DE2036908A1 - Chlorine substituted steroid compounds - Google Patents

Description

Dr.F.Zumstein sen, - Dr.E. Assmann 203690t Dr. R. Koenlgsberger - Dlpl.-Phys. R. Holzbauer - Dr. F. Zumstein Jun.

PATENT LAWYERS TELEPHONE: COLLECTIVE NO. SZ BS 41 '8 MDNOHENS, TELEX 8S9979 BRÄUHAU83TRA8SE 4 / III TELEGRAMS; ZUMPAT

Postal checking account! Munich 9nae

BANK ACCOUNT! BANK H. Aufhäu8er

Oestranes 15
91-108

Glaxo Laboratories limited, Greenford, Middlesex, UK

Chlorine substituted steroid compounds. ™

The present invention is concerned with new chlorine substitutes th steroids and their manufacture.

The same applicant has previously described that 9a-unsubstituted 11ß-chloro-19-nor-steroids show valuable hormone activity. It has now been found that particular steroids of this class, not previously described, are particularly valuable progesterone-like activity, more precisely pregnancy-influencing and anti-estrogenic activity as well as anti-androgenic activity exhibit.

The present invention thus relates to steroids of the general formula:

Cl

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in which a double bond is present or absent in the 6,7 position can be and in which R is a hydrogen or halogen atom,

ρ
R is a hydrogen atom, a hydroxyl group or an alkoxy

or acyloxy group with 1 to 6 carbon atoms,

R ^ is a hydrogen or halogen atom or an alkylthio group having 1 to 6 carbon atoms, mean, or wherein

2 3
R and R together represent an alkylidenedioxy or aralkylidenedioxy group.

R ^ means a hydrogen, fluorine or oxygen atom or one

Methyl group, gate exposed that R does not mean a hydrogen atom

2
tet, except when R is a formyloxy or alkoxy group, or except when R- 'is a halogen atom or an Al-

2 "5

kylthio group, or except when R and R a

Alkylidenedioxy or aralkylidenedioxy group, or from

taken when R is a fluorate cm or
and 3,5-dienol ethers and esters dairon.

taken when R is a fluorine or a methyl group

If R is a halogen atom, this can be a fluorine, chlorine, Bromine or iodine atom, preferably a fluorine or chlorine atom

If R is an acyloxy group, this can, for example a formyloxy, acetoxy, propionyloxy, butyryloxy, valeryl

P.
oxy or caproyloxy group, and where R 'is an alkoxy group

means, this can be, for example, a methoxy, ethoxy,
Be propoxy, butoxy, pentoxy or hexoxy group.

If R ^ is a halogen atom, it can be a fluorine, chlorine, bromine or iodine atom, preferably a chlorine atom. If R "^
is an alkylthio group, this can be, for example, a methyl, ethyl, propyl, butyl, pentyl or hexylthio group.

2 ^ 5
If R and Br together denote an alkylidanedioxy group, this can, for example, be an isopropylidenedioxy or isobutyric

2 3
be lidendioxygruppe, and if R and R together an aral-

mean kylidendioxygruppe, so this can, for example, a
Ί-Phenyläthylidendioxy- or Diphenylmethylidendioxygruppe be.

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When IF denotes a fluorine or chlorine atom or a methyl group, so there is preferably a double bond in the 6,7-position.

3,5-dienol ethers include, for example, dienol methyl and

For example, ethyl ether, dienol ester include acetic acid? Propionic acid? Benzoic acid, valeric acid and hexahydrobenzoic acid ester.

In general, the compounds of the invention show progeeteron-like Activity superior to the previously known and closely related compound and, in particular, anti-oestrogens Activity determined by subcutaneous administration to mice simultaneously with estradiol and determination of uterine carbonic anhydrase compared to estradiol alone for 5 days. One has anti-estrogenic activities that are a thousand times that were observed, like those of progesterone. Such high activities make the connections especially valuable as continuous Low dose contraceptive formulations containing only progestin alone "

Particularly valuable compounds of the invention in terms of their high progesterone-like activity include:

6.11 ß-dichloro-17 «x-formmyloxy-19-norpregna-4,6-diene-3,20-dione, 11β, 16a-dichloro-19-norpregn-4-en-3,20-dione, 11ß-chloro-16a, 17a-isopropylidenedioxy-19-norpregn-4-en-3,20-dione as compounds of particularly high activity, such as:

11ß-chloro-17a-formylo2y-19-norpregn-4-en-3 »20-dione, 17a-aceto3y-11ß-chloro-6-methyl-19-norpregna-4 ₁ 6-diene-3 , 20-dione, 17 <x-Acetoay-11 ß-chloro-21-fluoro-19-norpregn-4-en-3,20-dione, 6,11ß, 16cc-trichlor-19-norpregna-4 _f 6-di en-3 , 20-dione and 17α-acetoxy-11β, 21-dichloro-19-norpregn-4-ene-3,20-dione.

Other compounds which are of particular use in the present invention Interests include:

9α-unsubstituted-6β-halogen-11β-chloro-19-norpregne-5 (10) -ene-3,20-diones and dienol ethers and esters thereof,

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COPY

9a-unsubstituted-6ß- halogen-11ß-chloro-19-norpregnan-5a-o.l ~ 3.20-

dione,

9α-unsubstituted-6β-halogen ~ 11β-chloro-19-norpregnan-3β, 5α-diol

2O-one,

9a-unsubstituted-11ß-Clilor-5a, 6a-epoxy-19-norpregnan-3ß-ol-

20-one,

9a-unsubstituted-11ß-chloro-19-norpregn-5-en-3ß-ol-20-ones, 3 ethers and 3 esters of 9a-unsubstituted-11ß-chloro-6-dimethylaminomethyl-19-norpregna-3,5-dien-3-ol-20-one-borane adducts

9oc-unsubstituted-11ß-chloro-19-norpregn-4-en-16a, 17a-diol-

3,20-dione.

These compounds are particularly useful as intermediates in the preparation of compounds of Formula I.

The new steroids according to the invention can be used on any expedient Way to be established. Another object of the present invention is a process for the production of

Steroids of the general formula: _Λ

CH ₂ R ¹

J = O '
--IT,

wherein a double bond is present or absent in the 6,7 position can be and in which R is a hydrogen or halogen atom,

ρ
R denotes a hydrogen atom, a hydroxyl group or an alkoxy or acyloxy group with 1 to 6 carbon atoms, R denotes a hydrogen or halogen atom or an alkylthio group with 1 to 6 carbon atoms, or in which R and R ^ together denote an alkylidenedioxy or aralkylidenedioxy group,

009886/2283

R ^ is a hydrogen, fluorine or chlorine atom or a methyl group, provided that R is not a hydrogen atom

2
represents, except when R is a formyloxy or alkoxy group or except when R is a halogen atom or an alkylthlo-

2 3 group, or except when R and R are an alkylidene dioxy or Aralkylidenedioxy group, or excluded when R ^ is a fluorine atom or a methyl group, and the 3,5-dienol ether and -ester, which is a steroid of the general formula:

CH ₂ R ¹

Ka)

wherein a double bond is present or absent at the 6,7-position can be, and in which R is a hydrogen or halogen atom,

R is a hydrogen atom, a hydroxyl group or an alkoxy or acyloxy group having 1 to 6 carbon atoms, R is a hydrogen or halogen atom or a hydroxyl group or denotes an alkylthio group with 1 to 6 carbon atoms,

2 5
or R and Br together denote an alkylidenedioxy or aralkylidenedioxy group or a carbon-carbon bond, and R ^ denotes a hydrogen, fluorine or chlorine atom or a methyl group, or a 3,5-dienol ether or ester thereof is reacted with one Reagent of the general formula:

it λ

II - IT-CCR ¹

R- r4 R ⁶

II

1 2
wherein R and R, which can be the same or different, alkyl groups with 1 to 8 carbon atoms or aralkyl or aryl

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groups "mean, or together with the nitrogen atom to the they are bound to form a heterocyclic group, if desired may contain more heteroatoms, R "^ a chlorine-

4 5

or fluorine atom, R is a chlorine or fluorine atom and R is hydrogen, or R ^ and R together are a carbon-carbon bond, R is a chlorine or fluorine atom and R 'is a chlorine or fluorine atom or a trifluoromethyl group, the reaction is carried out in the presence of chloride ions, if neither R- ^ nor R ^ chlorine ", or with a triarylphosphine or triarylphosphite and chlorine or a chloroalkane, or with an arylsulphonylating or alkylsulphonylating agent (arylsulphonylating or alkylsulphonylating reagent), followed by reaction of the corresponding 11α-Ary, sulfonates or Ha-alkylsulfonates so formed with a compound that yields chloride ions, or in an inert solvent, with a compound that yields positive chlorine, an anhydrous sulfur dioxide form which is present or added subsequently is followed, if a compound of the formula I is not formed immediately, by reaction of a 16,17-dehydration ro-steroides with a hydrogen halide sm? Introduction of a 16a-halogen substance; atesiy .with elaea alkaxrthiol,. To suffUiren a 16a-alkylthio-substance, or with. a vicinal DihyärosylieiTOSigsiäittel, followed by reaction with a ketone to a 16a, 17a-Alkylidenäio3 ^ y »· or -aralkylidendi oxy group to introduce, or by reacting a ITSS-acetyl-ITa-hydroxy steroid with a Aeylierungs- or alkylating agent, or by introducing an eluant atom or a methyl group at the 6-position or by reaction with a halogenating agent to introduce a 21-halogen atom.

When implementing a YerTbinclraig; of the formula II, in which neither R ^ nor B7 chlorine is denoted, ₉ the chloride ion-supplying terbinae is preferably a salt which is soluble in organic solvents, but which is a cationic part compared to the reagent of the formula II In @ 2? t, for example the cation of a tertiary or quaxternary starch substance, for example Xriäthylaiiiixi, SslmethylsBiin, Sysi & in, GoIlMiIi ₅ , Te-

009886/2283

trabutylammoniurahydroxide, etc. In general, however, is the preferred one Chloride ion supplying compound lithium chloride.

