New aryl heteroaromatic compounds useful as tubulin polymerization inhibitors and tumor cell proliferation inhibitors

摘要

Aryl heteroaromatic compounds (I) are new. Aryl heteroaromatic compounds of formula (I) and their isomers, prodrugs and salts are new. [Image] A : N or C; L1>-G1>-R1>a piperazine residue of formula (i) or a 1,2,5,6-tetrahydropyridine residue of formula (ii); X, Y1>CR3>, N, NR3>, O or S; E1>CR4>, N, NR4> or S; R1>, R2>optionally substituted aryl or heteroaryl; L1>CO, CS or C=NR7>; R3>, R4>H, alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, OR7>, SR7>, SOR7>, SO2R7>, NR7>R8>, halo, aryl, heteroaryl, substituted cycloalkyl, substituted aryl or substituted heteroaryl; R5>, R6>H or 1-3C alkyl; and R7>, R8>H or optionally substituted 1-3C alkyl. Provided that (I) are not 1-phenyl-4-R2-3-(4-R1-1-piperazinecarbonyl)-1H-pyrazoles in which R1/R2 is 2-chlorophenyl/2-thienyl, 2-methoxyphenyl/2-thienyl, 2-methoxyphenyl/3,4-dimethoxyphenyl, 2-methoxyphenyl/3-pyridyl, 3-trifluoromethylphenyl/4-methoxyphenyl, 2-methoxyphenyl/4-chlorophenyl, phenyl/2-thienyl, phenyl/phenyl, 2-methoxyphenyl/4-fluorophenyl or phenyl/4-chlorophenyl, and (I) are not 1-(3-mesyl-2-naphthyl)-3-methyl-5-(4-(4-pyridyl)-1-piperazinecarbonyl)-1H-pyrazole, 1-phenyl-5-(4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1-piperazinecarbonyl)-1H-pyrazole, 3-(4-fluorophenyl)-4-(4-phenyl-1-piperazinecarbonyl)-isoxazole or 3-phenyl-4-(4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1-piperazinecarbonyl)-1,2,5-oxadiazole or its N-oxide or N,N-dioxide. [Image] ACTIVITY : Cytostatic; Antiarteriosclerotic. MECHANISM OF ACTION : Tubulin polymerization inhibitor; Tumor cell proliferation inhibitor. (4-(3-Chlorophenyl)-1-piperazinyl)-(1-phenyl-1H-imidazol-2-yl)-methanone had an IC50 of 2 mu M against tubulin polymerization and 0.0296 mu M against HCT116 cell proliferation.