17-hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-acyloxyalkylene phenyl derivatives, methods for the production thereof and use thereof for treating diseases
View Patent ↗The invention relates to 17-hydroxy-13-methyl-17-pentafluoroethyl-11-acyloxyalkylenephenyldodecahydrocyclopenta[a]phenanthren-3-one derivatives of the formula I with progesterone-antagonizing action and to processes for preparation thereof, to use thereof for treatment and/or prophylaxis of disorders and to the use thereof for production of medicaments for treatment and/or prophylaxis of disorders, especially of fibroids of the uterus (myomas, uterine leiomyomas), endometriosis, heavy menstrual bleeds, meningiomas, hormone-dependent breast cancers and complaints associated with the menopause, or for fertility control and emergency contraception.
1. A compound of the formula I
in which
X is oxygen or an NOR 3 or ═NNHSO 2 R 3 group,
R 1 is C 1 -C 10 -alkyl, (CH 2 ) n —Y or CHR 4 NR 5 PG,
R 2 is hydrogen or C 1 -C 10 -alkyl,
R 3 is hydrogen, C 1 -C 10 -alkyl, aryl or C 7 -C 20 -aralkyl,
n is 1 to 10,
Y is hydrogen, aryl or heteroaryl,
R 4 , R 5 are each independently hydrogen, C 1 -C 10 -alkyl, C 7 -C 10 -aralkyl, or together are a (CH 2 ) m — or a CH 2 CHOHCH 2 — group,
m is 3 or 4,
PG is hydrogen or an amino protecting group,
and the salts or α-, β- or γ-cyclodextrin clathrates thereof.
2. The compound of claim 1 , in which R 1 is C 1 -C 6 -alkyl.
3. The compound of claim 2 , wherein R 1 is methyl, isopropyl, isobutyl or neopentyl.
4. The compound of claim 1 , in which R 1 is (CH 2 ) n —Y where n=1-10 and Y is an aromatic mono- or bicyclic radical with 5 to 10 ring atoms and having up to 5 heteroatoms from the group of S, O and N.
5. The compound of claim 4 , in which n=1-5 and Y is an aromatic mono- or bicyclic radical of 5 to 9 ring atoms with up to 4 heteroatoms from the group of S, O and N.
6. The compound of claim 5 , in which n=1-3 and Y=imidazolyl, thiazolyl or pyridyl.
7. The compound of claim 1 , in which R 1 is an amino acid radical CHR 4 NR 5 PG wherein R 4 is hydrogen, C 1 -C 5 -alkyl, C 7 -C 10 -aralkyl, R 5 is hydrogen, or R 4 together with R 5 is an optionally hydroxyl-substituted ethylene or propylene group, and PG is C 1 -C 5 -acyl, C 1 -C 5 -alkyloxycarbonyl or C 3 -C 5 -alkyleneoxycarbonyl.
8. The compound of claim 7 , in which R 4 is hydrogen, C 1 -C 4 -alkyl, C 7 -C 8 -aralkyl, R 5 is hydrogen or R 4 together with R 5 is an optionally hydroxyl-substituted ethylene group, and PG is C 1 -C 5 -acyl, C 1 -C 5 -alkyloxycarbonyl or C 3 -C 5 -alkyleneoxycarbonyl.
9. The compound of claim 8 , in which R 4 is hydrogen, methyl, isopropyl, isobutyl, benzyl, R 5 is hydrogen or R 4 together with R 5 is an ethylene group or hydroxyethylene group, and PG is acetyl, propionyl, butyryl, isopropionyl, isobutyryl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl or allyloxycarbonyl.
10. The compound of claim 1 of the formula Ia
in which
R 1 is C 1 -C 10 -alkyl, (CH 2 ) n —Y where n=1-10 or CHR 4 NR 5 PG,
R 4 , R 5 are each independently hydrogen, C 1 -C 10 -alkyl, C 7 -C 10 -aralkyl, or together are a (CH 2 ) m — where m=3 or 4 or a CH 2 CHOHCH 2 — group,
PG is hydrogen or an amino protecting group
Y is aryl or heteroaryl.
11. The compound of claim 10 , in which R 1 is methyl, isopropyl, isobutyl or tertbutyl.
12. The compound of claim 10 , in which R 1 is (CH 2 ) 2 —Y and Y is 2-methylimidazol-1-yl or thiazol-1-yl.
13. The compound of claim 10 , in which R 1 is CHR 4 NR 5 PG and R 4 is methyl or isopropyl, R 5 is hydrogen or R 4 together with R 5 is a —(CH 2 ) 3 — group and PG is hydrogen, —COOC(CH 3 ) 3 or —COOCH 2 CH═CH 2 .
14. Acetic acid (RS)-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)phenyl]ethyl ester;
Isobutyric acid (RS)-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)phenyl]ethyl ester;
3-methylbutyric acid (RS)-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)phenyl]ethyl ester;
3,3-dimethylbutyric acid (RS)-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)phenyl]ethyl ester;
3-(2-methylimidazol-1-yl)propionic acid (S)-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)phenyl]ethyl ester;
3-(2-methylimidazol-1-yl)propionic acid (R)-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)phenyl]ethyl ester;
3-thiazol-2-ylpropionic acid (RS)-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)phenyl]ethyl ester;
(S)-2-tert-butoxycarbonylamino-3-methylbutyric acid (RS)-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)phenyl]ethyl ester;
(R)-2-tert-butoxycarbonylaminopropionic acid (RS)-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)phenyl]ethyl ester;
(S)-2-tert-butoxycarbonylaminopropionic acid (RS)-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)phenyl]ethyl ester;
(S)-2-aminopropionic acid (RS)-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)phenyl]ethyl ester;
(S)-2-allyloxycarbonylaminopropionic acid (R)-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)phenyl]ethyl ester;
(S)-2-allyloxycarbonylaminopropionic acid (S)-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)phenyl]ethyl ester;
(S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-{(RS)-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)phenyl]ethyl}ester;
(S)-pyrrolidine-2-carboxylic acid (RS)-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)phenyl]ethyl ester;
(S)-pyrrolidine-2-carboxylic acid (RS)-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)phenyl]ethyl ester hydrochloride; or
(S)-2-allyloxycarbonylamino-3-methylbutyric acid (R)-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)phenyl]ethyl ester.
15. The compound of claim 1 with a half-life in human plasma, determined in vitro, of greater than 100 hours.
16. A medicament comprising a compound of claim 1 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.
17. The medicament of claim 16 further comprising an active ingredient selected from a SERM, a SERD, an antioestrogen, an aromatase inhibitor, a kinase inhibitor, an angiogenesis inhibitor or a cytostatic.
18. The medicament according to claim 16 comprising a further active ingredient selected from gestagens or gestagen/oestrogen combinations.
19. A method for controlling fibroids of the uterus, endometriosis, heavy menstrual bleeds, meningiomas, and breast cancers by administering a compound as defined in claim 1 to a patient in need thereof.
20. A method for fertility control or emergency contraception by administering a compound as defined in claim 1 to a patient in need thereof.