IE57620B1

IE57620B1 - 13alpha-alkylgonanes,their preparation and pharmaceutical preparations containing them

Info

Publication number: IE57620B1
Application number: IE1484/84A
Authority: IE
Original assignee: Schering Ag
Priority date: 1983-06-15
Filing date: 1984-06-14
Publication date: 1993-02-10
Also published as: DK288184D0; AU572849B2; EP0129499A2; DK166729B1; DK288184A; JPH0369919B2; AU2936184A; GR82210B; DE3468030D1; HU191131B; FI78709C; ES8502612A1; NO842394L; FI842395A; IL72085A0; EP0129499B1; IE841484L; DD218624A5; CA1307784C; NZ208441A

Abstract

1. Claims for the Contracting States BE, CH, LI, DE, FR, GB, IT, LU, NL, SE 13 alpha-Alkyl gonanes of general formula I see diagramm : EP0129499,P14,F3 wherein R**1 means -N R**II -R**I wherein R**I and R**II are hydrogen or alkyl of 1-4 carbon atoms, or R**I and R**II with inclusion of N mean a saturated 5- or 6-membered ring, wherein the ring can contain, besides N, still another hetero atom, such as O, N, S, as well as the corresponding tertiary N-oxides and the acid addition salts, OR**III wherein R**III means methyl, ethyl, propyl, methoxyphenyl, allyl, or beta-dimethylaminoethyl, R**2 means a hydrogen atom, a methyl group or an ethyl group, R**3 means -(CH2 )n -CH3 with n=0-4, -(CH2 )n -CH2 -O(S)R**IV with n=0-4, and R**IV meaning hydrogen or alkyl of 1-4 carbon atoms, -CH=CH-(CH2 )n -OR**V with n=1-4, and R**V meaning hydrogen, alkyl, or alkanoyl of respectively 1-4 carbon atoms, -C -= C-X wherein X means hydrogen, alkyl of 1-4 carbon atoms, or halogen, -(CH2 )n -CH2 CN with n=0-3 or see diagramm : EP0129499,P14,F4 wherein Y means hydrogen or OR**V , R**4 is hydroxy, alkoxy, or alkanoyloxy of respectively 1-4 carbon atoms or R**3 /R**4 means see diagramm : EP0129499,P14,F2 wherein R**3 is in the alpha-position and R**4 is in the beta-position, or R**3 is in the beta-position and R**4 is in the alpha-position with respect to the steroid skeleton, and R**5 is a hydrogen atom or an alpha- or beta-positioned alkyl group of 1-4 carbon atoms. 1. Claim for the Contracting State AT Process for the preparation of 13 alpha-alkylgonanes of the general formula I see diagramm : EP0129499,P15,F4 wherein R**1 represents -N R**II -R**I , wherein R**I and R**II represent hydrogen or alkyl having from 1 to 4 carbon atoms, or R**I and R**II , with the inclusion of N, represent a saturated 5- or 6-membered ring, wherein the ring can contain, in addition to N, a further hetero atom, such as O, N or S, as well as the corresponding tertiary N-oxides and the acid addition salts, or represents -OR**III , wherein R**III represents methyl, ethyl, propyl, methoxyphenyl, allyl or beta-dimethylaminoethyl, R**2 represents a hydrogen atom, a methyl group or an ethyl group, R**3 represents -(CH2 )n -CH3 , where n=0-4, -(CH2 )n -CH2 -O(S)R**IV , where n=0-4 and R**IV represents hydrogen or alkyl having from 1 to 4 carbon atoms, -CH=CH-(CH2 )n -OR**V , where n=1-4 and R**V represents hydrogen, alkyl or alkanoyl each having from 1 to 4 carbon atoms, -C -= C-X, where X represents hydrogen, alkyl having from 1 to 4 carbon atoms, or halogen, -(CH2 )n -CH2 CN, where n=0-3, or see diagramm : EP0129499,P15,F7 where Y represents hydrogen or OR**V , where R**V has the meanings given above, R**4 represents hydroxy, alkoxy or alkanoyloxy each having from 1 to 4 carbon atoms, or R**3 /R**4 represents see diagramm : EP0129499,P16,F1 wherein R**3 is in the alpha-position and R**4 is in the beta-position, or R**3 is in the beta-position and R**4 is in the alpha-position with respect to the steroid skeleton, and R**5 represents a hydrogen atom or an alkyl group in the alpha- or beta-position having from 1 to 4 carbon atoms, characterised in that a compound of the general formula II see diagramm : EP0129499,P16,F3 wherein R**1 , R**2 and R**5 have the meanings given in formula I and Z is an ethylene or 2,2-dimethylpropylene group, is irradiated with ultraviolet light, and the 13-episteroid, obtained by UV irradiation, of the general formula III see diagramm : EP0129499,P16,F2 wherein R**1 , R**2 , R**5 and Z have the meanings given in formula II, is converted into the compounds of the general formula I in accordance with methods known per se by nucleophilic addition to the 17-ketone, cleavage of the 3-ketal protective group, and splitting off of water from the 4,5-position.

Description

The present invention provides 13a-alkylgonanes of the general formula in which represents a group of the general formula -N R1 and R11, R1 and R11 in which which may be the same or different, each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or together with the nitrogen, atom to which they are attached, represent a saturated 5- or 6-membered ring, which may, if desired, contain a further hetero atom, such as O,N,S as well as the corresponding tertiary N-oxides and the acid addition salts, OR11* in which R111 represents a methyl, ethyl, propyl, methoxyphenyl, allyl or β-dimethylaminoethyl group, R represents a hydrogen atom, a methyl group or an ethyl group, R^ represents a group of the general formula -(CH,) -CH, in which i n j n represents 0 or an integer from 1 to 4, a group of the general formula -(CH2)n-CH2~ORIV or TV -(CH,) -CH,-SR in which a n z n represents 0 or an integer from 1 to 4, and RIV represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, / a group of the general formula -CH=CH-(CH^)n~ORV in which . n represents an integer from 1 to 4, and RV represents a hydrogen atom or an alkyl or alkanoyl radical each having from 1 to 4 carbon atoms, a group of the general formula' -C=C-X in which represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms or a halogen atom, a group of the general formula -(CE2)n"CH2CN in which n represents 0 or an integer from 1 to 3, or II a group of the formula -C-CHjY in which ι Y represents a hydrogen atom of a group v of the general formula OR in which V R has the meaning given above, R represents a hydroxy group or an alkoxy or alkanoyloxy radical each having frcm 1 to 4 carbon atoms or 3 4 R and R , together with the carbon atom to which they are attached.represent a group of the formula and R is in the α-configuration and R is in the {^-configuration or R3 is in the β-configuration and R is in the o-configuration with respect to the steroid structure. and „5 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms and being in the a or β-configuration, These compounds have a strong affinity for the gestagen receptor without themselves having gestagenic activity. They are competitive antagonists of progesterone (antigestagens) and are suitable for inducing abortions since they expel from the receptor the progesterone necessary to maintain pregnancy. The compounds are therefore valuable and interesing with regard to their use for postcoital (p.c.) fertility control.

