Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-α suppressing and IL-10 augmenting activity

Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-α suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice, suggesting that 5k would be a promising drug candidate for the treatment of TNF-α associated diseases including septic shock. Scheme 2. Reagents and conditions: (a) Ac2O, NaOH, H2O, rt (87%); (b) cH2SO4, MeOH, reflux (72%); (c) LiAlH4, THF, 0 °C–rt (98%); (d) SOCl2, CHCl3, reflux (91%); (e) arylpiperazines, K2CO3, DMF, 80 °C (49–58%).