Hydroxyalkyl-substituted phenyltriazole derivatives and uses thereof

Abstract

The present invention relates to novel 5-(hydroxyalkyl)-1-phenyl-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 cardiovascular and renal diseases.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen or methyl, 
         and 
         R 2A  and R 2B  are independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy, and trifluoromethoxy; 
         or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof. 
       
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein
 R 1  is hydrogen or methyl,   and   R 2A  and R 2B  are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, and methoxy, wherein at least one of R 2A  and R 2B  is other than hydrogen;   or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof.   
     
     
         3 . The compound of formula (I) according to  claim 1 , wherein the compound is selected from the group consisting of
 5-(4-chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-{[5-(hydroxymethyl)-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   2-({1-(2-chloro-4-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   2-{[1-(2-chloro-4-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (diastereomer 1);   2-{[1-(2-chloro-4-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (diastereomer 2);   2-({1-(2-chloro-5-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   2-{[1-(2-chloro-5-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (diastereomer 1);   2-{[1-(2-chloro-5-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (diastereomer 2);   5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1R)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1R)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1R)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   and   5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof.   
     
     
         4 . The compound of formula (I) according to  claim 1 , wherein the compound is selected from the group consisting of
 5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   and   5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;   or a pharmaceutically acceptable salt, hydrate, and/or solvate thereof.   
     
     
         5 . Process for preparing a compound of formula (I) as defined in  claim 1 , wherein a compound of formula (II) 
       
         
           
           
               
               
           
         
         is first reacted with hydrazine to give the hydrazide of formula (III) 
       
       
         
           
           
               
               
           
         
         then condensed with an amidine of formula (IV) 
       
       
         
           
           
               
               
           
         
         or a salt thereof, 
         in the presence of a base to give a 1,2,4-triazole derivative of formula (V) 
       
       
         
           
           
               
               
           
         
         and/or a tautomer thereof, 
         and subsequently coupled with a phenylboronic acid of formula (VI) 
       
       
         
           
           
               
               
           
         
         in the presence of a copper catalyst and an amine base to yield the target compound of formula (I) 
       
       
         
           
           
               
               
           
         
         optionally followed, where appropriate, by (i) separating the compounds of formula (I) thus obtained into their respective diastereomers, 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. 
       
     
     
         6 . Compound as defined in  claim 1  for the treatment and/or prevention of diseases. 
     
     
         7 . Compound as defined in  claim 1  for use in a method for the treatment and/or prevention of acute and chronic heart failure, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema, or the syndrome of inadequate ADH secretion (SIADH). 
     
     
         8 . Use of a compound as defined in  claim 1  for the manufacture of a pharmaceutical composition for the treatment and/or prevention of acute and chronic heart failure, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema, or the syndrome of inadequate ADH secretion (SIADH). 
     
     
         9 . Pharmaceutical composition comprising a compound as defined in  claim 1 , and one or more pharmaceutically acceptable excipients. 
     
     
         10 . The pharmaceutical composition of  claim 9  further comprising one or more additional therapeutic agents selected from the group consisting of diuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors, activators of the soluble guanylate cyclase, stimulators of the soluble guanylate cyclase and positive-inotropic agents. 
     
     
         11 . The pharmaceutical composition as defined in  claim 9  for the treatment and/or prevention of acute and chronic heart failure, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema, or the syndrome of inadequate ADH secretion (SIADH). 
     
     
         12 . Method for the treatment and/or prevention of acute and chronic heart failure, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema, or the syndrome of inadequate ADH secretion (SIADH) in a human or other mammal; comprising administering to the human or other mammal in need thereof a therapeutically effective amount of one or more compounds as defined in  claim 1 ; or of a pharmaceutical composition comprising the compound, and one or more pharmaceutically acceptable excipients.