Practical Route to a New Class of LTD₄ Receptor Antagonists

Abstract

A general approach to the synthesis of a new class of LTD 4 antagonists is presented. The key diarylpropane framework was prepared by Claisen-Schmidt condensation and selective reduction of the enone. Depending on the bridge to the 7-chloroquinaldine moiety, alkylation or Heck coupling methodology was developed. The chiral sulfides were introduced by asymmetric reduction of the diarylpropanone intermediates and subsequent inversion of the chiral center.Since the discovery of the role played by the leukotrienes in asthma and associated inflammatory diseases the search for specific antagonists or inhibitors of this portion of the aracadonic acid cascade has been intensive. 1 An early candidate for the control of asthma was the LTD 4 antagonist MK-0571/MK-0679. 2,3 Elaboration of this original structure has advanced a new class of LTD 4 antagonists with the selection of L-691,698 (1) and L-699,392 (2) as active agents. 4 Here the 3-thiapropionamide side chain has been replaced with an arylethyl group, and in the case of the former, the trans-double bond has been changed to a phenyl quinaldine ether.Our goal was the development of a general approach to this new class of LTD 4 antagonists. 4,5 By incorporating the quinaldine portion of the molecule at the later stages of the synthesis the target became the diarylpropanol 3. A classical synthesis of a 1,3-diarylpropenone is condensation of an acetophenone and a benzaldehyde, the Claisen-Schmidt reaction, producing an enone known as a chalcone; 6 selective 3,4-reduction then provides the 1,3-diarylpropanone (Scheme 1). In the synthesis of 1 and 2 coupling of the 3′-substituted acetophenone 4 with a 2-carboxybenzaldehyde 5 afforded the backbone of 3 X Abstract published in Advance ACS Abstracts, May 1, 1996. (1) (a) Young, R. N.; Guindon, T. R.; Jones, T. R.; Ford-Hutchinson, A. W.; Bellanger, P.; Champion, E.; Charette, L.; DeHaven, R. N.; Denis, D.; Fortin, R.; Frenette, R.; Gauthier, J.-Y.; Gillard, J. W.; Kakushima, M.; Letts, L. G.; Masson, P.; Maycock, A.; McFarlane, C.; Piechuta, H.; Pong, S. S.; Rosenthal, A.; Williams, H.; Zamboni, R.; Yoakim, C.; Rokach, J. Zamboni, R.; Belley, M.; Champion, E.; Charette, L.; Ford-Hutchinson, A. W.; Frenette, R.; Gauthier, J.-Y.; Leger, S.; Masson, P.; McFarlane, C. S.; Piechuta, H.; Rokach, J.; Williams, H.; Young, R. N.; DeHaven, R. N.; Pong, S. S. Can. Jones, T.; Champion, E.; Charette, L.; Dehaven, R.; Ford-Hutchinson, A. W.; Hoogsteen, K.; Lord, A.; Masson, P.; Piechuta, H.; Pong, S. S.; Springer, J. P.; Therien, M.; Zamboni, R.; Young, R. N. J. Med. Chem. 1990, 33, 2841. (b) Zamboni, R.; Belley, M.; Champion, E.; Charette, L.; DeHaven, R.; Frenette, R.; Gauthier, J. Y.; Jones, T. R.; Leger, S.; Masson, P.; McFarlane, C. S.; Metters, K.; Pong, S. S.; Piechuta, H.; Rockach, J.; Therien, M.; Williams, H. W. R.; Young, R. N. J. Med. Chem. 1992, 35, 3832. (3) McNamara, J. M.; Leazer, J. L.; Bhupathy, M.; Amato, J. S.; Reamer, R. A.; Reider, P. J.; Grabowski, E. J. J. J. Org. Chem. 1989, 54, 3718. For the preparation of the ch...

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