The residues of the formula II in which neither R nor R ^ is chlorine include: IT- (2-chloro-1,1,2-trifluoroethyl) diethylamine, H- (1,1,2,2-tetrafluoroethyl ) -diethy lamin, H- (2-chloro-1,1,2-trifluoroethyl) -dimethylamine, li (2-chloro-1,1,2-trifluoroethyl) -dipropylamine, N- (2-chloro-1, 1,2-trifluoroethyl) -diisobutylamine, H- (2-chloro-1,1,2-trifluoroethyl) -dioctylamine, H- (2-chloro-1,1,2-trifluoroethyl) -methylethylamine, N- (2, 2-dichloro-1,1-difluoroethyl) diethylamine, N- (1,1,2,3,3,3-hexafluoropropyl) diethylamine and H- (1,1,2,2-tetrafluoroethyl) diisopropylamine. D s _a reagent of choice is II- (2-chloro-1,1,2-trif luoräthyl) -diäthy lamin.

Reagents of formula II in which one or both of R ^ and R ^ mean chlorine, include in particular: N, N-diethyl-trichlorovinylamine.

The reaction with the compound of the formula II is preferably carried out in an inert solvent, ie in any solvent which does not react with the reagents, for example in aromatic or aliphatic hydrocarbons, halogenated hydrocarbons, esters, ketones, nitriles, Ethers and tertiary alcohols. Examples of such solvents are benzene, toluene, chlorobenzene, methylene chloride, pentane, hexane, cyclohexane, Ätiiylacetat, butyl acetate, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, tert-butyl alcohol, tert-amyl alcohol, and the like. Since the starting materials are often only slightly soluble in the non-polar solvents, a polar solvent such as tetrahydrofuran is preferred.

If not more chlorine substituents are needed should active hydroxyl groups initially present in the steroid to be protected, for example by esterification, etherification wad like.

009886/2263

The Hß-chloro-19-norsteroids can be made like it mentioned above, by reacting the corresponding 11a-aryl sulfonates or 11oc-alkylsulfonates, with a compound that Provides chloride ions, for example a chloride of an alkali metal, for example lithium chloride, or a hydrochloride a tertiary organic base, v / ie triethylamine, or a chloride of a quaternary organic base, such as tetrabutylammonium chloride, advantageously in an inert polar Solvents such as tetrahydrofuran. The 11a sulfonates mentioned above can by reacting the corresponding 11 a-IIydroxyverbihdung with an alkyl or aryl sulfonyl halide.

The 11β-chloro-19-norsteroids can, as has been further described, by converting a 9a-unsubstituted-11a-hydroxy-19-nor-steroid with a triaryl phosphine or phosphite and chlorine or a chloroalkane, for example triphenylphosphine in letrachloromethane.

The Hß-chloro-19-norsteroids can additionally be prepared by reacting a 9a-unsubstituted-11a-hydroxy-19-norsteroid in an inert solvent with a compound which provides positive chlorine, such as elemental chlorine, a tertiary alkyl hypochlorite or a cyclic one or acyclic N-chloramide, imide or hydantoin, for example H-chloroacetamide, N-chloro- or N, N-dichlorodimethylhydantoin, or, preferably, N-chlorosuccinimidjye ^ -ne anhydrous form of sulfur dioxide, such as liquid or gaseous sulfur dioxide , or an alkali metal hyposulfite, is present, or is subsequently added. The inert solvent is preferably an aromatic or saturated aliphatic hydrocarbon, a halogenated hydrocarbon, an ether, a sub-substituted amide or a tertiary amine, and it is preferably used in the absence of light under anhydrous conditions and at low or slightly elevated temperature, ie from -40 ° to 5O ⁰ C, is employed.

Introduction of specific groups into the molecule, either before

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- y -

or after the introduction of the Hβ chlorine atom, according to a can be achieved using the following procedures.

Compounds of the formula I in which R is a halogen atom can be prepared by reacting the corresponding Λ -steroid with a hydrohalic acid, preferably in an inert solvent, "for example a cyclic ether, for example dioxane or tetrahydrofuran, or in a chlorinated hydrocarbon, for example methylene chloride , äthanolfreiem chloroform or carbon tetrachloride, are prepared. The reaction is conveniently carried out ⁰ C at a temperature between -25 ° and + 3O. for example, 6,11ß, 16a-trichloro-19-nor-pregna-4,6 ~ d dien -3,20-dione can be prepared from 6,11ß-dichloro-19-norpregna-4,6,16-triene-3,20-dione by reaction with hydrogen chloride in dioxane.

The alkylidenedioxy or aralkylidenedioxy compounds of the formula I can be prepared by reacting the corresponding 16a, 17'-diols with a suitable ketone under acidic conditions, for example using mineral acids such as hydrochloric acid or perchloric acid. The 16a, 17a-Dio-Ie can be prepared by subjecting the corresponding 16-Ene to vicinal dihydroxylation by oxidation with reagents such as permanganate, osmium tetroxide, etc. (Cooley, J. 1955, 4373). The oxidation with permanganate is proposed ^ preferably at low temperatures, ie -10 ° C to +10 ⁰ C, in a wet, water-miscible solvent, for example a ketone such as acetone, advantageously in the presence of a weak acid such as acetic acid, carried out .

• z

Steroids of the formula I in which R is an alkylthio group can be carried out by reacting the corresponding Δ -steroids with an alkanethiol, for example methanethiol, in the presence of an acid, for example a mineral acid, for example hydrochloric acid. The reaction is preferably carried out in a polar solvent such as glacial acetic acid, and · a temperature between -25 ° C and +30 ^0.

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- ΊΟ -

Steroids of the formula I, in which R denotes a halogen atom, can be prepared by direct halogenation of the corresponding 17-acetyl steroids. The iodination is expediently carried out by reaction with iodine in the presence of calcium oxide and hydroxide and a solvent such as methanol / methylene chloride, preferably by addition an initiator, the free radicals delivered as azobisisobutyronitrile. Steroids, in which H ¹ signifies chlorine, bromine or fluorine, can then be obtained from the 21-iodine steroids by reaction with a compound that delivers chloride, bromide or fluoride ions, for example a metal chloride, bromide or fluoride, for example lithium chloride, lithium bromide or silver fluoride. The reaction is preferably carried out in an ionizing medium, for example a water-miscible solvent for the steroid. Moist acetonitrile is preferred if silver fluoride is used. Dry acetone is preferred, if you use lithium chloride orid or bromide used »

Steroids of the formula I, in which R is an aoylosy group, can from the corresponding na-Hytacosy steroids by acylation, for example by Fmsetsuag with an acyl halide or arihydride, preferably in the presence of an acidic Catalyst, "for example p-toluenesulfonic acid or perchloric acid, can conveniently be prepared using an inert solvent such as methylene chloride or benzene.

If an acyl anhydride is used, the dienol esters can pass through partial hydrolysis can be obtained to give the desired 17-monoesters.

A method of choice for the production of 17 & -Aeylo2 [y-steroids is the reaction of the 1α-oil with trifluoroacetic anhydride and the corresponding carboxylic acid, for example glacial acetic acid. This acylation is preferably performed at elevated temperature, ie durehgeführt at about 80 ⁰ C.

The 17ot acylation can also be carried out using antimony

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pentachloride and the appropriate acyl chloride among non-hydroxylic Conditions using, for example, nitromethane / chloroform be carried out as a solvent.

The 17a-formyloxysteroids can expediently be prepared by reacting the 17a-oil with concentrated formic acid in the presence of phosphorus pentoxide. The reaction can be carried out in an excess of formic acid as solvent and at a temperature between ⁰ ° C. and room temperature.

The steroids of the formula I, in which R is an alkoxy group, are advantageously / eise by reacting the corresponding 17Ot-OIs with silver oxy d and an alkyl halide, preferably the iodide, expediently in a substituted amide *; Imide or hydantoin solvents such as dimethylformamide or dimethylacetamide. The silver oxide should be freshly made be.

The steroids of the formula I ₉ in which R ^ is a halogen atom and in which a 6,7 double bond is present, can be prepared by reacting the corresponding ^< i3-halogen-5 (10) -en-3-ona and / or 6β-halogen- 4-en-3-one under acidic conditions, for example in the presence of p-toluenesulfonic acid, sulfosalicylic acid or preferably sulfuric acid, with an enol ether or an enol ester, for example iriethyl orthoformate or an acyl anhydride or isopropenylate and then with a dehydrogenating agent such as hangandioxide or 2 chloroanilioxide , 3-dichloro-5,6-dicyano-benzoquinone (DDQ) can be obtained. The 6ß-halo-5 (10) -en-3-one can be prepared by yourself, generally in a mixture with the 6ß-halo-4-en-3-one from the corresponding 5-01-3-one by acid-catalyzed dehydrogenation , for example by reaction with dry hydrogen chloride, for example in acetic acid or a chlorinated hydrocarbon as solvent. The 5ct-Ol-3-one can be prepared by oxidizing the corresponding 3β, 5α-diol using a reagent which is capable of oxidizing a secondary hydroxyl group to an oxo group, for example chromic acid; the diol can be selected from the corresponding 5α, 6α-

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Epoxy-3ß-ol by opening the epoxy ring with hydrogen chloride or hydrogen fluoride or boron trifluoride (etherate) in one Hydrocarbon and / or ether solvents, "for example tetrahydrofuran, dioxane, diethyl ether, cyclohexane, toluene, benzene, etc. The epoxide can itself through again Epoxidation of the corresponding 5-en-3-ol, for example using peracid, "for example m-chloroperbenzoic acid, Perbenzoic acid, perphthalic acid etc. in a chlorinated one Hydrocarbon and / or ether solvent, "for example methylene chloride, Chloroform or diethyl ether. The 5-en-3-ol can be obtained from the 3 ~ ester of the corresponding 3,5-dicn-3-ol be produced by reduction, "for example with a Borohydride reducing agents such as sodium borohydride, expediently in an ether / alcohol solvent which may contain water, for example methanol, ethanol, tert-butanol etc., with! tetrahydrofuran, Dioxane or glycol ethers.

