Substituted dicyanopyridines and use thereof

Abstract

The present application relates to novel substituted dicyanopyridines, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prophylaxis of cardiovascular disorders.

1 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         A represents oxygen or sulfur, 
         G represents CH or N, 
         K represents CH, CF or N, 
         L represents CR 6  or N,
 where 
 R 6  represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or (C 1 -C 4 )-alkoxy,
 where (C 1 -C 4 )-alkoxy may be substituted by 1 or 2 hydroxyl substituents, 
 
 
         M represents CR 7  or N,
 where 
 R 7  represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or (C 1 -C 4 )-alkoxy,
 where (C 1 -C 4 )-alkoxy may be substituted by 1 or 2 hydroxyl substituents, 
 
 
         R 1  represents hydrogen or (C 1 -C 4 )-alkyl, 
         R 2  represents hydroxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 3 -C 7 )-cycloalkyl-aminocarbonyl, aminosulfonyl, (C 1 -C 4 )-alkylsulfonylamino or phenylsulfonylamino,
 where mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl and (C 3 -C 7 )-cycloalkylaminocarbonyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, hydroxy and amino, 
 
         R 3  represents hydrogen, fluorine or methoxy, 
         R 4  represents hydrogen, fluorine, (C 1 -C 6 )-alkoxy, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-alkylcarbonylamino, mono-(C 1 -C 4 )-alkylamino sulfonyloxy, di-(C 1 -C 4 )-alkylaminosulfonyloxy or 2-oxopyrrolidin-1-yl,
 where (C 1 -C 6 )-alkoxy may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of trifluoromethyl, hydroxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl and a group of the formula 
 
       
       
         
           
           
               
               
           
         
         
           in which
 # represents the point of attachment to the alkoxy group, 
 R 10  represents hydrogen or the side group of a natural α-amino acid or its homologs or isomers, 
 
         
         or 
         R 4  and R 6  together with the carbon atoms to which they are attached form a group of the formula —O—CH 2 —O—, —O—CHF—O—, —O—CF 2 —O—, —O—CH 2 —CH 2 —O— or —O—CF 2 —CF 2 —O—, or 
         R 4  and R 7  together with the carbon atoms to which they are attached form a group of the formula —O—CH 2 —O—, —O—CHF—O—, —O—CF 2 —O—, —O—CH 2 —CH 2 —O— or —O—CF 2 —CF 2 —O—, 
         R 5  represents hydrogen or —NR 8 R 9 ,
 where 
 R 8  represents hydrogen or (C 1 -C 4 )-alkyl, 
 R 9  represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,
 where (C 1 -C 6 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, hydroxy and (C 1 -C 4 )-alkoxy, 
 
 or 
 R 8  and R 9  together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
 where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy and 4- to 7-membered heterocycle, 
 
 
         or an N-oxide, salt of the N-oxide, or a salt thereof, 
         except for the compounds 
         4-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methy}-N-methylpyridine-2-carboxamide 
         3-[({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]pyridin-2-yl}sulfanyl)methyl]benzoic acid 
         3-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methy}benzoic acid. 
       
     
     
         2 . The compound of  claim 1  in which
 A represents oxygen or sulfur, 
 G represents CH or N, 
 K represents CH, CF or N, 
 L represents CR 6  or N,
 where 
 R 6  represents hydrogen or fluorine, 
 
 M represents CR 7  or N,
 where 
 R 7  represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl, methoxy or ethoxy,
 where ethoxy may be substituted by 1 or 2 hydroxy substituents, 
 
 
 R 1  represents hydrogen or methyl, 
 R 2  represents hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethyl-aminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, aminosulfonyl, methylsulfonylamino, ethylsulfonylamino or phenylsulfonylamino,
 where ethylaminocarbonyl, cyclopropylaminocarbonyl and cyclobutyl-aminocarbonyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy and amino, 
 
 R 3  represents hydrogen or fluorine, 
 R 4  represents hydrogen, fluorine, (C 1 -C 4 )-alkoxy, methylamino, ethylamino, dimethylamino, diethylamino, methylcarbonylamino, ethylcarbonylamino, dimethylaminosulfonyloxy, diethylaminosulfonyloxy or 2-oxopyrrolidin-1-yl,
 where (C 1 -C 4 )-alkoxy may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino, ethyl-amino, dimethylamino, diethylamino, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino and a group of the formula 
 
 
       
         
           
           
               
               
           
         
         
           where
 R 10  represents hydrogen, methyl, 2-methylpropan-1-yl, hydroxymethyl, 1-hydroxyethyl, 4-aminobutan-1-yl or 3-aminopropan-1-yl, 
 
         
         or 
         R 4  and R 6  together with the carbon atoms to which they are attached form a group of the formula —O—CH 2 —O—, —O—CF 2 —O— or —O—CH 2 —CH 2 —O—, or 
         R 4  and R 7  together with the carbon atoms to which they are attached form a group of the formula —O—CH 2 —O—, —O—CF 2 —O— or —O—CH 2 —CH 2 —O—, 
         R 5  represents hydrogen or —NR 8 R 9 ,
 where 
 R 8  represents hydrogen, methyl or ethyl, 
 R 9  represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 6 )-cycloalkyl,
 where (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl and hydroxy, 
 
 or 
 R 8  and R 9  together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
 where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and hydroxy, 
 
 
         or a salt thereof, 
         except for the compounds 
         4-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methy}-N-methylpyridine-2-carboxamide 
         3-[({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]pyridin-2-yl}sulfanyl)methyl]benzoic acid 
         3-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methy}benzoic acid. 
       
