Browse > Article

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

권순경 (덕성여자대학교 약학대학)
박해선 (덕성여자대학교 약학대학)
Publication Information
YAKHAK HOEJI / v.48, no.2, 2004 , pp. 135-140 More about this Journal
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
1,5-diarylhydantoin; 1,5-diaryl-2-thiohydantoin; COX-2 inhibitors;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Kwon, S. K. : SAR of COX-2 inhibitors. J. Appl. Pharmacol. 9, 69 (2001).
2 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)
3 Acheson, R. M. : An introduction to the chemistry of heterocyclic compounds, Wiely International Edition, pp. 300-327 (1967)
4 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).
5 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).
6 Li, J. P. : Synthesis of 1-substituted and 1,3-disubstituted 5hydantoin carboxylates. J. Org. Chem. 40, 3414 (1975)   DOI
7 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)
8 Smith, J. B. and Willis, A. L. : Aspirin selectivity inhibits prostaglandin production in human platelets. Nature (New BioI) 231, 235 (1971)   DOI
9 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)
10 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)
11 Graham Solomons, T. W. and Fryhle, C. B. : Organic chemistry, Wiley, pp. 366-402, 723 (2000)
12 Fletcher, B. S., Smith, W. L. and DeWittt, D. L. : J. Biol. Chem. 268, 6610 (1992)
13 Chang, H. W. and Jahang, Y. : Selective cyclooxygenase-2 inhibitors as anti-inflammatory Agents. Korean J. of Med. Chem. 8, 48 (1998)
14 Wilkerson, W. W. : Antiinflammatory 2-halo-4,5-diarylpyrrols, U.S. Pat. 4652582 (1987)
15 Kwon. S. K. and Park, M. S.: Synthesis of methoxybenzoylbenzisothiazine derivatives by Gabriel-Colman rearrangement. J. Kor. Chem. Soc. 40, 678 (1996)
16 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)   DOI   ScienceOn
17 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)
18 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)
19 Vane, J. R. : Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Boil) 231, 232 (1971)   DOI