Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro- N 2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)- N 4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials
The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.
Marsilje, Thomas H.,Pei, Wei,Chen, Bei,Lu, Wenshuo,Uno, Tetsuo,Jin, Yunho,Jiang, Tao,Kim, Sungjoon,Li, Nanxin,Warmuth, Markus,Sarkisova, Yelena,Sun, Frank,Steffy, Auzon,Pferdekamper, Annemarie C.,Li, Allen G.,Joseph, Sean B.,Kim, Young,Liu, Bo,Tuntland, Tove,Cui, Xiaoming,Gray, Nathanael S.,Steensma, Ruo,Wan, Yongqin,Jiang, Jiqing,Chopiuk, Greg,Li, Jie,Gordon, W. Perry,Richmond, Wendy,Johnson, Kevin,Chang, Jonathan,Groessl, Todd,He, You-Qun,Phimister, Andrew,Aycinena, Alex,Lee, Christian C.,Bursulaya, Badry,Karanewsky, Donald S.,Seidel, H. Martin,Harris, Jennifer L.,Michellys, Pierre-Yves
p. 5675 - 5690
(2013/08/23)
Use of nitriles as polar aprotic solvents
The invention concerns the use of aliphatic nitriles with relatively high molecular weight, as polar aprotic solvents, in particular in nucleophilic substitution reactions of the aromatic type. Said nitriles have a molecular mass more 79, preferably more than 90. The invention is useful for synthesis of fluorinated aromatic compounds.
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(2008/06/13)
Tetramethylammonium chloride as a selective and robust phase transfer catalyst in a solid-liquid halex reaction: The role of water
Tetramethylammonium chloride (TMAC) is an effective phase transfer catalyst for the selective chloride/fluoride exchange reaction of activated aryl chlorides with potassium fluoride provided that the amount of water in the system is limited and controlled.
Methylhexamethylenetetramine fluoride dihydrate: A new fluorodenitration reagent
Methylhexamethylenetetramine fluoride dihydrate has been prepared by conventional methods. It is moderately soluble in polar aprotic solvents, and shows good thermal stability, enabling it to be dried. The reagent is capable of converting activated nitroaromatics to the corresponding fluoroaromatics, with a high selectivity to monofluorodenitration being observed with some polysubstituted aromatics.