NO177350B - Steroids with 19.11 creates - Google Patents

Description

The invention relates to new steroids with a 19,lip bridge bond which have contraceptive properties.

The steroids with a 19,lip bridge bond according to the invention are characterized by having the general formula I

where

R<1> is a methyl or ethyl residue,

R<2> is a hydrogen or chlorine atom,

B is a hydrogen atom,

G is a hydrogen atom or a C₁-C₂ alkyl residue, or

B and G are together a second bond between carbon atoms 6 and 7, or

B and R<2> are together a methylene group,

Z is the remainder of a ring with formula

where

R<1> has the above meaning,

the dashed line starting from W means the possible presence of a double bond,

W is a CH2 or CH residue,

R<6> is H, C2-5-alkynyl, HO-C2-5-alkenyl, CN-C2-alkyl, HO-C2-5-alkynyl, C1-4-Alkoxy-C1-4-alkyl, halogen-<C>2-5<- >alkynyl, HO-C^-alkyl, C2.5-alkenyl, V is the residue of a phenyl ring of formula

where

R 4 is a hydrogen or halogen atom, or a hydroxy-, cyano-, C 1-4 -alkyl-, HO-C 1-4 -alkyl-, C 1-4 -alkyl-thio- or -sulfinyl-, N-C 1-4 -alkyl )2-amino-, CF3-sulf onyloxy-, (CH3 )3-Si-C2_5-alkynyl-, C2.5-alkenyl- or -alkynyl-, (C<H>3)3-Si-C1.4- alkyl, C 1-4 -alkyl or -alkanoyl-, (C 1-4 -alkoxy)2-phosphoryl-, C 1-4 -alkyl-phenyl-, cyanophenyl-, thiazolyl-, pyridyl-, thienyl- or furyl residue, and R 4 is a hydrogen atom , or

R4 and R<4>' are together a 4,5-methylenedioxy residue,

the ring A is

where M and N together are a second bond,

or M is a hydrogen atom and N is a hydroxy group, with B, R<2>, G, R<3>, D and E then being hydrogen atoms,

and X is an oxygen atom, two hydrogen atoms or a hydroxyimino group N-OH,

R<3> and D are each a hydrogen atom, and

E is a hydrogen atom, or R 3 is a hydrogen atom and

D and E are together a second bond between carbon atoms 1 and 2,

as well as physiologically acceptable acid addition salts thereof.

The new compounds with the general formula I are prepared by compounds with the general formula II

where

R<1> means a methyl or ethyl residue; 1 means the numbers 1 or 2;

K means an ethylenedioxyketal, ethylenedithioketal or 2,2-dimethyltrimethylenedioxyketal group; and

V stands for the residue of a phenyl ring of formula

where

Hal means a fluorine, chlorine, bromine or iodine atom,

R<4a>, apart from the cyanide residue, has the same meaning as R<4>, in that any hydroxy, mercapto, amino, oxo-£>g/or terminal acetylene groups present are protected, ring-closed under reductive radical conditions if Hal represents a bromine or iodine atom, or by treating a compound of the general formula II with an electropositive metal such as sodium, potassium, lithium or calcium in liquid ammonia if Hal represents a fluorine, chlorine, bromine or iodine atom, to the intermediates of the general formula IVb

where

K has the same meaning as in formula II;

V" stands for the residue of a phenyl ring of formula

where

R<4a>, apart from the cyanide residue, has the same meaning as R<4>, with any hydroxy, mercapto, amino, oxo and/or terminal acetylene groups present being protected;

and then either first

a) optionally oxidizes the C-17-hydroxy group and then b) optionally liberates a hydroxy group in the residue R<4a> in V" which has a protecting group, for this protecting group, if desired, conventionally prepares a corresponding trifluoroalkyl sulfonate from the hydroxy compound, optionally transfers trifluoro -alkylsulfonate either directly or through exchange with the outgoing trifluoroalkylsulfonate group for a tin trialkyl group above the corresponding tin trialkyl compound to a compound as in V",

optionally after conversion of the tin trialkyl group by reaction with halogen to the corresponding halogen-

group, exhibits the desired substitution pattern,

or first execute b) and then a) and then

c) functionalizes the ring D in the desired manner according to methods known per se, thereby subjecting it to

kept product the action of an acid or an acidic ion exchanger in a solvent which is miscible with water, for water splitting simultaneously with or after release of the 3-oxo group, and then, possibly after renewed protection of the intermediate released, in V and/or Z contained functional groups, in-

leads, if desired, to a 1,2- and/or 6,7-double bond in addition to the 3,4-double bond by reacting with dehydrating agents respectively by allyl or dienol ether halogenation and removal of hydrogen

halide;

a 6-methylene group by reacting a corresponding 3-amino-3(4),5(6)-diene with formalin in alcohol solution to the 6α-hydroxymethyl compound followed by water elimination in acidic medium;

a Cx-C4-alkyl group in the 7-position by 1,6-addition of the corresponding C-L-C^-alkylmagnesium iodide (or

-bromide) under copper(I) catalysis to a 4(5),6(7)-

dien-3-one; or a chlorine atom in the 6-position via epoxy

deration of a 4(5),6(7)-dien-3-one to the corresponding 6a,7a-epoxyd, opening of the epoxide by addition of chloride to the 7a-hydroxy-6|3-chloro compound and elimination of water, or

d) subjects the product thus obtained to the action of an acid or an acidic ion exchanger in a solution

agent which is miscible with water, for water splitting simultaneously with or after release of the 3-oxo group,

introduces, if desired, a 1,2- and/or 6,7-double bond

ing in addition to the 3,4-double bond by reacting with dehydrating agents or by allyl-

or dienol ether halogenation and cleavage of

hydrogen halide;

a 6-methylene group by reacting a corresponding 3-amino-3(4),5(6)-diene with formalin in alcohol solution to the 6 α-hydroxymethyl compound followed by water elimination in acidic medium;

a C^-C^-alkyl group in the 7-position by 1,6-addition of the corresponding C^-C^-alkylmagnesium iodide (or -bromide) under copper(I) catalysis to a 4(5),6(7 )-dien-3-one; or a chlorine atom in the 6-position via epoxidation of a 4(5),6(7)-dien-3-one to the corresponding 6a,7a-epoxyd, opening of the epoxide by addition of chloride to 7a-hydroxy-6p -the chlorine compound and water splitting;

and then functionalizes the ring D in the desired manner

after protection of the 3-oxo group,

or performs steps a) and b) after step c) or d), optionally frees the thus obtained product of protective groups, if desired, alkylates or acylates the hydroxy, mercapto and/or amino group(s) possibly contained in V, if desired introduces a cyanide residue in the aryl substituent(s), if desired oxidizes the one or those in the aryl substituent(s) contained sulphide group(s), reacts if desired with hydroxylamine hydrochloride to the product of the general formula I with X meaning the hydroxyimino group N~OH, and optionally produces a physiologically acceptable acid addition salt.

After protection of any functional groups present in V, the starting compounds of the general formula II are subjected to cyclization.

The hydroxy, mercapto and keto protecting groups

which are covered by V<1> and K, in acidic environments are easily cleavable groups such as e.g. the methoxymethyl, ethoxymethyl, tetrahydropyranyl, ethylenedioxyketal, ethylenedithioketal or 2,2-dimethyltrimethylenedioxyketal group.

Protecting groups for amino and terminal acetylene groups (e.g. the trimethylsilyl and tert.-butyl-dimethylsilyl group) are known to the person skilled in the art and are cleaved off according to the desired reaction sequence also according to methods known from the literature (Synthesis 1980,

p. 627, J. Org. Chem., 46 (1986), p. 2280).

The conversion of II to the intermediates by 19,11 (3-bridge bond of the general formula IVb

where , K and 1 have the meanings given above, and V"

has the same meaning as V, however in V even-

tually present hydroxy, mercapto, amino, oxo and/or terminal acetylene groups are protected, occurs in those cases where the α-halogen substituent in V is a bromine or iodine atom, according to procedures known per se (Tetrahedron Letters 1982, 2575, 1985, 6001, 1986, 2833, J. Am. Chem.

Soc. 1982, 104, 2321, Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press 1986) through reducing radical ring closure.

A similar method for fluorine- and chlorine-substituted aromatics was not previously known. It was now found that this cyclization surprisingly succeeded in good yield through treatment of the educt with an electropositive metal, such as e.g. sodium, potassium, lithium or calcium, in liquid ammonia, mixed with one or more suitable organic solvents, such as e.g. diethyl ether, dimethoxyethane (DME), dioxane or tetrahydrofuran, at temperatures between -100 and -30°C, preferably -78 -60°C. That this ring closure can also be carried out with the fluoride ion as leaving group must be considered particularly surprising.

This method can also be used in both bromine- and iodine-substituted aromatic compounds.

The conversion of the thus obtained cyclization product into the final desired end product with the general formula I takes place analogously to methods known from the literature (e.g. J. Fried, J.A. Edwards, 'tirganic Reactions in Steroid Chemistry', Van Nostrand Reinhold Company 1972, vols. 1 and 2, "Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, vols. 1-12) as indicated above, after which a physiologically acceptable acid addition salt is optionally prepared.

In the course of this reaction sequence, it may be necessary to re-introduce protecting groups into intermediates, e.g. functional groups found in Z, by associated functionalization of rings A and B, or for the 3-keto group by associated structure of ring D.

The oxidation of the 17(3-hydroxyl group, which is necessary for the production of almost all end products, is carried out in a manner known per se, e.g. through Oppenauer oxidation or with chromic acid reagents (Jones reagent or chromic acid-pyridine).

The release of the 3-keto group during simultaneous splitting off of water and formation of the 4(5) double bond takes place by treatment with acid or an acidic ion exchanger. The acid treatment takes place in a manner known per se, by dissolving the corresponding 5oc-hydroxy-3-ketal in a water-miscible solvent, such as aqueous methanol, ethanol or acetone, and leaving catalytic amounts of mineral or sulphonic acids, such as hydrochloric acid , sulfuric acid, phosphoric acid, perchloric acid or p-toluenesulfonic acid, or an organic acid, such as acetic acid, act on the solution for such a long time that the protective groups present are removed and water is possibly split off. The reaction, which takes place at temperatures of 0 - 100°C, can also be carried out with an acidic ion exchanger. The course of the turnover can be followed with analytical methods, for example through thin-layer chromatography of withdrawn samples.

In general, the removal of protective groups and the splitting off of water are carried out in one reaction step, allowing the relevant 5oc-hydroxy-3-ketal or 5-en-3-ketal react for a certain period of time in a strong, acidic medium, as described in example lc). Equally, however, according to the invention, it is possible to carry out the removal of protective groups and the splitting off of water in two successive reaction steps, the first concerning 5a-hydroxy-3-ketal in a shorter treatment in a moderately acidic medium and then the corresponding 5a-hydroxy-3-keto - compound is recovered and possibly isolated, as is for example shown in example 9. The 5a-hydroxy-3-keto compound is then transferred through further action of acid during water splitting into the 3-keto-4-ene compound.

A very special advantage of the present invention lies in the large bond width of the substituents that can be introduced on the carbocyclic or heterocyclic aryl residue V (M. Pereyre, J.-P. Quintard, A. Rahm, Tin in Organic Synthesis, Butterworths, 1987 ). Among other things, the substituents R<4->Y- or R4 -Y'- is introduced directly as an arylmethylhalide correspondingly substituted on the aryl residue with the general formula V, V^I^Hal, is connected by means of a Grignard reaction with a suitable 5a,10a-epoxide of the general formula III, and the obtained intermediate with the general formula II is further processed in the manner already described.

The number of compounds that can be prepared that are substituted on V is relatively limited, as not all substituents that are desired in the final product, and that must be carried out on V'CH2Hal before the binding to the relevant 5a, 10a-epoxyd-III, and especially the reducing conditions during the cyclization of the intermediate II to a steroid with a 19, ll(3-bridge bond of the general formula IV which appears undamaged.

In a further embodiment of the method, however, it succeeded in varying

the substituent(s) in aryl residue V over a wide range, the substituent(s) being introduced only after the ring closure, and that before, simultaneously with or only after the completion of the structure of rings A, B and D. Moreover, at least one of the hydroxy groups is freed which is present and protected in the residue V" or V, for its protecting group and the corresponding perfluoroalkylsulfonate compound is prepared from the free OH compound through reaction with perfluoroalkylsulfonyl acid anhydride (alkyl = C^-C^) according to methods known per se ( P. J. Stang, M. Hanack and L. R. Subramanian, Synthesis, 85_ (1982)).

Thereby one proceeds either so that the perfluoro transition group is displaced by the desired substituents or their precursors during essentially simultaneous substitution in a transition metal-catalyzed reaction (pre-stage Pd°) (J.E. McMurry and S. Mohanraj, Tetrahedron Letters, 24, no. 27, pp. 2723-2726, 1983, X. Lu and J. Zhu, Communications, pp. 726-727, 1987, Q.-Y. Chen and Z.-Y. Yang, Tetrahedron Letters 27, No. 10, pp. 1171-1174, 1986,

S. Cacchi, P.G. Ciattini, E. Morera and G. Ortar, Tetrahedron Letters, 2_7, No. 33, pp. 3931-3934, 1986, A.M. Echavarren and J.K. Stille, J. Am. Chem. Soc, 1987, 109,

pp. 5478-5486) or a corresponding tri-organylstannyl, preferably tri-n-alkylstannyl compound is prepared temporarily and by transition metal catalysis from the perfluoroalkylsulfonate compound (J.K. Stille, Angew. Chem., £8 (1986), pp. 504-519 ). This is then reacted in a one-step reaction with an aromatic halogen-, preferably bromine- or iodo-substituted, carbocyclic or hetero-

cyclic compound (Y. Yamamoto, Y. Azuma, H. Mitoh, Communications, pp. 564-565, 1986, T.J. Bailey, Tetrahedron Letters, 27, no. 37, pp. 4407-4410, 1986), which may also have additional substituents, to a steroid with a 19,11 Q bridge bond, the aryl residue V or V" then has the desired, or a precursor to the desired, substitution.

The intermediately appearing tri-n-alkylstannyl compounds can also be isolated, as shown vicariously in example 39a)cc) for the case of 11(3,19-(4-tri-n-butylstannyl-O-phenylene)-3, 3-(2,2-dimethyltrimethylenedioxy)-androstane-5α, 17β-diols.

