DE1668685A1 - New 17-hydroxy- and 17-acyloxy-6ss, ss-epoxy-1alpha, 2alpha-methylene-4-pregnen3,20-diones - Google Patents

Description

SCEKRTNG AG Berlin, November 4, 1969

Pa fcent department

New 17-Hvdro>: v - and 17-Aoyloxy-63.79- e-po: xy-

■ "'' ^l - '· ■ - ■" ■ L- *> »ι—— -« -> 1l I ■ ■ I. ·. '"If" III I -'. . ·. · .. π .J [I Μ Jf. L. (

lfy, 9n ~ yi \ cV nyl o n- ⁷ I - "crorr ion-3 ₇ 20 ~ di one

The invention relates to new 17-kydroxy- and 17 _{-acyloxy-6β}} 7ßejjoxy-α, 2a-Fietb.ylon-4-pregnen-3,20-diones. . . ■

By "acyl" SiiurereGto should v understood grounded ^r, derived from · acids which are used in steroid chemistry commonly used for esterification. Preferred acids are carboxylic acids with bic to 15 carbon atoms. The carboxylic acids can also be unsaturated, branched, polybasic or substituted in the customary manner, for example by hydroxyl, amino, oxo groups or halogen atoms. Cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which can likewise be substituted in the usual way, are also suitable. Preferred acids for the formation of the acyl radical are, for example: acetic acid, propionic acid, caproic acid, oenanthic acid, undecylic acid, oleic acid, trimethylacetic acid, haloacetic acid, dichloroacetic acid, cyolopentylpropionic acid, phenylpropionic acid, phenylacetic acid, phenoxyacetic acid, benzoic acid, benzoic acid, phenoxyacetic acid, benzoic acid, tri-acetic acid, phenoxyacetic acid, benzoic acid, tri-acetic acid, phenoxyacetic acid, benzoic acid, tri-acetic acid, phenoxyacetic acid, oleoacetic acid, benzoic acid, phenoxyacetic acid, benzoic acid, benzoic acid, phenoxyacetic acid, oleoacetic acid, benzoic acid, phenoxyacetic acid, benzoic acid, phenoxyacetic acid, benzoic acid, oleoacetic acid, oleoacetic acid, oleo-acetic acid, oleo-acetic acid In particular, esters of inorganic acids such as those of sulfuric and phosphoric acid come into consideration for the production of water-soluble preparations.

10 9 8 41/17 18 Nßue Unterluy>;>'>"^{> ι} ■ ■ - d ~

.SCHERILIS AG

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The new 6ß, 7ß-Epoxy-la, 2a-methylenöteroide have valuable pharnacological properties. They show a surprising Gestagenic activity, especially after oral administration. A particular advantage of the compounds according to the invention is that these have practically no antiandrogenic side effects. Surprisingly, the new ones unfold Gestagens do not have a central effect even in high doses (Ovulation onshenunung).

The following table shows the superiority of the invention Compounds using the example of 17-acetoxy-6ß, 7ß-epoxyla, 2a-methylene-4-pregnen-3,20-dione (I). The known gestagen 6-chloro-17-acetox, y-4, ßpregnadien-3,20-dione is used as a comparison substance (II).

substance Clauberg test Ovulation inhibition Homination Anti-androgen test inhibition ) Pr. p.c. p.o. p.o. (* 3 Threshold dose dose SbI. 0 (mg) (mg) 0 (Kg) 30th 0 0 45 I. 0.001 10.0 10.0 0 15th 50 3.0 44 0 1.0 18th II 0.03 1.0-3.0 3.0 0 1.0 0.3

The gestagenic effect was tested in the usual Clauberg test.

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The total dose that was determined as the SehY.'ellon value was at least κν, 'οΐ of three rabbits have a transformer! scli3 Conversion of the endoinetrium governed. The degree of ovulation is checked by inspection.

To the best of "the antiandrogenic side effect received castrated male had the test substance daily for 7 days administered by ob (p.o.). For the same period of time, the animals received 0.1 ng testosterone propionate subcutaneously daily. On the 8th day, the animals were sacrificed and the weights of the sex glands were determined. It was determined by the test substance "caused percent inhibition of seminal vesicle growth (sbl.) and the prostate (pr.) determined.

The main area of application of the active ingredients according to the invention is the treatment of the following gynecological disorders: primary amenorrhea and secondary amenorrhea of prolonged Duration, menstrual cycle disorders with inadequate corpus luteum function, endometriosis, uterine hypoplasia, premensirial complaints and castopathy.

The dosage is based on the severity of the illness. In general, between 5 and 100 mg will be administered daily. Me production of the pharmaceutical specialties takes place in the usual way by mixing the active ingredients with suitable

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SOHKRIIfe AG - Μ »~

Neten additives, carrier substances and taste correction processed into the commercially available forms of application. For Oral application comes in particular tablets, coated tablets, capsules, pills, suspensions or solutions in embossing.

