NZ208441A - Steroids and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £08441 2084-41 POSTIDATED UNDER SECT 12(1) to J5. Pill*.. I Priority Date(s): ^ »* * • ♦ ♦ • • w-u 3h t«i.» * jfi£i Complete Specification Filed: V<3 ci3S joo^avw i. i oq ; CQ^'ajoD. cp^Mccccqtio: 3.jco.-.Coa4*|< » ooit< aicQi <£Of.?A I®- 315 t-8 JAN 1988...

Publication Data. ,,,v«X"" .'.ao.5.

P.O. Journal, No: NEW ZEALAND Patents Act 1953 7 'JtiN 1984 i/ApEXVcO COMPLETE SPECIFICATION " 13a-ALKYLGONANES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM." We, SCHERING AKTIENGESELLSCHAFT, a body corporate organized according to the laws of Germany, of 170-178 Mullerstrasse, D-IOOO Berlin 65, Germany and Waldstrasse 14, 4619 Bergkamen, Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be - performed to be particularly described in and by the following statement (followed by 1A) 20844? - 1A- 1 3ot-alkylqonanes, their preparation and pharmaceutical preparations containing them The present invention provides 13cx-alkylgonanes of the general formula (I) in which © represents a group of the general formula -N X1 in which ,11 R1 and R11, R1 and R11, 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 208441 " .2 - , desired, contain a further hetero atom, or OR111 in which R111 represents a methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl or p-dimethylaminoethyl group, represents a hydrogen atom, a methyl group or an ethyl group, represents a group of the general formula -(CH_) —CH, in which 2. n 3 n represents 0 or an integer from 1 to 4, a group of the general formula -(Cf^ )n-CH2~0RIV or -(CH-) -CH0-SRIV in which 2. n z n represents 0 or an integer from 1 to 5, and IV R represents a hydrogen atom or an alkyl or alkanoyl radical each having from 1 to 4 carbon atoms, a group of the general formula -CH=CH-(CHj)n~0R^ 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 X represents a hydrogen atom or an alkyl qS, • V & JUN1984 / u 6T 208441 radical having from 1 to 4 carbon atoms or a halogen atom, a group of the general formula -(CE^)n~CH2CN in which n represents 0 or an integer from 1 to 3, or O II a group of the formula -C-CHjY in which Y represents a hydrogen atom of a group of the general formula OR^ in which R^ has the meaning given above, 4 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 are attached.represent a group of the formula 1 5 3 and R is in the oc-conf iguration and 4 R is m the p>-configuration or 3 R is in the p-configuration and 4 .

R is in the o-configuration 20 with respect to the steroid structure, and ^5 represents a hydrogen atom or an alkyl radical 20844* having from 1 to 4 carbon atoms and being in the ot-or ^-configuration, and the corresponding tertiary N-oxides and acid addition salts, preferably physiologically tolerable 5 acid addition salts, of such compounds in which R1 represents a group of the general _/"pI formula -N \r13 These compounds have a strong affinity for the gestagen receptor without themselves having gestagenic 10 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 interesting with 15 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), 20 page 253.

The structure-action relationships known hitherto fo^f^rrp^titive progesterone antagonists indicate that tls arrangement of an llp-aryl radical and a roup are absolutely necessary for the .ry- 208441 development of antigestagenic activity. All the more surprising, therefore, is the strong and selective antagonistic action of the 13oc-alkylgonanes of the general formula I which has a completely different 5 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 ^R11 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, 15 piperidino, piperazino, morpholino, oxazolidino and thiazolidino and thiadiazolidino rings. /rI The -N radical may also be in the form \IX of a tertiary N-oxide, such as, for example, dimethylamino-N-oxide, and pyrrolidino-, piperidino-, 20 piperazino-, morpholino-, oxazolidino-, thiadiazolidino and thiazolidino-N-oxide.

An alkyl radical represented by X and/or R^, an fftWr 0, ■J? • „.» " 15 JUNS984 208441 alkyl or alkanoyl radical represented by RIV or RV and an alkoxy or alkanoyloxy radical represented by R4 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: C=CH, C=CCH3, CH2CH2OH, CH=CHCH2OH, CH2CN and coch3, 4 3 for R : OH and, especially when R represents C0CH3, ococh3, for R5: H, C2H5* 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 (II), 12 5 • in which R , R and R have the meanings given above and Z represents an ethylene or 2,2-dimethyl- propylene group, or other ketone-protecting group, or an N-oxide or acid addition salt thereof, o,: 15JUNJ984 r.O . 20844T © Q with ultraviolet light, and converting the resulting 13-epi-steroid of the general formula .1 v /IX o 0 5 R (III), 12 5 m which R , R , R and Z have the meanings given 5 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 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 III or N-oxide or salt thereof by the steps of nucleophilic addition to the 17-ketone group, IV I 2034 41 Q cleavage of the 3-ketal protecting group and the splitting off of water from the 4,5-position.

If desired, a compound of the general formula I or salt thereof may be converted to a different compound of the general formula I or salt thereof or N-oxide thereof.