The introduction of 1,2- and/or 6,7-double bonds next to the 3,4-double bond follows known methods, e.g. with dehydrating agents, such as selenium dioxide, chloranil, thallium triacetate or dichlorodicyanbenzoquinone (DDQ), respectively. through allyl or dienol ether bromination and subsequent hydrogen bromide elimination.

(J. Fried, J.A. Edwards, Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, pp. 265-374, 1, Tetrahedron 42, (1986) 2971).

The allyl bromination is carried out e.g. with N-bromosuccinimide, N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin or dibromotetrachloroethane in the presence of such a radical generator as dibenzoyl peroxide in a solvent. Solvents include aprotic solvents, such as dioxane, and chlorinated hydrocarbons, such as e.g. carbon tetrachloride, chloroform or tetrachlorethylene. The reaction takes place between 0°C and the boiling point of the solution. The dienol ether bromination is carried out e.g. analogous to the regulations in Steroids I, 233.

The hydrogen bromide cleavage during formation of the A^ double bond takes place by heating the 6-bromo compound with basic agents, preferably with lithium bromide and lithium carbonate, or with lithium bromide and calcium carbonate, in an aprotic solvent such as dimethylformamide at temperatures of 50 - 120°C. A further possibility for HBr separation consists in heating

up the 6-bromo compound in collidine or lutidine.

When starting from a saturated ring A, double bonds in the 1,2- and 4,5-position can be introduced simultaneously, e.g. through bromination to 2,4-dibromo-3-ketone and dehydrobromination of the dibromide with e.g. lithium or calcium carbonate and lithium bromide in dimethylformamide.

The introduction of a 6-methylene group can e.g. take place by starting from a 3-amino-3(4),5(6)-diene derivative by reaction with formalin in alcoholic solution (Heiv. Chim. Acta, 5_6 (1973), p. 2396) to 6a- hydroxymethyl group and subsequent acidic water splitting, e.g. with hydrochloric acid in dioxane/water, or by starting from a 3-alkoxy-3(4),5(6)-diene derivative, analogous to the method described in US patent document no. 4,544,555, or directly by starting from a 3-oxo-4(5)-ene derivative analogous to the regulations in Synthesis, (1982), p. 34.

The methyleneation of the 6-methylene to 6,6-ethylene compound takes place with dimethylsulfoxonium methylide. Hereby, the 6-methylene steroid is added to a slurry of trimethylsulfoxonium iodide with sodium hydride in mineral oil and dimethylsulfoxide, or to a solution of trimethylsulfoxonium iodide and sodium hydroxide in dimethylsulfoxide. The reaction ends after 15 - 60 minutes at 20 - 40°C (J. Am. Chem. Soc. 8_4 (1962), p. 866, European patent application no. 0150157).

The introduction of a 2-methylene group takes place analogously to the method of A. J. Manson and D. Wood (J. Org. Chem., 32 (1967), p. 3434) or the methods referred to there.

The methyleneation of the 2-methylene to 2,2-ethylene compound occurs analogously to the methyleneation of the 6-methylene compound (see also Chem. Ber., 9J3 (1965),

p. 1470).

Mono or dialkylated compounds in the 2-position can be obtained, e.g. analogous to the method of L. Nedelec, Tetrahedron, 30 (1974), p. 3263.

Alkylated compounds in position 1 or 7 is obtained through 1.4- or 1,6-addition to the corresponding enone by known methods (J. Fried, J.A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, pages 75 - 82, 2, and J. Am. Chem. Soc. , _99 (1977), p. 1673).

Alkylated compounds in position 6 can be obtained, e.g. through opening of the corresponding 5a,6a-epoxide and subsequent reactions (J. Fried, J.A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, pages 82-86, 2).

1a,2a-r 6a,7a-, 6(3,7P-methylene compounds or a combination of the 1a,2a-methylene structure element with both 6,7-methylene structure elements can be obtained by adding diazomethane or dimethylsulfoxonium methylide to the corresponding enone or .through Simmons-Smith reaction (J. Fried, J.A. Edwards: Reactions in Steroid Chemistry, Van Nostrand Reinold Company 1972, pp. 100-126, Rev. Soc. Quim. Mex. (1969), p. 171A, Chem. Ber., 101

(1968), p. 935, Chem. Ber., 9_9 (1966), p. 1118 and Zeitschr. f. Naturf., 19b (1964), p. 944) to the corresponding allyl alcohol.

The production of the condensed isoxazole ring in positions 2 and 3 takes place through the synthesis of the 2-hydroxy-methylene compounds (Steroids, 6_ (1962), p. 178, J. Amer. Chem. Soc, 8_3 (1961), p. 1478 ) and their reaction with hydroxylamine (J. Med. Chem., 6^ (196 3), p. 1). [2,3-d]isoxazole are also good starting materials for the synthesis of 2-cyan steroids (J. Med. Chem., §_ (1963),

p. 1).

The preparation of the condensed pyrazole ring in positions 2 and 3 takes place through reaction of 2-hydroxy-methylene-3-oxo-educts with R^-substituted hydrazine (US patent no. 3,704,295).

The introduction of chlorine or the methyl substituents at C-6 in the steroid skeleton were successful, e.g. through those in the German interpretation document no. 1,158,966, respectively. in US Patent No. 4,544,555 and US Patent No. 4,196,203, stated methods above the corresponding 6,7-epoxyd or 6-methylene derivative, as well as through oxidation of 6-chloro-3,5-dienol ether with dichlorodicyanobenzoquinone (DDQ) under acidic conditions (Belgian Patent No. 621,197 (1962)).

The removal of the 3-oxo group to a final product of the general formula I with X meaning two hydrogen atoms can e.g. take place according to the regulations stated in DOS 2805490 through thioketalisation and subsequent reductive cleavage.

Educts with a D-homo-steroid skeleton can also be obtained, e.g. through Tiffeneau rearrangement analogous to that in Australian J. Chem., 8^ (1955), p. 519 and in "Organic Reactions in Steroid Chemistry", vol. 2, p. 388 published regulations. The necessary 17oc-aminomethyl-173-hydroxy compounds are available e.g. through the opening of the 17,20-spiroepoxide with ammonia, or also through lithium aluminum reduction of the acetylated 17f3-hydroxy-17a-cyan compounds. The spiroepoxide is available through reaction of the corresponding 17-ketone with dimethylsulfonium methylide in dimethylformamide (Journal f. prakt. Chemie, 314 (1972), pp. 667-668). The acetylated cyanohydrins are available through addition of hydrogen cyanide to the corresponding 17-ketone and subsequent acetylation according to known regulations (eg Australian J. Chem., 8 (1955), p. 519).

Educts with an unsaturated D-ring are available e.g. through modified Saegusa oxidation (Tetrahedron, 42 (1986), p. 2971) of the 17-ketone's corresponding enol compounds. E.g. allows the trimethylsilylenol ether to be prepared through the transfer of 17-ketones with lithium diisopropylamide in tetrahydrofuran to the corresponding enolate and absorption through trimethylchlorosilane (Synthesis 1983, 1).

The introduction of the substituents R^ and R^ takes place according to the usual methods by C-17 side chain addition through nucleophilic addition to the C-17 ketone obtained e.g. through Oppenauer oxidation of the C-17 hydroxy group, and subsequent reactions ("Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, vol. 1-12).

The introduction of the substituent -C5C-U as R^, where U has the above meaning, takes place by means of a compound of the general formula MCSC-U', where U' is the one with a protecting group, such as e.g. trimethylsilyl or tert.-butyldimethylsilyl, protected residue U, or in the case that U is an alkyl group with 1-4 C atoms, U<1 >the residue itself is U.

The organometallic compound can also be formed in situ and reacted with the 17-ketone. Thus, one can e.g. allow acetylene and an alkali metal, especially potassium, sodium or lithium, to act on the 17-ketone in a suitable solvent in the presence of an alcohol or in the presence of ammonia. The alkali metal can also act in the form of e.g. methyl or butyllithium. Dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene are particularly suitable as solvents.

The introduction of 3-hydroxypropyne, -propene or -propane in the 17-position occurs through reaction of the 17-ketone with the dianion of propargyl alcohol (3-hydroxypropyne), e.g. the in situ formed dipotassium salt of the propargyl alcohol, to. 17a-(3-hydroxyprop-1-ynyl)-17f3-hydroxy derivative, or with metal derivatives of the 3-hydroxypropyne, e.g. with 1-lithium-3-(tetrahydropyran-2'-yloxy)-prop-1-yn-1-ide, to 17-[3-(tetrahydropyran-2'-yloxy)-prop-1-ynyl]-17p- hydroxy derivative, which can then be hydrogenated to the 17-(3-hydroxypropyl or hydroxypropenyl)-17|3-hydroxy compounds. This was successful, e.g. through hydration at room temperature and normal pressure in a solvent such as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with the addition of noble metal catalysts such as platinum or palladium.

The introduction of homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups occurs in a similar way with homologues of the propargyl alcohol.

The connection with the double bond giving Z configuration in the hydroxypropenyl group occurs through hydrogenation of the acetylenic triple bond with a deactivated noble metal catalyst (J. Fried, J.A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company 1972, p. 134 and H.O. House: Modern Synthetic Reactions 1972, p. 19). As deactivated precious metal catalysts, there are e.g. namely 10% palladium on barium sulphate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead(II) acetate. The hydrogenation is interrupted after the absorption of an equivalent of hydrogen.

The connection with the double bond that gives the E-configuration in the hydroxopropenyl group occurs through reduction of the acetylenic triple bond in a manner known per se. In the literature, a large number of methods for the conversion of alkynes into trans-olefins are described, for example reduction with sodium in liquid ammonia (J. Am. Chem. Soc, 6_3 (1941), p. 216), with sodium amide in liquid ammonia (J . Chem. Soc, 1955, p. 3558), with lithium in low molecular weight amines (J. A. Chem. Soc, 7J7

(1955), p. 3378), with boranes (J. Am. Chem. Soc, 92

(1971), p. 3395 and 9_4 (1972), p. 6560), with diisobutylaluminum hydride and methyllithium (J. Am. Chem. Soc, 8_9_

(1967), p. 5085) and in particular with lithium aluminum hydride/alcoholate (J. Am. Chem. Soc, 89 (1967), p. 4245). A further possibility is reduction of the triple bond with chromium(II) sulfate in the presence of water or dimethylformamide in a weakly acidic environment (J. Am. Chem. Soc, 86_ ( 1964), p. 4358), as well as general reduction through the influence of transition -metal compounds alternate with the oxidation step.

The introduction of the hydroxyalkene can also take place directly through the addition of a corresponding metal hydroxyalkenyl compound, such as e.g. 1-lithium-3-(tetrahydropyran-2<1->yloxy)-prop-1(E)-ene (J. Org. Chem., 40, p. 2265) or 1-lithium-3-(tetrahydropyran-2 <1->yloxy)-prop-1(Z)-ene (Synthesis 1981, p. 999). Homologues can also be introduced on i e i

The introduction of 3-hydroxypropane in the 17-position can also take place directly through reaction of the 17-ketone with metal derivatives of 3-halopropanols, whereby the hydroxy group is present as an alcoholate in the metalation step (Tetrahedron Letters, 1978, p. 3013) or as a protected function ( J. Org. Chem., 3J7, 1947), to the 17-(3-hydroxypropyl)-173-hydroxy compound or to the terminal hydroxy-protected compound. As protection groups, there are e.g. in terms of ethoxyethyl, tetrahydropyranyl and methoxymethyl groups.

The construction of the 17-cyanomethyl side chain takes place in a manner known per se on the 17-ketone, e.g. over the 17-spiroepoxide and cleavage of the spiroepoxide with HCN according to Z. Chem., 18 (1978), pp. 259-260.

The introduction of the 17-hydroxyacetyl side chain also takes place according to methods known per se, for example according to those in J. Org. Chem., 47_ (1982), 2993-2995, Chem. Ber., 113 (1984), p. 1184, respectively US Patent No. 4,600,538 described methods.

For the introduction of the groups

the 17-ketone is transferred with tosylmethylisocyanate (Chem. Ind., 1972, p. 213) to the 17-nitrile compound (Tetrahedron, 31.

(1975). This sequential methyl addition to the nitrile and subsequent alkylation can also be carried out in reverse order.

Free hydroxy- or hydroxy, mercapto and/or amino groups present in Z, resp. V, can be alkylated or acylated in a manner known per se.

Sulfide and/or dialkylamine present in V can be transferred by means of a suitable oxidizing agent (e.g. hydrogen peroxide or peracids) to the desired sulfoxide (n=1), N-oxide (n=1) (see f .eg Kontakte (Darmstadt) 1986, p. 12), respectively sulfone (n=2).

Compounds with a dialkylamine substituent in V can be transferred in good yield to the corresponding (N-cyano-N-alkylaminoaryl) derivatives through reaction with cyanobromine in aprotic solvents, such as e.g. dioxane, benzene or toluene at elevated temperature (amine decomposition according to Braun) analogous to the e.g. in Org. Reactions 7_, p. 198 (1953), K.W. Bentley, Techniques of Organic Chemistry 11, p. 773 (1963) and Houben-Weyl, 5/4, p. 151 (1960) stated regulations.

These are then reduced according to the newly desired meaning of R to the final product in a manner known per se to the corresponding dialkylamine compounds (e.g. with diiso-butylaluminum hydride in toluene to the N-formyl-N-alkylamino-phenyl intermediates, and then with lithium aluminum hydride) or N-H-N alkyl compounds (e.g. with lithium aluminum hydride or with lithium in liquid ammonia). The latter are then acylated if desired in ways known from the literature, and are then reduced if desired in a known manner with e.g. lithium aluminum hydride to new dialkyl derivatives (see DE 36 23 038).

The obtained compounds of the general formula I where X has the meaning of an oxygen atom can, if desired, be transferred by reaction with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between -20 and +40°C to the oxime (formula I where X has the meaning of the hydroxyimino group N~OH, the hydroxy group can always be syn or anti). Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonen-5 (DBN) and 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) , pyridine being preferred.

The new compounds of the general formula I as well as their addition salts with physiologically compatible acids are valuable contraceptives. Thus, they have a strong affinity for the progestagen receptor and have a surprisingly large range of antigestagen properties. These important biological effects can be used for contraceptive purposes.

Active compounds within a technique with pronounced antigestagen activity are suitable for triggering abortions as they displace the progesterone required for the maintenance of pregnancy from the receptor. They are also valuable and interesting with regard to their application to postcoital fertility control.

