Crystallographic and Molecular Mechanics Study of Imidooxy Anticonvulsants

X-ray crystal structures have been determined of five compounds closely related to N-benzyl-2-azaspiro[4.4]-nonane-l,3-dione (1), which is inactive as an anticonvulsant, and N-(benzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (2), which is active. Conformational analyses have been carried out with (1), (2) and the new compounds N-(2',4'-dichlorobenzyloxy)-2-azaspiro[4.4]nonane-l,3-dione (3), N-(2'-bromobenzyloxy)-2-azaspiro[4.4]nonane-l,3-dione (4), N-(4'-(trifluoromethyl)benzyloxy)-2-azaspiro[4.4]nonane-l,3-dione (5), which are all active anticonvulsants, and N-(4'-chlorobenzyloxy)-2-azaspiro[4.4]nonane-l,3-dione (6) and N-(4'-bromobenzyloxy)-2-azaspiro[4.4]nonane-1,3-dione (7), which are inactive. Regardless of the substitution pattern, the conformations of compounds (2)-(7) in the crystals are very similar. Among the low-energy conformations, which are well distributed in the conformational space, that present in its solid state is dominant. Ortho-substitution considerably cuts down the number of conformations accessible within the set energy limit. The results of these studies alone do not explain the differences in activity.

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