Europaisches Patentamt ® Publication number: European Patent Office EUROPEAN PATENT @ Dateof publication of patent specification: 20.07.88 _® Application number: 84306715.8 5 0 4 B 1 Dffice europeen des brevets © 0 1 3 8 SPECIFICATION @ int. CI.4: C 07 J 4 1 / 0 0 , C 07 J 3 1 / 0 0 A 61 K 3 1 / 5 6 5 , @ Date of filing: 02.10.84 §) Steroid derivatives. (73) Proprietor: IMPERIAL CHEMICAL INDUSTRIES PLC Imperial Chemical House Millbank London SW1P 3JF(GB) (1) Priority: 12.10.83 GB 8327256 (§) Dateof publication of application: 24.04.85 Bulletin 85/17 (§) Publication of the grant of the patent: 20.07.88 Bulletin 88/29 (8) Designated Contracting States: AT BE CH DE FR GB IT LI LU NL SE (§) References cited: EP-A-0124 369 FR-A-2 235 949 O If) 00 CO 0111 COMPTE RENDUS DES SEANCES HEBDOMADAIRES DANS DE L'ACADEMIE DES SCIENCES, Serie C, vol. 284, April 4, 1977, pages 521-523 A. CHAABOUNI et al.: "Chimie macromoleculaire. Fixation de steroides aux extremites de chatnes de polyoxyethylene." ® Inventor: Bowler, Jean 9 Tatton Drive Sandbach Cheshire (GB) Inventor: Tait, Brian Steele 3, Batemill Close Macclesfield Cheshire (GB) (7§) Representative: Slatcher, Reginald Peter et al Imperial Chemical Industries PLC Legal Department: Patents P.O. Box 6 Bessemer Road Welwyn Garden City AL7 1HD (GB) Note: Within nine months from the publication of the mention ot the grant or tne turopean patenx, any perbun may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European patent convention). Courier Press, Leamington bpa, tngland. 0 138 504 Description 5 io This invention relates to new steroid derivatives which possess antioestrogenic activity. Various oestradiol derivatives are known which bear a carboxyalkyl substituent at the 7a-position. These have been used, when bound via the carboxy group to polyacrylamide resin or to agarose, for the purification of oestrogen receptors (Journal of Biological Chemistry, 1978, 253, 8221); and, when conjugated with bovine serum albumin, for the preparation of antigens (United Kingdom Specification No. 1,478,356). We have now found that certain 7a-substituted derivatives of oestradiol and related steroids possess potent antioestrogenic activity. According to the invention there is provided a steroid derivative of the formula: — ST— A—X—R1 15 wherein ST is a 7a-linked steroid nucleus of the general formula: — 20 25 30 35 40 wherein the dotted lines between carbon atoms 6 and 7, and carbon atoms 8 and 9, of the steroid nucleus indicate that there is an optional double bond between carbon atoms 6 and 7, or that there are two optional double bonds between carbon atoms 6 and 7 and carbon atoms 8 and 9; wherein the aromatic ring A may optionally bear one or two halogen or alkyl substituents; wherein R3 is hydrogen or alkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl or aroyl each of up to 10 carbon atoms; wherein R16 is hydrogen, alkyl of up to 6 carbon atoms which is preferably in the P-configuration, or hydroxy which is preferably in the a-configuration; wherein either R17 (in the p-configuration) is hydroxy or alkanoyloxy, carboxyalkanoyloxy or aroyloxy each of up to 10 carbon atoms; and R27 (in the a-configuration) is hydrogen or alkyl, alkenyl or alkynyl each of up to 6 carbon atoms; or R17 and R27 together form oxo (=0); wherein R18 is alkyl of up to 6 carbon atoms; wherein A is straight- or branched-chain alkylene, alkenylene or alkynylene each of from 3 to 14 carbon atoms, which may have one or more hydrogen atoms replaced by fluorine atoms, or has the formula —A1—Y—A11— 45 so 55 wherein A1 and A11 are each alkylene or alkenylene, optionally fluorinated, having together a total of 2 to 13 carbon atoms and Y is —0—, —S—, —SO—, —S02— , —CO— or —NR— wherein R is hydrogen or alkyl of up to 3 carbon atoms; or A1 is alkylene or alkenylene, optionally fluorinated, and A11 is a direct link or alkylene or alkenylene, optionally fluorinated, such that A1 and A11 together have a total of 1 to 12 carbon atoms, and Y is —NRCO—, —CONR —, —COO—, —OCO— or phenylene wherein R has the meaning stated above; wherein R1 is hydrogen, or alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl or arylalkyl each of up to 10 carbon atoms, or dialkylaminoalkyl wherein each alkyl is of up to 6 carbon atoms, or R1 is joined to R2 as defined below; and wherein X is —CONR2—, —CSNR2— , —NR12—CO— , —NR12—CS— , —NR12—CONR2— NR II —NR12—C—NR2—, so —S02NR2— or —CO—; or, when R1 is not hydrogen, is —O—, —NR2—, —(NO)R2— , —(P0)R2— , —NR12—COO— , —NR12—S02— , —S— , —SO— or —S02— ; wherein R2 is hydrogen or alkyl of up to 6 carbon atoms, or R1 and R2 together form alkylene or halogenoalkylene such that, with the adjacent nitrogen atom, they form a heterocyclic ring of 5 to 7 ring atoms, one of which atoms may be a second heterocyclic atom selected from oxygen, sulphur and 65 nitrogen; 2 0 138 504 wherein R12 is hydrogen or alkyl of up to 6 carbon atoms; and wherein R22 is hydrogen, cyano or nitro; or a salt thereof when appropriate. A suitable value for the halogen or alkyl substituent in ring A is, for example, fiuoro, chloro, bromo, iodo, methyl or ethyl. A suitable value for R3 when it is alkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl or aroyl is, for 5 example, methyl, ethyl, acetyl, propionyl, butyryl, pivalyl, decanoyl, isopropoxycarbonyl, succinyl or benzoyl. R3 is preferably hydrogen or alkanoyl or alkoxycarbonyl each of up to 5 carbon atoms. A suitable value for R16 when it is alkyl is, for example, methyl or ethyl. R16 is preferably hydrogen. A suitable value for R17 when it is alkanoyloxy, carboxyalkanoyloxy or aroyloxy is, for example, 10 acetoxy, propionyloxy, succinyloxy or benzoyloxy. R17 is preferably hydroxy. A suitable value for R27 when it is alkyl, alkenyl or alkynyl is, for example, ethyl, vinyl or ethynyl. R27 is preferably hydrogen. A suitable value for R18 is methyl or ethyl, especially methyl. The group ST- is preferably oestra-1,3,5(10)-triene-3,17(3-diol, 3-hydroxyoestra-1, 3,5(1 0)-trien-17-one 75 or 17a-ethynyloestra-1,3,5(10)-triene-3,17p-diol, all of which bear the —A—X— R1 substituent in the 7aposition, or a 3-alkanoyl ester thereof. One preferred value for the group —A— is a straight-chain alkylene group of the formula 20 25 30 35 40 45 50 55 -3 n_neXyi H n-hexyl H methyl (CH2)3 n-hexyl H methyl (CH2)3 n-hexyl methyl The pentenoic and pentanoic acids used as starting materials were obtained as follows: — Sodium hydride (0.069 g) was added to a stirred solution of triethylphosphonoacetate (0.413 g) in tetrahydrofuran (10 ml) which was maintained at 0°C, and the mixture was stirred at that temperature for 1 hour. A solution of 3-(17B-acetoxy-3-benzoyloxyoestra-1,3,5(10)-trien-7a-yl)propionaldehyde (Example 3, second paragraph relating to preparation of starting materials, 0.25 g) in tetrahydrofuran (5 ml) was added and the mixture was stirred at laboratory temperature for 30 minutes, neutralised with acetic acid and evaporated to dryness. The residue was shaken with water (15 ml), the mixture was extracted three times with ethyl acetate (30 ml each time) and the combined extracts were washed with water, dried and evaporated to dryness. There was thus obtained as residue ethyl 5-(17B-acetoxy-3-benzoyloxy-oestra1,3,5(10-trien-7a-yl)pent-2-enoate. Part of this was hydrolysed to the corresponding pent-2-enoic acid with aqueous sodium hydroxide solution for use as one starting material, and part of it was hydrogenated by a similar process to that described in Example 4, and the ethyl 5-(17B-acetoxy-3-benzoyloxyoestra-1,3,5-(10)trien-7a-yl)pentanoate thus obtained was hydrolysed to the corresponding dihydroxypentanoic acid with aqueous sodium hydroxide solution for use as the other starting material. 12 0 138 504 The amidoalkylamines used as starting materials for the compounds described in Table 2 were obtained as follows: — N-n-Hexyl-4-methylaminobutyramide A solution of 1-methylpyrrolidin-2-one (5 g) in aqueous 6N-sodium hydroxide solution (50 ml) containing methanol (0.1 ml) was heated under reflux for 3 hours, cooled to 0°C and benzyl chloroformate (9.5 g) was added dropwise. The mixture was kept at 0°C for 12 hours and then poured onto a mixture of equal volumes of ice and concentrated aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was washed with water, dried and evaporated to dryness. 10 Triethylamine (3.7 ml) and ethyl chloroformate (2.5 ml) were successively added to a stirred solution of the 4-(/V-benzyloxycarbonyl-/V-methylamino)butyric acid thus obtained (6.0 g) in ethyl acetate (100 ml) which was cooled to -20°C, and the mixture was stirred at that temperature for 15 minutes. A solution of nhexylamine (3.2 ml) in ethyl acetate (30 ml) was added and the mixture was allowed to warm up to laboratory temperature and stirred at that temperature for 16 hours, then washed successively with dilute is aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried and evaporated to dryness. A solution of the 4-(/V-benzyloxycarbonyl-/V-methylamino)-A/-n-hexylbutyramide thus obtained (6.6 g) in ethanol (100 ml) was shaken with hydrogen in the presence of a 10% palladium-on-charcoal catalyst (0.6 g) for 18 hours, filtered and evaporated to dryness. There was thus obtained as residual oil /V-n-hexyl-420 methylaminobutyramide. 5 N-n-Hexyl-N-methyl-4-methylaminobutyramide As above but using /V-n-hexyl-/V-methylamine in place of n-hexylamine. 25 so Glycine N-n-heptylamide As above from glycine and benzyl chloroformate (/V-benzyloxycarbonylglycine has m.p. 119 — 121°C), then triethylamine, ethyl chloroformate and n-heptyiamine. B-Alanine N-n-hexylamide As above using 3-alanine in place of glycine and n-hexylamine in place of n-heptylamine. N-n-hexyl-4-aminobutyramide As above using 4-aminobutyric acid in place of glycine and n-hexylamine in place of n-heptylamine. 35 40 45 so 55 so 65 Example 6 /V-Methylmorpholine (0.028 ml) and isobutyl chloroformate (0.038 ml) were successively added to a stirred solution of 11-(3-benzyloxy-176-hydroxyoestra-1,3,5(10)-trien-7a-yl)undec-10-enoic acid (0.109 g) in tetrahydrofuran (3 ml) which was cooled to -10°C. The mixture was stirred at -10°C for 30 minutes, Nmethylisobutylamine (0.05 ml) was added and the mixture was stirred at laboratory temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (5 ml) was added and the mixture was extracted 3 times with methylene chloride (10 ml each time). The combined extracts were washed with water (2 ml), dried and evaporated to dryness, and there was thus obtained as oily residue /V-isobutyl-/V-methyl-11-(3benzyloxy-176-hydroxyoestra-1,3,5(10)-trien-7a-yl)undec-10-enamide. A 10% palladium-on-charcoal catalyst (0.03 g) was added to a solution of the above compound (0.105 g) in ethyl acetate (10 ml) and the mixture was stirred at laboratory temperature under an atmosphere of hydrogen for 5 hours, and then filtered. The filtrate was evaporated to dryness and there was thus obtained as oily residue /V-isobutyl-/V-methyl-11-(3,17B-dihydroxyoestra-1,3,5(10)-trien-7a-yl)undecanamide, the structure of which was confirmed by proton magnetic resonance spectroscopy and elemental analysis. The undecenoic acid used as starting material was obtained as follows: — Diethyl aluminium cyanide (100 ml of a 1.2 molar solution in toluene) was added to a stirred solution of 6-dehydro-19-nortestosterone acetate (9 g) in tetrahydrofuran (400 ml) and the mixture was stirred at laboratory temperature for 1 hour and then poured into a mixture of ice (1000 ml) and aqueous 2N-sodium hydroxide solution (500 m). The mixture was extracted 3 times with methylene chloride (300 ml each time) and the combined extracts were washed with water (100 ml), dried and evaporated to dryness. The residue was stirred with petroleum ether (b.p. 40— 60°C; 100 ml) and there was thus obtained 17B-acetoxy-7acyano-oestr-4-ene-3-one, m.p. 183 —186°C. A solution of the above compound (3.38 g) in acetonitrile (15 ml) was added rapidly to a vigorously stirred suspension of cupric bromide (4.46 g) and lithium bromide (0.85 g) in acetonitrile (30 ml) which was heated under reflux under an atmosphere of argon. The mixture was stirred and heated under reflux for 10 minutes and then cooled, and saturated aqueous sodium bicarbonate solution (50 ml) was added. The mixture was extracted 3 times with ethyl acetate (50 ml each time) and the combined extracts were washed with water (20 ml), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 17:3 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained 17B-acetoxy-7a-cyanooestra-1,3,5(10)-trien-3-ol. Early fractions eluted from the column contained 13 0 138 504 17B-acetoxy-6-bromo-7a-cyano-oestra-1,3,5(10)-trien-3-ol which was used in Example 22. A stirred mixture of the above compound (0.69 g), benzyl bromide (0.29 ml), potassium carbonate (0.325 g) and acetone (20 ml) was heated under reflux for 16 hours, cooled and filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained 17B-acetoxy-3-benzyloxy-7acyano-oestra-1, 3,5(1 0)-triene. Diisobutyl aluminium hydride (3.1 ml of a 1.5 molar solution in toluene) was added to a stirred solution of the above compound (0.68 g) in toluene (10 ml) and the mixture was stirred at laboratory temperature for 150 minutes. Methanol (2 ml) and then aqueous 2N-hydrochloric acid (5 ml) were added and the mixture was stirred for 15 minutes and then extracted three times with ethyl acetate (10 ml each time). The combined extracts were washed with water (5 ml), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained 3-benzyloxy-17B-hydroxyoestra-1,3,5(10)-triene-7a-carboxaldehyde. Dimsyl sodium (4 ml of a 2-molar solution in dimethyl sulphoxide) was added dropwise to a solution of finely powdered (9-carboxynony!)triphenyiphosphonium bromide (1.94 g) in dimethyl sulphoxide (10 ml) which was maintained under an atmosphere of nitrogen, and a solution of the above aldehyde (0.3 g) in a mixture of toluene (2 ml) and dimethyl sulphoxide (2 ml) was then added. The mixture was stirred at laboratory temperature for 1 hour and then evaporated to dryness under reduced pressure, and the residue was shaken with water (5 ml) and diethyl ether (5 ml). The aqueous solution was separated, acidified to pH 3 with aqueous 2N-oxalic acid solution and extracted three times with diethyl ether (10 ml each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using an 11:9 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained 11-{3-benzyloxy-17B-hydroxyoestra-1,3,5(10)-trien-7a-yl)undec-10-enoic acid. Example 7 The process described in Example 6 was repeated using the appropriate a)-(3-benzyloxy-176-hydroxyoestra-1, 3,5(1 0-trien-7a-yl)alkenoic acid and the appropriate amine as starting materials. There were thus obtained the compounds described in the following table, all of which were oils the structures of which were confirmed by proton magnetic resonance and mass spectroscopy: — 'A-CONR1 R2 -(CH 2 11 -(CH 2 11* -(CH 2 10* , -(CH 2 10 -(CH2 9 " -(CH 2 a" -(CH CH(CH )• 3 2 6 , -(CH CH(CH )• 3 , 2 6 -(CH 2 -(CH CHFCH @ 8 2 * In the -CH=CH-(CH starting n-propyl H n-butyl methyl 1-methylbutyl methyl cyclopentyl H 1H, l H , h e p t a f l u o r o b u t y l methyl n-hexyl methyl n-butyl methyl n-heptyl H -CH H (CF ) CF 2 2 5 3 n-butyl material ) -CF=CH-. 