623152-12-5Relevant academic research and scientific papers
Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors
Dyckman, Alaric J.,Li, Tianle,Pitt, Sidney,Zhang, Rosemary,Shen, Ding Ren,McIntyre, Kim W.,Gillooly, Kathleen M.,Shuster, David J.,Doweyko, Arthur M.,Sack, John S.,Kish, Kevin,Kiefer, Susan E.,Newitt, John A.,Zhang, Hongjian,Marathe, Punit H.,McKinnon, Murray,Barrish, Joel C.,Dodd, John H.,Schieven, Gary L.,Leftheris, Katerina
scheme or table, p. 4633 - 4637 (2011/09/15)
Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38α have been prepared exploring functional group modifications at the C6 position. Incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models o
Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases
Liu, Chunjian,Lin, James,Wrobleski, Stephen T.,Lin, Shuqun,Hynes, John,Wu, Hong,Dyckman, Alaric J.,Li, Tianle,Wityak, John,Gillooly, Kathleen M.,Pitt, Sidney,Shen, Ding Ren,Zhang, Rosemary F.,McIntyre, Kim W.,Salter-Cid, Luisa,Shuster, David J.,Zhang, Hongjian,Marathe, Punit H.,Doweyko, Arthur M.,Sack, John S.,Kiefer, Susan E.,Kish, Kevin F.,Newitt, John A.,McKinnon, Murray,Dodd, John H.,Barrish, Joel C.,Schieven, Gary L.,Leftheris, Katerina
experimental part, p. 6629 - 6639 (2010/12/18)
The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
Process for preparing salts of 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide and novel stable forms produced therein
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Page/Page column 15; 21, (2010/11/24)
Processes are provided for selectively preparing novel stable crystalline salt forms, selectively and consistently, namely, preparing Form N-1 of the methanesulfonic acid salt, and Form N-1 and Form N-4 of the hydrochloric acid salt of the p38 kinase inhibitor 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide. The processes preferably employ solvent systems including formic acid/acetone and formic acid/methylethyl ketone which produce crystals having suitable flow properties and desired particle size, and solvents such as N,N-dimethylformamide and N,N-dimethylacetamide may be employed as well. Novel Form N-1 crystals of the Form N-1 and Form N-4 crystals of the hydrochloride salt and Form N-1 crystals of the methanesulfonic acid salt of the above free base, pharmaceutical compositions containing such novel forms and a method of treating p38 kinase associated conditions, including rheumatoid arthritis are also provided.
