New anti-inflammatory N-pyridinyl(alkyl)phthalimides acting as tumour necrosis factor-α production inhibitors

This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-tetrafluorophthalimides known to be inhibitors of tumour necrosis factor-alpha (TNF alpha) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and beta -picolyl), allowing significant inhibition of TNF alpha production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNF alpha production) inhibitory potency could be achieved, notably by 5-fluoro, 4- or 5-nitro, 5-amino and especially tetrafluoro substitution. The most active compound, N-(pyridin-3-ylmethyl)-4,5,6,7-tetrafluorophthalimide (32) (84% inhibition at 10 muM), also produced an anti-oedematous effect in the PMA-induced mouse-ear swelling test. Although less active than dexamethasone, it exerted a marked reduction in ear thickness after oral administration (63% vs. 85% for dexamethasone at 0.2 mM kg(-1)) and remained efficient after topical application (46% vs. 96% for the dexamethasone). It also induced potent inhibition in the rat carrageenan foot oedema test with an ID50 (0.14 muM kg(-1)) comparable with that of N-(2,6-diisopropylphenyl)phthalimide (4) (0.15 muM kg(-1)). (C) 2001 Editions scientifiques et medicales Elsevier SAS.