Corresponding compounds in the oestrane series have already been described as antigestagenically active compounds in Fertility and Sterility 40 (1982), page 253.

The structure-action relationships known hitherto for competitive progesterone antagonists indicate that a 1 , 3-diaxial arrangement of an Ιΐβ-aryl radical and a 13p-alkyl group are absolutely necessary for the development of antigestagenic activity. All the more surprising, therefore, is the strong and selective antagonistic action of the 13a-alkylgonanes of the general formula I which has a completely different molecular topography from the oestrane series.

An alkyl radical represented by R1 and/or R11 has from 1 to 4 carbon atoms, the methyl group and the ethyl group being preferred. Preferably R1 and R11 are the same.

The group - N may also represent a saturated 5- or 6-membered ring which, apart from carbon atoms and the nitrogen atom shown may also contain a further hetero atom, such, for example, as 0, N or S; examples of such groups are the pyrrolidino, piperidino, piperazino, morpholino, oxazolidino and thiazolidino and thiadiazolidino rings. radical may also be in the form of a tertiary N-oxide, such as, for example, dimerhylamino-N-oxide, and pyrrolidino-, piperidino-, piperazino-, morpholino-, oxazolidino-, thiadiazolidino and thiazolidino-N-oxide.

An alkyl radical represented by X and/or R3, an alkyl or alkanoyl radical represented by RIV or RV and an alkoxy or alkanoyloxy radical represented by R each has from 1 to 4 carbon atoms; methyl, ethyl, acetyl and propionyl are preferred.

The following groups should especially be mentioned: for R1: N(CH3)2, N(C2H5)2, OCH3, for R2: H, CH3, for R3: CsCH, CsCCH3, CH2CH2OH, CH=CHCH2OH, CH2CN and coch3, 3 for R : OH and, especially when R represents CQCHj, ococh3, for R5: H, C^.

A 13a-alkylgonane of the general formula I or 15 N-oxide or acid addition salt thereof may be prepared by irradiating a compound of the general formula OH in which R , R and R have the meanings given above and Z represents an ethylene or 2,2-dimethyl20 propylene group, - 7 with ultraviolet light, and converting the resulting 13-epi-steroid of the general formula in which R , R , R and Z have the meanings given above, or an N-oxide or acid addition salt thereof into a compound of the general formula I, for example by a method known per se by nucleophilic addition to the 17-ketone group, cleavage of the 3-ketal protection and the splitting off of water from the 4,5-position.

The present invention provides a process for the preparation of a compound of the general formula I or an N-oxide or salt thereof from a compound of the general formula II or N-oxide or salt thereof by the process described above.

The present invention also provides a 13-epi-steroid of the general formula, (III), in which III R represents - N\ jj with R and R representing hydrogen R or alkyl having 1 to 4 carbon atoms, or R^ and R1* together with N represent a saturated 5- or 6-membered ring, which apart from the N may also contain another hetero atom, such as 0,N or S, as well as the corresponding tertiary N-oxides and the acid addition salts, OR^^.'in which R111 represents methyl, ethyl, propyl, methoxyphenyl, allyl, or ^-dimethylaminoethyl, R represents a hydrogen atom, a methyl or an ethyl group, c R represents a hydrogen atom or an alkyl group in the et- or^-position having 1 to 4 carbon atoms and Z represents an ethylene or 2,2-dimethylpropylene group, -9By irradiation with ultraviolet light, a l3&-alkyl steroid of the general formula II is converted, with a good yield, into the 13-epi-steroid (I3a-alkyl steroid) of the general formula III.

The good yield of the conversion product is surprising. Although it has long been known that 17-οχρ steroids of the normal series can be converted by UV irradiation into 13-epi-steroids (A. Butenandt et al., Ber. Deutsch. Chem. Ges. 74, 1308 (1941)), mixtures of the starting material and the epimerised compound were always obtained, the irradiation times were several hours and the yields were extraordinarily low. The search for an alternative chemical means of obtaining the '.3-epi series is therefore still going on, as more recent work by Barton et al., J.C.S. Perkin I, 2163 (1977) shows. This alternative is, however, thought to be unsuitable for the manufacture of compounds of the general formula I. We have found that, under certain conditions, the irradiation of compounds of the general -10formula II (or their N-oxides or salts) is considerably more successful than in the series of 11-unsubstituted 17-oxo steroids: the average irradiation times are only from 10 to 30 minutes and the yields of 13-epi-steroid may be from 60 to 80 %. If desired, the irradiation products may be reacted further without chromatographic purification. Optimum results are believed to depend on a suitable choice of solvent, the concentration of the substrate to be irradiated, and exact adherence to the period of irradiation. These parameters must be ascertained individually for each substrate.

The irradiation may be carried out with the full light of a Hg-high pressure lamp in a quartz glass apparatus. The temperature of the reaction solution may be, for example, approximately 25°C and the concentration of the solution preferably from 0.1 to 1.0 % by weight. Tetrahydrofuran and dioxan are preferably used as solvents, but it is also possible to use non-polar aprotic solvents, such, for example, as hexane, cyclohexane, benzene, toluene, and mixtures thereof. The period of irradiation is advantageously from 10 to 50 minutes.

A 13-epi-steroid of the general formula III or N-oxide or salt thereof may then be converted into a compound of the general fbrmula I or N-oxide or salt -11thereof for example according to customary processes, for example by nucleophilic addition to the 17-ketone, and secondary reactions.