Nucleophilic addition to the 17-ketone group may be performed before or after the splitting off of water; advantageously the nucleophilic addition is performed and then de-protection of the 3-ketal group and the splitting off of water are performed simultaneously.

Accordingly, the present invention further provides a process for the preparation of a compound of the general formula I, in which R1, R2, R3, R4, R^ and Z have the meanings given above, or an N-oxide or salt thereof from a compound of the general formula IV or N-oxide or salt thereof, which comprises cleavage of 20 the 3-ketone protecting group and the splitting off: o^ .

JUN1984 " * ', v m 20844 water from the 4,5-position, or from a compound of the general formula ,R or N-oxide or salt thereof, which comprises nucleophilic addition to the 17-ketone group and cleavage of the 3-ketal protecting group.

If desired, a compound of the general formula IV or salt thereof may be converted to a different compound of the general formula IV or salt thereof or N-oxide thereof.

The present invention further provides a compound of the general formula IV or an N-oxide or acid 1 addition salt of such compound in which R represents a group of the general formula 208441 - 9a - The present invention also provides a compound of the general formula V or an N-oxide or acid addition 1 salt of such a compound in which R represents a group of the general formula -N .II The present invention also provides a compound of the general formula III or an N-oxide or acid addition salt of such compound in which R represents a group of the general formula —N >11 and a process for its preparation by irradiation of a compound of the general formula II or N-oxide or 1 acid addition salt of such compound m which R JUNI984 I V */ 20844 represents a group of the general formula with UV light.

By irradiation with ultraviolet light, a 13p-alkyl 5 steroid of the general formula II is converted, with a good yield, into the 13-epi-steroid (13a-alkyl steroid) of the general formula III.

The good yield of the conversion product is surprising. Although it has long been known that 17-oxo 10 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 materia] and the epimerised compound were always obtained, the irradiation times were several 15 hours and the yields were extraordinarily low. The search for an alternative chemical means of obtaining the 13-epi series is therefore still going on, as more recent work by Barton et a_l., J.C.S. Perkin I, 2163 (1977) shows. This alternative is, however, thought to 20 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 208441 t formula 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 formula I or N-oxide or salt ■-4-, 208441 12 thereof for example according to customary processes as described above, for example by nucleophilic addition to the 17-ketone, de-protection of the 3-ketone group and splitting off of water at the 4,5-position, and 5 including, if desired, conversion of a radical represented by R3 into another such radical and/or of a 4 radical represented by R into another such radical, at any suitable stage in the process.

Thus, for example, the process may include one or 10 more of the following steps as appropriate: 3 (i) introduction of a group represented by R of the general formula ~(CH_) CH- in which n 2 n 3 represents 0 or an integer from 1 to 4 or ~^H2^n^^2^^ where n represents 0 or an integer from 1 to 3 by an alkali metal-alky1 or alkali metal-alkylnitrile compound, (ii) introduction of a group represented by R3 of the general formula -C=CX in which X represents a hydrogen or halogen atom or an alkyl radical having from 1 to 4 carbon atoms, by means of a compound of the general formula MC=CX in which X has the meaning given above and M represents an alkali metal or by means of an alkali metal and a compound of the general formula HC=CX in which X has the meaning given above, (iii) hydration of a triple bond in a group of the 208441 - 1.2a - 3 general formula -C=CH represented by R to form a group of the group of the general formula coch3, ■3 introduction of a group represented by R of the general formula -C=C(CH_) OR in which R 2 n represents a hydroxy-protecting group and n represents an integer from 1 to 4, by means of a compound of the general formula MC=C(CH2)n0R in which R and n have the meanings given above and M represents an alkali metal, and hydrogenating the resulting compound to form the corresponding hydroxyalkenyl or hydroxyalkyl radical of the general formula -CH=CH- ( CH_ ) OH or -CH-CH-, (CH~ ) OH, 2 n 2 2 2 n oxidising a compound in which R3 represents a 4 3-hydroxypropyl group and R represents a hydroxy group to form, with the carbon atom to which they are attached, a group of the formula introducing a C^CN group represented by R via formation of a spiro compound and splitting the spiro compound with HCN, introducing a C^OH or COC^OH group represented by R3 by converting the 17-ketone^_ 0 208441 - 12b - to the corresponding 17-halo-17—alkoxycarbonyl compound, converting the halo group to an alkoxy group and reducing the 17-alkoxycarbonyl group to a CH20H group, and, if desired, 5 converting the 17-alkoxy group to a 17-hydroxy group and also, if desired, converting the CH2OH group to a COCH2OH group, 4 (viii) converting a hydroxy group represented by R into an alkoxy or alkanoyloxy radical and/or 10 converting a hydroxy group in a radical represented by R^ into an alkoxy or alkanoyloxy radical, 'R1 (ix) converting a compound having a -N' R11 1 group represented by R into an acid addition 15 salt thereof.

Nucleophilic addition at the C-17 position generally results in formation of both possible isomers; these are, however, readily separable by chromatography or fractional crystallisation. In many 20 cases, both isomers are pharmacologically active, even /•> 'OA 1SJUNI984 208441 13 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 -C=CH or -C^C-CH^.