2 6 14 -A- methyl* is 0 138 5 w is 20 25 30 35 40 45 50 55 50 65 504 The steroidal starting materials were prepared as described in the second part of Example 6 except that the appropriate (a)-carboxyalkyl)triphenylphosphonium bromide was used as intermediate. The starting material for the last-mentioned compound, marked with an asterisk*, is unusual in that during the reaction of the steroidal-7a-carboxaldehyde with (9-carboxy-8,8-difluorononyl)triphenylphosphonium bromide a molecule of hydrogen fluoride is eliminated and the starting material is the steroidal-7a-yl-3-fluoroundeca2,10-dienoic acid. The (9-carboxy-8,8-difluorononyl)triphenylphosphonium bromide used as intermediate was obtained as follows: — A solution of 8-bromooctanoyl chloride (1.2 g) in methylene chloride (5 ml) was added to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (0.72 g) and pyridine (0.8 ml) in methylene chloride (20 ml) which was kept at 5°C, and the mixture was stirred at that temperature for 1 hour and then at laboratory temperature for 90 minutes, washed successively with aqueous N-hydrochloric acid (20 ml) and water (20 ml), dried and evaporated to dryness. The residue was heated under reflux with methanol (20 ml) for 16 hours, the excess of methanol was removed by evaporation and the residue was distilled under reduced pressure. There was thus obtained methyl 10-bromo-3-oxodecanoate, b.p. 135 — 144°C/145 Pa (1 mm Hg). A mixture of the above ester (4.4 g) and sulphur tetrafluoride (10 g) was heated at 60°C for 6 hours in a sealed bomb (Hastelloy C) and the resulting tar was extracted with methylene chloride (150 ml). The extract was washed with saturated aqueous sodium carbonate solution (50 ml) and then with water (20 ml), dried and evaporated to dryness. The residue was distilled under reduced pressure and there was thus obtained methyl 10-bromo-3,3-difluorodecanoate, b.p. 175°C/29 Pa (0.2 mm Hg). A mixture of the above ester (1.1 g), acetic acid (1 ml) and 48% aqueous hydrobromic acid (1 ml) was heated under reflux for 2 hours and then poured into ice-water (20 ml). The mixture was extracted three times with ethyl acetate (10 ml each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was distilled under reduced pressure and there was thus obtained 10bromo-3,3-difluorodecanoic acid, b.p. 200°C/22 Pa (0.15 mm Hg). Triphenylphosphine (0.565 g) was added to a solution of the above acid (0.61 g) in acetonitrile (5 ml) and the mixture was heated under reflux for 18 hours and then evaporated to dryness. There was thus obtained as residual oil (9-carboxy-8,8-difluorononyi)triphenylphosphonium bromide which was used without further purification. Example 8 /V-Methylmorpholine (0.107 ml) and isobutyl chloroformate (0.133 ml) were successively added to a stirred solution of p-[4-(17B-hydroxy-3-methoxyoestra-1 ,3,5(1 0)-trien-7a-yl)but-1-enyl]cinnamic acid (0.17 g) in methylene chloride (10 ml) which was cooled to -30°C under an atmosphere of argon, and the mixture was allowed to warm up to laboratory temperature. n-Hexylamine (0.06 ml) was added, the mixture was stirred at laboratory temperature for 30 minutes, aqueous 2N-hydrochloric acid (10 ml) was added and the mixture was extracted three times with diethyl ether (20 ml each time). The combined extracts were washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. There was thus obtained, as an oil, /V-n-hexyl-p-[4-(17B-hydroxy-3-methoxyoestra1,3,5(10)-trien-7a-yl)but-1-enyl]cinnamide, the structure of which was confirmed by proton magnetic resonance spectroscopy and mass spectroscopy. Boron tribromide (0.5 ml) was added to a stirred solution of the above amide (0.12 g) in methylene chloride (10 ml) which was cooled to -78°C under an atmosphere of argon, and the mixture was allowed to warm up to -10°C and was kept at that temperature for 4 hours. Saturated aqueous sodium bicarbonate solution (10 ml) was added, the mixture was extracted three times with methylene chloride (15 ml each time) and the combined extracts were washed with water, dried over magnesium sulphate and evaporated to dryness. There was thus obtained, as an oil, p-[4-(3,17B-dihydroxyoestra-1,3,5(10)-trien-7a-yl)but-1enyl]-/V-n-hexyl-cinnamide, the structure of which was confirmed by nuclear magnetic resonance and mass spectroscopy. The cinnamic acid used as starting material was obtained as follows: — The process described in the first paragraph of Example 1 relating to the preparation of starting materials was repeated except that dimethyl-t-butylsiiyl chloride was reacted with 3-bromopropanol instead of 11-bromoundecanol. The Grignard reagent from this was reacted with 6-dehydro-19nortestosterone, and the sequence of reactions described in the succeeding two paragraphs of Example 1 was repeated. There was thus obtained 17B-acetoxy-7a-(3-acetoxypropyl)-oestra-1, 3,5(1 0)-trien-3-ol. Methyl iodide (6 ml) and potassium carbonate (6 g) were added to a stirred solution of the above diacetate (5 g) in acetone (80 ml), and the mixture was stirred and heated under reflux for 16 hours, cooled and filtered and the filtrate was evaporated to dryness. A solution of the residual 17B-acetoxy-7a-(3acetoxypropyl)-3-methoxyoestra-1 ,3,5(1 0)-triene (4.7 g) in methanol (50 ml) was cooled to 0°C, potassium carbonate (2.5 g) was added and the mixture was stirred at 0°C for 3 hours and then filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on a silica gel column (Merck 9385) using a 4:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained 17B-acetoxy-7a-(3hydroxypropyl)-3-methoxyoestra-1 ,3,5(1 0)-triene as an oil. Pyridinium chlorochromate (3.6 g) was added to a stirred solution of this oestratriene (3.2 g) in methylene chloride (100 ml) and the mixture was stirred for 2 hours and then filtered. The filtrate was 15 0 138 504 evaporated to dryness and the residue was purified by chromatography on a silica gel column (Merck 9385) using a 9:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained 3-(17B-acetoxy-3methoxyoestra-1 ,3,5(1 0)-trien-7a-yl)propionaldehyde. n-Butyl-lithium (0.67 ml of a 1.5 molar solution in hexane) was added to a stirred solution of 5 diisopropylamine (0.14 ml) in tetrahydrofuran (30 ml) which was cooled to 0°C under an atmosphere of argon. After 10 minutes the mixture was cooled to —78°C and a solution of ethyl p-(diethylphosphonylmethyUcinnamate (0.33 g; b.p. 175°C/2.2 kPa (15 mm Hg); prepared by heating ethyl p-bromomethylcinnamate with triethylphosphite at 120°C for 2 hours) in tetrahydrofuran (2 ml) was added dropwise. A solution of the above propionaldehyde (0.19 g) in tetrahydrofuran (1 ml) was added and the mixture was w allowed to warm up to laboratory temperature and was stirred at that temperature for 16 hours. Aqueous 2N-hydrochioric acid was added and the mixture was extracted three times with diethyl ether (15 ml each time). The combined extracts were washed with water (20 ml) and then with saturated aqueous sodium chloride solution (20 ml), dried over magnesium sulphate and evaporated to dryness. The residue was purified by chromatography on a silica gel column (Merck 9385) using a 17:3 v/v mixture of toluene and >5 ethyl acetate as eluant. There was thus obtained ethyl p-[4-(17B-acetoxy-3-methoxyoestra-1,3,5(10)-trien7a-yl)but-1-enyl]cinnamate. Aqueous 2N-sodium hydroxide solution (1 ml) was added to a stirred solution of the above cinnamate (0.2 g) in a mixture of methanol (1 ml) and tetrahydrofuran (1 ml), and the mixture was stirred at laboratory temperature for 3 hours, acidified with aqueous 2N-hydrochloric acid (2 ml) and extracted three times with 20 ethyl acetate (10 ml each time). The combined extracts were washed with water, dried over magnesium sulphate and evaporated to dryness. There was thus obtained as residual gum p-[4-(17B-hydroxy-3methoxyoestra-1,3,5(10)-trien-7a-yl)but-1-enyl]cinnamic acid. 25 30 35 Example 9 A solution of p-[4-(4-(3,17B-dihydroxyoestra-1,3,5(10)-trien-7a-yl)but-1-enyl]-/V-n-hexylcinnamide (Example 8; 0.05 g) in a mixture of ethyl acetate (10 ml) and ethanol (2 ml) was stirred with a 20% palladium-on-charcoal catalyst (0.01 g) under an atmosphere of hydrogen at laboratory temperature and atmospheric pressure for 2 hours, and the mixture was then filtered and evaporated to dryness. There was thus obtained 3-p-[4-(3,17B-dihydroxyoestra-1,3,5(10)-trien-7a-yl)butyl]phenyl-/V-n-hexylpropionamide, the structure of which was confined by proton magnetic resonance and mass spectroscopy. Example 10 The processes described in Examples 8 and 9 were repeated using the appropriate amine in place of nhexylamine as starting material in Example 8. There were thus obtained the compounds described in the following table, all of which were oils the structures of which were confirmed by proton magnetic resonance and mass spectroscopy: — OH 45 CH2CH2CONR1R2 50 R1 55 6o 65 1 R2 n-butyl H n-butyl n-pentyl methyl H n-hexyl methyl -CH2CF2CF2CF3 H -CH2CF2C1 H 1 16 504 0 138 s Example 11 The process described in Example 8 was repeated using the appropriate amine and the appropriate co(17B-hydroxy-3-methoxyoestra-1 ,3,5(1 0)-trien-7a-yl)alk-1-enylcinnamic acid or benzoic acid as starting materials. There were thus obtained the compounds described in the following table, all of which were oils the structures of which were confirmed by proton magnetic resonance and mass spectroscopy: — w A -CONR"1=2 R' is Position 20 A3 25 ) 2 2 -(CH2)2-(CH ) 2 4 -(CH ) 2 4 , -(CH^)^-(CH ) 2 4 -(CH ) 2 4 30 35 -(CH in A4 R1 meta - n-hexyl H meta -CH=CH- n-hexyl H para -CH=CH- n-butyl H para -CH=CH- n-butyl methyl para - n-pentyl H para ortho - n-hexyl H - n-hexyl H benzene ring r2 The steroidal starting material wherein A3 is —(CH2)4— was prepared by a similar process to that described in Example 8 except that in the third paragraph thereof 5-bromopentanol was used in place of 340 bromopropanol. The phosphonate intermediates were prepared from the appropriate ethyl bromomethylcinnamate or ethyl bromomethylbenzoate and triethylphosphite. Example 12 The hydrogenation described in Example 9 was repeated using the appropriate unsaturated 45 compound, described in Example 11, as starting material. There were thus obtained the compounds described in the following table, all of which were oils the structures of which were confirmed by proton magnetic resonance and mass spectroscopy: 50 1 ? 4 A -CONR R 55 60 65 17 0 138 A3 30 35 40 45 A4. ring R2 R1 H n-hexyl H n-butyl H -(CH ) 2 6 -(CH ) - para -(CH para - n-pentyl H para - n-hexyl H ortho - n-hexyl H meta para - n-hexyl meta ) 2 6 -(CH ) 2 6 -(CH ) 2 6 25 benzene in ) 2 4 -(CH2)4- -(CH 20 Position 504 -CH2CH2-CH CH 2 2 -CH CH - n-butyl methyl Example 13 . The process described in Example 8 was repeated using p[2 -(3 - benzyl oxy -176 - hydroxyoestra 1,3,5(10) - trien - 7a - yl)ethenyl]cinnamic acid and n-octylamine as starting materials. There was thus obtained, as an oil p -[2 -(3 -benzyloxy -173 - hydroxyoestra -1,3,5(10) -trien -7a -yl)ethenyl] -N n - octylcinnamide. The hydrogenation process described in the second paragraph of Example 6 was repeated using the above compound as starting material, and there was thus obtained as an oil 3 - p - [2 - (3,176 dihydroxyoestra - 1,3,5(10) - trien - 7a - yl)ethyl]phenyl - N - n - octylpropionamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The cinnamic acid used as starting material was obtained from 3 - benzyloxy -176 - hydroxyoestra 1,3,5(10) - trien - 7a - carboxaldehyde (described in the sixth paragraph of Example 6) and ethyl p (diethylphosphonylmethyl)cinnamate by a similar process to that described in the sixth and seventh paragraphs of Example 8. Example 14 Aqueous N-sodium hydroxide solution (0.15 ml.) and benzoyl chloride (0.023 ml.) were successively added at 0°C to a stirred solution of N -n -butyl -N -methyl -11 -(3,176 -dihydroxyoestra -1,3,5(10) trien - 7a - yl)undecanamide (Example 2; 0.06 g.) in acetone (1 ml.) and the mixture was stirred at 0°C. for 30 minutes and poured into saturated aqueous sodium bicarbonate solution (10 ml.). The mixture was extracted three times with diethyl ether (15 ml. each time) and the combined extracts were washed with water (3 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 3:2 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil N n - butyl - N - methyl - 11 - (3 - benzoyioxy - 176 - hydroxyoestra - 1,3,5(10) - trien - 7a yDundecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 15 Sodium hydride (0.005 g. of a 50% dispersion in mineral oil) was added to a stirred solution of N - n butyl - 11 - (3,176 - dihydroxyoestra - 1,3,5(10) - trien - 7a - yl) - N - ethylundecanamide (Example 2; 0.052 g.) in tetrahydrofuran (2 ml.) and the mixture was stirred at laboratory temperature for 3.5 hours. so Butyryl chloride (0.014 ml.) was added and the mixture was stirred at laboratory temperature for 16 hours, diluted with ethyl acetate (30 ml.) and filtered. The filtrate was washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 1:1 v/v mixture of ethyl acetate and toluene as eluant. There was thus obtained as an oil N -n - butyl -11 -(3 -butyryloxy 176 - hydroxyoestra -1,3,5(10) - trien -7a - yl) -N - methylundecanamide, the structure of which was 55 confirmed by proton magnetic resonance and mass spectroscopy. The process described above was repeated using the appropriate acid chloride or acyl anhydride in place of butyryl chloride, and there were thus obtained the corresponding: 3-acetyl 3-propionyl 60 3-pivalyl 3-decanoyl 3-isopropoxycarbonyl esters of N - n - butyl - 11 - (3,176 - dihydroxyoestra - 1,3,5(10) - trien - 7a - yl) - /V - methylundecanamide. 65 18 0 138 504 Example 16 Acetic anhydride (0.2 ml.) was added to a stirred solution of N - n - butyl - 11 - (3,173 dihydroxyoestra -1,3,5(10) - trien -7a - yl) -N - methylundecanamide (Example 2; 0.052 g.) in pyridine (0.5 ml.) and the mixture was stirred at laboratory temperature for 16 hours. Water (0.1 ml.) was added and 5 then toluene was added and distilled off until the mixture was free of acetic acid. The residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained as an oil N -n - butyl -11 -(3,17(3 - diacetoxyoestra -1,3,5 -(10) - trien 7a - yl) - N - methylundecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The process described above was repeated using succinic anhydride in place of acetic anhydride, and w there were thus obtained as oils N - n - butyl - 11 - [3,173 - di - (B - carboxypropionyl)oestra 1,3,5(10) - trien - 7a - yl] - N - methylundecanamide and N - n - butyl - 11 - [178 - (3 carboxypropionyl) - 3 - hydroxyoestra - 1,3,5(10) - trien - 7a - yl] - N - methylundecanamide, which were separated one from the other during the chromatographic purification procedure, and the structures 15 of which were confirmed as above. Example 17 Jones' Reagent (8N-chromic acid solution; 0.15 ml.) was added to a stirred solution of N - n - butyl N - methyl - 11 - (3,173 - dihydroxyoestra - 1,3,5 - (10) - trien - 7a - yl) - undecanamide (Example 2; 20 0.262 g.) in acetone (15 ml.) at 0°C, and after 15 minutes isopropanol (0.1 ml.) was added and the mixture was evaporated to dryness. Water (15 ml.) was added and the mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution and then extracted three times with methylene chloride (30ml. each time). The combined extracts were washed with water (15 ml.), dried and evaporated to dryness, and the residue was purified by chromatography on a silica gel column using a 7:3 v/v mixture of toluene and ethyl acetate as 25 eluant. There was thus obtained N - n - butyl - N - methyl - 11 - (3 - hydroxy - 17 - oxooestra 1,3,5(10) - trien - 7a - yl)undecanamide as an oil, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 18 Lithium acetylide-ethylenediamine complex (0.097 g.) was added to a solution of N - n - butyl - N methyl - 11 - (3 - hydroxy - 17 - oxooestra - 1,3,5(10) - trien - 7a - yl)undecanamide (Example 17; 0.138 g.) in dimethyl sulphoxide and the mixture was kept at laboratory temperature for 4 hours. Water (0.1 ml.) was added, the mixture was evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 7:3 v/v mixture of toluene and ethyl acetate as eluant. There was thus 35 obtained N - n - butyl - N - methyl - 11 - (17a - ethynyl - 3,173 - dihydroxyoestra - 1,3,5(10) - trien 7a - yl)undecanamide as an oil, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. 