Nucleophilic addition at the C-17 position generally results in formation of both possible isomers; these are, however, readily separable by chromatography pr fractional crystallisation. In many cases, both isomers are pharmacologically active, even though there may be differences in their strengths of action.

The nucleophilic addition of, for example, acetylene (ethyne) or propyne may be carried out using an agent that yields the radical -CSCH or -CSC-CH.J. Such agents are, for example, alkali metal acetylides, such as, for example, potassium and lithium acetylide or methylacetylide.

The organometallic compound may also be formed in situ and reacted with the 17-ketone of the general formula III. For example, acetylene and an alkali metal, especially potassium, sodium or lithium, may be made to act on the 17-ketone in a suitable solvent in the presence of an alcohol or in the presence of ammonia . -12To introduce a 17-alkyl or 17-cyanoaIkyl group, an alkali metal alkyl compound, for example methyl- or butyl-lithium, or alkali metal alkylnitrile, e.g.

Li(CH2)nCH2CN, may be used for reaction with the 17-ketone. Suitable solvents are, especially, dialkyl ethers, tetrahydrofuran, dioxan, benzene and toluene.

A 17-ethynyl-17-hydroxy compound may be hydrated in alcoholic solution with mercury salt catalysis to form a 17-acety1-17-hydroxy compound (Chem. Ber. 111 (1976) 3086 - 3093).

A 3-hydroxypropyl or 3-hydroxypropenyl radical may be introduced into the 17-position by reacting the corresponding 17-ketone with a metallated derivative of propargyl alcohol, for example with 1-lithium 3-tetrahydropyran-2'-yloxyprop-1-yne, to form the 17-(3-hydroxyrop-1-ynyl)-17-hydroxy compound which is then hydrogenated to form the 17-(3-hydroxyropyl or 3-hycroxypropenyl)-17-hydroxy compound. The hydrogenation must be carried out under conditions that ensure that only the C-C triple bond is affected and that the tetrasubstituted 9(10)-double bond is not saturated. This is possible, for example, if the hydrogenation is carried out at room temperature and normal pressure in a solvent such, for example, εε methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with -13the addition of a noble metal catalyst, such for example, as platinum or palladium. The introduction of the homologous hydroxyalkane and hydroxyalkene radicals of general formula -C=CH-(CH2) OH or -Ch^-CHg-(CHg)n0H is done accordingly with homologules of the propargyl alcahol.

A compound with ^-configured double bond in the hydroxypropenyl group may be formed, for example, by hydrogenating 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, page 134, and H.O. House: Modern Synthetic Reactions 1972, page 19). Suitable deactivated noble metal catalysts are, for example, 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 may be discontinued after the absorption of one equivalent of hydrogen.

A compound with E-configured double bond in the hydroxypropenyl group may be formed, for example, by reducing the acetylenic triple bond in a manner known per se. A whole series of methods for converting alkynes into trans-olefins are described in the literature, for example reduction with sodium in liquid ammonia (J· Am. Chem. Soc. 63 .(1941) 216), with sodium amide in liquid ammonia (J. Chem. Soc. 1955, 3558), with lithium in low-molecular weight amines (J. Am. -14Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem.

Soc. 93 (1971) 3395 and 94 (1971) 6560), with diisobutylaluminium hydride ane methyllithium (J. Am. Chem. Soc. 89 (1967) 5085) and especially with lithium aluminium hydride/alcoholate (J. Am. Chem. Soc. 89 (1967) 4245). A further possibility is the reduction of the triple bond with chromiumiII) sulphate in the presence of water or dimethylformamide in weakly acidic medium (J. Am. Chem. Soc. 86 (1964) 4358) and generally reduction by the action of transition metal compounds with a change in the oxidation stage. 4 If an end product in which CR R represents is desired, then a 17-(3-hydroxypropyl)-1 7-hydroxy compound may, for example, be oxidised in a manner known per se. The oxidation conditions generally depend on 1 the nature of the substituent R in formula I. If R represents, for example, a dialkylamino group, then chromic acid reagents are generally unsuitable for oxidation since they attack primarily the dialkylamino group. In such cases an oxidation agent such, for example, as silver carbonate/Celite (Fetizon reagent; M. Fetizon and M. Golfier, Compt. rend. 267 (1968) 900) or platinum/oxygen (H. Muxfeldt et al., Angewandte Chemie, Int. Ed. i (1962) 157) may be used. If, on the -15other hand, R1 represents an alkoxy radical, it is also possible to use an oxidising agent such, for example, as Jones reagent, chromic acid-pyridine, pyridinium dichromate or pyridinium chlorochromate. Ά 17-cyanomethyl side chain may be introduced, for example, in a manner known per se from the 17-ketone of the general formula III, for example via the 17-spiroepoxide and by cleaving the spiroepoxide with HCN according to Z. Chem. 18 (1978) 259 - 260.

The introduction of the cyanoalkane side chain n^CH2^n^H2^N* w^ere n is 1 to 3 is done by adding, for example Li-(CH^J^-CH^CN to the 17-ketone. The introduction of a 17-hydroxyacetyl side chain may also be carried out according to methods known per se, for example according to the method described in J. Org. Chem. 47 (1982), 2993 - 2995.

If desired, a free hydroxy group represented by r4 in the 17-position may be esterified or etherified, ( . for example, in a manner known per se.

Splitting off of water, with the formation of the 4(5)-double bond, and simultaneous cleavage of the ketal group in the 3-position (and removal of any other protecting groups present that can be split off with acid) may be effected with acid or an acidic ion exchanger.

The acid treatment may be carried out in a manner known per se. For example, the compound of the general -16formula IV which contains a 3-ketal group and a 5o-hydroxy group (and, in some cases, an optionally O-protected 17-hydroxy group and/or hydroxy-substituted 17-aliphatic hydrocarbon radical) is dissolved in a water-miscible solvent, e.g. aqueous methanol, ethanol or acetone, in the presence of a catalytic quantity of a mineral or organic, e.g. sulphonic, acid, e.g. hydrochloric acid, sulphuric acid, phosphoric acid, perchloric acid, p-toluenesulphonic acid or acetic acid, until water has been split off and protecting group(s) have been removed. The reaction, which generally proceeds at a temperature of from 0 to 100°C, may also be carried out with an acidic ion exchanger. The course of the reaction may be followed by analytical methods, for example by thin layer chromatography of samples taken.