Such agents are, for example, alkali metal acetylides, such as, for example, potassium and lithium acetylide or methylacetylide.

The organometallie 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.

To introduce a 17-alkyl or 17-cyanoalkyl group, an alkali metal alkyl compound, for example methyl- or butyl-lithium, or alkali metal alkylnitrile, e.g.

Li(CH~) CH-CN, may be used for reaction with the 2 n 2. 17-ketone. Suitable solvents are, especially, dialkyl ethers, tetrahydrofuran, dioxan, benzene and toluene. 2084 -13a- A 17-ethynyl-17-hydroxy compound may be hydrated in alcoholic solution with mercury salt catalysis to form a 17-acetyl-17-hydroxy compound (Chem. Ber. 111 (1978) 3086 - 3093).

A 3-hydroxypropy1 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-tetra-hydropyran-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-hydroxypropenyl)-17-hydroxy compound. The hydrogena-tion 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, as methanol, ethanol, propanol, tetrahydrofuran (THF) or ethyl acetate with , 15JUNI984 2084 4 the addition of a noble metal catalyst, such, for example, as platinum or palladium.

A compound with ^-configured double bond in the hydroxypropenyl group may be formed, for example, by 5 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 19 72, page 134, and H.O. House: Modern Synthetic Reactions 1972, page 19). 10 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 15 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 20 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. 25 Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1971) 6560), with diiso- 208441 butylaluminium 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 chromium(II) 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. 3 4 If an end product in which CR R represents is desired, then a 17-(3-hydroxypropy1)-17-hydroxy compound may, for example, be oxidised in a manner known per se. The oxidation conditions generally depend on 1 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. 1 (1962) 157) may be used. If, on the other 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.

A 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. 1_8 (1978) 259 - 260.

The introduction of a 17-hydroxyacety1 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 R in the 17-position may be esterified or etherified, for example, in a manner known per se. Similarly, a free hydroxy or mercapto group in the radical represen-ted by R may, if desired, be etherified or esterified.

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 208441 formula IV which contains a 3-ketal group and a 5a-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 5 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, £-toluenesulphonic acid or acetic 10 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 15 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. 20 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, 2084 4 I * for example, 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 R represents a group of the general f ormula in admixture or conjunction with a pharmaceutically 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- 208441 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-dime"thylpropane-1 , 3-dioxy) -5a-hydroxy-9(10)-oestren-17-one (m.p. 143 -145cC) in 300 ml of absolute tetrahydrofuran (THF) is irradiated for 16 minutes at 25°C 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/ 10 ethyl acetate. 1.46 g of 11P-(4-dimethylaminophenyl)-3,3-(2 ,2-di'methylpropane-1 ,3-dioxy) -5o-hydroxy-13o-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 ice-water. A solution of 2.7 g of 11B-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-5o-hydroxy-l3a-methyl-20 9-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 25 ethyl acetate. The resulting crude product (2.85 g) is used in the following stage without being further purified.

X A 208441 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 5 to a pH of 10.5 by adding concentrated aqueous NH^ solu-tion. 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: (5^ 10 1. 530 mg of 11B-(4-dimethylaminophenyl)-17a-ethynyl- 17B-hydroxy-13a-methyl-4,9-gonadien-3-one having a melting point of 120 - 123°C (ethyl acetate/diiso-propyl ether) and 2. 1.33 g of 11B-(4-dimethylaminophenyl)-17B-ethynyl- 17a-hydroxy-13a-methyl-4,9-gonadien-3-one having a melting point of 201 - 204°C (ethyl acetate). Analogously to b) and c), there are obtained using methylacetylene instead of acetylene: 1. 110—(4-dimethylaminophenyl)-17 B-hydroxv-13a-methyl- —v 17a-propynyl-4,9-gonadien-3-one in the form of an oil. 2. 11B - (4-dimethylaminophenyl)-17o-hydroxy-13a-methyl-17B-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 X V ) 10844f (HgO, red) in 20 ml of water is stirred for 30 minutes at €0°C. 9 ml of this mercury salt solution are added to a solution of 3.25 g of 110-(4-dimethylaminophenyl)-17B-ethynyl-1 7a-hvdroxy-1 3a-methyl-4 , S-gonadien-3-one in 32 nil 5 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 10.5 by adding concentrated aqueous NH^ solution and extracted with ethyl acetate. The resulting oily crude 10 product is crystallised from methylene chloride/diisopropyl ether. 2.37 g of 11B-(4-dimethylaminophenyl)-17o-hydroxy-13a-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)- 17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione 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 20 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 17a-acetoxy-11B-(4-dimethylaminophenyl)-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20-cione having a melting 25 point of 194 - 195cC are obtained.

