Novel DMARDs on the basis of a new concept of dual cytokine regulation, TNF-α suppression and IL-10 augmentation

A series of arylpiperazine derivatives was synthesized to obtain agents showing apparent therapeutic effects in a chronic inflammatory animal model, starting from a lead possessing potent dual cytokine regulatory activity in vivo. We found a pyrimidylpiperazine derivative 17c showing the dual regulatory activity and an excellent therapeutic effect in an adjuvant-induced arthritis model. Scheme 3. Reagents and conditions: (a) Curtius rearrangements (58–67%); (b) Ac2O, Et3N, CH2Cl2, 0 °C–rt (68–82%); (c) MOM-Cl, TiCl4, dichloroethane, rt (38–65%); (d) arylpiperazines, K2CO3, DMF, 80 °C (35–64%).