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US 8,138,176 B2Granted
Imidazo compounds
AssigneeNovartis AG
InventorsPeter Herold, Robert Mah, Vincenzo Tschinke, Aleksandar Stojanovic, Christiane Marti, Stjepan Jelakovic, Stefan Stutz
Life of this patent
Estimating the term…
Abstract
Heterocyclic compounds of the formula (I) and salts, preferably pharmaceutically acceptable salts thereof, are provided in which R, R1, R2, Q, m and n have the meanings explained in detail in the description. Also provided are a process for their preparation and the use of these compounds as medicaments, in particular as aldosterone synthase inhibitors.
Claims15
A compound of the formula
- in which
- R is deuterium, halogen or hydrogen;
- R1 is aryl-C0-C4-alkyl or heterocyclyl-C0-C4-alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C2-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4-alkylsilyl, trifluoromethoxy or trifluoromethyl;
- R2 is a) deuterium, halogen, hydroxy, cyano or hydrogen;
- or
- b) C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C1-C4 alkoxycarbonyl-C1-C4 alkyl, C1-C8 alkyl, C0-C4 alkylcarbonyl, aryl-C0-C4 alkyl, carboxy-C1-C4 alkyl, C3-C8 cycloalkyl or heterocyclyl-C0-C4 alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
- Q is sulphur;
- m is a number 1;
- and
- n is a number 1;
- or a pharmaceutically acceptable salt thereof,
- wherein the heterocyclyl in R1 and R2, independently of one another, stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, 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;
- the optional substituents on the optionally substituted aryl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl;
- and the optional substituents on the optionally substituted heterocyclyl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl.
11 more elements
A compound according to claim 1, which corresponds to the formula
- where the meanings of the substituents R, R1, R2, 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 than the compound of the formula (Ia) with the opposite configuration around the asymmetric carbon atom labelled “*”.
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
- in which
- R is deuterium, halogen or hydrogen;
- R1 is aryl-C0-C4-alkyl or heterocyclyl-C0-C4-alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4-alkylsilyl, trifluoromethoxy or trifluoromethyl;
- R2 is a) deuterium, halogen, hydroxy, cyano or hydrogen;
- or
- b) C2-C8 alkenyl, C2-C8 alkenyl, C1-C8 alkoxy, C1-C4 alkoxycarbonyl-C1-C4 alkyl, C1-C8 alkyl, C0-C4 alkylcarbonyl, aryl-C0-C4 alkyl, carboxy-C1-C4 alkyl, C3-C8 cycloalkyl or heterocyclyl-C0-C4 alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
- Q is sulphur;
- m is a number 1;
- and
- n is a number 1;
- wherein the heterocyclyl in R1 and R2, independently of one another, stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, 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;
- the optional substituents on the optionally substituted aryl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl;
- and the optional substituents on the optionally substituted heterocyclyl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl,
- or a pharmaceutically acceptable salt thereof, is used, wherein the pathological state is hypertension.
11 more elements
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
- in which
- R is deuterium, halogen or hydrogen;
- R1 is aryl-C0-C4-alkyl or heterocyclyl-C0-C4-alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4-alkylsilyl, trifluoromethoxy or trifluoromethyl;
- R2 is a) deuterium, halogen, hydroxy, cyano or hydrogen;
- or
- b) C2-C8 alkenyl, C2-C8 alkenyl, C1-C8 alkoxy, C1-C4 alkoxycarbonyl-C1-C4 alkyl, C1-C8 alkyl, C0-C4 alkylcarbonyl, aryl-C0-C4 alkyl, carboxy-C1-C4 alkyl, C3-C8 cycloalkyl or heterocyclyl-C0-C4 alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
- Q is sulphur;
- m is a number 1;
- n is a number 1;
- and
- * designates an asymmetric carbon atom,
- wherein the heterocyclyl in R1 and R2, independently of one another, stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, 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;
- the optional substituents on the optionally substituted aryl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl;
- and the optional substituents on the optionally substituted heterocyclyl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl,
- and which compound shows an aldosterone synthase and/or 11-β-hydroxylase inhibitory activity at least 10 times higher than the compound of the formula (Ia) with the opposite configuration around the asymmetric carbon atom labelled “*”,
- or a pharmaceutically acceptable salt thereof, is used, wherein the pathological state is hypertension.
13 more elements
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
- in which
- R is deuterium, halogen or hydrogen;
- R1 is aryl-C0-C4-alkyl or heterocyclyl-C0-C4-alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4-alkylsilyl, trifluoromethoxy or trifluoromethyl;
- R2 is a) deuterium, halogen, hydroxy, cyano or hydrogen;
- or
- b) C2-C8 alkenyl, C2-C8 alkenyl, C1-C8 alkoxy, C1-C4 alkoxycarbonyl-C1-C4 alkyl, C1-C8 alkyl, C0-C4 alkylcarbonyl, aryl-C0-C4 alkyl, carboxy-C1-C4 alkyl, C3-C8 cycloalkyl or heterocyclyl-C0-C4 alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
- Q is sulphur;
- m is a number 1;
- and
- n is a number 1;
- wherein the heterocyclyl in R1 and R2, independently of one another, stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, 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;
- the optional substituents on the optionally substituted aryl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl;
- and the optional substituents on the optionally substituted heterocyclyl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl,
- or a pharmaceutically acceptable salt thereof, is used, wherein the pathological state is Cushing's Syndrome.