The compounds according to the invention and their salts

can be processed according to per se known methods in galenic pharmacy into (preparations for enteral, percutaneous, parenteral or local use. They can be given in the form of tablets, dragees, gel capsules, granules, suppositories, implants, injectable, sterile, aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.

The active substance or active substances can

thereby being mixed with the excipients common in galenic pharmacy, such as e.g. gum arabic, talc, starch, mannitol, methylcellulose, lactose, surfactants such as Tween ® or "Myrj", magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting, dispersing, emulsifying, preserving and flavoring agents for flavor correction (e.g. . essential oils).

Preparations can thus be prepared which contain at least one compound according to the invention as active compound, or one of their addition salts with pharmaceutically compatible acids. As addition salts of the product according to the invention with acids, hydrochloride and methanesulfonate should be mentioned in particular. One dose unit contains approx. 1-100 mg active compound or active compounds. The dosage of the compounds according to the invention in humans is approx. 1-1000 mg per day.

For characterization of the antigestagen effect, the abortion effect was determined.

The experiment was carried out on female rats with a weight of approx. 200 g. After mating had occurred, the onset of pregnancy was confirmed through the detection of sperm in scrapings from the vagina. The day for sperm detection applies as day 1 of the pregnancy (= dl p.c).

The treatment of the animals with the substance to be tested, or the solvent, followed the nidation of the blastocysts on d5 p.c. to d7 p.c. On d9 p.c. the animals were euthanized, and the uteri were examined at implant and resorption sites. Photographs were taken of all the uteri. Absence of implants, pathological, hemorrhagic or otherwise abnormal nidation sites were considered abortion.

The test substances were dissolved in a benzyl benzoate-castor oil mixture (ratio 1+4). The carrier volume per single dose amounted to 0.2 ml. The treatment took place subcutaneously.

The superiority of the compounds according to the invention shall be demonstrated through comparison with the abortifacient effect of 17a-(prop-l-ynyl)-17(3-hydroxy-11|3,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one (A), 17a-(prop-l-ynyl)-173-hydroxy-11(3,19-( 4-acetyl-o-phenylene)-4-androsten-3-one (3), 17a-( 3-hydroxyprop -1-( Z )-enyl)-17(3-hydroxy-lip,19-(4-dimethylamino-o-phenylene)-4-androsten-3~one (C) and 17a-(3-hydroxyprop-1- (Z)-enyl)-173-hydroxy-11^3,19-(4-methylthio-o-phenylene)-4-androsten-3-one (d) with that described in European patent document 0 057 115 and that in European patent application 84730147.0 stated 113-(4-dimethylaminophenyl)-173-hydroxy-17a-(3-hydroxyprop-1-(Z)-enyl)-4,9(10)-estradien-3-one (F).

From table 1, it can be seen that only the compounds A-D according to the invention and the similar to the applicant's retroactive compound F give full abortifacient effect at a dose of

1.0 mg/d s.c. The comparison substance E shows only 50% effectiveness at this dose. Compound B according to the invention exhibits even at a dose of 0.3 mg/d s.c. full effect, while F at this dose no longer has any effect.

From the French patent application 86 400 057.5 very structurally similar steroids are known with a substituted aryl residue in the 10-position and a 9(11)-double bond; however, the known compounds have in all cases an alkyl, alkenyl or alkynyl group in the 17a position. The activity of these compounds towards the progesterone receptor, and thus their antigestagen effect, is negligible.

With the compounds according to the invention, substances are thus provided which have a new effect profile in relation to the closest known technique, namely a significantly increased antigestagen effect.

In the following examples, the chromatography was each time carried out with a mixture of glacial acetic acid and hexane unless otherwise stated.

Example 1

17B-hydroxy-IIB. 19-(o-phenylene)-4- androsten-3-one

a) 19-(2-chlorophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,17B-diol

4.9 g of magnesium shavings were placed in 40 ml of absolute diethyl ether at room temperature under protective gas and then 0.5 ml of 2-chlorobenzyl chloride was added and then carefully added 0.4 ml of 1,2-dibromoethane. After the reaction had started, the remaining amount (18.4 ml) of the 2-chloro-benzyl chloride dissolved in 135 ml of absolute diethyl ether was then added dropwise over the course of 40 minutes without the internal temperature in the reaction vessel rising above 30°C. After formation of the Grignard reagent had occurred, the reaction mixture was cooled to 0<6>C and 13.6 g of 5a,10a-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17p-ol dissolved in 75 ml of absolute tetra-hydrofuran is slowly added dropwise. After one hour of stirring at ice bath temperature, the reaction mixture was slowly heated overnight to room temperature and then poured into dilute ammonium chloride solution. The aqueous phase was extracted several times with ethyl ester. The combined organic phases were washed neutral with sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. The residue was chromatographed on aluminum oxide (neutral, grade III). 14.8 g of the above-mentioned compound were obtained.

[a]<22> = -2° (CHC13; c=0.51)

M.p.: 188-191°C (ethyl acetate)

b) 113,19-(o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

At -65°, 600 ml of anhydrous ammonia was condensed in the reaction flask to the exclusion of water and 970 mg of freshly cut lithium chips were added. Immediately after the onset of the characteristic blue coloration, a solution of 14 g of the product obtained under a) in 450 ml of absolute tetrahydrofuran was added dropwise in such a way that a fluctuation occurred between decolorization of the reaction solution and blue coloration. After addition, the excess lithium was removed by adding ethanol drop by drop, the predominant part of the ammonia was removed by evaporation and the reaction mixture completely poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were then washed with sodium chloride solution, dried with sodium sulfate and evaporated under vacuum. 13.9 g of impure product was isolated. Chromatography on aluminum oxide (neutral, grade III) gave 10.3 g of the above compound.

[cx]^<2> = +13° (CHC13; c=0.52)

Temp. = 164-167°C (ethyl acetate)

<1>H-NMR (CDCl 3 ) [i]: 7.0-7.45 (4H, m, aromatic protons); 3.13 (1H, d J=16 Hz, proton at C-19); 2.68 (1H, d J=16 Hz, proton at C-19); 0.98 (3H, s, protons in a ketalmethyl group); 0.95 (3H, s, protons in a ketalmethyl group); 0.25 (3H, s, protons on C-18).

The title compound indicated under b) can also be prepared in the following way: a) 19-(2-bromophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,17p-diol

Analogously to example la), 5 g of 5α,10α-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17f3-ol were reacted with 26.7 g of 2-bromobenzyl bromide. After chromatography, 5.9 g of the above compound was isolated as a white foam.

<1>H-NMR (CDCl 3 ) : 6.95-7.55 (4H, m, protons in aromatics); 5.45 (1H, s broad, proton on C-11); 3.7-3.82 (1H, m, proton at C-17); 3.4-3.6 (4H, m, protons in the ketalmethylene group); 3.16 and 3.07 (each [1H, d with cleavages at 15 Hz], A,B system to protons at C-19); 0.98 (3H, s, protons in a ketalmethyl group); 0.9 (3H, s, protons in a ketalmethyl group); 0.55 (3H, s, protons on C-18).

p) lip,19-(o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5α,17β-diol

2.5 g of the compound prepared under a) was dissolved in 250 ml of absolute toluene, 2.25 ml of tributyltin hydride and 250 mg of α,α-azoisobutyronitrile were added, and heated under reflux for 3 hours. Then the solvent was removed under vacuum, the residue was taken up in tetrahydrofuran and stirred with 50 ml of saturated aqueous potassium fluoride solution for 1 hour. The aqueous phase was then extracted with ethyl acetate and discarded. The organic phases were combined, dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on aluminum oxide (neutral, grade III). 1.75 g of the title compound was obtained.

The title compound indicated under b) can also be prepared from the following compound: f) 19-(2-fluorophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,17<p->diol

Analogously to example la), 750 mg of 5a,10a-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-17p-ol were reacted with 2 g of 2-fluorobenzyl chloride. After chromatography, 798 mg of the above compound was isolated as a white foam.

^■H-NMR (CD 2 Cl 2 ) [S] : 6.92-7.33 (4H, m, protons in aromatics); 5.09 (1H, m, proton on C-II); 3.62-3.72 (1H, m, proton at C-17); 3.45-3.58 (4H, m, protons in the ketalmethylene groups); 2.97 and 2.9 (each [1H, d with the splitting at 15 Hz], A, B system to protons at C-19); 0.99 (3H, s, protons in a ketalmethyl group); 0.9 (3H, s, protons in a ketalmethyl group); 0.61 (3H, s, protons on C-18).

£) 11(3,19-(o-phenylene)-3 , 3 - (2 , 2-dimethyltrimethylenedioxy) -

androstane-5α,170-diol

Analogously to example 1b), 750 mg of 19-(2-fluorophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,17(3-diol) were reacted with 60 mg of lithium. After chromatography 585 mg of the above compound was isolated as a white foam.

c) 17(3-hydroxy-11B, 19-(o-phenylene)-4-androsten-3-one

2 g of the product produced under b) was dissolved in

100 ml of acetone and added 5 ml of 4N hydrochloric acid. After 4 hours of stirring at room temperature, the reaction mixture was poured onto saturated sodium bicarbonate solution, and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed over silica gel.

1.13 g of the above-mentioned compound were obtained.

[a]<22> = +84° (CHC13;

■"■H-NMR (CDC13) [g]: 7-7.5 (4H, m, protons in aromatics); 5.88 (1H, s, proton on C-4); 3.68 (1H, tr J=9 Hz, proton on C-17); 3.3 (1H, m proton on C-ll); 3.26 (1H, d J=17 Hz, proton on C-19); 2.74 (1H , d 0^=17 Hz proton on C-19); 0.29 (3H, s, protons on C-18).-

Example 2

17( 3- hydroxy- 17-( prop- l- ynyl) - lift, 19-( o- phenylene) - 4- androsten-3- one

a) 113,19-(o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

To a mixture of 34.3 ml of pyridine and 287 ml of methylene chloride, 11.28 g of chromium trioxide was added portionwise at 0°C. Then the steroid obtained under example 1b) (8 g) was dissolved in 50 ml of methylene chloride, slowly added dropwise to the reaction mixture at the same temperature, and this was further stirred for two hours at ice bath temperature. After the end of the stirring, the solid reaction components were allowed to fall out, the upper phase was decanted and the precipitate was washed vigorously several times with methylene chloride. The combined organic phases were freed from remaining inorganic constituents by washing with aqueous 0.5 m potassium hydroxide solution, neutral washed with water, dried over sodium sulfate and evaporated under vacuum. 7 g of impure 113/19-(o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one were isolated, with a purity sufficient for the further reactions (see below). 500 mg was purified for analytical purposes by chromatography on aluminum oxide (neutral, grade III). 432 mg of the desired product was isolated.

[a]<22> = +31° (CHC13; c=0.505)

Temp. = 206-210°C (ethyl acetate)

b) 17-(prop-l-ynyl)-113,19-(o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

225 ml of absolute tetrahydrofuran was saturated with propyne at 0°C. Then, 1.6 m n-butyllithium solution (hexane) (27.7 ml) was added dropwise to this solution slowly without a major increase in temperature. After stirring for 15 minutes, a solution of 2 g of that under a) was prepared

crude product in 45 ml of absolute tetrahydrofuran was slowly added dropwise to this reaction mixture and allowed to stir for 30 minutes. The reaction mixture was then poured into water, the water phase was extracted with ethyl acetate, and the combined organic phases were washed with sodium chloride solution.

Drying over sodium sulfate and evaporation under vacuum gave 2.44 g of impure product. By chromatography on aluminum oxide (neutral grade III), 1.8 g of the above-mentioned compound was obtained.

IR (KBr): 2230 cm<-1> triple bond.

c) 17Q-hydroxy-17-(prop-l-ynyl)-11(3,19-(o-phenylene)-4-androsten-3-one

Analogous to the acidic cleavage described under example lc), 1.5 g of the product obtained under b) was converted to 738 mg of the title compound.

Example 3

17(3-hydroxy-17-(prop-l-ynyl)-11Q,19-(o-phenylene)-4,6-androstadien-3-one

a) 11(3,19 - (o-phenylene)-4-androstene-3,17-dione

20 g of it according to sequence example la), example lb)

and example 2a) obtained product was cleaved to 8.6 9 g of the title compound analogously to the indication in example lc).

[a]22 = +166° (CHC13; c=0.51)

Temp. = 284-288°C

b) 11(3,19-(o-phenylene)-3-ethoxy-3,5-androstadien-17-one

8 g of the product obtained under a) was placed in

a mixture of 85 ml of absolute methylene chloride, 25 ml of ethanol and 6.7 ml of triethyl orthoformic acid and added 170 mg of p-toluenesulfonic acid (monohydrate) at 0°C. Then it was

stirred overnight at ice bath temperature, then an excess of sodium bicarbonate solution was added, and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. 11.3 g of contaminated crude product was obtained. Crystallization from ethanol (with the addition of a few drops of pyridine) gave 5.43 g of crystalline title compound.

[a]<22> = +39° (CHC13; c=0.5)

Temp. = 182-186°C

c) 17-(prop-l-ynyl)-11(3,19-(o-phenylene)-3-ethoxy-3,5-androstadien-17(3-ol) 5 g of the product obtained after b) was reacted analogously to example 2b) to 5.4 g of impure product whose purity was sufficient for further turnover. Crystallization of 400 mg of the impure product from ethanol gave 268 mg of crystalline title compound.

[a]<22> = -91° (CHC13; c=0.5)

Temp. = +203-207°C.

d) 17-(prop-l-ynyl)-17|3-hydroxy-11Q, 19-(o-phenylene)-4,6-androstadien-3-one

5 g of the impure product obtained after c) was suspended in a mixture of 50 ml of 80% aqueous dioxane solution and 24 ml of 10% aqueous sodium acetate solution. To this suspension, 1.6 g of 1,3-dibromo-5,5-dimethylhydantoin was added in portions at 0°C. Thereby, the steroid slowly dissolved. After a two-hour reaction time, the reaction mixture was poured into water and the water phase extracted with methylene chloride. The combined organic phases were washed with saturated sodium thiosulfate solution and water, dried over sodium sulfate and evaporated under vacuum. The thus obtained, contaminated 17-(prop-l-ynyl)-178-hydroxy-11(3,19-(o-phenylene)-6|3-bromo-4-androsten-3-one was dissolved in 48 ml absolute dimethylformamide, added 2.4 g lithium bromide and 1.65 g lithium carbonate under protective gas and stirred for 1 hour at 100° C. After cooling the reaction mixture to room temperature, it was poured into water, the water phase neutralized with 4N hydrochloric acid, cooled at ice bath temperature, stirred one hour at this temperature and the precipitated steroid filtered off with suction. 4.14 g of lightly contaminated crude product was obtained with sufficient purity for further reactions. Crystallization from diisopropyl ether led to 638 mg of the above-mentioned compound starting from 1.14 g of the impure product.

