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Complex Combinatorial Chemical Libraries Encoded with Tags Europäisches Patentamt *EP000665897B1* (19) European Patent Office Office européen des brevets (11) EP 0 665 897 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C12Q 1/68, C07H 21/02, of the grant of the patent: C07H 21/04, A61K 48/00, 09.07.2003 Bulletin 2003/28 A61K 38/00 (21) Application number: 94900350.3 (86) International application number: PCT/US93/09345 (22) Date of filing: 01.10.1993 (87) International publication number: WO 94/008051 (14.04.1994 Gazette 1994/09) (54) COMPLEX COMBINATORIAL CHEMICAL LIBRARIES ENCODED WITH TAGS KOMPLEXE KOMBINATORISCHE CHEMISCHE BANKEN, DIE MIT MARKIERUNGEN VERSEHEN SIND BANQUES CHIMIQUES COMBINATOIRES COMPLEXES CODEES AVEC DES ETIQUETTES (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL WO-A-90/00626 WO-A-92/00091 PT SE WO-A-93/06121 WO-A-93/09668 WO-A-93/19205 WO-A-93/20242 (30) Priority: 01.10.1992 US 955371 WO-A-93/22684 US-A- 4 631 211 04.02.1993 US 13948 US-A- 4 755 558 (43) Date of publication of application: • JOURNAL OF THE AMERICAN CHEMICAL 09.08.1995 Bulletin 1995/32 SOCIETY., vol.114, no.27, 30 December 1992, GASTON, PA US pages 10997 - 8 B.A.BUNIN ET (73) Proprietors: AL. ’A General and Expedient Method for the • THE TRUSTEES OF COLUMBIA UNIVERSITY IN Solid-Phase Synthesis of 1,4-Benzodiazepine THE CITY OF NEW YORK Derivatives.’ New York, New York 10027 (US) • PROCEEDINGS OF THE NATIONAL ACADEMY • COLD SPRING HARBOR LABORATORY OF SCIENCES OF USA., vol.90, no.23, 1 Cold Spring Harbor New York 11724 (US) December 1993, WASHINGTON US pages 10922 - 10926 M.H.OHLMEYER ET AL. ’Complex (72) Inventors: Synthetic Chemical Libraries Indexed with • STILL, W., Clark Molecular Tags.’ Rhinebeck, NY 12572 (US) • P.N.A.S., Volume 89, issued June 1992, • OHLMEYER, Michael, H., J. BRENNER et al., "Encoded Combinatorial Plainsboro, NJ 08536 (US) Chemistry", pages 5381-5383, see entire • WIGLER, Michael, H. document. Lloyd Harbor, NY 11743 (US) • Nature, Volume 354, issued 07 November 1991, • DILLARD, Lawrence, W. LAM et al., "A New Type of Synthetic Peptide Plainsboro, NJ 08536 (US) Library for Identifying Ligand-Binding Activity", • READER, John, C. pages 82-84, see page 82, summary. Princeton, NJ 08540 (US) • Science, Volume 257, issued 17 July 1992, AMATO et al., "Speeding Up a Chemical Game of (74) Representative: VOSSIUS & PARTNER Change", pages 330-331, see entire document. Postfach 86 07 67 81634 München (DE) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 665 897 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 0 665 897 B1 • Nature, Volume 354, issued 07 November 1991, • J. AM. CHEM. SOC. vol. 115, 1993, pages 2529 - HOUGHTEN et al., "Generation and Use of 2531 Synthetic Peptide Combinatorial Libraries for • CLIN. CHEM. vol. 28, no. 9, 1982, pages 1844 - Basic Research and Drug Discovery", pages 1847 84-86, see entire document. • PROC. NATL. ACAD. SCI. vol. 90, 1993, pages • TRENDS ANAL CHEM vol. 2, 1983, page 166 10922 - 10926 • GEN vol. 14, 1994, pages 32 - 38 2 EP 0 665 897 B1 Description Introduction 5 Technical Field [0001] The field of this invention concerns combinatorial chemistry which involves syntheses having a plurality of stages, with each stage involving a plurality of choices, where large numbers of products having varying compositions are obtained. 10 Background of the Invention [0002] There is substantial interest in devising facile methods for the synthesis of large numbers of diverse com- pounds which can then be screened for various possible physiological or other activities. Typically such a synthesis 15 involves successive stages, each of which involves a chemical modification of the then existing molecule. For example, the chemical modification may involve the addition of a unit, e.g. a monomer or synthon, to a growing sequence or modification of a functional group. By employing syntheses where the chemical modification involves the addition of units, such as amino acids, nucleotides, sugars, lipids, or heterocyclic compounds where the units may be naturally- occurring, synthetic, or combinations thereof. One may create a large number of compounds. Thus, even if one re- 20 stricted the synthesis to naturally-occurring units or building blocks, the number of choices would be very large, 4 in the case of nucleotides, 20 in the case of the common amino acids, and essentially an unlimited number in the case of sugars. [0003] One disadvantage heretofore inherent in the production of large number of diverse compounds, where at each stage of the synthesis there are a significant number of choices, is the fact that each individual compound will 25 be present in a minute amount. While a characteristic of a particular compound, e.g. a physiological activity, may be determinable, it is usually impossible to identify the chemical structure of this particular compound present. [0004] Moreover, physiologically-active compounds have historically been discovered by assaying crude broths us- ing Edisonian or stochastic techniques, where only a relatively few compounds are assayed at a time, or where a limited number of structural similar homologs of naturally-occurring physiologically-active compounds are assayed. 