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WO1996023749A1 - Banques chimiques, leur marquage et leur deconvolution - Google Patents

Banques chimiques, leur marquage et leur deconvolution Download PDF

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Publication number
WO1996023749A1
WO1996023749A1 PCT/GB1996/000197 GB9600197W WO9623749A1 WO 1996023749 A1 WO1996023749 A1 WO 1996023749A1 GB 9600197 W GB9600197 W GB 9600197W WO 9623749 A1 WO9623749 A1 WO 9623749A1
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WIPO (PCT)
Prior art keywords
label
library
inert
chemical
solid supports
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Application number
PCT/GB1996/000197
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English (en)
Inventor
Philip Neil Edwards
Brian Geoffrey Main
Richard Eden Shute
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Zeneca Limited
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Publication of WO1996023749A1 publication Critical patent/WO1996023749A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/14—Esterification
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/18—Introducing halogen atoms or halogen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/26—Removing halogen atoms or halogen-containing groups from the molecule
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B20/00—Methods specially adapted for identifying library members
    • C40B20/04—Identifying library members by means of a tag, label, or other readable or detectable entity associated with the library members, e.g. decoding processes
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • C40B50/16—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support involving encoding steps
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00457—Dispensing or evacuation of the solid phase support
    • B01J2219/00459—Beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/005—Beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
    • B01J2219/00572—Chemical means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
    • B01J2219/00572—Chemical means
    • B01J2219/00581—Mass
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00585—Parallel processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00592—Split-and-pool, mix-and-divide processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00596—Solid-phase processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • Chemical libraries may be assembled by a number of methods, including the 'combine/mix/divide' process described by Furka et al (Abstr. 14th Int.Congr.Biochem... Prague. Czechoslovakia. 1988. 5. 47: Int.J.Pept.Prot.Res. 1991. 37. 487-493) for creating libraries on polymer beads, in which each bead contains one discrete chemical species.
  • the individual components of the library may be tested either still attached to the polymer bead on which they were synthesised (Lam et al. Nature. 1991. 354. 82-84) or after cleavage from the bead (Salmon et al. Proc.Nat.Acad.Sci.USA.
  • a novel method for labelling a chemical library wherein one or more inert labels are attached to the beads prior to and/or during chemical library synthesis and are not modified under the conditions of chemical library synthesis. Therefore in a first aspect of the invention we provide a method for the preparation of a labelled chemical library which method comprises synthesising the library o a plurality of solid supports each of which is firstly provided with at least one inert label, so to provide a chemical library comprising a plurality of solid supports to each of which is attached at least one inert label and at least one member of the chemical library.
  • Suitable inert labels are species which remain attached to a solid support durin library synthesis but are not modified. Synthesis of the chemical library may comprise any convenient number of individual reaction steps.
  • Convenient inert labels for attachment include phenols, such as substituted phenols, thiophenols. such as substituted thiophenols. bicyclic phenols, such as substituted naphthols. biaryl phenols, such as substituted arylphenols, polycyclic phenols, such as substituted hydroxy-phenanthrenes and -anthracenes, hydroxy- and mercapto-substituted heterocycles. such as hydroxy- or mercapto-pyridines, -quinolines and -indoles. alcohols, such as substituted alcohols, arylalcohols. such as substituted benzylalcohols, phenylsilanols, such as substituted phenylsilanols. and silanols, such as substituted silanols.
  • phenols such as substituted phenols, thiophenols. such as substituted thiophenols.
  • Preferred inert labels are phenols, such as substituted phenols, thiophenols suc as substituted thiophenols. bicyclic phenols, such as substituted naphthols, and biarylphenols such as substituted biarylphenols.
  • Suitable substituents include alkyl groups (including straight or branched chain C1-C20, C1-C12. C1-C6 and C1-C4 alkyl groups) and inert substituents such as one or more halogen groups (including Cl, Br. F and I). Also included are halogenated alkyl groups wherein the halogen and alkyl groups are as indicated above.
  • the inert label(s) may be removed, for identification purposes, once library synthesis is complete.
  • Identification is effected using any convenient analytical technique. Convenientl the inert label is cleaved and detected for example by gas chromatography-mass spectrometr (GC-MS) or by liquid chromatography-mass spectrometry (LC-MS).
  • GC-MS gas chromatography-mass spectrometr
  • LC-MS liquid chromatography-mass spectrometry
  • substituted phenols suitable for use in the present invention are: 3 Me: 3-F; 3-Et: 3-C1; 3,5-di-F; 4-Pr; 3-F.4-C1; 4-sec-Bu: 4-Cl,3,5-di-Me; 3,5-di-Cl; 3-Br. These are just a few of the many possible choices.
  • the solid supports are conveniently beads, such as resin beads, or any species which may be used in chemical library synthesis, for example in combine/mix/divide processes.
  • the solid support is either inherently adapted, by way of its chemical structure, f reaction with the chemical compounds or is pre-treated.
