N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein b secretion

Abstract

N-aryl piperidine substituted biphenylcarboxamides compounds of formula (I) methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
         the N-oxides, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein  
         R 1  is hydrogen, C 1-4 alkyl, halo, or polyhaloC 1-4 alkyl;  
         R 2  is hydrogen, Cl-alkyl, halo, or polyhaloC 1-4 alkyl;  
         R 3  is hydrogen or C 1-4 alkyl;  
         R 4  is hydrogen, C 1-4 alkyl, or halo;  
         n is an integer zero or 1;  
         X 1  and X 2  are either both carbon, or when one of X 1  or X 2  is nitrogen, than the other X 1  or X 2  is carbon;  
         X 3  is carbon, or nitrogen provided that only one of X 1  or X 2  is nitrogen;  
         Y is O or NR 6  wherein R 6  is hydrogen or C 1-4 alkyl; and  
         R 5  is hydrogen; C 1-6 alkyl optionally substituted with C 1-4 alkyloxy, cyano, polyhaloC 1-4 alkyl, or aryl; C 2-6 alkenyl optionally substituted with aryl; C 3-6 alkynyl optionally substituted with aryl; aryl or heteroaryl;  
         aryl is phenyl; phenyl substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkyloxy, polyhaloC 1-6 alkyl, amino, mono- or di(C 1-6 alkyl)amino;  
         heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl, or thienyl; and optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, amino, mono- or di(C 1-6 alkyl)amino.  
       
     
     
         2 . A compound as claimed in  claim 1  wherein X 1 , X 2  and X 3  are carbon.  
     
     
         3 . A compound as claimed in  claim 1  wherein X 1  is carbon, X 2  is nitrogen, and X 3  is carbon.  
     
     
         4 . A compound as claimed in  claim 1  wherein X 1  is nitrogen, X 2  is carbon, and X 3  is carbon.  
     
     
         5 . A compound as claimed in  claim 1  wherein n is the integer zero.  
     
     
         6 . A compound as claimed in  claim 1  n is the integer 1.  
     
     
         7 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claims  1 .  
     
     
         8 . A process for preparing a pharmaceutical composition as claimed in  claim 7  wherein a therapeutically active amount of a compound as claimed in  claim 1  is intimately mixed with a pharmaceutically acceptable carrier.  
     
     
         9 . (canceled)  
     
     
         10 . A process for preparing a compound of formula (I) wherein an intermediate of formula (II), wherein R 3 , R 4 , R 5 , n, Y, X 1 , X 2  and X 3  are defined as in  claim 1 ,  
       
         
           
           
               
               
           
         
         is reacted with a biphenylcarboxylic acid or halide having the formula (III), wherein R 1  and R 2  are as defined in formula (I) and Q 1  is selected from hydroxy and halo, in at least one reaction-inert solvent and optionally in the presence of a suitable base  
         
           
             
             
                 
                 
             
           
         
       
     
     
         11 . The method according to  claim 10  further comprising converting the compound of formula (I) into an acid addition salt.  
     
     
         12 . A compound as claimed in  claim 2  wherein n is the integer zero.  
     
     
         13 . A compound as claimed in  claim 3  wherein n is the integer zero.  
     
     
         14 . A compound as claimed in  claim 4  wherein n is the integer zero.  
     
     
         15 . A compound as claimed in  claim 2  wherein n is the integer 1.  
     
     
         16 . A compound as claimed in  claim 3  wherein n is the integer 1.  
     
     
         17 . A compound as claimed in  claim 4  wherein n is the integer 1.  
     
     
         18 . A method of treating a warm-blooded animal suffering from a disorder caused by an excess of very low density lipoproteins (VLDL) or low density lipoproteins (LDL) comprising administering to the animal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         19 . The method according to  claim 19  wherein the disorder is caused by the cholesterol associated with the VLDL or LDL.  
     
     
         20 . The method of treatment according to  claim 17  wherein the disorder is hyperlipidemia, obesity, atherosclerosis or type II diabetes.  
     
     
         21 . The method of treatment according to  claim 18  wherein the disorder is hyperlipidemia, obesity, atherosclerosis or type II diabetes.