17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives, method of production thereof and use thereof for the treatment of diseases

Abstract

The invention relates to 17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-dien-11-aryl derivatives of Formula I with progesterone antagonizing action and method of production thereof, use thereof for the treatment and/or prophylaxis of diseases and use thereof for the production of medicinal products for the treatment and/or prophylaxis of diseases, in particular of fibroids of the uterus (myomas, uterine leiomyoma), endometriosis, heavy menstrual bleeds, meningiomas, hormone-dependent breast cancers and complaints associated with the menopause or for fertility control and emergency contraception.

Claims

1. Method for the treatment of fibroid of the uterus, endometriosis, heavy menstrual bleed, meningioma, hormone-dependent breast cancer, fertility control, or emergency contraception comprising the step of administering (11?,17?)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one of the formula ##STR00045## or pharmaceutical acceptable salts thereof.

2. Method according to claim 1 for the treatment of endometriosis.

3. Method according to claim 1 for the treatment of fibroids of the uterus.

Description

(1) The following examples serve to explain the invention without limiting it in any way.

EXAMPLE 1

(11?,17?)-17-hydroxy-11-[4-(methylsulphanyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one

(2) ##STR00004##

a) (5R,8S,10R,13S,14S,17S)-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,7,8,12,13,14,15,16,17-decahydro-6H-spiro[1,3-dioxane-2,3-[5,10]epoxycyclopenta[a]phenanthrene]-17-ol

(3) ##STR00005##

(4) 50 g of (5R,8S,10R,13S,14S)-5,5,13-trimethyl-1,2,6,7,8,12,13,14,15,16-decahydro-17H-spiro[1,3-dioxane-2,3-[5,10]epoxycyclopenta[a]phenanthren]-17-one (for preparation see Tetrahedron Left. 26, 2069-2072 (1985) was added to 116 g of condensed pentafluoroiodoethane in 500 ml absolute toluene at ?70? C. 290 ml of a 1.5-molar solution of methyllithium-lithium bromide complex in diethyl ether was added to this at the same temperature. It was then stirred for one hour at 0? C. The reaction mixture was then added to saturated aqueous ammonium chloride solution and was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum. The raw product was dissolved in 200 ml acetone and 450 ml water was added. The precipitated product was filtered off and dried in vacuum.

(5) Yield 61.6 g

(6) 1H-NMR (400 MHz, CDCl3): ?=6.04 brd (1H); 3.60 d (1H); 3.35-3.50 m (3H); 2.51 dbr (1H); 1.06 s (3H); 0.93 s (3H); 0.85 s (3H).

b) (5R,8S,11R,13S,14S,17S)-5,5,13-trimethyl-11-[4-(methylsulphanyl)phenyl]-17-(pentafluoroethyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(7) ##STR00006##

(8) 1.23 g magnesium shavings were suspended in 5 ml THF and 50 ?l dibromoethane was added, while stirring. A solution of 10.31 g of 1-bromo-4-(methylthiopheny)benzene in 60 ml THF was added to the suspension in such a way that the reaction temperature did not go above 55? C. Then it was stirred for a further hour. The resultant solution was then cooled to 0? C. 151 mg CuCl was added and it was stirred for a further 15 minutes at 0? C. Then a solution of 5 g of the substance described in example 1a) in 50 ml THF was added. Then the reaction mixture was allowed to reach 23? C. in the space of approx. 3 hours, with stirring, and then it was stirred at this temperature for a further 10 hours. Then saturated aqueous NH.sub.4Cl solution was added to the reaction mixture, with external cooling. Stirring was continued for 30 minutes and it was then extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The raw product was purified by silica gel chromatography followed by crystallization from a mixture of dichloromethane and diisopropyl ether. This gave 5.72 g of the title compound.

(9) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.50 d (2H); 7.30 d (2H); 4.41 s (1H); 4.28 dbr (1H); 3.40-3.60 m (4H); 2.51 s (3H); 1.05 s (3H); 0.87 s (3H); 0.53 s (3H).

c) (11?,17?)-17-hydroxy-11-[4-(methylsulphanyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one

(10) ##STR00007##

(11) 500 mg of the compound described in 1b) was dissolved in 15 ml methanol. 360 ?l of semi-concentrated sulphuric acid was added and stirring was continued for 3 hours at 23? C. Then the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution. It was extracted several times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum. The raw product was purified by silica gel chromatography. This gave 297 mg of the title compound.

(12) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.20 d (2H); 7.13 d (2H); 5.80 sbr (1H); 4.45 dbr (1H); 2.51 s (3H); 0.68 s (3H).

EXAMPLE 2

(11?,17?)-11-[4-(ethylsulphanyl)phenyl]-17-hydroxy-17-(pentafluoroethyl)estra-4,9-dien-3-one

(13) ##STR00008##

a) (5R,8S,11R,13S,14S,17S)-11-[4-(ethylsulphanyl)phenyl]-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(14) ##STR00009##

(15) As in example 1b), 2.7 g of the title compound was prepared from 3 g of the compound described in 1a), 888 mg magnesium shavings, 91 mg CuCl and 7.94 g of 1-bromo-4-(ethylthiopheny)benzene in THF.

