+

WO2003033437A2 - Procede de fabrication d'inhibiteurs de la neuraminidase au moyen de la chimie combinatoire dynamique et composes ainsi obtenus - Google Patents

Procede de fabrication d'inhibiteurs de la neuraminidase au moyen de la chimie combinatoire dynamique et composes ainsi obtenus Download PDF

Info

Publication number
WO2003033437A2
WO2003033437A2 PCT/EP2002/011526 EP0211526W WO03033437A2 WO 2003033437 A2 WO2003033437 A2 WO 2003033437A2 EP 0211526 W EP0211526 W EP 0211526W WO 03033437 A2 WO03033437 A2 WO 03033437A2
Authority
WO
WIPO (PCT)
Prior art keywords
neuraminidase
groups
formula
group
compounds
Prior art date
Application number
PCT/EP2002/011526
Other languages
English (en)
Other versions
WO2003033437A3 (fr
Inventor
Christoph Steeneck
Alexey V. Eliseev
Matthias Hochguertel
Heiko Kroth
Original Assignee
Therascope Ag
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
Application filed by Therascope Ag filed Critical Therascope Ag
Publication of WO2003033437A2 publication Critical patent/WO2003033437A2/fr
Publication of WO2003033437A3 publication Critical patent/WO2003033437A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B30/00—Methods of screening libraries
    • C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/924—Hydrolases (3) acting on glycosyl compounds (3.2)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/20—Screening for compounds of potential therapeutic value cell-free systems

