6-CYCLOAMINO-S-(PYRIDAZIN-4-YL)IMIDAZO[1,2-B]-PYRIDAZINE AND DERIVATIVES THEREOF PREPARATION AND THERAPEUTIC APPLICATION THEREOF

摘要

6-Cycloamino-3-(pyridazin-4-yl)imidazo[1,2-b]-pyridazine compounds (I) and their base and acid addition salts are new. 6-Cycloamino-3-(pyridazin-4-yl)imidazo[1,2-b]-pyridazine compounds of formula (I) and their base and acid addition salts are new. R 2aryl (optionally substituted by one or more halo, 1-6C alkyl, 1-6C alkyloxy, 1-6C alkylthio, 1-6C fluoroalkyl, 1-6C fluoroalkyloxy or CN); A : 1-7C alkylene (optionally substituted by 1 or 2 R1a); B 11-7C alkylene (optionally substituted by R1a), where C of A, B 1is optionally substituted by one or more R1f; L : N (optionally substituted by R1c or R1d) or C (substituted by R1e, R1d, or 2 R2e); R1aR1a : 1-6C alkylene; R1aR1b, R1aR1c, R1bR1c : bond or 1-6C alkylene; R1d : H, 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, hydroxy-1-6C alkyl, 1-6C alkyloxy-1-6C alkyl, 1-6C alkylthio-1-6C alkyl, 1-6C fluoroalkyl or benzyl; R1e : -NR 4R 5or cyclic monoamine group (optionally including O, and substituted by one or more F or 1-6C alkyl, 1-6C alkyloxy or OH); C+R2eR2e : cyclic monoamine group (optionally including O, and substituted by one or more R1f); R1f : 1-6C alkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, 1-6C alkyloxy-1-6C alkyl, hydroxy-1-6C alkyl, 1-6C fluoroalkyl or benzyl; R 4, R 5H, 1-6C alkyl, 3-7C cycloalkyl or 3-7C cycloalkyl-1-6C-alkyl; and R 7, R 8H or 1-6C alkyl. Independent claims are included for the preparations of (I). [Image] ACTIVITY : Hypnotic; Antiaddictive; Cytostatic; CNS-Gen; Neuroprotective; Antidepressant; Neuroleptic; Tranquilizer; Nootropic; Antismoking. MECHANISM OF ACTION : Casein kinase 1 epsilon inhibitor; Casein kinase 1 delta inhibitor. The ability of (I) to inhibit casein kinase 1 delta was tested in human using fluorescence resonance energy transfer assay. The result showed that IC 5 0value of 2-(4-fluoro-phenyl)-6-(piperazin-1-yl)-3-(pyridazin-4-yl)-imidazo[1,2-b]pyridazine was 1 nM.