DE4413185A1 - 11beta, 19-bridged 13alpha alkyl steroids - Google Patents

Abstract

The invention discloses new 11 beta ,19-bridged 13 alpha -alkyl steroids of general formula (I), in which W, R<6a>, R<6b>, R<7>, R<15>, R<16>, R<17a> as well as R<17b>, R<18>, R<11'> and R<19'> are as defined in the description. Disclosed also is a method for preparing them. The new compounds have strong progestational activity and may be used in the manufacture of drugs.

Description

The present invention relates to 11β, 19-bridged 13α-alkyl steroids of the general Formula I.

wherein
W represents an oxygen atom, the hydroxyimino group (= N∼OH) or two hydrogen atoms,
R ^6a and R _6b each represent a hydrogen atom and R⁷ represents a hydrogen atom or a straight-chain or branched-chain saturated α- or β-position C₁-C₄-alkyl radical or
R ^6a and R _6b together represent a methylene group or a triple ring formed together with the carbon atom 6 and R⁷ represents a hydrogen atom or
R ^{6a represents} a fluorine, chlorine, bromine or iodine atom or a straight-chain or branched-chain saturated C₁-C₄alkyl radical, in which case R _6b and R⁷ each represent a hydrogen atom or together form an additional bond and if R _6b and R⁷ each represent a hydrogen atom, R ^{6a can be} α or β, or
R ^{6a represents} a hydrogen atom, in which case R _6b and R⁷ together represent an α- or β-position methylene bridge or an additional bond, or
R¹⁵ and R¹⁶ each represent a hydrogen atom or together for an additional bond or an α or β methylene bridge, or
R¹⁵ for a hydrogen atom and R¹⁶ for an α- or β-position C₁-C₄-alkyl group or R¹⁶ together with R¹⁷a for an α- or β-position methylene bridge and R₁₇b for a radical

stand, as well
R ^{11 '} and R ^19' each represent a hydrogen atom or together represent an additional bond,
R ^17a / R ^17b one of the substituent combinations

or R ^17a / R ^17b together

mean with
R²¹ and R²³ have the meaning of a hydrogen atom, a C₁-C₄-alkyl or a C₁-C₄-alkanoyl group,
R²² has the meaning of a C₁-C₃-alkyl or a 1-hydroxy-C₁-C₃-alkyl group,
A has the meaning of a hydrogen atom, the cyano group, a radical of the formula -COOR²⁴ or -OR²⁵, where R²⁴ represents a C₁-C₄-alkyl radical and R²⁵ represents a hydrogen atom, a C₁-C₄-alkyl or C₁-C₄-alkanoyl radical,
B has the meaning of a hydrogen, fluorine, chlorine, bromine or iodine atom, a C₁-C₄ alkyl, C₂ or C₃ alkynyl group, a hydroxyalkyl, alkoxyalkyl or alkanoyloxyalkyl group each having 1 to 4 carbon atoms in the alkyl -, alkoxy and / or alkanoyloxy part,
D is a hydrogen atom, a hydroxy, C₁-C₄ alkoxy or C₁-C₄ alkanoyloxy group,
n has the meaning 0, 1, 2, 3 or 4,
m has the meaning 0, 1 or 2,
p has the meaning 0 or 1,
k has the meaning 0, 1, 2 or 3 and
R¹⁸ represents a hydrogen atom or a methyl group.

The serpentine lines in the representation of the general formula I mean that the relevant Substituent can be α- or β-permanent.

According to the present invention, preference is given to those compounds of the general formula I in which
W for one oxygen atom or two hydrogen atoms,
R ^6a and R ^6b each represent a hydrogen atom or
R ^6a for a chlorine atom or for a straight-chain saturated, optionally α or β, C₁ C₄-alkyl radical, or
R ^6b and R⁷ each for a hydrogen atom or together for an additional bond, or
R¹⁵ and R¹⁶ each represent a hydrogen atom or together represent an additional bond,
R ^17b / R ^17a
-OH / -CH₃,
-OC (O) CH₃ / -CH₃;
-OH / -C≡CH,
-OC (O) CH₃ / -C≡CH;
-OH / -C≡C-CH _3,
-OC (O) CH₃ / -C≡C-CH₃;
-C (O) CH₃ / -OC (O) CH₃
-C (O) CH3 / -CH3
mean,
and the other substituents can all have the meanings given in formula I.

The compounds mentioned below are particularly preferred according to the invention:
9,11α-dihydro-17α-ethinyl-17β-hydroxy-6′H-benzo [10,9,1 1] -13α-estr-4-en-3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
9,11α-dihydro-17β-hydroxy-17α- (1-propynyl) -6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
9,11α-dihydro-17α-hydroxy-17β- (1-propynyl) -6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
9,11α-dihydro-17α-ethinyl-17β-hydroxy-6′H-benzo [10,9,11] -13α-estra-4,15-dien-3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -13α-estra-4,15-dien-3-one;
9,11α-dihydro-17β-hydroxy-17α- (1-propynyl) -6′H-benzo [10,9,1 1] -13α-estra-4,15-dien-3-one;
9,11α-dihydro-17α-hydroxy-17β- (1-propynyl) -6′H-benzo [10,9,11] -13α-estra-4,15-dien-3-one;
17- (acetyloxy) -9,11α-dihydro-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -9,11α-dihydro -6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-en-3,20-dione;
17- (acetyloxy) -6-chloro-9,11α-dihydro-6'H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-9,11α-dihydro-6H-benzo [10,9,11] -19-nor-13α, 17α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6-methyl-6'H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6-methyl-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregna-4,6-diene-3,20-dione ;
17- (Acety loxy) -9,11α-dihydro-6α-methyl-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6α-methyl-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-ene-3,20-dione;
9,11α-dihydro-17-methyl-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
9,11α-dihydro-17-methyl-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-en-3,20-dione;
9,11α-dihydro-6,17-dimethyl-6′H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3,20-dione;
9,11α-dihydro-6,17-dimethyl-6′H-benzo [10,9,14] -19-nor-13α, 17α-pregna-4,6-diene-3,20-dione;
9,11α-dihydro-17α-ethynyl-17β-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-3-one;
9,11α-dihydro-17β-hydroxy-17α- (1-propynyl) -6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-3-one;
9,11α-dihydro-17α-hydroxy-17β- (1-propynyl) -6′H-benzo [10,9,11] -18a-homo-13α -estr-4-en-3-one;
9,11α-dihydro-17α-ethynyl-17β-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estra-4,15-dien-3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estra-4,15-dien-3-one;
17- (acetyloxy) -9, 11α-dihydro-6′H-benzo [10,9,11] -18a-homo-19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6′H-benzo [10,9,11] -18a-homo-19-nor-13α, 17α-pregn-4-en-3,20-dione;
9,11α-dihydro-17α-ethynyl-6′H-benzo [10,9,11] -13α-estr-4-en-17β-ol;
9,11α-dihydro-17β-ethynyl-6′H-benzo- [10,9,11] -13α-estr-4-en-17α-ol;
9,11α-dihydro-17α-ethynyl-6′H-benzo [10,9,11] -13α-estra-4,15-dien-17β-ol;
9,11α-dihydro-17β-ethynyl-6H-benzo [10,9,11] -13α-estra-4,15-dien-17α-ol;
9,11α-dihydro-17α-ethinyl-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-17β-ol;
9,11α-dihydro-17β-ethynyl-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-17α-ol;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
17β-ethynyl-17α-hydroxy-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo-10,9,111-13α-estr-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
17α-hydroxy-17β- (1-propynyl) -4 ′, 5 ′, 9.11α-tetrahydro-6′H-benzo [10.9.11] -13α-estr-4-en-3-one;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-en-3,20-dione ;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3 , 20-dione;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregna-4,6-diene -3.20-dione.

