Derivatives of benzothiazepine and their use as modulators of AMPA and NMDA receptors

摘要

Benzothiadiazepine derivatives (I) and their optical and positional isomers, or addition salts with an acid or base, are new. Benzothiadiazepine derivatives of formula (I) and their optical and positional isomers, or addition salts with an acid or base, are new. R 1>, R 2> : H, halo, or 1-6C alkyl (optionally substituted by one or more halo, 1-6C alkoxy, 1-6C alkylthio, 1-6C alkoxycarbonyl, carboxy group, 1-6C acyl, hydroxyl group, 1-6C hydroxyalkyl group, CN, nitro, amino group (substituted by an 1-6C acyl and optionally substituted by one or more 1-6C alkyl), aminocarbonyl group (optionally substituted by one or more 1-6C alkyl), aminosulfonyl group (optionally substituted by one or more 1-6C alkyl), alkyl(1-6C)sulfonylamino1-6C alkyl, N-hydroxycarboximidamide or benzyloxy); R 3> : H, 1-6C alkyl, 3-8C cycloalkyl, or 3-8C-cycloalkyl-1-6C alkyl; and R 4> : H or 1-6C alkyl (optionally substituted by one or more halo). Independent claims are included for: (1) the preparation of (I); and (2) 1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[f][1,2,5]thiadiazepin-8-ol (VI) as an intermediate for the synthesis of (I). [Image] ACTIVITY : Neuroprotective; Nootropic; Antiparkinsonian; Cerebroprotective; Anticonvulsant; Antialcoholic; Neuroleptic; Vasotropic; Antidepressant; Tranquilizer. MECHANISM OF ACTION : Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulator; N-methyl-D-aspartate (NMDA) receptor antagonist. The NMDA receptor antagonistic activity of (I) was tested in rats. The result showed that 8-phenoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide exhibited an IC 50value of 9 microM.