Other öß-chloro-J-oxo- ^ I-steroids can by reacting a 3-acyloxy or 3-alkoxy, 4 * ^ - 1 iß-chloro-19-nor-steroides with a chlorinating agent such as molecular chlorine, preferably in the presence of a carboxylic acid such as acetic acid, propionic acid or pivalic acid and a tertiary base such as irimethylamine, Triethylamine or pyridine, or with an N-chloramide or -imide, for example N-chlorosuceinimide or N-chloroacetamide, Preferably in the presence of an inorganic or organic base, for example an alkali metal acetate, such as sodium or potassium acetate, or a tertiary amine such as triethylamine, Trimethylamine or pyridine, in the presence of a carboxylic acid such as acetic acid, propionic acid or pivalic acid. The 3-acyloxy group can, for example, be a 3-benzoyloxy or 3-acetoxy group and the 3-alkoxy group can be, for example be a methoxy or ethoxy group.

3-Oxo- <0 * 'steroids according to the invention can be prepared by reacting a 3-acyloxy- or 3-alkoxy-4 ^ ^> -steroid with a reagent which is able to convert an enol ether or ester into a conjugated ketone , for example chloranil or hangand dioxide.

009836/2261

Steroids of the formula I, in which Ir is a methyl group, can by hydrogenation or, preferably, transfer hydrogenation of the 3-ethers of the corresponding 3-hydroxy-6-dimethylarainomethyl-3,5-diene-borane adducts be prepared, "for example using a palladium catalyst in the presence of a cyclic Olefins, such as cyclohexene, advantageously at a pH in the range from 4 to 7 and dehydrogenation, for example with manganese dioxide, chloranil or DDQ. The 6-dimethylaminomethylsteroid borane adduct can come from the reaction of a 3-ether of the corresponding 3,5-dien-3-ol with a Vilsmeier reagent, followed by treatment with a reducing agent of the borohydride type. The Vilsmeier reagent can be reacted in the absence of water of an N-formylated secondary amine and an acid halide selected from such acid halides those that readily undergo nucleophilic exchange of the halogen ion upon treatment with N-formylated secondary amines will.

The N-formylated secondary amine can be, for example, dimethylformamide, Diethylformamide, methylethylformamide, methylphenylformamide, Ethylpheny! Formamide, N -]? Ormylpiperidine or N-pormylmorpholine. Of these, the preferred N-formylated amine is dimethylformamide.

Alternatively, a thio-formylated secondary amine can be used are, for example, dimethylthioformamide.

Acid halides suitable for the formation of a Vilsmeier reagent include phosphorus oxychloride, phosgene, phosphorus oxybromide, Phosphorus pentachloride, thionyl chloride and oxalyl chloride. The halide of choice is phosgene.

The Vilsmeier reaction is preferably carried out in a chlorinated Hydrocarbon solvents such as 1,2-dichloroethane are preferred carried out at a temperature of -10 ° to + 10 °.

The reducing agent of the borohydride type is preferably boron hy-

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drid of sodium, potassium, lithium, calcium, or zinc; Diborane, mono- or dialkyl derivatives of borane and their complexes with Bases such as pyridine, lithium cyanoborohydride, lithium or sodium alkoxyborohydrides. An alkali metal borohydride is preferred.

Treatment with the reducing agent is expedient filled in an ethereal solvent such as tetrahydrofuran.

The 3,5-dien-5-enolether can be obtained from the corresponding 4-en-3-one ' by enol etherification, for example by treatment with an orthoformate, for example triethyl orthoformate, under acidic conditions Conditions are established.

In general, the 3,5-dienol ethers of the compounds can Formula I by reacting the 3-one with enol etherifying agents, such as trialkyl orthoformates, in the presence of an acidic catalyst, for example a hydrocarbyl sulfonic acid, Sulphonsalycilic acid or, more preferably, sulfuric acid.

3,5-dienol esters according to the invention can be prepared by reacting the 3-ones with an enol esterification agent ₉ such as isopropenyl acetate, for example isopropenyl acetate or an acyl anhydride under acidic conditions, for example in the presence of p-toluenesulfonic acid or sulfosylic acid.

The invention furthermore relates to a pharmaceutical composition, the one or more steroids of general formula I as defined above, along with one pharmaceutical carrier or binding agent and / or one or more active compounds, for example hormones, contains. Compounds that have pregnancy-influencing activity can advantageously be used in conjunction with one or more hormones exhibiting estrogenic activity.

The compositions of the invention are to both humans and animals are administered "The Ausdruok ^ts pharmaceutical

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table "as used herein describes the compositions and! rager for it, both in human and used in veterinary medicine.

The compositions are preferably in unit doses and can be for daily oral administration in the form of Tablets, capsules, sachets, etc., can be formulated to be taken either directly or with a potion. Suppositories for rectal absorption can also be used. Injection preparations can be formulated, preferably for prolonged action, - while implantation pellets can be formulated which have the advantage that they only need to be administered very rarely. j

Usual pharmaceutical 'binders for solid preparations can include, for example, sugar alcohols, sugars, Starch, magnesium stearate, gelatin, polyethylene glycols and suitable ones Colorants. Tablets can be used, for example, for protection, for color differentiation or for a better appearance through usual Process to be coated, such as with film coating or sugar or pearl coatings SupposJ *: torien can be made, where you can use common raw materials, such as> ., k ^^ latine, cocoa butter or water-dispersible raw materials with a melting point above body temperature, such as polyglycols, are used

For injection preparations can for intramuscular or subcutaneous administration Λ in the usual sterile aqueous oily or emulsion basic materials in solution and / or suspension are made. Preferred carriers include physiologically acceptable vegetable oils, for example peanut oil, fractionated coconut oil, oily esters, for example isopropyl myristate, non-aqueous solvents, for example propylene glycol, aqueous carriers, such as sterile water or physiological saline, together with suitable formulating agents, such as suspending agents, for example aluminum stearate for oily Materials, carboxymethyl cellulose for aqueous preparations, physiologically compatible emulsifiers,

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for example Eween 81, buffering agent for the control of the pH, antioxidants, stabilizers and agents that improve solubility. The injections can be used for the un-. indirect use or as a dry powder for reconstitution used with a separate drag fabric before use will"

Unit lines that should work longer, for example during a month, may naturally contain an increased amount of the active material. ,

Each dose unit for daily administration to humans is - Holds preferably 0.01 to 5 mg of the active according to the invention * Material, most preferably 0.05 to 5.0, e.g. 0.05 up to 2.0 mg,

Implant pellets are generally a higher dose included to ensure prolonged activity, preferably for several months. Implants can be made aseptically sterile Material, for example by fusing or pressing under pressure, are produced.

Long-acting vaginal inserts such as tampons and pessaries can be used in veterinary medicine in particular Usual way to be made. The dose required to treat the blood varies, of course, according to its size the Iier «.

The pregnancy-influencing compounds can be considered as oral contraceptives, preferably either in continuous daily dosages of 0.01 to 0.5 mg, advantageously 0.05-0.5 mg, or they can be used intermittently with higher doses mixed with an estrogen (0.05 mg Ethinyl estradiol plus 0.1 to 5 mg, more preferably 0.5 to 2.0 mg Progestin). Regardless of their use as oral contraceptives, these prostagens can

009886/2263

clinical "used in the following conditions: dysmenorrhoea, functional uterine bleeding, premenstrual tension,> Diagnosis of pregnancy, endometriosis and threatening or habitual Abortion.

The following examples illustrate the invention without, however, restricting it.

example 1

11a, 17a-Dihydro3y-21 ~;} od ~ 19-norpregn-4-en-3,20 ~ dione.

A mixture of 11a, 17a-dihydro: xy-19-norpregn-4-en-3 »20 ~ dione i (1 g, 5 mmol), potassium oxide (3 g), calcium hydroxide (3 g), azo- * bis- butyronitrile (0.1 g), dry methylene chloride (15 ml) and dry methanol (15 ml) was stirred vigorously at room temperature. Iodine (0.9 g, 3.6 mmol) was added and stirring was continued for 1 hour after which time the brown color had disappeared. The reaction mixture was filtered and the piltrate was partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO *) and evaporated under reduced pressure. Purification by preparative layer chromatography and crystallization of the less polar fraction (0.71 g) from methyl acetate / petroleum ether (boiling point 60 to 80 °) yielded the vanity compound (0.464 g, 34 #) »5 ¹ P. - 126 ° (decomposition), [ a] _D + 34 ° (c 0.8, OHOl ₃ ), ^ ^ »239 nm (£» 16,800). |

Example 2

21-Eluor-11α, 17a ~ dihydroxy-1O-norpregn-4-ene-3,20-dione.

A solution of 11a, 17a-dihydroxy-21-iodine-19-norpregn-4-ene-3,20-dione (2.87 g) in acetonitrile (500 ml) and water (5 ml) was mixed with silver fluoride (20 ml, 50 # aqueous solution) at 40 ° for 4 hours treated. The reaction mixture was then filtered and the filtrate concentrated and partitioned between methylene chloride and water distributed. The organic layer was dried (MgSO-) and evaporated in vacuo. The residue (2.04 g) was prepared by preparative Purified layer chromatography and crystallization out

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Methyl acetate / petroleum ether (boiling point 60 Ms 80 ^b ) provided the title application (0.72 g, 33 #) »I ¹ P * = 223 Ms 225 °, W _B +10.6 (c 0.5, CHCl ₃ ), λ Jj _10x = 239 * 5 um (£ «16,000).

