17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-benzylidene derivatives, methods for the production thereof and use thereof for treating diseases

1. 17-Hydroxy-17-pentafluoroethylestra-4,9(10)-diene 11-benzylidene derivatives of the general formula (I)

in which

Y is a —CR 1 ═CHR 2 or a —CR 1 ═NR 3 group, each of which is joined to the phenyl ring in the meta (m) or para (p) position,

in which

R 1 is hydrogen or a C 1 -C 10 -alkyl radical,

R 2 is hydrogen, a C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, aryl, C 7 -C 20 -aralkyl, C 1 -C 10 -acyl, CO 2 R 4 , CN, CH═CH—CO 2 R 4 , CH 2 CH(CO 2 R 4 ) 2 , CH 2 CH(CN) 2 or a CH 2 NHCONHR 5 radical and

R 3 is a C 1 -C 10 -alkyl, O—(CH 2 ) n —COOR 4 , O—CH 2 -aryl, aryl, C 7 -C 20 -aralkyl or a CH 2 CO 2 R 4 radical in which

R 4 is hydrogen, or a C 1 -C 10 -alkyl group and

R 5 is a C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, aryl, C 7 -C 20 -aralkyl, (CH 2 ) n CO 2 R 4 group where n=1 or 2 and R 4 is defined as specified, or R 5 is a

group and

X is oxygen, an NOR 6 or an NNHSO 2 R 6 group,

in which

R 6 is hydrogen, a C 1 -C 10 -alkyl, aryl or C 7 -C 20 -aralkyl radical,

or a salts, or α-, β- or γ-cyclodextrin clathrate thereof.

2. Compound according to claim 1 in which X is oxygen.

3. Compound according to claim 1 in which the Y group is bonded to the phenyl ring in the para position.

4. Compound according to claim 1 , in which Y is a —CR 1 ═CHR 2 group where R 1 is defined as hydrogen and R 2 is defined as in claim 1 .

5. (8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-17-pentafluoroethyl-11-(4-vinylphenyl)-1,2,6,7,8,11,12,13,14,15,16, 17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((E)-3-hydroxypropenyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12, 13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

2-{(E)-3[4-(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}malonic acid;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-17-pentafluoroethyl-11-[4-((E)-2-pyridin-2-ylvinyl)phenyl]-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-17-pentafluoroethyl-11-[4-((E)-2-pyridin-3-ylvinyl)phenyl]-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-17-pentafluoroethyl-11-[4-((E)-2-pyridin-4-ylvinyl)phenyl]-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-{4-[(E)-2-(2-methylthiazol-4-yl)vinyl]phenyl}-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-{4-[(E)-2-(2-methylbenzothiazol-5-yl)vinyl]phenyl}-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-11-(4-isopropenylphenyl)-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]acrylic acid ethyl ester;

(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]acrylic acid;

(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]acrylonitrile;

(2E,4E)-5-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]penta-2,4-dienoic acid ethyl ester;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-{4-[(E)-3-oxobut-1-enyl)phenyl]-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15, 16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(2E,4E)-5-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]penta-2,4-dienoic acid;

(8S,11R,13S,14S,17S)-11-[((E/Z)-4-buta-1,3-dienyl)phenyl]-17-hydroxy-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15, 16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-17-pentafluoroethyl-11-[3-((E)-2-pyridin-4-ylvinyl)phenyl]-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

2-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}malonitrile;

3-{(E)-2-[44-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]vinyl}benzoic acid;

4-{(E)-2-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]vinyl}benzoic acid;

3-{(E)-2-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]vinyl}benzoic acid methyl ester;

4-{(E)-2-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]vinyl}benzoic acid methyl ester;

(8S,11R,13S,14S,17S)-17-hydroxy-11-{4-[(E)-2-(4-methanesulphonylphenyl)vinyl]phenyl}-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-{4-[(E)-2-(4-methylsulphanylphenyl)vinyl]phenyl}-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one;

4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)benzaldehyde O-benzyl oxime;