19,11β-bridged steroids as the compounds described herein structurally closest species emerge for the first time from DE-A 37 08 942 (EP-A 0 283 428). The In contrast to the compounds in question, known compounds, however, have no etheno or ethano bridges between C11 and C19; rather the two are there Carbon atoms are generally substituted by two adjacent carbon atoms Bridged phenylene ring. Both the known and the compounds described here stand out in the gestagen receptor binding test using cytosol  Rabbit uterine homogenate and of ³H-progesterone as reference substance by an extraordinary high affinity for the gestagen receptor.

While this strong bond is primarily too pronounced in the known compounds competitive progesterone-antagonistic activity and leads these compounds in the first place Line for triggering abortions, against hormonal irregularities, for Menstrual triggering and the induction of labor can be used Compounds according to the invention surprisingly by strong agonistic, ie. H. gestagene Efficacy out and are in the pregnancy maintenance test on the rat after subcutaneous Application very effective.

The compounds of general formula I according to the invention have very strong gestagenic compounds Efficacy with only weak androgenic or even weak antiandrogenic activity (Dissociation).

Because of their gestagenic activity, the new compounds of general formula I used alone or in combination with estrogen in contraceptive preparations.

The dosage of the compounds according to the invention in contraceptive preparations should preferably 0.01 to 2 mg per day.

The gestagenic and estrogenic active ingredient components are in contraceptive preparations preferably administered orally together. The daily dose is preferably administered once.

Preferred estrogens are synthetic estrogens such as ethinyl estradiol, 14α, 17α-ethano- 1,3,5 (10) -estratrien-3,17β-diol (WO 88/01275) or 14α, 17α-ethano-1,3,5 (10) -estratrien- 3,16α, 17β-triol (WO 91/08219) into consideration.

The estrogen is administered in an amount equal to that of 0.01 to 0.05 mg of ethinyl estradiol corresponds.

The new compounds of general formula I can also be used in preparations for treatment gynecological disorders and substitution therapy. Because of their cheap The activity profile of the compounds according to the invention are particularly suitable for treatment premenstrual complaints such as headaches, depressive moods, water retention and mastodynia. The daily dose for the treatment of premenstrual complaints is about 1 up to 20 mg.  

The formulation of the pharmaceutical preparations based on the new compounds takes place in known manner by the active ingredient, optionally in combination with an estrogen, with the carrier substances, diluents, used in galenics, if necessary Flavors, etc., processed and converted into the desired application form.

For the preferred oral application, tablets, coated tablets, capsules, pills, Suspensions or solutions in question.

For parenteral administration, in particular oily solutions, such as solutions in Sesame oil, castor oil and cottonseed oil, are suitable. Can increase solubility Solubilizers, such as benzyl benzoate or benzyl alcohol, can be added.

It is also possible to incorporate the substances according to the invention into a transdermal system and apply them transdermally.

Finally, the new compounds can also be used as a gestagen component in the recently known compositions for female fertility control, which are characterized by the feature additional use of a competitive progesterone antagonist (H. B. Croxatto and A. M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. By Runnebaum, Rabe & Kiesel - Vol. 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group - 1991, page 245).

The dosage is in the range already specified, the formulation can be as with conventional OC preparations are made. The application of the additional, competitive progesterone antagonist can also be done sequentially.

The new compounds of general formula I according to the invention are as follows described. The synthesis route for the one containing the novel bridging Basic structure with 13α-standing alkyl group is shown in Scheme 1:  

Scheme I

K is a common ketal protecting group, for example the ethylenedioxy or the 2,2- Dimethylpropylene-1,3-dioxy group. Other common keto protection groups are also considered. K can also represent a protected hydroxyl group and a hydrogen atom, the Hydroxy group then for example as methoxymethyl, methoxyethyl, tetrahydroxypyranyl or Silyl ether, e.g. B. is protected as tert-butyl-dimethyl-silyl ether. By splitting off the protective group and oxidation of the free hydroxy group leads to the keto group.  

According to Scheme 1, this is described, for example, in EP-A 0 110 434 and 0 127 864 Epoxy 1, in which R¹⁸ represents a hydrogen atom or a methyl group and K represents a Ketal protecting group, by opening with propargyl magnesium halides of the formula H-C≡CH₂MgHal (Hal = Cl, Br; representation see "Synthesis of Acetylenes, Allenes and Cumulenes ", L. Brandsma and H. D. Verkruÿsse, p. 16, Elsevier Scientific Publishing Company, Amsterdam, Oxford, New York (1981) converted into compound 2.

Compound 2 is then by oxidation of the 17-hydroxy group by known methods converted into a compound 3.

The configuration at C-13 is then reversed starting from a connection 3 by irradiation with UV light (see, for example, EP-A 0 259 248 or US-A 5,273,971).

As an alternative to the described procedure, the configuration reversal on C-13 can also starting, for example, from epoxide 1 by oxidation to 17-ketone and Irradiation takes place at the epoxy stage (the representation of the corresponding 13α-epoxide z. B. described in US-P 5,273,971 or DE-A 38 22 770). By analog Propargyl addition to the 13α-alkyl-17-ketone obtained can also be achieved in this way a connection 4. This procedure can protect the 17-keto function during the propargyl addition may be required to prevent undesired addition of the Propargylrestes to suppress also at the 17-carbon atom. As possible protective groups the groups given above under the definition of K come into question.

In general, the configuration reversal is also at a later intermediate stage feasible.

Compound 4 is finally obtained by a known method at the terminal end of the Triple bond brominated (H. Hofmeister, K. Annen, H. Laurent and R. Wiechert, Angew. Chem. 96, 720 (1984)) and the compound 5 obtained by hydrogenation or hydride Transfer converted to vinyl halide 6. The reaction is preferably carried out using Diimide reduction performed.

The radical cyclization of compound 6 takes place analogously to that already described Cyclization of corresponding aryl halides, i. H. of compounds in which the Double bond is part of a phenylene radical (see for example E. Ottow, G. Neef and R. Wiechert, Angew. Chem. 101, 776 (1989)).