Example 3

11 ß »0hlor-21« f luor »17a ~ hsrd £ oagM9» n ©: i? Pregn-4 ~ en-3

A mix of 21-1

3,20-dione (0.35 g, ImMoI) ₅ , üithitmohlorld (0.35 g) in the dry:! Tetrahydrofuran. (7 ml) was treated with H- (2 <^ loiv1t1j2 ~ trlfluo £ & th7l) -diethylamine (0.35 ml) toehaadelt. 3ie mixture was geriinrt 1 1/2 Stimden and daaa Ie ice / ¥ ags @ r Gegel? ® "· The solid was duroh Filtratioa-'abgetseaat xao & ssmimsX umicristallieiert from -Xtbylaoetat to give erhielt- the fltelimsMnimig (0 _f 09 g ₉ 22 ^) Pp. »196 Ms 197 ° (Zersetsmsg), [®l _s + 129» 5 ^tt ~ (o ^; 0.5, Bioxane), K max ^ 238 im C € «16 80 '

Blno Lösimg ται t1 £

dion (0 _s o6 f;) ia JSisessig Ct si) w & ü

(1.5 al) was poured under Stiekstaff 13 @ J, SO® '1 1/2 S Me EeaktioBSffiiselsssg was if necessary wd ia Wasrees. The solid (0.61 g) vnirde cteäX ³ © ii EHfeati © »trimmed iqad by means of preparatίτβ ScliieSriJgiisoiiSi'ßsgsaglie geseialgt« Iristsllisatioa from Mötaylaeetat / Sa-össlärllaes ¹ (0 delivered the Mg6 ° 80 ° _{p. 60 ss 60} 9 $) _g Sp. Β 189 ° _s . [A] _B + 62.5 °

(o 0.25, OHOI ₅ Kj ₁ ^^ »231.5 a {£ ^ 13 V

Example 5 '

11 α, 17a-BiliydrG ^ ™ 21 - j od-19-norpregii-4-en-3 »20-dloa (ö, 38 g), Mthiumchlorid (0 ^ 5 g) and dry Ae © toa (8 ml) were Heated under reflux for 3 hours, the reaction was carried out

Evaporated to dryness and the residue partitioned between methylene chloride and water. The organic layer was dried (MgSO.) And evaporated. The residue (0.33 g) was purified by preparative thin-slice chromatography and crystallization from methyl acetate / petroleum ether (boiling point «60 to 80 °), in which case the # itelT © rbiHdung was obtained (0.1 g), mp, * 150 ° (decomposition), [*) $ + 38.7 ° (o p _t 4f CHOl ₃ ), S _103x «241 nm (£ « 16,200).

Example 6

11 ß, 21 -Di chloro-17a-hydroaty-19-norpregn-4-en-3,20-di one.

A mixture of iron 21-Qhlor «-11α, 17α-dihydroxy-19-norpregn-4-en- ™ 3,20-dione (0.28 g), idthium chloride (0.3 g), N- (2-chlorine- 1,1,2-trifluoroethyl) diethylamine (0.3 ml) and dry tetrahydrofuran (6 ml) were stirred for 1 hour and then poured into ice water. B _e r Feetetoff (0.28 g) was separated by filtration. Purification by preparative layer chromatography and crystallization from Mathylaoetat / petroleum ether afforded the title compound (0.105 g) (b.p. 60 to 80 ° m), ip. = 183 ° (decomposition), [ajjj + 165 ° (c 0.4, CHOl ₃ ), X _184x «239 am (£« 17,600).

Example 7

17α-Aceto ^ y-11ß, 21'-dichlo ^ v19-norpregn-4-en-3,20-dione. j

A solution from

3,20-dione (0.65 g) in glacial acetic acid (7 ml) and irifluoroacetic anhydride (1.7 ml) was heated at 80 ° for 1.5 hours and then poured into water. The solid was separated by filtration. Purification by preparative layer chromatography and crystallization from methyl acetate / petroleum ether (boiling point = 60 to 80 °) yielded the vanity compound (0.113 g), melting point = 191 °, [a] _D + 86 ° (c 0.5, CHGl ₃ ), X ₉₆ ^ == 238 nm (£ = 17,200).

009886/2263

Example 8 (a)

11β-chloro-19-norpregna-4,16-diene-3,20-dione.

A solution of Hß-Chlor-ITa-hydroxy-ig-norpregn- ^ en-J, 20-dione (0.8 g) and semicarbazide hydrochloride (0.8 g) in methanol (40 ml) was heated to reflux for 2 hours. The solution was then concentrated by evaporation under reduced pressure and diluted with water. The pesticide was separated off by filtration. A solution of this solid, pyruvic acid (2.5 ml), water (5 ml) and acetic acid (16 ml) was heated on a steam bath for 1 hour.

The reaction mixture was then concentrated by evaporation under reduced pressure and partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried (MgSG,) and evaporated under reduced pressure. The residue (0.67 g) was divided into two fractions by preparative thin-layer chromatography. Crystallization of the less polar fraction (0.38 g) from methyl acetate / petroleum ether (boiling point> 60 to 80 °) yielded 11β-chloro-19-noypregna-4,16-diene-3,20-dione (0.246 g, 32 $> ), Pp. * 183 to 184 °, [a] ^ + 219 ° (c 0.8, CHCl ₃ ), ^ ^ _x (EtOH) = 237 to 238 nm (£ * 31,500).

Example 8 (b)

11 ß-chloro-16a-methylthio-19-norpregn-4-ön-3,20-dione.

A solution of 11β-chloro-19-norpregna-4,16-diene-3,20-dione (0.6 g, 1.8 ml ole) in glacial acetic acid (30 ml) was cooled and concentrated Hydrochloric acid (1.2 ml) was added. To this Solution, methyl mercaptan (1.1 ml) was added and the flask containing this mixture was capped and closed at 5 to Stored 7 ° for 40 hours. It was then concentrated in vacuo and the residue was extracted with methylene chloride, the organic Phase was made with aqueous sodium bicarbonate and water washed, dried (MgSO.) and evaporated to give a

0098 8 6/226 3

_ _{21- 2038908}

Foam (1 g) was obtained. Purification by preparative layer chromatography and crystallization from methyl acetate / petroleum ether (boiling point «60" to 80 °) yielded the title compound (0.248 g, 36 jS), Ep. - 194 Ms 195 °, ία] _Ώ + 128 ° (c 1.0, Chloroform),

K max ^{β 256 to 237 1} ^ ^ ^{= 17 800)} Example 9
11ß-chloro-17a-methyl-19-norpregn-4-en-3,20-dione.

11β-Ohlor-17a-hydroxy-19 ~ norpregn-4-en-3,20-dione (0.2 g) in methyl iodide (1 ml) and dry dimethylformamide (2 ml). _: J stirred with freshly made silver oxide (0.4 g) 2 layers. The reaction mixture was filtered and the filtrate was partitioned between ether and water. The organic layer was dried (MgSO.) And evaporated in vacuo. The residue (0.214 g) was crystallized from methyl acetate / petroleum ether (boiling point = 60 "to 80 °) and gave the title compound (0.096 g), pp. 163 to 165 °, [a] ^ + 168 ° (c 0.5 , OHCl ₃ ), = 237 to 239 nm (£ = 16,450).

Example 10

17 "-Acetoxy-11β-chloro-3β-hydroxy-19-norpregn-5-en-2O-one.

3.17ct-Diacetoxy-11ß-chloro-19-norpregna-3f 5-dien-20-one (1.0 g, 2.3 mmol) in i-tetrahydrofuran (55 ml) and ethanol (60 ml) was treated with lithium borohydride (1 , 00 g, 25.6 mmol) in water (2 ml). After 2 hours the solution was poured into Ither, washed with dilute hydrochloric acid and with water / water, dried (UTa ₂ SO.) And evaporated. The residue (0.865 g) was recrystallized from ether / low boiling petroleum ether, to give the Eitel compound (0.308 g), Pp. "" 189-196 ⁰ C, Ca] ₃₎ + 24.7 ° (c 0.71, Dioxane).

009886/2263

Example 11 (a)

17oc-ethoxy-11ß-ehlor-5oe, 6a-epoxy-19 * -norpregn-3ß-ol-2O-one

17α-Acetoxy-11β-chloro-3β-hydroxy-19 »norpregn-5-en-20-one (θ, 801 g, 2.02 mmol) in ethanol-free chloroform (20 ml) was treated with 90 # m-chloroperbeneäia 'e (O ₉ 466 g, 2.46 mmoles) dissolved in ethanol-free chloroform (10 ml). "After 2 hours the solution was poured into ether, washed with aqueous sodium carbonate and with water, dried (Wa ₂ SO *) and evaporated." Crystallization from ether ran the Xltelverbindungen (0.703 g, 82 #), Ip. e 198 Ma 200 °, [ßk - 3 »3 ° (o 0.76, Dloxan),

m, example 11

17o ^ acetoxy-11ß-

(0.407 g, 0.99 mmol) ia dry Bgnaol (20 ml) and "dry ether (20 ml) was treated with r @ S® @ tiXXlexrtem Boa? TrlfXuo? Idäthexat (0.4 ml)" * Iiie Mis-osag wmä® b @ i 2iBaaert @ mperatur 2 1/2 hours ttat wA ämm im, itkyiacetat eaten raid with wäSrigöi? MatriiiELiilearboastliSswig isM Suit "fetter gewasehen UNAE ämiii dried · Sinäaiapf ©» uaä! © IssSgea ä © s Bttoketandee ω # 451 g) Diti-eh präparaisiT © isfciiisiiteteosatogsaOhie TMAE Kristal * lization from acetone / ItJte? Liefex-fu ai ©! SiteXverbiadung (O _t 134 g) t Pp .. «137 Ms gO2® _e Ε © 3 _Ώ + ■ 13 _t 5 ° (o 1 ₉ .04 _$ dioxane).

