Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-08-20
2001-01-23
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S171000, C548S217000, C548S224000, C514S367000, C514S375000
Reexamination Certificate
active
06177572
ABSTRACT:
BACKGROUND OF THE INVENTION
The synthesis and screening of small molecule combinatorial libraries has become an important new technology for drug discovery. (For reviews see: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M.
J. Med. Chem.
1994, 37, 1233. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A.
J. Med. Chem.
1994, 37, 1385. (c) Moos, W. H.; Green, G. D.; Pavia, M. R. Recent Advances in Generation of Molecular Diversity. in
Annual Reports in Medicinal Chemistry;
Bristol, J. A., Ed.; Academic Press, Inc.; San Diego, Calif., 1993; Vol. 28, pp. 315-324. (d) Ecker, D. J.; Crooke, S. T.
Biotechnology
1995, 13, 351. (e) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele J. Tetrahedron 1995, 51, 8135. (f) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (g) Herkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Tetrahedron,
1996, 52, 4527. (h) Fruchtel, J. S.; Jung, G.
Angew. Chem. Int. Ed. Engl.
1996, 35, 17.) A convenient format for the generation of these libraries is synthesis of organic compounds on a solid phase. Solid phase synthesis is especially useful for reactions where excess reagents can be used to drive the reactions to completion. The excess reagents and soluble byproducts can be easily removed. (See, for example: (a) Kurth, M. J.; Randall, L. A. A.; Chen, C.; Melander, C.; Miller, R. B. J.
Org. Chem.
1994, 59, 5862. (b) Hiroshige, M.; Hauske, J. R.; Zhou, P. J.
Am. Chem. Soc.
1995,117,11590. (c) Wipf, P.; Cunningham, A.
Tetrahedron Lett.
1995, 36, 7819. (d) Goff, D. A.; Zuckermann, R. N.
J. Org. Chem.
1995, 60, 5744. (e) Plunkett, M. J.; Ellman, J. A.
J. Org. Chem.
1995, 60, 6006. (f) Kick, E. K.; Ellman, J. A.
J. Med. Chem.
1995, 38, 1427. (g) Forman, F. W.; Sucholeiki, I.
J. Org. Chem.
1995, 60, 523. (h) Holmes, C. P.; Jones, D. G.
J. Org. Chem.
1995, 60, 2318. (i) Holmes, C. P.; Chinn, J. P.; Look, G. C.; Gordon, E. M.; Gallop, M. A.
J. Org. Chem.
1995, 60, 7328.) Another important feature of solid phase synthesis is allowing “split and combine” methodology to be employed for library construction. Thus, generating diverse combinatorial libraries requires the development of solid phase syntheses of biologically active molecules on solid support, and the exploration of such synthetic methodologies for preparation of libraries.
Often compounds isolated from natural products have biological activity. For example, benzoxazole containing compounds, isolated from natural products or synthesized, have remarkable biological activities. (See: Boyd, G. V. In
Comprehensive Heterocyclic Chemistry,
Vol. 6; Part 4B, Katritzky, A. R.; Rees, C. W., Eds.; Pergammon: Oxford, 1984; p178.) The boxazomycins A, B, and C, isolated from a soil sample in Taiwan, are gram-positive antibacterial agents containing the benzoxazole ring system. (See: (a) Kusumi, T.; Ooi, T; Walchi, M. R.; Kakisawa, H.
J. Am. Chem. Soc.
1988, 110, 2954. (b) Suto, M. J.; Turner, W. R.
Tetrahedron Lett.
1995, 36, 7213.) The 4-carboxybenzoxazole ring system is found in nature in number of polycyclic antibiotics, such as X-14885A, Calcimycin and Cezomycin. (See: (a) Chaney, M. O.; Demarco, P. V.; Jones, N. D.; Occolowitz, J. L.
J. Am. Chem. Soc.
1974, 96, 1932. (b) David, L.; Dergomard, A.
J. Antibiotic.
1982, 35, 1409. (c) Westly, J. W.; Liu, J. W.; Blount, J. F.; Sello, L. H.; Troupe, N.; Miller, P. A.. J.
Antibiotic.
1983, 36, 1275.) A variety of 2-substituted benzoxazoles have been claimed to possess antiparasitic activity against
Turbatrix aceti, Syphacia obvelata, Nippostronglyus brasiliensis, helminths, Eimeria tenella
and
Eimeria necatrix,
and
S. obvelata
and
Aspicularis tetraptera.