The possible processes for generating the intermediate radicals also come here in particular two for use:

The reaction with trialkylstannanes, preferably with tri-n-butyltin hydride, is suitable Solvents, such as toluene, or the reaction with lithium in liquid Ammonia mixed with an organic solvent such as tetrahydrofuran at temperatures between -78 and -33 ° C.

In contrast to the aryl halides mentioned above, the reaction proceeds here  However, the case is not selective for the 6-endo-trig product (11β, 19-bridge), but is obtained also shares in 5-exo product (9β, 19 bridge), which, however, z. B. by column chromatography can be separated without problems.

The connections 7 are a central starting product in the representation of connections of the general formula I. They belong to the compounds of the general formula II Subject of the present invention.

If necessary, the vinyl bridge is hydrogenated by known methods (if R ^{11 '} and R ^{19' are} each to represent a hydrogen atom).

The next steps then include the desired functionalizations in the D-ring.

The introduction of a 15.16 double bond (R¹⁵ and R¹⁶ form a common one additional binding) takes place, for example, by a modified Saegusa oxidation (I. Minami, K. Takahashi, I. Shimizu, T. Kimura and J. Tsuji, Tetrahedron 42, 2971 (1986); EP- A 02 99 913) of the corresponding enol compounds of 17-ketone.

For examples in which R¹⁵ and R¹⁶ have a common α or β 3-ring represent, the introduction of this 3-ring takes place, for example, by implementing the corresponding 15,16-en-17-one verb. with dimethylsulfoxonium methylide (see e.g. DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291,029; E. J. Corey and M. Chaykovsky, J.Am. Chem. Soc. 84, 867 (1962)).

After the D-ring modification has taken place, the further steps initially apply to the introduction of the residues R¹⁷a and R ^17b on the C-17 atom. This introduction is carried out analogously to methods known from the literature (e.g. Fried Fried, JA Edwards, "Organic Reactions in Steroid Chemistry", van Nostrand Reinhold Company, 1972, Vol. 1 and 2; "Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society , London, Vol 1-2) by nucleophilic addition of the desired 17-side chain or a reactive precursor from it to the 17-keto group. Analogous to previously described 13α-configured compounds (see, for example, DE-A 38 22 770, US Pat. No. 5,273,971), the addition to C-17 is also not stereoselective in the present case. Depending on the nucleophile used, the ratio of the two isomers to one another varies, the α addition (entry of the substituent to be added from the rear) being mostly preferred due to the 11β, 19 bridge.

The introduction of the substituent -C≡CB as R ^17a with the meanings given for B takes place with the aid of the metalated compounds, which can also be formed in situ and reacted with the 17-ketone. The metalated compounds are formed, for example, by reacting the acetylenes with alkali metals, in particular potassium, sodium or lithium, in the presence of an alcohol or in the presence of ammonia. The alkali metal can also act in the form of, for example, methyl or butyllithium. Compounds in which B = bromine or iodine are prepared from the 17-ethynyl compounds in a known manner (see, for example, BH Hofmeister, K. Ahnen, H. Laurent and R. Wiechert, Angew. Chem. 96, 720 (1984 )).

3-Hydroxy-1-propyne in the 17-position is introduced by reacting the 17-ketone with the dianion of propargyl alcohol (3-hydroxypropine), e.g. B. the in situ generated dipotassium salt of propargyl alcohol or with corresponding, at the Hydroxyfunction protected derivatives, such as. B. the lithium compound of 3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-propyne.

The hydroxypropyl and hydroxypropenyl compounds can be derived from the hydroxypropinyl derivatives being represented. The hydroxypropyl chain is shown, for. B. by Hydrogenation at room temperature and normal pressure in solvents such as methanol, ethanol, Tetrahydrofuran or ethyl acetate with the addition of precious metal catalysts such as platinum or Palladium.

The representation of connections with a Z-configured double bond in the side chain is done by hydrogenating the acetylenic triple bond with a deactivated one Precious metal catalyst, e.g. B. 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate. The hydrogenation will canceled after taking up one equivalent of hydrogen.

Connections with an E-configured double bond in the side chain are created by Reduction of the triple bond z. B. with sodium in liquid ammonia (K. N. Cambell and L. T. Eby, J.Am. Chem. Soc. 63, 216 (1941)), with sodium amide in liquid ammonia or with lithium in low molecular weight amines (R.A. Benkeser et al., J.Am.Chem.Soc. 77, 3378 (1955)).

The introduction of the hydroxyalkenes and hydroxyalkanes can also be done directly by reaction of the 17-ketone with their metalated derivatives (E. J. Corey and R. H. Wollenberg, J.Org.Cem. 40: 2265 (1975); H. P. On, W. Lewis and G. Doubt, Synthesis 999 (1981); G. Gohiez, A. Alexakis and J.F. Normant, Tetrahedron Lett. 3013 (1978); P.E. Eaton et al., J. Org. Chem. 37, 1947 (1972)). The introduction of homologous hydroxyalkyne, hydroxyalkene and Hydroxyalkane groups are possible in an analogous manner.  

Products where R ^17a / R ^17b for

with x = 1 or 2, can be omitted the 17- (3-hydroxypropyl) - or 17- (4-hydroxybutyl) compounds by oxidation in known manner, e.g. B. with the Jones reagent, manganese dioxide, pyridinium dichromate, Represent pyridinium chlorochromate, chromic acid pyridine or the Fetizon reagent.

Products where R ^17a / R ^17b for

where x = 1 or 2, the corresponding (Z) -17α- (3- Hydroxyprop-1-enyl) or (Z) -17α- (4-hydroxy-1-butenyl) -17β-hydroxy compounds or the correspondingly saturated compounds in the side chain. Compounds with a saturated spiro ether can also be obtained by hydrogenation of the unsaturated spiroethers on platinum or palladium catalysts.

The 17-cyanomethyl side chain is either built up directly from the 17-ketone Addition of acetonitrile or by cleavage of the spiroepoxide with HCN according to K. Ponsold et al., Z. Chem. 18 (1978) 259-260.

The synthesis of 16.17 (α or β) -methylene-17 (β or α) -alkanoyl-substituted Connections are made using methods known from the literature. For example, starting from the 17-ketones represent Δ¹⁶-17-perfluorosulfonyloxy compounds, which in Presence of transition metal catalysts with alkoxyvinyltin or zinc compounds can be coupled (see e.g. M. Kosugi, T. Sumiya, Y. Obara, M. Suzuki, H. Sano and T. Migati, Bull.Chem.Soc.Jpn. 60: 767 (1987); P.G. Ciattini, E. Morera and G. Ortar, Tetrahedron Lett. 31, 1989 (1990)). Acid hydrolysis of the coupling products gives the Δ¹⁶-17-acetyl compounds. These enones can be classified according to the above for the cyclopropanation the Δ¹⁵-17-ketone specified method with trimethylsulfoxonium iodide to 16,17-methylene-17-acetyl compounds implement, or by conjugate addition of Convert alkyl copper compounds into the 16α- or β-alkyl progesterone derivatives.