30 Example 19 The process described in Example 1 was repeated except that 11 -(17a -ethynyl -3,173 -dihydroxyoestra -1,3,5(10) - trien -7a -yl)undecanoic acid and N - methyl -1H,1H - heptafluorobutylamine were used as starting materials. There was thus obtained 11 - (17a - ethynyl - 3,173 - dihydroxyoestra 1,3,5(10) - trien - 7a - yl) - d/V - (1H,1H - heptafluorobutyl) - N - methylundecanamide as an oil, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. 45 The undecanoic acid used as starting material was obtained as follows: The process described in Example 17 was repeated except that the corresponding undecanoic acid was used in place of the undecananamide, and that a 1:1 v/v mixture of toluene and ethyl acetate was used as eluant in the chromatographic purification. To a solution of the 11 - (3 - hydroxy - 17 - oxooestra 1,3,5(10) -trien -7a - yl)undecanoic acid thus obtained (0.075 g.) in dimethyl sulphoxide (1 ml.) was added so a 2-molar solution of dimsyl sodium in dimethyl sulphoxide (2 ml.) which had been saturated with acetylene gas, and the mixture was kept at laboratory temperature for 18 hours, diluted with water (15 ml., ) acidified to pH 1 with aqueous N-hydrochloric acid, and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 1:1 v/v mixture of toluene and ethyl 55 acetate as eluant. There was thus obtained the desired 11 - (17a - ethynyl - 3,173 - dihydroxyoestra 1, 3,5(1 0)trien -7a - yljundecanoic acid. 40 Example 20 A stirred mixture of cupric acetate (0.027 g.), iodine (0.038 g.), N - n - butyl - N - methyl - 11 so (3,173 -dihydroxyoestra -1,3,5(10) -trien -7a -yl)undecanamide (Example 2; 0.052 g.) and acetic acid (2 ml.) was heated at 55°C. for 18 hours and then poured into a mixture of ice (10 m.) and saturated aqueous sodium bicarbonate solution (5 ml.). The mixture was extracted three times with ethyl acetate (15 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 3:2 v/v mixture of toluene and ethyl acetate S5 as eluants and there were thus separately obtained N -n - butyl - N - methyl -11 -(3,173 -dihydroxy 19 0 138 504 2 - iodooestra - 1,3,5(10) - trien - 7a - yljundecanamide (eluted first) and N - n - butyl - N - methyl 11 -(3,17(3 - dihydroxy -4 - iodooestra -1,3,5(10) - trien -7a - yDundecanamide (eluted second). s '0 is 20 25 30 35 40 . 45 so 55 60 65 Example 21 The process described in the first two paragraphs of Example 1 was repeated except that 11 - (17(3 acetoxy - 3 - hydroxyoestra - 1,3,5(10),6 - tetraen - 7 - yl)undecanoic acid and /V-methyl-/V-butylamine were used as starting materials. There was thus obtained as an oil N - n - butyl - N - methyl - 11 (3,17(3 - dihydroxyoestra - 1,3,5(10),6 - tetraen - 7 - yl)undecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The oestra-tetraene used as starting material was obtained as follows: A solution of bromine (0.1 14 ml.) in acetic acid (2 ml.) was added dropwise to a stirred solution of 11 (173 - acetoxy - 3 - oxo - oestra - 4 - en - 7a - yl)undecanoic acid (Example 2; 0.5 g.) in a mixture of diethyl ether (5 ml.) and acetic acid (2 ml.) which was cooled to 15°C. and the mixture was stirred at that temperature for 30 minutes and then poured into water (50 ml.). The mixture was extracted three times with methylene chloride (30 ml. each time) and the combined extracts were washed with water, dried and rapidly evaporated to dryness under reduced pressure at a bath temperature below 20°C. A solution of the residue, which consisted of 11 - (173 - acetoxy - 2,6 - dibromo - 3 - oxooestr - 4 - en - 7a yl)undecanoic acid in dimethylformamide (3 ml.) was immediately added to a stirred mixture of lithium bromide (1.0 g.), lithium carbonate (1.0 g.) and dimethylformamide (10 ml.) which was heated under reflux, and the mixture was stirred and heated under reflux for 30 minutes and then evaporated to dryness under reduced pressure. Water (20 ml.) was added to the residue and the mixture was acidified to pH 1 with aqueous N-hydrochloric acid and extracted three times with methylene chloride (20 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 7:3 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 11 -(173 - acetoxy -3 - hydroxyoestra -1,3,5(10),6 - tetraen -7 -yl)undecanoic acid. Example 22 Butyl-lithium (0.8 ml. of a 1.6 molar solution in hexane) was added dropwise to a stirred solution of [9 (N - n - butyl - N - methylcarbamoyl)nonyl]triphenylphosphonium bromide (1.2 g.) in a mixture of dimethyl sulphoxide (2 ml.) and tetrahydrofuran (18 ml.), a solution of 3 - benzyloxy - 173 hydroxyoestra - 1,3,5(10),6,8(9),14(15) - hexaene -7 - carboxaldehyde (0.05 g.) in tetrahydrofuran (2 ml.) was then added and the mixture was stirred at laboratory temperature for 1 hour and then evaporated to dryness under reduced pressure. Water (15 ml.) was added and the mixture was extracted three times with ethyl acetate (10 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 3:1 v/v mixture of petroleum ether (b.p. 60— 80°C.) and acetone as eluant. There was thus obtained as an oil 11 - (3 benzyloxy - 173 - hydroxyoestra - 1,3,5(10),6,8(9),14(15) - hexaen - 7 - yl) - N - n - butyl - N methylundec - 10 - enamide. The above compound was hydrogenated by a similar process to that described in Example 4 and there was thus obtained as an oil N -n - butyl -N - methyl -11 -(3,173 - dihydroxyoestra - 1,3,5(1 0),6,8(9) pentaen - 7 - yf)undecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The phosphonium bromide used as starting material was obtained as follows: Triethylamine (6.5 ml.) and /V-methyl-/V-n-butylamine (5.5 ml.) were successively added to a stirred solution of 10-bromodecanoyl chloride (13 g.) in diethyl ether (100 ml.) which was maintained at 0°C. and the mixture was stirred at that temperature for 2 hours. Water (20 ml.) was added and the ethereal layer was separated, dried and evaporated to dryness. Triphenylphosphine (10.95 g.) was added to a stirred solution of the 10-bromo-/V-n-butyl-/V-methyldecanamide thus obtained (12.2 g.) in acetonitrile (125 ml.) and the mixture was stirred and heated under reflux for 16 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride (50 ml.), diethyl ether (200 ml.) was added and the solvent was decanted off. There was thus obtained as solid residue [9 -(N -n - butyl -N methylcarbamoyDnonyl] - triphenylphosphonium bromide which was used without further purification. The steroidal carboxaldehyde used as starting material was obtained as follows: 173-Acetoxy-6-bromo-7a-cyanooestra-1,3,5(10-trien-3-ol (Example 6, paragraph 4) was converted to the 3-benzyloxy derivative thereof by a similar process to that described in paragraph 5 of Example 6, and this compound was purified by chromatography on a silica gel column using a 19:1 v/v mixture of toluene and ethyl acetate as eluant. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.03 g.) was added to a stirred solution of the above 3benzyloxy compound (0.51 g.) in toluene (25 ml.) and the mixture was stirred and heated under reflux for 1 hour, cooled, diluted with diethyl ether (40 ml.) and washed three times with saturated aqueous sodium bicarbonate solution and once with water (50 ml. each time). The organic layer was dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 19:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained 173 - acetoxy - 3 - benzyloxyoestra 1,3,5(10),6,8(9),14(15) - hexaene - 7 - carbonitrile, which was reduced to the corresponding 7carboxaldehyde by a similar process to that described in paragraph 6 of Example 6. 20 0 138 5 w 15 20 25 30 35 40 45 50 55 60 504 Example 23 2,4-Bis-(p-methoxyphenyl) - 1,3 - dithia - 2,4 - diphosphetane - 2,4 - disulphide (Lawesson's Reagent; 0.375 g.) was added to a stirred solution of N -n - butyl -11 -(3 - methoxy -176 -tetrahydropyranyloxyoestra -1,3,5(10) -trien -7a -yl)undecanamide (0.25 g.) in xylene (14 ml.) and the mixture was stirred and heated at 130°C. for 5 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran (2 ml.), water (2 ml.) and acetic acid (4 ml.) and the solution was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained as an oil N - n - butyl - 11 - (17B hydroxy -3 - methoxyoestra -1,3,5(10) - trien -7a - yDthioundecanamide. Boron tribromide (0.5 ml.) was added to a stirred solution of the above thioamide (0.061 g.) in methylene chloride (3 ml.) which was cooled to -20°C, and the mixture was stirred at that temperature for 4 hours and then poured into saturated aqueous sodium bicarbonate solution (2 ml.). The mixture was extracted three times with methylene chloride (2 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography as described above and there was thus obtained as an oil N - n - butyl - 11 - (3,176 - dihydroxyoestra - 1,3,5(10) trien -7a -yDthioundecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The tetrahydropyranyloxy-undecanamide used as starting material was obtained as follows: The procedure described in the third, fourth, fifth and sixth paragraphs of example 6 was repeated except that methyl iodide was used in place of benzylbromide in the fifth paragraph. There was thus obtained 176 - hydroxy -3 - methoxyoestra -1,3,5(10) - trien -7a - carboxaldehyde. Dihydropyran (2.4 ml.) and p-toluenesulphonic acid (4.46 ml. of an 0.1 molar solution in tetrahydrofuran) were successively added to a stirred solution of this aldehyde (2.8 g.) in methylene chloride (50 ml. ) which was kept at 0°C, and after 5 minutes pyridine (0.2 ml.) was added and the mixture was washed with saturated aqueous sodium bicarbonate solution (5 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluant. The 3-methoxy-176-tetrahydropyranyloxyoestra-1,3,5(10)-trien-7a-carboxaldehyde thus obtained was then converted to the desired amide by a similar procedure to that described in the last paragraph of Example 6 [reaction with (9-carboxynonyl)triphenylphosphonium bromide] followed by that described in the first paragraph of Example 6, except that n-butylamine was used in place of /V-methylisobutylamine. Example 24 Triethylamine (0.053 g.) and methanesulphonyl chloride (0.44 g.) were successively added to a stirred solution of 176 - acetoxy - 3 - benzoyloxy - 7a - (11 - hydroxyundecyl)oestra - 1,3,5(10) - triene (penultimate paragraph of Example 1; 0.206 g.) in methylene chloride (3 ml.) at -10°C, and the mixture was stirred for 30 minutes and then shaken with diethyl ether (30 ml.) and saturated aqueous sodium bicarbonate solution. The layers were separated, the aqueous layer was extracted with diethyl ether (30 ml.) and the combined ethereal solutions were washed with water (5 ml.), dried and evaporated to dryness. A mixture of the 11-methanesulphonyloxyundecyl compound thus obtained (0.228 g.) and diethylamine (4 ml.) was heated under reflux for 16 hours and evaporated to dryness. The residue was purified by chromatography on a silica gel column (Kieselgel 60) using a 4% v/v solution of triethylamine in toluene as eluant. There was thus obtained as an oil 176 - acetoxy - 3 - benzoyloxy - 7a - (11 diethylaminoundecyl)oestra - 1,3,5(10) -triene, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The above compound was hydrolysed by a similar process to that described in the second part of Example 1. There was thus obtained as an oil 7a -(11 - diethylaminoundecyDoestra -1,3,5(10) - triene 3,176 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 25 A mixture of 176 - acetoxy - 3 - benzoyloxy - 7a - (11 - methanesulphonyloxyundecyDoestra 1,3,5(10) -triene (Example 24; 0.1 g.) and saturated methanolic ammonia solution (10 ml.) was heated in a sealed tube at 100°C. for 16 hours and was then evaporated to dryness. Butyryl chloride (0.2 ml.) was added to a stirred solution of the residue in pyridine (1 ml.) and the mixture was stirred at laboratory temperature for 16 hours, and then poured into water (10 ml.). The mixture was extracted three times with diethyl ether (10 ml. each time) and the combined extracts were washed with water (2 ml.), dried and evaporated to dryness. Aqueous N-sodium hydroxide solution (1 ml.) was added to a solution of the residue in methanol (5 ml.) and the mixture was kept at laboratory temperature for 18 hours, neutralised with aqueous Nhydrochloric acid and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (5 ml.), dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 1:1 v.v. mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil N - [N -(3,173 - dihydroxyoestra -1,3,5(10) - trien -7a - yDundecyl]butyramide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. 65 21 0 138 504 Example 26 The process described in the last paragraph of Example 6 was repeated except that (8used in place of (9-carboxynonyl)bromide was hexanamidooctyDtriphenylphosphonium triphenylphosphonium bromide. The hydrogenation process described in the second paragraph of 5 Example 6 was then repeated using the N -[9 -(3 - benzyloxy - 176 - hydroxyoestra -1,3,5(10) - trien 7a -yl)non -8 - enyl]hexanamide thus obtained as starting material, and there was thus obtained as an oil " N - [9 - (3,176 - dihydroxyoestra - 1,3,5(10) - trien - 7a - yl)nonyl]hexanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The (8-hexanamidooctyl)triphenylphosphonium bromide used as starting material was obtained as 10 follows: Triethylamine (0.35 ml.) and hexanoyl chloride (0.35 ml.) were successively added to a stirred solution of 8-bromooctylamine (0.5 g.) in diethyl ether (5 ml.) and the mixture was stirred at laboratory temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (5 ml.) was added, the ethereal layer was separated and the aqueous layer was extracted three times with diethyl ether (5 ml. each time). The 15 combined ethereal solutions were washed with water (2 mi.), dried and evaporated to dryness. Triphenylphosphine (0.331 g.) was added to a stirred solution of the above /V-(8-bromoethyl)hexanamide (0.385 g.) in acetonitrile (10 m.) and the mixture was stirred and heated under reflux for 16 hours and then evaporated to dryness. The residue was stirred with diethyl ether and the ethereal solution was decanted off. There was thus obtained as residual gum (8-hexanamidooctyl)triphenylphosphonium bromide which used without further purification. was 20 25 30 35 40 45 so 55 60 Example 27 The procedure described in the last paragraph of Example 6 was repeated except that (7 - N methylcarbamoylheptyDtriphenylphosphonium bromide (prepared from 8-bromo-/V-methyloctanamide and triphenylphosphine by a similar process to that described in the last part of Example 22) was used in place of (9-carboxynonyl)triphenylphosphonium bromide. The hydrogenation process described in the second paragraph of Example 6 was then repeated using the 9 - (3 - benzyloxy - 176 - hydroxyoestra 1, 3,5(1 ojtrien - 7a - yl) - N - methylnon - 8 - enamide thus obtained as starting material, and there was thus obtained as an oil 9 -(13,17(3 - dihydroxyoestra -1,3,5(10) - trien -7a - yl) -N - methylnonamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 