O X 208441 Example 2 a) A solution of 1.8 g of 11B-(4-diethylaminophenyl)- 3,3-(2,2-dimethylprcpane-1,3-dioxy)-5a-hydroxy-9-oestren-17-one (m.p. 223 - 226°C) in 300 ml of THF are irradiated 5 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)-5cr-hydroxy-13o-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-butyl-lithium in hexane. A solution of 3.53 g of the product described under 2 a) in 71 ml of absolute THF is then 15 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 11B-(4-diethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-13a-methyl-17a-[3-20 (tetrahydropyran-2-yloxy)-1-propynyl]-9-gonene-5a,17B-diol and 11B-(4-diethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-13a-methyl-17B-13-(tetrahydropyran-2-yloxy)-1-propynyl]-9-gonene-5a,17a-diol is used for hydrogenation without being further purified. c) After the addition of 400 mg of 10 % palladium/ 208441 r^. 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 5 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 60°C. After cooling, working-up is carried O 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 11B-(4-diethylaminophenyl)-17a-(3-hydroxy-propyl)-176-hydroxy-13«-methyl-4,9-gonadien-3-one in the form of a yellowish oil.

UV (methanol):£ = 19080, £30g = 19110. 2. 1.39 g of 11fi- (4-diethylaminophenyl)—17B —(3-hydroxy-propyl)-17a-hydroxy-13o-methyl-4,9-gonadien-3-one in the form of a solid foam.

© Analogously to b) to d), there are obtained when using 11B-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1 ,3-dioxy)-5a-hydroxy-13a-methyl-9-gonen-17-one as start- ing material: © 1.) 11 B-(4-dimethylaminophenyl)-17B-hydroxy-!7a- (3-hydroxy-propyl)-13a-methyl-4,9-gonadien-3-one in the form of an oil. 2.) 11 &-(4-dimethylaminophenyl)-17a-hydroxy-17B-(3-hydroxy- >""" ' . . ito iiV'. - A -■"•S 208441 propyl)-13a-methyl-4,9-gonadien-3-one in the form of an oil. t Example 3 a) A solution of 1.75 g of 3,3-(2,2-dimethylpropane-5 1,3-dioxy)-5a-hydroxy-11 B-(4-methoxyphenyl)-9-oestren-17- one in 290 ml of dioxan is irradiated for 19 minutes under the conditions of Example 1 a). After chromatography, 1.45 g of 3 , 3-(2,2-dimethvlpropane-1,3-dioxy)-5a-hydroxy-116—(4-methoxyphenyl)-1 3a-methyl-9-gonen-17-one are 10 obtained in the form of a colourless oil. b) A solution of 8.2 g of 3,3-(2,2-dimethylpropane- 1,3-dioxy)-5a-hydroxy-11 B-(4-methoxyphenyl)-13a-methyl-9-gonen-17-one in 130 ml THF is added dropwise to a suspension of lithium acetylide prepared from a saturated solution 15 of acetylene in 450 ml of THF and 130 ml of a 15 % solution of n-but'yllithium 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 20 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)-17a- ethynyl-11B- (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-1,3-dioxy)-17B- 20844 J # 3 ethynyl-1 IB- (4 -methoxyphenvl) - 1 3a-methyl-9-gonene-5 a, 17a-diol in the form of £ solid foam. c) A solution of 3.28 g of 3,3-(2,2-dimethylpropane- 11 3-dioxy)-17 B-ethynyl-11 B- (4-methoxyphenyl)-l 3c-methyl-9-5 gonene-5a,17a-diol in 33 ml of 70 % aqueous acetic acid is stirred for 30 minutes.at 60°C. 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. Crystallisa-10 tion of the crude product from ethyl acetate yields 2.0 g of 17B-ethynyl-17a-hydroxy-11B-(4-methoxyphenyl)-13a-methyl-4,9-gonadien-3-one having a melting point of 186 -187 °C.

Example 4 a) 20 minutes' irradiation of 1.84 g of 11B-(4-dimethyl aminophenyl) -3,3-(2,2-dimethylpropane-1,3-dioxy)-5a-hydroxy-l8-methyl-9-oestren-17-one in 280 ml of THF under the conditions of Example 1 a) results in 1.36 g of 11 B — <4 — dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-20 13a-ethyl-5a-hydroxy-9-gonen-17-one in the form of a foan._ 6,1 9 of 11 (4-dimethylaminophenyl)-3 ,3-(2 ,2-ai-• methylpropane-1,3-dioxy)-13a-ethyl-5a-hydroxy-9-gonen-17-^ one are reacted under the conditions of Example 1 b) with lithium acetylide and the resulting crude product is 25 cleaved with acetic acid under the conditions of Example /! , 2084 41 1c). After chromatography and crystallisation frbm ethyl acetate/diisopropyl ether, 3.2 g of 1 1 B-(4-dimethylaminophenyl) -170-ethynyl-13a-ethyl-l7a-hydroxy-4,9-gona-dien-3-one having a melting point of 197 - 198°C are 5 obtained. [o]25 + 450.4° (CHC13, C = 0.505). c) By hydration, catalysed with mercury salt, analo gous to Example 1 d) and subsequent acetylation analogous * to Example 1 e), there are obtained from 1.3 g of 11B—(4 — 1 0 dimethylaminophenyl)-17 B-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-one, after chromatographic purification, 720 mg of 17a-acetoxy-1 1 B-(4-dimethylaminophenyl)-1 3a-ethyl-18,19-dinor-4,9-pregnadiene-3,20-dione in the form of a solid foam. r i25 laJD + 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)-5a-hydroxy-13a-methyl-9-gonen-17-one with 10.7 g of 3-tetrahydropyran-2'-yloxy-20 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 11 B-(4-dimethylaminophenyl)—3,3—(2,2-dimethylpropane-1,3-dioxy) ■ 13a-methyl-170-[3-(tetrahydropyran-2-yloxy)-1-propynyl]-9-25 gonene-5a,17a-diol in the form of a yellowish foam.

