New 1-(cyclic amino-alkyl)-pyrimidin-2(1H)-one derivatives, are selective dopamine D3 receptor ligands useful for treating CNS disorders, especially schizophrenia or depression

摘要

1-(Aryl-substituted cyclic amino-alkyl)-pyrimidin-2(1H)-one derivatives (I) are new. Pyrimidinone derivatives of formula (I) (including derivatives and tautomers of formulae (I') and (I'')) and their acid addition salts are new. [Image] A : optionally branched 3-6C alkylene, optionally containing a double or triple bond and/or a group Z, provided that Z is not bonded directly to the pyrimidinone ring; B : a group of formula (i); Z : O, S, CO, NR 3>, CONR 3>, NR 3>CO, OCO or COO; X : CH 2or N; Y : CH-2 or CH 2CH 2; or X-Y : C=CH, C=CH-CH 2or CH-CH=CH; R 1>, R 2>H, CN, NO 2, halo, OR 3>, NR 4>R 5>, CONR 4>R 5>, OCONR 4>R 5>, SR 6>, SOR 6>, SO 2R 6>, SO 2NR 4>R 5>, COOR 7>, OCOR 8>, COR 8>, alkyl, haloalkyl, alkenyl, alkynyl, haloalkenyl, cycloalkyl; Het or phenyl (both optionally substituted (os) by 1 or 2 groups Q 1>); or alkyl or alkenyl, both substituted by a group Q 2>; Het : 5- or 6-membered heterocyclyl containing 1-3 heteroatoms selected from O, S and N; Q 1>T, OT, NR 4>R 5>, OH, 1-2C fluoroalkyl or halo; T : 1-4C alkyl; Q 2>OR 3>, NR 4>R 5>, CONR 4>R 5>, OCONR 4>R 5>, SR 6>, SOR 6>, SO 2R 6>, SO 2NR 4>R 5>, COOR 7>, OCOR 8>, COR 8>or cycloalkyl; or Het or phenyl (both os by 1 or 2 groups Q 2>); Ar : phenyl, pyridyl, pyrimidinyl or triazinyl (all os by 1-3 groups Q 3>); Q 3>alkyl (os by OH, OT, halo or phenyl), alkenyl or alkynyl; cycloalkyl, 4-10C bicycloalkyl or 6-10C tricycloalkyl (all os by halo or T); halo, CN, OR 3>, NR 4>R 5>, NO 2, SR 6>, SO 2R 6>, SO 2NR 4>R 5>, COOR 7>or COR 8>; or Het or phenyl (both os by 1 or 2 groups Q 2>); or two adjacent groups Q 3>together : 3-4C alkylene, a group completing a fused 5- or 6-membered carbocycle or a group completing a fused 5- or 6-membered heterocycle containing 1 or 2 N; R 3>- R 8>H, alkyl (os by OH, OT or phenyl), 1-8C haloalkyl or phenyl; and R 5>may also be COR 9>; or NR 4>R 5>5- or 6-membered, saturated or unsaturated ring, optionally containing an additional O, S or NR 1>0>heteroatom; R 9>H, T or phenyl (os by 1 or 2 groups Q 1>); R 1>0>, R : H or T; Q : halo or OR 3>; unless specified otherwise alkyl moieties have 1-6C, alkenyl or alkynyl moieties 2-6C and cycloalkyl moieties 3-6C. [Image] ACTIVITY : Neuroleptic; antidepressant; antimanic; nootropic; tranquilizer; vasotropic; antiaddictive; antismoking; antialcoholic; antiparkinsonian; anticonvulsant; nephrotropic; antidiabetic. MECHANISM OF ACTION : Dopamine D 3receptor ligand. In receptor binding assays 1-(2-tert. butyl-6-(trifluoromethyl)-pyrimidin-4-yl)-4-(4-(4-hydroxy-5-methyl-2-oxo-pyrimidin-1(2H)-yl)-butyl)-piperazine hydrochloride (Ia) had K i1.30 nM for D 3receptors and a selectivity for D 3receptors relative to D(2L) receptors of 246.