28 A mixture of 9 - (3,17(3 - dihydroxyoestra - 1,3,5(10) - trien - 7a - yl) - N - methylnonanamide (Example 27; 0.047 g.) and a molar solution of borane in tetrahydrofuran (5 ml.) was heated under reflux for 2 hours, cooled and concentrated aqueous hydrochloric acid (2 ml.) was added. The tetrahydrofuran was removed by evaporation and the residue was basified with aqueous 5N-sodium hydroxide solution and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (2 ml.), dried and evaporated to dryness. There was thus obtained as an oil 7a - (9 - methylaminononyUoestra - 1,3,5(10) - triene - 3,17(3 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 29 Hexanoyl chloride (0.5 ml.) was added to a solution of 7a -(9 - methylaminononyl)oestra -1,3,5(10) trien - 3,17(3 - diol (Example 28; 0.037 g.) in pyridine (5 ml.) and the mixture was kept at laboratory temperture for 16 hours and then extracted with ethyl acetate (20 ml.). The extract was washed successively with aqueous 2N-hydrochloric acid (5 ml.), saturated aqueous sodium bicarbonate solution (5 ml.) and water (2 ml.), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluant, and there was thus obtained N - [9 - (3,17(3 - dihexanoyloxyoestra - 1,3,5(10) - trien - 7a - yl)nonyl] - N - methylhexanamide. A solution of this compound (0.027 g.) in methanol (5 ml.) and aqueous 2N-sodium hydroxide solution (2 m.) were stirred at laboratory temperature for 16 hours and the mixture was then extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and there was thus obtained as residual oil N -[9 -(3,176 - dihydroxyoestra -1,3,5(10) - trien 7a - yl)nonyl] - N - methylhexanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 30 /V-Methylmorpholine (0.028 ml.) and isobutyl chloroformate (0.038 ml.) were successively added to a stirred solution of 7a -(9 - methylaminononyl)oestra -1,3,5(10) -trien -3,17(3 - diol (Example 28; 0.08 g.) in tetrahydrofuran (3 ml.) and the mixture was stirred at laboratory temperature for 150 minutes. Saturated aqueous sodium bicarbonate solution (2 ml.) was added and the mixture was extracted three times with methylene chloride (10 ml. each time). The combined extracts were washed with water (5 ml.), dried and evaporated to dryness and there was thus obtained as residual oil isobutyl N - [9 - (3,17(3 dihydroxyoestra -1,3,5(10) - trien -7a - yl)nonyl] - N - methylcarbamoate. 22 0 138 5 10 15 20 25 30 35 40 45 50 504 Example 31 The process described in Example 25 was repeated except that 178-acetoxy -3 - methoxy -7a -(9 methanesulphonyloxynonyl)oestra - 1,3,5(10) -triene was reacted with ammonia, and that the resulting 9aminononyl compound was reacted with n-butyl isocyanate. The 176-acetoxy group was removed by hydrolysis with aqueous methanolic sodium hydroxide solution, and the 3-methoxy group was converted to a hydroxy group with boron tribromide by a similar process to that described in the second paragraph of Example 8. There was thus obtained /V1 -n -butyl -N3 -[9 -(3,17(3 -dihydroxyoestra -1,3,5(10) -trien 7a - yl)nonyl]urea, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The steroidal starting material was prepared by a similar process to that described in Examples 1 and 24, except that 9-bromononanol was used in place of 11-bromoundecanol in the third paragraph of Example 1, and that the benzoylation step described in the eighth paragraph of Example 1 was replaced by the methylation step described in the fourth paragraph of Example 8. Example 32 A solution of sodium thiobutoxide [generated from butanethiol (0.045 g.) and a 60% dispersion of sodium hydride in mineral oil (0.02 g.)] in tetrahydrofuran (2 ml.) was added to a solution of 176 - actoxy 3 - benzoyloxy - 7a - (11 - methanesulphonyloxyundecyl)oestra - 1,3,5(10) - triene (Example 24; 0.078 g.) in tetrahydrofuran (1 ml.) and the mixture was kept for 1 hour at laboratory temperature, neutralised with aqueous N-hydrochloric acid and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (3 ml.), dried and evaporated to dryness, and the residue was dissolved in methanol (3 ml.). Aqueous N-sodium hydroxide solution (1 ml.) was added and the mixture was kept at laboratory temperature for 18 hours, neutralised with aqueous N-hydrochloric acid and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (10 ml.), dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 7a - (11 - n - butylthioundecyl)oestra - 1,3,5(10) - triene - 3,17(3 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 33 A solution of sodium metaperiodate (0.016 g.) in water (0.5 ml.) was added to a solution of 7a - (1 1 n -butylthioundecyl)oestra -1,3,5(10) -triene -3,176 -diol (Example 32; 0.035 g.) in methanol (1 ml.) and the mixture was stirred at laboratory temperature for 18 hours, evaporated to dryness and evaporated from toluene to remove the last traces of water. The residue was extracted three times with acetone and the combined extracts were evaporated to dryness. There was thus obtained as an oil 7a - (11 - n butyisulphinylundecyDoestra - 1,3,5(10) - triene - 3,176 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 34 /n-Chloroperbenzoic acid (0.026 g.) was added to a solution of 7a -(11 -n - butylthioundecyljoestra 1,3,5(10) -triene -3,17(3 - diol (Example 32; 0.035 g.) in chloroform (1 ml.) and the mixture was kept for 2 hours at laboratory temperature and then evaporated to dryness. The residue was shaken with water (2 ml.) and the mixture extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with saturated aqueous sodium bicarbonate solution and then with water, dried and evaporated to dryness. There was thus obtained as residual oil 7a -(11 -n - butylsulphonylundecyDoestra -1,3,5(10) triene - 3,176 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 35 The process described in Example 32, 33 and 34 was repeated using the appropriate thiol and the appropriate 7a-(co-methanesulphonyloxyalkyl)-steroidal derivative as initial starting materials in the process of Example 32. There were thus obtained as oils the compounds described in the following table: 55 60 65 23 0 138 504 OH 1 n X R 6 S n-nonyl 9 S n-hexyl 9 S n-heptyl 9 S 4, 4, 5, 5, 5 - p e n t a f l u o r o p e n t y l 9 S p-chlorophenyl 9 S p-chlorobenzyl 9 S p-chlorophenethyl 10 S n-pentyl 10 S 4, 4, 4 - t r i f l u o r o b u t y l 10 S 4, 4, 5, 5, 5 - p e n t a f l u o r o p e n t y l 10 S 1H, l H - h e p t a f l u o r o b u t y l 10 S m-chlorophenyl 10 S p-chlorophenyl 10 S p-f l u o r o p h e n y l 10 S P-bromophenyl 10 S p-chlorobenzyl 10 S p-chlorophenethyl 11 S 4, 4, 4 - t r i f l u o r o b u t y l 6 SO n-nonyl 9 SO n-hexyl 9 SO n-heptyl 9 SO 4, 4, 5, 5, 5 - p e n t a f l u o r o p e n t y l 9 SO p-chlorophenyl >4 0 138 504 n X R1 9 SO p-chlorobenzyl 9 SO P-chlorophenethyl 10 SO n-pentyl 10 SO 4, 4, 4 - t r i f l u o r o b u t y l 10 SO 4, 4, 5, 5, 5 - p e n t a f l u o r o p e n t y l 10 SO 1H, l H - h e p t a f l u o r o b u t y l 10 SO p-chlorophenyl 10 SO p-fluorophenyl 10 SO p-bromophenyl 10 SO p-chlorobenzyl 10 SO 11 SO p-chlorophenethyl 4, 4, 4 - t r i f l u o r o b u t y l 9 S02 n-heptyl 10 S02 p-chlorobenzyl 10 S02 p-chlorophenethyl 5 w 15 20 25 30 35 The 7a-((o-methanesulphonyloxyalkyl-steroidal derivatives used as starting materials were obtained as described in Example 24 from the corresponding 7a-(co-hydroxyalkyl)-steroidal derivatives which in turn were obtained as described in Example 1 using the appropriate o)-(dimethyl-t-butylsilyloxy)alkyl bromide in place of 11-(dimethyl-t-butylsilyloxy)undecyl bromide as intermediate. Example 36 The process described in the penultimate paragraph of Example 3 was repeated except that [4 - (A/ heptylsulphamoyl)butyl]triphenylphosphonium bromide was used in place of (4 - carboxybutyl)triphenyl40 phosphonium bromide. There was thus obtained as an oil N - heptyl - 7 - (3,176 - dihydroxyoestra 1,3,5(10) - trien - 7a - yljhept - 4 - enesulphonamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Both the 3-benzoyl and 17-acetyl groups were removed during the reaction, by contrast with Example 3 wherein only the 3-benzoyl group was removed. The phosphonium bromide used as starting material was obtained as follows: 45 Sodium iodide (1.1 g.) was added to a solution of 1,4-butanesultone (1.0 g.) in acetone (10 ml) and the mixture was heated under reflux for 1 hour, cooled and filtered. Dimethylformamide (0.05 ml.) and oxalyl chloride (0.475 ml.) were successively added to a stirred solution of the sodium 4-iodobutanesulphonate thus obtained (1 .32 g.) in toluene (20 ml.) and the mixture was stirred at laboratory temperature for 3 hours, filtered and the filtrate was evaporated to dryness. 50 Triethylamine (0.65 ml.) and n-heptylamine (0.68 ml.) were successively added to a solution of the 4iodobutanesulphonyl chloride thus obtained (1.3 g.) in diethyl ether (30 ml.) and the mixture was kept at laboratory temperature for 2 hours and then evaporated to dryness. The residue was dissolved in ethyl acetate and the solution was washed twice with water (5 ml. each time), dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using methylene chloride as eluant, 55 and there was thus obtained N-heptyl-4-iodobutanesulphonamide. A mixture of the above sulphonamide (0.25 g.), triphenylphosphine (0.18 g.) and toluene (10 ml.) was heated under reflux for 2 hours and then cooled, and the toluene solution was decanded off the oil which formed. The oil was washed with more toluene, and then used without further purification. It consisted of 4-(/V-heptylsulphamoyl)butyl]triphenylphosphonium bromide. 60 Example 37 A solution of N - heptyl - 7 - (3,178 - dihydroxyoestra - 1,3,5(10) - trien - 7a - yl)hept - 4 enesulphonamide (Example 36; 0.04 g.) in ethyl acetate (10 ml.) was stirred with a 10% palladium-oncharcoal catalyst (0.01 g.) at laboratory temperature for 90 minutes and then filtered, and the filtrate was 65 evaporated to dryness. There was thus obtained as residual oil N - heptyl -7 -(3,178 - dihydroxyoestra 25 0 138 504 1,3,5(10) - trien - 7a - yi) - heptanesulphonamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. 5 10 15 20 25 30 35 40 45 50 55 60 65 Example 38 n-Butyl-lithium (0.27 ml. of a 1.5 molar solution in diethyl ether) was added to a stirred solution of 11 (173 - acetoxy - 3 - hydroxyoestra - 1,3,5(10) - trien - 7a - yUundecanoic acid (Example 2; 0.046 g.) in tetrahydrofuran (1 ml.) and the mixture was stirred at laboratory temperature for 2 hours. Saturated aqueous sodium hydrogen tartrate solution (2 ml.) was added and the mixture was extracted three times with ethyl acetate (5 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 17:3 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 15 - (3,173 - dihydroxyoestra 1,3,5(10) -trien -7a -yUpendadecan -5 - one, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Example 39 n-Butyl-lithium (0.341 ml. of a 1.6 molar solution in hexane) was added to a stirred solution of 2oxotridecylphosphonate (0.193 g.) in tetrahydrofuran (10 ml.) which was maintained at -70°C. and the mixture was stirred at that temperature for 40 minutes. A solution of 3 - (173 - acetoxy - 3 benzoyloxyoestra - 1,3,5(10) - trien - 7a - yDpropionaldehyde (Example 3; 0.2 g.) in tetrahydrofuran (10 ml.) was added and the mixture was allowed to warm up to laboratory temperature and was stirred at that temperature for 4.5 hours. Acetic acid was added until the mixture was acidic and the mixture was evaporated to dryness. Water (10 ml.) was added and the mixture was extracted three times with ethyl acetate (30 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and there was thus obtained as residual oil 1 -(173 - acetoxy -3 - benzoyloxyoestra -1,3,5(10) trien - 7a - yl)hexadec - 3 - en - 5 - one. The above compound was hydrogenated by a similar process to that described in Example 4, and there was thus obtained as an oil 1 - (173 - acetoxy - 3 - benzoyloxyoestra - 1,3,5(10) - trien - 7a yl)hexadecan - 5 - one. The above compound was hydrolysed by a similar process to that described in the second paragraph of Example 1, and there was thus obtained 1 - (3,173 - dihydroxyoestra - 1,3,5(10) - trien - 7a yDhexadecan - 5 - one, which was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant. Example 40 The process described in Example 26 was repeated using [3 - (5 - N - n - butyl - N methylcarbamoyl pentyloxy)propyl]triphenylphosphonium bromide and 3 - benzoyloxy - 176 hydroxyoestra -1,3,5(10) -triene -7a - carboxaldehyde (Example 6) as starting materials. There was thus obtained after simultaneous hydrogenolysis and hydrogenation, as an oil, 6 - [4 - (3,173 - dihydroxyoestra -1,3,5(10) -triene -7a -yl)butoxy] -N -n -butyl -N -methylhexanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The triphenylphosphonium bromide used as starting material was obtained from 6-bromohexanoic acid by reaction with oxalyl chloride and /V-methyl-n-butylamine to form the amide, then with 1,3the in dimethylformamide and sodium to . form 6-(3trimethylene hydride glycol hydroxypropoxy)hexanamide, followed by conversion of the 3-hydroxy group to a 3-bromo group with bromine and triphenylphosphine in dimethylformamide and finally reaction with triphenylphosphine in toluene. Example 41 A mixture of 7a-(10)mesyloxydecyl)oestra-1,3,5(10)-triene-3,173-diol N(0.07 g.) and methylhexylamine (0.5 ml.) was heated at 75°C. for 2 hours and the excess of /V-methylhexylamine was removed by evaporation. The residue was purified by chromatography on a silica gel column using a 24:1 v/v mixture of ethyl acetate and triethylamine as eluant, and there was thus obtained as an oil 7a - (10 N - methylhexylaminodecyl) - oestra - 1,3,5(10) - trien - 3,173 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The process described above was repeated using A/-methyl-4,4,5,5,6,6,6-heptafluorohexylamine or Nmethyl-p-chlorophenethylamine in place of W-methylhexylamine, and there were thus obtained respectively 7a - [10 - [N - methyl - 4,4,5,5,6,6,6 - heptafluorohexylamino)decyl) - and 7a - (10 - N methyl -p - chlorophenethylaminodecyl) - oestra -1,3,5(10) - trien -3,173 - diol. The 7a-mesyloxydecyl-oestradiol used as starting material was obtained from 3 - benzyloxy - 17a hydroxyoestra - 1,3,5(10) - triene - 7a - carboxaldehyde (described in Example 6) by reaction with 9bromide from 9-bromononanol, (dimethyl-t-butylsilyloxynonyl)triphenylphosphonium (prepared dimethyl-t-butylsilyl chloride and triphenylphosphine) by a similar process to that described in the last paragraph of Example 6, followed by acid hydrolysis of the silyl group, mesylation of the decenol thus obtained and simultaneous hydrogenation of the mesyloxydecene side-chain to a mesyloxydecane sidechain and hydrogenolysis of the 3-benzyloxy group. 