UJ--' 2084411 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 tri-ethvlamine is hydrogenated at room temperature and normal 5 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 of Example 1 c). After crystallisation from ethyl acetate/diisopro-"S) 10 Pyl ether, 1.1 g of 11&-(4-dimethylaminophenyl)-17cc-hydroxy-17 0-(3-hydroxy-1 (Z)-propenyl)-13a-methyl-4,9-gonadien-3-one having a melting point of 133 - 135°C are obtained.

Example 6 Manufacture of 11B-(4-dimethylaminophenyl)-17B- ethynyl-160-ethyl-17a-hydroxy-13a-methyl-4,9- gonadien-3-one a) A suspension of 29.3 g of 3,3-(2,2-dimethylpropane- O 1,3-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 recrystal-lised from ethyl acetate. In this manner, 27.6 g of 16-25 dimethylaminomethylene-3,3-(2,2-dimethylpropane-1,3-dioxy)-5(10),9(11)-oestradien-17-one having a melting point of 208441 208 - 211°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--5 (2 ,2-dimethylpropane-1 ,3-dioxy) - 5(10) ,9(11) -oestradien- 17-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 approxi- O ' mately 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 chromatographies 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-1,3-15 dioxy)-16(E)-ethylidene-5(10),9(11)-oestradien-17-one having a melting point of 121 - 123°C 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 25°C. For working up, the reaction solution is diluted with approximately 100 ml of methylene chloride and washed in succession with 20844| % Na2S203 solution and water; the methylene chloride phase is dried over Na^O^ and concentrated. The resulting 5,iO-epoxide mixture is chromatographed over A1203, neutral, stage III, with hexane/ethyl acetate. 4.7 g of 3, 3-(2, 2-dimethylpropane-1,3-dioxy )-5a, 10a-epoxy- 16(E)-ethyliden-9(11)-oestren-17-one having a melting point of 139 - 141°C (ethyl acetate/diisopropyl ether) are obtained. d) After the addition of 930 mg of palladium/carbon (10 %), a solution of 8.2 g of 3, 3-(2,2-dimethylpropane-1, 3-dioxy)-5a, 10a-epoxy-16(E)-ethyliden—9 (11 )-oestren- 17-one in 400 ml of ethanol is hydrogenated at room temperature 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 ig of 3,3-(2,2-dimethylpropane-1, 3-dioxy )-5a, lOa-epoxy-l6p-ethyl-9 (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-dimethylaniline 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 of the product obtained under d) in 70 ml of absolute THF is then added, dropwise. Afterwards, the whole is stirred for 3.5 hours at room temperature. For working up, the reaction 08441 s - 30 - 1 . t 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 5 fraction from diisopropyl ether/ethvl acetate, 6.5 g of X) 116-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3- dioxy)-16B-ethyl-5a-hydroxy-9(10)-oestren-17-one having a ■ melting point of 180 - 181°C are obtained. o 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 1TB— (4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy) 16B-ethyl-5a-hydroxy-13a-methyl-9(10)-gonen-17-one having 15 a melting point of 192 - 194°C are obtained.

© O 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 11 0-(4-dimethylamino- phenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-170-ethynyl-16B-ethyl-13a-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 .... 208441 o Example 1 c). Crystallisation of the crude product from hexane/diethvl ether yields 460 mg of 116-(4-dimethylaminophenyl) -1 7B-ethynyl-1 6fJ-ethyl-1 7a-hydroxy-1 3a-methyl-4,9-gonadien-3-one having a melting point of 195 - 197°C.