(16) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.50 d (2H); 7.38 d (2H); 4.43 s (1H); 4.39 dbr (1H); 3.40-3.60 m (3H); 2.95 q (2H); 1.30 t (3H); 1.07 s (3H); 0.87 s (3H); 0.53 s (3H).

b) (11?,17?)-11-[4-(ethylsulphanyl)phenyl]-17-hydroxy-17-(pentafluoroethy)estra-4,9-dien-3-one

(17) ##STR00010##

(18) As in example 1c), 125 mg of the title compound was prepared from 200 mg of the compound prepared in 2a) by reaction with semi-concentrated sulphuric acid in methanol.

(19) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.21 d (2H); 7.08 d (2H); 5.78 sbr (1H); 4.43 dbr (1H); 2.93 q (2H); 1.29 t (3H); 0.60 s (3H).

EXAMPLE 3

(11?,17?)-17-Hydroxy-11-{4-[(RS)-methylsulphinyl]phenyl}-17-(pentafluoroethy)estra-4,9-dien-3-one

(20) ##STR00011##

(21) 180 ?l of 30% hydrogen peroxide solution was added to 0.5 ml of trifluoroacetic acid at 23? C. It was stirred for 30 minutes and then the mixture was added to a suspension, cooled to 10? C., of 533 mg of the compound prepared in example 1c), in 1.8 ml of trifluoroacetic acid. It was stirred for a further 2 hours at 10? C. Then the reaction mixture was poured into ice water. It was stirred for a further 2 hours and then the precipitated product was filtered off. The raw product obtained was purified by silica gel chromatography. This gave 146 mg of the title compound and 123 mg of the compound described in example 4.

(22) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.58 d (2H); 7.38 d (2H); 5.80 sbr (1H); 4.50 dbr (1H); 2.71 s (3H); 0.58 s (3H)+0.56 s (3H) (mixture of the diastereomers).

EXAMPLE 4

(11?,17?)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one

(23) ##STR00012##

(24) 5 g of the compound described in example 1 b) was dissolved in a mixture of 140 ml THF and 140 ml methanol. A solution of 20 g OXONE? (monopersulfate compound) in 94 ml water was slowly added dropwise at 0? C. Then it was stirred for a further 3.5 hours at 0? C. Then a mixture of water and dichloromethane was added to the reaction 20 mixture. The phases were separated and the aqueous phase was extracted several times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum. The raw product was purified by silica gel chromatography. This gave 3.8 g of the title compound.

(25) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.86 d (2H); 7.40 d (2H); 5.81 sbr (1H); 4.50 dbr (1H); 3.07 s (3H); 0.51 s (3H).

EXAMPLE 5

(11?,17?)-11-[4-(ethylsulphonyl)phenyl]-17-hydroxy-17-(pentafluoroethy)estra-4,9-dien-3-one

(26) ##STR00013##

(27) As in example 4), after purification by silica gel chromatography, 183 mg of the title compound was obtained by reaction of 400 mg of the compound described in example 2a) with 1.56 g OXONE? (monopersulfate compound) in a mixture of 10 ml THF and 10 ml methanol.

(28) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.82 d (2H); 7.40 d (2H); 5.80 sbr (1H); 4.52 dbr (1H); 3.13 q (2H); 1.28 t (3H); 0.51 s (3H).

EXAMPLE 6

(11?,17?)-11-[4-(benzylsulphanyl)phenyl]-17-hydroxy-17-(pentafluoroethy)estra-4,9-dien-3-one

(29) ##STR00014##

a) (5R,8S,11R,13S,14S,17S)-11-[4-(benzylsulphanyl)phenyl]-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(30) ##STR00015##

(31) As in example 1b), 6.65 g of the title compound was prepared from 8.5 g of the compound described in 1a), 2.64 g magnesium shavings, 171 mg CuCl and 30.36 g of 1-benzylsulphanyl-4-bromobenzene in THF.

(32) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.13-7.30 m (7H); 7.10 d (2H); 4.44 s (1H); 4.27 dbr (1H); 4.05 s (2H); 3.40-3.60 m (4H); 1.05 s (3H); 0.87 s (3H); 0.51 s (3H).

b) (11?,17?)-11-[4-(benzylsulphanyl)phenyl]-17-hydroxy-17-(pentafluoroethy)estra-4,9-dien-3-one

(33) ##STR00016##

(34) As in example 1c), 1.02 g of the title compound was prepared from 1.62 g of the compound described in example 6a) by reaction with semi-concentrated sulphuric acid in methanol.

(35) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.15-7.40 m (7H); 7.06 d (2H); 5.78 sbr (1H); 4.40 dbr (1H); 4.08 s (2H); 0.59 s (3H).