26 0 138 5 10 504 Example 42 m-Chloroperbenzoic acid (0.02 g.) was added to a solution of 7a - (10 - N - methylhexylaminodecyl)oestra - 1,3,5(10) - triene - 3,17(3 - diol (Example 41; 0.047 g.) in methylene chloride (8 ml.) and the mixture was kept at laboratory temperature for 2.5 hours. Methylene chloride (20 ml.) was added and the solution was washed successively with saturated aqueous sodium sulphite solution, saturated aqueous sodium bicarbonate solution and water (5 ml. each time), dried and evaported to dryness. The residue was purified by chromatography on a silica gel column using a 7:2:1 v/v/v mixture of ethyl acetate, methanol and triethylamine as eluant. There was thus obtained as an oil 7a - (10 - /V - methyl - N hexylaminodecyl)oestra - 1,3,5(10) - triene - 3,173 - diol - N - oxide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The /V-oxides of 7a -[10 - (A/ - methyl -4,4,5,5,6,6,6 - heptafluorohexylamino)decyl]- and 7a -(10 A/-methyl - p - chlorophenethylaminodecyl)oestra - 1,3,5(10) - triene - 3,173 - diol (also described in Example 41) were similarly obtained by oxidation with /n-chlorobenzoic acid. Example 43 The process described in Example 32 was repeated using 7a -(7 - mesyloxyheptyl)oestra -1,3,5(10) triene -3,17(3 - diol (obtained as described in Example 41 using initially 6-(dimethyl-t-butylsilyloxy)hexyltriphenylphonium bromide) and 2-n-pentylthio-ethanol (obtained from pentanethiol and 2-bromoethanol) as starting materials. There was thus obtained as an oil 7a - [7 - (2 - n - pentylthioethoxy)heptyl]oestra 20 1,3,5(10) - triene - 3,173 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The above compound was oxidised with sodium metaperiodate by a similar process to that described in Example 33, and there was thus obtained 7a - [7 - (2 - n - pentylsulphinylethoxy)heptyl]oestra 1,3,5(10) - triene -3,173 - diol. 25 Example 44 The process described in Example 32 was repeated using 7a-(6-mesyloxyhexyl)oestra-1, 3,5(1 0)-triene3,173-diol (obtained as described in Example 41 using initially 5-(dimethyl-t-butylsilyloxy)pentyltriphenylphosphonium bromide and 3-n-pentylthiopropanethiol (obtained from trimethylene-1,3-dithiol and pentyl 30 bromide) as starting materials. There was thus obtained as an oil 7a - [6 - (3 - n - pentylthiopropylthio)hexyl] - oestra - 1, 3,5(1 0)triene - 3,173 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The above compound was oxidised with sodium metaperiodate by a similar process to that described in Example 33, and there was thus obtained 7a - [6 - (3 - n - pentylsulphinylpropyl35 sulphinyl)hexyl]oestra -1,3,5(10) - triene -3,173 - diol. is 40 45 Example 45 The process described in Example 1 was repeated using N - methyl - n - butylamine and 3 - [7 (3,173 - dihydroxyoestra - 1,3,5(10) - triene - 7a - yl) - heptylthiojpropionic acid as starting materials. There was thus obtained as an oil 3 - [7 - (3,173 - dihydroxyoestra - 1,3,5(10) - triene - 7a yDheptylthio] - N - n - butyl - N - methylpropionamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. The propionic acid used as starting material was obtained by the reaction of 7a - (7 - mesyloxyheptyl)oestra -1,3,5(10) - triene -3,173 - diol (obtained as described in Example 41 using initially 6-(dimethyl t - butylsilyloxy)hexyltriphenylphosphonium bromide) with methyl 3-mercaptopropionate, followed by alkaline hydrolysis of the methyl ester. Example 46 A mixture of 7a-(10-mesyloxydecyl)oestra-1,3,5(10)-triene-3,173-diol (Example 41; 0.1 g.), sodium 50 iodide (0.034 g.), butylmethylphenylphosphine (0.039 ml.) and acetonitrile (5 ml.) was heated under reflux for 16 hours, evaporated to dryness and the residue was dissolved in methylene chloride (20 ml.). The mixture was filtered and the filtrate was diluted with diethyl ether (100 ml.). The mixture was filtered and the solid residue, which consisted of butyl[10 - (3,173 - dihydroxyoestra - 1,3,5(10) - triene - 7a yl)decyl]methylphenylphosphonium iodide, was dissolved in a mixture of tetrahydrofuran (6 ml.) and 55 dimethyl sulphoxide (1 ml.). n-Butyl-lithium (0.5 ml. of a 1.6M molar solution in hexane) was added and the mixture was stirred at laboratory temperature for 90 minutes. Water (10 ml.) was added and the mixture was extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 97:3 v/v mixture of methylene chloride and methanol as eluant. There were thus obtained 60 as oils a less polar substance 7a - (10 - butylphenylphosphinyldecyDoestra - 1,3,5(10) - triene - 3,173 diol and a more polar substance 7a -(10 - methylphenylphosphinyldecyl)oestra- -1, -3, -5 - (10)-triene3,178 - diol, the structures of both of which were confirmed by proton magnetic resonance and mass spectroscopy. 65 27 0 138 5 10 504 Example 47 A mixture of butyl[10 - (3,17(3 - dihydroxyoestra - 1,3,5(10) - triene - 7a - yl)decyl]methylphenylphosphonium iodide (Example 46; 0.05 g.), tetrahydrofuran (5 ml.) and aqueous 30% sodium hydroxide solution (2 ml.) was stirred at laboratory temperature for 18 hours, diluted with water (10 ml.) and extracted three times with ethyl acetate (1 ml. each time). The combined extracts were washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 25:1 v/v mixture of methylene chloride and methanol as eluant. There was thus obtained as an oil 7a - (10 butylmethylphosphinyldecyUoestra - 1,3,5(10) - triene - 3,17(3 - diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy. Claims for the Contracting States: BE CH DE FR GB IT LI LU NL SE 1. A sterioid derivative of the formula: '5 ST—A—X—R1 wherein ST is a 7a-linked steroid nucleus of the general formula: — 25 30 35 40 45 so 55 60 55 wherein the dotted lines between carbon atoms 6 and 7, and carbon atoms 8 and 9, of the steroid nucleus indicate that there is an optional double bond between carbon atoms 6 and 7, or that there are two optional double bonds between carbon atoms 6 and 7 and carbon atoms 8 and 9; wherein the aromatic ring A may optionally bear one or two halogen or alkyl substituents; wherein R3 is hydrogen or alkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl or aroyl each of up to 10 carbon atoms; wherein R16 is hydrogen, alkyl of up to 6 carbon atoms which is preferably in the (3-configuration, or hydroxy which is preferably in the a-configuration; wherein either R17 (in the (3-configuration) is hydroxy or alkanoyloxy, carboxyalkanoyloxy or aroyloxy each of up to 10 carbon atoms; and R27 (in the a-configuration) is hydrogen or alkyl, alkenyl or alkynyl each of up to 6 carbon atoms; or R17 and R27 together form oxo (=0); wherein R18 is alkyl of up to 6 carbon atoms; wherein A is straight- or branched-chain alkylene, alkenylene or alkynylene each of from 3 to 14 carbon atoms, which may have one or more hydrogen atoms replaced by fluorine atoms, or has the formula —A1—Y—A11— wherein A1 and A11 are each alkylene or alkenylene, optionally fluorinated, having together a total of 2 to 13 carbon atoms and Y is —O— —S—, —SO—, —S02— , —CO— or —NR— wherein R is hydrogen or alkyl of up to 3 carbon atoms; or A1 is alkylene or alkenylene, optionally fluorinated, and A11 is a direct link or alkylene or alkenylene, optionally fluorinated, such that A1 and A11 together have a total of 1 to 12 carbon atoms, and Y is —NRCO— , —CONR —, —COO—, —OCO— or phenylene wherein R has the meaning stated above; wherein R1 is hydrogen, or alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl or arylalkyl each of up to 10 carbon atoms, or dialkylaminoalkyl wherein each alkyl is of up to 6 carbon atoms, or R1 is joined to R2 as defined below; and wherein X is —CONR2—, —CSNR2— , — NR12—CO— , —NR12—CS— , —NR12—CONR2— , NR22 —NR12—C—NR2—, —S02NR2— or —CO—; or, when R1 is not hydrogen, is —0—, —NR2—, —(N0)R2— , —(PO)R2— , —NR12—COO— , —NR12—S02 —, —S—, —SO— or —S02— ; wherein R2 is hydrogen or alkyl of up to 6 carbon atoms, or R1 and R2 together form alkylene or 28 0 138 504 halogenoalkylene such that, with the adjacent nitrogen atom, they form a heterocyclic ring of 5 to 7 ring atoms, one of which atoms may be a second heterocyclic atom selected from oxygen, sulphur and nitrogen; wherein R12 is hydrogen or alkyl of up to 6 carbon atoms; and wherein R22 is hydrogen, cyano or nitro; or a salt thereof when appropriate. 2. A steroid derivative as claimed in claim 1 which has the formula: w 15 20 wherein R17 is hydroxy and R27 is hydrogen or ethynyl, or R17 and R27 together form oxo; wherein —A— is —(CH2)n—, wherein n is an integer from 3 to 14, or —A— is: wherein m is an integer from 2 to 9 and p is 0 to 2; wherein R1 is alkyl, fluoroalkyl or cycloalkyl each of up to 10 carbon atoms, or phenyl, chlorophenyl or benzyl, or is linked to R2 as stated below; wherein X is —CONR2—, —NR12CO— , —S— , —SO— or —S02— , wherein R2 is hydrogen or alkyl of up 30 to 3 carbon atoms or together with R1 forms alkylene of 5 or 6 carbon atoms, and wherein R12 is hydrogen or alkyl of up to 3 carbon atoms. 3. A steroid derivative as claimed in claim 2 wherein the number of carbon atoms in the two groups A and R1 adds up to between 12 and 16 inclusive. 4. The compound 35 /V-n-butyl-/V-methyl-, /V-2,2,3,3,4,4,4-heptafluorobutyl-A/-methyl- or N, A/-(3-methylpentamethylene)11-(3,17B-dihydroxyoestra-1,3,5(10)-trien-7a-yl)undecanamide; A/-n-butyl-or A/-2,2,3,3,4,4,4-heptafluorobutyl-3-p-[4-(3,17(3-d'hydroxyoestra-1,3,5(10)-trien-7ayl)butyl]phenylpropionamide; 7a-(10-p-chlorophenylthiodecyl)-, 7a-(10-p-chlorophenylsulphinyldecyl)-, 7a-[9-(4,4,5,5,5-pentafluoro40 pentylsulphinyl)nonyl]-,7a-[10-(4,4,4-trifluorobutylsulphinyl)-decyl]-or7a-[10-(p-chlorobenzylsulphinyl)decyl]oestra-1 ,3,5(1 0)-triene-3,1 7B-diol ; or 7a-(9-n-heptyisuiphinylnonyl)oestra-1,3,5(10)-triene-3,17B-diol. 5. A process for the manufacture of a steroid derivative claimed in Claim 1, which comprises: (a) when X has the formula —CONR2—, —CSNR2— or —S02NR2— , the reaction of a compound of the 45 formula ST1—A—Z1, wherein A has the meaning stated in claim 1, wherein ST1 either has the same meaning as stated in claim 1 for ST, or is an equivalent 7a-linked steroid nucleus which bears one or more protecting groups for functional derivatives, and wherein Z1 is an activated group derived from a carboxylic,thiocarboxylic or sulphonic acid, with an amine of the formula HNR1R2, wherein R1 and R2 have the meanings stated in claim 1 or (b) when X has the formula —CO—, the reaction of an acid of the formula ST1 —A—COOH, wherein ST1 so and A have the meanings stated above, with an organometallic compound of the formula R1—M, wherein R1 has the meaning stated above and M is a metal group; or (c) when X has the formula —S—, —0 —, —NR2— or (P0)R2, the reaction of a compound of the formula ST1—A—Z2, wherein ST1 and A have the meanings stated above and wherein Z2 is a displaceable group, 55 with a compound of the formula R1SH, R1OH, HNR1R2 or R1R2P— C6H5, wherein R1 and R2 have the meanings stated above, whereafter a phosphonium salt is hydrolysed to the phosphinyl compound; or (d) when X has the formula —NR12C0— , —NR12CS— , —NR12CONR2— , so 65 NR22 —NR12—C—NR2—, —NR12C00 — or —NR12S02— , the reaction of a compound of the formula ST1— A— NHR12, wherein ST1, A and R12 have the meanings stated above, with an acylating agent derived from an acid of the formula R1COOH, R1CSOH, R1OCOOH or R1S020H; or, for the manufacture of a urea, with an isocyanate of the 29 0 138 5 504 formula R1NCO; or, for the manufacture of a guanidine, with a cyanamide of the formula R1NR2—CN; or (e) when —A— is alkenylene of the formula —A3—CH=CH— A4— wherein A3 is a direct link or alkylene and A4 is alkylene, the reaction of a compound of the formula — ST1—A3CHO wherein ST1 and A3 have the meanings stated above, with a triphenylphosphonium salt of the formula: 'o R1X—A4—CH2—P+(Ph)3 Q" wherein R1, X and R4 have the meanings stated above and wherein Q~ is an anion; whereafter: (i) any protecting group in ST1 is removed by conventional means; or is (\\) a steriod derivative wherein ST is a 17B-hydroxy-steroid derivative may be converted by conventional reactions into the corresponding 17- keto steroid derivative, and thence to the corresponding 17B-hydroxy-17-hydrocarbyl steroid derivative (that is, a steroid derivative wherein R27 is alkyl, alkenyl or alkynyl); or (iii) a steroid derivative wherein R3 and/or R17 are other than hydrogen may be obtained from the 20 corresponding compound wherein R3 and/or R17 are hydrogen by a conventional etherification or esterification process; or (iv) a steroid derivative wherein R3 and/or R17 are hydrogen may be obtained by hydrolysis of the corresponding compound wherein R3 and/or R17 are other than hydrogen; or (v) a steroid derivative wherein A is alkenylene may be hydrogenated to provide the corresponding 25 compound wherein A is alkylene; or (vi) a steroid derivative wherein —X— is —CH2NR2— or —NR2CH2— may be obtained by the reduction of the corresponding compound wherein —X— is —CONR2 or —NR2CO—; or (vii) a steroid derivative wherein —X— is —CSNH— or —NHCS — may be obtained by the reaction of the corresponding compound wherein X is— CONH — or — NHCO— with 2,4 - bis -(4 - methoxyphenyl) 30 1,3 - dithia - 2,4 - diphosphetane - 2,4 - disulphide; or (viii) a steroid derivative wherein X is —(N0)R2, —SO — or —S02— may be obtained by the oxidation of the corresponding compound wherein X is —NR2— or —S—. 6. A pharmaceutical composition comprising a steroid derivative, claimed in claim 1, together with a pharmaceutical acceptable diluent or carrier. 35 7. a composition as claimed in claim 6 which contains, in addition to the steroid derivative, one or more antiandrogenic agents or antiprogestational agents. 8. A composition as claimed in claim 6 which is suitable for oral administration and which contains from 5 to 500 mg. of a steroid derivative. 40 Claims for the Contracting State: AT 1. A process for the manufactue of a steroid derivative of the formula: 45 ST— A—X—R1 wherein ST is a 7a-linked steroid nucleus of the general formula: — R17 R27 50 55 wherein the dotted lines between carbon atoms 6 and 7, and carbon atoms 8 and 9, of the steroid nucleus indicate that there is an optional double bond between carbon atoms 6 and 7, or that there are two 60 optional double bonds between carbon atoms 6 and 7 and carbon atoms 8 and 9; wherein the aromatic ring A may optionally bear one or two halogen or alkyl substituents; wherein R3 is hydrogen or alkyl, alkanoyl, alkoxycarbonyl, carboxyalkanoyl or aroyl each of up to 10 carbon atoms; wherein R16 is hydrogen, alkyl of up to 6 carbon atoms which is preferably in the B-configuration, or which is preferably in the a-configuration; hydroxy 65 30 0 138 5 504 wherein either R17 (in the (3-configuration) is hydroxy or alkanoyloxy, carboxyalkanoyloxy or aroyloxy each of up to 10 carbon atoms; and R27 (in the a-configuration) is hydrogen or alkyl, alkenyl or alkynyl each of up to 6 carbon atoms; or R17 and R27 together form oxo (=0); wherein R1s is alkyl of up to 6 carbon atoms; wherein A is straight- or branched-chain alkylene, alkenylene or alkynylene each of from 3 to 14 carbon atoms, which may have one or more hydrogen atoms replaced by fluorine atoms, or has the formula —A1—Y—A11— wherein A1 and A11 are each alkylene or alkenylene, optionally fluorinated, having together a total of 2 to 13 carbon atoms and Y is —0 —, —S—, —SO —, —S02 —, —CO— or —NR— wherein R is hydrogen or alkyl of up to 3 carbon atoms; or A1 is alkylene or alkenylene, optionally fluorinated, and A11 is a direct link or alkylene or alkenylene, optionally fluorinated, such that A1 and A11 together have a total of 1 to 12 carbon atoms, and Y is 15 —NRCO— , —CONR —, —COO —, —OCO— or phenylene wherein R has the meaning stated above; wherein R1 is hydrogen, or alkyl, alkenyl, cycloalkyl, halogenoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl or arylalkyl each of up to 10 carbon atoms, or dialkylaminoalkyl wherein each alkyl is of up to 6 carbon atoms, or R1 is joined to R2 as defined below; and wherein X is —CONR2—, —CSNR2— , —NR12—CO—, —NR12—CS— , —NR22—CONR2— , 20 NR22 II —NR12—C—NR2—, io 25 30 35 40 45 50 —S02NR2— or —CO—; or, when R1 is not hydrogen, is —0—, —NR2—, —(NO)R2— , —(PO)R2— , —NR12—COO— , —NR12—S02— , —S— , —SO— or —S02— ; wherein R2 is hydrogen or alkyl of up to 6 carbon atoms, or R1 and R2 together form alkylene or halogenoalkylene such