Example 7 Manufacture of 17B-cyanomethyl-11 B - (4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3-one a) 2.63 g of potassium tert.-butoxide are added in portions* while cooling with ice-water, to a suspension of 10 5.0 g of 11B-(4-dimethylaminophenyl)-3,3-(2,2-dimethylpropane- 1,3-dioxy)-5a-hydroxy-13 a-methyl-9(10)-gonen-17-one and 4.74 g of trimethylsulphonium iodide in 60 ml of dimethylformamide. The whole is stirred for A hours at 25°C, then poured into ice-water and extracted with ethyl 15 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-l, 3-dioxy)-5a-hydroxy-13a-methyl-9(10)-gonene-17a-spiro-11,2'-oxirane 20 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 V 2084 4 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, 10 1.4 g of 17e-cyanomethyl-116-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3-one having a melting point of 135 - 137cC are obtained. tvV-,1 .... . ^ , 2 08441 B. Tests on antiqestaqenic 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 5 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 10 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: A: 110-(4-dimethylaminophenyl)-17p-hydroxy-17a-pro-pynyl-4,9-oestradien-3-one (reference substance). B: 11(5-(4-dimethylaminophenyl )-1 7p-hydroxy-1 7a-( 3-hydroxypropyl)-1 3a-methyl-4,9-gonadien-3-one (compound of the invention). 20 C: 11 p-(4-dimethylaminophenyl)-1 7a-hyaroxy-1 7(3-( 3-hydroxypropy1)-1 3a-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 25 of vehicle per individual dose was 0.2 -1. The treatment was carried out subcutaneously (s.c.). 20844 f - 34 -• 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 5 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 sites. Photographs were taken of all the uteri. The lack of implants was assessed as abortion. 10 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 15 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 p.c.), the percentage of complete abortions with s.c. 20 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). 208441 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 rate of abortion mg/animal/day s.c. n abortion/n total (%) . 0 4/4 (100) .0 - - 3.0 4/4 (100) A 1.0 2/4 ( 50) 0.3 0/4 ( 0) 0.1 0/4 ( 0) .0 4/4 (100) 3.0 4/4 (100) B 1 .0 4/4 (100) 0.3 0/4 ( 0) 0.1 0/4 ( 0) .0 4/4 (100) 3.0 4/4 (100) C 1.0 4/4 (100) 0.3 0/4 ( 0) 0.1 0/4 ( 0) solvent as control: - 0/4 ( 0) 0.2 ml benzyl benzoate i j + castor oil (1:4). | n = 4 rats/group »ap«*4 20844 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 100 90 80 70 60 . 50 40 30 20 10 0 0 % (10) □ AG ( ) number of rats 3.5 % (6) 1 1 52.3 % (6) .4 % (6) control A B C 208UI

Claims (57)

WHAT WE CLAIM IS:

1. A compound of the general formula (I) in which represents a group of the general formula -N^ in which ,11 R* and R*1, which may be the same or different, each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or R1 and R11, 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, or a corresponding tertiary N-oxide group, or III OR in which 2 08 4 4t 38 * R111 represents a methyl, ethyl, propyl, isopropyl, methoxypheny1, allyl or 3-dimethylaminoethyl group, 2 R represents a hydrogen atom, a methyl group or an ethyl group, 3 R represents a group of the general formula -(CH_) -CH., in which 2 n j n represents 0 or an integer from 1 to 5, a group of the general formula -(CH2 )n~CH2-0RIV or -(CH-) -CH^-SR1V in which 2 n 2 n represents 0 or an integer from 1 to 4, and RIV represents a hydrogen atom or an alkyl or alkanoyl radical each having from 1 to 4 carbon atoms, a group of the general formula -CH=CH-(CH2)n~ORV in which n represents an integer from 1 to 4, and V R 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 - (CH2 )n~CH2CN in which ©£•>T bix r ' v-■ -v' %• *■» sV,:;.s. 208441 - 39 - n represents 0 or an integer from 1 to 3, or 0 II a group of the formula -C-CH^Y in which Y represents a hydrogen atom of a group of the general formula ORV in which R^ has the meaning given above, 4 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 are attached, represent a group of the formula 3 and R is an the a-configuration and 4 R is m the 0-configuration or 3 R is in the {J-configuration and 4 R is in the a-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 or p-configuration.

2. A compound as claimed in claim 1, wherein represents ,N(CH3)2, N(C2H5)2 or 0CH3. 2

;• 3. A compound as claimed in claim 1 or claim 2, in which R ^^presents a hydrogen atom or a methyl group. 20844 - 40 -

4. A compound as claimed in any one of claims 1 to 3, wherein R3 represents CHCH, C=£CH3, CH2CH2OH, CH=CHCH20H, CH2CN or C0CH3>

5. A compound as claimed in any one of claims 1 4 3 to 4, wherein R represents OH or, when R represents 4 COCHj, R represents OCOCH^.

6. A compound as claimed in any one of claims 1 3 4 to 3, wherein R + R together with the carbon atom to which they are attached represent a group of the formula A

7. A compound as claimed in any one of claims 1 5 to 6, wherein R represents H or C2H^.

8. 1ip-(4-Dimethylaminophenyl)-17a-ethynyl-17p-hydroxy-13a-methyl-4,9-gonadien-3-one.

9. 11P~( 4-Dimethylaminophenyl )-17p-ethynyl-1 7a-hydroxy-13a-methyl-4,9-gonadien-3-one.

10. 1113- ( 4-Dime thy laminophenyl) -1 7 {J-hydroxy-1 3 a-methyl-17a-propynyl-4,9-gonadien-3-one.

11. 113-(4-Dimethylaminophenyl)-17a-hydroxy-13a-methyl-17p-propynyl-4,9-gonadien-3-one.

12. 11p-(Dimethylaminophenyl)-17a-hydroxy-13a-methyl-18,19-dinor-4,9-pregnadiene-3,20-dione.

13. 1 7a-Acetoxy-11 p- ( 4 -dimethylaminophenyl) -'1 3a- 4 1 208441 methyl-18,19-dinor-4,9-pregnadiene-3,20-dione.

14. 11p-(4-Diethylaminophenyl)-1 7a- ( 3-hydroxy-propyl )-1 7p-hydroxy-13a-methyl-4,9-gonadien-3-one.

