Studies On The Synthesis Of Novel Roflumilast Analogues And α-ketoamides

Roflumilast, as the first listed selective phosphodiesterase-4(PDE-4) inhibitor in thetreatment of chronic obstructive pulmonary disease (COPD), has a wide range ofanti-inflammatory activity. It can improve the lung function, improve the levels ofintracellular cAMP, and keep neutrophils from releasing inflammatory mediators, such asreactive oxygen species (ROS), leukotriene β-4(LTβ-4), tumor necrosis factor-(TNF-), toreduce exacerbations in patients with COPD. Despite significant progress in this area,roflumilast is associated with dose-limiting side-effects such as gastrointestinal upset andheadache, weight loss, which limit its therapeutic potential. This further highlights the need todiscover novel pharmacophores for designing PDE4inhibitors with an improved therapeuticindex. At present, PDE4inhibitors have been designed mostly starting from the archetypalinhibitor roflumilast by replacing the pharmacophores and docking with PDE-4enzymes.Three parts were included in the research of roflumilast in this paper. Firstly, severalsynthetic routes of roflumilast had been tried although we could not get the key intermediate3-cyclopropylmethoxy-4-difluoromethoxy benzaldehyde. Secondly, we designed andsynthesized two series of eight roflumilast analogues F1，F2，K1-K6by combining thepharmacophores of roflumilast and the structures of well-known PDE-4inhibitors. Thesecompounds were characterized by1H NMR, IR, and ESI-MS. Thirdly, the antioxidant activityof these compounds was investigated using the1,1-diphenyl-2-picrylhydrazyl method and theresults showed that the roflumilast analogues exhibit no obvious antioxidant activity.-Ketoamides are key units of many natural products, biological compounds andpharmaceuticals. And they also are important targets in organic synthesis because of theirability to serve as building blocks in a wide variety of functional group transformations. Wesynthesized a series of substituted aryl-Ketoamides analogues L1-L8by a convenient,practical, environmental friendly method. These compounds were characterized by1H NMR,and13C NMR and HR-MS.