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

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 (60) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelopemediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC 5 0 =2.7 nM) and inhibitory effect (IC 5 0 =1.2 nM) 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.