YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Synthesis of Potential COX-2 Inhibitory 1,5-Diarylhydantoin Derivatives

잠재적 COX-2 억제작용이 있는 1,5-Diarylhydantoin유도체의 합성

  • 권순경 (덕성여자대학교 약학대학) ;
  • 박해선 (덕성여자대학교 약학대학)
  • Published : 2004.04.01
Download PDF
⟨ Previous Next ⟩

Abstract

For the development of new COX-2 inhibitors, 1,5-diarylhydantoins 5a∼5c and 1,5-diaryl-2-thiohydantoin 6a∼6c were synthesized from commercially available phenylacetic acids through esterification, bromination, C-N bond formation and cyclization. Esters 2a∼c were efficiently synthesized from the starting materials 1a∼c by refluxing in absolute methanol for 3 hours with catalytic concentrated sulfuric acid. Bromination of 2a∼c was carried out with use of N-bomosuccinimide at rt in dichloromethane. The bromine of 3a∼c was substituted with aniline in ethanol or N,N-dimethylformamide to provide 4a∼c. Hydantoins and 2-thiohydantoins were synthesized from 4a∼c by treatment of potassium isocyanate or potassium thiocyanate in dil-ethanol with triethylamine.

Keywords

References

  1. Vane, J. R. : Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Boil) 231, 232 (1971) https://doi.org/10.1038/newbio231232a0
  2. Chang, H. W. and Jahang, Y. : Selective cyclooxygenase-2 inhibitors as anti-inflammatory Agents. Korean J. of Med. Chem. 8, 48 (1998)
  3. Kwon, S. K. : SAR of COX-2 inhibitors. J. Appl. Pharmacol. 9, 69 (2001).
  4. Fletcher, B. S., Smith, W. L. and DeWittt, D. L. : J. Biol. Chem. 268, 6610 (1992)
  5. Gans, K. R., Galgraith, W., Roman, R. J., Haber, S. B., Kerr, J. S., Schmidt, W. K., Smith, C., Hewes, W. E. and Ackerman, N. R. : Antiinflammatory and safety profile of DuP-697, a novel orally effective prostaglandin synthesis inhibitor. J. Pharmacol. Exp. T her. 254, 180 (1990)
  6. Wilkerson, W. W. : Antiinflammatory 2-halo-4,5-diarylpyrrols, U.S. Pat. 4652582 (1987)
  7. Wilkerson, W. W., Galbraith, W., Gans-Brangs, K., Grubb, M., Hewes, W. E., Jaffee, B., Kenney, J. P., Kerr, J. and Wong, N : Antinflammatory 4,5-diarylpyrroles: synthesis and QSAR. J. Med. Chem. 37, 988 (1994)
  8. Graham Solomons, T. W. and Fryhle, C. B. : Organic chemistry, Wiley, pp. 366-402, 723 (2000)
  9. Wilkerson, W. W., Copeland, R. A. Covinton, M. and Trazaskos ，J. M. : Antiinflammatory 4,5-diarylpyrroles 2. Activity as a function of cyclooxygenase-2 inhibition. J. Med. Chem. 38, 3895 (1995)
  10. Janusz, J. M., Young, P. A., Ridgeway, J. M. and Scherz, M. W. : New cycloxygenase-2/5-lipoxygenase inhibitors. 1., J Med. Cham. 41, 1112 (1998)
  11. Acheson, R. M. : An introduction to the chemistry of heterocyclic compounds, Wiely International Edition, pp. 300-327 (1967)
  12. Janusz , J. M., Young, P. A., Scherz , M. W. and Enzweiler, K. : New cyclooxygenase-2/5-lipoxygenase inhibitors. 2, J. Med. Chem. 41, 1124 (1998) https://doi.org/10.1021/jm970680p
  13. Talley, J. J., Brown, D. L., Carter, J. S., Graneto, M. J., Koboldt, C. M., Masferrer, J. L., Perkins, W. E., Rogers, R. S., Shaffer, A. F., Zhang, Y. Y., Zweifel, B. S. and Seibert, K. : 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfo- namide, Valdecoxib: A potent and selective inhibitor of COX-2. J. Med. Chem. 43, 775 (2000).
  14. Kwon. S. K. and Park, M. S.: Synthesis of methoxybenzoylbenzisothiazine derivatives by Gabriel-Colman rearrangement. J. Kor. Chem. Soc. 40, 678 (1996)
  15. Penning, T. D., Talley, J. J., Bertenshaw, S. R., Carter，J. S., Collins, P. W., Docter, S., Graneto, M. J., Lee, L. F., Malecha, J. W., Niyashiro, J. M., Roger, R. S., Rogier, D. J. and Yu, S. S. : Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl)]benzenesulfonamide (SC-58635, Celecoxib). J. Med. Chem. 40, 1347 (1997).
  16. Li, J. P. : Synthesis of 1-substituted and 1,3-disubstituted 5hydantoin carboxylates. J. Org. Chem. 40, 3414 (1975) https://doi.org/10.1021/jo00911a024
  17. Park, M. S. and Park, H. S. : Synthesis of N-aryl pbromophenylglycine O-alkyl ester and its substitution of ester moiety. Yakhak Hoeji 47, 276 (2003)
  18. Smith, J. B. and Willis, A. L. : Aspirin selectivity inhibits prostaglandin production in human platelets. Nature (New BioI) 231, 235 (1971) https://doi.org/10.1038/newbio231235a0
  19. Copeland, R. A., Williams, J. N., Giannaras, J., Nurnberg, S., Covington, M., Pinto, D. and Pick, S. : Proc. Natl. Acad. Sci. USA 91, 11203 (1994)