  • a plurality of solid supports such as polystyrene beads is provided with chloromethyl, and/or aminomethyl and/or hydroxymethyl groups. Inert label(s) may be attached using appropriate chemistry to these groups.
  • Chloromethyl resins such as chloromethyl polystyrene beads are a particularly preferred solid support.
  • chloromethylpolystyrene beads are labelled by reaction with small amounts (for example 5-10%) of simple phenols containing inert substituents such as halogen and alkyl groups, in the presence of a base such as sodium methoxide.
  • small amounts for example 5-10%
  • inert substituents such as halogen and alkyl groups
  • a base such as sodium methoxide.
  • a library is then created, for example by the 'combine/mix/divide' or 'split synthesis' technique (Furka et al. opcit), utilising the remainder of the chloromethyl groups, then subsequent isolation of a bead which shows biological activity may be followed by identification of the substituent introduced last by reference to the reaction which produced it, as no 'mix' stage will have been done. Cleavage of the label(s) from the active bead allows identification of the batch of resin used for the first stage of the synthesis, and hence the nature of the first substituent used. Knowing these two substituents (first and last) limits the number of possible structures to a level where they may be identified by, for example. mass spectrometry or iterative resynthesis.
  • a method for the preparation of a labelled chemical library comprises synthesising the library on a plurality of solid supports each of which is firstly provided with at least one primary inert label, and introducing during library synthesis at least one further secondary inert label, so as to provide a chemical library comprising a plurality of solid supports to each of which is attached at least one primary inert label, at least one secondary inert label and at least one member of the library.
  • the secondary inert label is conveniently introduced by controlled modification of groups which form part of the one or more primary labels.
  • group(s) include bromo. iodo and trifluoromethanesulphonyloxy groups. Most convenient are bromo and iodo. These particular groups are conveniently presented on the solid support via substituted phenols. thiophenols. naphthols. arylphenols. aromatic hydroxy- or mercapto-heterocycles. aralkyl alcohols and phenylsilanols as defined hereinbefore, which are attached to the solid support by such methods as are also outlined above.
  • Preferred moieties are bromophenols. iodophenols. bromonaphthols.
  • iodonaphthols and bromo- or iodo-arylphenols Particularly preferred moieties are 3-bromophenol. 4-bromophenol. 3-iodophenol. 4- iodophenol. 6-bromo-2-naphthol and 4-(4'-bromophenyl)phenol.
  • the secondary inert label may be introduced via other groups present on the solid support.
  • latent groups that is to say they are inert with respect to compound library synthesis, but may participate in the introduction of one or mor inert secondary labels during library synthesis.
  • the particular chemistry which is used selectively to modify these latent groups and so introduce the secondary inert labels constitutes a further important aspect of this disclosure and is detailed hereinbelow.
  • the one or more secondary labels are conveniently introduced during library synthesis by for example such procedures as palladium-, nickel- or copper-catalysed cross- coupling reaction with an organometallic reagent, for example an arylboronate. an organostannane. organozinc or organolithium reagent, in a so-called Heck. Stille or Suzuki coupling reaction (see for example Deshpande. Tetrahedron Lett.. 1994, 35, 5613-4; Yu. et al Tetrahedron Lett., 1994. 35, 8919-22: Frenette and Friesen. Tetrahedron Lett., 1994, 35, 9177-80: Forman and Sucholeiki. J. Org. Chem.. 1995. 60. 523-8). Again if a mixture of fo example two secondary labels is used then a large number of combinations is possible for a relatively small number of secondary labels.
  • organometallic reagent for example an arylboronate. an organostannane. organozinc
  • the preferred synthesis of the secondary label is via a metal-catalysed cross- coupling reaction.
  • Particularly preferred is the palladium-catalysed cross-coupling of an arylboronic acid to a latent group in a so-called Suzuki coupling, where the intermedium moiety attached to the solid support is one of 3-bromophenol.
  • Preferred secondary inert labels include substituted phenols, naphthols or arylphenols.
  • Suitable phenol, naphthol or arylphenol substituents include alkenyl. alkynyl and aryl, especially phenyl, heterocyclyl and bicyclyl, and substituted aryl, especially substituted phenyl, heterocyclyl and bicyclyl.
  • Suitable aryl substitutents include chloro, fluoro, alkyl (C1-C4), alkoxy, aryl, trifiuorometh and mixtures of these, for example (methylfluorophenyl)phenol.
  • the secondary inert label(s may be removed, for identification pu oses. once library synthesis is complete. Identification is effected using any convenient analytical technique. Conveniently the secondary inert label(s) is(are) cleaved along with the primary inert label(s) as detailed above, and detected simultaneously by. for example. GC-MS or LC-MS.
  • chloromethylpolystyrene beads are derivatised by reaction with small amounts, between 1 % and 20%.
  • phenols for each library sub-pool.
  • These phenols are conveniently chosen from a set of between 5 and 50, and preferably between 5 and 20 primary label phenols, which contain inert substituents such as halogen and alkyl groups together with a small amount, between 1 and 20% and preferably between 5% and 10%. of a phenol containing a latent group, for example bromo or iodo. in the presence of a base such as sodium methoxide.
