Synthesis of 1-benzothiepine and 1-benzazepine derivatives as orally active CCR5 antagonists.
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.
Aramaki
Yoshio
Y
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Osaka, Japan. Aramaki_Yoshio@takeda.co.jp
Seto
Masaki
M
Okawa
Tomohiro
T
Oda
Tsuneo
T
Kanzaki
Naoyuki
N
Shiraishi
Mitsuru
M
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
D001552:Benzazepines; D001567:Benzocycloheptenes; D001582:Benzothiepins; D065100:CCR5 Receptor Antagonists