- LHMDS mediated tandem acylation-cyclization of 2-aminobenzenecarbonitriles with 2-benzymidazol-2-yl acetates: A short and efficient route to the synthesis of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones
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We herein describe the discovery of a mild, one-pot tandem acylation-cyclization for the synthesis of 4-amino-3-benzimidazol-2- ylhydroquinolin-2-ones from 2-aminobenzenecarbonitriles and ethyl 2-benzimidazol-2-yl acetates.
- Antonios-McCrea, William R.,Frazier, Kelly A.,Jazan, Elisa M.,Machajewski, Timothy D.,McBride, Christopher M.,Pecchi, Sabina,Renhowe, Paul A.,Shafer, Cynthia M.,Taylor, Clarke
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Read Online
- Method for preparing dovitinib intermediate with microchannel reaction device
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The invention discloses a method for preparing a dovitinib intermediate with a microchannel reaction device. The method comprises the following steps: (1) dissolving hydrochloric acid in ethanol to form a mixed solution, and enabling the mixed solution an
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- Preparation method of dovitinib
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The invention relates to a drug preparation method, in particular to a preparation method of dovitinib. A final product 4-amino-5-fluoro-3-(5-(4-methylpiperazine-1-yl)-1H- benzo[d]imidazol-2-yl) quinolone-2-(1H)-one is prepared by reacting ethyl 2-(5)-(4-methylpiperazine-1-yl)-1H-benzo[d]imidazol-2-yl) acetate with 2-amino-6-fluorobenzonitrile. The method is simple, convenient, high in safety and particularly suable for industrial production, the product yield and purity are high, and reaction conditions are mild.
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Paragraph 0028; 0029; 0030; 0031
(2016/11/17)
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- Design, structure-activity relationships and in vivo characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: Novel class of receptor tyrosine kinase inhibitors
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The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino- 3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP- competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRβ with IC50 values 0.1 μM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
- Renhowe, Paul A.,Pecchi, Sabina,Shafer, Cynthia M.,Machajewski, Timothy D.,Jazan, Elisa M.,Taylor, Clarke,Antonios-McCrea, William,McBride, Christopher M.,Frazier, Kelly,Wiesmann, Marion,Lapointe, Gena R.,Feucht, Paul H.,Warne, Robert L.,Heise, Carla C.,Menezes, Daniel,Aardalen, Kimberly,Ye, Helen,He, Molly,Le, Vincent,Vora, Jayesh,Jansen, Johanna M.,Wernette-Hammond, Mary Ellen,Harris, Alex L.
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experimental part
p. 278 - 292
(2009/10/17)
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- TREATMENT OF MELANOMA
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Methods of treating melanoma include administering a compound of Structure (I), a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt or the tautomer, or a mixture thereof to a subject. The comp
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- Formulation of Quinolinones
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A pharmaceutical formulation, comprising: a compound of formula (I), a tautomer of the compound, a salt of the compound, a salt of the tautomer, or a mixture thereof and at least one ingredient selected from the group consisting of (i) cellulose; (ii) sil
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- METHODS FOR TREATING DRUG RESISTANT CANCER
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A method for treating drug-resistant cancer, includes: administering to a patient in need thereof, a compound of formula I, a tautomer of the compound, a salt of the compound, a salt of the tautomer, a mixture thereof, or a pharmaceutical composition comp
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Page/Page column 66
(2008/06/13)
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- The chemical development of CHIR-258
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This paper is a case history of the early stage chemical development of CHIR-258 (4-amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]- 2(1H)-quinolinone, DL-lactate salt), a vascular endothelial growth factor (VEGF) kinase inhibitor for t
- Zhu, Shuguang,Harwood, Eric,Cai, Shaopei,Shang, Xiao,Galvin, Gabriel,Jin, Li,Yeung, Arthur,Diaz, Brian,Zheng, Minna,Ryckman, David
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p. 584 - 592
(2007/10/03)
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- TREATMENT OF METASTASIZED TUMORS
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Methods of treating metastatic cancer such as metastasized tumors include administering a compound of Structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable salt or the tautomer, or a mix
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Page/Page column 44-45; 46
(2008/06/13)
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- METHODS FOR SYNTHESIZING HETEROCYCLIC COMPOUNDS
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A method for synthesizing a heterocyclic compound includes: reacting 1-methylpiperazine with 5-chloro-2-nitroaniline at an internal temperature sufficient to provide a compound of Formula VIH The 1-methylpiperazine and the 5-chloro-2-nitroaniline are reac
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Page/Page column 70-71
(2008/06/13)
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- CRYSTALLINE AND OTHER FORMS OF 4-AMINO-5-FLUORO-3-[6-(4-METHYLPIPERAZIN-1-YL)-1H-BENZIMIDAZOL-2-YL]-1H-QUINOLIN-2-ONE LACTIC ACID SALTS
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The present invention relates to non-hydrate crystalline forms of 4-amino- 5-fluoro-3 -[6-(4-methylpiperazin- 1 -yl)- 1 H-benzimidazol-2-yl] - 1 H-quinolin-2-one lactic acid salts, solid pharmaceutical formulations containing the same and methods of use. The present invention also relates to crystalline hydrates of 4-arnino-5-fiuoro-3-[6-(4- methylpiperazin-l-yl)-lH-benzimidazol-2-yl]-lH-quinolin-2-one lactic acid salts, pharmaceutical formulations containing the same and methods of use related thereto. The present invention further relates to crystalline solvates of 4-amino-5-fluoro-3-[6-(4- methylpiperazin-l-yl)-lH-benzimidazol-2-yl]-lH-quinolin-2-one lactic acid salts.
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Page/Page column 69-70
(2008/06/13)
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- MODULATION OF INFLAMMATORY AND METASTATIC PROCESSES
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Methods of using compounds having Structure (I) or the salts or tautomers of the compounds in the treatment of disorders relating to cell adhesion and metastatic processes are presented herein.
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- Combination therapy with CHK1 inhibitors
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Compounds of Structure I, and salts, tautomers, stereoisomers, and mixtures thereof may be used in methods of inhibiting checkpoint kinase 1 in subjects, in methods for inducing cell cycle progression, and in methods for increasing apoptosis in cells. Such compounds may be used to prepare pharmaceutical compositions and may be used in conjunction with DNA damaging agents.
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- Inhibition of FGFR3 and treatment of multiple myeloma
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Methods of inhibiting fibroblast growth factor receptor 3 and treating various conditions mediated by fibroblast growth factor receptor 3 are provided that include administering to a subject a compound of Structure I, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer. Compounds having the Structure I have the following structure where and have the variables described herein. Such compounds may be used to prepare medicaments for use in inhibiting fibroblast growth factor receptor 3 and for use in treating conditions mediated by fibroblast growth factor receptor 3 such as multiple myeloma.
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- BENZIMIDAZOLE QUINOLINONES AND USES THEREOF
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Methods of inhibiting various enzymes and treating various conditions are provided that include administering to a subject a compound of Structure I or IB, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer. Compounds having the Structure I and IB have the following structures and have the variables described herein. Such compounds may be used to prepare medicaments for use in inhibiting various enzymes and for use in treating conditions mediated by such enzymes.
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