(See: (a) Haugwitz, R. D.; Maurer, B. V.; Jacobs, G. A.; Narayanan, V. L.; Cruthers, L. R.; Szanto, J.
J. Med. Chem.
1979, 22, 1113. (b) Haugwitz, R. D.; Angel, R. G.; Jacobs, G. A; Maurer, B. V.; Narayanan, V. L.; Cruthers; Szanto, J.
J. Med. Chem.
1982, 25, 969.) Evans and co-workers synthesized 2-aryl-6-benzoxazoleacetic acid derivatives and screened the compounds for anti inflammatory activity on the carrageenan-induced rat paw edema test. (See: (a) Dunwell, D. W. ; Evans, D.; Hicks, T. A.; Cashin, C. H.; Kitchen, A.
J. Med. Chem.
1975, 18, 53. (b) Dunwell, D. W.; Evans, D.; Hicks, T. A. J. Med. Chem. 1975, 18, 1158. (c) Evans, D.; Smith, C. E.; Williamson, W. R. N.
J. Med. Chem.
1977, 20, 169. (d) Dunwell, D. W.; Evans, D. J. Med. Chem. 1977, 20, 797.) Recently, a series of peptidyl-ketobenzoxazoles were synthesized and evaluated for their in vitro and in vivo inhibition of human neutrophil elastase. (See: (a) Edwards, P. D.; Meyer, E. F.; Vijahalakshmi, J.; Tuthill, P.A.; Andisik, D. A.; Gomes, B.; Strimpler, A.
J. Am. Chem. Soc.
1992, 114, 1854. (b) Edwards, P. D.; Damewood, J. R.; Steelman, G. B.; Bryant, C.; Gomes, B.; Williams, J.
J. Med. Chem.
1995, 38, 87. (c) Edwards, P. D.; Zottola, M. A.; Davis, M.; Williams, J.; Tuthill, P.A.
J. Med. Chem.
1995, 38, 3972.) A Japanese group reported that imidazo[1,2--]pyridinylbenzoxazoles exhibited antiulcer activity in the anti-stress ulcer screen in rats. (See: (a) Katsura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Takasugi, H.
Chem. Pharm. Bull.
1992, 40, 371. (b) Katsura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Itoh, H. Takasugi, H.
Chem. Pharm. Bull.
1992, 40, 1424.)
Preparation of heterocyclic containing compounds, such as, for example, benzoxazoles, can be synthetically challenging. Often multiple synthetic steps are required to prepare the desired heterocyclic compound. As a consequence of multistep syntheses, reaction conditions utilized to form heterocyclic compounds such as benzoxazoles and benzothiazoles can facilitate degradation of the remaining molecular functionality. Additionally, synthetic manipulation of a molecule which contains a benzoxazole, for example, can cause degradation of the benzoxazole portion of the molecule.
SUMMARY OF THE INVENTION
The invention relates to heterocyclic containing compounds, such as benzoxazoles and benzothiazoles, libraries of these compounds, and methods of preparing and using the compounds.
In one aspect, the invention provides methods for preparing a benzoxazole or a benzothiazole via solid phase synthesis. The method includes the step of treating a 2-amidophenol or a 2-amidothiophenol with a cyclization-dehydration agent under suitable conditions, wherein the 2-amidophenol or 2-amidothiophenol is coupled to a solid phase support through a linker group, such that a benzoxazole or a benzothiazole is formed.
In another aspect, the invention provides methods for preparing a compound represented by the formula (Formula I):
A is a substituted or unsubstituted aryl or heteroaryl group and Y is O or S. R
1
is a linear or branched, substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a linker group attached to a solid support, or a salt thereof. The method includes reacting a compound having the formula (Formula
wherein Y is O or S, with a cyclization-dehydration reagent under suitable conditions such that a compound of Formula I is formed.
In yet another aspect, the invention provides methods of preparing a compound represented by the formula (Formula III):
A is a substituted or unsubstituted aryl or heteroaryl group and Y is O or S. R
1
is a linear or branched, substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a linker group attached to a solid support. R
2
is a linear or branched, substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a salt thereof. The method includes reacting a compound having the formula (Formula IV)
wherein Y is O or S, with a cyclization-dehydration reagent under suitable conditions such that a compound of Formula III is formed.
In yet another aspect, the invention provides methods for preparing a library including benzoxazoles, benzothiazoles or both via solid phase synthesis. The method includes treating a plurality of 2-amidophenols, 2-
Foley Hoag & Eliot LLP
Gordon Dana M.
Higel Floyd D.
Sepracor Inc.
Vincent Matthew P.
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