[a]<22> = +80° (CHC13; c=0.5)

Temp. = 215-217°C.

Example 4

17-(prop-1-ynyl)-17(3-hydroxy-ll(3,19-(4-methoxy-o-phenylene)-4-androstene-3-one)

a) 19-(2-chloro-5-methoxyphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a, 17[3-diol

Analogously to the indication in example la), 15.5 g of the above-mentioned compound were obtained by reaction with 2-chloro-5-methoxybenzyl chloride when starting from 15 g of 5a,10a-epoxy-3,3-(2,2 -dimethyltrimethylenedioxy)-9(11)-estren-173-ol.

b) 113,19-(4-methoxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,17p-diol

Analogous to the description in example lb), when starting from 15 g of the compound obtained under a), 11.6 g of the title compound were produced as a white foam.

[a]<22> = +21.1° (CHC13; c=0.52)

Temp. = 223-224°C (diisopropyl ether)

The title compound b) can also be prepared by

the following synthesis route:

a) 19-(2-bromo-5-methoxyphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a, 17|3-diol

150 g of 2-bromo-5-methoxy-benzyl bromide was slurried in

1 liter of absolute diethyl ether under protective gas and added 13.3 g of magnesium shavings. After the Grignard reaction has started up, the reaction temperature was kept below 30°C by cooling. After complete formation of the Grignard reagent, 50 g of 5a,10a-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estrene-5a,17(3-diol) dissolved in 330 ml of absolute tetrahydrofuran was added dropwise under The reaction mixture was then stirred for 1.5 hours and worked up as described under example la).

Temp. 128-130°C (diisopropyl ether/hexane).

3) 113,19-(4-methoxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

Analogous to example 13), 66 g of 19-(2-bromo-5-methoxyphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,173-diol were converted into 1.7 1 absolute toluene with 34 ml of tributyltin hydride using 660 mg of 2,2-azoisobutyric acid nitrile as radical initiator. After complete reaction, the solvent was removed under vacuum and the residue crystallized from diisopropyl ether. 49 g of the above-mentioned compound were obtained in crystalline form.

c) 113,19-(4-methoxy-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

Analogous to example 2a), 11 g of the compound obtained according to b) was transferred to the corresponding keto compound. 9.53 g of the above compound was obtained as a white foam.

[et]<22> = +33° (CHC13;

Temp. = 235-238°C

d) 17-(prop-l-ynyl)-11(3,19-(4-methoxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

Analogously to example 2b), 4 g of the compound obtained under c) was transferred to the corresponding 17a-propynyl compound. 3.3 g of the above compound was isolated as a white foam after chromatography.

IR (KBr): 2230 cm<-1> triple bond

e) 17-(prop-l-ynyl)-173~hydroxy-113,19-(4-methoxy-o-phenylene)-4-androsten-3-one

Analogous to example lc), 3 g of the compound obtained under d) was converted into the corresponding 4-ene-keto compound. 1.5 g of the title compound was isolated as a white foam.

[α]22 = +18° (CHCl3; c=0.465).

Example 5

17-(3-hydroxyprop-1(Z)-enyl)-173-hydroxy-1L3, 19-(4-methoxy-o-phenylene)-4- androsten-3-one

a) 17-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-113,19-(4-methoxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane- 5α,173-diol

To a solution of 5.7 g of 3-(tetrahydropyran-2-yloxy)-prop-l-yne in 100 ml of absolute tetrahydrofuran, 28.3 ml of a 15% solution of n-butyllithium in hexane was slowly added dropwise at 0 °C under protective gas. It was then stirred at 0°C for 15 minutes, and then a solution of 4 g of the product obtained under example 4c) in 60 ml of absolute tetrahydrofuran was added dropwise at 0 - +5°C. It was stirred for a further 3 hours at room temperature, then poured into ice water and extracted with ethyl acetate. After drying the organic phase over sodium sulfate and evaporation under vacuum, the impure product was chromatographed on aluminum oxide (neutral, grade III). 4.36 g of the above compound was obtained as a white foam.

Temp. = 150-153°C (diisopropyl ether) [as 1:1 epimer mixture-with the respective tetra-hydropyranyl ether]

b) 17-[3-(tetrahydropyran-2-yloxy)-prop-1(Z)-enyl]-113,19-(4-methoxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy) -androstane-5α,173-diol

A solution of 4 g of the product obtained under a) 1 75 ml of tetrahydrofuran was hydrogenated after the addition of 5 ml of pyridine and 400 mg of palladium/barium sulfate (10% Pd) at room temperature and normal pressure. After the hydrogen uptake had stopped, the catalyst was filtered off and the filtrate was evaporated. 3.91 g of the above compound was obtained as a yellowish foam.

c) 17-[3-hydroxyprop-1(Z)-enyl]-173-hydroxy-11p,19-(4-methoxy-o-phenylene)-4-androsten-3-one

Analogously to example lc), 3.5 g of the compound prepared under b) was cleaved. 1.5 g of the title compound was isolated as a white foam.

[cx]2<2> = +60° (CHC13; c=0.5)

Example 6

17-(cyanomethyl) - 17| 3- hydroxy- llQ, 19-( 4- methoxy- o- phenylene) - 4- androsten- 3- one

a) 113,19-(4-methoxy-o-phenylene-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-[17(3-11)-spiro-3']-oxiran-5a-ol

Under protective gas, 1 g of the ketone obtained according to description 4c) was dissolved in 20 ml of absolute dimethylformamide and 2.04 g of trimethylsulfonium iodide and 1.40 g of potassium tertiary butylate were successively added at 0°C. The reaction mixture was then slowly heated with stirring

. overnight at room temperature, then completely poured into saturated ammonium chloride solution and the water phase extracted several times

with ethyl acetate. The combined organic phases were dried over sodium sulfate, evaporated under vacuum, and the residue was chromatographed on aluminum oxide (neutral/grade III). 895 mg of the above compound was isolated as a white foam.

b) 17-cyanomethy1-113,19-(4-methoxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a, 17(3-diol

Under protective gas, 850 mg of the epoxide produced under a) was dissolved in 17 ml of absolute ethanol and a solution of 1.7 g of potassium cyanide in 3.4 ml of water was added. The reaction mixture was then heated overnight at 50°C, then poured into ice water and the water phase extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness under vacuum. The residue was chromatographed on aluminum oxide (neutral/grade III). 815 mg of the above compound was isolated.

IR (KBr): 2250 cm"1 C=N triple bond.

c) 17-cyanomethyl-173-hydroxy-11|3,19-(4-methoxy-o-phenylene)-4-androsten-3-one

800 mg of the compound obtained under b) was converted analogously to example lc) into the corresponding 4-ene-3-keto compound. 575 mg of the title compound was isolated.

[a]<22> = 59° (CHC13; c=0.505)

Temp. = 155-156°C (ethyl acetate/hexane)

Example 7

17-(prop-l-ynyl)-17f3-hydroxy-ll(3,19-(4-methoxy-o-phenylene)-4,6- androstadien-3-one

a) lip,19-(4-methoxy-o-phenylene)-4-androstene-3,17-dione

Analogous to example lc), 11.2 g of the substance obtained according to description c) in example 4 was converted into the corresponding 4-ene-3-keto compound. 7.6 g of the above compound was isolated.

[et]<22> 130° (CHC13; c=0.5)

Temp. = 184-187°C (ethyl acetate)

b) lip,19-(4-methoxy-o-phenylene)-3-ethoxy-3,5-androstadien-17-o

Analogous to example 3b), 5 g of that under a)

obtained substance reacted with ethanol. 2.45 g of crystalline title compound were obtained.

[a]<22> 57° (CHC13; c=0.5)

Temp. = 174-176°C

c) 17-(prop-l-ynyl)-HP, 19-(4-methoxy-o-phenylene)-3-ethoxy-3,5-androstadien-17P-ol

Analogously to example 3c), 2.4 g of the keto compound obtained under b) was reacted. 2.45 g of impure product was isolated.

[ot]<22> = -86° (CHC13; c=0.505)

Temp. = 168-171°C (ethanol)

d) 17-(prop-l-ynyl)-173-hydroxy-llp,19-(4-methoxy-o-phenylene)-4,6-androstadien-3-one

Analogous to example 3d), 2.35 g of the impure product obtained under c) was converted to the corresponding 4,6-dien-3-keto compound. Chromatography of the crude product on silica gel afforded 1.43 g of the title compound.

[ot]<22> = 132° (CHC13; c=0.5)

Temp. = 237-242°C (ethyl acetate).

Example 8

17-( 3- hydroxyprop- 1( Z)-enyl)- 17B- hydroxy- llp, 19-( 4- methylthio-o- phenylene)- 4- androsten- 3- one

a) 19-(2-chloro-5-methylthiophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,17p-diol

Analogously to example la), 34 g of 5a, 10ct-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androsten-17β-ol were reacted with 94.5 g of 2-chloro-5-methylthiobenzyl chloride. After chromatography, 43.2 g of the above title compound was isolated as a white foam.

b) 113,19-(4-methylthio-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

40 g of the substance obtained under a) was dissolved in

750 ml of absolute tetrahydrofuran at -78°C and dropped into a mixture of 3.79 g of lithium and 3.4 L of liquid ammonia.

After 45 minutes of stirring, a mixture of 200 ml of methanol, 200 ml of tetrahydrofuran and 4.6 ml of methyl iodide was slowly added dropwise at the same temperature. After the addition was complete, the mixture was worked up analogously to description b) in example 1. From the impure product, 18.37 g of pure title compound was directly crystallized.

Temp. = 173-176°C (ethyl acetate)

c) 11(3,19-(4-methylthio-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

Analogous to example 13c), 18 g of the compound obtained under b) was reacted with 21.47 g of aluminum triisopropylate and 156 ml of cyclohexanone in 780 ml of absolute toluene to give the corresponding 17-keto compound. After chromatography on aluminum oxide (neutral, grade III), 13.98 g of the above compound was isolated as a white foam.

[a]<22> = 41.8° (CHC13; c=0.5)

Temp. = 224-225°C (ethyl acetate/hexane)

d) 17-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-11(3,19-(4-methylthio-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)- androstane-5ct,173-diol

Analogous to example 5a), 13.8 g of the substance obtained under c) was reacted with 19 g of 3-(tetrahydropyran-2-yloxy)-prop-l-yne. After chromatography, 15.65 g of the above compound was obtained as a white foam.

IR (KBr): 2230 cm<-1> triple bond.

e) 17-[3-(tetrahydropyran-2-yloxy)-prop-1(Z)-enyl]-lip,19-(4-methylthio-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy) -androstane-5cx, 17P~diol

Analogously to example 5b), 15.5 g of the substance obtained under d) was hydrogenated with hydrogen using 1.51 g of palladium-on-barium sulfate (10% Pd) poisoned with 18.9 ml of pyridine as catalyst. After chromatography, 14.15 g of the above compound was isolated as a white foam.

f) 17-(3-hydroxyprop-1(Z)-enyl)-17B-hydroxy-11|3,19-(4-methylthio-o-phenylene)-4-androsten-3-one

5.5 g of the olefin obtained under e) was reacted analogously to example lc) with 5 ml of 4N aqueous hydrochloric acid in 200 ml of acetone to give the 4-en-3-keto compound. After chromatography on silica gel, 2.34 g of the title compound were isolated

Else as white foam.

[ct]22 = 86° (CHC13; c=0.51)

Temp. = 146-148°C (ethyl acetate/hexane)

Example 9

17-(3-hydroxyprop-1(Z)-enyl)-5a,17{3-dihydroxy-11(3,19-(4-methylthio-o-phenylene)-androstan-3-one

a) 17-(3-hydroxyprop-1(Z)-enyl)-5a,17B-dihydroxy-11B,19-(4-methylthio-o-phenylene)-androstan-3-one 5 g of that under example 8e) the substance obtained was reacted at room temperature in 50 ml of 70% acetic acid to the desired 3-keto compound. The reaction mixture was then diluted with water and the aqueous phase extracted with methylene chloride. The combined organic phases were washed successively with saturated sodium hydrogen sulfate solution and saturated sodium chloride solution and then dried over sodium sulfate. After suctioning off the solvent under vacuum, the residue was chromatographed on silica gel. 2.66 g of the above compound was isolated as a white foam.

[a]<22> = 5° (CHC13; c=0.5)

Temp. = 193-195°C (ethyl acetate)

Example 10

17-( 3- hydroxyprop- 1( Z)-enyl)- 176- hydroxy- 11B, 19-( 4- methyl-sulfinyl- o- phenylene)- 4- androsten- 3- one

a) 17-[3-(tetrahydropyran-2-yloxy)-prop-1 (Z)-enyl]-11(3,19-(4-methylsulfenyl-o-phenylene)-3,3-(2,2- dimethyltrimethylenedioxy)-androstane-5ct,173-diol 5 g of the substance obtained under example 8e) was dissolved in a mixture of 4 5 ml of tetrahydrofuran, 4 5 ml of methanol and 10 ml of water and 5.1 g of sodium periodate was added. Overnight, the reaction mixture was stirred at room temperature, then filtered over celite, and the filtrate was diluted with ethyl acetate. The organic phase was washed with saturated sodium hydrogen sulfate solution, dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on aluminum oxide (neutral, grade III). 3.94 g of the above compound was obtained as a white foam.

b) 17-(3-hydroxyprop-1(Z)-enyl)-173~hydroxy-H3,19-(4-methyl-sulfinyl-o-phenylene)-4-androsten-3-one

Analogously to example lc), 3.8 g of the substance obtained under a) was converted to 4-ene-3-keto compound. After chromatography on silica gel, 1.66 g of the title compound was isolated.

[α]<22> = 51° (CHCl 3 ; c=0.5).

Example 11

17-(3-hydroxyprop-l-ynyl)-173-hydroxy-ll3, 19-(4-methylthio-o-phenylene)-4- androsten-3-one

a) 17-(3-hydroxyprop-1-ynyl)-17β-hydroxy-11(3,19-(4-methylthio-o-phenylene)-4-androsten-3-one

Analogously to example lc), 2.5 g of the substance obtained under example 8d) was cleaved to the corresponding 4-ene-3-keto compound. 1.13 g of the title compound was isolated as a white foam after chromatography on silica gel.

