313740-83-9Relevant academic research and scientific papers
Practical synthesis of an orally active CCR5 antagonist, 7-{4-[2-(Butoxy)-ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino] methyl}phenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide
Ikemoto, Tomomi,Ito, Tatsuya,Nishiguchi, Atsuko,Miura, Syotaro,Tomimatsu, Kiminori
, p. 168 - 173 (2012/12/24)
A practical method of synthesizing 7-{4-[2-(butoxy)ethoxy]-phenyl}-N-(4- {[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-phenyl)-1-propyl-2, 3-dihydro-1H-1-benzazepine-4-carboxamide (8), an orally active CCR5 antagonist, has been developed. Methyl 7-bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4- caboxylate (14a) was synthesized in good yield by the esterification of 4-[(4-bromo-2-formylphenyl)(propyl)amino]butanoic acid (13) followed by an intramolecular Claisen type reaction with 28% sodium methoxide in dimethyl carbonate as a solvent in one pot. The Suzuki-Miyaura reaction of 14a and 1-bromo-4-(2-butoxyethoxy)benzene (10) followed by hydrolysis and amidation gave 8. A new inexpensive method without chromatographic purification was established.
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
Seto, Masaki,Aramaki, Yoshio,Okawa, Tomohiro,Miyamoto, Naoki,Aikawa, Katsuji,Kanzaki, Naoyuki,Niwa, Shin-Ichi,Iizawa, Yuji,Baba, Masanori,Shiraishi, Mitsuru
, p. 577 - 590 (2007/10/03)
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-(C2-4 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 C2-4 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 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 (IC50=2.7 nM) and inhibitory effect (IC50=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.
BENZAZEPINE DERIVATIVES, PROCESS FOR THE PREPARATION OF THE SAME AND USES THEREOF
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Page 63, (2012/10/08)
Compounds of the general formula (I): or salts thereof, which exhibit CCR5 antagonism and exert preventive and therapeutic effects against HIV infections: wherein R1 is a 5- to 6-membered aromatic ring which bears a substituent represented by the general formula: R-Z1-X-Z2- (wherein R1 is hydrogen or optionally substituted hydrocarbyl; X is optionally substituted alkylene; and Z1 and Z2 are each a heteroatom) and may be further substituted, with R being optionally bonded to the aromatic ring to form another ring; Y is optionally substituted imino; and R2 and R3 are each optionally substituted aliphatic hydrocarbyl or an optionally substituted hetero-alicyclic group.
