title: 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.
abstract: 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.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. naitoxns@daiichipharm.co.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.forename: Satoru
authors.initials: S
authors.lastname: Ohsuki
authors.forename: Masamichi
authors.initials: M
authors.lastname: Sugimori
authors.forename: Ryo
authors.initials: R
authors.lastname: Atsumi
authors.forename: Megumi
authors.initials: M
authors.lastname: Minami
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Mineko
authors.initials: M
authors.lastname: Ishii
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirotani
authors.forename: Eiji
authors.initials: E
authors.lastname: Kumazawa
authors.forename: Akio
authors.initials: A
authors.lastname: Ejima
mesh_terms: 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
chemical_list: 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