Example 12

17-(3-hydroxyprop-1(Z)-enyl)-17(3-hydroxy-11(3,19-(4-ethylthio-o-phenylene)-4- androsten-3-one)

a) 11|3,19-(4-ethylthio-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a, 17/3-diol

Analogously to example 8b), 10 g of the substance prepared under example 8a) was reacted with 620 mg of lithium and instead of methyl iodide with 14.7 ml of ethyl iodide. From the impure product, 4.62 g of the above-mentioned compound was recovered as a crystalline product in a mixture of ethyl acetate/hexane.

[et]22 = 39° (CHC13;

Temp. = 164°C

b) 11(3,19-(4-ethylthio-o-phenylene)-50-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

Analogous to example 13c), 4.5 g of the substance prepared under a) was transferred to the corresponding 17-keto compound. After chromatography, 3.4 g of the above title compound was isolated.

[ot]<22>= 44° (CHCl 3 ; c=0.505);

IR (KBr): 1740 cm five-ring ketone.

c) 17-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-11(3,19-(4-ethylthio-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)- androstane-5ct, 17B-diol

Analogous to example 5a), 3.2 g of the ketone produced under b) was reacted with 4.31 g of 3-(tetrahydropyran-2-yloxy)-prop-l-yne. After chromatography, 3.25 g of the above compound was isolated as a white foam.

IR (KBr): 2230 cm 1 triple bond.

d) 17-[3-(tetrahydropyran-2-yloxy)-prop-1(Z)-enyl]-113,19-(4-ethylthio-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy) -androstane-5a, 173-diol

Analogously to example 5b), 3.1 g of the substance obtained under c) was hydrogenated with 300 mg of palladium-on-barium sulfate (10% Pd) poisoned with 3.75 ml of pyridine as catalyst. After chromatography, 2.85 g of the title compound was isolated as a white foam.

e) 17-(3-hydroxyprop-1(Z)-enyl)-17β-hydroxy-113,19-(4-ethylthio-o-phenylene)-4-androsten-3-one

2.7 g of the olefin obtained under d) was reacted analogously to example lc) with 2.5 ml of 4N aqueous hydrochloric acid in 100 ml of acetone to the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 1.35 g of the title compound was isolated as a yellowish foam.

[et]<22> = 85° (CHC13; c=0.5).

Example 13

17-(prop-l- ynyl)- 173- hydroxy- 113, 19-( 4- dimethylamino-o-phenylene)- 4- androsten- 3- one

a) 19-(2-chloro-5-dimethylaminophenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,173-diol

Analogously to example la), starting from 15 g of 5a,10a-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-173-ol, 14.39 g of the above compound through reaction with 2-chloro-5-dimethylaminobenzyl chloride.

b) 113,19-(4-dimethylamino-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

Analogous to example lb), starting from 14 g of the compound obtained under a), 9.9 g of the above compound was obtained as a white foam.

c) 11(3,19-(4-dimethylamino-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

11.5 g of the compound prepared under b) was dissolved in 500 ml of toluene and 13.8 g of aluminum triisopropylate and 100 ml of cyclohexanone were added one after the other. Then the reaction mixture was heated under reflux, and about one-third of the solvent was distilled off. After cooling, it was poured into ice water, the resulting emulsion was filtered over celite, the filter residue was washed thoroughly with ethyl acetate, the organic phase in the filtrate was separated, this was dried over sodium sulfate and evaporated under vacuum. After chromatography of the residue on aluminum oxide (neutral, grade III), 8.13 g of the title compound was obtained. Crystallization of 130 mg of this compound from ethyl acetate gave 67 mg of crystalline 113,19-(4-dimethylamino-o-phenylene)-5α-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one.

[a]22 28° (CHC13; c=0.5)

Temp. = 264-267°C

d) 17-(prop-l-ynyl)-113,19-(4-dimethylamino-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

Analogous to example 2b), 3 g of the compound obtained under c) was transferred to the corresponding 17a-propynyl compound. After the chromatography, 2.6 g of the above compound was isolated as a yellowish foam.

IR (KBr): 2235 cm<-1> triple bond

e) 17-(prop-l-ynyl)-173-hydroxy-113,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one

Analogously to example lc), 2.5 g of the product obtained under d) was converted into the corresponding 4-ene-3-keto compound. 1.58 g of the above compound was isolated as a white foam.

[a]22 = +28° (CHC13; c=0.51)

Temp. = 231-234°C (ethyl acetate)

The 2-chloro-5-dimethylaminobenzyl chloride required for reaction step 13a) was prepared in the following way:

a) 2-chloro-5-aminobenzyl alcohol

Under protective gas, 300 g of lithium aluminum hydride was formed

in 3 1 tetrahydrofuran placed at 0°C and 500 g of 5-amino-2-chlorobenzoic acid (technically 85%) added in portions. The reaction mixture was then slowly warmed to room temperature and stirred overnight at this temperature. For work-up, the reaction mixture was cooled to 0°C and the excess lithium aluminum hydride was carefully decomposed with saturated ammonium chloride solution. The organic phase was then separated from the precipitate and the precipitate was washed several times with ethyl acetate and methylene chloride. The combined organic phases were washed neutrally with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. 242 g of impure 2-chloro-5-aminobenzyl alcohol were obtained, but with a purity sufficient for the subsequent reactions. <1>H-NMR (CDCl 3 ) [J] : 6.3-7.15 (3H, m, aromatic protons);

4.55 (2H, s, benzyl protons).

3) 2-chloro-5-dimethylaminobenzyl alcohol

A suspension of 51.8 g of sodium borohydride in a mixture of 30 g of 2-chloro-5-aminobenzyl alcohol and 1 liter of tetrahydrofuran was then added dropwise while cooling to a stirred mixture of 235 ml of 2 M sulfuric acid and 88 ml of a 38% formalin solution, so that the temperature remained between -10 and 20°C. After the addition had taken place, the reaction mixture was made strongly basic with solid sodium hydroxide and a little water was added. The organic phase was separated, the aqueous phase extracted several times with methylene chloride, and the combined organic phases were washed neutral with saturated sodium chloride solution. They were then dried over sodium sulfate and evaporated under vacuum. 24 g of 2-chloro-5-dimethylaminobenzyl alcohol was obtained as an oil.

1 H-NMR (CDCl 3 ) [ 8 ] : 6.4-7.25 (3H, m, aromatic protons);

4.67 (3H, s, benzyl protons);

2.92 (6H, s, protons from both methyl groups).

7) 2-chloro-5-dimethylaminobenzyl chloride

23.8 g of N-chlorosuccinimide was placed in 600 ml of absolute methylene chloride, cooled to 0°C and 15.6 ml of dimethyl sulphide slowly added. Then the resulting suspension was cooled to -30°C and carefully added 20 g of 2-chloro-5-dimethylaminobenzyl alcohol. It was then heated to 0°C, and the reaction mixture was stirred at this temperature for 3 hours. It was then diluted with methylene chloride and the reaction mixture poured into ice water. The organic phase was separated, washed with saturated sodium chloride solution, dried over sodium sulfate solution and evaporated under vacuum. The residue was chromatographed on aluminum oxide (neutral grade III) with hexane. 17.2 g of 2-chloro-5-dimethylaminobenzyl chloride were obtained.

"'"H-NMR (CDCl 3 ) [S] : 6.4-7.3 (3H, m, aromatic protons);

4.61 (2H, s, benzyl protons);

2.9 2 (6H, s, protons from both methyl groups) .

Example 14

17P- hydroxy- 17- methoxymethyl- llf3 , 19-( 4- dimethylamino- o-phenylene)- 4- androsten- 3- one

a) 113,19-(4-dimethylamino-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-[17(P-1')-spiro-31]-oxiran-5a-ol

2.5 g of the compound prepared under example 13c) was dissolved in 50 ml of absolute dimethylformamide and

cooled to 0°C. To this solution, 5 g of trimethylsulfonium iodide and 3.4 g of potassium tert.-butylate were added one after the other. It was stirred until complete turnover had occurred (DC control). The reaction mixture was then poured into ice water, the aqueous phase extracted with ethyl acetate, the organic phase washed with sodium chloride solution and dried over sodium sulfate. After suctioning off the solvents, the residue was chromatographed on aluminum oxide (neutral, grade III). 2.1 g of the above compound was isolated as a white foam.

b) 17-methoxymethyl-11(3,19-(4-dimethylamino-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5oc, 17(3-diol) 2 g of the one prepared under a) compound was dissolved in 40 ml of 3 m methanolic sodium methylate solution and then heated to reflux under protective gas for 5 hours. After cooling, the reaction mixture was poured into water, the aqueous phase was extracted with methylene chloride and the organic phase was washed with sodium chloride solution. After drying the organic phase over sodium sulfate, evaporation under vacuum and chromatography of the residue on aluminum oxide (neutral, grade III), 1.41 g of the above compound was isolated as a white foam.

c) 173-hydroxy-17-methoxymethyl-11B,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one

Analogously to example lc), 1.3 g of the product obtained under b) was converted into the corresponding 4-ene-3-keto compound. 0.75 g of the title compound was isolated as a white foam.

[a]<22> = 80° (CHC13; c=0.505)

Temp. = 124-127°C

Example 15

17-cyanomethyl- 17| 3- hydroxy- lip, 19- ( 4- dimethylamino- o-phenylene)- 4- androsten- 3- one

a) 17-cyanomethyl-113,19-(4-dimethylamino-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a, 17/3-diol

Analogous to example 6b), 2.2 g of the epoxide was prepared according to description a) in example 14, reacted with a solution of 4.22 g of potassium cyanide in 8.4 ml of water in 42 ml of ethanol. After chromatography, 1.95 g of the above compound was isolated.

IR (KBr): 2245 cm"<1> C=N triple bond

b) 17-cyanomethyl-17p-hydroxy-113,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one

1.9 g of the cyanide obtained under a) was converted analogously to example lc) into the corresponding 4-ene-3-keto compound. From the impure product, 1.23 g of the title compound could be crystallized directly. Chromatography of the mother liquor yielded an additional 138 mg of the desired cyano compound

[a]<22> = 77° (CHC13; c=0.5)

Temp. = 172-176°C

Example 16

17-(3-hydroxyprop-l-ynyl)-17(3-hydroxy-ll(3,19-(4-dimethylamino-o-phenylene)-4-androstene-3-one)

a) 17-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-11Q,19-(4-dimethylamino-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane -5cx, 173-diol

Analogously to example 5a), 10 g of the keto compound was prepared according to description c) in example 13, reacted with 55.3 g of 3-(tetrahydropyran-2-yloxy)-propyne and 247 ml of a 15% solution of n-butyllithium in hexane. 11.74 g of the above compound was isolated as a white foam after chromatography.

IR (KBr): 2230 cm<-1> triple bond

b) 17-(3-hydroxyprop-1-ynyl)-173-hydroxy-11β,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one

Analogous to example lc), 11.74 g of the compound prepared under a) was transferred to 6.97 g of the title compound.

[a]<22> = 25.6° (CHC13; c=0.5)

Temp. = 251-253°C (ethyl acetate)

Example 17

17-(3-hydroxyprop-1(Z)-enyl)-17B-hydroxy-113, 19-(4-dimethylamino-o-phenylene)-4- androsten-3-one

a) 17-(3-hydroxyprop-1(Z)-enyl)-173~hydroxy-113,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one

Analogously to example 5b), 6.5 g of the acetylene compound produced according to example 16b) was converted to the corresponding Z-olefin. 4.76 g of the title compound was isolated as a white foam after chromatography on silica gel.

[a]<22> = 71° (CHC13; c=0.5)

Example 18

173~ hydroxy- 113, 19-( 4- hydroxy- o- phenylene)- 4- androsten- 3- one

a) 113,19-(4-hydroxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

50 g of the methoxy compound obtained analogously to description 3) in example 4 was dissolved in 500 ml of absolute dimethylformamide and 28.2 g of sodium methanethiolate were added under protective gas. Under an inert gas atmosphere, the reaction mixture was heated for 3 hours under reflux, then cooled to room temperature and then completely poured into 8 l of ice water. It was stirred at room temperature until

the impure product had flocculated as a solid. It was then suctioned off, washed with water and dried under vacuum. 49.2 g of the impure title compound were isolated as a white solid with a quality that was sufficient for further reactions.

[oe]<22> = 21° (CHC13; c=0.5)

Temp. = 267-270°C (ethyl acetate)

. b) 17|3-hydroxy-11G, 19-(4-hydroxy-o-phenylene)-4-androsten-3-one 2 g of the phenol obtained under a) was reacted analogously to example lc) with 3 ml of 4n aqueous hydrochloric acid in 60 ml of acetone to the 4-ene-3-keto compound. 1.05 g of the above compound was isolated as a white foam.

Temp. = 242-245°C (ethyl acetate).

Example 19

173- hydroxy- llj3, 19- ( 4- trifluoromethylsulfonyloxy- o- phenyl) - 4- androsten- 3- one

a) 173-hydroxy-11|3,19 - (4-trifluoromethyl sulfonyloxy-o-phenylene)-4-androsten-3-one

10 g of the phenol produced according to example 18b) was dissolved in 250 ml of absolute methylene chloride and 17.3 g of 4-dimethylaminopyridine was added. Under protective gas, this solution was then cooled to -50°C and 4.76 ml of trifluoromethanesulfonic anhydride dissolved in 30 ml of absolute methylene chloride was slowly added dropwise. After 15 minutes of stirring at -50°C, the reaction mixture was poured into saturated sodium bicarbonate solution and the aqueous phase extracted with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. 11.37 g of the title compound were obtained as a yellowish foam after chromatography of the residue on silica gel.

Temp. = 204-205°C (diisopropyl ether).

Example 20

17| 3- hydroxy- llj3, 19-[ 4-( 2- trimethylsilylethynyl) - o- phenylene j-4- androsten- 3- one

a) 17B-hydroxy-11(3,19-[4-(2-trimethylsilylethynyl)-o-phenylene]-4-androsten-3-one 1 g of the title compound prepared according to example 19a) was dissolved in 10 ml of absolute dimethylformamide and added 1.18 ral of triethylamine, 1.39 ml of trimethylsilylacetylene and 49 mg of palladium tetrakistriphenylphosphine under protective gas. The reaction mixture was then heated for 1 hour at 110°C, then cooled to room temperature and diluted with ethyl acetate. After filtration over celite, the filtrate was washed several times with saturated sodium chloride solution, the organic phase was separated, dried over sodium sulfate and evaporated under vacuum. Chromatography of the residue on silica gel gave 656 mg of the title compound as a white foam. Temp. = 267-271°C (diisopropyl ether).

