649735-41-1Relevant academic research and scientific papers
Commercial synthesis of a pyrrolotriazine-fluoroindole intermediate to brivanib alaninate: Process development directed toward impurity control
Pesti, Jaan A.,LaPorte, Thomas,Thornton, John E.,Spangler, Lori,Buono, Frederic,Crispino, Gerard,Gibson, Frank,Lobben, Paul,Papaioannou, Christos G.
, p. 89 - 102 (2014/05/20)
The development of a practical, commercial process for the preparation of 4-fluoro-2-methyl-indol-5-ol and its subsequent coupling with a pyrrolotriazine to form an advanced intermediate of the oncology therapy brivanib alaninate is described. A key aspect is the multikilogram-scale preparation of the fluoroindole intermediate from trifluoronitrobenzene and the subsequent coupling while achieving impurity minimalization. As brivanib alaninate is a high-dose drug, the synthesis of highquality API with low levels of impurities is critical.
Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol- 5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth
Cai, Zhen-Wei,Zhang, Yongzheng,Borzilleri, Robert M.,Qian, Ligang,Barbosa, Stephanie,Wei, Donna,Zheng, Xiaoping,Wu, Lawrence,Fan, Junying,Shi, Zhongping,Wautlet, Barri S.,Mortillo, Steve,Jeyaseelan Sr., Robert,Kukral, Daniel W.,Kamath, Amrita,Marathe, Punit,D'Arienzo, Celia,Derbin, George,Barrish, Joel C.,Robl, Jeffrey A.,Hunt, John T.,Lombardo, Louis J.,Fargnoli, Joseph,Bhide, Rajeev S.
, p. 1976 - 1980 (2008/12/22)
A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability t
Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol- 5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor
Bhide, Rajeev S.,Cai, Zhen-Wei,Zhang, Yong-Zheng,Qian, Ligang,Wei, Donna,Barbosa, Stephanie,Lombarde, Louis J.,Borzilleri, Robert M.,Zheng, Xiaoping,Wu, Laurence I.,Barrish, Joel C.,Kim, Soong-Hoon,Leavitt, Kenneth,Mathur, Arvind,Leith, Leslie,Chao, Sam,Wautlet, Barri,Mortillo, Steven,Jeyaseelan Sr., Robert,Kukral, Daniel,Hunt, John T.,Kamath, Amrita,Fura, Aberra,Vyas, Viral,Marathe, Punit,D'Arienzo, Celia,Derbin, George,Fargnoli, Joseph
, p. 2143 - 2146 (2007/10/03)
A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo-[2.1-f][1,2,4] triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The L-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
PROCESS FOR PREPARING CERTAIN PYRROLOTRIAZINE COMPOUNDS
-
Page 32; 33, (2008/06/13)
The present invention relates to a process for preparing certain pyrrolotriazine compounds of the formula (I) and pharmaceutically acceptable salts thereof. The formula (I) compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.
