Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. III. Optically active isomers of N-methyl-2-(2-(2-(4-phenylpiperazino)ethoxy)phenyl)thiazolidine-3-carboxamides.

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  • NATE HIROYUKI
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • SEKINE YASUO
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • ODA KUNIYUKI
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • AOE KEIICHI
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • NAKAI HIDEO
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • WADA HIROSHI
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • TAKEDA MIKIO
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • KOTERA KEISHI
    Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • YABANA HIDEO
    Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
  • NAGAO TAKU
    Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.

説明

Optically active isomers of N-methyl-2- (2- (2- (4-phenylpiperazino) ethoxy) phenyl) thiazolidine-3-carboxamides ((+) -2 and (-) -2) have been synthesized and tested for positive inotropic activity. The racemic thiocarboxamide ((±) -3) was resolved into the enantiomers ((+) -3 and (-) -3) via the L-and D-N- (2-naphthylsulfonyl) prolyl derivatives ((+) -4 and (-) -4). Conversion of the thiocarboxamides ((+) -3 and (-) -3) to the carboxamides ((+) -2 and (-) -2) was smoothly effected by treatment with the glycidic ester (7). The absolute stereochemistry of (-) -3 was determined to be 2S by X-ray crystallographic analysis. Hence, the absolute configuration of the carboxamide ((-) -2) is 2S. On i.v. administration to anesthetized dogs, the enantiomers of 2 showed only a threefold difference in positive inotropic activity, with the levo isomer ((-) -2) being the more active. In the isolated cat heart muscle, the enantiomers were nearly equipotent to each other. Thus, no significant difference between the positive inotropic activities of the optical isomers of 2 was observed.

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