that, with the adjacent nitrogen atom, they form a heterocyclic ring of 5 to 7 ring atoms, one of which atoms may be a second heterocyclic atom selected from oxygen, sulphur and nitrogen; wherein R12 is hydrogen or alkyl of up to 6 carbon atoms; and wherein R22 is hydrogen, cyano or nitro; or a salt thereof when appropriate characterised by: (a) when X has the formula —CONR2 —, —CSNR2 — or —S02NR2 —, the reaction of a compound of the formula ST1 —A—Z1, wherein A has the meaning stated above wherein ST1 either has the same meaning as stated above for ST, or is an equivalent 7a-linked steroid nucleus which bears one or more protecting groups for functional derivatives, and wherein Z1 is an activated group derived from a carboxylic, thiocarboxylic or sulphonic acid, with an amine of the formula HNR1R2, wherein R1 and R2 have the meanings stated above or (b) when X has the formula —CO—, the reaction of an acid of the formula ST1 —A—COOH, wherein ST1 and A have the meanings stated above, with an organometallic compound of the formula R1—M, wherein R1 has the meaning stated above and M is a metal group; or (c) when X has the formula —S—, —O—, —NR2— or (PO)R2, the reaction of a compound of the formula ST1—A—Z2, wherein ST1 and A have the meanings stated above and wherein Z2 is a displaceable group, with a compound of the formula R1SH, R1OH, HNR1R2 or R1R2P—C6H5, wherein R1 and R2 have the meanings stated above, whereafter a phosphonium salt is hydrolysed to the phosphinyl compound; or (d) when X has the formula —NR12CO—, —NR12CS— , —NR12CONR2— , NR22 II _NRi2_C— NR2—, 55 —NR12C00— or— NR12S02— , the reaction of a compound of the formula ST1— A— NHR12, wherein ST1, A and R12 have the meanings stated above, with an acylating agent derived from an acid of the formula R1COOH, R1CSOH, R1OCOOH or R1S02OH; or, for the manufacture of a urea, with an isocyanate of the formula R1NCO; or, for the manufacture of a guanidine, with a cyanamide of the formula R1NR2—CN; or (e) when —A— is alkenylene of the formula —A3—CH=CH —A4— wherein A3 is a direct link or alkylene and A4 is alkylene, the reaction of a compound of the formula — so ST1—A3CHO wherein ST1 and A3 have the meanings stated above, with a triphenylphosphonium salt of the formula: R1X—A4—CH2—P+(Ph)3 Q31 0 138 5 io is 20 504 wherein R\ X and A4 have the meanings stated above and wherein CT is an anion; whereafter: (i) any protecting group in ST1 is removed by conventional means; or (ii) a steriod derivative wherein ST is a 17-hydroxy-steroid derivative may be converted by conventional reactions into the corresponding 17- keto steroid derivative, and thence to the corresponding 17-hydroxy-17-hydrocarbyl steroid derivative (that is, a steroid derivative wherein R27 is alkyl, alkenyl or alkynyl); or (iii) a steroid derivative wherein R3 and/or R17 are other than hydrogen may be obtained from the corresponding compound wherein R3 and/or R17 are hydrogen by a conventional etherification or esterification process; or (iv) a steroid derivative wherein R3 and/or R17 are hydrogen may be obtained by hydrolysis of the corresponding compound wherein R3 and/or R17 are other than hydrogen; or (v) a steroid derivative wherein A is alkenylene may be hydrogenated to provide the corresponding compound wherein A is alkylene; or (vi) a steroid derivative wherein —X— is —CH2NR2— or —NR2CH2— may be obtained by the reduction of the corresponding compound wherein —X— is —CONR2 or —NR2CO—; or (vii) a steroid derivative wherein —X— is —CSNH — or —NHCS — may be obtained by the reaction of the corresponding compound wherein X is —CONH — or —NHCO— with 2,4 - bis -(4 - methoxyphenyl) 1,3 - dithia - 2,4 - diphosphetane - 2,4 - disulphide; or (viii) a steroid derivative wherein X is —(NO)R2, —SO — or —S02 — may be obtained by the oxidation of the corresponding compound wherein X is —NR2— or —S—. 2. A process as claimed in claim 1 for the manufacture of a steroid derivative of the formula ST —A—X—R1 wherein ST has the formula R17 R27 30 35 wherein R17 is hydroxy and R27 is hydrogen or ethynyl, or R17 and R27 together form oxo; wherein —A— is —(CH2)n— , wherein n is an integer from 3 to 14, or —A— is: 40 wherein m is an integer from 2 to 9 and p is 0 to 2, wherein R1 is alkyl, fiuoroalkyl or cycloalkyl each of up to 10 carbon atoms, or phenyl, chlorophenyl or 45 benzyl, or is linked to R2 as stated below; wherein X is —CONR2—, —NR12CO—, —S— , —SO— or —S02— , wherein R2 is hydrogen or alkyl of up to 3 carbon atoms or together with R1 forms alkylene of 5 or 6 carbon atoms, and wherein R12 is hydrogen or alkyl of up to 3 carbon atoms, characterised by: (a) when X reaction has the formula —CONR2 —, the reaction of a compound of the formula so ST1 —A—Z1, wherein A has the meaning stated above, wherein ST1 either has the same meaning as stated above for ST, or is an equivalent 7a-linked steroid nucleus which bears one or more protecting groups for functional derivatives, and wherein Z1 is an activated group derived from a carboxylic acid, with an amine of the formula HNR1R2, wherein R1 and R2 have the meanings stated above; or (b) when X has the formula —S—, the reaction of a compound of the formula ST1 —A—Z2, wherein ST1 55 and A have the meanings stated above and wherein Z2 is a displaceable group, with a compound of the formula R1SH, wherein R1 has the meaning stated above; or (c) when X has the formula —NR12CO—, the reaction of a compound of the formula ST1 —A—NHR12, wherein ST1, A and R12 have the meanings stated above, with an acylating agent derived from an acid of the formula R1COOH; or 60 (d) when —A— is alkylene of the formula —A3—CH2—CH2—A4— wherein A3 is a direct link or alkylene and A4 is alkylene, the reaction of a compound of the formula: ST1—A3CHO 65 wherein ST1 and A3 have the meanings stated above, with a triphenylphosphonium salt of the formula: 32 0 138 504 R1X—A4—CH2—P+(Ph)3 Q- 5 w wherein R1, X and A4 have the meanings stated above and wherein Cr is an anion, followed by the hydrogenation of the alkenylene group —A3—CH=CH— A4— thus formed; whereafter: (i) any protecting group in ST1 is removed by conventional means; or (ii) a steroid derivative wherein ST is a 17B-hydroxy-steroid derivative may be converted by conventional reactions into the corresponding 17-keto steroid derivative, and thence to the corresponding 178-hydroxy-17a-ethynyl steroid derivative; or (iii) a steroid derivative wherein X is —SO — or —S02 — may be obtained by the oxidation of the corresponding compound wherein X is —S—. Patentanspruche fur die Vertragsstaaten: BE CH DE FR GB IT LI LU NL is 1. Ein Steroidderivat der Formel: ST— A—X—R1 20 worin ST ein 7a-gebundener Steroidkern der allgemeinen Formel ist: 25 30 35 40 45 so worin die punktierten Linien zwischen den Kohlenstoffatomen 6 und 7 und den Kohlenstoffatomen 8 und 9 des Steroidkerns bedeuten, dalS die Kohlenstoffatome 6 und 7 durch eine Doppelbindung miteinander verknupft sein konnen oder dalS die Kohlenstoffatome 6 und 7 sowie die Kohlenstoffatome 8 und 9 durch zwei Doppelbindungen verknupft sein konnen; worin der aromatische Ring A gegebenenfalls einen oder zwei Halogen- oder Alkyl-Substituenten tragen kann; worin R3 Wasserstoff oder einen Alkyl-, Alkanoyl-, Alkoxycarbonyl-, Carboxyalkanoyl- oder Aroyl-Rest von jeweils bis zu 10 Kohlenstoffatomen bedeutet; worin R16 Wasserstoff, einen Alkylrest von bis zu 6 Kohlenstoffatomen, der vorzugsweise die (3Konfiguration aufweist, oder eine Hydroxylgruppe, die vorzugsweise die a-Konfiguration aufweist, bedeutet; worin entweder R17 (in der S-Konfiguration) eine Hydroxylgruppe oder einen Alkanoyloxy-, Carboxyalkanoyloxy- oder Aroyloxy-Rest von jeweils bis zu 10 Kohlenstoffatomen und R27 (in der aKonfiguration) Wasserstoff oder einen Alkyl-, Alkenyl- oder Alkinyl-Rest von jeweils bis zu 6 Kohlenstoffatomen bedeuten oder R17 und R27 zusammen eine Oxogruppe (=0) bilden; worin R18 einen Alkylrest von bis zu 6 Kohlenstoffatomen bedeutet; worin A einen gerad- oder verzweigtkettigen Alkylen-, Alkenylen- oder Alkinylen-Rest von jeweils 3 bis 14 Kohlenstoffatomen bedeutet, bei denen ein oder mehrere Wasserstoffatome durch Fluoratome ersetzt sein konnen, oder die Formel aufweist: —A1—Y—A11— worin A1 und A11 jeweils, gegebenenfalls fluorierte, Alkylen- oder Alkenylen-Reste sind und zusammen eine Gesamtzahl von 2 bis 13 Kohlenstoffatomen aufweisen und Y —0 —, —S—, —SO —, —S02 —, —CO— oder— NR— bedeutet, worin R Wasserstoff oder einen Alkylrest von bis zu 3 Kohlenstoffatomen bedeutet; oder A1 einen, gegebenenfalls fluorierten, Alkylen- oder Alkenyien-Rest bedeutet und A11 eine direkte 60 Bindung oder einen, gegebenenfalls fluorierten, Alkylen- oder Alkenylen-Rest bedeutet, und zwar so, date A1 und A11 zusammen eine Gesamtzahl von 1 bis 12 Kohlenstoffatomen aufweisen, und Y —NRCO—, —CONR —, —COO—, —OCO — oder Phenylen bedeutet, wobei R die oben angegebene Bedeutung aufweist; worin R1 Wasserstoff oder einen Alkyl-, Alkenyl-, Cycloalkyl-, Haiogenalkyl-, Carboxyalkyl-, 65 Alkoxycarbonylalkyl-, Aryl- oder Arylalkyl-Rest von jeweils bis zu 10 Kohlenstoffatomen oder einen 55 33 0 138 504 Dialkylaminoalkylrest, bei dem jede Alkylgruppe bis zu 6 Kohlenstoffatome aufweist, bedeutet, oder R1 an R2 wie nachfolgend definiert gebunden ist; und worin X —CONR2— —CSNR2, — NR12—CO—, —NR12—CS— , —NR12—CONR2— , 5 io 15 so NR22 II —NR12—C—NR2—, —S02NR2— oder— CO— bedeutet; oder,wenn R1 nicht Wasserstoff bedeutet,— 0—,—NR2—,— (N0)R2— —(P0)R2— , —NR12—COO— , —NR12—S02— , —S— , —SO— oder —S02— bedeutet; worin R2 Wasserstoff oder einen Alkylrest von bis zu 6 Kohlenstoffatomen bedeutet oder R1 und R2 zusammen einen Alkylen- oder Halogenalkylen-Rest bilden, so dalS sie zusammen mit dem benachbarten Stickstoffatom einen heterozyklischen ring mit 5 bis 7 Ringatomen bilden, wobei von diesen Atomen eines ein zweites heterozyklisches Atom sein kann, das ausgewahlt ist aus Sauerstoff, Schwefel und Stickstoff; worin R12 Wasserstoff oder einen Alkylrest von bis zu 6 Kohlenstoffatomen bedeutet; und worin R22 Wasserstoff, eine Cyano- oder Nitrogruppe bedeutet; oder erforderlichenfalls ein Salz davon. 2. Steroidderivat nach Anspruch 1, das die Formel aufweist: worin R17 eine Hydroxylgruppe ist und R27 Wasserstoff oder einen Ethinylrest bedeutet oder R17 und R27 zusammen eine Oxogruppe bilden; worin A —(CH2)n— bedeutet, worin n eineganze Zahl von 3 bis 14 bedeutet, oder A ein Rest der Formel ist: 35 worin m eine ganze Zahl von 2 bis 9 bedeutet und p eine von 0 bis 2; worin R1 einen Alkyl-, Fluoralkyl- oder Cycloalkyl-Rest von jeweils bis zu 10 Kohlenstoffatomen oder einen Phenyl-, Chlorphenyl- oder Benzyl-Rest bedeutet oder mit R2 wie nachfolgend angegeben verknupft ist; worin X —CONR2—, —NR12CO— , —S— , —SO— oder —S02— bedeutet, worin R2 Wasserstoff oder einen Alkylrest von bis zu 3 Kohlenstoffatomen bedeutet oder zusammen mit R1 einen Alkylenrest von 5 45 oder 6 Kohlenstoffatomen bildet, und worin R12 Wasserstoff oder einen Alkylrest von bis zu 3 Kohlenstoffatomen bedeutet. 3. Steroidderivat nach Anspruch 2, bei dem die Anzahl der Kohlenstoffatome in den beiden Gruppen A und R1 sich auf einen Wert von 12 bis einschlielSlich 16 aufaddiert. 4. Die Verbindung so N-n-Butyl-N-methyl-, N-2,2,3,3,4,4,4-Heptafluorbutyl-N-methyl- oder N,N-(3-Methylpentamethylen)-1 1(3,17B-dihydroxy6stra-1,3,5(10)-trien-7a-yl)undecanamid; N-n-Butyl- oder N-2,2,3,3,4,4,4-Heptafluorbutyl-3-p-[4-(3,17B-dihydroxy6stra-1,3,5(10)-trien-7ayl)butyl]phenylpropionamid; 7a-(10-p-Chlorphenylthiodecyl)-, 7a-(10-p-Chlorphenylsulfinyldecyl)-, 7a-[9-(4,4,5,5,555 PentafluorpentylsulfinyDnonyl]-, 7a-[10-(4,4,4-Trifluorbutylsulfinyl)decylj- oder 7a-[10-(pChlorbenzylsulfinyl)decyl]6stra-1,3,5(10)-trien-3,17B-diol oder 7a-(9-n-Heptylsuifinylnonyl)6stra-1,3,5(10)-trien-3,17B-diol. 5. Verfahren zur Herstellung eines Steroidderivats gemalS Anspruch 1, das umfaBt: (a) wenn X die Formel —CONR2, —CSNR2— oder —S02NR2— aufweist, die Umsetzung einer 60 Verbindung der Formel ST1 —A—Z1, worin A die in Anspruch 1 angegebene Bedeutung aufweist, worin ST1 entweder die gleiche Bedeutung aufweist wie in Anspruch 1 fur ST angegeben ist oder einen aquivalenten 7a-gebundenen Steroidkern bedeutet, der eine oder mehrere Schutzgruppen fur funtionelle Derivate enthalt, und worin Z1 eine aktivierte Gruppe ist, die sich von einer Carbonsaure, einer Thiocarbonsaure oder einer Sulfonsaure ableitet, mit einem Amin der Formel HNR1R2, worin R1 und R2 die in Anspruch 1 55 angegebenen Bedeutungen aufweisen; oder 40 34 0 138 504 (b), wenn X die Formel —CO— aufweist, die Umsetzung einer Saure der Formel ST1—A—COOH, worin ST1 und A die oben angegebenen Bedeutungen besitzen, mit einer organometallischen Verbindung der Formel R1—M, worin R1 die oben angegebene Bedeutung aufweist und M eine metallische Gruppe bedeutet; oder 5 (c), wenn X die Formel —S— , —0—, —NR2— oder —(PO)R2— , bedeutet, die Umsetzung einer Verbindung der Formel ST1—A—Z2, worin ST1 und A die oben angegebenen Bedeutungen aufweisen und Z2 eine verdrangbare Gruppe bedeutet, mit einer Verbindung der Formel R1SH, R1OH, HNR1R2 oder R1R2P—CSHB, worin R1 und R2 die oben angegebenen Bedeutungen aufweisen, wonach ein Phosphoniumsalz zu der Phosphinylverbindung hydrolysiert wird; oder 10 (d) wenn X die Formel —NR12CO— , —NR12CS— , —NR12C0NR2— , NR22 15 —NR12—C—NR2—, —NR12C00— oder— NR12S02— aufweist, die Umsetzung einer Verbindung der Formel ST1— A— NHR12— worin ST1, A und R12 die oben angegebenen Bedeutungen aufweisen, mit einem Acylierungsmittel, das, sich von einer Saure der Formel R1COOH, R1CSOH, R1OCOOH oder R1S02OH ableitet; oder, zur Herstellung eines Harnstoffs, mit einem Isocyanat der Formel R1NCO; oder, zur Herstellung eines Guanidins, mit einem 20 Cyanamid der Formel R1NR2— CN; oder (e), wenn A einen Alkenylenrest der Formel —A3—CH=CH— A4—, worin A3 eine direkte Bindung oder einen Alkylenrest und A4 einen Alkylenrest bedeuten, bedeutet, die Umsetzung einer Verbindung der Formel 25 ST1—A3CH0 worin ST1 und A3 die oben angegebenen Bedeutungen besitzen, mit einem Triphenylphosphoniumsalz der Formel: 30 R1X—A4—CH2—P+(Ph)3 Q-, worin R1, X und A4 die oben angegebenen Bedeutungen aufweisen und Q~ ein Anion bedeutet; wonach: (i) aile Schutzgruppen in ST1 auf herkommliche Weise entfernt werden; oder 35 (ii) ein Steroidderivat, worin ST ein 17B-Hydroxy-Steroidderivat ist, durch herkommliche Umsetzungen in das entsprechende 17-Keto-Steroidderivat umgewandelt wird und anschlieftend in das entsprechende (17B-Hydroxy-17a-koh!enwasserstoff-Steroidderivat (d. h. ein Steroidderivat, worin R27 ein Alkylrest, Alkenylrest oder Alkinylrest ist); oder (iii) ein Steroidderivat, worin R3 und/oder R17 eine andere Bedeutung ais Wasserstoff aufweisen, aus « der entsprechenden Verbindung, worin R3 und/oder R17 Wasserstoff bedeuten, nach einem herkommlichen Veretherungs- oder Veresterungs-Verfahren erhalten werden; oder (iv) ein Steroidderivat, worin R3 und/oder R17 Wasserstoff sind, durch Hydrolyse der entsprechenden Verbindung erhalten werden, worin R3 und/oder R17 eine andere Bedeutung als Wasserstoff aufweisen; oder '5 (v) ein Steroidderivat, worin A ein Alkenylenrest ist, hydriert werden kann, urn die entsprechende Verbindung zu erzeugen, in der A ein Alkylenrest ist; oder (vi) ein Steroidderivat, worin X— CH2NR2— oder —NR2CH2— ist, durch Reduktion der entsprechenden Verbindung erhalten werden kann, worin X —CONR2— oder —NR2CO— ist; oder (vii) ein Steroidderivat, worin X —CSNH— oder —NHCS— ist, durch Umsetzung der entsprechenden '0 Verbindung, in der X —CONH— oder — NHCO— ist, mit 2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4diphosphetan-2,4-disulfid erhalten werden kann; oder (viii) ein Steroidderivat, worin X —(N0)R2— , —SO— oder —S02— ist, durch Oxidation der entsprechenden Verbindung erhalten werden kann, worin X —NR2— oder— S— ist. 6. Pharmazeutische Zusammensetzung, die ein Steroidderivat, wie es in Anspruch 1 beansprucht wird, >5 zusammen mit einem pharmazeutisch annehmbaren Verdunnungsmittel oder Trager enthalt. 