Synthesis of 1-Benzothiepine and 1-Benzazepine Derivatives as Orally Active CCR5 Antagonists

Yoshio Aramaki; Masaki Seto; Tomohiro Okawa; Tsuneo Oda; Naoyuki Kanzaki; Mitsuru Shiraishi

doi:10.1248/cpb.52.254

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Synthesis of 1-Benzothiepine and 1-Benzazepine Derivatives as Orally Active CCR5 Antagonists

Yoshio Aramaki, Masaki Seto, Tomohiro Okawa, Tsuneo Oda, Naoyuki Kanzaki, Mitsuru Shiraishi

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Keywords: CCR5 antagonist, quaternary ammonium salt, tertiary amine moiety, 1-benzazapine, 1-benzothiepine

JOURNAL FREE ACCESS

2004 Volume 52 Issue 2 Pages 254-258

DOI https://doi.org/10.1248/cpb.52.254

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Abstract

Quaternary ammonium benzocycloheptene compound 1 has previously been reported as a clinical candidate for an injectable CCR5 antagonist. In order to develop an orally active CCR5 antagonist, derivatives of tertiary amine benzocycloheptene 2, the chemical precursor to 1, were investigated. The benzocycloheptene ring was converted to benzothiepine and benzazepine rings and it was found that these changes could enhance the potency of tertiary amine derivatives. In particular, the 1-benzothiepine-1,1-dioxide 11b and the N-methyl-1-benzazepine 18 showed increased activity and good preliminary pharmacokinetic properties. The synthesis of 1-benzothiepine and 1-benzazepine derivatives and their activity are described.

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