EP1585830A2 - Groupes protecteurs photoactivables subissant un traitement en deux etapes, destines a la synthese de biopolymeres - Google Patents

Groupes protecteurs photoactivables subissant un traitement en deux etapes, destines a la synthese de biopolymeres

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Publication number
EP1585830A2
EP1585830A2 EP03782479A EP03782479A EP1585830A2 EP 1585830 A2 EP1585830 A2 EP 1585830A2 EP 03782479 A EP03782479 A EP 03782479A EP 03782479 A EP03782479 A EP 03782479A EP 1585830 A2 EP1585830 A2 EP 1585830A2
Authority
EP
European Patent Office
Prior art keywords
group
synthesis
photoactivatable
optionally
groups
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03782479A
Other languages
German (de)
English (en)
Inventor
Barbro Beijer
Ramon GÜIMIL
Matthias Scheffler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Febit Holding GmbH
Original Assignee
Febit Biotech GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10260592A external-priority patent/DE10260592A1/de
Priority claimed from DE10260591A external-priority patent/DE10260591A1/de
Application filed by Febit Biotech GmbH filed Critical Febit Biotech GmbH
Publication of EP1585830A2 publication Critical patent/EP1585830A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • 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
    • C40B50/18—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 using a particular method of attachment to the solid support
    • 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
    • B01J2219/00576—Chemical means fluorophore
    • 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
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • 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
    • B01J2219/00709—Type of synthesis
    • B01J2219/00711—Light-directed synthesis
    • 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
    • B01J2219/00722—Nucleotides