The 13a-alkylgonanes of the general formula I and their N-oxides and physiologically tolerable salts may be used in the form of pharmaceutical preparations.

The preparations may be prepared, for example, according to methods of galenical pharmacy known per se by mixing with organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration.

In the case of human beings, the dosage of the active ingredients according to the invention may be, -17for exainple, from 10 to 1000 mg per day.

Thus, the present invention provides a pharmaceutical preparation which comprises a compound of the general formula I or an N-oxide or physiologically tolerable acid addition salt of such compound in which R1 represents a group of the general formula II in admixture or conjunction with a pharmaceutically 10 suitable carrier. Preferably, the pharmaceutical preparation is in dosage unit form containing, for example, 10 to 100 mg of active ingredient per dosage unit.

The following Examples illustrate the invention.

In addition to the compounds described in examples 1 to 7 the following compounds are preferred; ly^- (4-Di methyl aminophenyl )-1 TeR- (3-hydroxypropyl)1 Ip hydroxy-13-d-methyl-4,9-gonadien-3-one-N-oxide 17 17β-ethynyl -1 fci-hydroxy-13o(-methyl -11 methyl -11/f- (4-pi peri di no phenyl)-4,9-gonadien-3-one -1811^-(4-E t h o xy pheny 1)-17o(- hydroxy-17$- (3*hyd roxypropyl) -13o(-methy 1 4,9-gonadien-3-one 11^-(4-Di methylami nophenyl)-17 17/?- (3-Acetoxy-l Z-propenyl )-1 ΐβ- (4-di methyl ami 10 nophenyl )-17o(-hydroxy-13o\-methyl-4,9-gonadien-3-one lly£-( 4-Di me thy lami nophenyl )-17e(-hydro xy-17^(3-methoxy-lZ-propenyl)-13rt-methyl-4,9-gonadien-3-one νΛ Chloroethynyl-1 ΐβ- (4-di methyl ami no phenyl )-17^(hydroxy-130(-methyl -4,9-gonadien-3-one 15 17$- (2-Cyano-) -ethyl -1 ΐβ- (4-dimethyl ami nophenyl )-1 fc(hydroxy-13 - 1 7e<-21-Bi s-acetoxy-1 l?-(4 -dimethyl ami nophenyl )-13Λmethyl-18,19-di nor-4,9-pregnadiene-3,20-di one ΐβ- (4-Di methyl ami nophenyl )-21 -methoxy-13 19-di nor-4,9-pregnadi ene-3,20-di one 3- £l l/?- (4-Di methyl aminophenyl) -17 Examples A. Preparation of compounds of the invention Example 1 a) A solution of 2.0 g of 11B-(4-dimethylaminophenyl)3,3-(2 ,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-9(10)oe strain-17-one (m.p. 143 -145**C) in 300 ml of absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25eC with a Hg-high pressure lamp (Philips HPK 125, immersion lamp, quartz glass reactor). The solvent is then distilled off in vacuo and the residue is chromatographed over aluminium oxide (Merck, neutral, stage III) with hexane/ ethyl acetate. 1.46 g of 11β-(4-dimethylaminophenyl)-3,3(2,2-cimethylpropane-1,3-dioxy)-5e-hydroxy-13a-methyl-9(10)gonen-17-one are obtained in the form of a colourless oil. b) At 5"C, absolute THF (248 ml) is saturated with acetylene by introducing the latter over a period of 30 minutes. 51 ml of a 15 % solution of n-butyllithium in hexane are then slowly added dropwise and the whole is stirred for a further 15 minutes while cooling with icewater. A solution of 2.7 g of 11 B-(4-dimethylaminophenyl)3,3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-13a-methyl9-gonen-17-one in 40 ml of absolute THF is then added dropwise over a period of 15 minutes to the suspension of the lithium acetylide and stirring is carried out for a further 2 hours at room temperature. For working up, the whole is poured into ice-water and extracted with ethyl acetate. The resulting crude product (2.85 g) is used in the following stage without being further purified. c) 2.8 g of the crude product obtained under b) are suspended in 29 ml of 70 % aqueous acetic acid and stirred for 3 hours at 50°C. After cooling, the suspension is diluted with approximately 100 ml of water and adjusted to a pH of 10.5 by adding concentrated aqueous solution. After extracting with ethyl acetate, an oily mixture of isomers is obtained that is separated by column chromatography over silica gel with hexane/ethyl acetate. There are obtained in the order of elution: 1. 530 mg of 11B-(4-dimethylaminophenyl)-17c-ethynyl17B-hydroxy-13a-methyl-4,9-gonadien-3-one having a melting point of 120 - 123®C (ethyl acetate/diisopropyl ether) and 2. 1.33 g of 1lB-(4-dimethylaminophenyl)-17s-ethynyl17e-hydroxy-13a-methyl-4,9-gonadien-3-one having a melting point of 201 - 2O4°C (ethyl acetate).

Analogously to b) and c), there are obtained using methylacetylene instead of acetylene: 1. IIB—(4-dimethylaminophenyl)-1 7B-hydroxv-l3a-methyl17a-propynyl-4,9-gonadien-3-one in the form of an oil. 2. 11 β-(4-dimethylaminophenyl)-17e-hydroxy-13a-methyl17B-propynyl-4,9-gonadien-3-one in the form of an oil. d) After the addition of 0.87 ml of concentrated sulphuric acid, a suspension of 1.02 g of mercury oxide (HgO, red) in 20 ml of water is stirred for 30 minutes at 60°C. 9 ml of this mercury salt solution are added to a solution of 3.25 g of 11B-(4-dimethylaminophenyl)-17Bethynvl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one in 32 ml of glacial acetic acid. The whole is then stirred for 2 hours at 60 ®C. For working up, the cooled reaction solution is poured into ice-water, adjusted to a pH of .5 by adding concentrated aqueous NH^ solution and extracted with ethyl acetate. The resulting oily crude product is crystallised from methylene chloride/diisopropyl ether. 2.37 g of 11B-(4-dimethylaminophenyl)-17a-hydroxy13o-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione having a melting point of 224 - 225°C are obtained. e) A suspension of 2.3 g of 11B-(4-dimethylaminophenyl) 17o-hvdroxy-13u-methyl-18,19-dinor-4,9-pregnadiene-3,20dione in 58 ml of toluene is stirred for 20 hours at 25"C after the addition of 11.6 ml of acetic anhydride and 5.8 g of 4-dimethylaminopyridine. The suspension is then poured into saturated NaHCO^ solution and extracted with ethyl acetate. The crude product is chromatographed over 200 g of silica gel with hexane/ethyl acetate. After crystallising the main fraction from hexane/ethyl acetate, 1.71 g of 17eC are obtained.