Compounds in which R ^{17a is} an alkanoyl radical and R ^{17b is} an alkyl radical can be prepared, for example, from Δ¹⁶-17-alkanoyl compounds or 17α (or β) -hydroxy-17β (or α) - alkanoyl compounds by reducing in liquid with lithium Ammonia, mixed with tetrahydrofuran, 17-enolate anions, which can be alkylated with the corresponding alkyl halide to give the desired compounds (see e.g. BMJ Weiss, RE Schaub, GR Allen, Jr., JFPoletto, C. Pidacks, RB Conrow and CJ Coscia , Tetrahedron 20, 357 (1964).

As an alternative to this, it is also possible to use the corresponding 17-ketones Tosylmethyl isocyanate (TosMic) and e.g. B. Kaliumtert.butylat as base in suitable Solvents such as diethyl ether or dimethoxyethane, a mixture of 17α / 17β-nitriles getting produced. After separation of the isomers z. B. with lithium diisopropylamide or other strong bases deprotonated and then alkylated with alkyl halides. Finally, the nitriles can be reacted with alkyl magnesium halides or Alkyl lithium compounds are converted into the alkanoyl compounds.

The representation of derivatives, in the R ^17a and R ^17b together for

stand, starting from the 17-ketone according to methods known from the literature (e.g. EP-A-0 444,3951, 1991; and EP-A-0 154 429, 1989). For example, through reductive Allylation of the above-mentioned Δ¹⁶-17-acetyl compounds the corresponding 17α (or. β) - (2-propenyl) compounds shown. The final double bond is then either via hydroboration, e.g. B. with 9-BBN (9-borabicyclononane), oxidative Working up and further oxidation to the corresponding C₃ aldehyde or by ozonolytic degradation converted into the C₂ aldehyde. The 6-ring or 5-ring spiroketones can then be displayed via an aldol reaction. This creates the α, β-unsaturated Ketones, which if necessary according to known methods to the saturated Ketones can be reduced.

The hydroxyprogesterone substitution pattern (R ^17a = acetyl, R ^17b = hydroxy) is introduced by methods known from the literature. For example, the corresponding 17-ketone with trimethylsilyl cyanide in a suitable solvent, such as. B. dichloromethane, optionally in the presence of crown ethers, e.g. B. 18-crown-6, can be synthesized as a mixture of the isomeric 17-cyanohydrins. The silyl-protected cyanohydrins are then z. B. separated chromatographically and either directly with an alkyl magnesium halide or an alkyl lithium compound, e.g. B. methyl lithium, or initially reduced with diisobutyl aluminum hydride (DIBAH) to the aldehydes, which then give the 17α- or 17β-alkanoyl compounds after reaction with an alkylmagnesium halide or an alkyllithium compound and reoxidation to the 20-ketone.

Starting from the 17α- (or β-) hydroxy-17β- (or α-) alkanoyl compounds can then the 17α-alkanoyloxy in a known manner by esterification of the 17-hydroxy function derivatives are obtained.

Furthermore, the formal water addition to 17α- (or 17β-) ethynyl-17β (or 17α) -hydroxy derivatives, for example by means of Oxymercuration. Starting from the 17α-ethynyl isomer, the 17α-acetyl and starting from the 17β-ethynyl isomer, the 17β-acetyl compound. The introduction of the Hydroxyprogesterone substitution pattern is also from among the 17-ethynyl compounds Reversal of the original stereochemistry at C-17 possible (17α-ethynyl-17β-hydroxy results 17β-acetyl-17α-hydroxy and vice versa). The transfer of 17α- (or β) -ethynyl-17β- (or α) -nitrooxy compounds (see H. Hofmeister, K. Ahnen, H. Laurent and R. Wiechert, Chem.Ber. 111, 3086 (1978)) or from 17α- (or β) -ethynyl- 17β- (or α) -hydroxy compounds generated allene sulfoxides (see V. VanRheenen and K.P. Shephard, J.Org.Chem. 44, 1582 (1979)) into the corresponding 17β- (or α) -acetyl- 4 7α- (or β) -hydroxy compounds to be emphasized.

17β- (or α) -acetyl-17α- (or β) -fluorine compounds can e.g. B. from the corresponding 17β- (or α) -acetyl -17α- (or β) -hydroxy compounds by reaction with DAST (Diethylaminosulfur trifluoride) in suitable solvents such as Trichloromethane can be represented.

The subsequent release of the 3-keto function with elimination of water and The 4 (5) double bond is formed by treatment with acids or an acidic one Ion exchanger. The acidic treatment is carried out in a manner known per se by the corresponding 5α-hydroxy-3-ketal in a water-miscible solvent, such as Methanol, ethanol or acetone, dissolves and on the solution catalytic amounts of mineral or Sulfonic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid, or an organic acid, such as acetic acid, acts until existing protective groups are removed. The reaction runs at temperatures from 0 to 100 ° C.

The next steps usually apply the introduction of the residues R ^6a , R ^6b and R⁷. A 6,7-double bond can be introduced starting from 3-ketone (W = oxygen atom) via dienol ether bromination and subsequent elimination of hydrogen bromide (see, for example, JJ Fried, JA Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, p. 265- 374).

The dienol ether bromination can e.g. B. analogous to the instructions of J.A. Zderic, Humberto Carpio, A. Bowers and Carl Djerassi in Steroids 1, 233 (1963). The Hydrogen bromide can be eliminated by heating the 6-bromo compound with basic Means such. B. LiBr or Li₂CO₃ in aprotic solvents such as dimethylformamide at temperatures of 50-120 ° C or by combining the 6-bromo compounds in one Solvents such as collidine or lutidine can be heated.

A 6,7-methylene function is introduced from the 4,6-diene-3-one by reaction with dimethylsulfoxonium methylide, whereby a mixture of the α and β isomers is obtained (the ratio depends on the substrates used and is approx. 1: 1). B. can be separated into the individual isomers by column chromatography.

Compounds in which R⁷ is an alkyl radical, are from the 4,6-diene-3-one compounds prepared by 1,6 addition according to known methods (J. Fried, J.A. Edwards: "Organic Reactions in Steroid Chemistry," by Nostrand Reinhold Company 1972, Pages 75 to 82; and A. Hosomi and H. Sakurai, J.Am. Chem. Soc. 99, 1673 (1977)). Of particular note here is the addition of dialkyl copper lithium compounds.

Compounds in which R ^{6a represents} a chlorine atom and R _6b and R⁷ form a common additional bond are also prepared starting from the 4,6-diene-3-one compounds. For this purpose, the 6,7-double bond is first used using organic peracids, such as. B. meta-chloroperbenzoic acid in methylene chloride and optionally in the presence of sodium hydrogen carbonate (see W. Adam et al, J.Org.Chem. 38, 2269 (1973)). The opening of this epoxide and the elimination of the primary 7α-hydroxy group takes place z. B. by reaction with hydrogen chloride gas in glacial acetic acid (see, inter alia, DE-A 11 58 966 and DE-A 40 06 165).

