Benzoxazines. II. Synthesis, Conformational Analysis, and Structure-Activity Relationships of 3,4-Dihydro-2H-1,4-benzoxazine-8-carboxamide Derivatives as Potent and Long-Acting Serotonin-3 (5-HT_3) Receptor Antagonists
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概要
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A series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT_3) receptor antagonistic activities by means of assays of 5-HT_3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1,4-benzoxazine ring with a 1,4-benzthiazine ring or seven-membered ring (i.e., 1,5-benzoxepine or 1,5-benzthiepine) resulted in decreased affinity for 5-HT_3 receptor. Introduction of substituents at the 2 position of the 1,4-benzoxazine ring increased the antagonistic activities (dimethyl>methyl>dihydro>phenyl). The compounds bearing a 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety as the basic part of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives were equipotent to those bearing 1-azabicyclo[2.2.2]oct-3-yl moiety. The 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety was confirmed to adopt a boat-chair conformation on the basis of both NMR studies and X-ray analysis. In this series, endo-6-chloro-3,4-dihydro-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2,2,4-trimethyl-2H-1,4-benzoxazine-8-carboxamide showed the highest affinity for 5-HT_3 receptors (K_i=0.019 nM), and a long-lasting 5-HT_3 receptor antagonistic activity as evidenced by antagonism to the von Bezold-Jarisch reflex in rats. Such a long-lasting 5-HT_3 receptor antagonism would be attributed to the introduction of both two methyl groups at the 2 position of the benzoxazine ring and the 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety, which adopts the boat-chair conformation.
- 公益社団法人日本薬学会の論文
- 1996-11-15
著者
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Kanzaki Kouji
Research Laboratories Yoshitomi Pharmaceutical Industries Ltd.
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KUROITA Takanobu
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.,
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KAWAKITA Takeshi
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd.,
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Marubayashi Nobuhiro
Research Laboratories Yoshitomi Phamaceutical Industries Ltd.
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SANO Mitsuharu
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd.
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INABA Kenichi
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd.
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Kawakita T
Research Laboratories Yoshitomi Pharmaceutical Industries Ltd.
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Kawakita Takeshi
Research Laboratories Yoshitomi Pharmaceutical Industries Ltd.
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Kuroita Takanobu
Research Laboratories Yoshitomi Pharmaceutical Industries Ltd.
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Sano Mitsuharu
Research Laboratories Yoshitomi Pharmaceutical Industries Ltd.
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Inaba K
Okayama Univ. Okayama Jpn
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Marubayashi Nobuhiro
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd.
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KAWAKITA Takeshi
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd.
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