Pyridinone derivatives for treatment of atherosclerosis

Abstract

Compounds of formula (I): are inhibitors of the enzyme L p -PLA 2 and are of use in therapy, in particular for treating atherosclerosis.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  is an aryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C (1-6) alkyl, C (1-6) alkoxy, C (1-6) alkylthio, hydroxy, halogen, CN, mono to perfluoro-C (1-4) alkyl, mono to perfluoro-C (1-4) alkoxyaryl, and arylC (1-4) alkyl;  
 R 2  is halogen, C (1-3) alkyl, C (1-3) alkoxy, hydroxyC (1-3) alkyl, C (1-3) alkylthio, C (1-3) alkylsulphinyl, aminoC (1-3) alkyl, mono- or di-C (1-3) alkylaminoC (1-3) allyl, C (1-3) alkylcarbonylaminoC (1-3) alkyl, C (1-3) alkoxyC (1-3) alkylcarbonylaminoC (1-3) alkyl, C (1-3) alkylsulphonylaminoC (1-3) alkyl, C (1-3) alkylcarboxy, C (1-3) alkylcarboxyC (1-3) alkyl, and  
 R 3  is hydrogen, halogen, C (1-3) alkyl, or hydroxyC (1-3) alkyl; or  
 R 2  and R 3  together with the pyridone ring carbon atoms to which they are attached form a fused 5-or 6-membered carbocyclic ring; or  
 R 2  and R 3  together with the pyridone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, C (1-4) alkyl, cyano, C (1-3) alkoxyC (1-3) alkyl, C (1-4) alkoxy or C (1-4) alkylthio, or mono to perfluoro-C (1-4) alkyl;  
 R 4  is hydrogen, C (1-6) alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR 7 , COR 7 , carboxy, COOR 7 , CONR 9 R 10 , NR 9 R 10 , NR 7 COR 8 , mono- or di-(hydroxyC (1-6) allyl)amino and N-hydroxyC (1-6) alkyl-N—C (1-6) alkylamino; or  
 R 4  is Het-C (0-4) alkyl in which Het is a 5- to 7-membered heterocyclyl ring comprising N and optionally O or S, and in which N may be substituted by COR 7 , COOR 7 , CONR 9 R 10 , or C (1-6) alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR 7 , COR 7 , carboxy, COOR 7 , CONR 9 R 10  or NR 9 R 10 , for instance, piperidin4-yl, pyrrolidin-3-yl;  
 R 5  is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C (1-6) alkyl, C (1-6) alkoxy, C (1-6) alkylthio, arylC (1-6) alkoxy, hydroxy, halogen, CN, COR 7 , carboxy, COOR 7 , NR 7 COR 8 , CONR 9 R 10 , SO 2 NR 9 R 10 , NR 7 SO 2 R 8 , NR 9 R 10 , mono to perfluoro-C (1-4) alkyl and mono to perfluoro-C (1-4) alkoxy;  
 R 6  is an aryl or a heteroaryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C (1-6) alkyl, C (1-6) alkoxy, C (1-6) alkylthio, C (1-6) alkylsulfonyl, arylC (1-6) alkoxy, hydroxy, halogen, CN, COR 7 , carboxy, COOR 7 , CONR 9 R 10 , NR 7 COR 8 , SO 2 NR 9 R 10 , NR 7 SO 2 R 8 , NR 9 R 10 , mono to perfluoro-C 1-4) alkyl and mono to perfluoro-C (1-4) alkoxy, or C (5-10) alkyl;  
 R 7  and R 8  are independently hydrogen or C (1-12) alkyl, for instance C (1-4) alkyl (e.g. methyl or ethyl);  
 R 9  and R 10  which may be the same or different is each selected from hydrogen, or C (1-12) alkyl, or R 9  and R 10  together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C (1-4) alkyl, C (1-4) alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine; and  
 X is a C (2-4) alkylene group (optionally substituted by 1, 2 or 3 substituents selected from methyl and ethyl), CH═CH, (CH 2 ) n S or (CH 2 ) n O where n is 1, 2 or 3.  
 
     
     
         2 . A compound of formula (I) as claimed in  claim 1  in which R 1  is phenyl optionally substituted by halogen, C (1-6) alkyl, trifluoromethyl, C (1-6) alkoxy.  
     
     
         3 . A compound of formula (I) as claimed in  claim 1  or  2  in which R 2  and R 3  together with the pyridone ring carbon atoms to which they are attached form a fused thiazolyl ring substituted by methyl, or a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fused benzo, pyrido, thieno or pyrazolo ring.  
     
