Combinatorial approaches to pharmacophoric heterocycles: A solid-phase synthesis of 3,1-benzoxazine-4-ones

Biotechnology and Bioengineering

Volumn 61, Issue 1, 1998, Pages 13-16

  Gordeev, Mikhail F ^a  

^a Versicor Inc   (United States)

Author keywords

3,1 benzoxazine 4 ones; Heterocyclic acylating agents; Serine protease inhibitor; Solid phase synthesis

Indexed keywords

AGENTS; AMINO ACIDS; AROMATIC COMPOUNDS; BIOSYNTHESIS; CATALYST ACTIVITY; ENZYME INHIBITION; KETONES;

ACYLATING AGENTS; BENZOXAZINES; PHARMACOPHORES; SERINE PROTEASE; SOLID PHASE SYNTHESIS;

DRUG PRODUCTS;

3,1 BENZOXAZINE 4 ONE; UNCLASSIFIED DRUG;

ACETYLATION; ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CHEMICAL STRUCTURE; CYCLIZATION; ENZYME INHIBITION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; NUCLEAR MAGNETIC RESONANCE; PHARMACOPHORE; SYNTHESIS;

EID: 0032401950     PISSN: 00063592     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1097-0290(199824)61:1<13::AID-BIT5>3.0.CO;2-1     Document Type: Article

References (29)

1. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b) Gordon, E. M. Curr. Opin. Biotechnol. 1995, 6, 624; (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144; (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 134; (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555; (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527; (g); (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1997, 53, 5643.
2. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b) Gordon, E. M. Curr. Opin. Biotechnol. 1995, 6, 624; (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144; (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 134; (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555; (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527; (g); (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1997, 53, 5643.
3. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b) Gordon, E. M. Curr. Opin. Biotechnol. 1995, 6, 624; (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144; (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 134; (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555; (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527; (g); (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1997, 53, 5643.
4. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b) Gordon, E. M. Curr. Opin. Biotechnol. 1995, 6, 624; (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144; (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 134; (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555; (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527; (g); (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1997, 53, 5643.
5. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b) Gordon, E. M. Curr. Opin. Biotechnol. 1995, 6, 624; (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144; (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 134; (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555; (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527; (g); (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1997, 53, 5643.
6. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b) Gordon, E. M. Curr. Opin. Biotechnol. 1995, 6, 624; (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144; (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 134; (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555; (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527; (g); (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1997, 53, 5643.
7. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b) Gordon, E. M. Curr. Opin. Biotechnol. 1995, 6, 624; (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144; (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 134; (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555; (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527; (g); (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1997, 53, 5643.
8. SPS offers serious advantages in comparison with traditional solution-phase methodologies, such as high chemical efficiencies resulting from application of excess reagents, easy splitpool manipulations, and biological testing of nanomolar amounts of materials both in immobilized and solution-phase formats.
9. Kick, E. K.; Roe, D. C.; Skillman, A. G.; Liu, G.; Ewing, T. J. A.; Sun, Y.; Kuntz, I. D.; Ellman, J. A. Chem. Biol. 1997, 4, 297.
10. Edwards, P. D.; Bernstein, P. R. Med. Res. Rev. 1994, 14, 127.
11. (a) Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J.; Copp, L. J.; Thomas, E. M.; Rafferty, S. P. J. Med. Chem. 1990, 33, 464;
12. (b) Neumann, U.; Stuerzebecher, J.; Leistner, S.; Vieweg, H. J. Enzyme Inhib. 1991, 4, 227;
13. (c) Guetschow, M.; Neumann, U. Monats. Chem. 1995, 126, 1145;
14. (d) Yasuhide, U.; Jun-Ichi, O.; Hiroshi, K.; Masayuki, K.; Yoshinori, K.; Katsuhiko, F. Biochem. Pharmacol. 1994, 48, 426;
15. (e) Gilmore, J. L.; Hays, S. J.; Caprathe, B. W.; Lee, C.; Emmerling, M. R.; Michael, W.; Jaen, J. C. Bioorg. Med. Chem. Lett. 1996, 6, 679;
16. (f) Uejima, Y.; Kokubo, M.; Oshida, J.; Kawabata, H.; Kato, Y.; Fuji, K. Am. Rev. Respir. Dis. 1992, 145, A202;
17. (g) Jarvest, R. L.; Connor, S. C.; Gorniak, J. G.; Jennings, L. J.; Seafinowska, H. T.; West, A. Bioorg. Med. Chem. Lett. 1997, 7, 1733.
18. For a review on solution-phase chemistry of benzoxazinones, see: Sainsbury, M. In Comprehensive Heterocyclic Chemistry: Review of the Literature 1982-1995; The Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds. Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds. NY: Elsevier: New York 1996; Vol. 6, p 301.
19. For some prior routes to immobilized isocyanates and synthetic equivalents thereof, see: (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055; (b) Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589; (c) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439; (d) Scialdone, M. A. Tetrahedron Lett. 1996, 37, 8141-8144; (e) Xiao, X.-Y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968.
20. For some prior routes to immobilized isocyanates and synthetic equivalents thereof, see: (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055; (b) Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589; (c) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439; (d) Scialdone, M. A. Tetrahedron Lett. 1996, 37, 8141-8144; (e) Xiao, X.-Y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968.
21. For some prior routes to immobilized isocyanates and synthetic equivalents thereof, see: (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055; (b) Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589; (c) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439; (d) Scialdone, M. A. Tetrahedron Lett. 1996, 37, 8141-8144; (e) Xiao, X.-Y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968.
22. For some prior routes to immobilized isocyanates and synthetic equivalents thereof, see: (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055; (b) Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589; (c) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439; (d) Scialdone, M. A. Tetrahedron Lett. 1996, 37, 8141-8144; (e) Xiao, X.-Y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968.
23. For some prior routes to immobilized isocyanates and synthetic equivalents thereof, see: (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055; (b) Hauske, J. R.; Dorff, P. Tetrahedron Lett. 1995, 36, 1589; (c) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439; (d) Scialdone, M. A. Tetrahedron Lett. 1996, 37, 8141-8144; (e) Xiao, X.-Y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968.
24. In model cyclizations of the resin-bound urea 5d into respective BOX 6d, practically identical results were observed for each of reactions employing the aforementioned coupling reagents. DIC in THF has been selected for subsequent syntheses as a mild and non-acidic reagent compatible with a wide range of solid supports.
25. Side chains deprotected with 5% TES-40% TFA in DCM: Tyr(t-Bu), Lys(Boc), Glu(t-Bu), Asp(t-Bu).
26. Polystyrene-based 2-methoxy-4-alkoxybenzyl alcohol resin: Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P. Tetrahedron Lett. 1988, 29, 4005.
27. 13C NMR technique and underscores a need in a combination of analytical methods for studying chemical transformations on a solid phase.
28. 3 (δ, ppm): 1.98-2.17 (m, 4 H), 2.72 (s, 3 H), 3.60-3.80 (m, 2 H), 4.64 (m, 1 H), 7.02 (d, J = 7.4 Hz, 1 H), 7.11 (d, J = 8.2Hz, 1 H), 7.51 (m, 1 H).
29. Gordeev, M. F.; Hui, C. H.; Gordon, E. M.; Patel, D. V. Tetrahedron Lett. 1997, 38, 1729.