Example 11 (c)

(0.26 g, 0.6 per MoX) in Aoettm (20 ml) was "frozen at 0 ° and concentrated dropwise with Jones-Beagena (ice © solution ₉ - 'di © Oteoatriosyd [66.6 g] in ^ .SobwefeXeäure. [53.3 mX] contained and was made up to 250 ml with water), treated, the oxidation was not permanent. Di @ Jteaktlansmisohuiig .was poured into ether, washed with water, g @ trookaet (Ia ₂ SO ₄ ) wheel in the Ya-.

ORIGINAL INSPECTED

vacuum evaporated

Crystallization of the residue (0.198 g) from Ither yielded the oil compound (0.129 g), i * p. «169 to 175 °, [a] _D + .37 ° (c 0.84, dioxane).

Example 11 (d)

scsssscssfisssss

17tt * -Acet oxy-11 ß-chlo3v6-f luor-19-norpregna-4, 6-diene-3,20-dione.

17α-acetoxy-11β-chloro- "6β" "fluoro-19-norpregn-5oc-ol-3,20-dione (0.91 »g, 2.14 mmol) in dry acetic acid (35 ml) was with Treated hydrogen chloride. After 20 minutes the reaction mixture became poured into water and the product collected by filtration. The crude 17a-Aoetö3 ^ -11ß-chloro-6ß-fluoro-19 ~ norpregn-5 (10) -en-3 »20-uiim (0.86 g) was dissolved in dry dioxane (35 ml) and Iriäthylorthoformiat (5 ml) dissolved and concentrated with Sulfuric acid (0.2 ml). Hach was 3 hours the dark solution in a stirred dilute aqueous ITa * Triumhydroxydlösung given and the steroid extracted with ether. The extract was washed / dried with water ) and evaporated.

Ethyl acetate (40 ml) was added to the residue and the stirred solution was treated sequentially with activated hangan dioxide (5 g) and 90 # aqueous acetic acid (5 ml). After one hour the reaction mixture was filtered and the piltrate evaporated to give a gum. This was filtered through a column of neutral aluminum oxide from Woelm (20 ε) in ethyl acetate. The eluate was evaporated and the residue (0.548 g) was purified by preparative layer chromatography, whereby the title compound was obtained (0.132 g), [a] _D + 34.7 ° (c 0.95, dioxane), A ₁ Qa _x « 278 nm (£ = 20,100).

009886/2263

Example 12

17a ~ acetoxy-11 ß-chloro ^ -ethoaqr'-ig-norpregna-J, 5-dien-20-one.

(0.39 g, 1 mmol)

in dry dioxene (5 ml) and triethyl orthoformate (1 ml) were stirred with sulfosalicylic acid (0.005 g) under nitrogen, and pyridine (0.5 ml) and ether (200 ml) were added for 45 minutes. The solution was washed with aqueous sodium hydrogen carbonate solution and with waeeer, dried (Na ₂ SO ^) and evaporated. The residue in ether was filtered (20 g) through basic aluminum oxide and the J iltrat was evaporated and the residue (0.28 g) was crystallized from ether to ₉ wherein the Sitelverbindung (0.065 g), mp -. 146 to 148 ° , Ed] ₃₅ + 5.8 ° (c 0.77, dioxane), ^ ^ _x «24I nm (£ β 14 100), obtained

Example 13 (a)

17a-Acetoay-11 ß-chloro-3-etho ^ «6-dimethylaminomethyl ~ 19-norpregna-3,5 -! 'Dien-20-one-borane.

-11β-chloro-3-ethoxy-19-aorpregna-3,5-dien-20-one (417 day, 1 BMoI) was dissolved in 1,2-dichloroethane (4 ml) containing a drop of pyridine and added an ice-cold stirred Vilsmeier reagent, prepared from dry dimethylformamide (0.3 al) in 1,2-dichloroethane (1 ml) and 10 # (v / v) phosgene in 1,2-dichloroethane (5 ml) given. The red mixture was stirred for 2 hours and then treated with a solution of lithium borohydride in dry tetrahydrofuran until the red color disappeared. The mixture was partitioned between ether and aqueous sodium hydrogen carbonate solution and the organic layer was washed with 1 # aqueous succinic acid solution, dried (ITa ₂ SO ₄ ) and evaporated to give the title compound, \ "_" = 254 nm (£. «14 600).

009886/2263

Example 13 (b)

17a-Acetoxy-11β-chloro-S-ethoxy-ö-dimethylajnino-methyl-1 9-norpregna-3,5-dien-20-one-borane (0.491 g), sodium acetate (1.5 g) and 5% palladium on charcoal (150 mg) were added with stirring with ethanol (10 ml), cyclohexane (2 ml) and acetic acid (0.5 ml) heated to reflux, compartment 90 minutes, the reaction mixture was filtered and the filtrate between ether and aqueous sodium hydrogen carbonate solution "distributed

The organic layer, to which one drop of pyridine had been added, was evaporated to dryness. The residue (0.36 g) in ethyl acetate (10 ml) was added to a stirred manganese dioxide solution and 90% aqueous acetic acid (1 ml). After 25 minutes, the reaction mixture was filtered and the piltrate evaporated to dryness. The residue (0.282 g) was purified by preparative layer chromatography and crystallization from methyl acetate / ether, whereby the title compound (0.136 g) was obtained, pp. = 190 to 194 °, Ca] ₃₃ + 82.7 ° (o 0 dioxane), ^ ^ _x = 282 am (£ = 18 700). '

Example 14 '

11ß-Ohlor-17 "-formyloxy-19-norpregn-4-en-3,20-dione"

11β-Öhlor-17a-hydroxy-19-norpregn-4-en-3,20-dione (0.57 g) in stirred 98 to 100% formic acid (20 ml) was at 10 ° treated with phosphorus pentoxide (2.5 g) for 10 minutes. The mixture was stirred for an additional 10 minutes, poured into water and extracted with ether. The organic layer was dried (MgSO ^) and evaporated in vacuo. The residue was by preparative layer chromatography and crystallization Purified from acetone / hexane and provided the title compound (0.293 g), pp. = 218 to 220 ° (decomposition), [cc] ^ + 70 ° (c 0.86, dioxane), ^ ^ 237 nm (£ = 17,900).

009886/2269

Example 15 (a)

6,11ß-dichloro-19-norpregna-4 »6f16-trien ^ 3f20» άΙοη.

A © solution from e

dien «3» 20-dione (0.38 g »1 äjI? produced by hydrolysis of the 17a-acetoxy group of 6,11B-» J) ichl, Q »-tTei-ac © toay» 19-norpreg · - na-4, 6-diene-3,2O-dione with eelium moarfeonate in methanol) and semicarfcazide hydrochloride (0.58 g) in methanol (20 ml) was heated to reflux for 2 hours. It was then concentrated under reduced pressure with water. The solid was purified by filtration. · separated Bine Höeung of this solid acid, pyruvic acid (0 # -4 ϊβΙ) Masses (2 nl) and acetic acid (7 ml) was st, u £ © IAEA Bampfbaä heated for 1 hour. The reaction siselmag wus & e öasa äiueoh evaporation iiÄtaa? reduced Ifeuelc concentrated imä swiset ^ a Xthylacetat vmä ITatriumhydrocarbonatlcSfiiiag distributed "- The organic Sehioiit was wasßu.eB ₉ dried C% SO ^,) wnfi tarter reduced pressure, the residue C © _? 35 g) are preparative Dtinnse5hioht © 2s3? © SBäto§E ^ phi © Iä divided into two stages. Kjiistalllestioa ö © 3? weaiges' polar fieaktlonea. (.0.15 g) from methyl acetate / petxol ether (boiling point: € 0 rock 80 °) provided the 6.11 ß-Mshler ~ 1 9 ~ nomm ~ gsm ™ 4 ₉ 6 »16-t» ieft-3 «20- dien C0 _f 12. g, 33 Jt), Pp. = .158 to 160 °, Ca] ₂ yrs + 2? O ^ö 'C ^{2S0 m} ^ ^s B700, - 25 500}

max ^β
Example 15

A chilled solution of 6.11 @ «

trien «3f20-dioii (0.4 g) 'Ia Siexaii (50 ml) was with material saturated and "stored at 15 ° 2 Sage. The reaction mixture Was then awisehea methylene chloride unäfirigex KatriumhydrogencaörhonatlösMag distributed. She - organic layer was dried (MgSO.) And in vacuo aingedasi ^ ft ·. The residue (0.46 g) / was determined by preparative layer chromatography and crystallization from ethyl acetate purified, whereby the

00-988SA228 *

2036308

iDitel compound obtained (0.204 g, 46.5 #), pp. β-142 to 144 ° (decomposition), [a] _D + 198 ° (ο 1.0, CHCl ₅ ), ^ _max = 281 nm (e * 23 700).

Example 16 («)

17a-acetoxy-6,11ß-dichloro-19-norpregna-4,6-diene-3,20-dione,

A mixture of ron
Na-3,5-dien-20-one (0.6 g), manganese dioxide (3 g) and benzene (15 ml) were stirred for 1 hour and then filtered. Has piItrat was evaporated under reduced pressure and the residue (0.528 g) was purified by preparative thin layer chromatography and crystallization of a rope (0.448 g) from methyl acetate / petroleum ether (boiling point «60 to 80 °), whereby the Me thylacetatsolvat was obtained, which by heating was desolvated at 95 ° for 4 hours and 0.5 mm and the 17ct-aoetoxy-6,11S-dichloro-19-norpregna-4 _t 6- <iien-3,20-dione (0.37 g, 66? & ) yielded, Pp, - 211 to 212 ° (decomposition), t «] _D + 78 ° (c 1 _f 0 _t dioxane), λ max ^ ⁰¹¹ ) = 280 na (£« 22 100).

Example 16 (b)

6,11ß-dichloro-17a-hydroxy-19-norpregna-4,6-diene-5,2O> dione.

