Amine and amide derivatives as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders

Abstract

Amine and amide derivatives of the formula: which are ligands for the neuropeptide Y Y5 (NPY5) receptor, methods of preparation and pharmaceutical compositions containing amines and amides of formula A as the active ingredient are described. The amines and amides of formula A are useful in the treatment of disorders and diseases associated with NPY receptor subtype Y5.

1 - 9 . (canceled)  
   
   
       10 . A compound of  claim 17  selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       11 . A compound of  claim 17  selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       12 . (canceled)  
   
   
       13 . A compound of  claim 17  which is: 
 3-[(Phenylsulfonyl)amino]-N-[cis-1,2,3,4-tetrahydro-6-fluoro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-pyrrolidineacetamide bis-trifluoroacetate.    
   
   
       14 - 16 . (canceled)  
   
   
       17 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 1  is independently selected from the group consisting of H; alkyl; substituted alkyl; alkoxy; halo; substituted alkoxy; hydroxy; trifluoralkyl; nitro; amino; alkylamino; cycloalkylamino; cyano; carboxy; cycloalkyl; phenyl; and substituted phenyl; 
 R 2  is pyridyl;  
 B 1  is hydrogen;  
 B 2  is hydrogen; or B 1  and/or B 2  are methylene and joined together to form a five or six membered ring;  
 Y is methylene or carbonyl;  
 L is (N-methylene)pyrrolidin-3-yl;  
                     
 Z is selected from the group consisting of 
 aryl;  
                     
 N-sulfonamido;  
                     
 N-(aryl)sulfonamido;  
                     
 arylamido;  
                     
 arylureido;  
                     
 arylacetamido:  
                     
 (aryloxy)carbonylamino;  
                     
 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl;  
                     
 and 1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl;  
                     
 
 R 3  is independently selected from the group consisting of C 1-6  alkyl; substituted C 1-8 alkyl; cycloalkyl; substituted cycloalkyl; naphthyl; substituted naphthyl; heteroaryl; and substituted heteroaryl;  
 R 4  is independently selected from the group consisting of hydrogen; 
 C 1-8 alkyl; C 1-8 alkoxy; substitued C 1-8 alkoxy; hydroxy; halogen; cyano; nitro; amino;  
 C 1-8 alkylamino; and C 1-8 dialkylamino;  
 
 R 5  is independently selected from the group consisting of hydrogen; 
 C 1-8 alkyl; C 1-8 alkylcarbonyl; aroyl; carbamoyl; amidino; C 1-8 alkyl;  
 C 1-8 alkylaminocarbonyl; (arylamino)carbonyl; and arylC 1-8  alkylcarbonyl;  
 
 R 6  is independently selected from hydrogen and C 1-8 alkyl;  
 n is 1-2;  
 m is 0-3;  
 p is 1-3; and  
 q is 1-3;  
 provided that when L is (N-methylene)piperazin-4-yl, then Z is phenyl or naphthyl; when L is (N-methylene)piperidin-4-yl, then Z is N-sulfonamido, N(aryl)sulfonamido, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl, benzamido, phenylureido, phenylacetamido or (phenoxy)carbonylamino; when L is (N-methylene)-4-acetyl- piperidin-4-yl, then Z is phenyl or naphthyl and Y is carbonyl; and when L is (N-methylene)piperidin-4,4-diyl, then Z is 1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl and Y is carbonyl;  
 and enantiomers, diastereomers and pharamaceutically acceptable salts thereof.  
 
   
   
       18 . A method of treating disorders and diseases associated with NPY receptor subtype 5 selected from the group consisting of eating disorders, obesity, diabetes, memory loss, epileptic seizures, migraine, sleep disturbances, pain, sexual.reproductive disorders, depression and anxiety comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 17 .  
   
   
       19 . A pharmaceutical composition for the treatment of diseases or disorders associated with the NPY Y5 receptor subtype selected from the group consisting of eating disorders, obesity, diabetes, memory loss, epileptic seizures, migraine, sleep disturbances, pain, sexual.reproductive disorders, depression and anxiety comprising a therapeutically effective amount of a compound of  claim 17  and a pharmaceutically acceptable carrier