EXAMPLE 7

N-[{4-[(11?,17?)-17-hydroxy-3-oxo-17-(pentafluoroethy)estra-4,9-dien-11-yl]phenyl}(RS)(methyl) oxido-?6-sulphanylidene]-4-methylbenzene Sulphonamide

(36) ##STR00017##

a) N-[{4-[(5R,8S,11R,13S,14S,17S)-5,17-Dihydroxy-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-11-yl]phenyl}(RS)(methyl)-?4-sulphanylidene]-4-methylbenzene sulphonamide

(37) ##STR00018##

(38) 3 g of the substance described in example 1b) was suspended in 80 ml acetonitrile. 1.64 g of CHLORAMINE-T-TRIHYDRATE? (N-Chloro-p-toluenesulfonamide sodium salt hydrate) was added and stirring was continued for 20 hours at 23? C. Then the reaction mixture was diluted with 70 ml dichloromethane. After filtering off precipitated sodium chloride, it was concentrated in vacuum. The raw product was purified by silica gel chromatography. This gave 3.16 g of the title compound.

(39) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.74 d (2H); 7.49 d (2H); 7.38 d (2H); 7.18 d (2H); 4.40 s (1H); 4.33 dbr (1H); 3.40-3.70 m (4H); 2.80 (3H); 2.37 s (3H), 1.05 s (3H); 0.89 s (3H); 0.45 s (3H) (mixture of diastereomers).

b) N-[{4-[(5R,8S,11R,13S,14S,17S)-5,17-dihydroxy-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-11-yl]phenyl}(RS)(methyl) oxido-?6-sulphanylidene]-4-methylbenzene sulphonamide

(40) ##STR00019##

(41) 3.16 g of the compound obtained in 7a) was dissolved in 2.5 ml acetonitrile and 1.6 ml methanol. 1.22 g of sodium carbonate and 2.34 ml of 30% hydrogen peroxide solution were added. Then it was stirred for 2.5 hours at 23? C. The reaction mixture was then poured into water. It was extracted several times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum. The raw product was purified by silica gel chromatography. This gave 2.56 g of the title compound.

(42) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.78-8.00 m (4H); 7.51 d (2H); 7.31 d (2H); 4.50 s (1H); 4.44 dbr (1H); 3.45-3.67 m (7H); 2.46 s (3H); 1.09 s (3H); 0.91 s (3H); 0.51 s (3H) (mixture of diastereomers).

c) N-[{4-[(11?,17?)-17-hydroxy-3-oxo-17-(pentafluoroethy)estra-4,9-dien-11-yl]phenyl}(RS)(methyl) oxido-?6-sulphanylidene]-4-methylbenzene sulphonamide

(43) ##STR00020##

(44) As in example 1c), 2.2 g of the title compound was prepared from 2.72 g of the compound prepared in 7b) by reaction with semi-concentrated sulphuric acid in methanol.

(45) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.95 d (2H); 7.86 d (2H); 7.45 d (2H); 7.28 d (2H); 5.81 sbr (1H); 4.51 dbr (1H); 3.41 s (3H); 2.40 s (3H); 0.51 s (3H) (mixture of diastereomers).

EXAMPLE 8

(11?,17?)-17-Hydroxy-11-[4-(RS-methylsulphonimidoyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one

(46) ##STR00021##

(47) 500 mg of the compound prepared in example 7c) was dissolved in 10 ml chloroform. 1.15 ml of concentrated sulphuric acid was added at 0? C. and it was stirred for 7 hours at 0? C. Then the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution. It was then made basic by adding 5% NaOH. It was extracted several times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum. The raw product was purified by silica gel chromatography. This gave 306 mg of the title compound.

(48) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.91 d (2H); 7.39 d (2H); 5.81 sbr (1H); 4.50 dbr (1H); 3.12 s (3H)+3.10 s (3H); 0.56 s (3H)+0.40 s (3H) (mixture of diastereomers).

EXAMPLE 9

(11?,17?)-17-Hydroxy-11-[4-(methylsulphanyl)biphenyl-4-yl]-17-(pentafluoroethy)estra-4,9-dien-3-one

(49) ##STR00022##

a) (5R,8S,11R,13S,14S,17S)-11-[4-(benzyloxy)phenyl]-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(50) ##STR00023##

(51) 2.47 g magnesium shavings were suspended in 5 ml THF and 50 ?l dibromoethane was added, while stirring. A solution of 26.7 g of 1-bromo-4-(phenylmethoxy)benzene in 115 ml THF was slowly added to the suspension at 65? C. The resultant solution was cooled to 0? C. 301 mg CuCl was added to it. It was stirred for 10 minutes at 0? C. and then a solution of 10 g of the substance described in example 1a) in 70 ml THF was added slowly. The reaction mixture was allowed to warm to 23? C. while stirring in the space of approx. 3 hours and was then stirred at this temperature for a further 10 hours. Then saturated aqueous NH.sub.4Cl solution was added to the reaction mixture, with external cooling. It was stirred for a further 30 minutes and then extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The raw product was purified by silica gel chromatography followed by crystallization from a mixture of dichloromethane and diisopropyl ether. This gave 9.7 g of the title compound.