Definitions

  • the present invention relates to dynamic combinatorial chemistry (DCC), more particularly to the use of DCC to identify compounds which are active as neuraminidase inhibitors.
  • DCC dynamic combinatorial chemistry
  • New chemical or biological entities with useful properties are classically generated by identifying a chemical or biological compound (a so-called lead compound) with some desirable properties or activities, creating varieties of said compound to form a library, and evaluating the properties and activities of those variant compounds.
  • the conventional approach is limited by the relatively small pool of previously identified compounds which may be screened to identify new compounds with the desirable property or activity.
  • Combinatorial chemistry has experienced an explosive growth in recent years. It provides a powerful methology for exploring the molecular geometrical and interactional spaces through molecular diversity generation. This is in particular the case for the discovery of new biologically active substances and medical drugs. It resides on the constitution of vast combinatorial libraries (CLs), extensive collections of molecules derived from a set of units connected by successive and repetetive application of specific chemical reactions. It is thus based on a large population of different molecules that are present as discrete entities.
  • CLs combinatorial libraries
  • the constitution of a CL of components amounts to the fabrication of a large collection of components.
  • the CL is then screened against a target, with the goal that one of its constituents will fit the target lock/receptor, i.e. show an activity, and be retrievable from the mixture.
  • the present invention makes use of the so-called dynamic combinatorial chemistry which is a conceptionally different approach. It relies on a reversible connection process for the spontaneous and continuous generation of all possible combinations of a set of basic constituents, thus making virtually available all structural and interactional features that these combinations may present.
  • Such multicomponent self-assembly amounts to the presentation of a dynamic combinatorial library (DCL) which is a potential library made up of all possible combinations in number and nature of the available components.
  • DCL dynamic combinatorial library
  • the composition of the set of components/subunits depends on the extent to which the possible combinations cover the geometrical and interactional spaces of the targets.
  • Self-assembly in a multi-component system is a combinatorial process with a search procedure directed by the kinetic and thermodynamic parameters imposed by the nature of constituents and their interactions.
  • a substance library which library consists of molecular species which are bonded to a molecular pairing system.
  • the pairing system is composed of molecules, in the preferred embodiment, which are selected amongst specially designed nucleic acids which can bind to each other in a certain manner which results in a particular geometric form.
  • the molecular species are selected, in a preferred embodiment, from the group consisting of peptides, and these peptides are designed according to the particular requirements of a given component which is brought into contact with the library component.
  • the complex which forms upon contact with the component is identified, in order to evaluate the interaction between a component and complex.
  • Ivan Hue and Jean-Marie Lehn disclose a method for the generation of a dynamic combinatorial library of imines from structural fragments bearing aldehyde and amino groups.
  • the method is directed toward the synthesis of inhibitors of the enzyme carbonic anhydrase by recognition-involved assembly, and the synthesis of the above-mentioned imines is carried out in the presence of the said enzyme carbonic anhydrase. It was found that reversible combination of the used amines and aldehydes leads to the shift of the equilibrium population towards the imine product that was closest in structure to a known highly efficient inhibitor of the enzyme.
  • the application WO 01/64605 discloses a process for establishing a dynamic combinatorial library for a target which binds at least two functionalities.
  • the method comprises selecting a plurality of molecules carrying functionalities which, by combination with each other, are capable of forming an entity which may bind to the functionalities in the target.
  • the molecules carrying the functionalities are linked by a spacer group which allows a reversible formation and cleavage of bonds. The cleavage and formation of the bonds can occur in the spacer group, or at the terminus of it.
  • the spacer group will be selected such as to potentially fit into the binding site(s) of the target.
  • the spacer groups disclosed in the application are all linear entities like for example alkane derivatives, and contain a maximum of two linking groups allowing the formation and cleavage reversible bonds.
  • influenza A virus neuraminidase is appropiate, a viral surface enzyme that catalyzes the cleavage of sialic acid residues terminally linked to glycoproteins and glycolipids and plays an important role in the propagation of the virus.