Example 2 a) A solution of 1.8 g of 11B-(4-diethylaminophenyl)3,3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-9-oestren17-one (m.p. 223 - 226*C) in 300 ml of THF are irradiated for 26 minutes under the conditions of Example 1 a).

After chromatography of the crude product, 1.58 g of 116(4-diethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)5a-hydroxy-13a-methyl-9-gonen-17-one are obtained in the form of a colourless oil. b, · At 0’C, the organo-lithium compound is prepared from 3.94 g of 3-tetrahydropyran-2'-yloxy-1-propyne in 85 ml of absolute THF and 23.1 ml of a 15 % solution of n-butyllithium in hexane. A solution of 3.53 g of the product described under 2a) in 71 ml of absolute THF is then added dropwise and the whole is stirred for 4 hours at room temperature. The reaction solution is afterwards poured into ice-water and extracted with ethyl acetate.

The crude product (3.85 g, of 11 B-(4-diethylaminophenyl) 3.3- (2,2-dimethylpropane-1,3-dioxy)-13o-methyl-17a-(3(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonene-5a,17B-diol and 116-(4-diethylaminophenyl)-3,3-(2,2-dimethylpro?ane1.3- dioxy)-13a-methyl-l78-[3-( tetrahydropyran-2-yloxy)-1propyr.yl ]-9-gonene-5a, 17a-diol is used for hydrogenation without being further purified. c) After the addition of 400 mg of 10 % palladium/ carbon, 3.85 g of the crude product obtained under 2 b) are hydrogenated in 95 ml of ethanol at room temperature and normal pressure. After 191 ml of hydrogen have been taken up, the catalyst is filtered off and concentration is carried out. d) The crude hydrogenation product {3.85 g) obtained under 2 c) is stirred in 30 ml of 70 % acetic acid for 2 hours at 60eC. After cooling, working-up is carried out as under 1 c) and the resulting mixture of isomers is chromatographed. There are obtained in the order of elution: 1. 410 mg of 11fl-(4-diethylaminophenyl)-17e-(3-hydroxypropyl) -17B-hydroxy-13e-methyl-4,9-gonadien-3-one in the form of a yellowish oil.

UV Imethanol) : ε 266 s **3080, £ 30 2. 1.39 g of 11B-(4-diethylaminophenyl)-17B-(3-hydroxypropyl) -17e-hydroxy-13a-methyl-4,9-gonadien-3-one in the form of a solid foam.

Analogously to b) to d), there are obtained when using IIB-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane1,3-dioxy)-5e-hydroxy-13a-methyl-9-gonen-17-one as starting material: 1. ) 11B-(4-dimethylaminophenyl)-17B-hydroxy-17o-(3-hydroxypropyl) -1 3e-methyl-4 , 9-gonadien-3-one in the form of an oil. 2. ) 115-(4-dimethylaminophenyl)-17 β-hydroxy-178-(3-hydroxy24 propyl)-13a-methyl-4,9-gonadien-3-one in the form of an oil.

Example 3 a) A solution of 1.75 g of 3,3-(2,2-dimethylpropane1.3- dioxy)-5 1.45 g of 3,3-(2,2-dimethylpropane-l , 3-dioxy)-5 b) A solution of 8.2 g of 3,3-(2,2-dimethylpropane1.3- dioxy)-5e-hydroxy-118-(4-methoxyphenyl)-13a-methyl-9gonen-17-one in 130 ml THF is added dropwise to a suspension of lithium acetylide prepared from a saturated solution of acetylene in 450 ml of THF and 130 ml of a 15 % solution of n-butyllithium in hexane. Stirring is then carried out for 3 hours at room temperature and the reaction solution is afterwards poured into approximately 3 1 of ice-water and extracted with ethyl acetate. The crude product is chromatographed over aluminium oxide with hexane/ethyl acetate. There are obtained in the order of elution: 1. 1.8 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-17aethynyl-118-(4-methoxyphenyl)-13a-methyl-9-gonen-5a, 17B-diol in the form of a colourless oil. 2. 5.1 g of 3,3-(2,2-dimethylpropane-l,3-dioxy)-17β25 ethynyl-11B-(4-methoxyphenyl)-13a-methyl-9-gonene-5a,17ediol in the form of a solid foam. c) A solution of 3.28 g of 3,3-(2,2-dimethylpropane1,S-dioxy)-! 7B-ethynyl-11β-(4-methoxyphenyl)-13c-methyl-95 gonene-5a,17a-diol in 33 ml of 70 % aqueous acetic acid is stirred for 30 minutes at 60eC. After cooling, the solution is poured into ice-water and extracted with methylene chloride and the MeCl2 extracts are washed with saturated NaHCO^ solution and concentrated. Crystallisa10 tion of the crude product from ethyl acetate yields 2.0 g of 17B-ethynyl-17a-hydroxy-1IB-(4-methoxyphenyl)-13amethyl-4,9-gonadien-3-one having a melting point of 186 187eC.

Example 4 minutes' irradiation of 1.84 g of 11B-(4-dimethyl· aminophenyl)-3,3- (2,2-dimethylpropane-1,3-dioxy)-5e-hydroxy18-methyl-9-oestren-17-one in 280 ml of THF under the conditions of Example 1 a) results in 1.36 g of 116-(4dimethylaminophenyl)-3,3- (2,2-dimethylpropane-1,3-dioxy)20 13a-ethyl-5a-hydroxy-9-gonen-17-one in the form of a foam._ b) 6.1 g of 11B-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-13a-ethyl-5a-hydroxy-9-eonen-17one are reacted under the conditions of Example 1 b) with lithium acetylide and the resulting crude product is cleaved with acetic acid under the conditions of Example c). After chromatography and crystallisation from ethyl acetate/diisopropyl ether, 3.2 g of 11B-(4-dimethylaminophenyl) -1 7B-ethynyl-^1 3e-ethyl-17a-hycroxy-4,9-gonadien-3-one having a melting point of 197 198eC are obtained. Ια]25 + 450.4* (CHC13, c = 0.505). c) By hydration, catalysed with mercury salt, analogous to Example 1 d) and subsequent acetylation analogous to Example 1 e, , there are obtained from 1.3 g of 116-(410 dimethylaminophenyl)-170-ethynyl-13β-ethy1-17β-hydroxy4,9-gcnadien-3-one, after chromatographic purification, 720 me of l7e-acetoxy-11B-(4-dimethylaminophenyl)-13eethyl-18,19-dinor-4,9-pregnadiene-3,20-dione in the form of a solid foam. , l25lotJD * 290.8° (CHC13, c = 0.515).

