Synthesis of racemic 6,7,8,9-tetrahydro-3-hydroxy-1H-1-benzazepine-2,5-diones as antagonists of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors.

ABSTRACT

The synthesis and pharmacological properties of several racemic 6,7,8,9-tetrahydro-3-hydroxy-1H-1-benzazepine-2,5-diones (THHBADs) are described. Synthesis was accomplished via a Schmidt reaction with 5,6,7,8-tetrahydro-2-methoxynaphthalene-1,4-diones (THMNDs) followed by demethylation. THMNDs were prepared via a Diels-Alder reaction with 2-methoxybenzoquinone (5) or 2-bromo-5-methoxybenzoquinone (14) and substituted 1,3-butadienes. The pharmacology of THHBADs was characterized by electrical recordings in Xenopus oocytes expressing rat brain NMDA and AMPA receptors. THHBADs are antagonists of NMDA and AMPA receptors with functional potency being dependent upon the substitution pattern on the tetrahydrobenzene moiety. The 7,8-dichloro-6-methyl (18a) and 7,8-dichloro-6-ethyl (18b) analogs are the most potent THHBADs prepared and have apparent antagonist dissociation constants (Kb values) of 0.0041 and 0.0028 microM, respectively, for NMDA receptors and 0.51 and 0.72 microM, respectively, for AMPA receptors.