Substituted quinoxaline derivatives and their use as positive allosteric modulators of mglur4

Abstract

The present invention relates to novel quinoxaline derivatives as positive allosteric modulators for modulating metabotropic glutamate receptor subtype 4 (mGluR4) and/or altering glutamate level or glutamatergic signalling.

1 . Compounds of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         X independently from each other denotes N or C, with the proviso that only one X is N or no X is N; 
         R 1 , R 2  independently from each other denote aryl, heteroaryl or heterocyclyl, which can optionally be substituted by one or more identical or different substituents T; 
         R 3a , R 3b , R 4a , independently from each other denotes substituent T, 
         R 4b , R 5a , R 5b , if the individual X is C; if the individual X is N, then one 
         R 6a , R 6b  of the R 3/4/5/6a/b  substituents is absent and the other one of the R 3/4/5/6a/b  substituents denotes substituent T or forms a double bond with one of the R 3/4/5/6a/b  substituents of an adjacent X; 
         T denotes independently from each other H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN, NO 2 , NYY, CF 3 , OCF 3 , alkyl-OH, alkyl-NYY, alkyl-CN, O-alkyl, O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, C(O)-alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl, C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)O-alkyl, C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl, O-alkyl-NYY, C(O)H, C(O)OY, C(O)NY-alkyl-NYY, C(O)NYY, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties can optionally be substituted by one or more identical or different substituents Z; 
         Y denotes independently from each other H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl can optionally be substituted by one or more identical or different substituents Z; 
         Z denotes independently from each other alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN, NO 2 , NH 2 , NH-alkyl, N(alkyl) 2 , NH-alkyl-OH, NH-alkyl-O-alkyl, NH-alkyl-aryl, CF 3 , OCF 3 , alkyl-OH, alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N(alkyl) 2 , alkyl-CN, alkyl-C(O)-heterocyclyl, O-alkyl, O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, O-alkyl-NH 2 , C(O)H, C(O)OH, C(O)NH-alkyl-NH 2 , C(O)NH 2 , C(O)—C(O)—NH 2 , C(O)-alkyl-NH-alkyl, C(O)-alkyl-NH-alkyl-O-alkyl, C(O)-alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl, C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)-heterocyclyl-alkyl, C(O)O-alkyl, C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl, C(O)NH-aryl-halogen, C(O)NH-aryl-O-alkyl, C(O)N(alkyl)-aryl, C(O)N(aryl) 2 , S-alkyl, S-cycloalkyl, S-alkyl-cycloalkyl, S-aryl, S-alkyl-aryl, S-heteroaryl, S-alkyl-heteroaryl, S-heterocyclyl, S-alkyl-heterocyclyl; 
         and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         2 . Compounds according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
         denotes 
       
       
         
           
           
               
               
           
         