30 Two of the major problems has been associated with the use of such crude broths, namely, the necessity to purify the reaction mixture into individual component compounds and the time-consuming effort required to establish the structure of the compound once purified. [0005] To address these disadvantages and problems, techniques have been developed in which one adds individual units as part of a chemical synthesis sequentially, either in a controlled or a random manner, to produce all or a sub- 35 stantial proportion of the possible compounds which can result from the different choices possible at each sequential stage in the synthesis. However, for these techniques to be successful it is necessary for the compounds made by them to be amenable to methods which will allow one to determine the composition of a particular compound so made which shows a characteristic of interest. [0006] one such approach involves using a chip which allows for separate analysis at physically separate sites on 40 the surface of the chip (Fodor et al., Science 251: 767 [1991]). By knowing what reactant is added sequentially at each such site, one can record the sequence of events and thus the series of reactions. If one then subjects the chip to a screening method for a particular desired characteristic and detects the characteristic one can really determine the compound synthesized at the site which demonstrates that characteristic. [0007] Another such technique involves the theoretical synthesis of oligonucleotides in parallel with the synthesis of 45 oligopeptides as the compounds of interest (Brenner and Lerner, PNAS USA [1992] 81: 5381-5383). [0008] Further techniques are also disclosed in the following publications: Amoto, Science (1992) 257, 330-331 discusses the use of cosynthesized DNA labels to identify polypeptides. Lam, et al., Nature (1991) 354, 82-84 describe a method for making large peptide libraries. Houghton, et al., Nature (1991) 354, 84-86 and Jung and Beck-Sickinger, Angew. Chem. Int. Ed. Engl. (1992) 91, 367-383 describe methodology for making large peptide libraries. Kerr et al., 50 J. Amer. Chem. Soc., (1993) 115, 2529-31 teach a method of synthesizing oligomer libraries encoded by peptide chains. [0009] In WO 93/06121 there is provided a general stochastic method for synthesizing random oligomers which can be used to synthesise compounds to screen for desired properties. The use of identification tags on the oligomers is reported to facilitate identification of oligomers with desired properties. In the identification process the tags are read on a solid support or are amplified while on the solid support. 55 [0010] In WO 93/09668 there is described a method and device for forming large arrays of polymers on a substrate. According to a preferred aspect of the invention, the substrate is contacted by a channel block having channels therein. Selected reagents are delivered through the channels, the substrate is rotated by a rotating stage and the process is repeated to.form arrays of polymers on the substrate. The method may be combined with lights directed to method 3 EP 0 665 897 B1 arches. The reaction history is retained by virtue of the molecules' location. [0011] In WO 93/22684 there is provided a method and library for determining the sequence of monomers in a polymer which is complementary to a receptor. The method provides for formation of pooled and separate products. Separate products are subjected only to subsequent pooled coupling steps. Each pooled product is subsequently 5 divided for formation of pools and separate products. The resulting polymer library includes groups of polymer products. A first group of products is used to identify the monomer at a first location in a polymer that is complimentary to a receptor. A second group of products is used to identify the monomer at a second location in a polymer that is com- plementary to a receptor. [0012] In WO 93/20242 there is disclosed an encoded combinatorial chemical library comprised of a plurality of bi- 10 functional molecules having both a chemical polymer and an identifier oligonucleotide sequence that defines the struc- ture of the chemical polymer.
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