The invention also relates to a method of manufacture of 17-hydroxy ~ and 17-acyloxy-6ß, 7ß-npoxy-la, 2a-methylene-4-pregnen-3,20-dione, characterized in that 6β ~ Hydroxybsw. 6i2-acyloxy-7oc-halogen steroids of the general formula

where R is hydrogen or an acyl group, X is chlorine or bromine and Ac is an acyl group ", in one against the coalition partners Reacts inert solvent with bases and optionally esterifies a free 17-hydroxy group.

The inert solvents used are preferably water-miscible solvents such as methanol, ethanol, acetone, tetrahydrofuran, Dimethyl sulfoxide or mixtures of these solvents,

like ethanol with acetone. _c

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The bases for the oxirane ring connection according to the invention are, for example Alkali metal carbonates and hydrogen carbonates, such as potassium carbonate and sodium hydrogen carbonate, alkali metal hydroxides, such as potassium and sodium hydroxide, alkali metal alcoholates, such as potassium tert-butoxide, and others.

Depending on the strength of the base used and the level of the reaction f. temperate one obtains more or less large proportions of saponification product. By suitable choice of the reaction conditions. can be converted to free or esterified 17a-hydroxy compounds reach. Thus, with potassium carbonate in ethanol and acetone at room temperature, the 6β, 7β ~ epoxide with the unchanged Acyloxy group in 17a-position. With the same reactants In the heat, after a reaction time of about 20 hours, an epoxide is formed, the 17-acyloxy group of which is largely saponified is. With potassium hydroxide as the base, the 6ß, 7ß-3poxide is formed with the after a short reaction time at room temperature free 17a-hydroxy group.

The subsequent esterification or reacylation, if desired the 17oc-Kydroxygruppe is expediently with a reactive Acid derivative carried out in the presence of basic reagents. The conversion with acid anhydride or -halide in the presence of pyridine in the heat.

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The 63-hydroxy-hz \ -i, which are used as starting materials for the process according to the invention and have not been described in the literature so far. 63-Acyloxy-7a-halogen ^{steroids can be produced from the corresponding Δ D} -unsaturated steroids. -

For example, from 17-acyioxy-la, 2a-r.ethylene-4,6-pregnadien-y, 20-dione nit Ii-3rom- or S-chloro-succinir.iö and Water in the presence of perchloric acid in dioxane, the following 613-hydroxy-7cd-halogen steroids:

7a-Brma-63-hydroxy-17-acetoxy-la, 2a-3setbylen-4-pregiien-3 * 20-dione, 3 ?. 185-185.5 ° C

7a-3r on-6 ß-hydroxy-17-hexanoyloxy-la, 2a-iaefhylen-4-pregnen-3,20-Ciion than oil.

7a-chloro-6ß-hydrcxy-17-acetoxy-la, 2a-rsethylen-4-pregnene-3, 2odion, .. 239 - 239.5 ⁰ C

From 17-acetoxy-la, 2a-meth.ylen. ~ 4,6-pregnedien-3t20-dione with. i-Brora or K-chlorosuccininide and the corresponding carboxylic acid in Hydrogen chloride-saturated tetrahydrofuran arise "for example . _ 7 _

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BATH ORIGINAL

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i with e, s igsäure:

7a-3r & jr _i -6ß, 17-Qiacetoxy-la, 2a ~ methyl-4-pregnen-3, 20-dione,?. 194-195 ⁰ C.

7a-chloro-63,17 ~ oleetoxy-la, 2a-methylene-4-pregnen ~ 3,2C-dione,?. 237 - 238 ⁰ C-

Kit formic acid:

7a-Broni-6 £ -f orKyloxy-17-acetoxy-la, 2a ~ inethylene-4-pregnen-3,20-cion, ?. > 17 - 218.5 ° C

7a-chloro-6 £ ~ xorrnyloxy-17-acetoxy-la, 2a-liethylen-4-pregnen-3, 20-dione, P. 247 - 248 ⁰ C.

■ ^: o'ir ' i * iOj 1

>, 20-c: ii-n i-ierdeu dissolved in 200 ml of ethanol and 100 ml of acetone, mixed with a solution of 10 g of potassium carbonate and 25 ml of water and stirred at 25 ° 0 for 48 hours. Danac is poured into barrels, the precipitate is filtered off with suction, washed, dried and uracrystallized from acetone / hexane. Han receives 7.15 g of 17-acetoxy-6ß, 7ß-epoxy-la _t 2a-nethylene-4-p ^ egnen-3,20-dione with a melting point of 244 - 245 ° C UV: ε _{ο / Λ} = 15,800.

