Pyrimidinone derivatives and their use in the treatment of atherosclerosis

摘要

Compound of formula (I): are disclosed in which: R¹ 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, and mono to perfluoro-C_(1-4)alkyl; R² 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)alkyl, 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 R³ is hydrogen, halogen, C_(1-3)alkyl, or hydroxyC_(1-3)alkcyl; or R² and R³ together with the pyrimidone ring carbon atoms to which they are attached form a fused 5-or 6-membered carbocyclic ring; or R² and R³ together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring 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_(1-6)alkoxy, C_(1-6)alkylthio or mono to perfluoro-C_(1-4)alkyl; R⁴ is hydrogen, C_(1-6)alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁹R¹⁰, NR⁷COR⁸, mono- or di-(hydroxyC_(1-6)alkyl) amino and N-hydroxyC_(1-6)alkyl-N-C_(1-6)allkylamino; or R⁴ 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 COR⁷, COOR⁷, CONR⁹R¹⁰, or C_(1-6)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰ or NR⁹R¹⁰, for instance, piperidinyl-4-yl, pyrrolidin-3-yl; R⁵ is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selectd from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, arylC_(1-6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, NR⁷COR⁸, CONR⁹R¹⁰, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_(1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy; R⁶ 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_(1-18)alkyl, C_(1-18)alkoxy, C_(1-6)alkylthio, C_(1-6)alkylsulfonyl, arylC_(1-6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁷COR⁸, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_(1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy, or C_(5-10)alkyl; These compound are useful for treating diseases associated with abnormal activity of the phospholipase A₂ enzyme, for example athereosclosis.