  • a library for example by utilising the remainder of the chloromethyl groups, and by a combine/mix/divide or split synthesis technique, wherein a particular inert label or labels designate a particular primary library substituent that has been added in the first round of synthesis, and wherein a particular secondary inert label or labels, which have been derived from the latent group, designate a particular intermediate library substituent that has been added in an intermediate round of synthesis, then subsequent isolation of a bead which shows or is associated with biological activity may be followed firstly by identification of the library substituent introduced in the last round of synthesis by reference to the reaction which produced it.
  • the chemical library may comprise any convenient number of individual members, for example tens to hundreds to thousands to millions etc.. of suitable compounds for example peptides. peptoids and other oligomeric compounds (cyclic or linear), and template-based smaller molecules, for example benzodiazepines. hydantoins. biaryls. polycyclic compounds (eg. naphthalenes, phenothiazines. acridines. steroids etc.), carbohydrate and amino acid derivatives, dihydropyridines. benzhydryls and heterocycles (e triazines. indoles etc.).
  • the numbers quoted and the types of compounds listed are illustrative, but not limiting.
  • Preferred library compounds are chemical compounds of low molecular weig and potential therapeutic agents. They are for example of less than about 1000 daltons. such as less than 800. 600 or 400 daltons. Synthesis of the compound library on the solid supports may comprise any convenient number of individual reaction steps.
  • any convenient biological of interest such as a receptor, enzyme or the like m be contacted with the chemical library as above in an assay or test system apparent to the scientist of ordinary skill.
  • the inert label or labels may not interact with the biological of interest to any significant extent.
  • Chemical libraries prepared according to the method of the invention are nove and in a further aspect of the invention we provide a chemical library comprising a plurality solid supports to each of which is attached at least one inert label and at least one member of the chemical library. Convenient solid supports and inert labels are as disclosed above. In a still further aspect we provide a chemical library comprising a plurality of solid supports to each of which is attached at least one inert primary label, at least one inert secondary label and at least one member of the chemical library.
  • the labels may be cleaved from the resin by treatment with a suitable cleavage agent, for example boron tribromide, or iodotrimethylsilane. or hydrogen together with a suitable metal catalyst, or a strong acid such as hydrogen fluoride (HF) or hydrogen bromide (HBr), either in the form of a vapour or dissolved in a suitable solvent, a optionally in the presence of suitable scavengers.
  • a suitable cleavage agent for example boron tribromide, or iodotrimethylsilane. or hydrogen together with a suitable metal catalyst, or a strong acid such as hydrogen fluoride (HF) or hydrogen bromide (HBr), either in the form of a vapour or dissolved in a suitable solvent, a optionally in the presence of suitable scavengers.
  • HF hydrogen fluoride
  • HBr hydrogen bromide
  • This list of cleavage agents is illustrative but not limiting. Particularly preferred is
  • a cleavage agent mixture of HBr. AcOH. acetic anhydride, and p-hydroxyphenylacetic acid is used.
  • the acetic anhydride ensures conversion of all the phenols to their acetates, thus simplifying the identification procedure, although identification is still possible without its use.
  • the p-hydroxyphenylacetic acid is used as a scavenger to remove the traces of bromine normally present in HBr. as this can cause the formation of bromophenols during label excision.
  • the mixture is treated with excess sodium or potassium bicarbonate solution, extracted with ethyl acetate, and the extract analysed by a suitable analytical technique, such as mass spectrometry (MS), or by linked analytical techniques, such as gas chromatography (GC)-MS or liquid chromatography (LC)- MS. in order to identify the label(s).
  • a suitable analytical technique such as mass spectrometry (MS), or by linked analytical techniques, such as gas chromatography (GC)-MS or liquid chromatography (LC)- MS.
  • Figure 1 outlines the covalent attachment of a single, substituted phenol label to a chloromethylpolystyrene polymer.
  • Figure 2 outlines the covalent attachment of a double, substituted phenol label to a chloromethylpolystyrene polymer.
  • Figure 3 outlines the chemical cleavage of substituted phenol labels, as their O- acetates, from the polymers illustrated in Figures 1 and 2.
  • the resin was collected by vacuum filtration and washed successively with DMF (4 times), dioxan (4 times), 1 : 1 dioxan/water (6 times), dioxan (4 times) and methanol (4 times).
  • the resin so obtained was dried to constant weight under vacuum at ambient temperature to afford 5.17 g.
  • a suspension of poly(chloromethystyrene) resin beads (5 g. Polymer Laboratories. PL-CMS Resin. 150-300 micron, capacity 4.0 meq./g) in dry DMF (42 mL) was swirled and purged with inert gas at ambient temperature for 5 minutes.
  • Sodium methoxide (0.11 g, 0.1 equivalents) was added, followed by a solution of 4-propylphenol (0.14 g, 0.05 equivalents) and 2.3,4-Trifluorophenol (0.15 g, 0.05 equivalents) in DMF (4ml. dried over 4A molecular sieve). The mixture was shaken at 50°C for 72 hours under an atmosphere of inert gas.
  • the resin was collected by vacuum filtration and washed successively with DMF (4 times), dioxan (4 times), 1 : 1 dioxan/water (6 times), and methanol (4 times). The resin so obtained was dried to constant weight under vacuum at ambient temperature to afford 5.31 g.
  • reaction mixture was then allowed to cool to room temperature and the resin was collected by filtration, washed successively with DME (twice), a 20% mixture of DME i 10% aqueous ammonia (5 times).
  • DME once).
  • THF twice
  • methanol once
  • THF once
  • methanol twice
  • ether twice