     
         4 . A compound of formula (I) as claimed in any of  claims 1  to  3  in which R 4  is selected from the group consisting of 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperdin-4-yl or 1-ethylpyrrolidin-3-yl.  
     
     
         5 . A compound of formula (I) as claimed in any of  claims 1  to  4  in which R 5  is phenyl.  
     
     
         6 . A compound of formula (I) as claimed in any of  claims 1  to  5  in which R 6  is phenyl substituted by trifluoromethyl or ethyl in the 4-position.  
     
     
         7 . A compound of formula (I) as claimed in any of  claims 1  to  6  in which R 5  and R 6  together form a 4-(phenyl)phenyl or a 2-(phenyl)pyridinyl substituent in which the remote phenyl ring may be optionally substituted by halogen or trifluoromethyl, preferably at the 4-position.  
     
     
         8 . A compound of formula (I) as claimed in any of  claims 1  to  7  in which X is C (2-4) alkylene or CH 2 S.  
     
     
         9 . A compound of formula (I) as claimed in any of  claims 1  to  8  in which R 1  is phenyl substituted by 2,3-difluoro; R 2  and R 3 , together with the pyridone ring carbon atoms to which they are attached, form a fused 5-membered carbocyclic (cyclopentenyl) ring, or a fused benzo or pyrido ring; R 4  is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl; R 5  is phenyl; R 6  is phenyl substituted by ethyl or trifluoromethyl in the 4-position; and X is CH 2 S.  
     
     
         10 . A compound of formula (I) as claimed in any of  claims 1  to  9  in which R 1  is phenyl substituted by 2,3-difluoro; R 2  and R 3 , together with the pyridone ring carbon atoms to which they are attached, form a fused thiazolyl ring substituted by methyl, or a benzo or pyrido ring; R 4  is 2-(diethylamino)ethyl, 1-ethyl-piperidin-4-yl, 1-(2-methoxyethyl)piperidin-4-yl, 1-methylpiperidin-4-yl or 1-ethylpyrrolidin-3-yl; R 5  is phenyl; R 6  is phenyl substituted by trifluoromethyl in the 4-position; and X is (CH 2 ) 2 .  
     
     
         11 . A compound of formula (I) as claimed in any of  claims 1  to  10  in which R 1  is phenyl substituted by 2,3-difluoro; R 2  and R 3 , together with the pyridone ring carbon atoms to which they are attached, form a fused benzo or pyrido ring; R 4  is 1-(2-methoxyethyl)piperidin-4-yl; R 5  and R 6  together form a 4-(phenyl)phenyl substituent in which the remote phenyl ring is substituted by trifluoromethyl, preferably at the 4-position; and X is CH 2 S or (CH2) 2 .  
     
     
         12 . A compound of formula (I) as claimed in  claim 1  and as named in any one of Examples 1 to 115.  
     
     
         13 . A compound of formula (I) as defined in  claim 1  selected from the group consisting of 
 N-(1-(2-methoxyethyl)piperidin-4-yl)-2-[2-(2,3-difluorobenzylthio)-4-oxo-4H-quinolin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;  
 N-(1-(2-methoxyethyl)piperidin-yl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4H-[1,8]naphthyridin-1-yl]-N-(4′-trifluoromethylbiphenyl-4-ylmethyl)acetamide;  
 or a pharmaceutically acceptable salt thereof, in particular the bitartrate, hydrochloride, dihydrochloride or paratoluenesulfonate salt.  
 
     
     
         14 . A pharmaceutical composition comprising a compound of formula (I) as claimed in  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         15 . A compound of formula (I) as claimed in  claim 1  for use in therapy.  
     
     
         16 . The use of a compound of formula (I) as claimed in  claim 1  for the manufacture of a medicament for treating atherosclerosis.  
     
     
         17 . A method of treating a disease state associated with activity of the enzyme Lp-PLA 2  which method involves treating a patient in need thereof with a therapeutically effective amount of a compound of formula (1) as claimed in  claim 1 .  
     
     
         18 . A process for preparing a compound of formula (I) as defined in  claim 1  which process comprises reacting an acid compound of formula (II):  
       
         
           
           
               
               
           
         
       
       in which X, R 1 , R 2  and R 3  are as hereinbefore defined, with an amine compound of formula (III):  
       R 6 —R 5 —CH 2 NHR 4    (III)  
       in which R 4 , R 5  and R 6  are as hereinbefore defined; under amide forming conditions.