Bicyclic, Nitrogen-Containing Heterocycles and Aromatase Inhibitors
The application relates to novel heterocyclic compounds of the general formula (I) (I*) in which R, R 1 , R 2 , X, Y, Z and n have the meanings defined in the description, to a process for their preparation and to the use of these compounds as medicaments, in particular as aromatase inhibitors.
1 . Compound of the general formula
in which,
X is C;
Y is C or N;
Z is C;
R
a) is hydrogen; or
b) is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, halogen or trifluoromethyl;
R 1 is aryl-C 0 -C 4 -alkyl or unsaturated 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 -alkylsulfonyl, aryl-C 0 -C 4 -alkoxycarbonyl, aryl, cyano, halogen, heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl;
R 2
a) is hydrogen; or
b) is C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl, halogen, carboxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkyl, C 0 -C 4 -alkylcarbonyl, aryl-C 0 -C 4 -alkyl or unsaturated heterocyclyl-C 1 -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 -alkylsulfonyl, aryl-C 0 -C 4 -alkoxycarbonyl, aryl, cyano, halogen, heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl;
n is a number 0, 1 or 2;
whereby the term heterocyclyl stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, for a saturated, partially saturated or unsaturated, 7-12-membered bicyclic ring system and also for a saturated, partially saturated or unsaturated, 7-12-membered tricyclic ring system, in each case comprising an N, O or S atom in at least one ring;
* designates an asymmetric carbon atom
and its salt, prodrug or compound in which one or more atoms are replaced by their stable, nonradioactive isotopes, in particular pharmaceutically usable salt,
where, if X, Y and Z are C, R 1 is not an unsubstituted or alkoxy-substituted benzyl radical;
and excluding the compounds 5,6,7,8-tetrahydro-8-(4-pyridinyl)-isoquinoline and 5,6,7,8-tetrahydro-8-(4-pyridinyl)-isoquinoline.
2 . Compound according to claim 1 , characterized in that it corresponds to the general formula
where the meanings of R, R 1 , R 2 and n are as indicated for compounds of the formula (I) or (I*) according to claim 1 .
3 . Compound according to claim 1 , where R is hydrogen or C 1 -C 8 -alkyl, particularly preferably hydrogen or methyl.
4 . Compound according to claim 1 , where R 1 is aryl or unsaturated heterocyclyl, very particularly preferably optionally mono- or disubstituted benzofuranyl, benzothiophenyl, indazolyl, indolyl, phenyl, pyrrolyl, thiazolyl, thiophenyl or oxazolyl.
5 . Compound according to claim 1 , where R 2 is hydrogen, halogen, C 1 -C 8 -alkyl or aryl-C 1 -C 4 -alkyl.
6 . Compound according to claim 1 , where n is a number 0 or 1.
7 . Compound according to claim 2 , where
R is hydrogen or C 1 -C 8 -alkyl;
R 1 is aryl or unsaturated heterocyclyl, in each case optionally substituted by halogen, cyano, trifluoromethyl, heterocyclyl or C 1 -C 8 -alkylcarbonyl; and
R 2 is hydrogen, halogen, C 1 -C 8 -alkyl or aryl-C 1 -C 4 -alkyl.
8 - 9 . (canceled)
10 . Method for the prevention, for delaying the progression or for the treatment of a disease or condition which responds to aromatase inhibition where a therapeutically effective amount of a compound of the general formula (I) or (I*) according to claim 1 is used.
11 . Pharmaceutical product comprising a compound of the general formula (I) or (I*) according to claim 1 , and conventional excipients.
12 . Compound according to claim 2 , where R is hydrogen or C 1 -C 8 -alkyl, particularly preferably hydrogen or methyl.
13 . Compound according to claim 2 , where R 1 is aryl or unsaturated heterocyclyl, very particularly preferably optionally mono- or disubstituted benzofuranyl, benzothiophenyl, indazolyl, indolyl, phenyl, pyrrolyl, thiazolyl, thiophenyl or oxazolyl.
14 . Compound according to claim 2 , where R 2 is hydrogen, halogen, C 1 -C 8 -alkyl or aryl-C 1 -C 4 -alkyl.
15 . Method for the prevention, for delaying the progression or for the treatment of a disease or condition which responds to aromatase inhibition, where a therapeutically effective amount of a compound of the general formula (Ia), (Ib), (Ic) or (Id) according to claim 2 is used.
16 . Method for the prevention, for delaying the progression or for the treatment of a disease or condition which is a proliferative disease, where a therapeutically effective amount of a compound of the general formula (I) or (I*) according to claim 1 is used.
17 . Method for the prevention, for delaying the progression or for the treatment of a disease or condition which is a proliferative disease, where a therapeutically effective amount of a compound of the general formula (Ia), (Ib), (Ic) or (Id) according to claim 2 is used.
18 . Pharmaceutical product comprising a compound of the general formula (Ia), (Ib), (Ic) or (Id) according to claim 2 , and conventional excipients.