  • a class of compounds being neuraminidase inhibitors and active against the propagation of the virus is composed of cyclohexene carboxylic acid derivatives. This class of compounds is the object of several patent applications.
  • the application WO 99/31047 discloses cyclohexene carboxylate derivatives which are active as neuraminidase inhibitors.
  • the compounds carry two amino substituents in 3- and 5- position and a -NHCOO " substituent in 4-position.
  • neuraminidase inhibitors which are based on cyclohexene carboxylic acid derivatives carrying amino groups in 3- and 5-position.
  • the carbon atom in 3- or 5-position however carries, besides the amino substituent, a further substitutent which is not a hydrogen atom.
  • neuraminidase inhibitors which are based on cyclohexene carboxylic acid derivatives are disclosed in WO 98/07685, US 6,057,459, US 6,204,398 and US 5,859,284.
  • the molecules disclosed in these documents all carry an alkoxy substituent.
  • the object underlying the present invention is to provide further neuraminidase inhibitors.
  • R is hydrogen or a C ⁇ -C 4 alkyl group
  • R 1 to R 4 are independently of each other selected from the group consisting of: hydrogen, C 1 -C 20 alkyl groups, C 2 -C 2 o-alkenyl groups, C 4 -C 2 o aryl groups, C 5 -C 20 -aralkyl groups and C 5 -C 2 o- lkaryl groups, all of which groups can contain one or more hetero atoms from the group consisting of N, O, and S, and which groups can carry one or more substituents from the group consisting of hydroxyl groups and C ⁇ -C 4 -alkyl ester groups; or one of the substituents NR ! R 2 and NR 3 R 4 is a guanidino group of the formula
  • R 9 is a C ⁇ -C 4 -alkyl group, or a physiologically acceptable salt or solvate thereof in any stereoisomeric form or mixtures thereof in any ratio, with the proviso that the compounds in which
  • R 1 is H
  • R 2 is CH(CH 2 CH 3 ) 2
  • R 3 , R 4 are H and R is ethyl
  • R 1 is H
  • R 2 is -CH 2 CH 2 CH 3
  • R 3 , R 4 are H and R is ethyl are excluded.
  • the compounds of formula I are novel compounds and are an object of the present invention.
  • the compounds according to formula I are used as a scaffold for the finding of neuraminidase inhibitors by a DCC-process.
  • the library of potential inhibitors can be designed in such a way that the components will be formed from a scaffold according to formula I having a basic affinity for the target active site.
  • the scaffold can, for example, react with molecules carrying an aldehyde linking group or molecules carrying a keto group. In case ketones are used, higher concentrations of the compounds are required, in general.
  • each of the amino groups in the scaffold is in principle capable of reacting with any of the aldehyde groups to form a set of transient species A to D existing in a rapid dynamic equilibrium with each other and with the building blocks. Subsequent chemical reduction of the transient compounds with an externally added reagent irreversibly converts them a the set of amines E to H giving rise to a large array of stable library components, each containing up to four substituents attached to the scaffold
  • the compounds 1 to 13 showing a neuraminidase inhibiting activity could be identified (see below).
  • Particularly preferred compounds are those according to the formulae 9 to 13 in which Ac is -C(O)CH 3 .
  • the most preferred compound is 7, which inhibits neuraminidase with an efficiency similar to or even better than the known influenza drug oseltamivir.
  • the compound is synthesized according to the above scheme.
  • Another preferred compound is 8 (see Fig 5) which is synthesized in a way analogous to the above scheme.
  • Still a further object of the present invention are compounds according to formula I in which in which one of the groups -NR'R 2 and -NR 3 R 4 is a guanidinium group and the other group is an amino group which is not substituted by hydrogen.
  • the compounds 14 and 15 which can be synthesized as depicted in the following scheme are preferred.
  • a further object of the present invention are medicaments which contain an effective amount of a compound according to the formula I as defined above. This preferrably applies to the molecules which have above been denoted as being preferred compound classes, in particular to the compounds 7 to 15.
  • the compounds according to formula I are hence appropriate for the use as a medicament, preferably for inhibiting the activity of neuraminidase, in particular for inhibiting the activity of influenza neuraminidase.
  • Still a further object is the treatment of a mammal, in particular a human, with a compound according to formula I, preferrably against the action of neuraminidase.
  • the compounds can be used in any appropriate form, e.g. as such, in form of a physiologically acceptable salt or a physiologically active solvate.
  • compositions which comprise an effective dose of a compound of the formula I and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances and or additives.
  • the compounds according to the formula I can also be used in combination with other pharmaceutically active compounds, preferably compounds which are able to enhance the effect of the compounds according to the formula I.
