Polyarylcarboxamides useful as lipid lowering agents

Abstract

Polyarylcarboxamide compounds of formula (I) are useful as lipid lowering agents.

1 . Polyarylcarboxamide compounds of formula (I) 
       
         
           
           
               
               
           
         
         the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
 Z 1  is selected from (CH 2 ) n  wherein n is 1 to 3, CH 2 CH 2 O and OCH 2 CH 2 ; 
 Z 2  is (CH 2 ) m  wherein m is 1 or 2; 
 X 1  represents O, CH 2 , CO, NH, CH 2 O, OCH 2 , CH 2 S, SCH 2  or a direct bond; 
 X 2  and X 3  are each independently selected from CH, N and a sp 2  carbon atom; 
 R 1  is hydrogen or C 1-4 alkyl; 
 Ar 1  is an aromatic ring selected from phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted with one or two R 3  substituents; 
 Ar 2  is an aromatic ring selected from phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted with one, two or three R 4  substituents; 
 each R 2  and R 3  is independently selected from C 1-4 alkyl, C 1-4 alkyloxy, halo and trifluoromethyl; 
 each R 4  is independently selected from C 1-4 alkyl, C 1-4 alkyloxy, halo, hydroxy, mercapto, cyano, nitro, C 1-4 alkylthio or polyhaloC 1-6 alkyl, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; 
 p 1  and p 2  are each 0 to 2; 
 p 3  is 0 to 3; 
 X 1  and R 4  taken together with the aromatic rings Ar 1  and Ar 2  to which they are attached may form a fluoren-1-yl or a fluoren-4-yl group; 
 A represents a C 1-6 alkanediyl substituted with one or two groups selected from aryl, heteroaryl, and C 3-10 cycloalkyl; or when X 3  is CH, A may also represent a nitrogen atom substituted with hydrogen, C 1-10 alkyl, aryl, heteroaryl, arylC 1-10 alkyl, heteroarylC 1-10 alkyl or C 3-10 cycloalkyl; 
 B represents hydrogen; C 1-10 alkyl; aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, nitro, C 1-4 alkyloxy, amino, C 1-10 alkylamino, di(C 1-10 alkyl)amino, C 1-10 acyl, C 1-10 alkylthio, C 1-10 alkoxycarbonyl, C 1-10 alkylaminocarbonyl and di(C 1-10 alkyl)aminocarbonyl; arylC 1-6 alkyl; heteroarylC 1-10 alkyl; C 3-10 cycloalkyl; polyhaloC 1-6 alkyl; C 3-6 alkenyl; C 3-6 alkynyl; NR 6 R 7 ; or OR 8 ; 
 R 6  and R 7  each independently represent hydrogen, C 1-10 alkyl, aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, C 1-4 alkyloxy, amino, C 1-10 alkylamino, di(C 1-10 alkyl)amino, C 1-10 acyl, C 1-10 alkylthio, C 1-10 alkylaminocarbonyl and di(C 1-10 alkyl)aminocarbonyl; arylC 1-10 alkyl, heteroarylC 1-10 alkyl, C 3-10 cycloalkyl, C 7-10 polycycloalkyl, polyhaloC 1-6 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, fused benzo-C 5-8 cycloalkyl, and wherein R 6  and R 7  taken together with the nitrogen atom to which they are attached may form a C 4-8  saturated heterocyclic radical; 
 R 8  represents C 1-10 alkyl, aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, nitro, C 1-4 alkyloxy, amino, C 1-10 alkylamino, di(C 1-10 alkyl)amino, C 1-10 acyl, C 1-10 alkylthio, C 1-10 alkylaminocarbonyl and di(C 1-10 alkyl)aminocarbonyl; arylC 1-10 alkyl; heteroarylC 1-10 alkyl; and C 3-10 cycloalkyl; C 7-10 polycycloalkyl; polyhaloC 1-6 alkyl; C 3-8 alkenyl; C 3-8 alkynyl; or fused benzo-C 5-8  cycloalkyl. 
 
