Synthesis of Novel 4(5)-(5-Aminotetrahydropyran-2-yl)imidazole Derivatives and Their in Vivo Release of Neuronal Histamine Measured by Brain Microdialysis

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書誌事項

公開日
2007
資源種別
journal article
DOI
  • 10.1248/cpb.55.1245
公開者
公益社団法人 日本薬学会

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説明

The (2R,5S)-trans- and (2S,5S)-cis-stereoisomers 1a and 1b of 4(5)-(5-aminotetrahydropyran-2-yl)imidazole, which have two chiral centers and adopt a stable chair conformation, were synthesized via cyclization of diol intermediates 7 using L-glutamine as the starting material. Their enantiomers, (2S,5R)-trans-1c and (2R,5R)-cis-1d, were synthesized by the same methodology from D-glutamine. Stereo isomers 1a—d were converted into cyanoguanidines 11a—d, and into N-isopropyl and N-3,3-dimethylbutyl derivatives 12a—d and 13a—d, respectively. The results of in vivo brain microdialysis of the derivatives apparently indicated that only (2S,5R)-isomers increased the release of neuronal histamine. Among the many (2S,5R)-N-alkyl derivatives, 13c (OUP-133) and 18 (OUP-153) increased histamine release to 180—190% and 180—200% of basal levels, respectively, and were found to be novel histamine H3 antagonists.

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