4,10-Dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives: highly potent and selective AMPA receptors antagonists with in vivo activity

A novel series of 2-substituted-4,5-dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine derivatives was synthesised. One of them, Figure 1 and Scheme 1—a highly water soluble compound—exhibited a nanomolar affinity and demonstrated competitive antagonist properties at the ionotropic AMPA receptors. This compound also displayed potent anticonvulsant properties against electrically or sound-induced convulsions in mice after systemic administration, thus suggesting adequate brain penetration. Figure 1. Scheme 1. Synthesis of compounds Figure 1 and Scheme 1. Experimental conditions: (a) 7a: 6a, NaH, DMF, 15 °C, 45 min then 5a, CH2Cl2, rt, 48 h, flash chromatography on silica gel (CH2Cl2), 42%; 7b: 6a, 5b, K2CO3, acetone, reflux, 2 h, flash chromatography on silica gel (cyclohexane:EtOAc 30:70), 47%; (b) 6b, NaH, DMF, 15 °C, 45 min then 5a, CH2Cl2, rt, 48 h, flash chromatography on silica gel (cyclohexane:EtOAc 50:50), 49%; (c) Figure 1 and Scheme 1: 7a, AcOH, NH4Ac, reflux, 2 h, 38%; Figure 1 and Scheme 1: 7b, AcOH, NH4Ac, reflux, 2h, 16%; (d) 8a: 7a, MeOH, NH3 (gas), 30 min then rt, 48h, 70%; 8b: 7c, MeOH, NH3 (gas), 30 min then rt, 20 h, 80%; (e) Figure 1 and Scheme 1, concd H2SO4, −5 °C to 0 °C, 30 min then potassium nitrate, 0 °C (30 min) to rt (12 h), 96% (f) H2 (pressure of hydrogen: 28 psi), cat.Pd/C (10%), DMF, rt, 24 h, 58%; (g) 6N HCl, reflux, 24 h, 59% (h) MeNCO, DMF, rt, 12 h, 46%; (i) 1N NaOH, dioxane, rt, 12 h then 1N HCl until pH=1 and precipitation, 67%; (j) AcOH, reflux, 7 h, 83%; (k) 6N HCl, reflux, 16 h, 39.5% (l) AcOH, reflux, 7h, 54%.