       
     
     
         2 . Polyarylcarboxamide compounds according to  claim 1 , wherein Z 1 , Z 2 , X 2  and X 3  taken together form a six-membered heterocycle. 
     
     
         3 . Polyarylcarboxamide compounds according to  claim 1 , wherein Z 1 , Z 2 , X 2  and X 3  taken together form a piperidine or piperazine group and X 1  is a direct bond. 
     
     
         4 . Polyarylcarboxamide compounds according to  claim 1 , wherein R 2  and R 3  are each hydrogen and R 4  is hydrogen, trifluoromethyl, chloro or tert-butyl. 
     
     
         5 . A process for preparing a polyarylcarboxamide compound according to  claim 1 , wherein an intermediate phenylene amine having the formula (II) 
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , X 2 , X 3 , p 1 , R 1 , R 2 , A and B are as defined in formula (I), is reacted with a polyarylcarboxylic acid or halide having the formula (III), 
       
       
         
           
           
               
               
           
         
         wherein X 1 , Ar 1 , Ar 2 , p 1 , p 2 , R 3  and R 4  are as defined in formula (I) and Y 1  is selected from hydroxy and halo, in at least one reaction-inert solvent and optionally in the presence of a suitable base, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof. 
       
     
     
         6 . A process for preparing a polyarylcarboxamide compound according to  claim 1  wherein X 3  is nitrogen, wherein an intermediate having the formula (IV) 
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , X 1 , X 2 , p 1 , p 2 , p 3 , Ar 1 , Ar 2 , R 1 , R 2 , R 3  and R 4  are as defined in formula (I) and X 3  is nitrogen, is reacted with a reactant having the formula (V) 
       
       
         
           
           
               
               
           
         
         wherein A and B are as defined in formula (I) and Y 2  is selected from halo, tosyloxy, mesyloxy, naphtylsulfonyloxy, or -A-Y 2  is R 15 COR 5 , wherein R 5  and R′ 5  are such that the radical R 15 CHR 5  is encompassed by the definition of A in formula (I), in at least one reaction-inert solvent and optionally in the presence of at least one suitable nucleophilic substitution activator and/or a suitable base, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof. 
       
     
     
         7 . A process for preparing a polyarylcarboxamide compound according to  claim 1 , wherein an intermediate having the formula 
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , X 1 , X 2 , X 3 , p 1 , p 2 , p 3 , Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4  and A are as defined in formula (I) and Y 3  is selected from halo and hydroxy, is reacted with a reactant of the formula BH, wherein B is NR 6 R 7  or OR 8  and R 6 , R 7  and R 8  are as defined in formula (I), in at least one reaction-inert solvent and optionally in the presence of at least one suitable coupling reagent and/or a suitable base, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof. 
       
     
     
         8 . A process for preparing a polyarylcarboxamide compound according to  claim 1  wherein X 3  is nitrogen and wherein A is a group suitable for a Michael addition reaction, wherein an intermediate having the formula 
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , X 1 , X 2 , Ar 1 , Ar 2 , R 1 , R 2 , R 3  and R 4  are as defined in formula (I) and X 3  is nitrogen, is reacted with a reactant of the formula (VII) 
       
       
         
           
           
               
               
           
         
         wherein B is as defined in formula (I), and Y 4  and Y′ 4  are such that the radical 
       
       
         
           
           
               
               
           
         
         is encompassed by the definition of A in formula (I), in at least one reaction 
         inert solvent, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof. 
       
     
     
         9 . A process for preparing a polyarylcarboxamide compound according to  claim 1 , wherein an intermediate having the formula (VIII) 
       
         
           
           
               
               
           
         
         wherein X 1 , p 1 , p 2 , p 3 , Ar 1 , Ar 2 , R 1 , R 2 , R 3  and R 4  are as defined in formula (I) and Y 5  is selected from halo, B(OH) 2 , alkylboronates and cyclic analogues thereof, is reacted with a reactant having the formula (IX) 
       
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , X 3 , A and B are as defined in formula (I), in at least one reaction-inert solvent and optionally in the presence of at least one transition metal coupling reagent and/or at least one suitable ligand, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof. 
       