7. Zusammensetzung nach Anspruch 6, die zusatzlich zu dem Steroidderivat eines oder mehrere antiandrogene Mittel oder antiprogestationale Mittel enthalt. 8. Zusammensetzung nach Anspruch 6, die fur die orale Verabreichung geeignet ist und von 5 bis 500 mg des Steroidderivats enthalt. Patentanspriiche fur den Vertragsstaat: AT 1. Ein Verfahren zur Herstellung eines Streoidderivats der Formel: « ST—A—X— R1 S5 0 138 504 worin ST ein 7a-gebundener Steroidkern der allgemeinen Formel ist: R17R27 R18\/ _« io worin die punktierten Linien zwischen den Kohlenstoffatomen 6 und 7 und den Kohlenstoffatomen 8 15 und 9 des Steroidkerns bedeuten, daS die Kohlenstoffatome 6 und 7 durch eine Doppelbindung miteinander verknupft sein konnen oder daS die Kohlenstoffatome 6 und 7 sowie die Kohlenstoffatome 8 und 9 durch zwei Doppelbindungen verknupft sein konnen; worin der aromatische Ring A gegebenenfalls einen oder zwei Halogen- oder Alkyl-Substituenten kann; tragen . 2o worin R3 Wasserstoff oder einen Alkyl-, Alkanoyl-, Alkoxycarbonyl-, Carboxyalkanoyl- oder Aroyl-Rest von jeweils bis zu 10 Kohlenstoffatomen bedeutet; worin R16 Wasserstoff, einen Alkylrest von bis zu 6 Kohlenstoffatomen, der vorzugsweise die 8-Konfiguration aufweist, oder eine Hydroxylgruppe, die vorzugsweise die a-Konfiguration aufweist, bedeutet; worin entweder R17 (in der B-Konfiguration) eine Hydroxylgruppe oder einen Alkanoyloxy-, 25 Carboxyalkanoyloxy- oder Aroyloxy-Rest von jeweils bis zu 10 Kohlenstoffatomen und R27 (in der aKonfiguration) Wasserstoff oder einen Alkyl-, Alkenyl- oder Alkinyl-Rest von jeweils bis zu 6 Kohlenstoffatomen bedeuten oder R17 und R27 zusammen eine Oxogruppe (=0) bilden; worin R18 einen Alkylrest von bis zu 6 Kohlenstoffatomen bedeutet; 30 worin A einen gerad- oder verzweigtkettigen Alkylen-, Alkenylen- oder Alkinylen-Rest von jeweils 3 bis 14 Kohlenstoffatomen bedeutet, bei denen ein oder mehrere Wasserstoffatome durch Fluoratome ersetzt sein konnen, oder die Formel aufweist: 35 40 45 50 —A1—Y—A11— worin A1 und A11 jeweils, gegebenenfalls fluorierte, Alkylen- oder Alkenylen-Reste sind und zusammen eine Gesamtzahl von 2 bis 13 Kohlenstoffatomen aufweisen und Y —0 —, —S—, —SO —, —S02 —, —CO— oder —NR— bedeutet, worin R Wasserstoff oder einen Alkylrest von bis zu 3 Kohlenstoffatomen bedeutet; oder A1 einen, gegebenenfalls fluorierten, Alkylen- oder Alkenylen-Rest bedeutet und A11 eine direkte Bindung oder einen, gegebenenfalls fluorierten, Alkylen- oder Alkenylen-Rest bedeutet, und zwar so, dalS A1 und A11 zusammen eine Gesamtzahl von 1 bis 12 Kohlenstoffatomen aufweisen, und Y —NRCO— , —CONR —, —COO—, —OCO— oder Phenylen bedeutet, wobei R die oben angegebene Bedeutung aufweist; worin R1 Wasserstoff oder einen Alkyl-, Alkenyl-, Cycloalkyl-, Haiogenalkyl-, Carboxyalkyl-, Alkoxycarbonylalkyl-, Aryl- oder Arylalkyl-Rest von jeweils bis zu 10 Kohlenstoffatomen oder einen Dialkylaminoalkylrest, bei dem jede Alkylgruppe bis zu 6 Kohlenstoffatome aufweist, bedeutet, oder R1 an R2 wie nachfolgend definiert gebunden ist; und worin X —CONR2—, —CSNR2, —NR12—CO—, —NR12—CS— , —NR12—CONR2— , NR22 55 —NR12—C—NR2—, —S02NR2— oder— CO— bedeutet; oder, wenn R1 nicht Wasserstoff bedeutet,— O—,— NR2—,— (NO)R2— , —(PO)R2— , —NR12—COO— , —NR12—S02— , —S— , —SO— oder —S02— bedeutet; worin R2 Wasserstoff oder einen Alkylrest von bis zu 6 Kohlenstoffatomen bedeutet oder R1 und R2 zusammen einen Alkylen- oder Halogenalkylen-Rest bilden, so dalS sie zusammen mit dem benachbarten so Stickstoffatom einen heterozyklischen Ring mit 5 bis 7 Ringatomen bilden, wobei von diesen Atomen eines ein zweites heterozyklisches Atom sein kann, das ausgewahlt ist aus Sauerstoff, Schwefel und Stickstoff; worin R12 Wasserstoff oder einen Alkylrest von bis zu 6 Kohlenstoffatomen bedeutet; und worin R22 Wasserstoff, eine Cyano- oder Nitrogruppe bedeutet; oder erforderiichenfalls eines Salzes davon, gekennzeichnet durch: 65 (a) wenn X die Formel —CONR2, —CSNR2— oder —S02NR2— aufweist, die Umsetzung einer 36 0 138 504 Verbindung der Formel ST1 —A—Z\ worin A die oben oben angegebene Bedeutung aufweist, worin ST1 entweder die gleiche Bedeutung aufweist wie oben fur ST angegeben ist oder einen aquivalenten 7agebundenen Steroidkern bedeutet, der eine oder mehrere Schutzgruppen furfunctionelle Derivate enthalt, und worin Z1 eine aktivierte Gruppe ist, die sich von einer Carbonsaure, einer Thiocarbonsaure oder einer 5 Sulfonsaure ableitet, mit einem Amin der Formel HNR1R2, worin R1 und R2 die oben angegebenen Bedeutungen aufweisen; oder (b) , wenn X die Formel —CO— aufweist, die Umsetzung einer Saure der Formel ST1 —A—COOH, worin ST1 und A die oben angegebenen Bedeutungen besitzen, mit einer organometallischen Verbindung der Formel R1—M, worin R1 die oben angegebene Bedeutung aufweist und M eine metallische Gruppe w bedeutet; oder (c) , wenn X die Formel —S—, —0 —, —NR2— oder —(P0)R2 —, bedeutet, die Umsetzung einer Verbindung der Formel ST1—A—Z2, worin ST1 und A die oben angegebenen Bedeutungen aufweisen und Z2 eine verdrangbare Gruppe bedeutet, mit einer Verbindung der Formel R1SH, R1OH, HNR1R2 oder R1R2P—C6H5, worin R1 und R2 die oben angegebenen Bedeutungen aufweisen, wonach ein Phosphonium15 salz zu der Phosphinylverbindung hydrolysiert wird; oder (d) wenn X die Formel —NR12CO—, —NR12CS— , —NR12CONR2— , 20 NR22 II —NR12—C—NR2—, —NR12COO— oder— NR12S02— aufweist, die Umsetzung einer Verbindung der Formel ST1— A— NHR12—, worin ST1, A und R12 die oben angegebenen Bedeutungen aufweisen, mit einem Acylierungsmittel, das sich von einer Saure der Formel R1COOH, R1CSOH, R1OCOOH oder R1S02OH ableitet; oder, zur Herstellung 25 eines Harnstoffs, mit einem Isocyanat der Formel R1NCO; oder, zur Herstellung eines Guanidins, mit einem Cyanamid der Formel R1NR2—CN; oder (e) , wenn A einen Alkenylenrest der Formel —A3—CH=CH —A4—, worin A3 eine direkte Bindung oder einen Alkylenrest und A4 einen Alkylenrest bedeuten, bedeutet, die Umsetzung einer Verbindung der Formel 30 ST1—A3CHO 35 worin ST1 und A3 die oben angegebenen Bedeutungen besitzen, mit einem Triphenylphosphoniumsalz der Formel: R1X—A4—CH2—P+(Ph)3 Q-, worin R1, X und A4 die oben angegebenen Bedeutungen aufweisen und Q~ ein Anion bedeutet; wonach: (i) alle Schutzgruppen in ST1 auf herkommliche Weise entfernt werden; oder 40 (ii) ein Steroidderivat, worin ST ein 17B-Hydroxy-Steroidderivat ist, durch herkommliche Umsetzungen in das entsprechende 17-Keto-Steroidderivat umgewandelt wird und anschielSend in das entsprechende 17B-Hydroxy-17a-kohlenwasserstoff-Steroidderivat {d. h. ein Steroidderivat, worin R27 ein Alkylrest, Alkenylrest oder Alkinylrest ist); oder (iii) ein Steroidderivat, worin R3 und/oder R17 eine andere Bedeutung als Wasserstoff aufweisen, aus 45 der entsprechenden Verbindung, worin R3 und/oder R17Wasserstoff bedeuten, nach einem herkommlichen Veretherungs- oder Veresterungs-Verfahren erhalten werden; oder (iv) ein Steroidderivat, worin R3 und/oder R17 Wasserstoff sind, durch Hydroiyse der entsprechenden Verbindung erhalten werden, worin R3 und/oder R17 eine andere Bedeutung als Wasserstoff aufweisen; so oder (v) ein Steroidderivat, worin A ein Alkenylrest ist, hydriert werden kann, um die entsprechende Verbindung zu erzeugen, in der A ein Alkylenrest ist; oder (vi) ein Steroidderivat, worin X —CH2NR2— oder —NR2CH2— ist, durch Reduktion der entsprechenden Verbindung erhalten werden kann, worin X —CONR2 — oder —NR2C0 — ist; oder 55 (vii) ein Steroidderivat, worin X —CSNH — oder —NHCS — ist, durch Umsetzung der entsprechenden Verbindung, in der X —CONH— oder — NHCO— ist, mit 2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4diphosphetan-2,4-disulfid erhalten werden kann; oder (viii) ein Steroidderivat, worin X —(NO)R2 —, —SO — oder —S02 — ist, durch Oxidation der entsprechenden Verbindung erhalten werden kann, worin X —NR2— oder —S— ist. 60 2. Verfahren nach Anspruch 1 zur Herstellung eines Steroidderivats der Formel ST —A—X—R1, worin ST die Formel aufweist: 65 37 0 138 504 R17 R27 HO ' 10 15 20 25 30 35 40 . 45 50 55 60 '• worin R17 eine Hydroxylgruppe ist und R27 Wasserstoff oder einen Ethinylrest bedeutet oder R17 und R27 zusammen eine Oxogruppe bilden; worin A —(CH2)n— bedeutet, worin n eine ganze Zahl von 3 bis 14 bedeutet, oder A ein Rest der Formel ist: worin m eine ganze Zahl von 2 bis 9 bedeutet und p eine von 0 bis 2; worin R1 einen Alkyl-, Fluoralkyl- oder Cycloalkyl-Rest von jeweils bis zu 10 Kohlenstoffatomen oder einen Phenyl-, Chlorphenyl- oder Benzyl-Rest bedeutet oder mit R2 wie nachfolgend angegeben verknupft ist; worin X —CONR2—, —NR12CO—, —S— , —SO— oder —S02— bedeutet, worin R2 Wasserstoff oder einen Alkylrest von bis zu 3 Kohlenstoffatomen bedeutet oder zusammen mit R1 einen Alkylenrest von 5 oder 6 Kohlenstoffatomen bildet, und worin R12 Wasserstoff oder einen Alkylrest von bis zu 3 Kohlenstoffatomen bedeutet, gekennzeichnet durch: (a) wenn X die Formel —CONR2—, aufweist, Umsetzung einer Verbindung der Formel ST1 —A—Z1, worin A die oben angegebene Bedeutung aufweist, worin ST1 entweder die gleiche Bedeutung wie oben fur ST angegeben aufweist oder einen aquivalenten 7a-gebundenen Steroidkern bedeutet, der eine oder mehrere Schutzgruppen fiirfunctionelle Derivate enthalt, und worin Z1 eine aktivierte Gruppe ist, die sich von einer Carbonsaure ableitet, mit einem Amin der Formel HNR1R2, worin R1 und R2 die oben angegebenen Bedeutungen aufweisen; oder (b) , wenn X die Formel —S— aufweist, Umsetzung einer Verbindung der Formel ST1 —A—Z2, worin ST1 und A die oben angegebenen Bedeutungen aufweisen und worin Z2 eine verdrangbare Gruppe bedeutet, mit einer Verbindung der Formel R1SH, worin R1 die oben angegebene Bedeutung aufweist; oder (c) , wenn X die Formel —NR12CO— aufweist, Umsetzung einer Verbindung der Formel ST1 —A—NHR12, worin ST1, A und R12 die oben angegebenen Bedeutungen aufweisen, mit einem Acylierungsmittel, das sich von einer Saure der Formel R1COOH ableitet; oder (d) wenn A einen Alkylenrest der Formel —A3—CH2—CH2—A4— bedeutet, worin A3 eine direkte Bindung oder einen Alkylenrest bedeutet und A4 einen Alkylenrest bedeutet, Umsetzung einer Verbindung der Formel ST1—A3CHO worin ST1 und A3 die oben angegebenen Bedeutungen aufweisen, mit einem Triphenylphosphoniumsalz der Formel: R1X—A4—CH2—P+(Ph)3 Q~, worin R1, X und A4 die oben angegebenen Bedeutungen aufweisen und worin Q~ ein Anion ist, sowie anschlielSende Hydrierung der so gebildeten Alkenylengruppe —A3—CH=CH —A4—; wonach: (i) alle Schutzgruppen in ST1 auf herkommliche Weise entfernt werden; oder (ii) ein Steroidderivat, worin ST ein 173-Hydroxy-Steroidderivat ist, durch herkommliche Umsetzungen in das entsprechende 17-Keto-Steroidderivat umgewandelt werden kann und anschlielSend in das entsprechende 17B-Hydroxy-17a-ethinyl-Steroidderivat; oder (iii) ein Steroidderivat, worin X —SO — oder —S02 — ist, durch Oxidation der entsprechenden Verbindung erhalten werden kann, worin X —S— ist. Revendications pour les Etats contractants: BE CH DE FR GB IT LI LU NL SE 1. Derive steroTdique de formule: 65 ST—A—X—R1 38 0 138 504 dans laquelle ST est un noyau de steroi'de en liaison 7a de formule generale 's dans laquelle les segments en pointille entre les atomes de carbone 6 et 7 et entre les atomes de carbone 8 et 9 du noyau de steroi'de indiquent qu'il existe une double liaison facultative entre les atomes de carbone 6 et 7 ou qu'il existe deux doubles liaisons facultatives entre les atomes de carbone 6 et 7 et les atomes de carbone 8 et 9; le noyau aromatique A peut facultativement porter un ou deux substituants halogeno ou alkyle; 20 R3 est I'hydrogene ou un groupe alkyle, alcanoyle, alkoxycarbonyle, carboxyalcanoyle ou aroyle ayant chacun jusqu'a 10 atomes de carbone; R16 est I'hydrogene, un groupe alkyle ayant jusqu'a 6 atomes de carbone qui a de preference la configuration B ou un groupe hydroxy qui a de preference la configuration a; R17 (dans la configuration B) est un groupe hydroxy ou alcanoyloxy, carboxyalcanoyloxy ou aroyloxy 25 avec chacun jusqu'a 10 atomes de carbone; et R27 (dans la configuration a) est I'hyhdrogene ou un groupe alkyle, alcenyle ou aicynyle ayant chacun jusqu'a 6 atomes de carbone; ou bien R17 et R27 formen conjointement un groupe oxo (=0); R18 est un groupe alkyle ayant jusqu'a 6 atomes de carbone; A est un groupe alkylene, alcenylene ou alcynylene a chaTne droite ou ramifiee ayant chacun 3 a 14 30 atomes de carbone, dont un ou plusieurs atomes d'hydrogene peuvent etre remplaces par des atomes de fluor, ou repond a la formule —A1—Y—A11— 35 dans laquelle A1 et A11 sont chacun un groupe alkylene ou alcenylene facultativement fluore, totalisant 2 a 13 atomes de carbone et Y represente —O—, —S— , —SO—, —S02— , —CO— ou —NR— ou R est I'hydrogene ou un groupe alkyle ayant jusqu'a 3 atomes de carbone; ou A1 est un groupe alkylene ou alcenylene, facultativement fluore, et A" est une liaison simple ou un groupe alkylene ou alcenylene facultativement fluore, de telle sorte que A1 et A11 totalisent 1 a 12 atomes 40 de carbone, et Yest un groupe— NRCO—,— CONR— ,— COO— ,—OCO—ou un groupe phenylene ou R a la definition indiquee ci-dessus; R1 est I'hydrogene ou un groupe alkyle, alcenyle, cycloalkyle, halogenalkyle, carboxyalkyle, alcoxycarbonylalkyle, aryie ou arylalkyle ayant chacun jusqu'a 10 atomes de carbone ou un groupe dialkylaminoalkyle dont chaque radical alkyle comprend jusqu'a 6 atomes de carbone, ou bien R1 est lie a 45 R2 comme defini ci-dessous; et X represente —CONR2—, —CSNR2—, — NR12—CO—, —NR12—CS— , —NR12—CONR2— , so NR II _NR12_C— NR2—, —S02NR2 ou —CO—; ou bien, lorsque R1 n'est pas I'hydrogene, X represente —0—, — NR2—, —(NO)R2— , —(PO)R2— , —NR12—COO—, —NR12—S02— , —S—, —SO—, ou —S02— ; 55 R2 est I'hydrogene ou un groupe alkyle ayant jusqu'a 6 atomes de carbone, ou bien R1 et R2 forment conjointement un groupe alkylene ou halogenalkylene de telle sorte que, avec I'atome adjacente d'azote, ils forment un noyau heterocyclique pentagonal a heptagonal dont I'un des atomes peut etre un second atome heterocyclique choisi entre oxygene, soufre et azote; R12 est I'hydrogene ou un groupe alkyle ayant jusqu'a 6 atomes de carbone; et 60 R22 est I'hydrogene, un groupe cyano ou nitro; ou un sel de ce derive dans le cas appropries. 2. Derive steroTdique suivant la revendication 1, qui repond a la formule: ss 39 0 138 504 R17 f HO ' 10 '-A-X-R1 dans laquelle R17 est un groupe hydroxy et R27 est I'hydrogene ou un groupe ethynyle, ou bien R17 et R27 forment conjointement un groupe oxo; _A— est un groupe —(CH2)„— , ou n est un nombre entier de 3 a 14, ou bien —A—.est un groupe: j £ > ( C H 2 ) p -(CH2)m/V_/ 20 25 30 35 40 45 50 55 dans lequel m est un nombre entier de 2 a 9 et p a une valeur de 0 a 2; R1 est un groupe alkyle, fluoralkyle ou cycloalkyle ayant chacun jusqu'a 10 atomes de carbone ou un groupe phenyle, chlorophenyle ou benzyle; ou est lie a R2 comme indique ci-dessous; X est un groupe —CONR2—, —NR12CO—, —S— , —SO— ou —S02— , ou R2 est I'hydrogene ou un groupe alkyle ayant jusqu'a 3 atomes de carbone ou forme conjointement avec R1 un groupe alkylene de 5 ou 6 atomes de carbone, et R12 est I'hydrogene ou un groupe alkyle ayant jusqu'a 3 atomes de carbone. 