Example 5 a) By reacting 7.3 g of 11B-(4-dimethylaminophenyl)3,3-(2,2-dimethylpropane-1,3-dioxy)-5e-hydroxy-13e-methyl9-gonen-17-one with 10.7 g of 3-tetrahydropyran-2'-yloxy20 1-propyne under the conditions of Example 2 b) there are obtained, after chromatography of the crude product over aluminium oxide with hexane/ethyl acetate, 4.83 g of lie— (4-dimethylaminophenyl)-3,3-(2,2-dimethyl?ropane-1,3-dioxy) 13e-methyl-17B-(3-(tetrahydropyran-2-yloxy)-1-propynyl]-925 gonene-5e,17e-diol in the form of a yellowish foam. b) After the addition of 210 mg of palladium on barium sulphate (10 I), a solution of 2.2 g of the adduct obtained under a) in 67 ml of ethanol and 0.56 ml of triethylamine is hydrogenated at room temperature and normal pressure. After 83.5 ml of hydrogen have been taken up, the catalyst is filtered off and concentrated. The resulting crude hydrogenation product is cleaved with 14 ml of 70 % acetic acid under the conditions cf Example 1 c). After crystallisation from ethyl acetate/diisopropyl ether, 1.1 g of 11B-(4-dimethylaminophenyl)-17ahydroxy-17B-(3-hydroxy-1(Z)-propenyl)-13a-methy1-4,9gonadien-3-one having a melting point of 133 - 135"C are obtained.

Example 6 Manufacture of 11B-(4-dimethylaminophenyl)-17Bethynyl-16fl-ethyl-17a-hydroxy-13a-methyl-4,9gonadien-3-one a) A suspension of 29.3 g of 3,3-(2,2-dimethylpropane1,3-dioxy)-5(10),9(11)-oestradien-17-one and 28.6 g of bis-dimethylamino-tert.-butoxymethane is stirred under argon for 60 minutes at 160°C. After cooling, the crude product is triturated with approximately 50 ml of ethyl acetate, filtered,and the filtration residue is recrystallised from ethyl acetate. In this manner, 27.6 g of 16dimethylaminomethylene-3,3-(2,2-dimethylpropane-1,3-dioxy)5 (10),9(11)-oestradien-17-one having a melting point of 208 - 2 Π °C are obtained. b) 85 ml of a 5 % solution of methyllithium in diethyl ether are added dropwise while cooling with ice-water to a solution of 14.4 g of 16-dimethylaminomethylene-3,3(2,2-dimethylpropane-1,3-dioxy)-5(10),9(11)-oestradien17-one in 220 ml of toluene. When the addition is complete, the whole is stirred for 15 minutes at +5 to +10°C, excess reagent is decomposed by the careful addition of approximately 20 ml of water and the reaction solution is then poured into approximately 3 1 of ice-water and extracted with methylene chloride. The crude product is chromatographed over neutral aluminium oxide with hexane/ethyl acetate. After crystallisation of the main fraction from ethyl acetate, 13.0 g of 3,3-(2,2-dimethylpropane-1,3dioxy)-16(E)-ethylidene-5 (10),9 (11)-oestradien-17-one having a melting point of 121 - 123eC are obtained. c) 4.3 ml of 30 % hydrogen peroxide are added dropwise while cooling with ice-water to a solution of 9.4 g of 3,3-(2,2-dimethylpropane-1,3-dioxy)-16(E)-ethylidene-5(10), 9(11)-oestradien-17-one in 43 ml of methylene chloride, 0.34 ml of hexachloroacetone and 0.01 ml of pyridine and then the whole is stirred for 16 hours at 25eC. For working up, the reaction solution is diluted with approximately 100 ml of methylene chloride and washed in succession with % Na2S2O3 solution and water; the methylene chloride phase is dried over Na2SO^ and concentrated. Tne resulting 5,10-epoxide mixture is chromatographed over AljO^, neutral, stage III, with hexane/ethyl acetate. 4.7 g of 3,3-( 2,2-dimethylpropane-1,3-dioxy )-5 d) After the addition of 930 mg of palladiun\/carbon (10 %), a solution of 8.2 g of 3,3-(2,2-dimethylpropane1O 1,3-dioxy)-5a, l0a-epoxy-l6(E)-ethyliden—9( 11 )-oestren17-one in 400 ml of ethanol is hydrogenated at room tenperature and normal pressure. After 510 ml of hydrogen have been taken up, the catalyst is filtered off and concentration is carried out in vacuo. 7.7 g of 3,315 (2,2-dimethylpropane-1,3-dioxy)-5a, lOa-epoxy-l6g-ethyl9(11)-oestren-17-one are obtained in the form of a colourless oil. e) An organo-magnesium compound is prepared from 1.4 g of magnesium, 0.05 ml of methyl iodide and 17.9 g of 4-bromo-N, N-dime thyl anil ine in 150 ml of absolute THF.