  • the compounds I can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceutical by itself, or in the form of pharmaceutical preparations.
  • the pharmaceutical according to the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion.
  • Suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods.
  • the preferred administration form depends, for example, on the disease to be treated and on its severity.
  • Neuraminidase is a major target for drug action on influenza.
  • the enzyme structure is well characterized and multiple SAR data on the active site ligands are available in the literature. It has been shown that the presence and particular spatial arrangement of a number of linking groups in the neuraminidase ligands are crucial and conserved in a majority of known inhibitors.
  • influenza A virus neuraminidase was used, a viral surface enzyme that catalyzes the cleavage of sialic acid residues terminally linked to glycoproteins and glycolipids and plays an important role in the propagation of the virus. For solubility reasons, neuraminidase was expressed and the extra-cellular domain containing the active site was purified, see below.
  • each of the amino groups in the scaffold is in principle capable of reacting with any of the aldehyde groups to form a set of transient species A to D existing in a rapid dynamic equilibrium with each other and with the building blocks.
  • the addition of the target enzyme to the dynamic library shifts the equilibrium between the transient species toward the components with the highest affinity for the target. Chemical reduction of the library, after re-equilibriation in the presence of the target, should result in the distribution of stable components reflecting the enrichment in the transient best binders.
  • the substituents were initially grouped in two sets.
  • the first set contained 10 aldehydes, some of which showed statistically significant inhibition of neuraminidase activity in the mixture with the scaffold in a preliminary screening.
  • the second set included the aldehydes A4, Al l, A14, A 17, A18 that did not show inhibitory activity in the preliminary screen.
  • the aldehydes employed are depicted in Fig. 1.
  • the potential diversity of the virtual libraries is very high, for example the set of 20 aldehydes potentially yields over 40.000 stable components.
  • the library is biased toward formation of the monosubstituted components.
  • Esquire 3000 ion trap mass spectrometer connected to an Agilent 1100 HPLC.
  • MS data were acquired in the full scan mode and scanned for protonated molecular ions [M + H] + of potential products in extracted ion chromatograms.
  • Corresponding peak areas plotted in Figures 1 -5 are proportional to the concentration of each component, but generally cannot be used to compare concentrations of two or more different components.
  • the neuraminidase activity was determined using the synthetic substrate 2'-(4- methylumbelliferyl)-a-D-N-acetylneuraminic acid (MU-NANA).
  • the enzyme was incubated for 30 min at 37°C with 50 ⁇ M MU-NANA in 100 mM sodium acetate pH 5.5, 2 mM CaC12 and subsequently the reaction was stopped with 200mM glycine pH10.5, 120mM NaCl for measuring the fluorescence of released 4-methylumbelliferone (4-MU) at an excitation wavelength of 355nm and an emission of 460nm.
  • neuraminidase activity testing we either used purified tNA-His protein originating of the avian influenza A/FPV/Rostock/34 (H7N1) strain (see above) or virus preparations of different human Influenza A [A/Panama /2007/99 (H3N2); A/Johannesburg/33/94 (H3N2)] and Influenza B (B/Harbin 7/94; B/Victoria/504/2000) strains.
  • the neuraminidase cDNA of the Influenza A/FPV/Rostock/34 was amplified and modified by PCR (forward primer: GGGGACAAGTTTGTACAAAAAAGCAGGCTGCCACCATGAA TCCAAATCAGAAAATAATAACC; reverse primer: GGGGACCACTTTGTACAAGAAAGCTGGGTTT
  • pDEST8-tNA-His which encodes for a neuraminidase with six histidines fused to the C-terminus (tNA-His).
  • Spodoptera frugiperda Sf-9 insect cells were cultivated at 27°C in the serum-free medium ExCell400 (JRH Bioscience). Exponentially growing cells (2 x 106 cells/ml) were infected with baculovirus at a multiplicity of infection (MOI) of 10. After 72h of expression the cells were harvested and the extra-cellular domain of the neuraminidase (sol-tNA-His) was released by treatment with pronase (Ref. ).
  • MOI multiplicity of infection
  • sol- tNA-His was purified by metal chelate affinity chromatography using Ni-NTA superflow beads (Qiagen). The purification yielded an average of 3mg of sol-tNA-His out of 11 of culture, with a purity of >80% and a specific activity of -4000 U/mg.
  • the structure of the scaffold was modified by replacing the amino group which in the active components had not been substituted with a guanidinium group, see compound 2.
  • Such a replacement yields better binding of the known inhibitors, as can be seen from the Kj value of 5 (Fig. 5).
  • the experiments with the virtual libraries were performed similarly to those described in Example 2, and the subset of substitutes selected with the scaffold 2 was identical to that with 1.
