Heterocyclic spiro-compounds
View Patent ↗The patent application relates to new heterocyclic compounds of the general formula (I), in which R, R 1 , R 2 , Q, T, n and p have the definitions elucidated in more detail in the description, to a process for preparing them and to the use of these compounds as medicaments, particularly as aldosterone synthase inhibitors.
1. A compound of formula (I)
in which
Q is —C(R 3 )(R 4 )— or a bond;
T is —C(R 3 )(R 4 )—;
R is hydrogen or deuterium;
R 1 is C 1 -C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, amino, mono- or di-C 1 -C 8 -alkylamino, C 0 -C 8 -alkyl-carbonylamino, C 0 -C 8 -alkylcarbonyl-C 1 -C 8 -alkylamino, carbamoyl, mono- or di-C 1 -C 8 -alkylaminocarbonyl, carboxyl, carboxy-C 1 -C 4 -alkyl, halogen, cyano, methylsulfonyl, nitro, trifluoro-methyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, heterocyclyl or aryl, which radicals may be unsubstituted or substituted by 1-4 C 1 -C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, C 0 -C 8 -alkylcarbonylamino, C 0 -C 8 -alkylcarbonyl-C 1 -C 8 -alkylamino, carbamoyl, mono- and di-C 1 -C 8 -alkylaminocarbonyl, carboxy-C 0 -C 4 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, aryl or heterocyclyl;
R 2 is, if p is not 0, independently of one another, C 1 -C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, amino, mono- and di-C 1 -C 8 -alkylamino, C 0 -C 8 -alkylcarbonylamino, C 0 -C 8 -alkylcarbonyl-C 1 -C 8 -alkyl-amino, carbamoyl, mono- or di-C 1 -C 8 -alkylaminocarbonyl, carboxyl, carboxy-C 1 -C 4 -alkyl, halogen, cyano, methylsulfonyl, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, heterocyclyl or aryl, which radicals may be unsubstituted or substituted by 1-4 C 1 -C 8 -alkyl, C 0 -C 8 alkylcarbonyl, halogen, cyano, oxo, trifluoromethyl, trifluoromethoxy, C 0 -C 8 -alkylcarbonylamino, C 0 -C 8 -alkylcarbonyl-C 1 -C 8 -alkylamino, carbamoyl, mono- and di-C 1 -C 8 -alkylaminocarbonyl, carboxy-C 0 -C 4 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, aryl or hetero-cyclyl;
R 3 is, independently of one another:
a) hydrogen or C 1 -C 8 -alkyl; or
b) together with R 4 oxo;
R 4 is, independently of one another:
a) hydrogen or C 1 -C 8 -alkyl; or
b) together with R 3 oxo;
n is a number 0, 1 or 2;
p is a number 0, 1 or 2;
or its pharmaceutically useful salt.
2. The compound according to claim 1 , wherein it conforms to formula (I′)
wherein the definitions of the substituents R, R 1 , R 2 , Q, T, n and p are as defined according to the compounds of the formula (I) according to claim 1 , having a specific configuration at the asymmetric carbon atom labelled “*”, and which compound shows an aromatase inhibitory activity at least 10 times lower than the compound of the formula (I′) with the opposite configuration around the asymmetric carbon atom labelled “*”.
3. The compound according to claim 1 , wherein R 1 is C 1 - C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, halogen, cyano, methylsulfonyl, nitro, trifluoromethyl, trifluoromethoxy, C 0 -C 8 -alkylcarbonylamino, C 0 -C 8 -alkylcarbonyl-C 1 -C 8 -alkylamino, carbamoyl, mono- and di-C 1 -C 8 -alkylaminocarbonyl, carboxy-C 0 -C 4 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl or heterocyclyl.
4. The compound according to claim 1 , wherein R 2 is, if p is not 0, independently of one another, halogen, cyano, methylsulfonyl, nitro, trifluoromethyl, trifluoromethoxy, or C 1 -C 8 -alkyl.
5. The compound according to claim 1 , wherein n is a number 0 or 1.
6. The compound according to claim 1 , wherein
R 1 is acetyl, halogen, cyano, methylsulfonyl or nitro; and
R 2 is, if p is not 0, independently of one another, halogen, cyano, methylsulfonyl, nitro or C 1 -C 8 -alkyl.
7. The compound according to claim 1 , wherein
R 1 is cyano or halogen;
R 2 is, if p is not 0, cyano or halogen;
n is a number 0 or 1; and
p is a number 0 or 1.
8. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically useful salt thereof, according to claim 1 , and a conventional excipient.
9. A pharmaceutical combination in the form of a product or kit composed of individual components consisting of a) a compound of the formula (I) or a pharmaceutically useful salt thereof, according to claim 1 , and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, an antidiabetic, an obesity reducing or a lipid-lowering effect.
10. The compound according to claim 2 , having a specific configuration at the asymmetric carbon atom labelled “*”, which compound shows an aromatase inhibitory activity at least 20 times lower than the compound of the formula (I′) with the opposite configuration around the asymmetric carbon atom labelled “*”.
11. The compound according to claim 3 , wherein R 1 is acetyl, halogen, cyano, methylsulfonyl or nitro.
12. The compound according to claim 4 , wherein R 2 is, if p is not 0, independently of one another, halogen, cyano, methylsulfonyl, nitro or C 1 -C 8 -alkyl.
13. The compound according to claim 7 , wherein R 1 is cyano or fluoro.