17-hydroxy-17-pentafluoroethyl-estra-4,9(10)-diene-11-methylene oxyalkylene aryl derivatives, process for preparation thereof, and use thereof for treatment of diseases
View Patent ↗The invention relates to 17-hydroxy-17-pentafluoroethylestra-4,9(10)-diene-11-methyleneoxyalkylenearyl derivative of the formula I with progesterone-antagonising 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. Compound of the formula I
in which
the phenyl substituent bearing the R 1 and R 2 radicals is joined to the phenyl ring in the
m or p position,
n is 0 or 1,
R 1 is hydrogen, C 1 -C 10 -alkyl, CH 2 OR 4 , CO 2 R 5 , CN, aryl or heteroaryl,
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,
R 4 is hydrogen, —CH 2 -CH 2 —OH or CH 2 CO 2 R 5 ,
R 5 is hydrogen or C 1 -C 10 -alkyl,
X is oxygen, an NOR 3 or ═NNHSO 2 R 3 group, and the stereoisomers, or the salts thereof, and the α-, (β- or γ-cyclodextrin clathrates thereof.
2. Compound according to claim 1 in which R 1 is hydrogen, C 1 -C 4 -alkyl, CH 2 OR 4 , CO 2 R 5 , CN, aryl or heteroaryl.
3. Compound according to claim 1 in which R 2 is hydrogen, methyl or ethyl.
4. Compound according to claim 1 in which X is oxygen.
5. Compound according to claim 1 in which the phenyl substituent bearing the R 1 and R 2 radicals is joined to the phenyl ring in the
p position,
n is 0 or 1,
R 1 is hydrogen, C 1 -C 10 -alkyl, CH 2 OR 4 , CO 2 R 5 , CN, aryl or heteroaryl,
R 2 is hydrogen or C 1 -C 4 -alkyl,
R 3 is hydrogen, C 1 -C 4 -alkyl, aryl or C 7 -C 12 -aralkyl,
R 4 is hydrogen, —CH 2 —CH 2 —OH or CH 2 CO 2 R 5 ,
R 5 is hydrogen or C 1 -C 4 -alkyl, and
X is oxygen, an NOR 3 or ═NNHSO 2 R 3 group.
6. Compound according to claim 1 of the formula Ia:
in which
n is 0 or 1,
R 1 is —H, —CH 2 OH, —COOH, —COOC(CH 3 ) 3 , —CN or 2-methylbenzothiazol-5-yl, and
R 2 is —H or —CH 3 .
7. A compound that is (8S, 11R, 13S,14S, 17S)-17-hydroxy-11-{4-[(1RS)-1-(2-hydroxyethoxy)ethyl]-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-11-[4-((1RS)-1-methoxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-cyclopenta[a]phenanthren-3-one,
{(1RS)-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]ethoxy}acetic acid tert-butyl ester,
{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]prop-2-ynyloxy}acetic acid,
{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]ethoxy}acetic acid tert-butyl ester,
{(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]ethoxy}acetonitrile,
{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]ethoxy}acetic acid,
(8S,11R,13S,14S,17S)-17-hydroxy-11-{4-[2-(2-hydroxyethoxy)ethyl]phenyl}-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-cyclopenta[a]phenanthren-3-one or
(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-{4-[(RS)-1-(2-methyl-benzothiazol-5-ylmethoxy)ethyl]phenyl}-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one.
8. Medicament comprising a compound as defined in claim 1 in combination with one or more inert nontoxic pharmaceutically suitable excipients.
9. Medicament according to claim 8 comprising a further active ingredient selected from SERMs, SERDs, antioestrogens, aromatase inhibitors, kinase inhibitors, angiogenesis inhibitors or cytostatics.
10. Medicament according to claim 8 comprising a further active ingredient selected from gestagens or gestagen/oestrogen combinations.
11. Method for controlling fibroids of the uterus, myomas, uterine leiomyomas, endometriosis, heavy menstrual bleeds, meningiomas, or breast cancer by administering an effective amount of at least one compound as defined in claim 1 to a patient in need thereof.
12. Method for fertility control or emergency contraception by administering an effective amount of at least one compound as defined in claim 1 to a patient in need thereof.