Aryl fused 2,4-disubstituted pyridines: NK3 receptor ligands

Abstract

Disclosed are compounds of formula (I) or pharmaceutically acceptable non-toxic salts or pharmaceutically acceptable solvates thereof wherein: (II) represents (a), (b), (c) or (d) and W, X, Y, A, B, C, D, E are variables as described herein. These compounds are highly selective agonists or antagonists at NK3 receptors or prodrugs thereof. The novel tachykinin NK-3 receptor antagonists contained in this invention have potential utility in the treatment of a broad array of disorders and diseases of the central nervous system (CNS) and periphery in mammals in which activation of NK-3 receptors is of importance.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable non-toxic salts or pharmaceutically acceptable solvates thereof wherein:  
       Y is  
       hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms,  
       halogen, amino, hydroxyl, or lower alkoxy having 1-6 carbon atoms; or  
       Y is  
       straight or branched chain lower alkyl having 1-6 carbon atoms or lower alkoxy having 1-6 carbon atoms each of which is substituted on the alkyl chain with an amino or mono or dialkylamino group where each alkyl is independently lower alkyl;  
       W is  
       phenyl, thienyl, or pyridyl, each of which may be mono or disubstituted with halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or  
       R 1 , R 3  and R 4  are the same or different and represent  
       hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms:  
       X is dihydroimidazolyl, —CONR 6 R 7 , or —NR 7 COR 6 ;  
       R 6  is C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, alkyl substituted with optionally substituted phenyl, or cycloalkyl fused to phenyl;  
       R 7  represents hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; or  
       R 6  and R 7  together form a 6-membered ring fused to a benzene to form a tetrahydroisoquinoline group.  
     
   
   
       2 . A compound according to  claim 1 , which is N-[(S)-1-phenyl-1-propyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.  
   
   
       3 . A compound according to  claim 1 , which is N-[(S)-1-phenyl-1-propyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.  
   
   
       4 - 6 . (canceled)  
   
   
       7 . A compound according to  claim 1 , which is N-(Diphenylmethyl)N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.  
   
   
       8 - 19 . (canceled)  
   
   
       20 . A compound according to  claim 1 , which is selected from the group consisting of: 
 N-[1-(phenyl)ethyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(phenyl)butyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(phenyl)pentyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(phenyl)hexyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(diphenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(1,2-diphenyl)ethyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(1-phenyl-2-cyclohexyl)ethyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-indanyl-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(phenyl)isobutyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(phenyl)2-methylbutyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    1-isobutyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone; and    1-(2-methylphenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone.    
   
   
       21 . A compound according to  claim 1 , which is selected from the group consisting of 
 1-(2-chlorophenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-methyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-propyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-butyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-cyclopentyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-pentyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-benzyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-cyclohexylmethyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-isopropyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone; and    N-[1-(phenyl)octyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.    
   
   
       22 . A compound according to  claim 1 , which is selected from the group consisting of 
 1-(2-methylbutyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    N-[1,3-(diphenyl)propyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1,4-(diphenyl)butyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-benzyl-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-benzyl-N-ethyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-benzyl-N-isopropyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-benzyl-N-butyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-benzyl-N-isobutyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-benzyl-N-cyclopentyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide; and    N-benzyl-N-pentyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.    
   
   
       23 . A compound according to  claim 1 , which is selected from the group consisting of 
 N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(phenylcyclopentyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(phenylcyclohexyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(1-phenyl-2cyclopentyl)ethyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(1,3-diphenyl)propyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(1,4-diphenyl)butyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    1-phenyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-cyclohexyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-cyclopentylmethyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone; and    1-hexyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone.    
   
   
       24 . A compound according to  claim 1 , which is selected from the group consisting of 
 1-(2-fluorophenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-(3-methylphenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-(4-methylphenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-(4-fluorophenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-cycloheptyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-(3-chlorophenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    1-(4-chlorophenyl)(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    5,7-dimethoxy(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    6,7-dimethoxy-1-methyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone;    6,7-dimethoxy-1-phenyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone; and    6,7-dimethoxy-3-methyl(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)ketone.    
   
   
       25 . A compound according to  claim 1 , which is selected from the group consisting of 
 2-[6,7-dimethoxy-2-(2-1,2,3,4-tetrahydroisoquinolyl)(2-phenylpyridino[4,3-b]pyridin-4-yl)]ethanenitrile ketone;    N-[1-(4-bromophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-methylphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-methylphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-fluorophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-fluorophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-methoxyphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-methoxyphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-chlorophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide; and    N-[1-(3-chlorophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.    
   