After the addition of 344 g of CuCl, the whole is stirred for 15 minutes at 0°C and a solution of 7.7 g cf the product obtained under d) in 70 ml of absolute TKF is then added dropwise. Afterwards, the whole is stirred for 3.5 hours at room temperature. For working up, the reaction solution is poured into a mixture of ice-water and NH^ solution and extracted with ethyl acetate. After chromatography of the crude product over aluminium oxide with hexane/ethyl acetate and crystallisation of the main fraction from diisopropyl ether/ethyl acetate, 6.5 g of 11B-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3dioxy)-16B-ethyl-5e-hydroxy-9(10)-oestren-17-one having a melting point of 180 - 181eC are obtained. f) A solution of 4.0 g of the product obtained under e) in 600 ml of dioxan is irradiated under the conditions of Example 1 a). After crystallisation of the crude irradiation product from diisopropyl ether, 1.74 g of 11B(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy) 16B-ethyl-5eC are obtained. g) 1.4 g of the product obtained under f) are reacted with lithium acetylide under the conditions of Example 1 b) After crystallisation of the crude product from ethyl acetate/diisopropyl ether, 960 mg of 11B-(4-dimethylamino20 phenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-178-ethynyl16B-ethyl-13e-methyl-9(10)-gonene-5a,17a-diol having a melting point of 132 - 134°C are obtained. h) 760 mg of the product obtained under g) are reacted with 8 ml of 70 % acetic acid under the conditions of Example 1 c). Crystallisation of the crude product from hexane/diethyl ether yields 460 mg of 118-(4-dimethylaminophenyl)-17 B-ethynyl-16 B-ethyl-17 α-hydroxy-13 a-methyl4,9-gonadien-3-one having a melting point of 195 - 197®C.

Example 7 Manufacture of 17β-cyanomethyl-11β-(4-dimethylaminophenyl)17a-hydroxy-1 3a-methyl-4,9-gonadien-3-one' a) 2.63 g of potassium tert.-butoxide arexadded in portions, while cooling with ice-water, to a suspension of .0 g of 11B-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-5e-hydroxy-13a-methyl-9(10)-gonen-17one and 4.74 g of trimethylsulphonium iodide in 60 ml of dimethylformamide. The whole is stirred for 4 hours at 25°C, then poured into ice-water and extracted with ethyl acetate. After removing the solvent, the crude product, which is at first oily, is crystallised from ethyl acetate/ diisopropyl ether and, in this manner, 4.2 g of 11B-(4" dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)5a-hydroxy-13a-methyl-9(10)-gonene-17a-spiro-1*,2 ’ -oxirane having a melting point of 234 - 236°C are obtained. b) 2.0 g of the spiro-oxirane obtained under a) are dissolved in 84 ml of ethanol and, after the addition of 4.6 g of potassium cyanide, the whole is heated under reflux for 4 hours. The cooled solution is poured into saturated NaHCO^ solution and extracted with ethyl acetate. The crude product obtained after concentration is taken up in 26 ml of 70 % acetic acid without being further purified and stirred for 60 minutes at 60’C.

After cooling, the whole is poured into ice-water, adjusted to a pH of 10.5 by adding NH^ solution and extracted with methylene chloride. After chromatography of the crude product over silica gel with hexane/acetone and crystallisation of the main fraction from ethanol, 1.4 g of 17B-cyanomethyl-11B-(4-dimethylaminophenyl)-17a hydroxy-13a-methyl-4,9-gonadien-3-one having a melting point of 135 - 137eC are obtained.

/ B. Tests on antigestaqenic action In order to identify the antigestagenic action of the compounds according to the invention, the abortive action was investigated at an early stage post nidationem (Experiment I) and at an advanced stage post nidationem (Experiment II).

The experiments were carried out on female rats weighing approximately 200 g. After mating had taken place, the commencement of pregnancy was ascertained by the detection of spermatozoa in vaginal smears. The day on which sperm was detected is designated day 1 of gravidity (* d 1 p.c.).

The following were investigated for antigestagenic action: t A: 1 1ip-(4-dimethylaminophenyl)-17p-hydroxy-17o-propynyl-4,9-oestradien-3-one (reference substance).

B: 11β—(4-dimethylaminophenyl )-17β-hydroxy-17a-( 3hydroxypropyl)-13a-methyl-4,9-gonadien-3-one (compound of the invention).

C: Π β-{ 4-dimethylaminophenyl )-17a-hydroxy-l7f)-( 3hydroxypropyl)-13a-methyl-4,9-gonadien-3-one (compound of the invention).

The test substances were dissolved in a mixture of benzyl benzoate and castor oil (ratio 1:4). The volume of vehicle per individual dose was 0.2 ml. The treatment was carried out subcutaneously (s.c.). i The treatment of the animals with the particular substance to be tested or with the solvent as control was carried out after the nidation of the blastocysts from day 5 p.c. to day 7 p.c. (Experiment I) and day 13 I p.c. to day 15 p.c. (Experiment II). On day 9 p.c. and day 17 p.c., respectively, the animals were killed and the uteri were examined for implants and absorption I I sites. Photographs were taken of all the uteri. The lack of implants was assessed as abortion.

The results are given in Tables 1 and 2 below.

Compounds B and C of the general formula I of the invention had a completely abortive action in rats at an early stage of pregnancy in doses 1.0 mg/day (abortion rate: 4/4). In contrast, the reference substance A exhibited maximum abortion-inducing (antigestagenic) action only at doses of 3.0 mg/day (Table 1).

At an advanced stage of pregnancy (day 13 to 15 ι p.c.), the percentage of complete abortions with s.c. administration for 3 days of 3.0 mg/day was 35.4 % for B, 52.3 % for C and 3.5 % for the comparison substance A (Table 2).

Table 1 (Experiment I) Abortive action at an early stage of pregnancy in rats Treatment from d 5 p.c. to d 7 p.c., autopsy d 9 p.c. compound dose mg/animal/day s.c. 1 rate of abortion n abortion/n total (%) 30.0 4/4 (100) 10.0 - - 3.0 4/4 (100) A 1.0 2/4 ( 50) 0.3 0/4 ( 0) 0.1 0/4 ( 0) .0 3.0 4/4 4/4 (100) (100) B 1 .0 4/4 (100) 0.3 0/4 ( 0) 0.1 0/4 ( 0) C 10.0 3.0 1.0 0.3 0.1 4/4 4/4 4/4 0/4 0/4 (100) (100) (100) ( ( o o solvent as control: - 0/4 ( 0) 0.2 ml benzyl benzoate ♦ castor oil (1 : 4) n = 4 rats/group Table 2 (Experiment II) Abortive action at an advanced stage of pregnancy in rats Treatment with 3.0 mg/d s.c. antigestagen (AG) from d 13 p.c. to d 15 p.c., autopsy d 17 p.c. % complete abortions = empty nidation sites