Definitions

  • the present invention relates to a method for the synthesis of biopolymers by step-by-step construction from protected synthetic building blocks which carry two-stage protective groups.
  • the two-stage protective groups are activated by a first exposure step and a subsequent chemical treatment step is split off. Photoactivatable components are used which significantly accelerate the activation process via intramolecular triplet sensitizers and / or have fluorescence properties.
  • the two-stage protection groups can be used in particular as part of a quality control.
  • Biochips have become significantly more important for research and diagnostics because they allow fast and highly parallel processing of complex biological questions. For this, however, chips of the highest quality are required, so that there is great interest in new, more effective synthesis methods.
  • Photolabile nucleoside derivatives are used in the light-controlled synthesis of nucleic acid chips.
  • the chain structure of the nucleic acid fragments usually takes place by means of phosphoramidite synthons.
  • the blocks each have a temporary photo protection group that can be removed by exposure to light.
  • the synthesis principle sees a cyclic sequence of condensation and deprotection steps (through light).
  • the efficiency with which such a light-controlled synthesis can take place is essentially determined by the photolabile protective groups used, in particular by the efficiency with which these can be removed in the irradiation step.
  • the photo-protecting groups hitherto used for light-controlled synthesis are usually the protective groups NVOC (SPA Fodor et al., Science 251 (1991), 767 ff.), MeNPOC (AC Pease et al., Proc. Natl. Acad. 91 (1994), 5022 ff.), DMBOC (MC Pirrung, J. Chem. 60 (1995), 1116 ff.) And NPPOC (A. Hassan et al., Tetrahedron 53 (1997), 4247 ff.) , Further known photolabile protective groups in nucleoside or nucleotide chemistry are o-nitrobenzyl groups and their derivatives (see, for example, Pillai, Org. Photochem.
  • the photolabile protecting groups currently used for light-controlled synthesis of nucleic acids are generally characterized by a comparatively low
  • the photolabile nucleoside derivatives are usually irradiated with mercury
  • Wavelength means that only a very small proportion of the incident light can be used to excite the molecules.
  • the two-stage protective groups are preferably trityl derivatives which are coupled to a photoactivatable protective group.
  • the trityl derivatives can also contain fluorescent groups.
  • photoactivatable groups are linked according to the present invention with a second component, the cleavage conditions of which are orthogonal to those of the photoactivatable groups, and the removal of which only leads to the release of the actual protective group, which by chemical means, eg acid catalyzed, can be split off.
  • the protective group split off by chemical agents, which is preferably colored or / and fluorescent, can be used for quality control in the synthesis of biopolymers.
  • a novel protective group in which the activation step is light-induced and the actual deprotection step at the reaction center by chemical means, e.g. acid catalyzed, takes place (Fig. 1).
  • This novel protective group or molecules carrying this protective group can be used for the synthesis of biopolymers.
  • the invention thus relates to a process for the synthesis of biopolymers by step-wise construction from synthetic building blocks which carry protective groups, with at least one synthetic building block used, which bears a two-stage protective group, which is activated by an exposure step and is split off by a subsequent chemical treatment step, the triplet-sensitized group, a labeled, for example fluorescent, triplet-sensitized group and / or a marked, for example fluorescent and triplet-sensitized group, as the photoactivatable group is used.
  • the exposure step preferably comprises the cleavage of a first photolabile component of the protective group, a second component of the protective group remaining which is essentially stable to the conditions prevailing when the first component is cleaved and which can subsequently be cleaved off by a chemical treatment step.
  • the chemical treatment step preferably comprises a treatment with base, a treatment with acid, an oxidation, a reduction and / or catalytic, for example an enzymatic, reaction.
  • the chemical treatment step particularly preferably comprises an acid treatment.
  • a derivatized trityl group is used as the two-stage protective group. Trityl groups are distinguished by their excellent cleavage, in particular by treatment with acid.
  • the two-stage trityl protective groups according to the invention are preferably not acid-labile, but are only converted into an acid-labile form after activation and removal of one or more photolabile components.
  • Triplet-sensitized photoactivatable groups or labeled, e.g. fluorescent, and triplet-sensitized photoactivatable groups have on the one hand a high molar extinction coefficient at the irradiated wavelength to contribute to a significant increase in the population in the triplet state, and on the other hand are able to carry a tertiary radical in the aci -Nitro form to stabilize via I or M effects. This leads to an increase in the overall quantum yield of the Activation step. Labeled photoactivatable groups (without triplet sensitization) only show a high molar extinction coefficient at the irradiated wavelength, but do not have a direct influence on the activation process. All of the types of photoactivatable groups mentioned are particularly suitable in quality control, for example in fluidic microprocessors, as described, for example, in WO 00/13018.
  • a synthesis building block with a two-stage protecting group which has the general formula (I), is therefore particularly preferably used:
  • R., and R 2 are each independently selected from hydrogen, (L) - R 3 , O- (L) -R 3 , N (R 3 ) 2.
