Template for solution phase synthesis of combination libraries

Details Template for solution phase synthesis of combination libraries Template for solution phase synthesis of combination libraries

1998-04-07

2001-02-27

Venkat, Jyothsna (Department: 1627)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C435S007100, C435S091500, C436S501000, C436S518000, C436S536000, C530S334000, C562S869000, C562S887000, C564S152000, C564S155000, C564S159000, C564S163000, C564S166000, C564S168000, C564S169000, C564S180000, C564S185000, C564S186000, C564S193000, C564S194000, C564S195000, C564S196000, C564S197000, C564S199000, C564S200000

Reexamination Certificate

active

06194612

ABSTRACT:

BACKGROUND OF THE INVENTION
Two approaches have been used in efforts to discover novel chemicals useful in medicine, agriculture, or basic research. In the first approach of rational design, researchers perform structural studies to determine the three-dimensional structure of a target molecule in order to design compounds which are likely to interact with that structure. In the second approach, large libraries of compounds are screened for a desired biological activity. Compounds exhibiting activity in these screening assays become lead chemical compounds. Further study of compounds with structural similarity to the lead compounds can then lead to the discovery of other compounds with optimal activity.
Although traditional screening assays have focused on the screening of naturally occurring compounds, the ability to synthesize large combinatorial libraries of compounds with diverse structures has greatly increased the number of compounds available for screening. In combinatorial chemistry, each reactant from a first group of reactants is reacted with each reactant from a second group of reactants to yield products containing all the combinations possible from the reaction. If desired, all of the products from the first reaction are then reacted with each reactant from a third group of reactants to yield a large array of products. Additional reactions, if desired, can further increase the size of the library of compounds. Where it is desirable to use protection/deprotection protocols to prevent reactive groups from participating in a given reaction step, typically the same protocols are used for each compound in the growing library.
The generation and use of combinatorial chemical libraries for the identification of novel lead compounds or for the optimization of a promising lead candidate has emerged as a promising and potentially powerful method for the acceleration of the drug discovery process. (Terrett, N. K., et al., Tetrahedron 51:8135 (1995); Gallop, M. A., et al., J. Med. Chem. 37:1385 (1994); Janda, K. D., Proc. Natl. Acad. Sci. U.S.A. 91:10779 (1994); Pavia, M. R. et al., Bioorg. Med. Chem. Lett. 3:387 (1993)).
Initial studies focused on the synthesis of peptide or oligonucleotide libraries and related oligomeric structures. (See Gallop, supra, Geysen, H. M., et al., Proc. Natl. Acad. Sci. U.S.A. 81:3998 (1984); Lam, K. S., et al., Nature 354:82 (1991); Houghten, R. A., et al., Nature 354:84 (1991); Salmon, S. E. et al., Proc. Natl. Acad. Sci. U.S.A. 90:11708 (1993); Owens, R. A., et al., Biochem. Biophys. Res. Commun. 181:402 (1991); Bock. L. C., et al., Nature 355:564 (1992); Scott, J. K. and Smith, G. P., Science 249:386 (1990); Cwirla, S. E., et al., Proc. Natl. Acad. Sci. U.S.A. 87:6378 (1990); Devlin, J. J., et al., Science 249:404 (1990); Simon, R. J., et al., Proc. Natl. Acad. Sci. U.S.A. 89:9367 (1992); Zuckermann, R. N., et al., J.Am. Chem. Soc. 114:10646 (1992); Miller, S. M., et al., Bioorg. Med. Chem. Lett. 4:2657 (1994); Zuckerman, R. N., et al, J. Med. Chem. 37:2678 (1994); Terrett, N. K., et al., J. Bioorg. Med. Chem. Lett. 5::917 (1995); Cho, C. Y., et al., Science 261:1303 (1993); Winkler et al, WO93/09668 (PCT/US92/10183)); Ostresh, J. M., et al., Proc. Natl. Acad. Sci. U.S.A. 91:11138 (1994).
