Synthesis 2008(2): 253-266  
DOI: 10.1055/s-2007-1000852
PAPER
© Georg Thieme Verlag Stuttgart · New York

Regiospecific and Highly Flexible Synthesis of 1,4,5-Trisubstituted 2-Sulfanylimidazoles from Structurally Diverse Ethanone Precursors

Stefan A. Laufer*, Dominik R. J. Hauser, Andy J. Liedtke
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Fax: +49(7071)295037; e-Mail: stefan.laufer@uni-tuebingen.de; e-Mail: dominik.hauser@uni-tuebingen.de; e-Mail: andy.liedtke@uni-tuebingen.de;
Further Information

Publication History

Received 4 October 2007
Publication Date:
18 December 2007 (online)

Abstract

Imidazoles represent important bioactive scaffolds in medicinal chemistry. More than 2,500 structures are listed in drug discovery databases and over 3,000 patents have been claimed for imidazole-based structures. Recent imidazole pharmacophores have targeted various MAP kinases. p38 Mitogen-activated protein (MAP) kinase plays a central role in the signaling network responsible for the upregulation of proinflammatory cytokines like IL-1β and TNFα and offers, therefore, a valid target for small molecule anti-inflammatory drugs. 2-Sulfanylimidazole derivatives offer some advantages over prototype inhibitors (SB203580), e.g. lower cytochrom P450 interactions and better kinetic properties. We report here three novel regioselective and, at the same time, highly flexible synthetic approaches towards 1,4,5-trisubstituted 2-sulfanylimidazoles starting from different ethanone regioisomers allowing maximum variability of all substituents introduced. As a result, a variety of selective and highly potent p38 MAPK inhibitors were prepared and selected for further preclinical development. Synthesis of structurally diverse inhibitor candidates, p38 inhibition data, and selectivity profiling of some selected compounds are specified. Furthermore, the benefits of the useful, brief synthetic sequences are outlined and contrasted with already published multistep routes.

