4-(Aminoalkylamino)-3-benzimidazole-quinolinones as potent CHK-1 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 12, 2006, Pages 3121-3124

  Ni, Zhi Jie ^a   Barsanti, Paul ^a   Brammeier, Nathan ^a   Diebes, Anthony ^a   Poon, Daniel J ^a   Ng, Simon ^a   Pecchi, Sabina ^a   Pfister, Keith ^a   Renhowe, Paul A ^a   Ramurthy, Savithri ^a   Wagman, Allan S ^a   Bussiere, Dirksen E ^a   Le, Vincent ^a   Zhou, Yasheen ^a   Jansen, Johanna M ^a   Ma, Sylvia ^a   Gesner, Thomas G ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

CHK 1 kinase inhibitor; Kinase; Synergy

Indexed keywords

ANTINEOPLASTIC AGENT; BENZIMIDAZOLE DERIVATIVE; CAMPTOTHECIN; CHECKPOINT KINASE 1; CHECKPOINT KINASE 1 INHIBITOR; ENZYME INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CELL MEMBRANE PERMEABILITY; CONTROLLED STUDY; DRUG POTENCY; DRUG POTENTIATION; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL;

ALKYLATION; AMINATION; BENZIMIDAZOLES; CELL LINE, TUMOR; CRYSTALLOGRAPHY, X-RAY; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; QUINOLONES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33646198996     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.03.059     Document Type: Article

References (28)

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22. General procedure for the preparation of 4-[((3S)-quinuclidin-3-yl)amino]-3-benzimidazol-2-yl-6-chloro-hydroquinolin-2- one (11): 3-(1H-benzimidazole-2yl)-4-hydroxyl-1-(4-methoxybenzyl)-6-chloro-1H- quinolinone (1 equiv) was suspended in dichloromethane (DCM) in the presence of pyridine (20 equiv). The mixture was warmed to dissolve the solid. The mixture was cooled to -5 °C and triflic anhydride (8 equiv) in DCM was added dropwise. After the reaction was stirred at -5 °C for 4 h, saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with 1 M citric acid, 1 M sodium bicarbonate, water, and brine, dried over sodium sulfate, and concentrated to give 1-[(4-methoxyphenyl)methyl]-2-oxo-3-{1-[(trifluoromethyl)-sulfonyl]benzimidazol-2-yl}-6-chloro-4-hydroquinolyl(trifluoromethyl)sulfonate, which was used for the next reaction without further purification. A solution of the bis-triflate prepared above, (S)-3-aminoquinuclidine (1.2 equiv), and Hünig's base (4 equiv) in acetonitrile was heated at 80 °C for 20 h. After cooling down to room temperature, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, and concentrated to give a solid. The solid was dissolved in a mixture of trifluoroacetic acid and concentrated HCl (7:1), and heated at 90 °C for 20 h. The reaction was diluted with water and ethyl acetate, and slowly basified to pH 9 with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, and dried over sodium sulfate, and concentrated. The product was purified with preparative HPLC to give the desired product 11.
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27. 490 (DMSO-treated cells)} × 100%. Synergy was defined as the effect observed by the combination of the two compounds being greater than the sum of the effect of each compound alone.
28. Detailed isobologram analysis of the synergistic effect will be published elsewhere (see Ref. 21).