Synthesis of Di‐(N‐tropinonyl)alkanes and Di‐(N‐tropinonyl)benzenes.

Jung, Dai‐Il; Song, Jeong Sup; Kim, Yong-Hwan; Lee, Do‐Hun; Song, Hyun-Ae; Lee, Yong‐Gyun; Park, Yu‐Mi; Choi, Seok Reyol; Hahn, Jung‐Tai; Cho, Seong‐Jin

doi:10.1002/chin.200523149

Cited by 2 publications

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“…The homologue 60e and the tropine–morpholine hybrid 60f were prepared from ketones 62e and 62f , respectively. Compounds 62e and 62f were obtained by a one pot Robinson synthesis from 61 using glutaraldehyde and 2-(2,2-diethoxyethoxy)-1,1-diethoxyethane, respectively. Reduction of the ketones with NaBH 4 gave alcohols 63e and 63f , which were subsequently borylated to provide 60e and 60f .…”

Section: Results and Discussionmentioning

confidence: 99%

The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents

et al. 2015

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The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 μM), displayed low off-target activity (>500×), and microsomal stability (T(1/2) > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.

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Section: Results and Discussionmentioning

confidence: 99%

The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents

et al. 2015

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“…In order to synthesize biologically active com-pounds, when the reaction of amines (aniline, m-toluidine, 3chloroaniline, 4-chloroaniline), 2,5-dimethoxytetra-hydrofuran, 1,3-acetone dicarboxylic acid and silylaryl triflate 2 (Tables 2 and 3), good yields of the N-arylated products are still obtained (Schemes II and III). Substantially we reported 20,21 the synthesis of N-substituted pyrroles and nortropinones in the reaction of amines with 2,5dimethoxytetrahydrofuran and 1,3-acetone dicarboxylic acid. When the reaction of aniline, 2,5-dimethoxytetrahydrofuran and silylaryltriflate 2 with CsF in MeCN executed, good yield of diphenylamine as a N-arylated product is still obtained.…”

Section: Resultsmentioning

confidence: 99%