   
       26 . A compound according to  claim 1 , which is selected from the group consisting of 
 N-[1-(4-trifluoromethylphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-trifluoromethylphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-methylphenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-methylphenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-fluorophenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-fluorophenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-methoxyphenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-methoxyphenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-chlorophenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide; and    N-[1-(3-chlorophenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.    
   
   
       27 . A compound according to  claim 1 , which is selected from the group consisting of 
 N-[1-(4-trifluoromethylphenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-trifluoromethylphenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-bromophenyl)methyl]-N-methyl(2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-methylphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-fluorophenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-methoxyphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-chlorophenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-trifluoromethylphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-methylphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide; and    N-[1-(2-fluorophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-.yl)carboxamide.    
   
   
       28 . A compound according to  claim 1 , which is selected from the group consisting of 
 N-[1-(2-methoxyphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-chlorophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2-trifluoromethylphenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(2,4-dichlorophenyl)ethyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-methylphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-methylphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-fluorophenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-fluorophenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-methoxyphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-methoxyphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide; and    N-[1-(4-chlorophenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide.    
   
   
       29 . A compound according to  claim 1 , which is selected from the group consisting of 
 N-[1-(3-chlorophenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-trifluoromethylphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(3-trifluoromethylphenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    N-[1-(4-bromophenyl)methyl](2-phenylpyridino[4,3-b]pyridin-4-yl)carboxamide;    4-ethyl-4-phenyl-2-(2-phenylpyridino[2,3-b]pyridin-4-yl)imidazoline;    4-isobutyl-4-phenyl-2-(2-phenylpyridino[2,3-b]pyridin-4-yl)imidazoline;    4-ethyl-4-phenyl-2-(2-phenylpyridino[4,3-b]pyridin-4-yl)imidazoline; and    4-isobutyl-4-phenyl-2-(2-phenylpyridino[4,3-b]pyridin-4-yl)imidazoline.    
   
   
       30 - 31 . (canceled)  
   
   
       32 . A pharmaceutical composition comprising a compound according to  claim 1  combined with at least one pharmaceutically acceptable carrier or excipient.  
   
   
       33 . A method for the treatment of schizophrenia, anxiety, depression, pain, obesity, or chronic pulmonary obstructive disorder, said method comprising administering to a patient in need of such treatment an effective amount of a compound of  claim 1 .  
   
   
       34 - 35 . (canceled)  
   
   
       36 . A method according to  claim 33  for the treatment or prevention of schizophrenia.  
   
   
       37 . A method according to  claim 33  for the treatment of pain.  
   
   
       38 . A method according to  claim 33  for the treatment of obesity.  
   
   
       39 . A method according to  claim 33  for the treatment of chronic pulmonary obstructive disorder.  
   
   
       40 - 43 . (canceled)  
   
   
       44 . A packaged pharmaceutical composition comprising a pharmaceutical composition and at least one pharmaceutically acceptable carrier or excipient in a container with instructions for using the composition to treat a patient suffering from anxiety, depression, schizophrenia, obesity or chronic pulmonary obstructive disorder, where the pharmaceutical composition comprises a compound of the formula  
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable non-toxic salts or pharmaceutically acceptable solvates thereof wherein:  
       Y is hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, halogen, amino, hydroxyl, or lower alkoxy having 1-6 carbon atoms; or  
       Y is straight or branched chain lower alkyl having 1-6 carbon atoms or lower alkoxy having 1-6 carbon atoms each of which is substituted on the alkyl chain with an amino or mono or dialkylamino group where each alkyl is independently lower alkyl;  
       W is phenyl, thienyl, or pyridyl, each of which may be mono or disubstituted with halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;  
       R 1 , R 3  and R 4  are the same or different and representhydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms:  
       X is dihydroimidazolyl, —CONR 6 R 7 , or —NR 7 COR 6 ; and 
 R 6  is C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, alkyl substituted with optionally substituted phenyl, or cycloalkyl fused to phenyl;  
 R 7  represents hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; or  
 R 6  and R 7  together form a 6-membered ring fused to a benzene to form a tetrahydroisoquinoline group.  
 
     
   
   
       45 . (canceled)