title: Synthesis of 1-benzothiepine and 1-benzazepine derivatives as orally active CCR5 antagonists.
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.
authors.affiliation: Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Osaka, Japan. Aramaki_Yoshio@takeda.co.jp
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Aramaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Seto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okawa
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Oda
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shiraishi
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001567:Benzocycloheptenes / Q000737:chemistry; D001582:Benzothiepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015394:Molecular Structure
chemical_list: D001552:Benzazepines; D001567:Benzocycloheptenes; D001582:Benzothiepins; D065100:CCR5 Receptor Antagonists