15. 11 p- (4-Die thy laminophenyl) -1 7|3- ( 3-hydroxy-propyl )-1 7a-hydroxy-13a-methyl-4,9-gonadien-3-one.

16. 11p-(4-Dimethylaminophenyl)-l 7p-hydroxy-17a-(3-hydroxypropyl)-13a-methyl-4,9-gonadien-3-one.

17. 11p-(4-Dimethylaminophenyl)-1 7a-hydroxy-17p-(3-hydroxypropyl)-13a-methyl-4,9-gonadien-3-one.

18. 170-Ethynyl-17a-hydroxy-11p-(4-methoxyphenyl )-13a-methyl-4,9-gonadien-3-one.

19. 110-(4-Dimethylaminophenyl)-17p-ethynyl-13a-ethyl-17a-hydroxy-4,9-gonadien-3-one.

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

21. 11p-(4-Dimethylaminophenyl-1 7a-hydroxy-17p- (3-hydroxy-1(Z)-propenyl)-13a-methyl-4,9-gonadien-3-one.

22. 11p-(4-Dimethylaminophenyl)-17p-ethynyl-16p-ethyl-17a-hydroxy-13a-methyl-4,9-gonadien-3-one.

23. 1 7p-Cyanomethyl-11p-(4-dimethylaminophenyl)-17a-hydroxy-13a-methyl-4,9-gonadien-3-one.

24. An acid addition salt of a compound of the general formula I in which R^ represents a group of R I as claimed in any one 268441 - 42 - of claims 1 to 17 and 19 to 22.

25. A physiologically tolerable acid addition salt of a compound of the general formula I in which R., represents a group of the formula -N as >11 claimed in any one of claims 1 to 17 and 19 to 22.

26. A process for the preparation of a compound as claimed in claim 1 or an acid addition salt of such 1 a compound in which R represents a group of the general formula -N , which comprises .II (a) cleaving the 3-ketal protecting group and eliminating water from the 4,5-position in a compound of the general formula IV 1 2 3 4' 5 in which R , R , R , R and R have the meanings given % 200441 - 43 - in claim 1 and Z represents an ethylene or 2,2-dimethylpropylene group, or other ketone-protecting group, or an acid addition salt of such a compound in 1 which R represents a group of the general formula -n' or ,11 (b) converting a compound of the general formula .1 p2 o III 12 5 • in which R , R , R and Z have the meanings given above, or an acid adition salt of such a compound in which R1 represents a group of the general formula -N^ by nucleophilic addition to the ,11 "-1.7-ketone group, cleavage of the 3-ketal group and elimination 0£ Water from the 4, 5-position, or c irradiating a compound of the general formula Sffty R Ey.^' 20844 JL - - (d) converting a compound of the general formula (V) 12 5 an whach R , R , R and Z have the meanings given above, or an acid addition salt of such a compound in 1 which R represents a group of the general formula -N by nucleophilic addition to the ,11 17-ketone group, followed by cleavage of the 3-ketal group.

27. A process as claimed in claim 26, wherein the cleavage of the 3-ketal protecting group and elimination of water are carried out substantially as described in any one of Examples 1c, 2d, 3c, 4b, 5b, 6h and 7b herein.

28. A process as claimed in claim 26 or claim & EC# 208441 - -4 5 - 27, which includes one or more of the following steps as appropriate: (i) introduction of a group represented by R of the general formula -(CH2)nCH3 in which n represents 0 or an integer from 1 to 4 or -(CHj^CI^CN where n represents 0 or an integer from 1 to 3 by an alkali metal-alkyl or alkali metal-alkylnitrile compound, 3 (ii) introduction of a group represented by R of the general formula -C=CX in which X represents a hydrogen or halogen atom or an alkyl radical having from 1 to 4 carbon atoms, by means of a compound of the general formula MCSCX in which x has the meaning given above and M represents an alkali metal or by means of an alkali metal and a compound of the general formula HC=CX in which X has the meaning given above, (iii) hydration of a triple bond in a group of the 3 general formula -C=CH represented by R to form a group of the group of the general formula coch3, 3 (iv) introduction of a group represented by R of the general formula -C=C(CH2)nOR in which R represents a hydroxy-protecting group and n represents an integer from 1 to 4, by means of a compound of the general formula MC^CfCI^^OR in which R and n have the meanings given above and M represents an alkali metal, and 15 J UNf984^ * 208441 - 46 - hydrogenating the resulting compound to form the corresponding hydroxyalkeny1 or hydroxyalkyl radical of the general formula -CH=CH-(CH2)n0H or -CH2CH2(CH2) OH, (v) oxidising a compound in which R^ represents a 3-hydroxypropyl group and R4 represents a hydroxy group to form, with the carbon atom to which they are attached, a group of the formula 0 3 (vi) introducing a CH2CN group represented by R via formation of a spiro compound and splitting the spiro compound with HCN, (vii) introducing a CH20H or C0CH20H group represented by R^ by converting the 17-ketone to the corresponding 17-halo-17- alkoxycarbonyl compound, converting the halo group to an alkoxy group and reducing the 17-alkoxycarbonyl group to a CH20H group, and, if desired, converting the 17-alkoxy group to a 17-hydroxy group and also, if desired, converting the CH20H group to a C0CH20H group, 4 (viii) converting a hydroxy group represented by R into an alkoxy or alkanoyloxy radical and/or converting a hydroxy group in a radical 2 08 4 4 - 47 - represented by R^ into an alkoxy or alkanoyloxy radical, (ix) converting a compound having a -N group represented by R into an acid addition salt thereof.