(52) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.30-7.50 m (5H); 7.12 d (2H); 6.88 d (2H); 5.02 s (2H); 4.43 s (1H); 4.28 dbr (1H); 3.50-3.60 m (3H); 3.42 d (1H); 1.06 s (3H); 0.87 s (3H); 0.56 s (3H).

b) (5R,8S,11R,13S,14S,17S)-11-[4-(benzyloxy)phenyl]-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(53) ##STR00024##

(54) 5.53 g ammonium formate and 972 mg palladium on activated charcoal (10%) were added to a solution of 9.72 g of the compound described in 9a) in 100 ml methanol. It was stirred for 2 hours at 23? C. and then filtered on CELITE? (diatomaceous earth) The filtrate was concentrated under vacuum. This gave 8.5 g of raw product, which was used in the next stage without purification.

(55) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.05 d (2H); 6.70 d (2H); 4.43 sbr (1H); 4.27 dbr (1H); 3.50-3.58 m (3H); 3.41 sbr (1H); 1.94 s (3H); 0.86 s (3H); 0.54 s (3H).

c) 4-[(5R,8S,11R,13S,14S,17S)-5,17-Dihydroxy-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxan]-11-yl]phenyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate

(56) ##STR00025##

(57) 14.64 ml of a 1.6-molar solution of n-butyllithium in hexane was added at 0? C. to a solution of 9.16 g of the compound described in 9b) in 100 ml absolute THF. It was stirred for 30 minutes at 0? C. and then 5.62 ml perfluorobutane-1-sulphonyl fluoride was added slowly. Then it was stirred for a further 1.5 hours at 0? C. Then the reaction mixture was poured into a mixture of 300 ml of saturated sodium hydrogen carbonate solution and 90 ml of 2N sodium hydroxide solution. It was stirred for 45 minutes and then extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The raw product obtained was purified by silica gel chromatography. This gave 10.1 g of the title compound.

(58) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.28 d (2H); 7.18 d (2H); 4.42 s (1H); 4.34 dbr (1H); 3.50-3.58 m (3H); 3.42 d (1H); 1.05 s (3H); 0.86 s (3H); 0.50 s (3H).

d) (5R,8S,11R,13S,14S,17S)-5,5,13-trimethyl-11-[4-(methylsulphanyl)biphenyl-4-yl]-17-(pentafluoroethyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(59) ##STR00026##

(60) 2 ml of a 2-molar aqueous sodium carbonate solution, 131 mg of lithium chloride, 240 mg of 4-(methylthio)phenylboronic acid and 192 mg of tetrakis(triphenylphosphine)palladium were added to a solution of 1.2 g of the compound described in 9c) in a mixture of 12 ml toluene and 6 ml ethanol. Then it was boiled under reflux for 2 hours. Then a mixture of ethyl acetate and water was added to the reaction mixture. It was extracted several times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum. The raw product was purified by silica gel chromatography. This gave 927 mg of the title compound.

(61) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.45-7.55 m (4H); 7.30 d (2H); 7.27 d (2H); 4.45 s (1H); 4.35 dbr (1H); 3.40-3.60 m (4H); 2.50 s (3H); 1.07 s (3H); 0.97 s (3H); 0.58 s (3H).

e) (11?,17?)-17-hydroxy-11-[4-(methylsulphanyl)biphenyl-4-yl]-17-(pentafluoroethy)estra-4,9-dien-3-one

(62) ##STR00027##

(63) As in example 1c), 82 mg of the title compound was prepared from 120 mg of the compound prepared in 9d) by reaction with semi-concentrated sulphuric acid in methanol.

(64) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.45-7.58 m (4H); 7.30 d (2H); 7.24 d (2H); 5.80 sbr (1H); 4.50 dbr (1H); 2.50 s (3H); 0.62 s (3H).

EXAMPLE 10

(11?,17?)-17-hydroxy-11-[4-(methylsulphonyl)biphenyl-4-yl]-17-(pentafluoroethy)estra-4,9-dien-3-one

(65) ##STR00028##

a) (5R,8S,11R,13S,14S,17S)-5,5,13-trimethyl-11-[4-(methylsulphonyl)biphenyl-4-yl]-17-(pentafluoroethyl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(66) ##STR00029##

(67) As in example 9d), 256 mg of the title compound was prepared from 500 mg of the compound described in example 9c) and (4-methylsulphonylphenyl)boronic acid in the presence of tetrakis(triphenylphosphine)palladium, lithium chloride, 2-molar aqueous sodium carbonate solution in a mixture of toluene and ethanol.

(68) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=8.03 d (2H); 7.80 d (2H); 7.58 d (2H); 7.39 d (2H); 4.48 s (1H); 4.45 dbr (1H); 3.45-3.65 m (4H); 3.12 s (3H); 1.10 s (3H); 0.91 s (3H); 0.62 s (3H).

b) (11?,17?)-17-hydroxy-11-[4-(methylsulphonyl)biphenyl-4-yl]-17-(pentafluoroethyl)estra-4,9-dien-3-one

(69) ##STR00030##

(70) As in example 1c), 62 mg of the title compound was prepared from 110 mg of the compound prepared in 10a) by reaction with semi-concentrated sulphuric acid in methanol.

