Amide-substituted pyridinyltriazole derivatives and uses thereof

Abstract

The present invention relates to novel 5-(carboxamide)-1-pyridinyl-1,2,4-triazole derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of renal and cardiovascular diseases.

1 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           in which 
           # 1  represents the point of attachment to the nitrogen atom, 
         
         Ar represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           in which 
           # 2  represents the point of attachment to the nitrogen atom, 
           R 2A  represents a group selected from a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl and —C(═O)NH 2 , 
           R 2B  represents a group selected from a chlorine atom, trifluoromethyl, and ethoxycarbonyl, 
         
         or a pharmaceutically acceptable salt, hydrate and/or solvate thereof. 
       
     
     
         2 . A compound of general formula (I) according to  claim 1 , wherein
 R 1  represents a group of the formula   
       
         
           
           
               
               
           
         
         
           in which 
           # 1  represents the point of attachment to the nitrogen atom, 
         
         Ar represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           in which 
           # 2  represents the point of attachment to the nitrogen atom, 
           R 2A  represents a group selected from a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl and —C(═O)NH 2 , 
         
         or a pharmaceutically acceptable salt, hydrate and/or solvate thereof. 
       
     
     
         3 . A compound of general formula (I) according to  claim 1 ,
 wherein
 R 1  represents a group of the formula 
   
       
         
           
           
               
               
           
         
         
           in which 
           # 1  represents the point of attachment to the nitrogen atom, 
         
         Ar represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           in which 
           # 2  represents the point of attachment to the nitrogen atom, 
           R 2A  represents a group selected from a chlorine atom, trifluoromethyl and trifluoromethoxy, 
         
         or a pharmaceutically acceptable salt, hydrate and/or solvate thereof. 
       
     
     
         4 . A method of preparing a compound of general formula (I) according to  claim 1  said method comprising the step of
 [A] of allowing an intermediate compound of formula (II): 
 
       
         
           
           
               
               
           
         
         
           in which R 1  is as defined for the compound of general formula (I) according to  claim 1 , 
           R 3  represents a (C 1 -C 4 )-alkyl group, in particular a methyl group, to react in a first step in the presence of a base, and optionally a copper salt, with a compound of general formula (III): 
         
       
       
         
           
           
               
               
           
         
         
           in which 
           R 4  represents a (C 1 -C 4 )-alkyl group, in particular a methyl group, to give an intermediate compound, which is then allowed to react in the presence of a base in a second step with a hydrazine compound of general formula (IV) or a respective salt thereof 
         
       
       
         
           
           
               
               
           
         
         in which Ar is as defined for the compound of general formula (I) according to  claim 1 , 
         thereby giving a compound of general formula (V): 
       
       
         
           
           
               
               
           
         
         
           in which R 1  and Ar are as defined for the compound of general formula (I) according to  claim 1 , and 
           R 4  represents a (C 1 -C 4 )-alkyl group, in particular a methyl group, followed by a subsequent step 
         
         [B] of allowing the compound of formula (V) obtained in step [A] to react with ammonia thereby giving a compound of general formula (I): 
       
       
         
           
           
               
               
           
         
         
           in which R 1  and Ar are as defined for the compound of general formula (I) according to  claim 1 , 
         
         optionally followed by step 
         [C] conversion of the alcohols of general formula (I-A): 
       
       
         
           
           
               
               
           
         
         
           in which Ar is as defined for the compound of general formula (I) according to  claim 1 , 
         
         to the ketones of general formula (I-B): 
       
       
         
           
           
               
               
           
         
         
           in which Ar is as defined for the compound of general formula (I) according to  claim 1 , 
         
         using known oxidation methods, 
         each [A], [B] and [C] optionally followed, where appropriate, by (i) separating the compounds of formula (I) thus obtained into their respective enantiomers, and/or (ii) converting the compounds of formula (I) into their respective hydrates, solvates, salts and/or hydrates or solvates of the salts by treatment with the corresponding solvents and/or acids or bases. 
       
     
     
         5 . The compound as defined in  claim 1  for the treatment and/or prevention of a diseases. 
     
     
         6 . Compound as defined in  claim 1  for use in a method for the treatment and/or prevention of a disease selected from the group consisting of
 acute kidney disease, 
 chronic kidney disease, 
 diabetic nephropathy, 
 acute heart failure, 
 chronic heart failure, 
 preeclampsia, 
 peripheral arterial disease (PAD), 
 coronary microvascular dysfunction (CMD), 
 Raynaud's syndrome, and 
 dysmenorrhea. 
 
     
     
         7 . A method for the manufacture of a pharmaceutical composition for the treatment and/or prevention of a disease selected from the group consisting of
 acute kidney disease,   chronic kidney disease,   diabetic nephropathy,   acute heart failure,   chronic heart failure,   preeclampsia,   peripheral arterial disease (PAD),   coronary microvascular dysfunction (CMD),   Raynaud's syndrome, and   dysmenorrhea,   
       the method comprising manufacturing the pharmaceutical composition with a compound of  claim 1 . 
     
     
         8 . Pharmaceutical composition comprising a compound as defined in  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         9 . Pharmaceutical composition of  claim 8  comprising one or more first active ingredients, in particular compounds of general formula (I) according to  claim 1 , and one or more further active ingredients. 
     
     
         10 . The pharmaceutical composition as defined in  claim 8  for the treatment and/or prevention of a disease selected from the group consisting of
 acute kidney disease, 
 chronic kidney disease, 
 diabetic nephropathy, 
 acute heart failure, 
 chronic heart failure, 
 preeclampsia, 
 peripheral arterial disease (PAD), 
 coronary microvascular dysfunction (CMD), 
 Raynaud's syndrome, and 
 dysmenorrhea. 
 
     
     
         11 . Method for the treatment and/or prevention of a disease selected from the group consisting of
 acute kidney disease,   chronic kidney disease,   diabetic nephropathy,   acute heart failure,   chronic heart failure,   preeclampsia,   peripheral arterial disease (PAD),   coronary microvascular dysfunction (CMD),   Raynaud's syndrome, and   dysmenorrhea,   
       in a human or other mammal, comprising administering to a human or other mammal in need thereof a therapeutically effective amount of one or more compounds as defined in  claim 1 . 
     
     
         12 . Method for the treatment and/or prevention of a disease selected from the group consisting of
 acute kidney disease,   chronic kidney disease,   diabetic nephropathy,   acute heart failure,   chronic heart failure,   preeclampsia,   peripheral arterial disease (PAD),   coronary microvascular dysfunction (CMD),   Raynaud's syndrome, and   dysmenorrhea,   
       in a human or other mammal, comprising administering to a human or other mammal in need thereof a therapeutically effective amount of a pharmaceutical composition as defined in  claim 8 . 
     
     
         13 . The pharmaceutical composition of  claim 8  wherein the one or more additional therapeutic agents comprises at least one selected from the group consisting of
 diuretic, 
 angiotensin AII antagonist, 
 ACE inhibitor, 
 beta-receptor blocker, 
 mineralocorticoid receptor antagonist, 
 antidiabetic, 
 organic nitrate, 
 NO donor, 
 activator of soluble guanylate cyclase (sGC), 
 stimulator of soluble guanylate cyclase (sGC), 
 antiinflammatory agent, 
 immunosuppressive agent, 
 phosphate binder, and 
 
       compound which modulate vitamin D metabolism.