90604-02-7Relevant articles and documents
PROCESSES OF PREPARING A JAK1 INHIBITOR
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, (2021/12/17)
The present application provides processes for preparing 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H, 1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, and phosphoric acid salt thereof, which is useful as a selective (Janus kinase 1) JAK1 inhibitor, as well as salt forms and intermediates related thereto.
PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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Paragraph 0154, (2014/09/29)
This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors
Claffey, Michelle M.,Helal, Christopher J.,Verhoest, Patrick R.,Kang, Zhijun,Fors, Kristina S.,Jung, Stanley,Zhong, Jiaying,Bundesmann, Mark W.,Hou, Xinjun,Lui, Shenping,Kleiman, Robin J.,Vanase-Frawley, Michelle,Schmidt, Anne W.,Menniti, Frank,Schmidt, Christopher J.,Hoffman, William E.,Hajos, Mihaly,McDowell, Laura,Oconnor, Rebecca E.,MacDougall-Murphy, Mary,Fonseca, Kari R.,Becker, Stacey L.,Nelson, Frederick R.,Liras, Spiros
, p. 9055 - 9068 (2013/01/15)
Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimers disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