17a-Acetoxy-6,11ß-dichloro-19-norpregna-4,6-diene-3 »20-dione-methyl acetate-solvate (104 ag) ia methanol (5 ml) and water (0.1 ml) was treated with potassium bicarbonate (22 mg) and the solution was refluxed in a stream of nitrogen for 4 hours. The solution was diluted with ether, washed with dilute aqueous hydrochloric acid and with water, dried (MgSO,), filtered and evaporated to give a foam obtained, which on recrystallization from aqueous methanol gave the 6,11ß-dichloro-17a-hydroxy-19-norpregna-4,6-diene-3,20-dione (34 mg) as prisms, pp. = 215 to 218 °, λ max ^s 280.5 nm (£ a 22 100).

009886/2263

Example 16 (c)

6.11β ~ dichloro-17a-formyloxy-19-norpregna-4,6-diene-3,20-dione.

6.11 ß-dichloro-17a-hydroxy-19 ~ norpregna-4,6-diene-3,20-dione (0.375 g, 0.98 mmol) in vigorously stirred 98 to 100% formic acid (20 ml) at 10 °, phosphorus pentoxide (2.5 g) was treated in small quantities over a period of 10 minutes. After a further 10 minutes the solution was poured into ice water (200 ml) and the product was separated by filtration. Purification by preparative layer chromatography and crystallization from methyl acetate / hexane provided the title compound (0.170 g, 42 %) , pp. = 210 to 212 ° (decomposition), Co] ₃ J + 97 ° (c 1.7, dioxane), ^ _max = 279 mn (£ = 23,000).

Example 17

11β, 16a-dichloro-19-norpregn-4-en-3,20-dione.

A cooled dioxane solution (75 ml) containing 1iss-chloro-19-norpregna-4,16-diene-3,20-dione (1 g, 0.003 mol) was saturated with hydrogen chloride. After 3 days at 15 °, the solution was poured into cooled aqueous sodium hydrogen carbonate solution and then extracted into chloroform. The organic layer was washed with water, dried (MgSO.) And evaporated. The residue (1 g) was purified by preparative layer chromatography and crystallization from methyl acetate to give the title compound (0.279 g, 25 SO, mp = 151.5-152.5 °, [alp + 166 ° (CHCl ₃ , c 1.0), ^ ^ _x = 236 mn (£ = 17 650).

Example 18

11.beta.-chloro-1 6a, 1 7a-dihydroxy-19-norpregn-4-ene-3,20-dione.

To a stirred, ice-cold solution of Hß-chloro-19-norpreg na-4,16-diene-3, 20-dione (0.20 g, 0.6 mmol) in acetone (5.7 ml) and glacial acetic acid (0.057 ml) became a solution of potassium permanganate (92 mg) in 85 # strength aqueous acetone (5.3 ml) for 15 minutes

009886/2263

■. - 29 -

given. Sulfur dioxide was then bubbled through the brown solution until it turned yellow. The mixture was filtered and the filtrate was concentrated by evaporation. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried (MgSO . and evaporated). the residue was purified by preparative layer chromatography and crystallization from acetone, to the SDitelverbindung mg (22, 10 ° ß>) received, Pp. = 176-180 ⁰ O.

Example 19

11ß-chloro-16a, ^ a-isopropylidendioxy-ig-norpregn ^ -en ^, 20-dione.

Crude 11β-chloro-16a, 17a-dihydroxy-19-norpregn-4-ene-3,20-dione (0.557 g) in hot acetone (30 ml) was treated with concentrated hydrochloric acid (3 drops).

The solution was heated to boiling for 2 minutes and then left to stand overnight. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was dried (MgSO.) And evaporated. The residue (0.602 g) was purified by preparative layer chromatography and crystallization from methyl acetate, giving the vanity compound (0.213 g, 17.5 10) , pp. = 203-205 °, [a] _D + 150 ° (c 1 , 0, CHCl ₅ ), A _max = 236 mn (£ = 18 150).

Example 20

11β-chloro-17a-hydroxy-21-iod-19-norpregn-4-en-3,20-dione.

A mixture of 11ß-chloro-17a-hydroxy-19-norpregn-4-en-3,20-dione (1.4 g, 4 mmol), calcium oxide (4 g), calcium hydroxide (4 g), azobisisobutyronitrile (0.14 g), dry methylene chloride (20 ml) and dry methanol (23 ml) was stirred vigorously at room temperature. Iodine (1.2 g, 4.8 mmol) was added and stirring was continued for a further 30 minutes, after which the brown color disappeared. The reaction mixture was filtered and

009886/2263

the filtrate partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO.) And evaporated in vacuo. Purification of the residue (1.85 g) by preparative layer chromatography and crystallization of the less polar fraction from methyl acetate / petroleum ether (boiling point = 60 to 80 °) yielded the title compound (0.264 g, 14 #), 3? P. = 116 ° (decomposition), [ccjp + 110 ° (c 0.8, CHCl ₃ ),

λ max = ^{1 238 nm (} * - ^{21 000)} '

The following examples describe pharmaceuticals according to the invention Compositions.

A. Oral tablets (for continuous daily administration)

a) 6.11 ß-dichloro-17 <* - formyloxy-19-norpregna-4,6-

diene-3,20-dione (microfine) 0.25 mg

Thickness (particle size corresponding to a sieve with a mesh size of 0.25 mm; 60 mesh) 10.0 mg

lactose (particle size that fits a sieve with a clear mesh size v. Corresponds to 0.25 mm;

60 mesh) 64.0 mg

Magnesium stearate (with a particle size! Particle size that fits a sieve with a corresponds to a clear mesh size of 0.15 mm; 0.75 mg 100 mesh)

The steroid is ground into a fine powder with twice its weight in lactose in a ball mill, into a Particle size below 5 microns. Thereafter, the reaction mixture with five successively added parts of lactose diluted, always grinding in between. Then the starch is rubbed in and the remaining lactose is formed a homogeneous powder mixed in. It is granulated with 50 # strength ethanol in water and sieved through a sieve a mesh size of 1.7 mm (No. 12 mesh BS-Sieve). The granulate is dried to constant weight and thoroughly a sieve with a mesh size of 0.65 mm (20 mesh BS Sieve) and mixed with the magnesium stearate. Then the magnesium stearate is added and 75 mg tablet

0Q98SS / 22S3

They are pressed onto a 0.52 mm (7/32 inch) die, preferably notched to identify the tablets. The pressure is adjusted so that the tablets are within Disintegrate for 10 minutes. The! Tablets can be coated with a film to distinguish them by color and they should be used for the public use only in specially labeled packs in order to precisely regulate the use of the tablets.

Oral tablets for intermittent administration

(b) Hβ-chloro-16a, 17a-dodpropylidenedio3qjr-19-norpregn-4-cn-3,20-dione (microfine) 2.0 mg

(c) Ethinylestradiol (microfine) 0.05 mg |

Starch (with a particle size that matches a 10.5 mg sieve with an internal mesh size of Correspond to 0.25 mm; 60 mesh)

Lactose (with a particle size equal to a

Sieve with a mesh size of

Correspond to 0.25 mm; 60 mesh) 66.65 mg

Magnesium stearate (with a particle size that a sieve with a mesh size of

Correspond to 0.15 mm; 100 mesh) 0.8 mg

(b) and (c) are ground separately with small amounts of the lactose in a ball mill, mixed together and then, as described in Example 1, the mixture of (b) and (c) instead of (a) as in Example 1 described, treated. The tablets are pressed onto punches at 80 mg per tablet and they can then be weighed if desired.

Long-acting injection (deep intramuscular)

(d) 6.11 ß, 16a-trichloro-19-norpregna-4,6-diene-

3.20-dione (sterile). 10.0 mg

Aluminum stearate 1.5 # (w / w) (gelled in winterized peanut oil to make 0.5 ml

The raw material is prepared by mixing, heats the aluminum stearate dispersed in the peanut oil, is to Solve reached and thickening occurs at about 90 ⁰ C. The reaction

009886/2263

tion vessel is closed while Stirring is continued and / sterilized raw material by heating to 150 ⁰ C for 1 hour. The mixture is cooled quickly to 55 ⁰ C and triturated the basic material aseptically with (d), and outputs the mixture through a Raffinati.onsmühle and mixed to obtain a homogeneous dispersion. The mixture is packed in unit packages.

D. Aqueous injection (long acting)

(e) 11 ß, 1βα-dichloro-i9-norpregn-4-en-

3,20-dione 10.0 mg

(f) sodium arboxymethyl cellulose 10.0 mg

(g) Honex 52 (a polyethylene glycol oleate, that at Union Carbide of Grafton St.,

London W. 1 is available) 0.01 f> (wt /

Weight) (in the final injection)

(h) Usual strength 20.0 mg

Carrier (in a separate container) A sterile sorbitol solution $ 10 (w / w) 1 ml

(f) and (h) are sterilized separately by dry air.

(g) is dissolved in a little chloroform, sterilized by filtration and over the mixed sterilized powders (f) and (h) dispersed. The chloroform is removed and the powders are ground in a ball mill, a homogeneous mixture being obtained receives. Prepare sterile crystals of (e) in two particle size ranges about 15 to 25 microns and 30 to 40 microns, working to get equal parts of each receives. These crystals are mixed with the base and then 55 mg of the resulting dry mixture is made into sterile Vessels filled and hermetically sealed. Before use, the injection is carried out by adding 1 ml of the sorbitol carrier reconstituted to the dry mixture and with shaking a suspension is obtained.

009886/2263

E. Tablet Implants

jYppyy 19 "-norpregn-4-en-3,20 ~ dione (microfine) 60 mg

Tablet implants can be made by known methods such as pressing under pressure of the sterile material or by fusing or by fusing and deforming in a mold. The implants are in sterile moisture-proof Container packed.

The amount of active ingredient in the implant is related with the required duration of the shape and the surface area and the average absorption necessary for the formulation is required.