  • the preferred components, 7 and 8 were also synthesized individually and showed Kj values of 16 and 52 nM, respectively.
  • the identity of the individually synthesized stable components with the ones formed in the presence of the enzyme was confirmed by the HPLC -MS analysis.
  • Ketone stock solutions were prepared by dissolving in DMSO in 1M or 5M concentration.
  • a 43 ⁇ M solution of Neuraminidase (50 ⁇ l) in imidazole buffer (pH 7.8) was added the scaffold 1 or 2 (5 ⁇ l of a 1 mM solution in the imidazol buffer pH 7.8) and premixed stock solutions of ketones (0.25 ⁇ l of 5M solution in DMSO each).
  • the reaction mixture was incubated for 10 min. and then tetrabutylammonium cyano borhydride (TBC) (4 ⁇ l of 0.1 mM solution in acetonitril) was added. After incubation at 25°C the reaction mixture was analyzed by HPLC/MS.
  • TBC tetrabutylammonium cyano borhydride
  • HPLC -MS analyses were performed with electrospray ionization (positive mode) on a Micromass Quattro Ultima quadrupole-hexapole-quadrupole mass spectrometer connected to a Waters allianceTM 2695 HPLC.
  • Eluent composition was kept isocratic at 0 % B for 3 min.
  • Re- equilibration time was 3 min.
  • MS data were acquired in the selective reaction monitoring (SRM) mode and scanned for specific ion transitions of potential products. Suitable ion transitions for SRM measurements were determined by flow injection and MS/MS analysis (recording of product ion spectra) of standard compounds.
  • SRM selective reaction monitoring
  • Ki (nM) of selected inhibitors determined for neuraminidases from different virus subtypes
  • mice were infected with different Influenza strains in the presence or absence of the inhibitors to be tested or the inhibitors were added only after the infection.
  • mice C57BI/6 were either infected intranasal with 200 TCID50 (2.5 LD50) of Influenza A/PR/8/34 (H1N1) or intraperitoneal with 100 TCID50 of A/FPV/ Bratislava (H7N7).
  • the inhibitor HK103 42nMol was added at time 0 and again after 24h intranasal or intraperitoneal, respectively.
  • the efficacy of the inhibitor was measured by the survival of animals within a time period of 12 days.
  • mice C57BI/6 were infected intranasal with 200 TCID50 (2.5 LD50) of Influenza A/PR/8/34 (H1N1) either in the presence of the inhibitors (0,lmg/kg body weight) at time point 0 or the inhibitors were applied after infection at 5 consecutive days (day 1 to 5).
  • the efficacy of the inhibitors were measured by the survival of animals within a time period of 21 days. In the complete absence of inhibitor (PBS) or if treated with inhibitor from day 1-5 (HK103 and Oseltamivir) the mice started to die after 7 days.
  • mice Only 1 (in case of PBS or oseltamivir) or 2 (in case of HK103) mice survived the Influenza infection. In case of infection and direct treatment with the inhibitors (HK103 or oseltamivir) at day 0 all mice survived.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Physics & Mathematics (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Cell Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne des composés selon la formule I, dans laquelle la ligne en pointillé représente une double liaison présente dans l'une des deux positions possibles; R1 à R4 sont choisis indépendamment l'un de l'autre dans le groupe comprenant hydrogène, des groupes alkyle C1-C20, des groupes alcényle C2-C20, des groupes aryle C4-C20, des groupes aralkyle C5-C20 et des groupes alkaryle C5-C20, tous ces groupes pouvant contenir un ou plusieurs hétéroatomes du groupe comprenant N, O et S, et pouvant porter au moins un substituant du groupe comprenant des groupes hydroxyl et des groupes alkyle ester C1-C4; ou l'un des substituants NR1R2 et NR3R4 est un groupe guanidino de la formule NR5-C(NR6R7)=NR8, dans laquelle les substituants R5 à R8 ont indépendamment l'un de l'autre la signification donnée ci-dessus aux substituants R1 à R4. R9 est un groupe alkyle C1-C4, ou un sel ou un solvate physiologiquement acceptable de ceux-ci dans n'importe quelle forme stéréo-isomère ou des mélanges de ceux-ci dans n'importe quel rapport. L'invention concerne également un procédé de fabrication d'une bibliothèque de composants qui peuvent se lier à la neuraminidase, notamment la neuraminidase de la grippe. Ledit procédé consiste: i) à choisir plusieurs molécules portant une fonctionnalité susceptible d'interagir avec un site de liaison de la neuraminidase, lesdites molécules présentant également un groupe de liaison pouvant interagir avec d'autres groupes de liaison sous la formation de liaisons réversibles; ii) à faire réagir les molécules portant la fonctionnalité avec une molécule selon la formule I définie dans la revendication 1 en présence de la cible, dans les cas où survient une formation de liaisons réversibles entre les groupes de liaison sur la molécule I et sur les molécules portant une fonctionnalité.
PCT/EP2002/011526 2001-10-15 2002-10-15 Procede de fabrication d'inhibiteurs de la neuraminidase au moyen de la chimie combinatoire dynamique et composes ainsi obtenus WO2003033437A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US32880201P 2001-10-15 2001-10-15
US60/328,802 2001-10-15
US35673102P 2002-02-15 2002-02-15
US60/356,731 2002-02-15