The introduction of a 6-methylene group can, for example, start from a 3-amino 3,5-diene derivative by reaction with formalin in alcoholic solution to form a 6α-hydroxymethyl group and subsequent acidic dehydration z. B. with hydrochloric acid Dioxane / water take place. The elimination of water can also be done in such a way that first exchanged the hydroxy group for a better escape group and then is eliminated. As escape groups are e.g. B. the mesylate, tosylate or benzoate suitable (see DE-A 34 02 3291, EP-A. 0 150 157, US-A 4,584,288; K. Nickisch et al., J. Med. Chem. 34, 2464 (1991)).

Another possibility for the preparation of the 6-methylene compounds is direct  Reaction of the 4 (5) unsaturated 3-ketones with acetals of formaldehyde in the presence of sodium acetate with e.g. B. phosphorus oxychloride or phosphorus pentachloride in suitable Solvents such as chloroform (see e.g. K. Ahnen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).

The 6-methylene compounds can be used to prepare compounds of the general formula 1 in which R ^6a is methyl and R ^6b and R⁷ together form an additional bond.

You can do this e.g. B. one by D. Burn et al. in Tetrahedron 21, 1619 (1965) Use a method in which an isomerization of the double bond by heating the 6-methylene compounds in ethanol with 5% palladium-carbon catalyst, either with Hydrogen or pretreated by heating with a small amount of cyclohexene was achieved. The isomerization can also be done with a non-pretreated one Catalyst take place when a small amount of cyclohexene is added to the reaction mixture becomes. The occurrence of small amounts of hydrogenated products can be increased by adding a Excess sodium acetate can be prevented.

However, 6-methyl-4,6-dien-3-one derivatives can also be prepared directly (see K. Ahnen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983)).

Compounds in which R ^{6a represents} an α-methyl function can be prepared from the 6-methylene compounds by hydrogenation under suitable conditions. The best results (selective hydrogenation of the exo-methylene function) are achieved by transfer hydrogenation (EA Brande, RP Linstead and PWD Mitchell, J. Chem. Soc. 3578 (1954)). The 6-methylene derivatives are heated in a suitable solvent, such as. As ethanol, in the presence of a hydride donor, such as. B. cyclohexene, 6α-methyl derivatives are obtained in very good yields. Small amounts of 6β-methyl compound can be acid isomerized (see, for example, BD Burn, DN Kirk and V. Petrow, Tetrahedron 1619 (1965)).

The targeted representation of 6β-alkyl compounds is also possible. For this, the 4 (5) unsaturated 3-ketones e.g. B. with ethylene glycol, trimethyl orthoformate in dichloromethane in the presence of catalytic amounts of an acid (e.g. p-toluenesulfonic acid) to the corresponding 3-ketals implemented. The isomerizes during this ketalization Double bond in position 5 (6). A selective epoxidation of this 5 (6) double bond succeeds z. B. by using organic peracids, e.g. B. m-chloroperbenzoic acid, in suitable solvents such as dichloromethane. Alternatively, epoxidation can also be used with hydrogen peroxide in the presence of e.g. B. hexachloroacetone or 3-nitrotrifluoroacetophenone  respectively. The 5,6α-epoxides formed can then under Use of appropriate alkyl magnesium halides or alkyl lithium compounds axially be opened. This leads to 5α-hydroxy-6β-alkyl compounds; The cleavage of the 3-keto protective group can maintain the 5α-hydroxy function by treatment under mild acidic conditions (acetic acid or 4N hydrochloric acid at 0 ° C). Basic elimination the 5α-hydroxy function with z. B. dilute aqueous sodium hydroxide solution gives the 3-keto-4-ene compounds with a β-6-alkyl group. Alternatively, ketal splitting results under more drastic conditions (aqueous hydrochloric acid or another strong acid) the corresponding 6α-alkyl compounds.

The compounds of general formula I obtained, in which W represents an oxygen atom stands, if desired by reaction with hydroxylamine hydrochloride in Presence of a tertiary amine at temperatures between -20 and + 40 ° C in your corresponding oximes (general formula I with W in the meaning of N∼OH, where the hydroxy group can be syn- or anti-resistant). Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,5- Diazabicyclo [4.3.0] non-5-ene (DBN) and 1,5-diazabicyclo [5.4.0] undec-5-ene (DBU), where Pyridine is preferred.

Removal of the 3-oxo group to produce a final product of the general formula I with W in the meaning of two hydrogen atoms can, for example, according to the in DE-A 28 05 490 specified rule by reductive cleavage of a thioketal of the 3-keto compound respectively.

The following examples serve to explain the invention in more detail:  

example 1 9,11α-dihydro-17α-ethinyl-17β-hydroxy-6′H-benzo [10,9,11] -13α-estr-4-en-3-one a) 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 19-ethynyl-5α-androst-9 (11) -en-5,17β-diol

1.5 g of mercury (II) chloride are added to a suspension of 24.3 g of magnesium shavings in 350 ml of absolute diethyl ether. The mixture is stirred for 30 minutes and then cooled to 0 ° C. 4 ml of 3-bromopropyne are then first added under argon. After the reaction has started (temperature rise), the mixture is cooled to 5 ° C. Then a further 33.5 ml of 3-bromopropyne are added dropwise at such a rate that the internal temperature does not exceed 0 ° C. After the addition is complete, the mixture is stirred at 0 ° C. for 30 minutes and then a solution of 25 g of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5,10α-epoxy-5α-estr-9 (11) -en-17β-ol slowly added dropwise in 300 ml of absolute tetrahydrofuran. The mixture is left to stir for one hour at 0 ° C. and then decanted from the excess magnesium. Then 500 ml of saturated aqueous ammonium chloride solution are carefully added and the mixture is stirred for one hour at room temperature (strong gas evolution). It is extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. It is filtered and concentrated in vacuo. The residue is recrystallized from diisopropyl ether. 22.5 g 1a) are obtained as white crystals.
1 H-NMR (CDCl₃): δ = 5.42 m (1H, H-11); 4.40 s (1H, OH); 3.75 dd (J = 14, 7.5Hz, 1H, H-17); 3.40-3.60 m (4H, ketal); 1.93 t (J = 1.5 Hz, 1H, ethyne); 0.99 s (3H, Me ketal); 0.92 s (3H, Me-ketal); 0.76 s (3H, C-18)

b) 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 19-ethynyl-5-hydroxy-5α-androst-9 (11) -en-17-one