(71) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=8.00 d (2H); 7.75 d (2H); 7.55 d (2H); 7.30 d (2H); 5.80 sbr (1H); 4.50 dbr (1H); 3.09 s (3H); 0.65 s (3H).

EXAMPLE 11

N-[{4-[(11?,17?)-17-hydroxy-3-oxo-17-(pentafluoroethy)estra-4,9-dien-11-yl]biphenyl-4-yl}(RS)(methyl) oxido-?6-sulphanylidene]-4-methylbenzene Sulphonamide

(72) ##STR00031##

a) N-[{4-[(5R,8S,11R,13S,14S,17S)-5,17-dihydroxy-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-11-yl]biphenyl-4-yl}(RS)(methyl)-?4-sulphanylidene]-4-methylbenzene sulphonamide

(73) ##STR00032##

(74) As in example 7a), 715 mg of the title compound was prepared from 800 mg of the compound prepared in example 9d) with CHLORAMINE-T-TRIHYDRATE? (N-Chloro-p-toluenesulfonamide sodium salt hydrate) in acetonitrile.

(75) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.65-7.80 (6H); 7.47 d (2H); 7.30 d (2H); 7.18 d (2H); 4.45 s (1H); 4.39 dbr (1H); 3.40-3.60 m (4H); 2.87 (3H); 2.35 s (3H), 1.03 s (3H); 0.87 s (3H); 0.56 s (3H) (mixture of diastereomers).

b) N-[{4-[(5R,8S,11R,13S,14S,17S)-5,17-dihydroxy-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxan]-11-yl]biphenyl-4-yl}(RS)(methyl)oxido-?6-sulphanylidene]-4-methylbenzene sulphonamide

(76) ##STR00033##

(77) As in example 7b), 638 mg of the title compound was obtained from 709 mg of the compound obtained in example 11a) by reaction with 30% hydrogen peroxide solution and sodium carbonate in a mixture of acetonitrile and methanol.

(78) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=8.04 d (2H); 7.87 d (2H); 7.78 d (2H); 7.50 d (2H); 7.35 d (2H); 7.27 d (2H); 4.46 s (1H); 4.40 dbr (1H); 3.40-3.60 m (4H); 3.46 s (3H); 2.39 s (3H); 1.07 s (3H); 0.87 s (3H); 0.56 s (3H) (mixture of diastereomers).

c) N-[{4-[(11?,17?)-17-hydroxy-3-oxo-17-(pentafluoroethyl)estra-4,9-dien-11-yl]biphenyl-4-yl}(RS)(methyl)-oxido-?6-sulphanylidene]-4-methylbenzene sulphonamide

(79) ##STR00034##

(80) As in example 1c), 523 mg of the title compound was prepared from 633 mg of the compound prepared in 11b) by reaction with semi-concentrated sulphuric acid in methanol.

(81) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=8.06 d (2H); 7.87 d (2H); 7.78 d (2H); 7.52 d (2H); 7.20-7.35 m (4H); 5.80 sbr (1H); 4.51 dbr (1H); 3.45 s (3H); 2.39 s (3H); 0.62 s (3H) (mixture of diastereomers).

EXAMPLE 12

(11?,17?)-17-hydroxy-11-[4(RS-methylsulphonimidoyl)biphenyl-4-yl]-17-(pentafluoroethy)estra-4,9-dien-3-one

(82) ##STR00035##

(83) As in example 8, 325 mg of the title compound was obtained from 500 mg of the compound prepared in example 11c) by reaction with concentrated sulphuric acid in chloroform.

(84) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=8.07 d (2H); 7.74 d (2H); 7.55 d (2H); 7.30 d (2H); 5.80 sbr (1H); 4.51 dbr (1H); 3.15 s (3H); 0.64 s (3H) (mixture of diastereomers).

EXAMPLE 13

(11?,17?)-17-hydroxy-17-(pentafluoroethyl)-11-(4-sulphanylbiphenyl-4-yl)estra-4,9-dien-3-one

(85) ##STR00036##

a) (5R,8S,11R,13S,14S,17S)-5,5,13-trimethyl-17-(pentafluoroethyl)-11-(4-sulphanylbiphenyl-4-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-5,17(4H)-diol

(86) ##STR00037##

(87) As in example 9d), 478 mg of the title compound was prepared from 1 g of the compound described in example 9c) and (4-mercaptophenyl)boronic acid in the presence of tetrakis(triphenylphosphine)palladium, lithium chloride, 2-molar aqueous sodium carbonate solution in a mixture of toluene and ethanol.

(88) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.14-7.32 m (8H); 4.42 s (1H); 4.30 dbr (1H); 3.40-3.60 m (4H); 1.05 s (3H); 0.88 s (3H); 0.54 s (3H).

b) (11?,17?)-17-hydroxy-17-(pentafluoroethyl)-11-(4-sulphanylbiphenyl-4-yl)estra-4,9-dien-3-one

(89) ##STR00038##

(90) As in example 1c), 103 mg of the title compound was prepared from 200 mg of the compound prepared in 13a) by reaction with semi-concentrated sulphuric acid in methanol.