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  • Medicinal Chemistry (AREA)
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Abstract

Cette invention concerne un procédé de préparation d'une banque chimique marquée, consistant à synthétiser la banque sur plusieurs supports solides. Chacun de ces supports comporte au moins un marqueur inerte, lequel marqueur reste attaché à la phase solide et ne subit aucune altération lors de la synthèse de la banque. Ce procédé permet d'obtenir une banque chimique comportant plusieurs supports solides à chacun desquels est attaché au moins un marqueur inerte, et au moins un élément de la banque chimique.
PCT/GB1996/000197 1995-02-04 1996-01-30 Banques chimiques, leur marquage et leur deconvolution WO1996023749A1 (fr)

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US5961923A (en) * 1995-04-25 1999-10-05 Irori Matrices with memories and uses thereof
US6100026A (en) * 1995-04-25 2000-08-08 Irori Matrices with memories and uses thereof
US6284459B1 (en) 1995-04-25 2001-09-04 Discovery Partners International Solid support matrices with memories and combinatorial libraries therefrom
US6878557B1 (en) 1995-01-20 2005-04-12 Arqule, Inc. Logically ordered arrays of compounds and methods of making and using the same
US7034110B2 (en) 1994-01-05 2006-04-25 Arqule, Inc. Method of identifying chemical compounds having selected properties for a particular application

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CA2285175A1 (fr) * 1997-03-28 1998-10-08 Smithkline Beecham Corporation Lieur de type rink-chlorure pour synthese organique en phase solide de molecules organiques
CA2289719A1 (fr) * 1997-05-08 1998-11-12 Ravi S. Garigipati Lieur chlorure pour syntheses organiques en phase solide
US6096496A (en) * 1997-06-19 2000-08-01 Frankel; Robert D. Supports incorporating vertical cavity emitting lasers and tracking apparatus for use in combinatorial synthesis
GB9718415D0 (en) * 1997-08-29 1997-11-05 Smithkline Beecham Plc Formulation

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GB2297551A (en) 1996-08-07

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