Example 21

17-(prop-l-ynyl)-17[3-hydroxy-113,19-[4-(2-trimethylsilylethynyl)-o-phenylene]-4- androsten-3-one

a) 113,19-(4-trifluoromethylsulfonyloxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstene-5cx, 173-diol

40 g of the phenol produced according to example 18a).

was analogously to example 19a) reacted with 14.93 ml of trifluoromethanesulfonic anhydride. After chromatography, 37.3 g of the above compound was isolated as a white foam.

b) 11(3,19-[4-(2-trimethylsilylethynyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol 15 g of the compound prepared according to a) was analogously to example 20a) reacted with 17.3 ml of trimethylsilylacetylene. After chromatography on aluminum oxide (neutral, grade III), 11.7 g of the above compound was isolated as a white foam.

IR (KBr): 2150 cm triple bond in the aromatic part

c) 113 /19- [ 4-(trimethylsilylethynyl)-o-phenylene]-5ct-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

11.2 g of the substance obtained under b) was oxidized analogously to example 2a) with 11.69 g of chromium trioxide to the corresponding 17-keto compound. Chromatography on aluminum oxide (neutral, grade III) afforded 9.05 g of the title compound as a white foam.

[α]<22> =51° (CHCl 3 ; c=0.5);

Temp. = 245-248°C (diisopropyl ether).

d) 17-(prop-l-ynyl)-113,19-[4-(2-trimethylsilylethynyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol 1 g of the ketone produced under c) was reacted analogously to example 2b) with propyne. After chromatography on alumina (neutral grade III), 956 mg of the above compound was isolated as a white foam.

IR (KBr): 2250 cm 1 triple bond in the aromatic part

2235 cm 1 triple binding

e) 17-(prop-1-ynyl)-173-hydroxy-113,19-[4-(2-trimethylsilylethynyl)-o-phenylene]-4-androsten-3-one

900 mg of the compound prepared under d) was cleaved analogously to example lc) to the corresponding 4-ene-

3- keto compound. After chromatography on silica gel, 471 mg of the title compound was isolated as a white foam.

[α]<22> = 59° (CHCl 3 ; c=0.505).

Example 2 2

17- (prop-l- ynyl) - 17( 3- hydroxy- ll[ 3 , 19- ( 4- ethynyl- o- ph enylene) - 4- androsten- 3- one

a) 11(3,19-(4-ethynyl-o-phenylene)-50-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

1.5 g of the ketone prepared according to example 21c) was dissolved in 26 ml of absolute methanol and 1.1 g of anhydrous potassium carbonate was added. Under protective gas, the reaction mixture was stirred for 3 hours at room temperature, then poured into saturated sodium chloride solution and the aqueous phase extracted several times with methylene chloride. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. The quality of the impure product (1.31 g) is sufficient for further sales. Chromatography of 100 mg of the impure product on aluminum oxide (neutral,

degree III) led to 67 mg of pure title compound as a white foam.

b) 17-(prop-l-ynyl)-lip,19-(4-ethynyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5oc, 173-diol

1.2 g of the product obtained under a) was reacted analogously to example 2b) with propyne. After chromatography on aluminum oxide (neutral, grade III), 1.12 g of the above compound was isolated as a white foam.

IR (KBr): 2110 cm triple bond in the aromatic part

2235 cm 1 triple bond

c) 17-(prop-l-ynyl)-17|3-hydroxy-11|3,19-(4-ethynyl-o-phenylene)-4-androsten-3-one

1.1 g of the substance prepared according to b) was converted analogously to example lc) into the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 612 mg of the title compound was isolated as a white foam.

[ot]2<2> = 41° (CHCl3; c=0.5).

Example 23

17-(prop-l-ynyl)-17(3-hydroxy-liP, 19-[4-(2-trimethylsilyl-ethyl)-o-phenylene]-4- androsten-3-one

a) 113,19-[4-(2-trimethylsilylethyl)-o-phenylene]-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one 1 g of the preparation according to example 21c) ketone was dissolved in 10 ml of absolute ethanol and hydrogenated with 100 mg of palladium-on-carbon (10% strength) as catalyst at normal pressure. After absorption of 2 equivalents of hydrogen, the reaction mixture was filtered off over celite, the filter residue was washed with ethyl acetate and the filtrate was evaporated under vacuum. After chromatography of the residue on alumina (neutral, grade III), 884 mg of the above compound was isolated as a white foam.

b) 17-(prop-l-ynyl)-113,19-[4-(2-trimethylsilylethyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

850 mg of the ketone produced under a) was reacted analogously to example 2b) with propyne. After chromatography on alumina (neutral, grade III), 845 mg of the above compound was isolated as a white foam.

IR (KBr): 2235 cm<-1> triple bond.

c) 17-(prop-l-ynyl)-17B-hydroxy-113,19-[4-(2-trimethyl-silylethyl-o-phenylene]-4-androsten-3-one

800 mg of the substance prepared under b) was converted analogously to example lc) into the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 512 mg of the above compound was isolated as a white foam.

[α]<22> = 24° (CHCl 3 ; c=0.505).

Example 2 4

17- (prop-1-ynyl) - 17| 3- hydroxy- llj3, 19-( 4- ethyl- o- phenylene) - 4-androstene- 3- one

a) 11(3,19-(4-ethyl-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one 4 g of the acetylene compound obtained according to example 22a) was analogous to example 23a) hydrogenated to the corresponding ethyl compound. After chromatography on alumina (neutral, grade III), 3.63 g of the above compound was isolated as a white foam.

b) 17-(prop-l-ynyl)-lip,19-(4-ethyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

1.5 g of the compound prepared under a) was reacted analogously to example 2b) with propyne. After chromatography on aluminum oxide (neutral, grade III), 1.43 g of the above compound was obtained as a white foam.

IR (KBr): 2240 cm 1 triple bond

c) 17-(prop-l-ynyl)-173-hydroxy-113,19-(4-ethyl-o-phenylene)-4-androsten-3-one

1.3 g of the substance obtained under b) was converted analogously to example lc) into the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 879 mg of

the above compound obtained as white foam.

[a]<22> = 18° (CHC13; c=0.5)

Temp. = 283-285°C (ethyl acetate).

Example 25

17-(3-hydroxy-prop-1(Z)-enyl)-17| 3- hydroxy- llQ, 19-( 4- ethyl-o- phenylene) - 4- androsten- 3- one

a) 17-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-113,19-(4-ethyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane- 5a,173-diol 2 g of the ethyl compound prepared under example 24a) was reacted analogously to the recipe described under example 5a) with 3-(tetrahydropyran-2-yloxy)-prop-l-yne. After chromatography on aluminum oxide, 2.29 g of the title compound was isolated as a white foam.

IR (KBr): 2240 cm<-1> triple bond

b) 17-[3-(tetrahydropyran-2-yloxy)-prop-1(Z)-enyl]-113,19-(4-ethyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy) -androstane-5α,173-diol

2.2 g of the acetylene compound obtained under a).

was analogously to example 5b) hydrogenated to Z-olefin.

After chromatography on aluminum oxide (neutral, grade III), 1.95 g of the title compound was isolated as a white foam.

c) 17-(3-hydroxyprop-1(Z)-enyl)-173-hydroxy-113,19-(4-ethyl-o-phenylene)-4-androsten-3-one

1.9 g of the compound prepared under b) was cleaved analogously to example lc) to the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 706 mg of the above title compound was isolated as a white foam.

[α]22 = 62° (CHC13; c=0.505)

Temp. = 127-129°C (ethyl acetate).

Example 26

17- (prop-1-ynyl) - 17| 3- hydroxy- ll( 3 , 19- ( 4- vinyl- o- f enylene) - 4- androsten- 3- one

a) 11(3,19-(4-hydroxy-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one 20 g of the 11( 3,19-(4-methoxy-o-phenylene)-5oc-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one was converted analogously to example 18a) into the corresponding phenol. 16.8 g were isolated as an impure product with a purity that was sufficient for further reactions. 500 mg of the crude product was chromatographed on aluminum oxide for analytical purposes to give 412 mg of the title compound.

b) 11(3,19-(4-trifluoromethylsulf onyloxy-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

16.3 g of the phenol obtained under a) was converted analogously to example 19a) into the corresponding triflate. After chromatography on silica gel, 15.1 g of the title compound was isolated as a white foam.

IR (KBr): 1740 cm-1 five-ring ketone

1215 and 1420 cm<-1> triflate

c) 11(3,19-(4-vinyl-o-phenylene)-5α-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

1.5 g of the substance prepared under b) was dissolved in 18 ml of absolute dimethylformamide and 146 mg of palladium tetrakistriphenylphosphine and 207 mg of lithium chloride were added under protective gas. After 5 minutes of stirring, 0.89 ml of tri-n-butylvinyltin was added to the reaction mixture and heated to 110°C. After 1 hour, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered off over celite. The filtrate was washed with saturated sodium chloride solution, the organic phase dried over

sodium sulfate and evaporated under vacuum. The residue was chromatographed on aluminum oxide (neutral, grade III) and 1.1 g of the title compound was obtained as a white foam.

d) 17-(prop-l-ynyl)-113,19-(4-vinyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol 1 g of the under a) produced ketone was analogously to example 2b) reacted with propyne. After chromatography on aluminum oxide (neutral, grade III), 912 mg of the title compound was isolated as a white foam.

IR (KBr): 2240 cm<-1> triple bond

e) 17-(prop-l-ynyl)-173-hydroxy-113,19-(4-vinyl-o-phenylene)-4-androsten-3-one

850 mg of the compound obtained under d) was converted analogously to example lc) into the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 485 mg of the title compound was isolated as a white foam.

[a]2<2> = 50° (CHC13; c=0.505)

Temp. = 243-245°C (diisopropyl ether)

Example 27

17-( prop- l- ynyl)- 173- hydroxy- 113, 19-[ 4-( 2- propenyl)- o-phenylene]- 4- androsten- 3- one

a) H3,19-[4-(2-propenyl)-o-phenylene]-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

1.5 g of the substance prepared according to example 26b) was reacted analogously to example 26c) with 0.36 ml of tetraallyl tin. After chromatography on silica gel, 1.06 g of the title compound was isolated as a white foam.

b) 17-(prop-l-ynyl)-11(3,19-[4-(2-propenyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5ct, 173- diol 1 g of the substance obtained according to a) was reacted analogously to example 2b) with propyne. After chromatography on aluminum oxide (neutral, grade III), 942 mg of the title compound was isolated as a white foam.

IR (KBr): 2240 cm<-1> triple bond

c) 17-(prop-l-ynyl)-173-hydroxy-liP,19-[4-(2-propenyl)-o-phenylene]-4-androsten-3-one

900 mg of the substance prepared according to b) was converted analogously to example lc) into the corresponding 4-ene-3-keto compound. Chromatography on silica gel gave 397 mg of the title compound as a white foam.

[a]22 = 18° (CHC13; c=0.5)

Temp. = 275-277°C (methylene chloride)

Example 28

17B- hydroxy- ll( 3, 19- ( 4- acetyl- o- phenylene)- 4- androsten- 3- one

a) 113,19-(4-acetyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol 30 g of the triflate prepared according to example 21a) was analogous to example 26c ) reacted with 22.06 g of 1-ethoxy-vinyl-tributyltin. After chromatography on silica gel, 18.75 g of the title compound was isolated as a white foam.

[ot]<22> = 146° (CHC13; c=0.5)

Temp. = 179-181°C (diisopropyl ether)

b) 173-hydroxy-113,19-(4-acetyl-o-phenylene)-4-androsten-3-one

18 g of the substance obtained according to a) was analogous to

example lc) converted to the corresponding 4-ene-3-keto compound. It was isolated after chromatography on silica gel

10.8 g of the title compound as a yellowish foam.

Temp. = 135-138°C (ethyl acetate/hexane)

EXAMPLE 29

17- (prop-1-ynyl) - 17| 3- hydroxy- ll( 3, 19- ( 4- acetyl- o- phenylene) - 4- androsten- 3- one

a) lip,19-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene}-3,3-(2,2-dimethyltrimethylenedioxy)-5-androsten-173-ol 10 g of the substance obtained according to 28b) was dissolved in 250 ml of absolute toluene and 25.7 g of 1,3-dimethylpropanediol and 1.86 g of pyridinium paratoluenesulfonate were added one after the other. The reaction mixture was then heated for 4 hours under reflux, and simultaneously formed water was removed azeotropically.

The reaction mixture was then cooled to room temperature, poured into ice-cold 5% aqueous sodium hydroxide solution and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. Chromatography of the residue on alumina (neutral, grade III) afforded 10.7 g of the title compound as a white foam.

b) 113,19-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene}-3,3-(2,2-dimethyltrimethylenedioxy)-5-androsten-17-one

10.5 g of the substance obtained according to a) was converted analogously to example 2a) into the corresponding 17-keto compound. 10.2 g of impure product with purity sufficient for further reactions was isolated. 500 mg was analytically chromatographed on aluminum oxide (neutral, grade III) to give 443 mg of the title compound as a white foam.

[ct]<22> = 43° (CHC13; c=0.5)

Temp. = 244-246°C (ethyl acetate)

c) 17-(prop-l-ynyl)-113,19-£4-[1,1-(2,2-dimethyltrimethylenedioxy )-ethyl]-o-phenylene}-3,3-(2,2-dimethyltrimethylenedioxy ) -5-androstene-173~ol

1.5 g of the impure product obtained according to b), was analogously to example 2b) reacted with propyne. After chromatography on aluminum oxide (neutral, grade III), 1.35 g of the title compound was obtained as a white foam.

IR (KBr): 2240 cm<-1> triple bond.

d) 17-(prop-l-ynyl)-173-hydroxy-113,19-(4-acetyl-o-phenylene)-4-androsten-3-one

1.3 g of the substance prepared according to c), was cleaved analogously to example lc) to the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 747 mg of the title compound was isolated as a yellowish foam.

