19 research outputs found
Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin
By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies
Access to Highly Substituted 7âAzaindoles from 2âFluoropyridines via 7âAzaindoline Intermediates
A versatile
synthesis of 7-azaindoles from substituted 2-fluoropyridines
is described. C3-metalation and 1,4-addition to nitroolefins provide
substituted 2-fluoro-3-(2-nitroethyl)Âpyridines. A facile oxidative
Nef reaction/reductive amination/intramolecular S<sub>N</sub>Ar sequence
furnishes 7-azaindolines. Finally, optional regioselective electrophilic
C5-substitution (e.g., bromination or nitration) and subsequent in
situ oxidation delivers highly functionalized 7-azaindoles in high
overall efficiency
Kiloscale BuchwaldâHartwig Amination: Optimized Coupling of Base-Sensitive 6âBromoisoquinoline-1-carbonitrile with (<i>S</i>)â3-Amino-2-methylpropan-1-ol
This
work describes the optimization and scale-up of a BuchwaldâHartwig
amination reaction for the preparation of a pharmaceutical intermediate.
This CâN bond formation is challenged by the use of a chiral
primary amine, which both adds cost and favors formation of biaryl
byproducts. In order to develop a scalable process, a number of factors
had to be investigated including catalyst selection and stoichiometry
of the chiral amine. These all needed to be optimized while maintaining
low palladium levels in the isolated product. The reaction was found
to be most effective using PdÂ(dba)<sub>2</sub> with BINAP and Cs<sub>2</sub>CO<sub>3</sub> in THF. When executed on 2.5 kg scale, these
conditions provided 2.06 kg of the desired product in 80% yield with
only 73 ppm residual palladium. To date, this process has been successfully
executed to produce more than 12 kg of compound <b>(</b><i><b>S</b></i><b>)-3</b>
Anti-nicotine antibody titer and function in mice.
<p>Panel A: BALB/c mice (n = 12/gp) were immunized by IM injection with 10 ”g of different nicotine Hapten-DT conjugates adjuvanted with Al(OH)<sub>3</sub> (40 ”g Al<sup>3+</sup>) + CpG 24555 (50 ”g) on days 0, 28 and 42. Plasma was collected on day 54 and anti-nicotine antibody levels determined by ELISA (Panel A). On day 56 animals received an IV injection of <sup>3</sup>H-nicotine (0.05 mg/kg) and plasma and brains collected. Panel B shows nicotine levels in plasma (ng-eq/mL), and Panel C shows nicotine levels in brain (ng-eq/g).</p