(91) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.20-7.38 m (6H); 7.11d (2H); 5.78 sbr (1H); 4.42 dbr (1H); 0.61 s (3H).

EXAMPLE 14

4-[(11?,17?)-17-hydroxy-3-oxo-17-(pentafluoroethyl)estra-4,9-dien-11-yl]-N,N-dimethylbiphenyl-4-sulphonamide

(92) ##STR00039##

a) 4-[(5R,8S,11R,13S,14S,17S)-5,17-dihydroxy-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxane]-11-yl]-N,N-dimethylbiphenyl-4-sulphonamide

(93) ##STR00040##

(94) As in example 9d), 235 mg of the title compound was prepared from 300 mg of the compound described in example 9c) and [4-[(dimethylamino)sulphonyl]phenyl]boronic acid in the presence of tetrakis(triphenylphosphine)palladium, lithium chloride, 2-molar aqueous sodium carbonate solution in a mixture of toluene and ethanol.

(95) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.83 d (2H); 7.73 d (2H); 7.52 d (2H); 7.33 d (2H); 4.47 s (1H); 4.39 dbr (1H); 3.40-3.60 m (4H); 2.75 s (6H); 1.06 s (3H); 0.88 s (3H); 0.57 s (3H).

b) 4-[(11?,17?)-17-hydroxy-3-oxo-17-(pentafluoroethyl)estra-4,9-dien-11-yl]-N,N-dimethylbiphenyl-4-sulphonamide

(96) ##STR00041##

(97) As in example 1c), 113 mg of the title compound was prepared from 230 mg of the compound prepared in 14a) by reaction with semi-concentrated sulphuric acid in methanol.

(98) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.83 d (2H); 7.72 d (2H); 7.55 d (2H); 7.30 d (2H); 5.80 sbr (1H); 4.52 dbr (1H); 2.75 s (6H); 0.64 s (3H).

EXAMPLE 15

4-[(11?,17?)-17-Hydroxy-3-oxo-17-(pentafluoroethy)estra-4,9-dien-11-yl]-N,N-dimethylbenzene Sulphonamide

(99) ##STR00042##

a) 4-[(5R,8S,11R,13S,14S,17S)-5,17-Dihydroxy-5,5,13-trimethyl-17-(pentafluoroethyl)-1,2,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxan]-11-yl]-N,N-dimethylbenzene sulphonamide

(100) ##STR00043##

(101) 5.1 ml of a 2-molar solution of diisopropylmagnesium chloride in diethyl ether was diluted with 10 ml THF, with cooling (?10? C.). Then 8.12 ml of a 2.5-molar solution of n-butyllithium in hexane was added dropwise at ?10? C. in the space of 30 minutes. It was stirred for a further 2 hours and then 15.1 mg CuCl was added. After stirring for a further 5 minutes, a solution of 500 mg of the substance described in example 1a) in 5 ml THF was added. It was stirred for a further 3 hours at ?10? C. and then heated slowly to 23? C. It was stirred for a further 12 hours at 23? C. Then saturated aqueous NH.sub.4Cl solution was added to the reaction mixture, with external cooling. It was stirred for a further 30 minutes and then extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The raw product was purified by silica gel chromatography. This gave 214 mg of the title compound.

(102) .sup.1H-NMR (300 MHz, CDCl.sub.3): ?=7.65 d (2H); 7.40 d (2H); 4.45 s (1H); 4.38 dbr (1H); 3.40-3.60 m (4H); 2.69 s (6H); 1.03 s (3H); 0.89 s (3H); 0.49 s (3H).

b) 4-[(11?,17?)-17-Hydroxy-3-oxo-17-(pentafluoroethyl)estra-4,9-dien-11-yl]-N,N-dimethylbenzene Sulphonamide

(103) ##STR00044##

(104) As in example 1c), 74 mg of the title compound was prepared from 100 mg of the compound prepared in 15a) by reaction with semi-concentrated sulphuric acid in methanol.

(105) .sup.1H-NMR (400 MHz, CDCl.sub.3): ?=7.69 d (2H); 7.38 d (2H); 5.80 sbr (1H); 4.04 dbr (1H); 2.68 s (6H); 0.52 s (3H)

EXAMPLE 16 PROGESTERONE RECEPTOR-ANTAGONISTIC ACTION IN STABLE TRANSFECTANTS OF HUMAN NEUROBLASTOMA CELLS (SK-N-MC CELLS) WITH THE HUMAN PROGESTERONE A OR PROGESTERONE B RECEPTOR AND AN MTV-LUC REPORTER CONSTRUCT

