Synthesis and biological evaluation of novel pyrimidine derivatives as sub-micromolar affinity ligands of GalR2

Abstract

GalR1 and GalR2 represent unique pharmacological targets for treatment of seizures and epilepsy. A novel series of 2,4,6-triaminopyrimidine derivatives were synthesized and found to have sub-micromolar affinity for GalR2. Optimization of a series of 2,4,6-triaminopyrimidines led to the discovery of several analogs with IC50 values ranging from 0.3 to 1 μM.

Figure 1

Structures of nonpeptide ligands of the Galanin receptor.

Figure 2

Structures of 4 (CYM2024) and general structures of 2,4,6-triamino pyrimidines and triazines.

Scheme 1

General strategy for the synthesis of triaminopyrimidine derivatives. Reagents and conditions: (a) R₁R₂NH₂ (1.0 equiv), Et₃N (1.1 equiv), 0 °C–rt, 30 min, 75–85%; Ar₁NH₂ (2.0 equiv), Na₂CO₃ (2.0 equiv), EtOH, reflux, 2–4 h, 85–95%; (b) Ar₂NH₂ (1.5 equiv), DIPEA (5.0 equiv), n-BuOH, reflux, 1–4 days or n-BuOH, microwave, 160 °C, 4–7 h, 85–90%; R₃R₄NH₂ (1.5 equiv), DIPEA (2.0 equiv), n-BuOH, rt, overnight, 90–95%; (c) Ar₃NH₂, Pd₂(dba)₃, XPhos, t-BuOK, dioxane, 85 °C, overnight, 80-90%; R₅R₆NH₂, n-BuOH, microwave, 160 °C, 2–5 h, 90–95%.

Scheme 2

General strategy for the synthesis of triaminotriazine derivatives. Reagents and conditions: (a) R₁R₂NH₂ or Ar₁NH₂, NaHCO₃, acetone, H₂O, 0–5 °C, 80–85%; (b) R₃R₄NH₂ or Ar₂NH₂, K₂CO₃, THF, rt, 2–4 h, 80–85%; (c) R₅R₆NH₂ or Ar₃NH₂, K₂CO₃, dioxane, microwave, 120 °C, 1–4 h, 90–95%.