The same 63,75-spoxide arises analogously from 7a-bromo-6B, 17-diacetoxy-la, 2a-methylene-4-pregnen-3,20-dione and from 7 «-3rom-6ß-f omyloxy-17-acetoxy-la, 2a-ir.ethylene-4-pregnen ~ 3> 20-dione.

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Example 2

A solution of 1.2 g 7-chloro ~ 6ss-hydroxy-17-acetoxy-la, 2ctmethylen-4-pregnene-3,20 dione ~ i _n 24 ml of methanol "is mixed with 600 ing of potassium carbonate in 3 ml of water 3 After that, it is poured into water, the precipitate is filtered off with suction, taken up in methylene chloride, washed with water, dried and concentrated in vacuo. After chromatography on silica gel, 650 mg of 17-acetoxy-6β are recrystallized from isopropyl ether. 7β-epoxy ~ la, 2ct-ethylene-4-pregnen-3,20-dione with a melting point of 240-242 ° C. UV: ε _24Ό = 15,000.

The same 6β, 7β-epoxide is produced analogously from 7α-chloro-6β, 17-diacetoxy-1a, 2a-methy.len-4-pregn.en-3,20-dione and from 7a-chloro-6ß-formyloxy-17-acetoxy-la, 2a-methylene-4-pregnen-3 »20-dione.

Example 3

3.0 g of 7a-bromo-6ß-hydroxy-17-acetoxy-la, 2a-methylene-4-pregnen-3,20-dione are dissolved in 60 ml of ethanol, with a solution of 1.5 g of potassium carbonate in 7, 5 ml of water are added and the mixture is heated to boiling for 24 hours. It is then poured into water, the precipitate is filtered off with suction, washed, dried and recrystallized from acetone / hexane. This gives 1.56 g of 17-hydroxy-6ß, 7.beta.-epoxy-la, 2a-methylene-4-pregnene-3,20-dione of melting point 280-283 ⁰ C. UV: E ₂₄₀ = 15 100 - 9 -

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Example 4

A solution of 500 mg of 7a-bromo-6ß-hydroxy-17-acetoxy-la, 2a-methylene-4-pregnen-3,20-dione in 10 ml of ethanol and 5 ml of acetone is mixed with 2.5 ml of a 20 $ -igen aqueous potassium hydroxide solution and stirred for 30 minutes at room temperature. The mixture is poured into water, the precipitated substance is filtered off with suction, washed with water, dried in vacuo and recrystallized from acetone / hexane. This gives 297 mg of 17-hydroxy-6ß _t, 7.beta.-epoxy-la, 2a ~ methylene-4-pregnene-3,20-dione of melting point 279-281 ° C.

Example 5

1 »0 g of 7a ~ bromo-6ß-hydroxy-17-hexanoyloxy-la, 2a-methylene-4-pregnen-3,20-dione are reacted under the conditions described in Example 1. The crude product is chromatographed on silica gel. With 9 to 11% acetone / pentane, 550 mg of 17-hexanoyloxy-6ß, 7ß-epoxy-la, 2α-methylene-4-pregnen-3,20-dione are eluted as a viscous oil. TJV: ε ^ ΑΟ ~ ¹ ^ ^ ⁰ ' ^ ^{& s 01 ers} " ^tarr ' ^fc after some time to a crystalline mass that melts at 129-130 ° C.

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Claims (1)

Claims 17-hydroxy-oß _} 7ß-epoxy-lKj 2e-roethylene-4-pregn5n-3 »20-dicm. 2.) 17-Acyloxy-oß, 7ß ~ epoxy-la / 2a-E ^ thylen-4-pregnen-3, 20-dionc. 5.) 17-Acetoxy-6ß, 73-epoxy-lcc, 2a-Jä3thylen-4-pregnen-3,20-üion. 4.) 17 ~ hexanoyloxy-6ß, JQ- epoxy-loc, 2a-iaetliylen-4-pr? * Nen-3 , 20-dione. 5.) Medicines based on active ingredients according to Ansprucii 1 Ms 4th ... " 6.) Verv ^ end of active ingredients according to claim 1 to 4 for Treatment of gynecological disorders. 7.) Process for the production of 17-hydroxy- and 17-aeylox 6β, 7β-epoxy-la, 2a-methylene-4-pregnen-3,20-dione, dadtirel . characterized in that one 63-hydroxy ~ "or 6S-acyloxy-7ahalogensteroide the general onnel - 11 - Documents (·,
109841/1718 _BATH SCHERIIiG AG wherein R V 'ssei'stoiT or an acyl group, X is chlorine or porridge "lind Ac represents an acyl group, in an against the Eeak- inert solvent ir.it bases urn et st and ls a free 17-Hydjpoxygruppe \ ^r ereßtert. 109841/1718