     
     
         10 . A process for preparing a polyarylcarboxamide compound according to  claim 1 , wherein an intermediate having the formula (X) 
       
         
           
           
               
               
           
         
         wherein p 1 , p 2 , p 3 , Ar 1 , Ar 2 , X 1 , R 1 , R 2 , R 3  and R 4  are as defined in formula (I), is reacted with a reactant having the formula (XI) 
       
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , X 3 , A and B are as defined in formula (I), one of Y 6  and Y 7  is selected from bromo, iodo and trifluoromethylsulfonate and the other of Y 6  and Y 7  is selected from tri(C 1-4 alkyl) tin, B(OH) 2 , alkylboronates and cyclic analogues thereof, in at least one reaction-inert solvent and optionally in the presence of at least one transition metal coupling reagent and/or at least one suitable ligand, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof 
       
     
     
         11 . A process for preparing a polyarylcarboxamide compound according to  claim 1 , wherein an intermediate having the formula (XII) 
       
         
           
           
               
               
           
         
         wherein Z 1 , Z 2 , X 2 , X 3 , P, p 2 , Ar 1 , R 1 , R 2 , R 3 , A and B are as defined in formula (I) and Y 8  is selected from bromo, iodo and trifluoromethylsulfonate, is reacted either with an arylboric acid having the formula (XIII a) 
       
       
         
           
           
               
               
           
         
         wherein p 3 , Ar 2  and R 4  are as defined in formula (I), or with an aryl-tin reactant having the formula (XIII b) 
       
       
         
           
           
               
               
           
         
         wherein R 3 , R 4 , Ar 2  and p 3  are as defined in formula (I), in at least one reaction-inert solvent and optionally in the presence of at least one transition metal coupling reagent and/or at least one suitable ligand, the said process further optionally comprising converting a compound of formula (I) into an addition salt thereof, and/or preparing or stereochemically isomeric forms thereof. 
       
     
     
         12 . A process for preparing a polyarylcarboxamide compound according to  claim 1 , wherein B is NR 6 R 7 , from a polyarylcarboxamide compound according to  claim 1  wherein B is OR 5 , comprising in a first step hydrolyzing the latter and in a second step reacting the resulting corresponding carboxylic acid with an amine having the formula HNR 6 R 7  in at least one reaction-inert solvent and further optionally comprising converting the resulting compound of formula (I) wherein B is NR 6 R 7  into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof. 
     
     
         13 . Compounds of any of the formulae: 
       
         
           
           
               
               
           
