, for example tetrabutylammonium fluoride, at 20 to Work at 120 OC.

The released 3-hydroxy group can then, if desired be esterified in the usual way. Mixed esters can also be obtained in this way will.

That used as the starting material of the process according to the invention 3-Methoxy-16β-methyl-8a-oestra-1,3,5 (10) -trien-17-one can be obtained from 8a-oestrone methyl ether can be produced as follows: a) 16β- (Dimethylaminomethyl) -3-methoxy-8α-oestra-1,3,5 (10) -trien-17-one To a solution of 8.12 ml of N, M, N ', N'-tetramethyldiaæinomethane (63.36 mmol) in 80 ml abs. 4.5 ml of acetyl chloride (63 mmol) in 60 ml of abs. Ether. To The crystals are filtered off with suction for 30 minutes and taken up in 80 ml of acetonitrile. 9 g of 8α-estrone methyl ether (31.69 mmol) are added to the salt at room temperature In the course of the reaction (at 80 ° C.) the reagent and the title compound dissolve crystallizes out in the form of the hydrochloride. After cooling, the solution becomes medium distilled off, the residue dissolved in 100 ml of a 1N HCl solution and washed with ether extracted; 385 mg (3%) of 3-methoxy-16methylene-8a-estra-1,3,5 (10) -trien-17-one are obtained from the ether phase. The aqueous phase is made alkaline with sodium hydroxide solution (pH: 10-11) and with ether extracted. After evaporation of the ether phase, 10.47 g of the title compound are obtained (Yield: 96%) 0 An analysis sample is crystallized from ether; Melting point 108-110 ° C; [α] 20 D = +26.3 ° (c = 0.5 in chloroform).

b) 3-Methoxy-16-methylene-8α-oestra-1,3,5 (10) -trien-17-one Man heated 10.47 g (30.70 mmol) 16β- (dimethylaminomethyl) -3-methoxy-8α-estra-1,3,5 (10) -trien-17-one and 65 ml of acetic anhydride to 140 ° C under argon. After 2 hours, the cooled one is poured Reaction solution in 100 ml of a saturated NaHCO3 solution. After extraction with methylene chloride, Washing with saturated NaHCO3 solution, water and saturated NaCl solution is evaporated. 9.95 g of crude 3-methoxy-16-methylene-8α-oestra-1,3,5 (10) -trien-17-one are obtained (Yield: 95%), which is slightly contaminated by more polar compounds. The title compound is obtained by gradient chromatography (hexane / acetone O - 20% acetone) with a melting point of 98-100 ° C. (from hexane) in a yield of 80%.

[α] 20 D = +54.8 ° (0.5 in chloroform).

c) 3-methoxy-16β-methyl-8α-estra-1,3,5 (10) -trien-17-one 7.8 g (26.44 mmol) L) 3-methoxy-16-methylene-8α-estra-1,3,5 (10) -trien-17-one hydrogenated in 200 ml of ethanol with 800 mg of Pd / C at room temperature and normal pressure. After uptake of 590 ml (99.7%) H2 (1 hour) the hydrogenation is stopped. The filtrate is concentrated in vacuo. 7.8 g of the title compound are obtained in one 99.6% yield.

By gradient chromatography (hexane / acetone; acetone O - 20,) 90% of the title compound are obtained with a melting point of 93-96 ° C. (from methanol); 20 [α] D = + 82.9 ° (c = 0.5 in chloroform).

Example 1 3-Methoxy-16β-methyl-8a-estra-1,3,5 (10) -trien-17β-ol One Solution of 7.2 g (24.4 mmol) of 3-methoxy-16β-methyl-8a-estra-1,3,5 (10) -trien-17-one in 100 ml absolute Tetrahydrofuran is added dropwise to a suspension while cooling with ice of 700 mg (18.4 mmol) of LiAlS4 in 100 ml of tetrahydrofuran. The mixture is stirred for 30 minutes Ice cooling, then 0.7 ml of water, 0.7 ml of a 15% strength drop in succession NaOH solution and 2.10 ml of water are added, the mixture is filtered and concentrated. 7 g of the are obtained Title compound. By gradient chromatography (hexane / acetone; acetone 0 - 20%) 80% of the title compound are obtained with a melting point of 168-170 ° C. (from hexane); [α] 20 = 13.2 ° = +13.2 (c = 0.5 in chloroform).

