Synthesis Of Nintedanib And Its PROTACs

Idiopathic pulmonary fibrosis(IPF)is a chronic,progressive,and fibrotic interstitial lung disease,whose mortality is higher than cancer,with a reported median survival of 2–3 years from diagnosis.IPF is most commonly diagnosed in the elderly,and it seriously affects the physical and mental health of patients.As the population aging,the incidence and prevalence of IPF are increasing in the past few years.Nintedanib,a multiple tyrosine kinase inhibitor,was noted to have potent activity against fibroblasts,and was approved for the treatment of IPF by FDA in 2014.PROTACs,which are useful in tumor therapy,can induce selective degradation of their target protein associated with disease via the ubiquitin-proteasome system.PROTACs have attracted much attention because of its high generality,high potency and great application prospects,so that this strategy becomes very popular in tumor therapeutics.We repeated and optimized the synthesis route of nintedanib.Starting with 4-chloro-3-nitrobenzoic acid,we synthesized the intermediate 5;and intermediate 10 was obtained by the route protecting the nitrogen atom of intermediate 5 with chloracetyl;the intermediate 13 was synthesized by the starting material N-Methyl-4-nitroaniline;Finally,intermediate 10 and intermediate 13 were refluxed in methanol to get nintedanib.Then,we designed and synthesized the PROTACs based on nintedanib and pomalidomide,on the basis of the previous work in our laboratory.However the later phenotypic screening experiment indicated that the inhibitory activity of these 6compounds was not as good as that of nintedanib.