Publications (2)

Publication Number Publication Date
WO2003033437A2 true WO2003033437A2 (fr) 2003-04-24
WO2003033437A3 WO2003033437A3 (fr) 2003-12-18

Family

ID=26986521

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2002/011526 WO2003033437A2 (fr) 2001-10-15 2002-10-15 Procede de fabrication d'inhibiteurs de la neuraminidase au moyen de la chimie combinatoire dynamique et composes ainsi obtenus
PCT/EP2002/011520 WO2003034071A2 (fr) 2001-10-15 2002-10-15 Procede de formation d'une bibliotheque combinatoire dynamique faisant appel a une structure d'echafaudage

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/011520 WO2003034071A2 (fr) 2001-10-15 2002-10-15 Procede de formation d'une bibliotheque combinatoire dynamique faisant appel a une structure d'echafaudage

Country Status (2)

Country Link
AU (1) AU2002346915A1 (fr)
WO (2) WO2003033437A2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092727A2 (fr) * 2003-04-11 2004-10-28 Structural Genomix, Inc. Bibliotheques de composes et procedes de decouverte de medicaments
EP1496038A1 (fr) * 2003-07-11 2005-01-12 Therascope AG Méthode de synthèse d'une chimiothèque combinatoire dynamique faisant intervenir des nitrones
EP1496039A1 (fr) * 2003-07-11 2005-01-12 Therascope AG Méthode de création d'une chimiothèque combinatoire dynamique
US7149280B2 (en) 2002-12-23 2006-12-12 Astex Therapeutics Limited Synthesis and screening of ligands using X-ray crystallography
WO2009068321A1 (fr) * 2007-11-26 2009-06-04 Forschungsverbund Berlin E.V. Criblage haut débit dirigé
JP2014532633A (ja) * 2011-10-28 2014-12-08 クリスチャン−アルブレヒト大学キールＣｈｒｉｓｔｉａｎ−Ａｌｂｒｅｃｈｔｓ−Ｕｎｉｖｅｒｓｉｔａｔ ｚｕ Ｋｉｅｌ インフルエンザを処置するための化合物
WO2017186138A1 (fr) * 2016-04-28 2017-11-02 广州市恒诺康医药科技有限公司 Dérivé du cyclohexène ou son sel pharmaceutiquement acceptable et leur application

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6754997B2 (ja) * 2013-08-26 2020-09-16 国立大学法人 東京大学 大環状ペプチド、その製造方法、及び大環状ペプチドライブラリを用いるスクリーニング方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999031047A1 (fr) * 1997-12-12 1999-06-24 Gilead Sciences, Inc. Carboxylates de cyclohexene utilises comme inhibiteurs de neuraminidase

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6008058A (en) * 1993-06-18 1999-12-28 University Of Louisville Cyclic peptide mixtures via side chain or backbone attachment and solid phase synthesis
JPH10501818A (ja) * 1994-06-16 1998-02-17 スミスクライン・ビーチャム・コーポレイション 鋳型指向性環化
US5958702A (en) * 1995-02-06 1999-09-28 Benner; Steven Albert Receptor-assisted combinatorial chemistry
DE19619373A1 (de) * 1996-05-14 1997-11-20 Hoechst Ag Neue Substanzbibliothek und damit hergestellte supramolekulare Komplexe
US20020068301A1 (en) * 1997-05-28 2002-06-06 Hung-Sen Lai Cyclic peptide libraries and methods of use thereof to identify binding motifs
CA2284459C (fr) * 1999-10-04 2012-12-11 Neokimia Inc. Synthese combinatoire de bibliotheques de composes macrocycliques utiles pour la decouverte de medicaments
EP1130009A1 (fr) * 2000-03-01 2001-09-05 Therascope AG Préparation et screening d'une bibliothèque de chimie combinatoire dynamique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999031047A1 (fr) * 1997-12-12 1999-06-24 Gilead Sciences, Inc. Carboxylates de cyclohexene utilises comme inhibiteurs de neuraminidase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEW W ET AL: "A new series of C3-aza carbocyclic influenza neuraminidase inhibitors: synthesis and inhibitory activity" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 23, 1 December 1998 (1998-12-01), pages 3321-3324, XP004143751 ISSN: 0960-894X *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7149280B2 (en) 2002-12-23 2006-12-12 Astex Therapeutics Limited Synthesis and screening of ligands using X-ray crystallography
WO2004092727A2 (fr) * 2003-04-11 2004-10-28 Structural Genomix, Inc. Bibliotheques de composes et procedes de decouverte de medicaments
WO2004092727A3 (fr) * 2003-04-11 2005-12-01 Structural Genomix Inc Bibliotheques de composes et procedes de decouverte de medicaments
EP1496038A1 (fr) * 2003-07-11 2005-01-12 Therascope AG Méthode de synthèse d'une chimiothèque combinatoire dynamique faisant intervenir des nitrones
EP1496039A1 (fr) * 2003-07-11 2005-01-12 Therascope AG Méthode de création d'une chimiothèque combinatoire dynamique
WO2009068321A1 (fr) * 2007-11-26 2009-06-04 Forschungsverbund Berlin E.V. Criblage haut débit dirigé
JP2014532633A (ja) * 2011-10-28 2014-12-08 クリスチャン−アルブレヒト大学キールＣｈｒｉｓｔｉａｎ−Ａｌｂｒｅｃｈｔｓ−Ｕｎｉｖｅｒｓｉｔａｔ ｚｕ Ｋｉｅｌ インフルエンザを処置するための化合物
WO2017186138A1 (fr) * 2016-04-28 2017-11-02 广州市恒诺康医药科技有限公司 Dérivé du cyclohexène ou son sel pharmaceutiquement acceptable et leur application
CN107325040A (zh) * 2016-04-28 2017-11-07 广州市恒诺康医药科技有限公司 环己烯类衍生物或其药学上可接受的盐及其用途
EP3450427A4 (fr) * 2016-04-28 2019-07-03 Guangzhou Henovcom Bioscience Co. Ltd. Dérivé du cyclohexène ou son sel pharmaceutiquement acceptable et leur application

