Quinoline derivatives

Abstract

Quinoline derivatives are useful as neuropeptide Y (NPY) receptor ligands and are particularly effective as neuropeptide Y (NPY) antagonists. These compounds are useful in pharmaceutical preparations for the treatment or prevention of arthritis, cardiovascular diseases, diabetes, renal failure, eating disorders, or obesity.

1 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH 2 —SO 2 —, monoalkylamino-SO 2 —, dialkylamino-SO 2 —, alkyl-SO 2 —, aryl, NH 2 -alkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aryl-SO 2 —O-alkyl, cycloalkyl, or cycloalkylalkyl;  
 R 2  is hydrogen, halogen, alkyl, alkenyl, alkinyl, aralkyl, heteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxyalkyl, aryloxy, arylamino, heteroarylamino, NH 2 —, monoalkylamino, dialkylamino, heterocyclyl, arylalkylamino, heteroarylalkylamino, aryl, arylalkoxy, or heteroarylalkoxy;  
 R 3  is alkyl;  
 R 4  is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH 2 —, monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl, heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl, carboxy, heterocyclylalkyl, alkyl-SO 2 —, or aryl-SO 2 —;  
 R 5  is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, NH 2 —, monoalkylamino, dialkylamino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkoxy, alkoxyalkoxy, cycloalkylalkoxy, heterocyclyl, heterocyclyloxy, heterocyclyloxyalkoxy, hydroxyalkoxy, alkoxycarbonyl, carboxy, heterocyclylalkyl, alkyl-SO 2 —, or aryl-SO 2 —;  
 A is pyrrolidinyl, azepanyl, morpholinyl, 1,4-dioxa-8-aza-spiro(4.5)dec-8-yl, or piperidinyl;  
 or a pharmaceutically acceptable salt or ester thereof.  
 
     
     
         2 . The compound according to  claim 1 , wherein 
 R 1  is hydrogen, alkyl, alkoxyalkyl, alkenyl, alkinyl, hydroxyalkyl, aralkyl, heterocyclylalkyl, cycloalkylalkyl, NH 2 —SO 2 —, monoalkylamino-SO 2 —, dialkylamino-SO 2 —, or alkyl-SO 2 —;    R 4  is hydrogen, alkyl, alkoxy, hydroxy, NH 2 —, monoalkylamino, dialkylamino, acetylamino, or cyano; and    R 5  is hydrogen.    
     
     
         3 . The compound according to  claim 1 , wherein R 1  is hydrogen, cycloalkylalkyl, aralkyl, or heteroarylalkyl.  
     
     
         4 . The compound according to  claim 3 , wherein R 1  is hydrogen, aralkyl or heteroarylalkyl.  
     
     
         5 . The compound according to  claim 4 , wherein R 1  is hydrogen, phenylalkyl, pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted by one to three substituents independently selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by one to three substituents independently selected from the group consisting of alkoxy, cyano and halogen.  
     
     
         6 . The compound according to  claim 5 , wherein R 1  is hydrogen, cyclopropylmethyl, (methoxyphenyl)methyl, (cyanophenyl)methyl, (chlorophenyl)methyl, pyridinylmethyl, chloropyridinylmethyl, or fluoropyridinylmethyl.  
     
     
         7 . The compound according to  claim 1 , wherein R 2  is hydrogen, alkyl or halogen.  
     
     
         8 . The compound according to  claim 7 , wherein R 2  is hydrogen.  
     
     
         9 . The compound according to  claim 7 , wherein R 2  is alkyl.  
     
     
         10 . The compounds according to  claim 7 , wherein R 2  is hydrogen, butyl, fluoro, chloro or bromo.  
     
     
         11 . The compound according to  claim 1 , wherein R 3  is methyl.  
     
     
         12 . The compound according to  claim 1 , wherein R 4  is hydrogen, alkoxy, alkoxyalkyl, hydroxyalkyl or hydroxy.  
     
     
         13 . The compound according to  claim 12 , wherein R 4  is hydrogen.  
     
     
         14 . The compound according to  claim 1 , wherein A is a pyrrolidinyl or azepanyl ring.  
     
     
         15 . The compound according to  claim 14 , wherein A is a pyrrolidinyl ring.  
     
     
         16 . The compound according to  claim 1 , wherein R 5  is hydrogen.  
     
     
         17 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1′  is hydrogen, phenylalkyl, pyridinylalkyl, phenylalkyl wherein the phenyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen, and pyridinylalkyl wherein the pyridinyl cycle is substituted by a substituent selected from the group consisting of alkoxy, cyano and halogen;  
 R 2′  is is hydrogen, alkyl or halogen;  
 R 3′  is alkyl;  
 A′ is selected from the group consisting of pyrrolidinyl, pyrrolidinyl substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl, and azepanyl;  
 or a pharmaceutically acceptable salt or ester thereof.  
 
     
     
         18 . The compound according to  claim 17 , wherein R 3′  is hydrogen or methyl.  
     
     
         19 . The compound according to  claim 18 , wherein R 3′  is hydrogen.  
     
     
         20 . The compound according to  claim 19 , wherein A′ is pyrrolidinyl.  
     
     
         21 . The compound according to  claim 20 , wherein R 2′  is alkyl.  
     
     
         22 . The compound according to  claim 21 , wherein R 2′  is butyl.  
     
     
         23 . The compound according to  claim 22 , wherein R 1′  is hydrogen.  
     
     
         24 . The compound according to  claim 23  which is 6-butyl-4-pyrrolidin-1-yl-quinolin-7-ol or a pharmaceutically acceptable salt or ester thereof.  
     
     
         25 . The compound according to  claim 22 , wherein R 1′  is (cyanophenyl)methyl.  
     
     
         26 . The compound according to  claim 25  which is 4-(6-butyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile or a pharmaceutically acceptable salt or ester thereof.  
     
     
         27 . The compound according to  claim 18 , wherein R 3′  is methyl.  
     
     
         28 . The compound according to  claim 27 , wherein A′ is azepanyl.  
     
     
         29 . The compound according to  claim 28 , wherein R 2′  is hydrogen.  
     
     
         30 . The compound according to  claim 29 , wherein R 1′  is pyridinylmethyl.  
     
     
         31 . The compound according to  claim 30  which is 4-azepan-1-yl-2-methyl-7-(pyridin-4-ylmethoxy)-quinoline or a pharmaceutically acceptable salt or ester thereof.  
     
     
         32 . The compound according to  claim 29 , wherein R 1′  is (cyanophenyl)methyl.  
     
     
         33 . The compound according to  claim 32  which is 4-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or a pharmaceutically acceptable salt or ester thereof.  
     
     
         34 . The compound according to  claim 32  which is 3-(4-azepan-1-yl-2-methyl-quinolin-7-yloxymethyl)-benzonitrile or a pharmaceutically acceptable salt or ester thereof.  
     
     
         35 . The compound according to  claim 27 , wherein A′ is pyrrolidinyl or pyrrolidinyl which is substituted by hydroxy, alkyloxy, hydroxyalkyl or alkyloxyalkyl.