Claims

1. Patent Claims

1. A compound of the general formula in which „1 (I) represents a group of the general formula -IN in which II R 1 and R 11 * * * 6 , which may be the same or different, each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R 1 and R 11 , together with the nitrogen atom to which they are attached, represent a saturated 5- or 6-membered ring, which may, if desired, contain a further hetero atom, such as O,N,S as well as the corresponding tertiary N-oxides and the acid addition salts, OR^I in which represents a methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl or β-dimethylaminoethyl group, R represents a hydrogen atom, a methyl group or an ethyl group, R 3 represents a group of the general formula -(CH.,) -CH-, in which n represents 0 or an integer from 1 to 4 IV a group of the general formula ” CH 2^ n “ CH 2 _0R or -(CH_) -CH O -SR IV in which

2. Η z n represents 0 or an integer from 1 to 4, and IV R represents a hydrogen atom or an alkyl radical each having from 1 to 4 carbon atoms, a group of the general formula -CH=CH-(CH2) n ~OR V in which n represents an integer from 1 to 4, and R V represents a hydrogen atom or an alkyl or alkanoyl radical each having from 1 to 4 carbon atoms, a group of the general formula -C=C-X in which X represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms or a halogen atom, a group of the general formula -(CHj) n ~ CH 2 CN in which n represents Ο or an integer from 1 to 3, or II a group of the formula -C-CH 2 Y in which Y represents a hydrogen atom of a group of the general formula 0R V in which 5 R V has the meaning given above, R represents a hydroxy group or an alkoxy or alkanoyloxy radical each having from 1 to 4 carbon atoms or 3 4 R and R , together with the carbon atom to which they 10 are attached, represent a group of the formula O and R 3 is in the α-configuration and R is in the β-configuration or R 3 is in the β-configuration and R is m the α-configuration 15 with respect to the steroid structure, and R 5 represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms and being in the aor β-configuration. -402. 11β-(4-Dimethylaminophenyl )-17a-ethynyl-17βhydroxy-13a-methy1-4,9-gonadien-3-one.

3. 11 β- (

4. -Dimethylaminophenyl)-1 7B-ethynyl-17ahydroxy-13a-methyl-4,9-gonadien-3-one. 5. 4. 11β-(4-Dimethylaminophenyl)-17B-hydroxy-13amethyl-17a-propynyl-4, 9-gonadien-3-one.

5. 11B-(4-Dimethylaminophenyl)-17a-hydroxy-13amethyl-173-propynyl-4,9-gonadien-3-one.

6. 11β-(Dimethylaminophenyl )-17a-hydroxy-13a10 methyl-18,19-dinor-4,9-pregnadiene-3,20-dione.

7. 17a-Acetoxy-11β-(4-dimethylaminophenyl)-13amethyl-18,19-dinor-4,9-pregnadiene-3,20-dione.

8. 11 β- ( 4-Diethylaminophenyl)-17a-( 3-hydroxypropyl )-1 7B-hydroxy-13a-methyl-4,

9. -gonadien-3-one. 15 g. 11 β-( 4-Diethylaminophenyl )-17β-( 3-hydroxypropyl )-17a-hydroxy-13a-methyl-4,9-gonadien-3-one.

10. 11β-( 4-Dimethylaminophenyl)-17B-hydroxy-17a-(3 hydroxypropyl)-1 3a-methyl-4,9-gonadien-3-one.

11. 1 ΐβ-( 4-Dimethylaminophenyl ,-17a-hydroxy-17β20 (3-hydroxypropyl)-13a-methyl-4,9-gonadien-3-one.

12. 1 7B-Ethynyl-17a-hydroxy-11β-( 4-methoxyphenyl ,-13a-methyl-4,9-gonadien-3-one.

13. 11B-(4-Dimethylaminophenyl,-17B-ethynyl-13aethyl-17a-hydroxy-4,9-gonadien-3-one. -4110

14. 17o-Acetoxy-11β-(4-dimethylaminophenyl )-13aethyl-18,19-dinor-4,9-pregnadiene-3,20-dione.

15. 11p-(4-Dimethylaminophenyl-i7a-hydroxy-l7p(3-hydroxy-1(Z)-propenyl)-13a-methyl“4,9-gonadien-3-one.

16. · 11β-(4-Dimethylaminophenyl)-17p-ethynyl-16pethyl-17a-hydroxy-13o-methyl-4,9-gonadien-3-one.

17. 178-Cyanomethy1-118-(4-dimethylaminophenyl)17a-hydroxy-13o-methyl-4,9-gonadien-3-one.

18. An acid addition salt of a compound of the general formula I in which R^ represents a group of J the general formula -N as claimed in any one JI of claims 1 to 11 and 13 tol6

19. A physiologically tolerable acid addition salt of a compound of the general formula I in which R 1 represents a group of the formula -N as J1 claimed in any one of claims 1 to 11 and 13 to 16

20. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 17, in admixture or conjunction with a pharmaceutically suitable carrier.

21. A pharmaceutical preparation as claimed in claim 20, which is in dosage unit form. -4222. A process for the preparation of 13rt-alkyl gonanes of the formula as defined in claim 1 by irradiating a compound of the general formula 12 5 in which F , R ano R have the meanings given above and Z represents an ethylene or 2,2-dimethy1propylene group, with ultraviolet light, and converting the resulting 13-epi-steroid of the general formula 12 5 in which R , R , R and Z have the meanings given above, or an N-oxide or acid addition salt thereof into a compound of the general formula I, for example by a method known per se by nucleophilic addition to the 17-ketone group, cleavage of the 3-ketal protection and the splitting off of water from the 4,5-position. -4323. A 13-Episteroid of the general formula III in which in 1 I R represents - with R R or alkyl having 1 to 4 carbon atoms, N represent a saturated 5- o and R representing hydrogen or rI and together with r 6-membered ring, which apart from the N may also contain another hetero atom, such as 0,N or S, as well as the corresponding tertiary N-oxides and the acid addition salts, OR^^, in which represents methyl, ethyl, propyl, methoxyphenyl, allyl, or 10 ^-dimethyl aminoethyl , R represents a hydrogen atom, a methyl or an ethyl grouo, r5 represents a hydrogen atom or an alkyl group in the Z represents an ethylene or 2,2-dimethylpropylene group, -4424. A compound substantially as hereinbefore described with reference to the Examples.

22. 25. A process substantially as hereinbefore described with reference to the Examples.

23. 26. A preparation substantially as hereinbefore described with reference to the Examples.