Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. II. Optimization of the phenylpiperazine moiety of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes.
A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.
Naito
Hiroyuki
H
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. naitoxns@daiichipharm.co.jp
Ohsuki
Satoru
S
Sugimori
Masamichi
M
Atsumi
Ryo
R
Minami
Megumi
M
Nakamura
Yoshihide
Y
Ishii
Mineko
M
Hirotani
Kenji
K
Kumazawa
Eiji
E
Ejima
Akio
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005354:Fibrosarcoma / Q000188:drug therapy; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy; D014407:Tumor Cells, Cultured
C467587:3-(4-(3,5-dichlorophenyl)-1-piperazinyl)-1-(5-methyl-1-(2-pyrimidinyl)-4-1H-pyrazolyl)-1-trans-propen; C467588:3-(4-(3,5-difluorophenyl)-1-piperazinyl)-1-(5-methyl-1-(2-pyrimidinyl)-4-1H-pyrazolyl)-1-trans-propen hydrochloride; D000970:Antineoplastic Agents; C408507:DZ 3358; D011720:Pyrazoles; D011743:Pyrimidines