         and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         3 . Compounds according to  claim 1 , wherein
 R 1 , R 2  independently from each other denote phenyl, furanyl, pyridinyl, thiophenyl, pyrrolidinyl, naphthalenyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, quinolinyl, indolyl, indazolyl or benzooxazolonyl, which can optionally be substituted by one or more identical or different substituents T;   and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         4 . Compounds according to  claim 3 , wherein
 R 1 , R 2  independently from each other are selected from the group consisting of: phenyl, furan-2-yl, furan-3-yl, 4-dimethylamino-phenyl, 2-fluorophenyl, 4-fluorophenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-hydroxy-phenyl, thiophen-2-yl, thiophen-3-yl, 4-methoxy-phenyl, 4-ethoxy-phenyl, 4-ethyl-phenyl, 4-fluoro-3-methyl-phenyl, 4-methylsulfanyl-phenyl, 4-trifluoromethoxy-phenyl, 3,4-difluorophenyl, 4-benzaldehyde, 4-tert-butyl-phenyl, 4-isopropyl-phenyl, pyrrolidin-1-yl, 3-chloro-4-methoxy-phenyl, 3-chloro-4-methyl-phenyl, 4-cyanomethyl-phenyl, 2-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 6-methoxy-naphthalen-1-yl, 3,4-dichlorophenyl, morpholin-4-yl, 4-dimethylamino-phenyl, 4-methyl-piperazin-1-yl, azetidin-1-yl, piperidin-1-yl, quinolin-4-yl, quinolin-8-yl, 4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, indol-4-yl, 4-acetamide, 4-(2,2,2-trifluoro)-acetamide, 4-amino-phenyl, indazol-5-yl, 4-hydroxymethyl-phenyl, benzooxazol-2-one-6-yl;   and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         5 . Compounds according to  claim 2 , wherein
 T denotes independently from each other H, fluoro, chloro, methyl, methoxy, hydroxy, ethoxy, isopropoxy, hydroxyl-methyl, methyl-carbonyl, 4-methyl-piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, 4-methyl-piperazin-1-yl-carbonyl, (2-hydroxy-1,1-dimethyl-ethyl)-carboxylic acid amide, pyrrolidin-1-yl-carbonyl, carboxylic acid cyclopentylamide, piperidin-1-yl-carbonyl, carboxylic acid cyclohexylamide, azetidin-1-yl-carbonyl, carboxylic acid cyclohexylmethylamide, carboxylic acid (3-methyl-butyl)-amide, carboxylic acid (5-methyl-isoxazol-3-yl)-amide, carboxylic acid pyridin-2-ylamide, carboxylic acid pyridin-3-ylamide, carboxylic acid pyridin-4-ylamide, carboxylic acid (4-hydroxy-cyclohexyl)-amide, carboxylic acid (2-cyano-ethyl)-amide, carboxylic acid (2-hydroxy-propyl)-amide, carboxylic acid cyclopropylmethyl-amide, carboxylic acid methylamide, carboxylic acid dimethylamide, carboxylic acid (2-hydroxy-ethyl)-amide, carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide, carboxylic acid thiazol-2-ylamide, carboxylic acid ethyl ester, carboxylic acid isopropyl ester, carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide, carboxylic acid (2-dimethylamino-ethyl)-amide, carboxylic acid (6-chloro-benzothiazol-2-yl)-amide, methoxymethyl, 4-methyl-piperazin-1-yl-methyl, morpholin-4-ylmethyl, pyrrolidin-1-yl-methyl, 4-hydroxy-piperdin-1-yl, [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-aminomethyl, methylaminomethyl, 2-pyrrolidin-1-yl-ethoxy, 1-methyl-pyrrolidin-3-yloxy, 4-methyl-piperazin-1-yl)-propoxy, 2-dimethylamino-ethyloxy, 3-dimethylamino-propyloxy, 4-methyl-piperazin-1-yl)-ethoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 1-methyl-tetrazol-5-yl, 2-methyl-tetrazol-5-yl;   and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.   
     
     
         6 . Compounds according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
         denotes 
       
       
         
           
           
               
               
           
         