Because many ligands for biologically important receptors are non-peptide ligands, and because non-peptide compounds can mimic or block the effects of peptide ligands as well as non-peptide ligands, more recent efforts have been directed at exploiting the greater diversity and range of useful properties embodied in more conventional small molecule libraries. (See. e.g., Simon, R. J., et al., Proc. Natl. Acad. Sci. U.S.A. 89:9367 (1992); Zuckermann, R. N., et al., J.Am. Chem. Soc. 114:10646 (1992); Miller, S. M., et al., Bioorg. Med. Chem. Lett. 4:2657 (1994); Zuckerman, R. N., et al, J. Med. Chem. 37:2678 (1994); Terrett, N. K., et al., J. Bioorg. Med. Chem. Lett. 5::917 (1995); Cho, C. Y., et al., Science 261:1303 (1993); Winkler et al, WO93/09668 (PCT/US92/10183)); Ostresh, J. M., et al., Proc. Natl. Acad. Sci. U.S.A. 91:11138 (1994); Bunin, et al., J. Am. Chem. Soc. 114:10997 (1992); Bunin, et al., Proc. Natl. Acad. Sci. U.S.A. 91:4708 (1994); Virgilio, A. A. and Ellman, J. A., J. Am. Chem. Soc. 116:11580 (1994); Kick, E. K., and Ellman, J. A., J. Med. Chem. 38:1427 (1995); DeWitt, S. H., et al., Proc. Natl. Acad. Sci. U.S.A. 90:6909 (1993); Chen, C., et al., J. Am. Chem. Soc. 116:2661 (1994); Beebe, X., et al., J. Am. Chem. Soc. 114:10061 (1992); Moon, H. -S., et al., Tetrahedron Lett. 35:8915 (1994); Kurth, M. J., et al., J. Org. Chem. 59:5862 (1994); Gordon, D. W., and Steele, J., J. Bioorg. Med. Chem. Lett. 5;47 (1995); Patek, M., et al., Tetrahedron Lett. 35:9169 (1994); Patek, M., et al., Tetrahedron Lett. 36:2227 (1995); Campbell, D. A., et al., J. Am. Chem. Soc. 117:5381 (1995); Forman, F. W., and Sucholeiki, I., J. Org. Chem. 60:523 (1995); Rano, T. A, and Chapman, K. T., Tetrahedron Lett. 36:37879 (1995); Dankwardt, S. M., et al., Tetrahedron Lett. 36: 4923 (1995); Deprez, B., et al., J. Am. Chem. Soc. 117:5405 (1995); Ellman, U.S. Pat. No. 5,288,514).
A range of approaches to the synthesis of diverse chemical libraries have been disclosed including several methods utilizing solid supports. In solid support synthesis, a first reactant is linked to a solid support. This linkage may include a spacer linker arm connecting a functional group on the first reactant to a functional group on the solid support. Reaction of the first reactant bound to the solid support with a second reactant produces a desired product which is bound to the solid support, while unreacted second reactant remains unbound in solution. If desired, additional reactants can be added to the product of the first reaction in subsequent reactions.
Solid phase synthesis has been adapted from solid phase synthesis of peptides and oligonucleotides for use in the synthesis of small chemical libraries. Methods of synthesizing diverse chemical libraries on solid supports include split or mixed synthesis (Furka, A., et al., Abst. 14th Intl. Congress Biochem., Prague 5:47 (1988); Furka, A., et al., Int. J. Peptide Protein Res. 37:487 (1991); Houghten, R. A., Proc. Natl. Acad. Sci. U.S.A. 82:5131 (1985)); Erb, E., et al., Proc. Natl. Acad. Sci. U.S.A. 91:11422 (1994)), encoded synthesis (Brenner, S., and Lerner, R. A., Proc. Natl. Acad. Sci. U.S.A. 89:5381 (1992); Nielsen, J., et al., J. Am. Chem. Soc. 115:9812 (1993); Needels, M. C., et al., Proc. Natl. Acad. Sci. U.S.A. 90:10700 (1993); Nikolaiev, V., et al., Peptide Res. 6:161 (1993); Kerr, J. M., et al., J. Am. Chem. Soc. 115:2529 (1993); Ohlmeyer, M. H. J., et al., Proc. Natl. Acad. Sci. U.S.A. 90:10922 (1993); Nestler, et al., J. Org. Chem. 59:4723 (1994); Baldwin, J. J., et al., J. Am. Chem. Soc. 117:5588 (1995)), indexed synthesis (Pirrung, M. C. and Chen, J., J. Am. Chem. Soc. 117:1240 (1995); Smith, P. W., et al., Bioorg. Med. Chem. Lett. 4:2821 (1994)), or parallel and spatially addressed synthesis on pins (Geysen, et al., Proc. Natl. Acad. Sci. U.S.A. 81:3998 (1984); DeWitt, S. H., et al., Proc. Natl. Acad. Sci. U.S.A. 90: 6909 (1993)), beads (Merrifield, R. B., J. Am. Chem. Soc. 85:2149 (1963)), chips (Fodor, S. P. A., et al., Science 251: 767 (1991)), and other solid supports (Atherton, E. and Sheppard, R. C.,
Solid Phase Peptide Synthesis: A Practical Approach
(IRL Press: Oxford, 1989); Grubler, G., et al., in
Peptides: Chemistry, Structure, and Biology
(Proceedings of the Thirteenth American Peptide Symposium) (Hodges, R. A. and Smith, J. A., Eds., ESCOM-Leiden, The Netherlands, 1994) at 51; Englebretsen, D. R. and Harding, D. R. K., Int. J. Peptide Protein Res. 40:487 (1992); Frank, R., Bioorg. Med. Chem. Lett. 3:425 (1993); Frank, R. and Doring, R. Tetrahedron 44:031 (1988); Schmidt. M., et al., Bioorg. Med. Chem. Lett. 3:441 (1993); Eichler, J., et al., Peptide Res. 4:296 (1991)).
Some of the features of solid phase synthesis responsible for its widespread use in chemical synthesis are its repetitive coupling reactio

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