892397-56-7Relevant articles and documents
Alkali-metal- and alkaline-earth-metal-mediated C-O activation of an anisole-substituted phosphido-borane ligand
Izod, Keith,Watson, James M.,El-Hamruni, Salima M.,Harrington, Ross W.,Waddell, Paul G.
, p. 2218 - 2227 (2017)
The reaction between {(Me3Si)2CH}PH(C6H4-2-OMe) (4) and 1 equiv of BH3·SMe2 yields the phosphine-borane {(Me3Si)2CH}PH(BH3)(C6H4-2-OMe) (5). Subsequent reaction between 5 and 1 equiv of n-BuLi in THF gives the phosphido-borane complex [{(Me3Si)2CH}P(BH3)(C6H4-2-OMe)]Li(THF) (6a), which was isolated as a colorless microcrystalline solid. Treatment of 5 with 1 equiv of PhCH2M yields the corresponding complexes [{(Me3Si)2CH}P(BH3)(C6H4-2-OMe)]ML (ML = Na(THF) (6b), K(pmdeta) (6c); pmdeta = N,N,N′,N″,N″-pentamethyldiethylenetriamine), after crystallization in the presence of the corresponding coligand. While compounds 6b,c are stable toward heat, compound 6a decomposes on heating to 50 °C in toluene to give the cluster [[{(Me3Si)2CH}PH(C6H4-2-O)]Li]6 (7) and the tertiary phosphine-borane {(Me3Si)2CH}P(BH3)(Me)(C6H4-2-OMe) (8). Related C-O cleavage reactions are observed when MgI2 is treated with 2 equiv of 6a and when CaI2 is treated with 2 equiv of [{(Me3Si)2CH}P(BH3)(C6H4-2-OMe)]K in THF, giving [{(Me3Si)2CH}P(BH3)(C6H4-2-O)Mg(THF)2]2 (9) and [{(Me3Si)2CH}P(BH3)(C6H4-2-O)Ca(THF)]4 (10), respectively, along with 1 equiv of 8 in each case. In contrast, the reaction between SrI2 and 2 equiv of [{(Me3Si)2CH}P(BH3)(C6H4-2-OMe)]K in THF yields [{(Me3Si)2CH}P(BH3)(C6H4-2-OMe)Sr(THF)4] (11).
Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors
Han, Jin,Henriksen, Silje,N?rsett, Kristin G.,Sundby, Eirik,Hoff, B?rd Helge
supporting information, p. 583 - 607 (2016/09/14)
The present study describes our continuous effort to develop epidermal growth factor receptor (EGFR) inhibitors based on the 6-aryl-pyrrolo[2,3-d]pyrimidin-4-amine scaffold. The activity-ADME space has been evaluated by synthesizing 43 new structures, including four variations of the 4-amino group and 34 different substitution patterns in the 6-aryl moiety. Most of the new pyrrolopyrimidines were highly active, with twelve analogues possessing lower IC50values than the commercial drug Erlotinib in enzymatic assays. Ten EGFR inhibitors were also profiled in cell studies using the Ba/F3-EGFRL858Rreporter cells, and all revealed nanomolar activity. However, some of the privileged structures in terms of potency had ADME short-comings: compounds containing amides, sulfonamides, amine and hydroxymethyl substituents in the 6-aryl group had low permeability and high efflux, derivatives having (R)-3-amino-3-phenylpropan-1-ol at C-4 induced hERG inhibition properties, and metabolic lability was seen for compounds having (S)-2-methoxy-1-phenylethan-1-amine at C-4. Based on a trade-off between enzymatic activity, cellular potency and ADME properties, (S)-2-phenyl-2-((6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethan-1-ol appeared as the most promising drug candidate. Cellular studies indicate this compound to have therapeutic use in EGFR driven diseases.