F. Intravaginal pessaries for use in veterinary medicine (for sheep)

(k) 6,11ß-Diehlor-17a-formyloxy-19-norpregna-4,6-diene-

3,20-dione 20.0 mg

(k) is dissolved in sufficient ethanol and sterilized by filtration. The pessaries or tampons can be manufactured by known methods by adding the required amount Ethanol solution on gauze rolls or a fine, porous plastic sponge adsorbed, the ethanol evaporates in a vacuum and the vaginal inserts in sterile packs that are suitable for administration are packed. The dose required for the veterinary preparations required depends of course on the size of the animal to be treated.

009 886/2 263

Claims (1)

Claims 1 yTerfahren for the production of steroids of the general] oriel: CH ₂ R ¹ I ² C = O Cl (where there is a double bond in the 6,7-position or may be absent, and wherein R is a hydrogen or halogen atom means, 2
R is a hydrogen atom, a hydroxyl group or an alkpxy or acyloxy group having 1 to 6 carbon atoms, R ^ is a hydrogen or halogen atom, or an alkylthio group 2 ^ 5 with 1 to 6 carbon atoms, or R and R "^ together one Alkylidenedioxy or aralkylidenedioxy groups, R ^ a hydrogen, fluorine or chlorine atom or a methyl group means provided that R is not a hydrogen atom ρ
means if not R is a formyloxy or alkoxy group or if not R ^ is a halogen atom or an alkylthio group or if not R and R ^{5 are} an alkylidenedioxy or aralkylidenedioxy group or if not R is a fluorine atom or a methyl group) and 3,5-dienol ether and esters thereof, characterized in that a steroid of the general formula: 009886/2263 Yes (where there is a double bond at the 6,7-position or J may be absent, and in which R is a hydrogen or halogen atom, R denotes a hydrogen atom, a hydroxyl group or an alkoxy or acyloxy group with 1 to 6 carbon atoms, R ^y denotes a hydrogen or halogen atom or a hydroxyl group or an alkylthio group with 1 to 6 carbon atoms or R and R ^ together represent an alkylidenedioxy or aralkylidenedioxy group or mean a carbon-carbon bond R * is a hydrogen, fluorine or chlorine atom or a methyl group means) or a 3,5-dienol ether or ester thereof with a reagent of general formula: R ¹ '7 -R ¹ II 12th converts, wherein R and R, which can be the same or different, Alkyl groups with 1 to 8 carbon atoms or aralkyl or aryl groups / oaer together with the nitrogen atom to which they are bound to form a heterocyclic radical, if desired may contain further heteroatoms, R ^ a chlorine 009886/2263 / Fluorine atom, Ir is a chlorine or fluorine atom, and R is hydrogen or B. and R together are a carbon-carbon bond, R is a chlorine or fluorine atom and R 'is a chlorine or fluorine atom or a trifluoromethyl group, the reaction being carried out in the presence of chloride ions is carried out if neither R ^ nor R ^ signify chlorine, or with a triarylphosphine or triarylphosphite and chlorine or a chloroalkane, or with an arylsulfonylating or alkylsulfonylating agent and subsequent reaction of the "corresponding 11a-arylsulfonates or Ha-alkylsulfonates, the so with a compound that provides chloride ions, or in an inert solvent with a compound that provides positive chlorine, an anhydrous form of sulfur dioxide that is present or is subsequently added, and when a compound of formula I is not formed immediately is followed by reaction of a 16,17-dehydrosteroid with a hydrogen halide to the egg Introduction of a löa-halogen substituent, with an alkanethiol to introduce a 16a-alkylthio substituent, or with a vicinal dihydroxylating agent, followed by reaction with a ketone to introduce a löotjiTa-alkylidenedioxy or aralkylidenedioxy group, or by reaction of a "! Tß-acetyl -IYa-hydroxysteroides with an acylating or alkylating agent or by introducing a fluorine atom or a methyl group in the 6-position, or by reaction with a halogenating agent to introduce a 21-halogen atom. 2. The method according to claim 1, characterized in that the compound which supplies chloride ions is a salt ψ that is soluble in organic solvents. 3. The method according to claim 2, characterized in that the salt is a lithium salt or the salt of a tertiary or quaternary Is nitrogen base. 4. The method according to claim 3, characterized in that the Salt is lithium chloride. 009886/2263 5. The method according to any one of claims 1 to 4, characterized in that that the reagent of the formula II N- (2-0hlor-1,1,2-trifluoroethyl) diethylamine, N- (1,1,2,2-tetrafluoroethyl) diethylamine, N ~ (2-chloro-1,1,2-trifluoroethyl) -dimethylamine, N- (2-chloro-1,1,2-trifluoroethy1) -dipropylamine, Ii- (2-chloro-1,1,2-trifluoroethyl) -diisobutylamine, N- (2-chloro-1,1,2-trifluoroethyl) -dioctylamine, lf- (2-chloro-1,1,2-trifluoräthy l) -methylamine, N- (2,2-dichloro-1,1-difluoroethyl) -diethylamine, N- (1,1,2,3,3,3-hexafluoropropyl) diethylamine or H- (1,2,2-tetrafluoroethyl) diisopropylamine is. 6. The method according to claim 1, characterized in that the reagent of I'ormel II Ν, Ν-diethyl-trichlorovinylamine. J 7. The method according to any one of claims 1 to 6, characterized in, that the reaction is carried out with the reagent of formula II in an inert solvent. 8. The method according to claim 7, characterized in that the Solvent an aromatic or aliphatic hydrocarbon, contains a halogenated hydrocarbon or an ester, ketone, nitrile, ether or a tertiary alcohol. 9. The method according to claim 8, characterized in that the Solvent! Is tetrahydrofuran. 10. The method according to any one of claims 1 to 9, characterized in that that any reactive hydroxyl groups except ' the 11a-hydroxy group, prior to reaction with a reagent of the general formula II are protected. 11. The method according to claim 10, characterized in that the hydroxyl groups are protected by esterification or etherification. 12. The method according to claim 1, characterized in that the Iriary! Phosphine used is triphenylphosphine. 009886/2263 13. The method according to claim 1 or claim 12, characterized in that that the chloroalkane which is used in conjunction with the triaryl phosphine or phosphite is tetraohlomethane. 14. The method according to any one of the preceding claims, characterized in that a compound of formula I wherein Ir is a Represents chlorine atom, represented by reaction of an initially formed 16,17-dehydrosteroid with hydrochloric acid will. 15. The method according to any one of the preceding claims, characterized characterized in that the implementation of a 16,17-dehydrosteroid with hydrohalic acid using a cyclic Ether or a chlorinated hydrocarbon as solvent is carried out. 16. The method according to claim 15, characterized in that the cyclic ether is dioxane. 17. The method according to any one of claims 1 to 13, characterized in that that an alkylidenedioxy or aralkylidenedioxy compound of the formula I is prepared by reacting one corresponding 16,17-dehydrosteroides formed at the beginning with Permanganate or osmium tetroxide and that the resulting 16a, 17oc-diol is reacted with the appropriate ketone under acidic conditions will. 18. The method according to claim 17, characterized in that the reaction with permanganate or osmium tetroxide at low temperature in a damp, water-miscible solvent is carried out. 19. The method according to claim 18, characterized in that the reaction is carried out at a 1O ⁰ C! Temperature of -10 ° to +. 009886/2263 20. The method according to claim 18 or 19, characterized in that that the solvent is a ketone. 21. The method according to any one of claims 18 to 20, characterized in that that the reaction is carried out in the presence of a weak acid. 22. The method according to any one of claims 17 "to 21, characterized in that the reaction of the diol with the ketone under acidic conditions. 23. The method according to claim 22, characterized in that " a mineral acid is used. 24. The method according to any one of claims 1 to 13, characterized in that a compound of the general formula I _f wherein Ή? means an alkylthio group, is prepared by reacting a 16,17-dehydrosteroid formed first with an alkanethiol in the presence of acid. 25. The method according to claim 24, characterized in that the Acid is mineral acid. 26. The method according to claim 24 or 25, characterized in * that the reaction is carried out with the alkane thiol in a polar solvent. 27. The method according to any one of claims 24 to 26, characterized in that the reaction is carried out with the alkane thiol at a temperature of -25 ° C to +30 ^0. 28. The method according to any one of claims 1 to 13, characterized in, that a compound of the general formula I, wherein R ¹ denotes an iodine atom, is prepared by direct iodination of a corresponding compound of the general formula I, 009886/2263 wherein R represents a hydrogen atom. 29. The method according to claim 28, characterized in that the iodination with iodine in the presence of GaIciumoxyd and hydroxide and a solvent. 30. The method according to claim 29, characterized in that the iodination in the presence of a free radical initiator carried out v / ird. 31. The method according to claim 30 .., characterized in that the initiator is azobisisobutyronitrile. 32. The method according to any one of claims 28 to 31, characterized in that •1 indicates that steroids, wherein R is chlorine, bromine or Fluorine atom means, from the corresponding 21 »iodine steroids by reaction with a compound, the chloride, bromide or Supplies fluoride ions. 33 · The method according to claim 32, characterized in that the compound for chloride, bromide or fluoride ions is lithium chloride or bromide or silver fluoride. 34 · Process according to claim 32 or 33 »characterized in that the reaction with the compound which supplies chloride, bromide or fluoride ions is carried out in an ionizing medium . 35. The method according to claim 34, characterized in that the medium is moist acetonitrile when using silver fluoride, or dry acetone when using lithium bromide or chloride . 36i method according to one of claims 1 to 13, characterized in that that a steroid dteL · general formula I, in which ORIGINAL! WSPECTSO R is an acyloxy group, is prepared by acylation of the corresponding 1? A-hydroxysteroids. 