Condensed imidazole derivatives as aromatase inhibitors
View Patent ↗The application relates to novel heterocyclic compounds of the general formula (I) and salts, preferably pharmaceutically acceptable salts, thereof, in which R, R 1 , R 2 , R 3 , Q, m and n have the meanings explained in detail in the description, and * designates an asymmetric carbon atom, a process for their preparation and the use of these compounds as medicaments, in particular as aromatase inhibitors.
1. A compound of the formula
in which
R is deuterium, halogen, or hydrogen;
R 1 is aryl-C 0 -C 4 -alkyl or heterocyclyl-C 0 -C 4 -alkyl, which radicals are unsubstituted or substituted by 1-4 C 1 -C 8 alkoxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl, C 0 -C 8 alkylcarbonyl, C 1 -C 8 alkylsulphonyl, unsubstituted or substituted aryl, aryl-C 0 -C 4 alkoxycarbonyl, cyano, halogen, unsubstituted or substituted heterocyclyl, hydroxy, nitro, oxide, oxo, tri-C 1 -C 4 alkylsilyl, trifluoromethoxy or trifluoromethyl, wherein the heterocyclyl of the heterocyclyl-C 0 -C 4 -alkyl stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, or a saturated, partially saturated or unsaturated, 7-12-membered bicyclic ring system, or a partially saturated or unsaturated, 9-12-membered tricyclic ring system which comprises an N, O or S atom in at least one of the rings, it being possible for an additional N, O or S atom to be present in one ring;
R 2 is
a) deuterium, halogen, hydroxy, cyano or hydrogen; or
b) C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C 1 -C 4 alkoxycarbonyl-C 1 -C 4 alkyl, C 1 -C 8 alkyl, C 0 -C 4 alkylcarbonyl, aryl-C 0 -C 4 alkyl, carboxy-C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or heterocyclyl-C 0 -C 4 alkyl, which radicals are unsubstituted or substituted by 1-4 C 1 -C 8 alkoxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl, C 0 -C 8 alkylcarbonyl, C 1 -C 8 alkylsulphonyl, unsubstituted or substituted aryl, aryl-C 0 -C 4 alkoxycarbonyl, cyano, halogen, unsubstituted or substituted heterocyclyl, hydroxy, nitro, oxide, oxo, tri-C 1 -C 4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
R 3 is C 1 -C 8 alkyl;
Q is oxygen;
m is a number 0, 1 or 2;
n is 1;
or a pharmaceutically acceptable salt thereof,
where
R 1 is not C 1 -C 8 alkyl-substituted aryl if R 2 is hydrogen, and which compound shows an aromatase inhibitory activity at least 10 times higher, than the compound of the formula (I) with the opposite configuration around the asymmetric carbon atom labelled “*”.
2. A compound according to claim 1 , where R is deuterium or hydrogen.
3. A compound according to claim 1 , where R 1 is optionally substituted phenyl, optionally substituted naphthyl, benzofuranyl, benzo[b]thiophenyl, benzoimidazolyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[b]thiophenyl, imidazolyl, indazolyl, oxazolyl, pyridyl, pyrrolyl, thiazolyl or thiophenyl.
4. A compound according to claim 1 , where R 2 is C 1 -C 8 alkoxy, hydroxy, C 1 -C 8 alkyl, optionally substituted aryl-C 0 -C 4 alkyl, deuterium, halogen, cyano or hydrogen.
5. A method for the treatment of estrogen-dependent breast cancer, which comprises administering to a subject having the disease a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .
6. A method for the treatment of gynaecomastia, which comprises administering to a subject having gynaecomastia a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .
7. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.