    References

  • 1 Bellina F. Cauteruccio S. Rossi R. Tetrahedron  2007,  63:  4571 
  • 4 Isanbor C. O’Hagan D. J. Fluorine Chem.  2006,  127:  303 
  • 5 Noble MEM. Endicott JA. Johnson LN. Science  2004,  303:  1800 
  • 6 Hopkins AL. Groom CR. Nat. Rev. Drug Discovery  2002,  1:  727 
  • 7 Manning G. Whyte DB. Martinez R. Hunter T. Sudarsanam S. Science  2002,  298:  1912 
  • 8 Margutti S. Laufer SA. ChemMedChem  2007,  2:  1116 
  • 9 Keri G. Orfi L. Eros D. Hegymegi-Barakonyi B. Szantai-Kis C. Horvath Z. Waczek F. Marosfalvi J. Szabadkai I. Pato J. Greff Z. Hafenbradl D. Daub H. Muller G. Klebl B. Ullrich A. Curr. Signal Transduction Ther.  2006,  1:  67 
  • 10 Gallagher TF. Seibel GL. Kassis S. Laydon JT. Blumenthal MJ. Lee JC. Lee D. Boehm JC. Fier-Thompson SM. Abt JW. Soreson ME. Smietana JM. Hall RF. Garigipati RS. Bender PE. Erhard KF. Krog AJ. Hofmann GA. Sheldrake PL. McDonnell PC. Kumar S. Young PR. Adams JL. Bioorg. Med. Chem.  1997,  5:  49 
  • 11 Liverton NJ. Butcher JW. Claiborne CF. Claremon DA. Libby BE. Nguyen KT. Pitzenberger SM. Selnick HG. Smith GR. Tebben A. Vacca JP. Varga SL. Agarwal L. Dancheck K. Forsyth AJ. Fletcher DS. Frantz B. Hanlon WA. Harper CF. Hofsess SJ. Kostura M. Lin J. Luell S. O’Neill EA. Orevillo CJ. Pang M. Parsons J. Rolando A. Sahly Y. Visco DM. O’Keefe SJ. J. Med. Chem.  1999,  42:  2180 
  • 12 Boehm JC. Adams JL. Expert Opin. Ther. Pat.  2000,  10:  25 
  • 13 Jackson PF. Bullington JL. Curr. Top. Med. Chem.  2002,  2:  1011 
  • 14 Tong L. Pav S. White DM. Rogers S. Crane KM. Cywin CL. Brown ML. Pargellis CA. Nat. Struct. Biol.  1997,  4:  311 
  • 15 Wilson KP. McCaffrey PG. Hsiao K. Pazhinisamy S. Galullo V. Bemis GW. Fitzgibbon MJ. Caron PR. Murcko MA. Su MSS. Chem. Biol.  1997,  4:  423 
  • 16 Wang Z. Canagarajah BJ. Boehm JC. Kassisa S. Cobb MH. Young PR. bdel-Meguid S. Adams JL. Goldsmith EJ. Structure  1998,  6:  1117 
  • 17 Young PR. McLaughlin MM. Kumar S. Kassis S. Doyle ML. McNulty D. Gallagher TF. Fisher S. McDonnell PC. Carr SA. Huddleston MJ. Seibel G. Porter TG. Livi GP. Adams JL. Lee JC. J. Biol. Chem.  1997,  272:  12116 
  • 18 Zhang J. Shen B. Lin A. Trends Pharmacol. Sci.  2007,  28:  286 
  • 19 Traxler P. Furet P. Pharmacol. Ther.  1999,  82:  195 
  • 20 Chen Z. Gibson TB. Robinson F. Silvestro L. Pearson G. Xu B. Wright A. Vanderbilt C. Cobb MH. Chem. Rev.  2001,  101:  2449 
  • 21 Schieven GL. Curr Top. Med. Chem.  2005,  5:  921 
  • 22 Goldstein DM. Gabriel T. Curr. Top. Med. Chem.  2005,  5:  1017 
  • 23 Fabian MA. Biggs WH. Treiber DK. Atteridge CE. Azimioara MD. Benedetti MG. Carter TA. Ciceri P. Edeen PT. Floyd M. Ford JM. Galvin M. Gerlach JL. G rotzfeld RM. Herrgard S. Insko DE. Insko MA. Lai AG. Lelias JM. Mehta SA. Milanov ZV. Velasco AM. Wodicka LM. Patel HK. Zarrinkar PP. Lockhart DJ. Nat. Biotechnol.  2005,  23:  329 
  • 24 Kuma Y. Sabio G. Bain J. Shpiro N. Marquez R. Cuenda A. J. Biol. Chem.  2005,  280:  19472 
  • 25 Kammerer B. Scheible H. Albrecht W. Gleiter CH. Laufer S. Drug Metab. Dispos.  2007,  35:  875 
  • 26 Laufer SA. Wagner GK. Kotschenreuther DA. Albrecht W. J. Med. Chem.  2003,  46:  3230 
  • 27 Toledo LM. Lydon NB. Elbaum D. Curr. Med. Chem.  1999,  6:  775 
  • 28 Wagner G. Laufer S. Med. Res. Rev.  2006,  26:  1 
  • 29 Traxler P. Expert Opin. Ther. Patents  1998,  8:  1599 
  • 30 Claiborne CF. Liverton NJ. Nguyen KT. Tetrahedron Lett.  1998,  39:  8939 
  • 31 Bender PE. inventors; DE  2742725.  ; Chem. Abstr. 1978, 89, 24305
  • 32 Lantos I. Gombatz K. McGuire M. Pridgen L. Remich J. Shilcrat S. J. Org. Chem.  1988,  53:  4223 
  • 33 Ferrini PG, and Goeschke R. inventors; EP  0004648.  ; Chem. Abstr. 1980, 92, 76510
  • 34 Laufer S. Wagner G. Kotschenreuther D. Angew. Chem. Int. Ed.  2002,  41:  2290 
  • 35 Laufer SA. Zimmermann W. Ruff KJ. J. Med. Chem.  2004,  47:  6311 
  • 36 Minor JT. Hawkins GF. VanderWerf CA. Roe A. J. Am. Chem. Soc.  1949,  71:  1125 
  • 37 Fukuhara T. Yoneda N. Suzuki A. J. Fluorine Chem.  1988,  38:  435 
  • 38 Marckwald W. Ber. Dtsch. Chem. Ges.  1892,  25:  2354 
  • 39 Buchman ER. Reims AO. Sargent H. J. Org. Chem.  1941,  6:  764 
  • 40 Thompson JE. Cubbon RM. Cummings RT. Wicker LS. Frankshun R. Cunningham BR. Cameron PM. Meinke PT. Liverton N. Weng Y. DeMartino JA. Bioorg. Med. Chem. Lett.  2002,  12:  1219 
  • 41 Laufer SA. Liedtke AJ. Tetrahedron Lett.  2006,  47:  7199 
  • 42 Wagner GK. Kotschenreuther D. Zimmermann W. Laufer SA. J. Org. Chem.  2003,  68:  4527 
  • 43 Revesz L. inventors; WO  01030778.  ; Chem. Abstr. 2001, 134, 340507
  • 44 Ridge DN. Hanifin JW. Harten LA. Johnson BD. Menschik J. Nicolau G. Sloboda AE. Watts DE. J. Med. Chem.  1979,  22:  1385 
  • 45 Stevens KL. Jung DK. Alberti MJ. Badiang JG. Peckham GE. Veal JM. Cheung M. Harris PA. Chamberlain SD. Peel MR. Org. Lett.  2005,  7:  4753 
  • 46 Grimmett MR. Science of Synthesis   Vol. 12:  Neier R. Georg Thieme Verlag; Stuttgart: 2002.  p.325 
  • 47 Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
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