29. A process as claimed in claim 28, which includes the step of introducing or converting a group in the 17-position substantially as described in any one of Examples 1b, 1d, 1e, 2b, 2c, 3b, 4c, 5a, 6g, 7a and 7b herein.

30. A process as claimed in any one of claims 26 to 29, wherein the irradiation step is carried out in a 0.1 to 1 % by weight solution.

31. A process as claimed in any one of claims 26 to 30, wherein the irradiation step is carried out in solution in tetrahydrofuran or dioxan.

32. A process as claimed in any one of claims 26 to 30, wherein the irradiation step is carried out in hexane, cyclohexane, benzene, toluene or a mixture of two or more thereof.

33. A process as claimed in any one of claims 26 to 32, wherein the irradiation step is carried out for a period of from 10 to 50 minutes.

34. A process as claimed in any one of claims 26 20844 - 48 - to 29, wherein the irradiation step is carried out substantially as described in any one of Examples 1a, 2a, 3a, 4a and 6f herein.

35. A process as claimed in any one of claims 26 to 34, wherein the starting material of the general formula II is prepared substantially as described in Examples 6a to 6e herein.

36. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 26 to 35.

37. An acid addition salt as claimed in claim 24, whenever prepared by a process as claimed in any one of claims 26 to 35.

38. A physiologically tolerable acid addition salt as claimed in claim 25, whenever prepared by a process as claimed in any one of claims 26 to 35.

3 9. A pharmaceutical preparation which comprises a compound as claimed in any one of claims 1 to 23, 25, 36 and 38, in admixture or conjunction with a pharmaceutically suitable carrier.

40. A pharmaceutical preparation as claimed in claim 39, which is in dosage unit form.

41. A compound of the general formula III shown 12 5 in claim 26, in which R , R , R and Z have the meanings given in claim 26, or an acid addition salt of such a compound in which R^ represents a group of the general formula -N - 49 - R1 R11 2084- 4-1

42. A compound as claimed in claim 41, wherein 1 R has the meaning given in claim 2.

43. A compound as claimed in claim 41 or claim ^ . 2 42, wherein R has the meaning given in claim 3.

44. A compound as claimed in any one of claims 5 41 to 43, wherein R has the meaning given in claim 7.

45. 11(3-(4-Dimethylaminophenyl)-3,3-(2,2- © dimethylpropane-1, 3-dioxy) -5oc-hydroxy-1 3a-methyl-9(10)-gonen-17-one.

46. 1 1 (3-( 4-Diethylaminophenyl)-3,3-(2,2-diethylpropane-1,3-dioxy)-5a-hydroxy-13a-methyl-9-gonen-17-one.

4 7. 3,3-(2,2-Dimethy1propane-1,3-dioxy)-5 a-hydroxy-11|3-(4-methoxyphenyl)-13a-methyl-9-gonen-17- one.

48. 110-(4-Dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-13a-ethyl-5a-hydroxy-9-gonen-17-one.

49. 11p-(4-Dimethylaminophenyl)-3,3-(2,2-dimethylpropane-1,3-dioxy)-1€p-ethyl-5a-hydroxy-13a-methyl-9(10)-gonen-17-one.

50. A process for the preparation of a compound as claimed in claim 41, which comprises irradiating a compound of the general formula II shown in claim 26, 12 5 ... in which R , R , R and 2 have the meanings given in ) " '■/A' "••f-.V- 20644 - 50 - - " claim 26, or an acid addition salt of such a compound

51. A process as claimed in claim 50, which is as specified in any one of claims 30 to 34.

52. A compound as claimed in claim 41, whenever prepared by a process as claimed in claim 50 or claim 51 .

53. A compound as claimed in any one of claims 41 to 4 9 and 52, whenever used to pepare a compound as claimed in claim 1 or claim 24.

54. A compound as claimed in claim 1 or claim 24, whenever prepared from a compound as claimed in any one of claims 41 to 49 and 52.

55. A compound of the general formula IV shown 1 2 3 4 5 in claim 26, in which R , R , R , R , R and 2 have the meanings given in claim 26 or an acid addition salt of such a compound m which R represents a group

56. A compound as claimed in claim 55, which is any one of those mentioned herein.

57. A compound of the general formula V shown 1 m which R represents a group of the formula with UV light. of the general formula -N 208441 - 50A - 12 5 in claim 26, in which R , R , R and Z have the meanings given in claim 26, or an acid addition salt of such a compound in which R1 represents a group of the ^/rI general formula -N, ^ -R11 SCHERING AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED Per: i 4 o: ■to!. •V