Example 2 16β-methyl-8α-estra-1,3,5 (10) -triene-3,17β-diol 7 g (23.4 mmol) of 3-methoxy-16β-methyl-8α-oestra-1,3,5 (10) -trien-17β-ol become dissolved in 290 ml of toluene. 195 ml (234 mmol) of a 1.2 m diisobutylaluminum hydride solution are added to this and heated 7 hours to 120 & under argon protection gas. After cooling down, the vigorous stirring carefully with water destroys the excess of the reagent. The precipitation is washed with ethyl acetate and with methylene chloride / methanol (4: 1). You get 6 g of the title compound (yield: 90%). An analytical sample crystallized from methanol melts at 173-195 ° C; [α] D20 = +18 0 (c = 0.5 in chloroform).

Example 3 3-Acetoxy-16β-methyl-8a-oestra-1,3,5 (tO) -trien-17β-ol To 5.7 g (19.93 mmol) of 16β-methyl-8a-estra-1,3,5 (10) -triene-3,17β-diol in 67 ml of dimethylformamide 665 mg of lead (II) acetate and 13.2 ml of acetic anhydride are added and the mixture is stirred for 1.5 hours 50 OC. After cooling, the reaction solution is poured into 50 ml of a 10% sodium acetate solution and extracted with ethyl acetate.

The crude product obtained after evaporation (6.5 g) was taken for 3 hours Freed from traces of dimethylformamide at room temperature in an oil pump vacuum and removed Diisopropyl ether crystallizes.

Melting point 138-144 OC.

- 20 = +12 ° (c = 0.5 in chloroform).

Example 4 3,17β-Diacetoxy-16β-metht1-8a-ötra-1,3,5 (10) -triene 1,2 g of 16β-methyl-8α-oestra-1,3,5 (10) -triene-3,17β-diol are dissolved in 15 ml of pyridine and after adding 6 ml of acetic anhydride, heated to 100 ° C. for 2 hours. After cooling down is stirred into ice / water, the precipitate is filtered off, washed out and dried and crystallized from diisopropyl ether. 0.96 g of diacetate with a melting point are obtained 167-171 OC.

Example 5 3,17β-Dibenzoyloxy-16β-methyl-8-estra-1,3,5110) -triene Die Solution of 3.21 g of 16β-methyl-8α-estra-1,3,5 (10) -triene-3,17β-diol in 55 ml of pyridine is cooled to 0 OC, partially treated with 6.7 g of benzoyl chloride and then stirred for 24 hours at 40 ° C. It is poured into 250 ml of ice / water and filtered the precipitate washes off Precipitation with water neutral, dried in vacuo at 50 ° C. and the crude product (4.02 g) crystallized from diisopropyl ether. 3.17 g of dibenzoate with a melting point of 145 ° -146 ° C. are obtained.

Claims (7)

Claims ½); 16ß-methyl-8a-estradiols of the general formula 1 where R1 and R2 are identical or different and hydrogen is acetyl, propionyl, butyryl or benzoyl. 2.) 16β-methyl-8α-estra-1,3,5t10) -triene-3,17β-diol. 3.) 3-Acetoxy-16β-methyl-8 "-estra-1,3,5 (10) -trien-17β-ol. 4.) 3,17β-Diacetoxy-16β-methyl-8α-estra-1,3,5 (10) -triene. 5.) 3,17β-Dibenzoyloxy-16β-methyl-8α-estra-1,3,5 (10) -triene. 6.) Pharmaceutical preparations, characterized by a content of a compound according to claims 1 to 5. 7.) Process for the preparation of 16ß-methyl-8a-estradiols of the general formula I. in which R1 and R2 are identical or different and are hydrogen, acetyl, propionyl, butyryl or benzoyl, characterized in that in a manner known per se in 3-methoxy-16ß-methyl-8 "-estra-1,3,5 ( 10) -trien-17-one reduces the 17-keto group, cleaves the 3-methyl ether and, if necessary, esterifies the hydroxyl groups in the 3- and / or 17-position.