  • R 3 is a C r C 8 alkyl group, represents a C 2 -C 8 alkenyl group, a C 2 -C 8 alkynyl group, a C 6 -C 25 aryl group or / and a C 5 -C 25 heteroaryl group which may optionally have one or more substituents
  • L one optionally existing linker group is, for example - (CH 2 ) n -, - (CH 2 ) n -COO-, - (CH 2 ) n -CONH- or - (CH 2 ) n -SO 2 O-, - (CH 2 ) n -O-, - (CH 2 ) n -S- or - (CH 2 ) n -NH-, and n is an integer of 0 to 20,
  • the alkyl, alkenyl and alkynyl groups can be linear or cyclic, straight-chain or branched.
  • the aryl or heteroaryl groups for example N, O or / and S heteroaryl groups, can be mono- or polycyclic.
  • substituents of alkyl, alkenyl, alkynyl, aryl and heteroaryl groups are halogen, for example F, Cl, Br, I, OH, SH, -O-, -S-, -S (O) 2 -, NO 2 , CN, COOH, CO-C r C 8 -alkyl, COO-C r C 8 -alkyl, OCO-C r C 8 -alkyl, CONH-C r C 8 -alkyl, CON- (C r C 8 - Alkyl) 2 , C r C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C r C 8 -alkoxy, -SC C 8 -alkyl, di- (CC 8 -alkyl) - Amino and NHZ, where the alkyl, alkenyl, alkynyl and alkoxycarbonyl
  • R. and R 2 are hydrogen, dialkylamine, for example N, N-dimethyl, O-methyl, OCOO-methyl or a protected amino group, for example an amino group converted into an amide function with a suitable carboxylic acid.
  • the number of carbon atoms in the radicals R, and R 2 of the compound is preferably limited to 25 each.
  • the invention also relates to compounds which carry a plurality of photoactivatable protective groups, in particular compounds of the formula (I) in which at least one of R., or R 2 is replaced by a photoactivatable protective group Y.
  • photoactivatable protective groups There are preferably 1 to 3 photoactivatable protective groups.
  • one or more marker groups can be present, which are attached to the photoactivatable component and / or to the chemically active component can be bound.
  • one or more labeling groups can be present at the o- and / or m-positions of the phenyl rings in the trityl system.
  • the acid lability can be adapted to the desired requirements.
  • labeled photoactivatable groups of the formula (II) are used:
  • Ar is a condensed polycyclic, preferably tetra-, penta- or hexacyclic, fluorescent aryl or heteroaryl
  • S, and S 2 are each independently selected from hydrogen, a CC 8 alkyl group, a C 2 -C 8 alkenyl group, one C 2 -C 8 alkynyl group, a C 6 -C 25 aryl or / and a C 5 -C 25 heteroaryl group, which may optionally have substituents
  • Q is a group for binding the photolabile component to the chemically removable component
  • the number of carbon atoms in the radicals Ar, S T and S 2 of the compound (II) is preferably limited to 25 in each case.
  • fluorescent aryl radicals examples include benzo [b] fluoranthrene, fluoranthrene, 9,10-diphenylanthracene, acenaphthylene or pyrene.
  • Substituents of the groups Ar, S., and S 2 are as previously defined for the compounds of the formula (I).
  • Q is preferably SO 2 , OCO, OCS or CS 2 .
  • UU 2 , U 4 and U 5 are each independently selected from hydrogen, halogen, NO 2 , U 6 , (L) -U 6 , O- (L) -U 6 , N (U 6 ) 2 and NHZ, U 6 C r C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 25 aryl or C 5 -C 25 heteroaryl, which may optionally have substituents, L one optionally existing linker group, for example as for compounds (I)
  • U 3 is a marker group, for example a fluorescent group, possibly bound via a linker group, for example as defined for the compound (I), and Q is a group for binding the photolabile component to the chemically cleavable component.
  • the number of carbon atoms in the radicals U, - U 5 is preferably limited to 25 in each case. Adjacent radicals can optionally form a 5- or 6-membered carbocyclic or heterocycl
  • the definition of the possible substituents on the radicals UU 2 , U 4 and U 5 is as described for the compounds (I).
  • Q is preferably SO 2 , OCO, OCS, CS 2 , CH 2 SO 4 CH 2 OCO ,. CH 2 OCS, CH 2 CS 2 etc.
  • the radical U 3 preferably has the structure -OL-NHCOM, where L is a linker with a chain length of preferably 1-10 atoms, for example C atoms, and optionally heteroatoms, such as O, S. or N, and M is a labeling group, for example a fluorescent group such as a pyrene or coumarin group.
  • the compounds of this type are based on conventional O-nitrobenzyl groups, e.g. NPPOC, NVOC, MeNPOC, into which a fluorophore was also introduced.
  • NPPOC O-nitrobenzyl groups
  • NVOC NVOC
  • MeNPOC MeNPOC
  • the resulting photoactivatable molecule has a label, but not triplet sensitization.
  • photoactivatable groups of the formula (V) are used, which are preferably triplet-sensitized and optionally labeled groups:
  • V u V 2 , V 3 , V 4 , V 5 and V 6 are each independently selected from hydrogen, halogen, NO 2 , V 7 , (L) -V 7 , O- (L) -V 7 , N ( V 7 ) 2 , NHZ and M, where V 7 C r C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 6 -C 25 aryl or C 5 -C 25 heteroaryl means, which may have substituents, L may be an optionally present linker group, for example as defined for the compounds (I), V 5 and V 6 may additionally be trialkylsilyl, M is a label which may be bonded via a linker group and Q is a group for binding the photolabile component to the chemically cleavable component.
  • the number of carbon atoms in the residues V, -V 6 is preferably limited to 25 each. Adjacent radicals can optionally form a 5- or 6-
  • the V 5 radical is particularly preferably an aryl, aryloxy, heteroaryl or heteroaryloxy group, which may be unsubstituted or may have up to three substituents (as previously defined).
  • Particularly preferred are polycyclic aryl, aryloxy, heteroaryl or heteroaryloxy groups, which show triplet sensitization and can optionally have their own fluorescence, especially if they have four or more contain condensed or fused rings, for example pyrenes, benzotb] fluoranthrenes, fluoranthrenes, 9,10-diphenylanthracenes, acenaphthylenes or corresponding oxy derivatives etc.
  • the invention also encompasses compounds that have multiple labels that are independently detectable.
  • suitable labels are fluorescent groups, luminescent groups, electrically detectable groups, for example ferrocenes, colored groups, radioactive groups, groups detectable by NMR, etc.
