Heterocyclic compounds and their use as aldosterone synthase inhibitors

Abstract

Heterocyclic compounds of the general formula (I) in which R, R 1 , R 2 , W, X, Y, Z and n have the meanings defined in the description, a process for their preparation and the use of these compounds as medicaments, in particular as aldosterone synthase inhibitors.

1 - 14 . (canceled) 
   
   
       15 . A method for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by hyperaldosteronism in a patient, which comprises administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof, 
     
       
         
         
             
             
         
       
       W is C or, if Z is a bond and X is C, is also N; 
       X is C or, if Z is a bond, is also N; 
       Y is C or, if Z is C, is also N; 
       Z is C or a bond; 
       R a) is hydrogen; or 
       b) is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, halogen or trifluoromethyl; 
       R 1  a) is C 3 -C 8 -cycloalkyl-C 0 -C 4 -alkyl or heterocyclyl-C 0 -C 4 -alkyl, where the heterocyclyl radical is at least partially saturated and the 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, unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl; or
 b), if W is N, is also C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl; 
 
       R 2  a) is hydrogen; or
 b) is C 1 -C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, C 3 -C 8 -cycloalkyl-C 0 -C 4 -alkyl or heterocyclyl-C 0 -C 4 -alkyl, where the heterocyclyl radical is at least partially saturated and the radicals are unsubstituted or substituted by 1-4 C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkyl, CO—C 8 -alkylcarbonyl, C 1 -C 8 -alkylsulfonyl, aryl-CO—C 4 -alkoxycarbonyl, aryl, cyano, halogen, unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl; 
 
       n is 0-2; 
       and its salt or compound in which one or more atoms are replaced by their stable, nonradioactive isotopes, 
       where, if W, X, Y and Z are C, R 1  is not an C 1 -C 8 -alkyl substituted piperazinyl radical and where aryl stands for an aromatic hydrocarbon radical which comprises 5-14 carbon atoms and where 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, it also being possible for an additional N, O or S atom to be present in one ring. 
     
   
   
       16 . A method for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by excessive cortisol release in a patient, which comprises administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof, 
     
       
         
         
             
             
         
       
       W is C or, if Z is a bond and X is C, is also N; 
       X is C or, if Z is a bond, is also N; 
       Y is C or, if Z is C, is also N; 
       Z is C or a bond; 
       R a) is hydrogen; or
 b) is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, halogen or trifluoromethyl; 
 
       R 1  a) is C 3 -C 8 -cycloalkyl-CO—C 4 -alkyl or heterocyclyl-CO—C 4 -alkyl, where the heterocyclyl radical is at least partially saturated and the 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-CO—C 4 -alkoxycarbonyl, aryl, cyano, halogen, unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl; or
 b), if W is N, is also C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl; 
 
       R 2  a) is hydrogen; or
 b) is C 1 -C 8 -alkyl, CO—C 8 -alkylcarbonyl, C 3 -C 8 -cycloalkyl-CO—C 4 -alkyl or heterocyclyl-C 0 -C 4 -alkyl, where the heterocyclyl radical is at least partially saturated and the 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, unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl; 
 
       n is 0-2; 
       and its salt or compound in which one or more atoms are replaced by their stable, nonradioactive isotopes, 
       where, if W, X, Y and Z are C, R 1  is not an C 1 -C 8 -alkyl substituted piperazinyl radical and where aryl stands for an aromatic hydrocarbon radical which comprises 5-14 carbon atoms and where 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, it also being possible for an additional N, O or S atom to be present in one ring. 
     
   
   
       17 . A pharmaceutical combination in the form of a product or of a kit comprising individual components consisting a) of a compound of formula (I), and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect, 
     
       
         
         
             
             
         
       
       W is C or, if Z is a bond and X is C, is also N; 
       X is C or, if Z is a bond, is also N; 
       Y is C or, if Z is C, is also N; 
       Z is C or a bond; 
       R a) is hydrogen; or
 b) is C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, halogen or trifluoromethyl; 
 
       R 1  a) is C 3 -C 8 -cycloalkyl-CO—C 4 -alkyl or heterocyclyl-CO—C 4 -alkyl, where the heterocyclyl radical is at least partially saturated and the radicals are unsubstituted or substituted by 1-4 C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkyl, CO—C 8 -alkylcarbonyl, C 1 -C 8 -alkylsulfonyl, aryl-CO—C 4 -alkoxycarbonyl, aryl, cyano, halogen, unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl; or
 b), if W is N, is also C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl; 
 
       R 2  a) is hydrogen; or
 b) is C 1 -C 8 -alkyl, C 0 -C 8 -alkylcarbonyl, C 3 -C 8 -cycloalkyl-C 0 -C 4 -alkyl or heterocyclyl-C 0 -C 4 -alkyl, where the heterocyclyl radical is at least partially saturated and the 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, unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or tri-C 1 -C 4 -alkylsilyl; 
 
       n is 0-2; 
       and its salt or compound in which one or more atoms are replaced by their stable, nonradioactive isotopes, 
       where, if W, X, Y and Z are C, R 1  is not an C 1 -C 8 -alkyl substituted piperazinyl radical and where aryl stands for an aromatic hydrocarbon radical which comprises 5-14 carbon atoms and where 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, it also being possible for an additional N, O or S atom to be present in one ring. 
     
   
   
       18 . A method for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by hyperaldosteronism in a patient, which comprises administering a therapeutically effective amount of a compound of formula (Ia), (Ib), (Ic) or (Id) to a patient in need thereof, 
     
       
         
         
             
             
         
       
       where the meanings of the substituents R, R 1  and R 2  are as indicated for compounds of the formula (I) according to  claim 15 . 
     
   
   
       19 . A method for the prevention, for delaying the progression or for the treatment of pathological states which are caused or partly caused by excessive cortisol release in a patient, which comprises administering a therapeutically effective amount of a compound of formula (Ia), (Ib), (Ic) or (Id) to a patient in need thereof, 
     
       
         
         
             
             
         
       
       where the meanings of the substituents R, R 1  and R 2  are as indicated for compounds of the formula (I) according to  claim 16 . 
     
   
   
       20 . A pharmaceutical combination in the form of a product or of a kit comprising individual components consisting a) of a compound of formula (Ia), (Ib), (Ic) or (Id), and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect, 
     
       
         
         
             
             
         
       
       where the meanings of the substituents R, R 1  and R 2  are as indicated for compounds of the formula (I) according to  claim 17 .