[a]22 = 36° (CHC13; c=0.5)

Temp. = 186-187° (ethyl acetate)

Example 30

17-( prop- 2- ynyl)- 173~ hydroxy- 113, 19-( 4- acetyl- o- phenylene)-4- androsten- 3- one

a) 17-(3-trimethylsilylprop-2-ynyl)-113,19-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene)-3,3-(2,2 -dimethyltrimethylenedioxy)-5-androstene-173_ol

1.5 g of the compound prepared according to example 29b), was reacted analogously to example 5a) with 2.3 ml of 1-trimethyl-silylprop-1-yne. After chromatography on aluminum oxide (neutral, grade III), 1.31 g of the title compound was isolated as a white foam.

IR (KBr): 2170 cm 1 triple bond

b) 17-(prop-2-ynyl)-17β-hydroxy-11|3,19-(4-acetyl-o-phenylene)-4-androsten-3-one

1.2 g of the substance prepared according to a), was transferred analogously to example lc) to the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 547 mg of the title compound was isolated as a white foam.

[oe]<22> 91° (CHC13; c=0.5)

Temp. , = 257-259°C

Example 31

17- ( prop- l- ynyl)- 17{ 3- hydroxy- liP, 19- ( 4- acetyl- o- phenylene)- 4, 15- androstadien- 3- one

a) 11[3,19-{4-[ 1,1-(2, 2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-5,15-androstadien- 17-Wed

1.89 g of the compound prepared according to example 29b), was dissolved in a solution of 9.9 mmol of lithium diisopropylamide in 40 ml of absolute tetrahydrofuran and added dropwise to 20 ml of absolute tetrahydrofuran under protective gas at 0°C. Then 2.39 ml of chlorotrimethylsilane was added dropwise to the reaction mixture. After stirring for 30 minutes, the reaction solution was poured into ice-cold, saturated sodium hydrogen carbonate solution, the aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated ammonium chloride solution. After drying over sodium sulfate, the organic phase was evaporated under vacuum. 1.96 g of 17-trimethylsilyloxy-11(3,19-£4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene}-3,3-(2,2- dimethyltrimethylenedioxy)-5,16-androstadiene in impure form as a yellowish foam. This impure product was slurried in 23 ml of absolute acetonitrile and 1 g of palladium(II) acetate was added. After 2 hours of stirring at room temperature, the reaction mixture was filtered off over celite, the filter residue after -washed with ethyl acetate and the filtrate evaporated under vacuum.

The residue was chromatographed on aluminum oxide (neutral,

grade III), and 1.33 g of the title compound was obtained as a white foam.

IR (KBr): 1710 cm unsaturated pentaring ketone

b) 17-(prop-l-ynyl)-11(3,19-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene}-3,3-(2,2 -dimethyltrimethylenedioxy) -5,15-androstadien-17(3-ol

1.3 g of the substance prepared according to a), was analogous

with example 2b) reacted with propyne. After chromatography on aluminum oxide (neutral, grade III), 1.23 g of the title compound was isolated as a white foam.

IR (KBr): 2230 cm<-1> triple bond

c) 17-(prop-l-ynyl)-173-hydroxy-11(3,19-(4-acetyl-o-phenylene)-4,15-androstadien-3-one

1.1 g of the substance prepared according to b), was cleaved analogously to example lc) to the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 617 mg of the title compound was isolated as a yellowish foam.

[a]<22> = 114° (CHC13; c=0.5)

Temp. = 189-191°C (ethyl acetate)

Example 32

17- methoxymethyl- 17( 3- hydroxy- lip, 19- ( 4- acetyl- o- phenylene)- 4- androsten- 3- one

a) 11(3,19-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene}-3,3-(2,2-dimethyltrimethylenedioxy)-5-androstene-[17 (3-1<1>)-spiro-3<1>]-oxirane 4 g of the compound prepared according to example 29b), was reacted analogously to example 14a) with 7.13 g of trimethylsulfonium iodide. After chromatography on aluminum oxide (neutral, grade III), 3.76 g of the title compound was isolated as a white foam.

b) 17-methoxymethyl-llf3,19-{4-[ 1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-5-androstene- 173-ol

1.8 g of the substance prepared according to a), was reacted analogously to example 14b) with sodium methylate. After chromatography on aluminum oxide (neutral, grade III), 1.55 g of the title compound was isolated as a white foam.

c) 17-methoxymethyl-17(3-hydroxy-11(3,19-(4-acetyl-o-phenylene)-4- androsten-3-one

1.5 g of the substance obtained according to b), was cleaved analogously to example lc) to the corresponding 4-ene-3-keto compound. After chromatography on silica gel, 561 mg of the title compound was isolated as a yellowish foam.

[α]22 = 76° (CHC13; c=0.5)

Example 33

17- cyanomethyl- 17P- hydroxy- 113, 19-( 4- acetyl- o- phenylene)- 4-androstene- 3- one

a) 17-cyanomethyl-113,19-{4-[1,1-(2,2-dimethyltrimethylenedioxy)-ethyl]-o-phenylene}-3,3-(2,2-dimethyltrimethylenedioxy)-5-androstene- 173~ol

1.8 g of the substance obtained according to example 32a), was reacted analogously to example 6b) with potassium cyanide. After chromatography on aluminum oxide (neutral, grade III), 1.67 g of the title compound was isolated as a white foam.

IR (KBr):2250 cm"<1> C=N triple bond.

b) 17-cyanomethyl-173-hydroxy-113,19-(4-acetyl-o-phenylene)-4-androsten-3-one

1.5 g of the substance obtained according to a), was cleaved analogously to example lc) to the corresponding 4-ene-3-keto compound.

After chromatography on silica gel, 732 mg of the title compound was isolated as a white foam.

[a]<22> 83° (CHC13; c=0.5)

Temp. = 184-185°C (methylene chloride)

EXAMPLE 34

17-(prop-l-ynyl)-17(3-hydroxy-ll(3,19-(4-isopropenyl-o-phenylene)-4- androsten-3-one

a) 11(3,19-(4-isopropenyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a, 17(3-diol

Under protective gas, 1.94 g of sodium hydride in 20 ml of absolute dimethyl sulfoxide was heated at 70° C. until no gas evolution could be detected. The solution was then cooled to 0°C and methyltriphenylphosphonium bromide dissolved in 61 ml of absolute dimethylsulfoxide was added dropwise. After stirring for 1 hour at room temperature, 10.3 g of the compound prepared according to example 28a), dissolved in 10 ml of absolute dimethylsulfoxide, was added dropwise, and the reaction mixture was stirred for 3 hours. The reaction mixture was then poured into cold, saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate and the organic phases were washed with saturated sodium chloride solution. The combined organic phases were dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on aluminum oxide (neutral, grade III). 8.3 g of the title compound was obtained as a white foam.

Temp. = 155-157°C (diisopropyl ether)

b) 11|3 ,19 - (4-isopropenyl-o-phenylene)-50-hydroxy-3 , 3 - (2 , 2-dimethyltrimethylenedioxy)-androstan-17-one

8.1 g of the substance prepared according to a), was oxidized analogously to example 2a) with chromium trioxide. After chromatography on aluminum oxide (neutral, grade III), 7.8 g of the title compound was isolated as a white foam.

Temp. = 238-240°C (diisopropyl ether)

c) 17-(prop-l-ynyl)-113,19-(4-isopropenyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5oc,173-diol

1.5 g of the substance obtained according to b) was reacted analogously to example 2b) with propyne. After chromatography on aluminum oxide (neutral, grade III), 1.34 g of the title compound was isolated as a white foam.

IR (KBr): 2240 cm<-1> triple bond

d) 17-(prop-l-ynyl)-173_hydroxy-113,19-(4-isopropenyl-o-phenylene)-4-androsten-3-one

1.3 g of the compound obtained according to c), was converted analogously to example lc) to the 4-ene-3-keto compound. After chromatography on silica gel, 706 mg of the title compound was isolated as a white foam.

[a]<22> = 41° (CHC13; c=0.5)

Temp. = 247-250°C (diisopropyl ether)

As a byproduct, 17-(prop-l-ynyl)-173-hydroxy-113,19-[ 4-(1-methylhydroxyethyl)-o-phenylene]-4-androsten-3-one (354 mg) was isolated as a white foam .

[a]<22> = 17° (CHC13; c=0.5)

Temp. = 222-224°C

Example 35

17-(prop-l- ynyl)- 173~ hydroxy- 113, 19-( 4- isopropyl-o- phenylene)-4- androsten- 3- one

a) 113,19-(4-isopropyl-o-phenylene)-5oc-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one 2 g of the substance obtained according to example 34b), was hydrogenated as described under example 23a), but only until uptake of an equivalent of hydrogen, with palladium as catalyst. After chromatography on aluminum oxide (neutral, grade III), 1.83 g of the title compound was isolated as a white foam.

b) 17-(prop-l-ynyl)-113,19--(4-isopropyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

1.8 g of the compound prepared according to a), was reacted analogously to example 2b) with propyne. After chromatography on aluminum oxide (neutral, grade III), 1.81 g of the title compound was isolated as a white foam.

c) 17-(prop-l-ynyl)-173-hydroxy-113,19-(4-isopropyl-o-phenylene)-4-androsten-3-one

1.7 g of the compound prepared according to b) was cleaved analogously to example lc) to the 4-ene-3-keto compound. After chromatography on silica gel, 932 mg of the title compound was isolated as a white foam.

[ot]<22> 21° (CHC13; c=0.505)

Temp. = 240-243°C (ethyl acetate)

Example 36

17-( 3- hydroxyprop- 1( Z)-enyl)- 173- hydroxy- 113, 19-( 4- isopropenyl- o- phenylene)- 4- androsten- 3- one

a) 17-[3-(tetrahydropyran-2-yloxy)-prop-l-ynyl]-113,19-(4-isopropenyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane- 5ot, 173-diol 2 g of the substance obtained according to example 34b), was analogously to example 5a) reacted with 3-(tetrahydropyran-2-yloxy)-prop-l-yne. After chromatography on aluminum oxide (neutral, grade III), 2.1 g of the title compound was isolated as a white foam.

b) 17-[3-(tetrahydropyran-2-yloxy)-prop-1(Z)-enyl]-113,19-(4-isopropeny1-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy) -andros tan-5ot, 173-diol

2 g of the compound obtained according to a), was analogous

with example 5b) hydrogenated with Lindlar catalyst. After

chromatography on alumina (neutral, grade III) isolated 1.78 g of the title compound as a white foam.

c) 17-(3-hydroxyprop-1(Z)-enyl)-173-hydroxy-11j3,19-(4-isopropenyl-o-phenylene)-4-androsten-3-one

1.7 g of the compound obtained according to b), was cleaved analogously to example lc) to the 4-ene-3-keto compound. After chromatography on silica gel, 567 mg of the title compound was isolated as a white foam.

[ot]<22> = 79° (CHC13; c=0.5)

Temp. = 143-145°C (ethyl acetate)

As a byproduct, 178 mg of 17-(3-hydroxyprop-1(Z)-enyl)-17|3-hydroxy-11|3,19-[ 4-(1-methyl-1-hydroxyethyl)-o-phenylene] - 4-androsten-3-one isolated as white foam.

[α]<22> = 61° (CHC13;

Temp. = 208-211°C (ethyl acetate)

Example 37

17-(4-hydroxybut-1(Z)-enyl)-17! 3- hydroxy- ll{ 3 , 19- ( 4- isopropenyl-o- phenylene) - 4- androsten- 3- one

a) 17-(4-hydroxybut-1-ynyl)-113,19-(4-isopropenyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol 2 g of the substance obtained according to example 34b), was dissolved in 60 ml of absolute tetrahydrofuran and 2.27 ml of n-but-l-yn-4-ol and 4.09 g of potassium ethylate were added one after the other under protective gas. During the addition and subsequent 14-hour stirring, the reaction mixture was maintained at a temperature of 0°C. It was then poured into water and the water phase extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on aluminum oxide (neutral, grade III) and 1.2 g of the title compound was isolated as a white foam.

IR (KBr): 2240 cm<-1> triple bond.

b) 17-(4-hydroxybut-1 (Z)-enyl)-11(3,19-(4-isopropenyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5<x , 173-diol 1 g of the substance obtained according to a), was analogously to example 5b) hydrogenated using a Lindlar catalyst. After chromatography on aluminum oxide (neutral, grade III), 836 mg of the title compound was obtained as a white foam.

c) 17-(4-hydroxybut-1(Z)-enyl)-17(3-hydroxy-11|3,19-(4-isopropenyl-o-phenylene)-4-androsten-3-one

800 mg of the substance obtained according to b) was cleaved analogously to example 1c) to the 4-ene-3-keto compound. After chromatography on silica gel, 306 mg of the title compound was isolated as a white foam.

[α]22 = 78° (CHC13; c=0.515)

Example 38

17-( prop- l- ynyl)- 17P- hydroxy- llp, 19-( 4- diethoxyphosphoryl- o-phenylene)- 4- androsten- 3- one

a) 11(3,19-(4-diethoxyphosphory 1-o-phenylene)-5ct-hydroxy-3 , 3 - (2 , 2-dimethyltrimethylenedioxy)-androstan-17-one

1.5 g of the triflate obtained according to example 26b), was dissolved in 10 ml of absolute triethylamine and 122 mg of tetrakistriphenylphosphine palladium and 0.46 ml of phosphoric acid diethyl ester were added under protective gas. Then the reaction mixture was heated for 1.5 hours under reflux. After addition of a further 100 mg of tetrakistriphenylphosphine palladium and 0.46 ml of phosphoric acid diethyl ester, the reaction mixture was heated for a further 1.5 hours to reflux, then allowed to cool to room temperature and evaporated under vacuum. The residue was chromatographed on silica gel to give 1.05 g of the title compound as a white foam.

b) 17-(prop-l-ynyl)-11(3,19-(4-diethoxyphosphoryl)-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-andros tan-5ct, 17(3- diol 1 g of the compound prepared according to a), was analogously to example 2b) reacted with propyne. Chromatography on alumina (neutral, grade III) afforded 832 mg of the title compound as a white foam.

IR (KBr): 2240 cm-1 triple bond.

c) 17-(prop-l-ynyl)-17(3-hydroxy-118,19-(4-diethoxyphosphoryl-o-phenylene)-4-androsten-3-one

800 mg of the substance prepared according to b), was cleaved analogously to example lc) to the 4-ene-3-keto compound. After chromatography on silica gel, 440 mg of the title compound was isolated as a white foam.

