1206824-89-6Relevant articles and documents
Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride
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, (2021/01/29)
The invention discloses a preparation method of a tofacitinib intermediate cis-1benzyl-N, 4-dimethyl piperidine-3-amine dihydrochloride. The synthetic method comprises the following steps: taking 3-bromo-4-methylpyridine as an initial raw material, performing substitution reaction with amine to obtain a compound III, and performing acetyl or tert-butyloxycarbonyl protection and catalytic hydrogenation on the compound III to obtain a piperidine compound V. The compound V and benzaldehyde are subjected to reductive amination or react with benzyl halide to obtain a compound VI. A protecting groupis removed from the compound VI, and a hydrochloride compound I. 2HCl is formed at the same time. The synthesis method is simple to operate, high in total yield, high in product purity, stable in quality and suitable for industrial production.
Novel Hinge-Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure-Activity Relationship Study on Tofacitinib Bioisosteres
Gehringer, Matthias,Forster, Michael,Pfaffenrot, Ellen,Bauer, Silke M.,Laufer, Stefan A.
supporting information, p. 2516 - 2527 (2015/08/24)
The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7H-pyrrolo[2,3-d]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure-activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.
IMIDAZOPYRIDINE DERIVATIVES AS JAK INHIBITORS
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Page/Page column 125-126, (2011/07/09)
New imidazopyridine derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