  • the labels contain at least one fluorescent group which is linked to another, independently detectable fluorescent group or another type of label , as mentioned above, can be combined.
  • one label is bound to the photolabile component of the protective group and the other label is bound to the chemically cleavable component, so that the selective cleavage of the photolabile component by loss of the first label but retention of the second label and the cleavage of the chemical component by loss of the second marker can be detected.
  • the invention encompasses compounds (I) which carry a plurality of fluorescent groups, for example compounds in which Y represents a fluorescent photo protective group or / and R 3 or Z fluorescent groups on the trityl structure (R. Ramage, FO Wahl, Tetrahedron Lett., 34 (1993), 7133) or molecules in which fluorescence was introduced by substitution on the trityl framework (JL Fourrey et al., Tetrahedron Lett., 28 (1987), 5157).
  • the labeling group on the chemically cleavable component is a fluorescent group, for example a coumarin or pyrene group, which is coupled to the trityl backbone via a linker group, for example a group as defined above, for example in p-, o- or / and m position of the phenyl rings in the trityl system.
  • a linker group for example a group as defined above, for example in p-, o- or / and m position of the phenyl rings in the trityl system.
  • the method according to the invention is used for the synthesis of biopolymers, the biopolymer to be synthesized being built up step by step from several synthesis building blocks.
  • the method for the synthesis of nucleic acids e.g. DNA or RNA used.
  • the method is also suitable for the synthesis of other biopolymers, such as peptides, peptide nucleic acids (PNA) or saccharides.
  • the synthesis building block can be a monomeric building block, e.g. a nucleoside derivative, or a peptide derivative, but also an oligomeric building block, e.g. a dimer or trimer, i.e.
  • the synthesis building block is particularly preferably a phosphoramidite building block.
  • nucleotide synthesis building blocks e.g. Phosphate or phosphonate building blocks can be used.
  • linker or spacer building blocks e.g. as phosphoramidites. Particularly preferred linkers or spacers as carriers of two-stage protective groups are described in DE 100 41 539.3.
  • the synthesis components according to the invention which carry a two-stage protective group, generally have more lipophilic properties than the synthesis components previously used in the prior art.
  • This lipophilicity increases the solubility of the synthesis building blocks, especially the phosphoramidite synthons, in organic solvents.
  • the possible more homogeneous reaction leads to a higher compared to the pure photolabile phosphoramidite synthons Coupling efficiency.
  • the cleavage of the colored trityl cation of the photo protection groups according to the invention which has a significantly higher absorption coefficient than the cleavage products in other photo deprotection processes, also opens up the possibility of direct online process control. This leads to an improvement in quality control for biochips.
  • the trityl group of the photo protection groups according to the invention also enables the selective functionalization of the 5'-hydroxy function. This leads to an enormous reduction in costs, since there is no need to separate the 3'-5 'isomers.
  • phosphoramidite building blocks which carry the two-stage protective group on the 5′-O atom of the sugar, in particular the ribose or the deoxyribose.
  • biopolymers can be carried out in the usual way, for example on a solid phase.
  • biopolymers which carry a different sequence of synthetic building blocks are particularly preferably produced in situ on a single carrier in the form of an array.
  • the invention further relates to compounds of the general formula (I)
  • R 1, Y, M and m are as previously defined and X represents a synthesis building block for the synthesis of biopolymers or a leaving group and where R-, or / and R 2 can optionally be replaced by Y.
  • X When X is a leaving group, it is a group that can be split off when the compound (I) reacts with another compound. X is preferably a leaving group which can be split off by reaction with a nucleophile, optionally in the presence of an auxiliary base such as pyridine. Preferred examples of X are: Cl, Br, I, tosylate, mesylate, trifluorosulfonate etc.
  • the schematic concept of the inven tive protection group concept is shown in Figure 1.
  • the synthesis building block (A) carries a two-stage protective group (BC).
  • the photolabile portion (B) of the protective group is split off.
  • the chemically labile component (C) of the protective group is split off by a second chemical treatment step, for example by adding acid, so that the synthesis component (A) is in active form.
  • Figures 2 and 3 show example substances from a preferred class of two-stage protective groups according to the invention. They are based on the acid-labile trityl group, but contain a photolabile triplet-sensitized component (V) in the p-position of a phenyl radical, which reduces or completely blocks the sensitivity to acid of the trityl group.
  • the photolabile component in Figure 3 shows its own fluorescence.
  • the protective group is converted into an acid-labile form by exposure and elimination of the photolabile component and can then be cleaved in the presence of acid with the liberation of the unprotected synthesis building block.
  • Figure 4 shows a further example substance according to the present invention, in which, in addition to the photolabile protective group Y, a fluorescent radical (instead of R is coupled to the trityl structure.
  • Figure 5 shows a preferred example of a compound (II), where Q is a group for coupling the photolabile component to the trityl backbone.
  • Figure 6 shows a preferred example of a compound (III), where L is a linker group and Q is a group for coupling the photolabile component to the trityl backbone.