         R 1 , R 2  independently from each other are selected from the group consisting of: phenyl, furan-2-yl, furan-3-yl, 4-dimethylamino-phenyl, 2-fluorophenyl, 4-fluorophenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-hydroxy-phenyl, thiophen-2-yl, thiophen-3-yl, 4-methoxy-phenyl, 4-ethoxy-phenyl, 4-ethyl-phenyl, 4-fluoro-3-methyl-phenyl, 4-methylsulfanyl-phenyl, 4-trifluoromethoxy-phenyl, 3,4-difluorophenyl, 4-benzaldehyde, 4-tert-butyl-phenyl, 4-isopropyl-phenyl, pyrrolidin-1-yl, 3-chloro-4-methoxy-phenyl, 3-chloro-4-methyl-phenyl, 4-cyanomethyl-phenyl, 2-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 6-methoxy-naphthalen-1-yl, 3,4-dichlorophenyl, morpholin-4-yl, 4-dimethylamino-phenyl, 4-methyl-piperazin-1-yl, azetidin-1-yl, piperidin-1-yl, quinolin-4-yl, quinolin-8-yl, 4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, indol-4-yl, 4-acetamide, 4-(2,2,2-trifluoro)-acetamide, 4-amino-phenyl, indazol-5-yl, 4-hydroxymethyl-phenyl, benzooxazol-2-one-6-yl; 
         T denotes independently from each other H, fluoro, chloro, methyl, methoxy, hydroxy, ethoxy, isopropoxy, hydroxyl-methyl, methyl-carbonyl, 4-methyl-piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, 4-methyl-piperazin-1-yl-carbonyl, (2-hydroxy-1,1-dimethyl-ethyl)-carboxylic acid amide, pyrrolidin-1-yl-carbonyl, carboxylic acid cyclopentylamide, piperidin-1-yl-carbonyl, carboxylic acid cyclohexylamide, azetidin-1-yl-carbonyl, carboxylic acid cyclohexylmethylamide, carboxylic acid (3-methyl-butyl)-amide, carboxylic acid (5-methyl-isoxazol-3-yl)-amide, carboxylic acid pyridin-2-ylamide, carboxylic acid pyridin-3-ylamide, carboxylic acid pyridin-4-ylamide, carboxylic acid (4-hydroxy-cyclohexyl)-amide, carboxylic acid (2-cyano-ethyl)-amide, carboxylic acid (2-hydroxy-propyl)-amide, carboxylic acid cyclopropylmethyl-amide, carboxylic acid methylamide, carboxylic acid dimethylamide, carboxylic acid (2-hydroxy-ethyl)-amide, carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide, carboxylic acid thiazol-2-ylamide, carboxylic acid ethyl ester, carboxylic acid isopropyl ester, carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide, carboxylic acid (2-dimethylamino-ethyl)-amide, carboxylic acid (6-chloro-benzothiazol-2-yl)-amide, methoxymethyl, 4-methyl-piperazin-1-yl-methyl, morpholin-4-ylmethyl, pyrrolidin-1-yl-methyl, 4-hydroxy-piperdin-1-yl, [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-aminomethyl, methylaminomethyl, 2-pyrrolidin-1-yl-ethoxy, 1-methyl-pyrrolidin-3-yloxy, 4-methyl-piperazin-1-yl)-propoxy, 2-dimethylamino-ethyloxy, 3-dimethylamino-propyloxy, 4-methyl-piperazin-1-yl)-ethoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 1-methyl-tetrazol-5-yl, 2-methyl-tetrazol-5-yl; 
         and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         7 . Compounds selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                     
                 
                   Com- 
                     
                     
                 
                   pound 
                     
                     
                 
                   No. 
                   Chemical Structure 
                   Chemical Name 
                 
                     
                 
                     
                 
                 
                 
                 
               
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2-Phenyl-3-quinolin- 4-yl-quinoxaline 
                 
                     
                 
                   2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   4-(3-Phenyl- quinoxalin-2-yl)- phenol 
                 
                     
                 
                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   1-(3-Phenyl- quinoxalin- 2-yl)-piperidin- 4-ol 
                 
                     
                 
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2-(3,4-Difluoro- phenyl)-3-(1H- indol-4-yl)- quinoxaline 
                 
                     
                 
                   5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   5-Methyl-2,3- diphenyl- quinoxaline 
                 
                     
                 
                   6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2-Phenyl-3- quinolin-8-yl- quinoxaline 
                 
                     
                 
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   1-(2,3-Diphenyl- quinoxalin-5-yl)- ethanone 
                 
                     
                 
                   8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2,3-Diphenyl- 5,6,7,8- tetrahydro- quinoxaline 
                 
                     
                 
                   9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2,3-Bis-(2- fluoro-phenyl)- quinoxaline 
                 
                     
                 
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   2-(3,4-Difluoro- phenyl)-3- phenyl- quinoxaline 
                 
                     
                 
             
                
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         and the physiologically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 
       
     
     