(106) SK-N-MC cells (human neuroblastoma cells), which have been stably transfected with plasmids, which express the human progesterone receptor B (pRChPR-B-neo) or the human progesterone receptor A (pRChPR-A-neo) and a reporter construct (pMMTV-LUC), were incubated for 24 hours either in the absence (negative control) or in the presence of increasing amounts of the respective test compound (0.01 nmol/l, 0.1 nmol/l 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 ?mol/l), in order to determine the agonistic efficacy. As positive control of reporter gene induction, the cells were treated with the synthetic gestagen promegestone (0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 ?mol/l). For determination of the antagonistic activity, the cells were treated with 0.1 nmol/1 promegestone and additionally with increasing amounts of the respective test compound (0.01 nmol/l, 0.1 nmol/l, 1 nmol/l, 10 nmol/l, 100 nmol/l and 1 ?mol/l). The activity of the LUC reporter gene (LUC=luciferase) was determined in the cell lysates and was measured as RLU (relative light units). All measured values are given as percentage efficacy and as EC.sub.50 or IC.sub.50 concentrations.

(107) 11?-(4-Acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17?-pregna-4,9-dien-3-one and 20,20,21,21,21-pentafluoro-17-hydroxy-11?-[4-(hydroxyacetyl)phenyl]-19-nor-17?-pregna-4,9-dien-3-one, very potent and therefore preferred examples from WO98/34947 and WO2008/058767, were tested as comparative compounds along with the test compound.

(108) a) Agonistic Activity:

(109) None of the stated test compounds shows agonistic activity.

(110) b) Antagonistic Activity:

(111) All of the stated compounds show 100% antagonistic efficacy.

(112) The antagonistic efficacy of the compounds is presented in Table 1.

(113) TABLE-US-00001 Progesterone Progesterone receptor receptor A (PR-A) B (PR-B) Potency Effi- Potency Effi- IC.sub.50 cacy IC.sub.50 cacy Compound [nmol/l] [%] [nmol/l] [%] 11?-(4-Acetylphenyl)- 0.014 100 0.02 100 20,20,21,21,21- pentafluoro-17-hydroxy- 19-nor-17?-pregna- 4,9-dien-3-one 20,20,21,21,21-Pentafluoro- 0.18 100 0.28 100 17-hydroxy- 11?-[4-(hydroxyacatyl)phenyl]- 19-nor-17?-pregna- 4,9-dien-3-one dien-3-one Example 1 0.011 100 0.012 100 Example 2 0.01 100 0.01 100 Example 3 0.11 100 0.12 100 Example 4 0.096 100 0.087 100 Example 5 0.1 100 0.09 100 Example 6 0.2 100 0.23 100 Example 7 1.0 100 0.8 100 Example 8 0.9 100 0.9 100 Example 9 0.01 100 0.01 100 Example 10 0.011 100 0.013 100 Example 11 0.01 100 0.01 100 Example 12 0.08 100 0.08 100 Example 13 0.072 100 0.072 100 Example 14 0.01 100 0.01 100 Example 15 0.1 100 0.2 100

EXAMPLE 17 ABORTION TEST ON FEMALE RATS

(114) The action of progesterone and of the progesterone receptor is a fundamental precondition for successful pregnancy or gestation in mammals. The progesterone-antagonistic action of the compounds according to the invention was tested on pregnant rats (6 rats per group) on day 5 to 7 post coitum with conventional housing and feeding conditions.

(115) After successful hand mating, the pregnant animals (presence of sperm in the vaginal smear on day 1 of pregnancy=d1 p.c.) were randomized and divided into the treatment group and the control group. The animals then each received subcutaneously or orally 0.15; 0.5; 1.5 or 5 mg/kg of the test compound or 1.0 ml/kg of vehicle (benzyl benzoate/castor oil: 1+4 [v/v]) daily from day 5 to day 7 (d5-d7 p.c.).

(116) Autopsy was carried out on day 9 (d9 p.c.). As a characteristic of progesterone receptor antagonistic action, the uterus was examined for the presence of nidation sites. Complete absence, or also the presence of pathological, haemorrhagic or otherwise abnormal nidation sites on day 9 (d9 p.c.) was assessed as abortion. The results of the tests are shown in Table 3.

(117) TABLE-US-00002 TABLE 3 Results for the rat (termination of early pregnancy) Daily dose Abortion [mg/kg] rate Test compound according to s.c. or p.o. [%] Vehicle 0 Example 1 0.5 80 (11?,17?)-17-hydroxy-11-[4- 1.5 100 (methylsulphanyl)phenyl]-17- 5.0 100 (pentafluoroethyl)estra-4,9-dien-3- one Example 4 0.15 40 (11?,17?)-17-hydroxy-11-[4- 0.5 100 (methylsulphonyl)phenyl]-17- 1.5 100 (pentafluoroethyl)estra-4,9-dien-3- 5.0 100 one Example 8 0.15 40 (11?,17?)-17-hydroxy-11-[4-(RS- 0.5 100 methylsulphonimidoyl)-phenyl]-17- 1.5 100 (pentafluoroethyl)estra-4,9-dien-3- 5.0 100 one

EXAMPLE 18 METABOLIC STABILITY OF (11?,17?)-17-HYDROXY-11[4-(METHYLSULPHONYL)PHENYL]-17-(PENTAFLUOROETHYL)ESTRA-4,9-DIEN-3-ONE AND (11?,17?)-17-HYDROXY-11-[4-(METHYLSULPHONYL)-BIPHENYL-4-YL]-17-(PENTAFLUOROETHYL)ESTRA-4,9-DIEN-3-ONE IN HUMAN LIVER MICROSOMES (HLM)

(118) Isolated human liver microsomes (HLM) were used for assessing the metabolic stability of compounds of general formula I.