33 g of chromium trioxide are added to 110 ml of pyridine in 900 ml of dichloromethane at 0 ° C. The mixture is stirred at 0 ° C for 30 minutes and then a solution of 22.5 g of the substance described in 1a) in 250 ml of dichloromethane is added. Then allowed to stir at 0 ° C for one hour. The reaction solution is then decanted off and the residue is washed three times with dichloromethane. The combined organic phases are washed twice with 5% aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride solution and dried over sodium sulfate. It is filtered and concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 21 g 1b) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.43 ppm dbr (J = 5.5 Hz, 1H, H-11); 4.40 s (1H, OH); 3.40-3.60 m (4H, ketal); 1.92 t (J = 1.5 Hz, 1H, ethyne); 1.02 s (3H, C-18); 0.95 s (3H, Me ketal); 0.91 s (3H, Me ketal)

c) 3,3- [2,2-Dimethyl-1,3-propanediylbis (oxy)] - 19-ethynyl-5-hydroxy-5α, 13α-androst-9 (11) - en-17-on

21 g of the compound described under 1b) are dissolved in 1.5 l of dioxane. The solution is then irradiated with UV light in a quartz glass apparatus for 1.5 hours. The mixture is then concentrated in vacuo and the crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 13.8 g 1c) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.35 ppm m (1H, H-11); 4.30 s (1H, OH); 3.45-3.60 m (4H, ketal); 1.90 t (J = 1.5 Hz, 1H, ethyne); 1.12 s (3H, C-18); 1.00 s (3H, Me ketal); 0.96 s (3H, Me ketal)

d) 19- (2-bromoethynyl) -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5α, 13α-androst-9 (11) -en- 17-one

13.8 g of the substance described under 1c) are dissolved in 400 ml of acetone. You add up under argon 580 mg silver nitrate and 7.32 g N-bromosuccinimide. Then turns 20 Stirred minutes at room temperature. Then the reaction solution is poured into 350 ml ice cold saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. It is filtered and concentrated in vacuo. 15.6 is obtained 1d), which is used in the next step without cleaning.  

e) 19- (2-bromoethenyl) -3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] -5-hydroxy-5α, 13α- androst-9 (11) -en-17-one

15.6 g of the substance described under 1d) are dissolved in 300 ml of a mixture of tetrahydrofuran and water (1: 1). 24 g of p-toluenesulfonic acid hydrazide and 15.6 g of sodium acetate are added under argon. The mixture is then boiled under reflux for 4 hours. After cooling, the reaction solution is poured onto 150 ml of ice-cold saturated aqueous sodium hydrogen carbonate solution. It is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. It is filtered and concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 9.4 g 1e) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 6.12 ppm dbr (J = 7 Hz, 1H, vinyl); 5.70 q (J = 7 Hz, 1H, vinyl); 5.26 m (1H, H-11); 4.32 s (1H, OH); 3.50-3.60 m (4H, ketal); 1.12 s (3H, C-18); 0.99 s (3H, Me-ketal); 0.98 s (3H, Me ketal)

f) 9,11α-dihydro-3,3- (2,2-dimethyl-1,3-propanediylbis (oxy)] - 5-hydroxy-6′H-ben-zo- [10,9,11] - 5α, 13α-estran-17-one

9.4 g of the substance described under 1e) are dissolved in 250 ml of absolute toluene. 9 ml of tributyltin hydride and 25 mg of azobisisobutyronitrile are added under argon and the mixture is boiled under reflux for one hour (with simultaneous irradiation with a UV lamp). After the reaction is complete, the reaction solution is concentrated in vacuo and the residue is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 4.6 g of 1f) and 2.4 g of 3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5-hydroxy-3'H-cyclopenta [9.10] -9β are obtained , 13α-estran-17-one as white foams.
1 H-NMR (CDCl₃): δ = 5.43 ppm m (1H, bow); 5.36 dbr (J = 10 Hz, 1H, bow); 4.40 s (1H, OH); 3.50-3.60 m (4H, ketal); 2.35 m (1H, H-11); 1.00 s (6H, C-18 + Me ketal); 0.97 s (3H, Me ketal)

g) 9.11 α-dihydro-3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 1 7α-ethynyl-6′H-benzo [10,9,11] -5α, 13α-estran-5,17β-diol

30 ml of absolute tetrahydrofuran are saturated with Ethingas at 0 ° C for 30 minutes. 6 ml of a 1.6 molar solution of butyllithium in hexane are then added under argon and the mixture is stirred at 0 ° C. for a further 30 minutes. A solution of 400 mg of the substance described under 1f) in 10 ml of absolute tetrahydrofuran is then added. The mixture is left to stir at 0 ° C. for one hour and then quenched with saturated aqueous ammonium chloride solution. It is extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Then it is filtered and concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 261 mg 1g) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.65 ppm m (1H, bow); 5.52 dbr (J = 10 Hz, 1H, bow); 4.37 s (1H, OH); 3.50-3.65 m (4H, ketal); 2.50 s (1H, ethyne); 2.49 m (1H, H-11); 1.15 s (3H, C-18); 1.00 s (6H, Me-Ketal)

h) 9,11α-dihydro-17α-ethynyl-17β-hydroxy-6′H-benzo [10,9,11] -13α-estr-4-en-3-one

261 mg of the substance described under 1g) are dissolved in 12 ml of acetone. 0.6 ml of 4 normal aqueous hydrochloric acid is added and the mixture is stirred for 1 hour at room temperature. The reaction solution is then diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. It is dried over sodium sulfate, filtered and concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 160 mg 1h) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.80 ppm sbr (1H, H-4); 5.71 m (1H, bow); 5.59 dbr (J = 10 Hz, 1H, bow); 2.60 m (1H, H-11); 2.50 s (1H, ethyne); 1.15 s (3H, C-18)

Example 2 9.11 α-Dihydro-17β-hydroxy-17α- (1-propynyl) -6'H-benzo [10.9.11] -13α-estr-4-en-3-one a) 9,41α-Dihydro-3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 17α- (1-propynyl) -6′H- benzo [10,9,11] -5α, 13α-estran-5,17β-diol

30 ml of absolute tetrahydrofuran are saturated at 0 ° C for 30 minutes with propyne gas. 6 ml of a 1.6 molar solution of butyllithium in hexane are then added under argon and the mixture is stirred at 0 ° C. for 30 minutes. A solution of 400 mg of the compound described under 1f) in 10 ml of absolute tetrahydrofuran is then added. The mixture is stirred for one hour at 0 ° C. and then quenched with saturated aqueous ammonium chloride solution. It is extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. It is filtered and concentrated in vacuo. The crude product obtained is purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 276 mg 2a) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.61 ppm m (1H, bow); 5.53 dbr (J = 10 Hz, 1H, bow); 4.35 s (1H, OH); 3.50-3.65 m (4H, ketal); 2.47 m (1H, H-11); 1.93 s (3H, propyne); 1.13 s (3H, C-18); 1.00 s (6H, Me-Ketal)

