Conjugated aromatic compounds with a pyridine substituent

Abstract

The present invention relates to compounds of formulae The compounds of the present invention are NMDA (N-methyl-D-aspartate)-receptor subtype blockers and are used in the treatment of diseases related to this receptor.

1 . A compound of formulae  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5  and —(CH 2 ) n+1 OH;  
       R 5  and R 5 ′ are each independently hydrogen or lower alkyl;  
       R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy;  
       Ar is selected from the group phenyl and thiophenyl;  
       The dotted line is selected from the group two hydrogens not forming a bridge, and —CH 2 —CHR′—, wherein R′ is selected from the group lower alkyl and hydrogen; and  
       n is 0, 1 or 2;  
       or a pharmaceutically acceptable acid addition salt thereof, with the proviso that when ar is unsubstituted phenyl and R 2  is H, R 1  is not 2-amino.  
     
   
   
       2 . A compound of formula  
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are each independently selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5  and —(CH 2 ) n+1 OH;  
       R 5  and R 5 ′ are each independently hydrogen or lower alkyl; and  
       R 3  and R 4  are each independently selected from the group of hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy  
       or a pharmaceutically acceptable acid addition salt thereof.  
     
   
   
       3 . A compound of formula IA-1 according to  claim 2 , selected from the group 
 trans-4-methyl-6-styryl-pyridin-2-yl-amine,    trans-2-styryl-pyridin-4-yl-amine and    trans-C-(6-styryl-pyridin-2-yl)-methylamine.    
   
   
       4 . A compound of formula  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5  and —(CH 2 ) n+1 OH;  
       R 5  and R 5 ′ are each independently hydrogen or lower alkyl;  
       R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy; and  
       R′ is selected from the group lower alkyl and hydrogen;  
       or a pharmaceutically acceptable acid addition salt thereof.  
     
   
   
       5 . A compound of formula IA-2 according to  claim 4 , wherein R′ is hydrogen.  
   
   
       6 . A compound of formula IA-2 according to  claim 5 , selected from the group 
 2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,    2-(3,4-dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-amine,    [4-amino-6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methanol,    2-(3,4-dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine,    2-(3,4-dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine,    2-(3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl]-methyl-amine,    C-[6-(3,4-dihydro-naphthalen-2-yl)-pyridin-2-yl]-methylamine,    2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,    2-(5,7-dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,    2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-6-ethyl-pyridin-4-yl-amine,    2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-6-methyl-pyridin-4-yl-amine and    2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-5-methyl-pyridin-4-yl-amine.    
   
   
       7 . A compound of formula IA-2 according to  claim 4 , wherein R′ is methyl.  
   
   
       8 . A compound of formula IA-2 according to  claim 7 , selected from the group 
 rac.-2-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine,    rac.-2-methyl-6-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine and    rac.-5-methyl-2-(4-methyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine.    
   
   
       9 . A compound of formula  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5  and —(CH 2 ) n+1 OH;  
       R 5  and R 5 ′ are each independently hydrogen or lower alkyl; and  
       R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy;  
       R′ is selected from the group lower alkyl and hydrogen; and  
       n is 0, 1 or 2;  
       or a pharmaceutically acceptable acid addition salt thereof.  
     
   
   
       10 . A compound of formula IA-4 according to  claim 9 , wherein R′ is hydrogen.  
   
   
       11 . A compound of formula IA-4 according to  claim 10 , selected from the group 
 2-(6,7-dihydro-benzo[b]thiophen-5-yl)-pyridin-4-yl-amine and 2-(6,7-dihydro-benzo[b]thiophen-5-yl)-5-methyl-pyridin-4-yl-amine.    
   
   
       12 . A compound of formula  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are each independently selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5 ′ and —(CH 2 ) n+1 OH;  
       R 5  and R 5 ′ are each independently hydrogen or lower alkyl; and  
       R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy;  
       or a pharmaceutically acceptable acid addition salt thereof.  
     
   
   
       13 . A compound of formula IB-1 according to  claim 12 , which is trans-6-methyl-4-styryl-pyridin-2-yl-amine.  
   
   
       14 . A compound of formula IA or IB according to  claim 1 , wherein one of R 1  or R 2  is amino.  
   
   
       15 . A pharmaceutical composition comprising a compound of formula IA or IB of  claim 1 , combinations thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
   
   
       16 . A method of treatment of diseases responsive to therapeutic indications for NMDA receptor subtype specific blockers, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, depression and chronic or acute pain comprising administering a therapeutically effective amount of a compound of formulae 1A or IB according to  claim 1 , combinations thereof or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.  
   
   
       17 . A process for preparing a compound of formula IA-la comprising 
 a) reacting a compound of formula                          with diphenyl phosphoryl azide, forming a compound of formula                          wherein    R 2  is selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5 ′ and —(CH 2 ) n+1 OH;    R 5  and R 5 ′ are each independently hydrogen or lower alkyl; and    R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy;    Ar is selected from the group phenyl and thiophenyl and    n is 0, 1 or 2.    
   
   
       18 . A process for preparing a compound of formula IA-1b comprising 
 reacting the amino group of a compound of formula                          with a compound of formula R 5 X,    forming a compound of formula                          wherein    R 2  is selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5′  and —(CH 2 ) n+1 OH;    R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy;    Ar is selected from the group phenyl and thiophenyl;    R 5  is lower alkyl;    X is halogen; and;    n is 0, 1 or 2.    
   
   
       19 . A process for preparing a compound of formulae IIB-1a, comprising: 
 reacting a compound of formula                          with diphenyl phosphoryl azide forming a compound of formula                          wherein    R 2  is selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5  and —(CH 2 ) n+1 OH;    R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy;    Ar is selected from the group phenyl and thiophenyl;    R 5  is lower alkyl; and;    n is 0, 1 or 2.    
   
   
       20 . A process for preparing a compound of formula IIB-1b comprising: 
 reacting the amino group of a compound of formula                          with a compound of formula R 5 X    forming a compound of formula                          wherein    R 1  is selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5  and —(CH 2 ) n+1 OH;    R 5  and R 5′  are each independently hydrogen or lower alkyl;    R 3  and R 4  are each independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy;    Ar is selected from the group phenyl and thiophenyl;    X is halogen; and    n is 0, 1 or 2.    
   
   
       21 . A process for preparing a compound of formulae IA-2 comprising: 
 reacting a compound of formula                          with a compound of formula                          forming a compound of formula                          wherein    R 1  and R 2  are each independently selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5′  and —(CH 2 ) n+1 OH;    R 5  and R 5  are each independently hydrogen or lower alkyl; and    R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy; and    n is 0, 1 or 2.    
   
   
       22 . A process for preparing a compound of formula IB-2 comprising: 
 reacting a compound of formula                          with a compound of formula                          forming a compound of formula                          wherein    R 1  and R 2  are each independently selected from the group hydrogen, lower alkyl, —(CH 2 ) n NR 5 R 5  and —(CH 2 ) n+1 OH;    R 5  and R 5′  are each independently hydrogen or lower alkyl; and    R 3  and R 4  are each independently selected from the group hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl and hydroxy; and    n is 0, 1 or 2.