(119) Incubations were carried out with 2.4 ml of HLM solution (0.5 mg/ml protein content), 30 ?l of the test compound (final concentration 1 ?M) and 0.6 ml of the cofactor mixture (=NADPH-generating system of 3 IU glucose-6-phosphate dehydrogenase, 14.6 mg glucose-6-phosphate, 1.2 mg NADP) at 37? C. in 100 mM phosphate buffer at pH 7.4. Samples are taken at 6 time points (2-60 min), precipitated with an equal volume of methanol and the recovery of the test substances used in the supernatant is determined by LC-MS/MS analysis. The intrinsic clearance of the substance in the liver microsome preparation can be calculated from the half-life found for the breakdown of the substance. Based on this, together with various physiological characteristics according to the well-stirred model, it is then possible to predict a (metabolic) in vivo clearance with respect to phase I reactions. The (metabolic) in vivo clearance in humans predicted correspondingly for the test compounds (11?,17?)-17-hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one and (11?,17?)-17-hydroxy-11-[4-(methylsulphonyl)biphenyl-4-yl]-17-(pentafluoroethyl)-estra-4,9-dien-3-one was very low: 0.1 L/h/kg and <0.01 L/h/kg, respectively.

EXAMPLE 19 PERMEATION OF (11?,17?)-17-HYDROXY-11-[4-(METHYLSULPHONYL)PHENYL]-17-(PENTAFLUOROETHYL)ESTRA-4,9-DIEN-3-ONE IN CACO-2 CELLS

(120) For the permeation studies, Caco-2 cells with a cell count of 300000 cells/ml were cultivated on Transwell Clear filter inserts (polyester; pore size 0.4 ?m) in 12-well cell culture plates for at least 14 days in cell culture medium (1.5 ml) at 37? C., 5% CO.sub.2 and 95% air humidity. Before the test, to verify the compactness of the cell monolayer, the transepithelial resistance (TEER value) was determined, which must be greater than 300 ?cm.sup.2. Then the cell culture medium was replaced with hot transport buffer (0.5 ml apical, 1.5 ml basolateral) and the cells were equilibrated in it for 5 min. The permeability test was performed in duplicate at a substance concentration of 2 ?M. At the start of the experiment, 100 ?l (Ap0 min) was taken from the apical compartment and 100 ?l of ice-cold stopping solution was added to it immediately. The filters were then incubated at 37? C. with gentle shaking for 90 min, then 100 ?l was taken again from the apical side (Ap90 min) and 400 ?l from the basolateral side (Bas90 min) and in each case the same volume of stopping solution was added. After further dilution of the samples with 4 times the volume of stopping solution/transport buffer (1+1) they were sedimented overnight at ?20? C. and the supernatant was analysed by LCMS/MS. The Papp value of the substances was calculated from the following formula.

(121) $\begin{array}{c}\mathrm{Papp}=\frac{V_{\mathrm{res}}}{A.Math.C_{t0,\mathrm{don}}}.Math.\frac{?C_{\mathrm{res}}}{?t}\end{array}$

(122) V.sub.res: buffer volume on the receptor side; A: filter area=1 cm.sup.2; C.sub.t0, don: concentration of substance on the donor side; ?C.sub.res/?t: change in concentration of substance over time on the receptor side

(123) (11?,17?)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethy)estra-4,9-dien-3-one showed a very high permeation of 104 nm/s in this assay.

EXAMPLE 20 INVESTIGATION OF THE ACTION ON THE CARDIOVASCULAR SYSTEM (INCL. ECG) OF ANAESTHETIZED BEAGLE DOGS

(124) (11?,17?)-17-Hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethy)estra-4,9-dien-3-one, dissolved in a mixture of PEG 400 and HP-?-CD (60% PEG 400, 40% HP-?-CD 30%), was administered intravenously to anaesthetized female beagle dogs. The body weight of the dogs was >9 kg. 3 dogs were treated per group and additionally 3 dogs in the control group. 0.1; 0.33 and 1 mg/kg of the substance was administered in 3 consecutive infusions, in each case over a period of 30 minutes. The maximum amount of vehicle was 0.4 ml per kg for 30 minutes. Blood samples were taken from the animals at various time points. The highest plasma level (average for all 3 animals) was 1650 ng/ml at the end of the third infusion.

(125) In the tested dose range, in comparison with the control, no biologically relevant effects on the cardiovascular system (pulmonary artery pressure, systemic arterial blood pressure, heart rate, ECG) were observed.