         8 . Process for manufacturing a compound of formula (I) according to  claim 1  comprising the steps of:
 (a) reacting a compound of formula (II) 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2  are as defined as for the compound of formula (I), 
         with a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein 
         X, R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b  are as defined as for the compound of formula (I), 
         to yield the compound of formula (I) 
         or 
         (b) reacting a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein 
         X is OH or halogen, and 
         R 1  is as defined as to the compound of formula (I), 
         with a compound of formula (V)
   Z—R 2   (V)
 
 
         wherein 
         Z denotes halogen, boronic acid or a ester of boronic acid and 
         R 2  is as defined as to the compound of formula (I), 
         to yield the compound of formula (I) 
         and optionally, 
         (c) converting in the compound or formula (I) one or more radicals R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b  as in any of  claims 1  to  6  into one or more other radicals R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b  optionally by introducing a heterocyclyl(alkyl) or an alkyl group, 
         and optionally 
         (d) converting a base or an acid of the compound of formula (I) into a salt thereof. 
       
     
     
         9 . A method for modulating metabotropic glutamate receptor subtype 4 (mGluR4) and/or altering glutamate level or glutamatergic signaling, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         10 . comprising at least one compound according to  claim 1 . 
     
     
         11 . A method for the treatment and/or prophylaxis of physiological and/or pathophysiological conditions selected from the group consisting of: “condition which is affected or facilitated by the neuromodulatory effect of mGluR4 allosteric modulators, central nervous system disorders, addiction, tolerance or dependence, affective disorders, such as anxiety, agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), social phobia, other phobias, substance-induced anxiety disorder, and acute stress disorder, mood disorders, bipolar disorders (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, and substance-induced mood disorder, psychiatric disease, such as psychotic disorders and attention-deficit/hyperactivity disorder, Parkinson's disease, and movement disorders such as bradykinesia, rigidity, dystonia, drug-induced parkinsonism, dyskinesia, tardive dyskinesia, L-DOPA-induced dyskinesia, dopamine agonist-induced dyskinesia, hyperkinetic movement disorders, Gilles de la Tourette syndrome, resting tremor, action tremor, akinesia, akinetic-rigid syndrome, akathisia, athetosis, asterixis, tics, postural instability, postencephalitic parkinsonism, muscle rigidity, chorea and choreaform movements, spasticity, myoclonus, hemiballismus, progressive supranuclear palsy, restless legs syndrome, and periodic limb movement disorder, cognitive disorders such as delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer's type, substance-induced persisting dementia, and mild cognitive impairment, neurological disorders such as neurodegeneration, neurotoxicity or ischemia such as stroke, spinal cord injury, cerebral hypoxia, intracranial hematoma, memory impairment, Alzheimer's disease, dementia, delirium tremens, other forms of neurodegeneration, neurotoxicity, and ischemia, inflammation and/or neurodegeneration resulting from traumatic brain injury, inflammatory central nervous system disorders, such as multiple sclerosis forms such as benign multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, and progressive-relapsing multiple sclerosis, migraine, epilepsy and tremor, temporal lobe epilepsy, epilepsy secondary to another disease or injury such as chronic encephalitis, traumatic brain injury, stroke or ischemia, medulloblastomas, inflammatory or neuropathic pain, metabolic disorders associated with glutamate dysfunction, type 2 diabetes, diseases or disorders of the retina, retinal degeneration or macular degeneration, diseases or disorders of the gastrointestinal tract including gastroesophageal reflux disease (GERD), lower esophageal sphincter diseases or disorders, diseases of gastrointestinal motility, colitis, Crohn's disease or irritable bowel syndrome (IBS), cancers”, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         12 . The medicament according to  claim 10 , wherein such medicament comprises at least one additional pharmacologically active substance. 
     
     
         13 . The method according to  claim 11 , wherein the compound of formula (I) is administered before and/or during and/or after treatment with at least one additional pharmacologically active substance. 
     
     
         14 . Pharmaceutical composition comprising at least one compound according to  claim 1 , and at least one additional compound selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, diluents, and carriers and optionally a pharmaceutically active substance other than the compound of formula (I). 
     
     
         15 . Kit comprising a therapeutically effective amount of at least one compound according to  claim 1  and a therapeutically effective amount of at least one further pharmacologically active substance other than the compound of formula (I).