37. The method according to claim 36, characterized in that acylation by reaction with an acyl halide or anhydride or a carboxylic acid and irifluoroacetic anhydride is carried out. 38. The method according to claim 37, characterized in that the reaction with trifluoroacetic anhydride and the carboxylic acid is carried out at an elevated temperature. 39. The method according to claim 36, characterized in that the acylation by reaction with antimony pentachloride and the suitable acyl chloride under non-hydroxylic conditions is carried out. 40. The method according to claim 36, characterized in that the iOrmylation is carried out by reaction with concentrated formic acid and phosphorus pentoxide « 41. The method according to any one of claims 1 to 13, characterized P indicates that a steroid of the general formula I, in which R is an alkoxy group, is prepared by reacting the corresponding 17a-oil M with freshly prepared silver oxide and an alkyl halide. 42. The method according to claim 41, characterized in that da3 Halide is the iodide. 43. The method according to claim 41 or claim 42, characterized in that that the reaction in a substituted amide, Imtd or hydantoin solvent is carried out. 009886/2263 - 4c - 44. The method according to any one of claims 1 to 13, characterized in that that a steroid of the general formula I in which R ^ is a halogen atom and a 6,7 double bond is present is, by reacting the corresponding first formed 5 (1O) -En-3-one and / or 4-Ea-3-one with an enol ether or Esterifying agent is prepared under acidic conditions and then with a dehydrating agent. 45. The method according to claim 44, characterized in that the enol etherification agent iriethyl orthoformate or the enol esterification agent is an acyl anhydride or an isopropenylate. 46. The method according to claim 44 or claim 45, characterized in that that the dehydrogenating agent is manganese dioxide, chloranil or 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ). 46. The method according to claim 44 or claim 45, characterized in that that the hydrogenating agent manganese dioxide, chloranil or 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ). 47. The method according to any one of claims 1 to 13, characterized in that the steroid of the general formula I, wherein R ^{4 is} a Ghloratom, by reacting a corresponding 3-acyloxy- or 3-alkoxy- Δ - * »-steroid with a Chlorinating agent is produced. 48. The method according to claim 47, characterized in that the chlorinating agent is molecular chlorine or an IT chloramide or -imide. 49. The method according to claim 48, characterized in that the reaction in the presence of a carboxylic acid and a tertiary Base is carried out. 50. The method according to any one of claims 1 to 13, characterized in that a steroid of the general formula I, wherein R ⁴ "denotes a methyl group, followed by reaction of the corresponding 3,5-diene-3-enol ether with a Vilsmeier reagent from 009836/2253 COPY 2038908 Treatment with a reducing agent of the borohydride type, producing the corresponding δ-dimethylaminoinethylsteroidborane adduct and then produced by hydrogenation or transfer hydrogenation of this borane adduct. 51. Verfaliren according to claim 50, characterized in that the ViIsmeier reagent by "reaction in the absence of water a li-formylated secondary amine and an acid halide is prepared, the acid halide being among such acid halides is selected in which the halide ion is upon treatment slightly n-nucleophilic with an N-formylated secondary amine Suffers repression, 52. The method according to claim 51, characterized in that the acid halide phosphorus oxychloride, phosgene, phosphorus oxybromide, 'Is phosphorus pentachloride, thionyl chloride or oxalyl chloride. 53. The method according to any one of claims 50 to 53, characterized in that that the reducing agent is the borohydride of sodium, potassium, lithium, calcium or zinc; Diborane; a mono or dialkylborane or a complex thereof with a base such as pyridine; Lithium cyanoborohydride; or a lithium or sodium alkoxyborohydride is. 54. The method according to any one of claims 50 to 53, characterized in that that transfer hydrogenation using a palladium catalyst in the presence of a cyclic olefin is carried out. 55. The method according to any one of the preceding claims, characterized in that a 5,5-dienol ether of a steroid of the general formula I is prepared by reacting the corresponding 3-one with a trialkyl orthoformate in the presence of an acidic catalyst. 009886/2263 COPY 56. The method according to any one of claims 1 to 54, characterized in that that a 3,5-dienol ester of a steroid is the general Formula I prepared by reacting the corresponding 3-one with an isopropenyl anhydride or acyl anhydride under acidic conditions will. 57. Compounds of the general formula I, prepared by a process according to claim 1. 58. Steroids of the general formula: GH ₂ R ¹ C = O Cl (wherein a double bond is present or absent at the 6,7 position can be, and in which R is a hydrogen or halogen atom, R denotes a hydrogen atom, a hydroxyl group or an alkoxy or acyloxy group with 1 to 6 carbon atoms, R * denotes a hydrogen or halogen atom or an alkylthio group with 1 to 6 carbon atoms or R and R ^ together denote an alkylidenedioxy or aralkylidenedioxy group, Br a Hydrogen, fluorine or chlorine atom or a methyl group, provided that R is not a hydrogen atom if not R is a formyloxy or an alkoxy group or if not Br is a halogen atom or an alkylthio group, or if not R and R * are an alkylidenedioxy or aralkylidenedioxy group, or if not R ^ is a fluorine atom or a methyl group) and 3 , 5-dienol ethers and esters of these compounds 009886/2263 ■ tvt sr · « Λ fr ■: - ,,. 59. Steroids of the general formula: ^iH 2 ^R C = O Cl (where there is a double bond in the 6,7-position or may be absent, and in which II is a hydrogen or halogen atom, 2
R denotes a hydrogen atom, or a hydroxyl group or an acyloxy group with 1 to 6 carbon atoms, R ^ denotes a hydrogen or Ilalogen atom or R and R together denote an alkylidenedioxy or aralkylidenedioxy group, R ^ "denotes a hydrogen or chlorine atom or a methyl group, provided that R does not mean a hydrogen atom 2 3 tet, if not R a pormyloxy, or if not Rr a 2 3 Halogen atom, or if not.R and R an alkylidene dioxy or aralkylidenedioxy group, or if R ^ is not a methyl group) and 3,5-dienolether and -ester of these compounds. 60. Compounds according to claim 58 or claim 59, characterized in that that R ^ means a chlorine atom. 61. Compounds according to any one of claims 58 to 60, characterized characterized in that R is a fluorine, chlorine or iodine atom, 62. Compounds according to claim 58 or 59, characterized 2
net that R is a formyloxy, acetoxy, propionyloxy, butyryloxy, valeryloxy or caproyloxy group. 009886/2263 63. Compounds according to claim 58 or claim 59, characterized characterized in that Rr represents a chlorine atom ". 64. Compounds according to claim 58 or 59 * characterized by 2 5
net that R and R together represent an isopropylidenedioxy or isobutylidenedioxy group or a 1-phenylethylidenedioxy or diphenylmethylidenedioxy group. 65. Compounds according to any one of claims 58 to 64, characterized characterized in that R7 is a fluorine or chlorine atom or a methyl group means and that in the 6,7-position a double bond is available. · 66. Compounds according to any one of claims 58 to 64, in the form of their dienolethyl or methyl ether or their dienolacetic acid, propionic acid, benzoic acid, valeric acid or hexahydrobenzoic acid ester. 67. 6.11 ß-dichloro-17a-formyloxy = »19-norpregn-4,6-diene-r3,20-dione. 68, 11β, 16a ~ dichloro-19-norpregn-4-en-; 5,20-dione. 69. 11β-chloro-16a, 17a-isopropylidenedioxy-19-norpregn-4'-en-3,20-dione. 70. 11 β-chloro-17a-formyloxy-19-norpregn-4-ene-3,20-dione. 71. 17a-acetoxy-11ß-chloro-6-fluoro-19-norpregna-4,6 ~ diene-3,20 « dion. 72. 17α-acetoxy-11β-chloro-6-methyl-19-norpregna-4,6-diene-3,20- dione. 73 . 17a-acetoxy-11β-clilor-21 -f luor-1 9-norpregn ~ 4-en-3,20-dione. 009886/2263 74. 6.11 β, 16a-trichloro-19-norpregna-4-, 6-diene-3,20-dione. 75. 17α-acetoxy-11β, 21-dichloro-19-norpregn-4-ene-3,20-dione. 76. 11 ß-chloro-16a-methylthio-19-norpregn-4-en-3,20-HÜon. 77. iiß-chloro-na-methoxy-ig-norpregn ^ -en ^, 20-dione. · 70. Pharmaceutical compositions, characterized in that that they are one or more steroids of the general formula I as defined in claim 58, together with a pharmaceutical Contain carriers or binders and / or one or more hormones with estrogenic activity. 79. Compositions according to claim 78 in the form of unit doses. 80. Compositions according to claim 79, characterized in that each dose unit for daily administration to humans Contains 0.01 "to 5.0 mg of active material according to the invention. 81. Compositions according to claim 80, characterized in that each dose unit 0.05 to 2.0 mg of active according to the invention Contains material. 82. Compositions according to claim 80, for the intermittent Administration, characterized in that each dose unit contains 0.1 to 5.0 mg of active material according to the invention. 83. Compositions according to claim 82, characterized in that each dose unit contains 0.5 to 2.0 mg of active material according to the invention. 84. Compositions according to claim 82 or claim 83, there- 009886/2263 ORIGINAL INSPECTED characterized in that each dose unit 0.05 mg ethinyl estradiol contains. 85 · 9α-unsubstituted-6β-IIalogen-11β-chloro-19-norpregn-5 (10) -ene-3,20-diones and their dienol ethers and esters, 9a-unsubstituted-6ß-halogen-11ß-chloro-19 ~ norpregnan-5® <= ol « 3,20-dione, 9a-unsubstituted-6ß-halogen-11ß-chloro-19-norpregnan ~ 3ß, 5o £ - diol-20-one, 9a-unsubstituted-11ß-chloro-5a, 6a-epoxy-19-norpregnan-3ß-ol-. ■ 20-cne, 9a-unsubstituted-11ß-chloro-19-norpregn-5-en-3ß-ol-20-one, the 3-ethers and 3-esters of got-unsubstituted-Hß-chloro-ediraethylarainomethyl-19-n.orpregna-3,5-dien-3-ol-20-one-borane-ad- products and 9a-unsubstituted se-11 ß-chloro-19-norpregn-4-en-16a, 17oc-diol-3,20-diones. 009886/2263