11 more elements
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
- in which
- R is deuterium, halogen or hydrogen;
- R1 is aryl-C0-C4-alkyl or heterocyclyl-C0-C4-alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4-alkylsilyl, trifluoromethoxy or trifluoromethyl;
- R2 is a) deuterium, halogen, hydroxy, cyano or hydrogen;
- or
- b) C2-C8 alkenyl, C2-C8 alkenyl, C1-C8 alkoxy, C1-C4 alkoxycarbonyl-C1-C4 alkyl, C1-C8 alkyl, C0-C4 alkylcarbonyl, aryl-C0-C4 alkyl, carboxy-C1-C4 alkyl, C3-C8 cycloalkyl or heterocyclyl-C0-C4 alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
- Q is sulphur;
- m is a number 1;
- n is a number 1;
- and
- * designates an asymmetric carbon atom,
- wherein the heterocyclyl in R1 and R2, independently of one another, stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, 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;
- the optional substituents on the optionally substituted aryl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl;
- and the optional substituents on the optionally substituted heterocyclyl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl,
- and which compound shows an aldosterone synthase and/or 11-β-hydroxylase inhibitory activity at least 10 times higher than the compound of the formula (Ia) with the opposite configuration around the asymmetric carbon atom labelled “*”,
- or a pharmaceutically acceptable salt thereof, is used, wherein the pathological state is Cushing's Syndrome.
13 more elements
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
- in which
- R is deuterium, halogen or hydrogen;
- R1 is aryl-C0-C4-alkyl or heterocyclyl-C0-C4-alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4-alkylsilyl, trifluoromethoxy or trifluoromethyl;
- R2 is a) deuterium, halogen, hydroxy, cyano or hydrogen;
- or
- b) C2-C8 alkenyl, C2-C8 alkenyl, C1-C8 alkoxy, C1-C4 alkoxycarbonyl-C1-C4 alkyl, C1-C8 alkyl, C0-C4 alkylcarbonyl, aryl-C0-C4 alkyl, carboxy-C1-C4 alkyl, C3-C8g cycloalkyl or heterocyclyl-C0-C4 alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
- Q is sulphur;
- m is a number 1;
- and
- n is a number 1;
- wherein the heterocyclyl in R1 and R2, independently of one another, stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, 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;
- the optional substituents on the optionally substituted aryl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl;
- and the optional substituents on the optionally substituted heterocyclyl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl,
- or a pharmaceutically acceptable salt thereof, and
- b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.
12 more elements
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
- in which
- R is deuterium, halogen or hydrogen;
- R1 is aryl-C0-C4-alkyl or heterocyclyl-C0-C4-alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4-alkylsilyl, trifluoromethoxy or trifluoromethyl;
- R2 is a) deuterium, halogen, hydroxy, cyano or hydrogen;
- or
- b) C2-C8 alkenyl, C2-C8 alkenyl, C1-C8 alkoxy, C1-C4 alkoxycarbonyl-C1-C4 alkyl, C1-C8 alkyl, C0-C4 alkylcarbonyl, aryl-C0-C4 alkyl, carboxy-C1-C4 alkyl, C3-C8 cycloalkyl or heterocyclyl-C0-C4 alkyl, which radicals are unsubstituted or substituted by 1-4 C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, optionally substituted aryl, aryl-C0-C4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy or trifluoromethyl;
- Q is sulphur;
- m is a number 1;
- n is a number 1;
- and
- * designates an asymmetric carbon atom,
- wherein the heterocyclyl in R1 and R2, independently of one another, stands for a saturated, partially saturated or unsaturated, 4-8-membered monocyclic ring system, 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;
- the optional substituents on the optionally substituted aryl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl;
- and the optional substituents on the optionally substituted heterocyclyl in R1 and R2, independently of one another, are selected from the group consisting of C1-C8 alkoxy, C1-C8 alkoxycarbonyl, C1-C8 alkyl, C0-C8 alkylcarbonyl, C1-C8 alkylsulphonyl, aryl, aryl-Co-C4 alkoxycarbonyl, cyano, halogen, heterocyclyl, hydroxy, nitro, oxo, tri-C1-C4 alkylsilyl, trifluoromethoxy and trifluoromethyl,
- and which compound shows an aldosterone synthase and/or 11-β-hydroxylase inhibitory activity at least 10 times higher than the compound of the formula (Ia) with the opposite configuration around the asymmetric carbon atom labelled “*”,
- or a pharmaceutically acceptable salt thereof, and
- b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.
14 more elements
Dependencies are inferred from the claim text.