Imidazo compounds
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 , Q, m and n have the meanings explained in detail in the description, a process for their preparation and the use of these compounds as medicaments, in particular as aldosterone synthase 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, optionally substituted aryl wherein the optional substituents on the aryl are 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, optionally substituted aryl, aryl-C 0 -C 4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, tri-C 1 -C 4 alkylsilyl, trifluoromethoxy or trifluoromethyl, aryl-C 0 -C 4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl wherein the optional substituents on the heterocyclyl are 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, optionally substituted aryl, aryl-C 0 -C 4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C 1 -C 4 , alkylsilyl, trifluoromethoxy or trifluoromethyl, hydroxy, nitro, oxide, oxo, tri-C 1 -C 4 -alkylsilyl, trifluoromethoxy or trifluoromethyl;
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, optionally substituted aryl, aryl-C 0 -C 4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C 1 -C 4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
Q is oxygen;
m is 1;
n is 1;
and a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , which corresponds to the formula
where the meanings of the substituents R, R 1 , R 2 , Q, m and n are as indicated for compounds of the formula (I) according to claim 13 , and * designates an asymmetric carbon atom and which compound shows an aldosterone synthase and/or 11-β-hydroxylase inhibitory activity at least 10 times higher, but preferably 20 times higher, or more preferably 40 times higher, than the compound of the formula (Ia) with the opposite configuration around the asymmetric carbon atom labelled “*”.
3. A compound according to claim 1 , where R is deuterium or hydrogen.
4. A compound according to claim 1 , where R 1 is optionally mono-, di- or tri-substituted phenyl or optionally mono-, di- or tri-substituted benzofuranyl, benzo[b]thiophenyl, benzoimidazolyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl, benzo[b]thiophenyl, imidazolyl, indazolyl, oxazolyl, pyridyl, pyrrolyl, thiazolyl or thiophenyl.
5. A compound according to claim 1 , where R 2 is C 1 -C 8 alkoxy, hydroxy, C 1 -C 8 alkyl, aryl-CC 4 alkyl, deuterium, halogen, cyano or hydrogen.
6. A method for delaying the progression or for the treatment of pathological states which are caused or partly caused by hyperaldosteronism, where a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 is used, wherein the pathological state is hypertension.
7. A method for delaying the progression or for the treatment of pathological states which are caused or partly caused by hyperaldosteronism, where a therapeutically effective amount of a compound of the formula (Ia) or a pharmaceutically acceptable salt thereof according to claim 2 is used, wherein the pathological state is hypertension.
8. A method for delaying the progression or for the treatment of pathological states which are caused or partly caused by excessive cortisol release, where a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 is used, wherein the pathological state is Cushing's Syndrome.
9. A method for delaying the progression or for the treatment of pathological states which are caused or partly caused by excessive cortisol release, where a therapeutically effective amount of a compound of the formula (Ia) or a pharmaceutically acceptable salt thereof according to claim 2 is used, wherein the pathological state is Cushing's Syndrome.
10. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , and conventional excipients.
11. A pharmaceutical composition comprising a compound of the formula (Ia) or a pharmaceutically acceptable salt thereof according to claim 2 , and conventional excipients.
12. A pharmaceutical composition in the form of a product or of a kit composed of individual components consisting a) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.
13. A pharmaceutical composition in the form of a product or of a kit composed of individual components consisting a) of a compound of the formula (Ia) or a pharmaceutically acceptable salt thereof according to claim 2 , and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.