- 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-(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.
- 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)
-
- ARYLSULFONYLHYDROXAMIC ACID AND AMIDE DERIVATIVES AND THEIR USE AS PROTEASE INHIBITORS
-
This invention is directed generally to hydroxamic acid and amide compounds (including salts of such compounds), and, more particularly, to aryl- and heteroaryl--arylsulfonylmethyl hydroxamic acids and amides that, inter alia, inhibit protease activity, particularly matrix metalloproteinase (also known as "matrix metalloprotease" or "MMP") activity and/or aggrecanase activity. These compounds generally correspond in structure to formula (I): wherein Al, A2, A3, El, E2, E3, and E4 are as defined in this patent. This invention also is directed to compositions of such compounds, intermediates for the syntheses of such compounds, methods for making such compounds, and methods for treating conditions associated with MMP activity and/or aggrecanase activity, particularly pathological conditions.
- -
-
Page 124-125
(2010/02/05)
-
- Anilide derivative, production and use thereof
-
This invention is to provide a compound of the formula: wherein R1is an optionally substituted 5- to 6-membered ring; the ring A is an optionally substituted 6- to 7-membered ring; the ring B is an optionally substituted benzene ring; n is an integer of 1 or 2; Z is a chemical bond or a divalent group; R2is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: ?wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5and R6are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5and R6may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof , which is useful for antagonizing CCR5 and also for the prevention and treatment of infectious disease of HIV.
- -
-
-