4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)benzaldehyde O-ethyl oxime;

4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)benzaldehyde O-isobutyl oxime;

1-ethyl-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)benzyl]urea;

1-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)benzyl]-3-isopropylurea;

1-tert-butyl-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)benzyl]urea;

1-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}-3-phenylurea;

1-(4-fluorophenyl)-3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}urea;

1-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}-3-p-tolylurea;

1-benzyl-3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}urea;

1-tert-butyl-3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}urea;

1-(3,5-dimethylisoxazol-4-yl)-3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}urea;

3-(3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}ureido)propionic acid ethyl ester;

(3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}ureido)acetic acid ethyl ester;

1-(4-chlorophenyl)-3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}urea;

1-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}-3-(4-methoxyphenyl)urea;

4-(3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}ureido)benzoic acid ethyl ester; or

1-allyl-3-{(E)-3-[4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-pentafluoroethyl-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl]allyl}urea.

6. Process for preparing the compounds of the general formula I according to claim 1 comprising the steps of

converting an epoxide of the general formula II

in which

X′ is a C 2 -C 10 -alkylene-α,ω-dioxy group which is straight-chain or branched, in an organometallic coupling reaction into a compound of the general formula III

in which

R 1 is defined as in claim 1 , and X′ is defined as specified herein above and

R 8 is hydrogen,

R 9 is a hydroxyl group, or

R 8 , R 9 together are a bond,

and converting the compound of the general formula III to give a compound of the general formula I′

wherein Y is as defined in claim 1 and X′, R 8 and R 9 is defined as specified herein above, and

converting the compound of general formula I′ to give a compound of the general formula I

wherein X and Y are as defined in claim 1 , wherein in the case that R 8 is hydrogen and R 9 is a hydroxyl group in the compound of the general formula (I′), a double bond is obtained by elimination of water, and so R 8 and R 9 together are a bond.

7. Pharmaceutical formulation comprising at least one compound according to claim 1 and a pharmaceutically suitable carrier.

8. Method of treatment of fibroids of the uterus, endometriosis, heavy menstrual bleeds, meningiomas, breast cancers, or for fertility control and emergency contraception by administering a compound according to claim 1 to a patient in need thereof.

9. Process for preparing the compounds of the general formula I according to claim 1 comprising the steps of

converting an epoxide of the general formula II

in which

X′ is an oxygen atom,

in an organometallic coupling reaction into a compound of the general formula III

in which

R 1 is defined as in claim 1 , and X′ is defined as specified herein above and

R 8 is hydrogen,

R 9 is a hydroxyl group, or

R 8 , R 9 together are a bond,

and converting the compound of general formula III to give a compound of the general formula I′

wherein Y is as defined in claim 1 and X′, R 8 and R 9 is defined as specified herein above, wherein the compound of the general formula I′ is a compound of the general formula I, wherein X is O, and R 8 and R 9 together are a bond;

when R 8 is hydrogen and R 9 is a hydroxyl group the process further comprises a step of converting the compound of the general formula I′ into the compound of the general formula I by eliminating water to form a second bond between R 8 and R 9 ; and

optionally converting the compound of general formula I′ to the compound of general formula I, wherein X is NOR 6 or NNHSO 2 R 6 , wherein R 6 is defined as in claim 1 .

10. Process for preparing the compounds of the general formula I according to claim 1 comprising the steps of

converting an epoxide of the general formula II

in which

X′ is two alkoxy groups OR 7 , and R 7 is a C 1 -C 4 -alkyl group

in an organometallic coupling reaction into a compound of the general formula III

in which

R 1 is defined as in claim 1 , and X′ is defined as specified herein above and

R 8 is hydrogen,

R 9 is a hydroxyl group, or

R 8 , R 9 together are a bond,

and converting the compound of general formula III to give a compound of the general formula I′

wherein Y is as defined in claim 1 and X′, R 8 and R 9 is defined as specified herein above, and

converting the compound of general formula I′ to give a compound of the general formula I

wherein X is O, and Y is defined in claim 1 .