Also Published As

Publication number Publication date
AU2002346915A1 (en) 2003-04-28
WO2003034071A2 (fr) 2003-04-24
WO2003033437A3 (fr) 2003-12-18
WO2003034071A3 (fr) 2004-03-11

Similar Documents

Publication Publication Date Title
Abrecht et al. The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu®): a challenge for synthesis & process research
EP1218544B1 (fr) Peptides de fixation de'l élément d'ARN TAR
JP5223391B2 (ja) 蛍光システイン誘導体を用いる感作性検定方法及び蛍光システイン誘導体
PL176362B1 (pl) Nowe związki, podstawione pochodne kwasu pipekolinowego i ich terapeutycznie dopuszczalne sole addycyjne z kwasem
EP3127912B1 (fr) Composé époxycétone tripeptidique construit à partir d'un hétérocycle et procédé pour le préparer et l'utiliser
Wen et al. Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses
WO2003033437A2 (fr) Procede de fabrication d'inhibiteurs de la neuraminidase au moyen de la chimie combinatoire dynamique et composes ainsi obtenus
EP3328854A1 (fr) Analogues d'adamantylurées utilisés en tant qu'inhibiteurs d'hydrolase époxyde soluble
Yan et al. Divalent oseltamivir analogues as potent influenza neuraminidase inhibitors
US6140361A (en) Use of 2-deoxystreptamine as a molecular scaffold for the preparation of functionally and spatially diverse molecules and pharmaceutical compositions thereof
US20030232815A1 (en) Non-peptidic cyclophilin binding compounds and their use
Flipo et al. A library of novel hydroxamic acids targeting the metallo-protease family: design, parallel synthesis and screening
WO2010075636A1 (fr) Composés et méthodes pour le traitement du virus influenza
US5763464A (en) Retroviral agents containing anthranilamide, substituted benzamide and other subunits, and methods of using same
CN111303235B (zh) 一种抗流感病毒化合物及其制备方法与应用
Sheha et al. Brain delivery of HIV protease inhibitors
JP2002514438A (ja) チトクロームｐ４５０基質としての７−アルコキシクマリン類
Yu et al. Structure-based design of bacterial transglycosylase inhibitors incorporating biphenyl, amine linker and 2-alkoxy-3-phosphorylpropanoate moieties
CN105837632B (zh) 神经氨酸酶抑制剂及制备方法及在制备抗流感病毒药物中的应用
US5734082A (en) Hydroxyethyl aminimides
JP2008530083A (ja) 核酸のトランスフェクション用のカチオン性脂質
Elumalai et al. Development of potent cholinesterase inhibitors based on a marine pharmacophore
CN104693194A (zh) 3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物及其制备方法及应用
Herforth Antimalarial Activity of 5', N6-and 3', N6-Disubtituted Adenosines
Herforth Antimalarial activity of 5', N 6-and 3', N 6-disubstituted adenosines: polymer-assisted synthesis, analytical characteristics and biological evaluation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VC VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载