[a]22 = 17° (CHC13; c=0.5)

Example 39

17-(prop-l-ynyl)-173-hydroxy-liP, 19-[4-(2-thienyl)-o-phenylene]-4- androsten-3-one

a) lip,19-[4-(2-thienyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5cc, 173-diol

1.26 g of the substance prepared according to example 21a), was dissolved in 36 ml of absolute dioxane and 3.04 ml of hexa-n-butylditin, 254 mg of lithium chloride and 100 mg of tetrakistriphenylphosphine palladium were added under protective gas. Then the reaction mixture was heated to 110°C and held at this temperature for 1 hour before 1.94 ml of 2-bromothiophene was added and it was stirred for a further 18 hours at 110°C. The reaction mixture was then brought to room temperature and filtered over celite. After evaporation of the filtrate, the residue was chromatographed on silica gel. 545 mg of the title compound were obtained as a yellowish foam.

As an example of this type of coupling, the following tin compound was isolated: a) 113,19-(4-tri-n-butylstannyl-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173 -diol

1.26 g of the substance prepared according to example 21a), was reacted analogously to the conditions described under a) with 3.04 ml of hexa-n-butylditin. After 1 hour of heating to 110°C, the reaction mixture was worked up in the normal way. Chromatography on silica gel afforded 625 mg of the title compound as a white foam.

[a]<22> = 25° (CHC13; c=0.5)

Temp. = 137-139°C (diisopropyl ether)

b) 113,19-[4-(2-thienyl)-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

400 mg of N-chlorosuccinimide was placed in 5 ml of absolute methylene chloride at 0°C. After adding 0.3 ml of dimethylsulphide dropwise, the mixture was stirred for 30 minutes at 0°C. Then 510 mg of the substance obtained according to a) was dissolved in 5 ml of absolute methylene chloride, slowly added dropwise. After 2 hours of stirring under exclusion of moisture, 0.6 ml of triethylamine was added dropwise to the reaction mixture. It was then poured into water, the aqueous phase extracted with methylene chloride and the organic phase washed with saturated sodium chloride solution. It was then dried over sodium sulfate and evaporated under vacuum. After chromatography of the residue on aluminum oxide (neutral, grade III), 387 mg of the title compound was isolated as a yellowish foam.

IR (KBr): 1740 cm 1 femrihg ketone

c) 17-(prop-l-ynyl)-113,19-[4-(2-thienyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5ct, 173-diol

350 mg of the substance obtained according to b), was analogous to

example 2b) reacted with propyne. After chromatography on aluminum oxide (neutral, grade III), 343 mg of the title compound was isolated as a yellowish foam.

IR (KBr): 2240 cm<-1> triple bond.

d) 17-(prop-l-ynyl)-17[3-nydroxy-11|3,19-[ 4-(2-thienyl)-o-phenylene]-4-androsten-3-one

320 mg of the compound obtained according to d), was cleaved analogously to example lc) to the 4-ene-3-keto compound. After chromatography on silica gel, 234 mg of the title compound was isolated as a yellowish foam.

[ct]<22> = 65° (CHC13; c=0.5)

Example 40

17-(prop-l-ynyl)-17p-hydroxy-llf3, 19-[4-(3-thienyl)-o-phenylene]-4- androsten-3-one

a) 11(3,19-[4-(3-thienyl)-o-phenylene]-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

1.26 g of the substance obtained according to example 26b), was reacted analogously to the conditions mentioned under process example 39a) with 2 ml of 3-bromothiophene. After chromatography on aluminum oxide (neutral, grade III), 546 mg of the title compound was isolated as a yellowish foam.

b) 17-(prop-1-ynyl)-11(3,19-[4-(3-thienyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5oc, 1< 7>3-diol

520 mg of the substance prepared according to a), was reacted analogously to example 2b) with propyne. After chromatography on aluminum oxide (neutral, grade III), 462 mg of the title compound was isolated as a yellowish foam.

IR (KBr): 2250 cm 1 triple bond.

c) 17-(prop-l-ynyl)-176-hydroxy-llp,19-[4-(3-thienyl)-o-phenylene]-4-androsten-3-one

410 mg of the substance obtained according to b) was cleaved to the 4-ene-3-keto compound analogously to example lc). After chromatography on silica gel, 287 mg of the title compound was isolated as a yellowish foam.

[a]<22> = 61° (CHC13; c=0.51)

Example 41

17-(prop-l-ynyl)-17(3-hydroxy-ll(3,19-[4-(3- furyl)-o-phenylene)-4-androstene-3-one

a) 11(3,19-[4-(3-furyl)-o-phenylene]-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

1.26 g of the substance prepared according to example 26b), was reacted analogously to example 39a) with 1.8 ml of 3-bromofuran. After chromatography on silica gel, 660 mg of the title compound was isolated as a white foam.

Temp. = 240-243°C (ethyl acetate)

b) 17-(prop-l-ynyl)-11(3,19-[4-(3-furyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5oc, 17f3- diol

630 mg of the substance obtained according to a), was analogously to example 2b) reacted with propyne. After chromatography on aluminum oxide (neutral, grade III), 615 mg of the title compound was isolated as a white foam.

IR (KBr): 2240 cm<-1> triple bond.

c) 17-(prop-1-ynyl)-17(3-hydroxy-11!3,19-[4-(3-furyl)-o-phenylene]-4-androsten-3-one

590 mg of the substance obtained according to b) was converted analogously to example lc) into the 4-ene-3-keto compound. After chromatography on silica gel, 289 mg of the title compound

the ice isolated as white foam.

[a]<22> 49° (CHC13; c=0.51)

Example 42

17-(prop-l-ynyl)-17p-hydroxy-ll(3,19-[4-(3-methoxyphenyl)-o-phenylene]-4- androsten-3-one

a) 11(3,19-[4-(3-methoxyphenyl)-o-phenylene]-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

1.26 g of the substance prepared according to example 26b), was reacted analogously to example 39a) with 2.53 ml of 3-bromoanisole. After chromatography on silica gel, 685 mg of the title compound was isolated as a white foam.

b) 17-(prop-l-ynyl)-113,19-[4-(3-methoxyphenyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5cx,173-diol

650 mg of the substance prepared under a), was reacted with propyne analogously to the method described under example 2b). After chromatography on aluminum oxide (neutral, grade III), 635 mg of the title compound was isolated as a white foam.

IR (KBr): 2230 cm<-1> triple bond

c) 17-(prop-l-ynyl)-173-hydroxy-11B,19-[4-(3-methoxyphenyl)-o-phenylene]-4-androsten-3-one

600 mg of the substance prepared under b), was converted analogously to the conditions described under example lc) into the 4-ene-3-keto compound. After chromatography on silica gel, 366 mg of the title compound was isolated as a white foam.

[α]22 66° (CHCl3; c=0.5)

Temp. = 158-162°C (ethyl acetate/hexane)

Example 43

17-(prop-l- ynyl)- 17ft- hydroxy- lip, 19-[ 4-( 4- methoxyphenyl)- o-phenylene]- 4- androsten- 3- one

a) IIP,19-[4-(4-methoxy<y>phen<y>l)-o-phen<y>lene]-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstane- 17-Wed

1.26 g of the substance prepared according to preparation example 26b) was reacted analogously to example 39a) with 2.53 ml of 4-bromoanisole. After chromatography on silica gel, 522 mg of the title compound was isolated as a white foam.

[cx]<22> = 48° (CHC13; c=0.5)

Temp. = 171-173°C (ethyl acetate)

b) 17-(prop-l-ynyl)-llp,19-[4-(4-methoxyphenyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-5oate, 17P-diol

500 mg of the substance prepared under a), was reacted with propyne analogously to the method described under example 2b). After chromatography on aluminum oxide (neutral, grade III), 498 mg of the title compound was isolated as a white foam.

IR (KBr): 2240 cm"<1> triple bond

c) 17-(prop-l-ynyl)-17β-hydroxy-liP,19-[4-(4-methoxyphenyl)-o-phenylene]-4-androsten-3-one

450 mg of the substance prepared under b), was converted analogously to example lc) into the 4-ene-3-keto compound. After chromatography on silica gel, 276 mg of the title compound was isolated as a white foam.

[cx]<22> = 70° (CHC13; c=0.505)

Temp. = 165-169°C (ethyl acetate/hexane)

Example 44

17-(prop-l- ynyl)- 173- hydroxy- 113, 19-[ 4-( 2- methoxyphenyl)- o-phenylene]- 4- androsten- 3- one

a) 113,19-[4-(2-methoxyphenyl)-o-phenylene]-5c-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

1.26 g of the substance obtained according to example 26b), was reacted analogously to example 39a) with 2.53 ml of 2-bromoanisole. After chromatography on silica gel, 448 mg of the title compound was isolated as a white foam.

b) 17-(prop-l-ynyl)-113,19-[4-(2-methoxyphenyl)-o-phenylene]-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

410 mg of the substance prepared according to a), was reacted analogously to example 2b) with propyne. After chromatography on aluminum oxide (neutral, grade III), 405 mg of the title compound was isolated as a white foam.

IR (KBr): 2240 cm<-1> triple bond

c) 17-(prop-l-ynyl)-173-hydroxy-113,19-[4-(2-methoxyphenyl)-o-phenylene]-4-androsten-3-one

380 mg of the substance prepared according to b) was converted analogously to example lc) into the 4-ene-3-keto compound. After chromatography on silica gel, 205 mg of the title compound was isolated as a white foam.

[a]2<2> = 49° (CHC13; c=0.51)

Example 45

17-( prop- l- ynyl)- 173- hydroxy- 113, 19-( 4, 5- methylenedioxy- o-phenylene)- 4- androsten- 3- one

a) 19-(2-chloro-4,5-methylenedioxyphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5a,173-diol

Analogously to example la), 10.3 g of 19-(2-chloro-4,5-methylenedioxyphenyl)-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-androstene-5cc, 173-diol were obtained from 10 g of 5a,10a-epoxy-3,3-(2,2-dimethyltrimethylenedioxy)-9(11)-estren-173-ol through reaction with 6-chloropiperonyl chloride.

b) 11(3,19-(4,5-methylenedioxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

Analogously to example lb), 5.9 g of 113,19-(4,5-methylenedioxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)- were prepared from 10 g of the compound obtained under a) androstane-5α,173-diol as a white foam.

c) 113,19-(4,5-methylenedioxy-o-phenylene)-5a-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one

Analogously to example 2a), 5.5 g of the compound obtained under b) was transferred to the corresponding keto compound. 4.2 g of 113,19-(4,5-methylenedioxy-o-phenylene)-5α-hydroxy-3,3-(2,2-dimethyltrimethylenedioxy)-androstan-17-one were obtained as a white foam.

[a]<22> = +45° (CHC13;

Temp. = 219-222°C (ethyl acetate)

d) 17-(prop-l-ynyl)-113,19-(4,5-methylenedioxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a,173-diol

Analogously to example 2b), 4 g of the compound obtained under c) was transferred to the corresponding 17a-propynyl compound. After chromatography, 3.5 g of 17-(prop-l-ynyl)-113,19-(4,5-methylenedioxy-o-phenylene)-3,3-(2,2-dimethyltrimethylenedioxy)-androstane-5a were isolated ,173-diol as white foam.

IR (KBr): 2230 cm"<1> triple bond

e) 17-(prop-1-ynyl)-17|3-hydroxy-11(3,19-(4,5-methylenedioxy-o-phenylene)-4-androsten-3-one

Analogously to example lc), 3 g of the compound obtained under d) was converted into the corresponding 4-ene-3-keto compound. 1.36 g of 17-(prop-l-ynyl)-17/3-hydroxy-lip,19-(4,5-methylenedioxy-o-phenylene)-4-androsten-3-one were isolated.

[a]22 = +2° (CHC13; c=0.485)

Claims (5)

1. Steroids with a 19,llp bridge bond, characterized in that they have the general formula I where R<1> is a methyl or ethyl residue, R<2> is a hydrogen or chlorine atom, B is a hydrogen atom, G is a hydrogen atom or a C1-C4 alkyl radical, or B and G together are a second bond between carbon atoms 6 and 7, or B and R2 are together a methylene group, Z is the remainder of a ring with formula where R<1> has the above meaning, the dashed line starting from W means the possible presence of a double bond, W is a CH2 or CH residue, R<5> is -OH or - C-C-15-alkyl, and II 0 R<6> is H, C2.5-alkynyl, HO-C2.5-alkenyl, CN-C4-alkyl, HO -C2-5-alkynyl, C1.4-alkoxy<y->C1-4-alkyl, halogen-<C>2-5<->alkynyl, HO-C 1 -alkyl, C 2-5 -alkenyl, V is the residue of a phenyl ring of formula where R 4 is a hydrogen or halogen atom, or a hydroxy-, cyano-, C 1 -C 4 -alkyl-, HO -C 4 -C 5 -alkyl-, C 1 -C 4 -alkyl-thio- or -sulfinyl-, N-(C 4 -alkyl )2-amino-, CF3-sulf onyloxy-, (CH3 )3-Si-C2.5-alkynyl-, C2.5-alkenyl- or -alkynyl-, (CH3)3-Si-C1.4-alkyl- . hydrogen atom, or R4 and R<4>' are together a 4,5-methylenedioxy residue, the ring A is where M and N together are a second bond, or M is a hydrogen atom and N is a hydroxy group, with B, R<2>, G, R<3>, D and E then being hydrogen atoms, and X is an oxygen atom, two hydrogen atoms or a hydroxyimino group N~OH, R 3 and D are each a hydrogen atom, and E is a hydrogen atom, or R3 is a hydrogen atom and D and E together are a second bond between carbon atoms 1 and 2, as well as physiologically acceptable acid addition salts thereof. 2. Compound according to claim 1, characterized in that it is 17a-(prop-l-ynyl)-17B-hydroxy-110,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one. 3. Compound according to claim 1, characterized in that it is 17a-(prop-1-ynyl)-17B-hydroxy-11B,19-(4-acety1-o-phenylene)-4-androsten-3-one. 4. Compound according to claim 1, characterized in that it is 17a-(3-hydroxyprop-1-(Z)-enyl)-17B-hydroxy-11B,19-(4-dimethylamino-o-phenylene)-4-androstene- 3-Mon. 5. Compound according to claim 1, characterized in that it is 17a-(3-hydroxyprop-1 - ( Z )-enyl)-17 (3-hydroxy-11 (3,19 - (4 -methy 1 thio - o - f enylene) - 4-androsten-3-one.