Orally Active CCR5 Antagonists as Anti-HIV-1 Agents : Synthesis and Biological Activity of 1-Benzothiepine 1, 1-Dioxide and 1-Benzazepine Derivatives Containing a Tertiary Amine Moiety

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The search for orally active CCR5 antagonists was performed by chemical modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of methyl group with a 2-(C_<2-4> alkoxy) ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C_<2-4> alkyl, phenyl or (hetero) arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy) ethoxy group led to further increase of activity. Among the 1-benzazepine derivatives, the isobutyl (6i), benzyl (6o) or l-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC_<50>=2.7nM) and inhibitory effect (IC_<50>=1.2nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biological activity are described.
2004-05-01