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Abstract

L'invention concerne un procédé pour réaliser la synthèse de biopolymères par synthèse progressive à partir d'unités de synthèse protégées comportant des groupes protecteurs subissant un traitement en deux étapes. Lesdits groupes protecteurs sont activés lors d'une première étape d'exposition et séparés lors d'une étape de traitement chimique consécutive. Les constituants photoactivables utilisés accélèrent considérablement le processus d'activation par l'intermédiaire de sensibilisateurs intramoléculaires à l'état triplet et/ou présentent des propriétés de fluorescence. Lesdits groupes protecteurs peuvent être utilisés notamment dans le cadre d'un contrôle de qualité.
EP03782479A 2002-12-23 2003-12-23 Groupes protecteurs photoactivables subissant un traitement en deux etapes, destines a la synthese de biopolymeres Withdrawn EP1585830A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10260592 2002-12-23
DE10260592A DE10260592A1 (de) 2002-12-23 2002-12-23 Intramolekular triplettsensibilisierte o-Nitrophenylethyl-Photoschutzgruppen
DE10260591 2002-12-23
DE10260591A DE10260591A1 (de) 2002-12-23 2002-12-23 Photoaktivierbare zweistufige Schutzgruppen für die Synthese von Biopolymeren
PCT/EP2003/014822 WO2004058391A2 (fr) 2002-12-23 2003-12-23 Groupes protecteurs photoactivables subissant un traitement en deux etapes, destines a la synthese de biopolymeres

Publications (1)

Publication Number Publication Date
EP1585830A2 true EP1585830A2 (fr) 2005-10-19

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Country Link
US (1) US7737089B2 (fr)
EP (1) EP1585830A2 (fr)
AU (2) AU2003290117A1 (fr)
WO (2) WO2004058392A2 (fr)

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US20060111564A1 (en) 2006-05-25
US7737089B2 (en) 2010-06-15
WO2004058391A2 (fr) 2004-07-15
AU2003290117A1 (en) 2004-07-22
AU2003298235A1 (en) 2004-07-22
WO2004058391A3 (fr) 2004-08-26
AU2003290117A8 (en) 2004-07-22
WO2004058392A2 (fr) 2004-07-15
AU2003298235A8 (en) 2004-07-22
WO2004058392A3 (fr) 2004-08-26

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