3. Derive steroTdique selon la revendication 2, dans lequel le nombre d'atomes de carbone dans les deux groupes A et R1 represente un total de 12 a 16 inclus. 4. Le A/-n-butyl-A/-methyl-, A/-2,2,3,3,4,4,4-heptafluorobutyl-A/-methyl- ou A/,A/-(3-methylpentamethylene)-! 1-(3,17B-dihydroxyoestra-1,3,5(10)-triene-7a-yl)undecamide; le/V-n-butyl-ou A/-2,2,3,3,4,4,4-heptafluorobutyl-3-p-[4-(3,17p-dihydroxyoestra-1,3,5(10)-triene-7a-yl)butyljphenylpropionamide; le 7a-(10-p-chlorophenylthiodecyl)-, 7a-(10-p-chlorophenylsulfinyldecyl)-, 7a-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-,7a-[10-(4,4,4-trifluorobutylsulfinyl)decyl]-ou 7a-[10-(p-chlorobenzylsulfinyl)decyl]oestra-1,3,5-(10)-triene-3,17B-diol; ou le7a-(9-n-heptylsulfinylnonyl)oestra-1,3,5(10)-triene-3,17B-diol. 5. Procede de preparation d'un derive steroTdique suivant la revendication 1, qui comprend: (a) lorsque X repond a la formule —CONR2 —, —CSNR2 — ou —S02NR2 —, la reaction d'un compose de formule ST1 —A—Z1, dans laquelle A a la definition indiquee dans la revendication 1, ST1 a la meme definition que ST dans la revendication ou est un noyau de steroi'de equivalent en liaison 7a qui porte un ou plusieurs groupes protecteurs pour des derives fonctionnels et Z1 est un groupe active derive d'un acide carboxylique, thiocarboxylique ou sulfonique, avec une amine de formule HNR1R2 dans laquelle R1 et R2 ont les definitions indiquees dans la revendication 1; ou bien (b) lorsque X repond a la formule —CO—, la reaction d'un acide de formule ST1—A—COOH, dans laquelle ST1 et A ont les definitions indiquees ci-dessus, avec un compose organometallique de formule R1—M, dans laquelle R1 a la definition indiquee ci-dessus et M est un metal; ou bien (c) lorsque X repond a la formule —S—, —0 —, —NR2— ou (PO)R2, la reaction d'un compose de formule ST1 —A—Z2, dans laquelle ST1 et A ont les definitions indiquees ci-dessus et Z2 est un groupe deplacable, avec un compose de formule R1SH, R1OH, HNR1R2 ou R1R2P—C6H5, ou R1 et R2 ont les definitions indiquees ci-dessus, apres quoi un sel de phosphonium est hydrolyse en le compose phosphinylique; ou bien (d) lorsque X repond a la formule —NR12C0— , —NR12CS— , —NR12CONR2, NR12 —NR12C— NR2—, —NR12COO— ou —NR12S02— , la reaction d'un compose de formule ST1—A— NHR12, dans laquelle ST1, A et R12 ont les definitions indiquies ci-dessus, avec un agent acylant derive d'un acide de formule R1COOH, 60 R1CSOH, R^COOH ou R1S02OH; ou bien, pour la preparation d'une uree, avec un isocyanate de formule R1NCO; ou bien, pour la preparation d'une guanidine, avec un cyanamide de formule R1Nr2— CN; ou bien (e) lorsque —A— est un groupe alcenylene de formule —A3—CH=CH —A4— ou A3 est une liaison simple ou un groupe alkylene et A4 est un groupe alkylene, la reaction d'un compose de formule: 65 ST1—A3CHO 40 0 138 504 dans laquelle ST1 et A3 ont les definitions indiquees ci-dessus, avec un sel de triphenylphosphonium de formule: 5 io 15 20 25 30 35 R1X—A4—CH2—P+(Ph)3 Qdans laquelle R1, X et A4 ont les definitions indiquees ci-dessus et Q" est un anion; apres quoi: (i) tout groupe protecteur contenu dans ST1 est elimine par des moyens classiques; ou bien (ii) un derive steroTdique dans lequel ST est un derive de 173-hydroxysteroT'de peut etre converti par des reactions classiques en les derives de 17B-cetosteroTde correspondants puis en le derive de 173hydroxy-17a-hydrocarbyl-steroTde correspondant (c'est-a-dire un derive de steroi'de dans lequel R27 est un radical alkyle, alcenyle ou alcynyle); ou bien (iii) un derive de steroi'de dans lequel R3 et/ou R17 represented autre chose que I'hydrogene peut etre obtenu a partir du compose correspondant dans lequel R3 et/ou R17 sont de I'hydrogene par un procede classique d'etherification ou d'esterification; ou bien (iv) un derive de steroi'de dans lequel R3 et/ou R17 represented I'hydrogene peut etre obtenu par hydrolyse du compose correspondant dans lequel R3 et/ou R17 represented autre chose que i'hydrogene; ou bien (v) un derive de steroi'de dans lequel A est un groupe alcenylene peut etre hydrogene pour former le compose correspondant dans lequel A est un groupe alkylene; ou bien (vi) un derive de steroi'de dans lequel —X—@ est un groupe— CH2NR2— ou —NR2CH2— peut etre obtenu par reduction du compose correspondant dans lequel —X— est un groupe —CONR2— ou —NR2CO— ; ou bien (vii) un derive de steroi'de dans lequel —X— est un groupe —CSNH— ou —NHCS— peut etre obtenu par reaction du compose correspondant dans lequel X est un groupe —CONH — ou — NHCO— avec le 2,4disulfure de 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane; ou bien (viii) un derive de steroi'de dans lequel X est un groupe —(NO)R2, —SO — ou —S02— peut etre obtenu par oxydation du compose correspondant dans lequel X est un groupe —NR2— ou —S—. 6. Composition pharmaceutique comprenant un derive steroTdique suivant la revendication 1, ainsi qu'un diluant ou support pharmaceutiquement acceptable. 7. Composition suivant la revendication 6, qui contient en plus du derive steroTdique, un ou plusieurs agents anti-androgeniques ou agents antiprogestatifs. 8. Composition suivant la revendication 6, qui convient pour ('administration orale et qui contient 5 a 500 mg d'un derive steroTdique. Revendications pour I'Etat contractant: AT 1. Procede de preparation d'un derive steroTdique de formule: 40 ST— A—X—R1 dans laquelle ST est un noyau de steroi'de en liaison 7a de formule generate dans laquelle les segments en pointille entre les atomes de carbone 6 et 7 et entre les atomes de carbone 8 55 et 9 du noyau de steroi'de indiquent qu'il existe une double liaison facultative entre les atomes de carbone 6 et 7 ou qu'il existe deux doubles liaisons facultatives entre les atomes de carbone 6 et 7 les atomes de carbone 8 et 9; le noyau aromatique A peut facultativement porter un ou deux substituants halogeno ou alkyle; R3 est I'hydrogene ou un groupe alkyle, alcanoyle, alkoxycarbonyle, carboxyalcanoyle ou aroyle ayant 60 chacun jusqu'a 10 atomes de carbone; R16 est I'hydrogene, un groupe alkyle ayant jusqu'a 6 atomes de carbone qui a de preference la configuration 3 ou un groupe hydroxy qui a de preference la configuration a; R17 (dans la configuration 3) est un groupe hydroxy ou alcanoyloxy, carboxyalcanoyloxy ou aroyloxy avec chacun jusqu'a 10 atomes de carbone; et R27 (dans la configuration a) est I'hydrogene ou un groupe 65 alkyle, alcenyle ou alcynyle ayant chacun jusqu'a 6 atomes de carbone; 41 0 138 5 504 ou bien R17 et Rz7 forment conjointement un groupe oxo (=0); R1S est un groupe alkyle ayant jusqu'a 6 atomes de carbone; A est un groupe alkylene, alcenylene ou alcynylene a chame droite ou ramifiee ayant chacun 3 a 14 atomes de carbone, dont un ou plusieurs atomes d'hydrogene peuvent etre remplaces par des atomes de fluor, ou repond a la formule —A1—Y—A11— 10 75 20 25 30 35 40 45 50 dans laquelle A1 et A11 sont chacun un groupe alkylene ou alcenylene facultativement fluore, totalisant 2 a 13 atomes de carbone et Y represente —0—, —S— , —SO—, —S02— , —CO— ou —NR— ou R est I'hydrogene ou un groupe alkyle ayant jusqu'a 3 atomes de carbone; ou A1 est un groupe alkylene ou alcenylene, facultativement fluore, et A11 est une liaison simple ou un groupe alkylene ou alcenylene facultativement fluore, de telle sorte que A1 et A11 totalisent 1 a 12 atomes de carbone, etY est un groupe —NRCO—,— CONR —,— COO—, —0C0 — ou un groupe phenylene ou R a la definition indiquee ci-dessus; R1 est I'hydrogene ou un groupe alkyle, alcenyle, cycloalkyle, halogenalkyle, carboxyalkyle, alcoxycarbonylalkyle, aryie ou arylalkyle ayant chacun jusqu'a 10 atomes de carbone ou un groupe dialkylaminoalkyle dont chaque radical alkyle comprend jusqu'a 6 atomes de carbone, ou bien R1 est lie a R2 comme defini ci-dessous; et X represente —CONR2—, —CSNR2—, —NR12—CO—, —NR12—CS— , —NR12—CONR2— , NR22 II —NR12—C—NR2—, —S02NR2 ou —CO—; ou bien, lorsque R1 n'est pas I'hydrogene, X represente —0 —, —NR2—, —(N0)R2— , —(P0)R2— , —NR12—COO—, —NR12—S02— , —S—, —SO—, ou —S02— ; , R2 est I'hydrogene ou un groupe alkyle ayant jusqu'a 6 atomes de carbone, ou bien R1 et R2 forment conjointement un groupe alkylene ou halogenalkylene de telle sorte que, avec I'atome adjacente d'azote, ils forment un noyau heterocyclique pentagonal a heptagonai dont I'un des atomes peut etre un second atome heterocyclique choisi entre oxygene, soufre et azote; R12 est I'hydrogene ou un groupe alkyle ayant jusqu'a 6 atomes de carbone; et R22 est I'hydrogene, un groupe cyano ou nitro; ou un sel de ce derive dans le cas appropries, caracterise en ce qu'il comprend: (a) lorsque X repond a la formule —CONR2 —, —CSNR2 — ou —S02NR2 —, la reaction d'un compose de formule ST1 —A—Z\ dans laquelle A a la definition donnee ci-dessus, ST1 a la meme definition que ST donnee ci-dessus ou est un noyau de steroi'de equivalent en liaison 7a qui porte un ou plusieurs groupes protecteurs pour des derives fonctionnels et Z1 est un groupe active derive d'un acide carboxylique, thiocarboxylique ou sulfonique, avec une amine de formule HNR1R2 dans laquelle R1 et R2 ont les definitions indiquees ci-dessus; ou bien (b) lorsque X repond a la formule —CO—, la reaction d'un acide de formule ST1—A—COOH, dans laquelle ST1 et A ont les definitions indiquees ci-dessus, avec un compose organometallique de formule R1—M, dans laquelle R1 a la definition indiquee ci-dessus et M est un metal; ou bien (c) lorsque X repond a la formule —S—, —0 —, —NR2— ou (P0)R2, la reaction d'un compose de formule ST1—A—Z2, dans laquelle ST1 et A ont les definitions indiquees ci-dessus et Z2 est un groupe deplagable, avec un compose de formule R1SH, R1OH, HNR1R2 ou R1R2P—C6HS, ou R1 et R2 ont les definitions indiquees ci-dessus, apres quoi un sel de phosphonium est hydrolyse en le compose phosphinylique; ou bien (d) lorsque X repond a la formule —NR12CO—, —NR12CS— , —NR12CONR2, NR22 —NR12C— NR2—, 55 60 —NR12C00— ou —NR12S02— , la reaction d'un compose de formule ST1—A— NHR12, dans laquelle ST1, A et R12 ont les definitions indiquees ci-dessus, avec un agent acylant derive d'un acide de formule R1COOH, R1CSOH, R1OCOOH ou R1S02OH; ou bien, pour la preparation d'une uree, avec un isocyanate de formule R1NCO; ou bien, pour la preparation d'une guanidine, avec un cyanamide de formule R1NR2—CN; ou bien (e) lorsque —A— est un groupe alcenylene de formule —A3—CH=CH —A4— ou A3 est une liaison simple ou un groupe alkylene et A4 est un groupe alkylene, la reaction d'un compose de formule: ST1—A3CHO 65 dans laquelle ST1 et A3 ont les definitions indiquees ci-dessus, avec un sel de triphenylphosphonium de formule: 42 0 138 504 R1X—A4—CH2—P+(Ph)3 Q- 5 10 15 20 25 dans laquelle R1, X et A4 ont les definitions indiquees ci-dessus et Q~ est un anion; apres quoi: (i) tout groupe protecteur contenu dans ST1 est elimine par des moyens classiques; ou bien (ii) un derive steroTdique dans lequel ST est un derive de 176-hydroxysteroTde peut etre converti par des reactions classiques en les derives de 17B-cetosteroTde correspondants puis en le derive de 17Bhydroxy-17a-hydrocarbyl steroi'de correspondant (c'est-a-dire un derive de steroi'de dans lequel R27 est un radical alkyle, alcenyle ou alcynyle); ou bien (iii) un derive de steroi'de dans lequel R3 et/ou R17 represented autre chose que I'hydrogene peut etre obtenu a partir du compose correspondant dans lequel R3 et/ou R17 sont de I'hydrogene par un procede classique d'etherification ou d'esterification; ou bien (iv) un derive de steroi'de dans lequel R3 et/ou R17 represented I'hydrogene peut etre obtenu par hydrolyse du compose correspondant dans lequel R3 et/ou R17 represented autre chose que I'hydrogene; ou bien (v) un derive de steroi'de dans lequel A est un groupe alcenylene peut etre hydrogene pour former le compose correspondant dans lequel A est un groupe alkylene; ou bien (vi) un derive de steroi'de dans lequel —X— est un groupe —CH2NR2— ou — NR2CH2— peut etre obtenu par reduction du compose correspondant dans lequel —X— est un groupe —CONR2— ou —NR2C0 — ; ou bien (vii) un derive de steroi'de dans lequel —X— est un groupe —CSNH — ou —NHCS — peut etre obtenu par reaction du compose correspondant dans lequel X est un groupe —CONH — ou —NHCO— avec le 2,4disulfure de 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane; ou bien (viii) un derive de steroi'de dans lequel X est un groupe —(NO)R2, —SO — ou —S02 — peut etre obtenu par oxydation du compose correspondant dans lequel X est un groupe — NR2— ou —S—. 2. Procede suivant la revendication 1 pour la preparation d'un derive steroTdique de formule ST —A—X—R1, dans laquelle ST repond a la formule ou R17 est un groupe hydroxy et R27 est I'hydrogene ou un groupe ethynyle, ou bien R17 et R27 forment conjointement un groupe oxo; —A— est un groupe —(CH2)n— dans lequel n est un nombre entier de 3 a 14, ou bien —A— est un groupe de formule: 45 so 55 so 65 dans laquelle m est un nombre entier de 2 a 9 et p a une valeur de 0 a 2; R1 est un groupe alkyle, fluoralkyle ou cycloalkyle ayant chacun jusqu'a 10 atomes de carbone ou un groupe phenyle, chlorophenyle ou benzyle ou est lie a R2 comme indique ci-dessous; X est un groupe —CONR2—, — NR12CO—, —S— , —SO— ou —S02— , ou R2 est I'hydrogene ou un groupe alkyle ayant jusqu'a 3 atomes de carbone ou forme conjointement avec R1 un groupe alkylene de 5 ou 6 atomes de carbone et R12 est I'hydrogene ou un groupe alkyle ayant jusqu'a 3 atomes de carbone, caracterise par: (a) lorsque X repond a la formule —CONR2—, la reaction d'un compose de formule ST1—A—Z1, dans laquelle A a la definition donnee ci-dessus, ST1 a la meme definition que ST donnee ci-dessus ou est un noyau equivalent de steroi'de en liaison 7a qui porte un ou plusieurs groupes protecteurs pour des derives fonctionnels, et Z1 est un groupe active derive d'un acide carboxylique, avec une amine de formule HNR1R2, dans laquelle R1 et R2 ont les definitions donnees ci-dessus; ou bien (b) lorsque X repond a la formule —S—, la reaction d'un compose de formule ST1—A—Z2, dans laquelle ST1 et A ont les definitions donnees ci-dessus et Z2 est un groupe deplagable, avec un compose de formule R1SH dans laquelle R1 a la definition indiquee ci-dessus; ou bien (c) lorsque X repond a la formule —NR12CO—, la reaction d'un compose de formule ST1— A— NHR12, dans laquelle ST1, A et R12 ont les definitions indiquees ci-dessus, avec un agent acylant derive d'un acide de formule R1COOH; ou bien 43 0 138 504 (d) lorsque —A— est un groupe alkylene de formule —A3—CH2—CH2—A4— dans laquelle A3 est une liaison simple ou un groupe alkylene et A4 est un groupe alkylene, la reaction d'un compose de formule: ST1—A3CHO dans laquelle ST1 et A3 ont les definitions indiquees ci-dessus, avec un sel de triphenylphosphonium de formule: 70 15 R1X—A4—CH2—P+(Ph) Q" dans laquelle R1, X et A4 ont les definitions indiquees ci-dessus et Or est un anion, suivies de I'hydrogenation du groupe alcenylene —A3—CH=CH —A4— ainsi forme; apres quoi: (i) tout groupe protecteur contenu dans ST1 est elimine par des moyens classiques; ou bien (ii) un derive steroTdique dans lequel ST est un derive de 17p-hydroxysteroTde peut etre converti par des reactions classiques en le derive de 17-cetosteroTde correspondant puis en le derive de 17B-hydroxy17a-ethynylsteroi'de correspondant; ou bien (iii) un derive de stero'fde dans lequel X est un groupe —SO — ou —S02 — peut etre obtenu par oxydation du compose correspondant dans lequel X represente —S—. 20 25 30 35 40' 45 50 55 50 55 44