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

• Published in: European journal of medicinal chemistry 2001-07, Vol.36 (7), p.639-649
• Main Authors: Collin, Xavier, Robert, Jean-Michel, Wielgosz, Gaétane, Le Baut, Guillaume, Bobin-Dubigeon, Christine, Grimaud, Nicole, Petit, Jean-Yves
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrageenan - antagonists & inhibitors; carrageenan-induced oedema; Ear Diseases - chemically induced; Edema - chemically induced; Foot Diseases - chemically induced; Male; Medical sciences; Mice; Microbial Sensitivity Tests - methods; N-pyridinylphthalimides; non-acidic NSAIDs; Pharmacology. Drug treatments; Phthalimides - chemical synthesis; Phthalimides - chemistry; Phthalimides - pharmacology; PMA oedema; Pyridines - chemistry; Pyridines - pharmacology; Rats; Rats, Wistar; Schiff Bases; Tetradecanoylphorbol Acetate - antagonists & inhibitors; TNFα inhibitors; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(01)01254-5

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-α (TNFα) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and β-picolyl), allowing significant inhibition of TNFα production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNFα 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 μM), 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 ID 50 (0.14 μM kg −1) comparable with that of N-(2,6-diisopropylphenyl)phthalimide ( 4) (0.15 μM kg −1).