     
     
         3 . The compound of  claim 1  in which
 A represents sulfur, 
 G represents N, 
 K represents CH, CF or N, 
 L represents CR 6  or N,
 where 
 R 6  represents hydrogen or fluorine, 
 
 M represents CR 7  or N,
 where 
 R 7  represents hydrogen, fluorine, trifluoromethyl, methoxy or 2-hydroxyethoxy, 
 
 wherein, only one of the groups K or M represents N, 
 R 1  represents hydrogen, 
 R 2  represents hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl or cyclopropylaminocarbonyl, 
 R 3  represents hydrogen, 
 R 4  represents hydrogen, fluorine or (C 1 -C 4 )-alkoxy,
 where (C 1 -C 4 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, hydroxy, amino and a group of the formula 
 
 
       
         
           
           
               
               
           
         
         
           where
 R 10  represents hydrogen or methyl, 
 
         
         R 5  represents hydrogen or —NR 8 R 9 ,
 where 
 R 8  represents hydrogen, 
 R 9  represents hydrogen, (C 1 -C 6 )-alkyl or cyclopropyl, or 
 R 8  and R 9  together with the nitrogen atom to which they are attached form an azetidinyl, a pyrrolidonyl or a piperidinyl ring, 
 
         or a salt thereof, 
         except for the compound 
         4-{[(6-amino-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methy}-N-methylpyridine-2-carboxamide. 
       
     
     
         4 . The compound of  claim 1  in which
 A represents sulfur, 
 G represents CH, 
 K represents CH, CF or N, 
 L represents CR 6  or N,
 where 
 R 6  represents hydrogen or fluorine, 
 
 M represents CR 7  or N,
 where 
 R 7  represents hydrogen, fluorine, trifluoromethyl, methoxy or 2-hydroxyethoxy, 
 
 provided, that only one of the groups K or M represents N, 
 R 1  represents hydrogen, 
 R 2  represents hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl or cyclopropylaminocarbonyl, 
 R 3  represents hydrogen, 
 R 4  represents hydrogen, fluorine or (C 1 -C 4 )-alkoxy,
 where (C 1 -C 4 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, hydroxy, amino and a group of the formula 
 
 
       
         
           
           
               
               
           
         
         
           where
 R 10  represents hydrogen or methyl, 
 
         
         R 5  represents —NR 8 R 9 ,
 where 
 R 8  represents hydrogen, 
 R 9  represents hydrogen, 
 
         or a salt thereof. 
       
     
     
         5 . A process for preparing a compound of the formula (I) as defined in  claim 1  comprising:
 [A] reacting a compound of the formula (II) 
 
       
         
           
           
               
               
           
         
         
           in which A, K, L, M, R 3 , R 4  and R 5  each have the meanings given in  claim 1 , 
           in an inert solvent in the presence of a base with a compound of the formula (III) 
         
       
       
         
           
           
               
               
           
         
         
           in which G, R 1  and R 2  each have the meanings given in  claim 1  and 
           X 1  represents a suitable leaving group, preferably represents halogen, in particular chlorine, bromine or iodine, or represents mesylate, tosylate or triflate, 
         
         or 
         [B] in the case that A represents O, reacting a compound of the formula (IV) 
       
       
         
           
           
               
               
           
         
         
           in which K, L, M, R 3 , R 4  and R 5  each have the meanings given in  claim 1 , 
           in an inert solvent in the presence of a base with a compound of the formula (V) 
         
       
       
         
           
           
               
               
           
         
         
           in which G, R 1  and R 2  each have the meanings given in  claim 1 , 
         
         or 
         [C] converting a compound of the formula (I-A) 
       
       
         
           
           
               
               
           
         
         
           in which A, G, K, L, M, R 1 , R 2 , R 3  and R 4  each have the meanings given in  claim 1  and 
           R 5A  represents amino, 
           in a suitable solvent with copper(II) chloride and isopentyl nitrite into a compound of the formula (VI) 
         
       
       
         
           
           
               
               
           
         
         
           in which A, G, K, L, M, R 1 , R 2 , R 3  and R 4  each have the meanings given in  claim 1 , 
           and reacting the compound of formula (VI) in an inert solvent, optionally, in the presence of a base, with a compound of the formula (VII) 
         
       
       
         
           
           
               
               
           
         
         
           in which R 8  and R 9  each have the meanings given in  claim 1  and 
           where at least one of the two radicals R 8  and R 9  is different from hydrogen, 
           to give a compound of the formula (I-B) 
         
       
       
         
           
           
               
               
           
         
         
           in which A, G, K, L, M, R 1 , R 2 , R 3 , R 4 , R 8  and R 9  each have the meanings given in  claim 1 , and 
           where at least one of the two radicals R 8  and R 9  is different from hydrogen, 
         
         any protective groups present are then removed and the resulting compounds of the formulae (I), (I-A) and (I-B) are, optionally, converted with the appropriate (i) solvents and/or (ii) bases or acids into salt thereof. 
       
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A pharmaceutical composition, comprising a compound of  claim 1  and an inert nontoxic pharmaceutically suitable auxiliary. 
     
     
         10 . The pharmaceutical composition of  claim 9 , further, comprising at least one active ingredient selected from the group consisting of a lipid metabolism-modifying active ingredient, an antidiabetic, a antihypertensive drug, and an antithrombotic drug. 
     
     
         11 . (canceled) 
     
     
         12 . A method for the treatment and/or prophylaxis of hypertension, coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction, atrial fibrillation, diabetes, metabolic syndrome and dyslipidemias comprising administering an effective amount of at least one compound of  claim 1  to a human or animal in need thereof. 
     
     
         13 . A method for the treatment and/or prophylaxis of hypertension, coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction, atrial fibrillation, diabetes, metabolic syndrome and dyslipidemias comprising administering an effective amount of at least one pharmaceutical composition of  claim 9  to a human or animal in need thereof.