         
         Z 1  is selected from (CH 2 ) n  wherein n is 1 to 3, CH 2 CH 2 O and OCH 2 Ch 2 ; 
         Z 2  is (CH 2 ) m  wherein m is 1 or 2; 
         X 1  represents O, CH 2 , CO, NH, CH 2 O, OCH 2 , CH 2 S, SCH 2  or a direct bond; 
         X 2  and X 3  are each independently selected from CH, N and a sp2 carbon atom; 
         R 1  is hydrogen or C 1-4  alkyl; 
         Ar 1  is an aromatic ring selected from phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted with one or two R 3  substituents; 
         Ar 2  is an aromatic ring selected from phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted with one, two or three R 4  substituents; 
         each R 2  and R 3  is independently selected from C 1-4  alkyl, C 1-4  alkyloxy, halo and trifluoromethyl; 
         each R 4  is independently selected from C 1-4  alkyl, C 1-4  alkyloxy, halo, hydroxy, mercapto, cyano, nitro, C 1-4  alkylthio or polyhaloC 1-6 alkyl, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; 
         p 1  and p 2  are each 0 to 2; 
         p 3  is 0 to 3; 
         X 1  and R 4  taken together with the aromatic rings Ar 1  and Ar 2  to which they are attached may form a fluoren-1-yl or a fluoren-4-yl group; 
         A represents a C 1-6  alkanediyl optionally substituted with one or two groups selected from aryl, heteroaryl and C 3-10  cycloalkyl; oxygen; or a direct bond; 
         B represents hydrogen; C 1-10 alkyl; aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, nitro, C 1-4 alkyloxy, amino, C 1-10  alkylamino, di(C 1-10 alkyl)amino, C 1-10 acyl, C 1-10 alkylthio, C 1-10 alkoxycarbonyl, C 1-10 alkylaminocarbonyl and di(C 1-10 alkyl)aminocarbonyl; arylC 1-10 alkyl; heteroarylC 1-10 alkyl; C 3-10 cycloalkyl; polyhaloC 1-6 alkyl; C 3-6  alkenyl; C 3-6 alkynyl; NR 6 R 7 ; or OR 8 ; 
         R 6  and R 7  each independently represent hydrogen, C 1-10 alkyl, aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, C 1-4 alkyloxy, amino, C 1-10 alkylamino, di(C 1-10 alkyl)amino, C 1-10 acyl, C 1-10 alkylthio, C 1-10 alkylaminocarbonyl and di(C 1-10 alkyl)aminocarbonyl; arylC 1-10 alkyl, heteroarylC 1-10 alkyl, C 3-10 cycloalkyl, C 7-10 polycycloalkyl, polyhaloC 1-6 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, fused benzo-C 5-8 cycloalkyl, and wherein R 6  and R 7  taken together with the nitrogen atom to which they are attached may form a C 4-8  saturated heterocyclic radical; 
         R 8  represents C 1-10 alkyl, aryl or heteroaryl each optionally substituted with a group selected from halo, cyano, nitro, C 1-4 alkyloxy, amino, C 1-10 alkylamino, di(C 1-10 alkyl)amino, C 1-10 acyl, C 1-10 alkylthio, C 1-10 alkylaminocarbonyl and di(C 1-10 alkyl)aminocarbonyl; arylC 1-10 alkyl; heteroarylC 1-10 alkyl; C 3-10 cycloalkyl; C 7-10  polycycloalkyl; polyhaloC 1-6 alkyl; C 3-8 alkenyl; C 3-8 alkynyl; or fused benzo-C 5-8  cycloalkyl; 
         when X 3  is CH, A may also represent a nitrogen atom substituted with hydrogen, C 1-10 alkyl, aryl, heteroaryl, arylC 1-10 alkyl, heteroarylC 1-10 alkyl or C 3-10 cycloalkyl; 
         Y 1  and Y 3  are each independently selected from hydroxy and halo; 
         Y 5  is selected from halo, B(OH) 2 , alkylboronates and cyclic analogues thereof; and 
         Y 6  and Y 8  are each independently selected from bromo, iodo and trifluoromethylsulfonate, 
         useful as intermediates for the preparation of polyarylcarboxamide compounds according to  claim 1 . 
       
     
     
         14 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         15 . (canceled) 
     
     
         16 . A polyarylcarboxamide compound according to  claim 13  for use in the treatment of hyperlipidemia, obesity, type II diabetes, atherosclerosis, ischemic heart disease, peripheral vascular disease, cerebral vascular disease, hypercholesterolemia, hypertriglyceridemia, pancreatitis or coronary artery disease. 
     
     
         17 . A pharmaceutical composition according to  claim 14 , further comprising at least one additional lipid-lowering agent. 
     
     
         18 . A method of treating a condition selected from hyperlipidemia, obesity, type II diabetes, atherosclerosis, ischemic heart disease, peripheral vascular disease, cerebral vascular disease, hypercholesterolemia, hypertriglyceridemia, pancreatitis or coronary artery disease, comprising administering to a mammal in need of such treatment a polyarylcarboxamide compound according to  claim 1  in an amount sufficient to decrease the secretion of apolipoprotein B.