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Synthesis 2011(24): 3965-3974  
DOI: 10.1055/s-0031-1289607
FEATUREARTICLE
© Georg Thieme Verlag Stuttgart ˙ New York

Novel σ1 Receptor Ligands by Oxa-Pictet-Spengler Reaction of Pyrazolylethanol

Torsten Schläger, Dirk Schepmann, Bernhard Wünsch*
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstraße 58-62, 48149 Münster, Germany
Fax: +49(251)8332144; e-Mail: wuensch@uni-muenster.de;
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Publication History

Received 30 August 2011
Publication Date:
15 November 2011 (online)

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Abstract

The oxa-Pictet-Spengler reaction of 2-(1-phenylpyrazol-5-yl)ethanol required the weak acid pyridinium p-toluenesulfonate to provide pyrano[4,3-c]pyrazoles with additional functional groups in the side chain. These functional groups allow the introduction of various amino substituents into the side chain in position 4. In receptor binding studies the aminoethyl-substituted pyranopyrazoles revealed higher σ1 receptor affinities and σ1/σ2 selectivities than the shorter aminomethyl homologues. The pyranopyrazole bearing the phenylpiperidine substituent (K i = 0.99 nM) represents the most potent and that bearing the piperidine substituent the most selective (σ1/σ2 = 180) σ1 ligands of this series of compounds.

Keywords

σ1 receptor ligands - oxa-Pictet-Spengler reaction - annulated pyrazoles - pyrazolylethanol - structure affinity relationships

    References

  • 1 Kitaichi K. Chabot JG. Moebius FF. Flandorfer A. Glossmann H. Quirion R. J. Chem. Neuroanat.  2000,  20:  375 
    Search in Google Scholar
  • 2 Alonso G. Phan V. Guillemain I. Saunier M. Legrand A. Anoal M. Maurice T. Neuroscience  2000,  97:  155 
    Search in Google Scholar
  • 3 Hayashi T. Su TP. CNS Drugs  2004,  18:  269 
    Search in Google Scholar
  • 4 Cobos EJ. Entrena JM. Nieto FR. Cendan CM. DelPezo E. Curr. Pharmacol.  2008,  6:  344 
    Search in Google Scholar
  • 5 Maurice T. Su TP. Pharmacol. Ther.  2009,  124:  195 
    Search in Google Scholar
  • 6 Ishikawa M. Hashimoto K. J. Receptor Ligand Channel Res.  2010,  3:  25 
    Search in Google Scholar
  • 7 Mach RH. Wheeler KT. Cent. Nerv. Syst. Agents Med. Chem.  2009,  9:  230 
    Search in Google Scholar
  • 8 Diaz JL. Zamanillo D. Corbera J. Baeyens JM. Maldonado R. Pericas MA. Vela JM. Torrens A. Cent. Nerv. Syst. Agents Med. Chem.  2009,  9:  172 
    Search in Google Scholar
  • 9 Corbera AJ. Vaño D. Martínez D. Vela JM. Zamanillo D. Dordal A. Andreu F. Hernandez E. Perez R. Escriche M. Salgado L. Yeste S. Serafini MT. Pascual R. Alegre J. Calvet MC. Cano N. Carro M. Buschmann H. Holenz J. ChemMedChem  2006,  1:  140 
    Search in Google Scholar
  • 10 Entrena JM. Cobos EJ. Nieto FR. Cendan CM. Gris G. Del Pozo E. Zampanillo D. Baeyens JM. Pain  2009,  143:  252 
    Search in Google Scholar
  • 11 Corbera AJ, Cuberes-Altisent MR, Holenz J, Martinez-Olmo D, and Vano-Domenech D. inventors; WO  2006,021,463. 
  • 12 Schläger T. Schepmann D. Lehmkuhl K. Holenz J. Vela JM. Buschmann H. Wünsch B. J. Med. Chem.  2011,  54:  6704 
    Search in Google Scholar
  • 13 Wünsch B. Zott M. Liebigs Ann. Chem.  1992,  39 
  • 14 Larghi EL. Kaufman TS. Synthesis  2006,  187 
  • 15 Larghi EL. Kaufman TS. Eur. J. Org. Chem.  2011,  5195 
  • 16 Bouguerne B. Lherbet C. Baltas M. Lett. Org. Chem.  2010,  7:  420 
    Search in Google Scholar
  • 17 Bouguerne B. Hoffmann P. Lherbet C. Synth. Commun.  2010,  40:  915 
    Search in Google Scholar
  • 18 Schläger T. Oberdorf C. Tewes B. Wünsch B. Synthesis  2008,  1793 
  • 19 Schomaker JM. Pulgam VR. Borhan B. J. Am. Chem. Soc.  2004,  126:  13600 
    Search in Google Scholar
  • 20 Dess DB. Martin JC. J. Org. Chem.  1983,  48:  4155 
    Search in Google Scholar
  • 21 Abdel-Magid AF. Mehrmann SJ. Org. Process Res. Dev.  2006,  10:  971 
    Search in Google Scholar
  • 22 Maier CA. Wünsch B. J. Med. Chem.  2002,  45:  438 
    Search in Google Scholar
  • 23 Große Maestrup E. Wiese C. Schepmann D. Hiller A. Fischer S. Scheunemann M. Brust P. Wünsch B. Bioorg. Med. Chem.  2009,  17:  3630 
    Search in Google Scholar
  • 24 Holl R. Schepmann D. Fröhlich R. Grünert R. Bednarski PJ. Wünsch B. J. Med. Chem.  2009,  52:  2126 
    Search in Google Scholar