2b) 9,11α-Dihydro-17β-hydroxy-17α- (1-propynyl) -6H-benzo [10,9,11] -13α-estr-4-en-3-one

Analogously to Example 1h), 276 mg of the substance described under 2a) in 12 ml of acetone are reacted with 0.6 ml of 4 normal aqueous hydrochloric acid. After purification of the crude product by column chromatography on silica gel with a mixture of hexane / ethyl acetate 170 mg 2b) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.80 ppm sbr (1H, H-4); 5.65 m (1H, bow); 5.59 dbr (J = 10 Hz, 1H, bow); 2.57 m (1H, H-11); 1.88 s (3H, propyne); 1.10 s (3H, C-18)

Example 3 17- (acetyloxy) -9,11α-dihydro-6′H-benzo [10,9,11] -19-nor-13α17α-pregn-4-en-3,20-dione 3a) 9,11α-dihydro-3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5-hydroxy-17β- [(trimethylsilyl) oxy] -6′H-benzo [10,9,11] -5α, 13α-estran-17α-carbonitrile

1.88 g of the compound described under 1f) are dissolved in 10 ml of dichloromethane. 15 mg of potassium cyanide, 15 mg of 48-crown-6 and 0.7 ml of trimethylsilyl cyanide are added and the mixture is stirred at room temperature for 8 hours. The reaction solution is purified directly by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 1.165 g 3a) are obtained.
1 H-NMR (CDCl₃): δ = 5.45-5.52 m (2H, bow); 4.30 s (1H, OH); 3.50-3.60 m (4H, ketal); 2.40 m (1H, H-11); 1.25 s (3H, C-18); 1.00 s (3H, Me ketal); 0.98 s (3H, Me ketal); 0.20 s (9H, SiMe₃)

3b) 9,11α-dihydro-3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5-hydroxy-17β- [(trimcthylsilyl) oxy] -6′H-benzo [10,9,11] -5α, 13α-estran-17α-carbaldehyde

11 ml of a 1 molar solution of diisobutylaluminum hydride in hexane are added at -10 ° C. to a solution of 1.165 g of the substance described under 3a) in 20 ml of absolute tetrahydrofuran. The mixture is left to stir at 0 ° C. for 6 hours and then the reaction mixture is carefully poured onto water. It is extracted with ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product obtained is dissolved in 20 ml of ethyl acetate. 10 ml of saturated ammonium chloride solution and 0.5 ml of saturated aqueous oxalic acid are added, and the mixture is stirred for two hours at room temperature. The organic phase is then separated off and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After purification of the crude product by column chromatography on silica gel with a mixture of hexane / ethyl acetate 644 mg 3b) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 9.60 s (1H, aldehyde), 5.50-5.55 m (2H, bow); 4.40 s (1H, OH); 3.50-3.60 m (4H, ketal); 2.40 m (1H, H-11); 1.05 s (3H, C-18); 1.00 s (3H, Me ketal); 0.98 s (3H, Me ketal); 0.20 s (3H, SiMe₃); 0.10 (6H, SiMe₃)

3c) 9,11α-dihydro-3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 17 - [(trimethylsil-yl) oxy] -6′H- benzo [10,9,11] -19-nor-5α, 13α, 17α-pregnan-5,20ξ-diol

To a solution of 644 mg of the substance described under 3b) in 20 ml of absolute Diethyl ether are at 0 ° C in 2.5 ml of a 1.6 molar solution of methyl lithium in Diethyl ether added. The mixture is left to stir for one hour at 0 ° C. and then poured in Reaction mixture with ice cooling on saturated aqueous ammonium chloride solution. Man extracted with ethyl acetate, the organic phase washes with saturated aqueous Sodium chloride solution, dries over sodium sulfate, filtered and concentrated in vacuo. Man receives 530 mg 3c) as a mixture of the 20 isomers, which without separation into the next stage is used.

3d) 9,11α-dihydro-3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 5-hydroxy-17- [(trimethylsilyl) oxy] -6′H-benzo [10,9,11] -19-nor-5α, 13α, 17α-pregnan-20-one

Analogously to Example 1b), 530 mg of the substance described under 3c) are reacted with 600 mg of chromium trioxide and 2.2 ml of pyridine in dichloromethane. After purification by column chromatography, 385 mg 3d) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.50-5.55 m (2H, bow); 4.30 s (1H, OH); 3.50-3.60 m (4H, ketal); 2.40 m (1H, H-11); 2.20 s (3H, acetyl); 1.00 s (3H, Me ketal); 0.98 s (3H, Me ketal); 0.82 s (3H, C-18); 0.15 s (9H, SiMe₃)

e) 9,11α-dihydro-5,17-dihydroxy-3,3- [2,2-dimethyl-1,3-propanediylbis (oxy)] - 6′-H- benzo [10,9,11] -19-nor-5α, 13α, 17α-pregnan-20-one

To a solution of 385 mg of the substance described under 3d) in 15 ml of tetrahydrofuran 1.5 ml of a 1.1 molar solution of Tetrabutylammonium fluoride added in tetrahydrofuran. The mixture is stirred for 1.5 hours,  then pours the reaction mixture onto saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase becomes saturated with aqueous Washed sodium chloride solution, dried over sodium sulfate, filtered and in vacuo constricted. The crude product obtained (315 mg) is passed to the next stage without purification used.

3f) 9,11α-dihydro-17-hydroxy-6'H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-en-3,20-dione

Analogously to Example 1h), 315 mg of the substance described under 3e) are reacted with 0.8 ml of 4 normal hydrochloric acid in acetone. After purification by column chromatography, 195 mg 3f) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.80 ppm sbr (1H, H-4); 5.65 m (1H, bow); 5.55 dt (J = 10, 2.5 Hz, 1H, bow); 3.10 s (1H, H-11); 2.26 s (3H, acetyl); 0.95 s (3H, C-18)

3g) 17- (acetyloxy) -9.11α-dihydro-6′H-benzo [10.9.11] -19-nor-13α, 17α-pregn-4-en-3.20- dion

1.2 ml of trifluoroacetic anhydride are added at 0 ° C. to a suspension of 195 mg of the compound described under 31) in 3.5 ml of glacial acetic acid. The mixture is stirred for 4 hours at room temperature and then the reaction mixture is carefully added dropwise to saturated aqueous sodium hydrogen carbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. After purification by column chromatography on silica gel with a mixture of hexane / ethyl acetate, 150 mg 3g) are obtained.
1 H-NMR (CDCl₃): δ = 5.80 sbr (1H, H-4); 5.68 m (1H, bow); 5.62 dt (J = 10, 2.5 Hz, 1H, bow); 2.53 m (IH, H-11); 2.10 s (3H, acetyl); 2.09 s (3H, acetoxy); 0.90 s (3H, C-18)

Claims (5)

