Substituted pyridines as HMG-COA reductase inhibitors

摘要

Pyridine compounds (I) are claimed for therapeutic application. Substituted pyridine compounds of formula (I) and their oxidation products are claimed for therapeutic application. [Image] A : heteroaryl or aryl (both optionally substituted (os)); or alkyl; B' : cycloalkyl, or alkyl (os); D, E : H, CN, NO 2 or cycloalkyl; alkyl, heteroaryl or aryl (all os); or NR 3R 4, COR 5 or -CR 1 1R 1 2-Y, or D + E : -C(O)-Z-(CH 2) m- or -W-Z-CR 13R 14-(CH 2) m- (bonded to adjacent C to complete a fused ring); R 3, R 4H, Q, Ar, Ara, COR 6 or SO 2R 7; or R 3 + R 4alkylidene; Q : alkyl; Ar : aryl; Ara : aralkyl; R 6H, NHR 8 or OQ; or Q, Ar, OAr, Ara, OAra or heteroaryl (all os); R 7cycloalkyl; or Q, Ar, Ara or heteroaryl (all os); R 8H or as R 7; R 5H, cycloalkyl, OH, OQ, trimethylsilylalkoxy, OAr, OAra or NR 9R 10; or pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino (all os); R 11, R 12H, Q (os) or cycloalkyl, or CR 11R 12a ring; Y : NR 13R 14, COR 15, SR 16, SOR 16, SO 2R 16, OR 17 or N 3; R 13, R 14H, Q, COR 15 or SO 2R 16; or Ar or Ara (both os); or R 13 + R 14alkylene; R 15H, NR 18R 19, Q or OQ; or Ar, OAr, Ara, OAra or heteroaryl (all os); R 16cycloalkyl; Q (os); Ar, Ara or heteroaryl (all os); or SiMe 3, SiMe 2Et or NR 9R 10; R 17H or cycloalkyl; alkyl, aryl or heteroaryl (all os); or 2,5-dioxo-tetrahydropyrryl, tetrahydropyranyl, SiQ 3 or COR 16; R 18, R 19H or cycloalkyl; or Q, Ar, Ara or heteroaryl (all os); W : CO or CH(OH); m : 1-3; Z : O, S, CH 2 or NR 20; R 20H, Q, Ar, CONH 2 or COOQ; X : CH 2CH 2 or CH=CH; R : optionally lactonized 4-carboxy-1,3-dihydroxybutyl derivative group of formula (a) or (b); R 21H or Q, and R 22H, Q, Ar, Ara or cation. [Image] The full definitions are given in the 'DEFINITIONS - Full Definitions' field. An independent claim is included for a medicament containing (I), specifically at 0.5-98 wt. %. ACTIVITY : Antilipemic; antiarteriosclerotic. In tests in dogs, oral administration of methyl erythro-(E)-7-(3-benzoyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-5-yl)-3,5-dihydroxy-hept-6-enoate (Ia) at 8 mg/kg per day for 2 weeks reduced the serum cholesterol level by 66%. MECHANISM OF ACTION : Cholesterol biosynthesis inhibitor; 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methyl erythro-(E)-7-(3-benzoyloxymethyl-2,6-diisopropyl-4-(4-fluorophenyl)-pyrid-5-yl)-3,5-dihydroxy-hept-6-enoate (Ia) exhibited 20 times stronger HMG-CoA inhibiting activity than mevinolin in tests in vitro.