8-Methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazines: highly potent in vivo AMPA antagonists

A novel series of readily water soluble 8-methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines were synthesized. The -10-yl acetic acid ((+)-3) and -10-carboxylidene (4) derivatives exhibit potent affinities (IC50=4 and 19 nM, respectively) and antagonist properties (IC50=2 and 3 nM, respectively) at the ionotropic AMPA receptor. These compounds also display anticonvulsant properties against both electrically and sound-induced convulsions in mice after ip, sc and iv administration with ED50 values between 0.9 and 11 mg/kg, thus suggesting adequate brain penetration. Scheme 3. Synthesis of (±) -3, (+)-3, (−)-3 and 4. Reagents and conditions: (a) HCOCO2H, NaH, DMF, rt then 1 N HCl, rt, 64%; (b) ZnCl2, Ac2O, reflux, 23%; (c) KNO3, concd H2SO4, rt, 92%; (d) MeOH, concd HCl, Fe, 65 °C, 83.5%; (e) MeNCO, K2CO3, DMF, 6 h, rt, 84.5%; (f) 1 N NaOH, 35 °C then 1 N HCl, 46%; (g) preparative HPLC (see text), (+)-14: 26%, (−)-14: 27%; (h) 8 N HCl, dioxane, 40 °C, (+)-3: 67%, (−)-3: 63.5%, (i) SnCl2, concd HCl, 40 °C, 94%; (j) MeNCO, K2CO3, DMF:dioxane 1:1, rt, 35%.