1. 11β, 19-bridged 13α-alkyl steroids of the general formula I wherein
W for an oxygen atom, the hydroxyimino group (= N∼OH) or two hydrogen atoms
stands,
R ^6a and R ^6b each represent a hydrogen atom and R⁷ represents a hydrogen atom or a straight-chain or branched-chain saturated α- or β-position C₁-C₄-alkyl radical or
R ^6a and R _6b together represent a methylene group or a triple ring formed together with the carbon atom 6 and R⁷ represents a hydrogen atom or
R ^{6a represents} a fluorine, chlorine, bromine or iodine atom or a straight-chain or branched-chain saturated C₁-C₄alkyl radical, in which case R _6b and R⁷ each represent a hydrogen atom or together form an additional bond and if R ^6b and R⁷ each represent a hydrogen atom, R ^{6a can be} α or β, or
R ^{6a represents} a hydrogen atom, in which case R ^6b and R⁷ together represent an α- or β-methylene bridge or an additional bond, or
R¹⁵ and R¹⁶ each represent a hydrogen atom or together for an additional bond or an α or β methylene bridge, or
R¹⁵ for a hydrogen atom and R¹⁶ for an α- or β-position C₁-C₄-alkyl group or R¹⁶ together with R ^17a for an α- or β-position methylene bridge and R ^17b for a radical stand, as well
R ^{11 '} and R ^19' each represent a hydrogen atom or together represent an additional bond,
R ^17a / R ^17b one of the substituent combinations or R ^17a / R ^17b together mean with
R²¹ and R²³ have the meaning of a hydrogen atom, a C₁-C₄-alkyl or a C₁-C₄-alkanoyl group,
R²² has the meaning of a C₁-C₃-alkyl or a 1-hydroxy-C₁-C₃-alkyl group,
A has the meaning of a hydrogen atom, the cyano group, a radical of the formula -COOR²⁴ or -OR²⁵, where R²⁴ represents a C₁-C₄-alkyl radical and R²⁵ represents a hydrogen atom, a C₁-C₄-alkyl or C₁-C₄-alkanoyl radical,
B has the meaning of a hydrogen, fluorine, chlorine, bromine or iodine atom, a C₁-C₄ alkyl, C₂ or C₃ alkynyl group, a hydroxyalkyl, alkoxyalkyl or alkanoyloxyalkyl group each having 1 to 4 carbon atoms in the alkyl -, alkoxy and / or alkanoyloxy part,
D is a hydrogen atom, a hydroxy, C₁-C₄ alkoxy or C₁-C₄ alkanoyloxy group,
n has the meaning 0, 1, 2, 3 or 4,
m has the meaning 0, 1 or 2,
p has the meaning 0 or 1,
k has the meaning 0, 1, 2 or 3 and
R¹⁸ represents a hydrogen atom or a methyl group. 2. 9,11α-dihydro-17α-ethinyl-17β-hydroxy-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
9,11α-dihydro-17β-hydroxy-17α- (1-propynyl) -6′H-benzo [10,9,11] -13α -estr-4-en-3-one;
9.44 α-dihydro-17α-hydroxy-17β- (1-propynyl) -6′H-benzo [10.9.11] -13α-estr-4-en-3-one;
9,11α-dihydro-17α-ethinyl-17β-hydroxy-6′H-benzo [10,9,11] -13α-estra-4,15-dien-3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -13 α-estra-4,15-dien-3-one;
9,11α-dihydro-17β-hydroxy-17α- (1-propynyl) -6′H-benzo [10,9,11] -13α-estra-4,15-dien-3-one;
9.11 α-dihydro-17α-hydroxy-17β- (1-propynyl) -6′H-benzo [10.9.11] -13α-estra-4.15-dien-3-one;
17- (acetyloxy) -9,11α-dihydro-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-en-3,20-dione;
17- (acetyloxy) -6-chloro-9,11α-dihydro-6'H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-9,11α-dihydro-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregna-4,6-diene-3,20-dione ;
17- (Acetyloxy) -9,11α-dihydro-6-methyl-6'H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6-methyl-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregna-4,6-diene-3,20-dione ;
17- (acetyloxy) -9,11α-dihydro-6α-methyl-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6α-methyl-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-ene-3,20-dione;
9,11α-dihydro-17-methyl-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
9,11α-dihydro-17-methyl-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-en-3,20-dione;
9,11α-dihydro-6,17-dimethyl-6′H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3,20-dione;
9,11α-dihydro-6,17-dimethyl-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregna-4,6-diene-3,20-dione;
9.11 α-dihydro-17α-ethynyl-17β-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-3-one;
9,11α-dihydro-17β-hydroxy-17α- (1-propynyl) -6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-3-one;
9,11α-dihydro-17α-hydroxy-17β (1-propynyl) -6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-3-one;
9,11α-dihydro-17α-ethynyl-17β-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estra-4,15-diene -3-one;
9,11α-dihydro-17β-ethynyl-17α-hydroxy-6′H-benzo [10,9,11] -18a-homo-13α-estra-4,15-dien-3-one;
17- (acetyloxy) -9,11α-dihydro-6′H-benzo [10,9,11] -18a-homo-19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -9,11α-dihydro-6′H-benzo [10,9,11] -18a-homo-19-nor-13α, 17α-pregn-4-en-3,20-dione;
9,1α-dihydro-17α-ethinyl-6′H-benzo [10,9, 11] -13α-estr-4-en-17β-ol;
9,11α-dihydro-17β-ethynyl-6′H-benzo [10,9,11] -13α-estr-4-en-17α-ol;
9,11α-dihydro-17α-ethynyl-6′H-benzo [10,9,11] -13α-estra-4,15-dien-17β-ol;
9,11α-dihydro-17β-ethynyl-6′H-benzo [10,9,11] -13α-estra-4,15-dien-17α-ol;
9,11α-dihydro-17α-ethinyl-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-17β-ol;
9,11α-dihydro-17β-ethynyl-6′H-benzo [10,9,11] -18a-homo-13α-estr-4-en-17α-ol;
17α-ethynyl-17β-hydroxy-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
17β-ethynyl-17α-hydroxy-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -13α-estr-4-en-3-one;
17α-hydroxy-17β- (1-propynyl) -4 ′, 5 ′, 9,11α-tetrahydro-6H-benzo [10,9,11] -13α-estr-4-en-3-one;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregn-4-en-3,20-dione ;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α-pregna-4,6-diene-3 , 20-dione;
17- (acetyloxy) -6-methyl-4 ′, 5 ′, 9,11α-tetrahydro-6′H-benzo [10,9,11] -19-nor-13α, 17α-pregna-4,6-diene -3.20-dione. 3. Pharmaceutical preparations, characterized in that they have at least one Compound of general formula I according to claim 1 and a pharmaceutical compatible carriers included. 4. Use of the compounds of general formula I according to claim 1 for Manufacture of drugs. 5. Intermediate compounds of the general formula II wherein
K for a keto protecting group or a protected hydroxy group and a hydrogen atom as well
R¹⁸ represent a hydrogen atom or a methyl group.