WO1998020013A1 - Nouveaux produits de condensation de knoevenagel, leur procede de production et leur utilisation - Google Patents

Nouveaux produits de condensation de knoevenagel, leur procede de production et leur utilisation Download PDF

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Publication number
WO1998020013A1
WO1998020013A1 PCT/EP1997/006184 EP9706184W WO9820013A1 WO 1998020013 A1 WO1998020013 A1 WO 1998020013A1 EP 9706184 W EP9706184 W EP 9706184W WO 9820013 A1 WO9820013 A1 WO 9820013A1
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Prior art keywords
compound
compounds according
compounds
treatment
pharmaceutical composition
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Application number
PCT/EP1997/006184
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German (de)
English (en)
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WO1998020013A9 (fr
Inventor
Andreas Johannes Kesel
Walter Oberthür
Original Assignee
Andreas Johannes Kesel
Oberthuer Walter
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 to AU54798/98A priority Critical patent/AU728345B2/en
Application filed by Andreas Johannes Kesel, Oberthuer Walter filed Critical Andreas Johannes Kesel
Priority to CA002270973A priority patent/CA2270973A1/fr
Priority to EP97951145A priority patent/EP0937089A1/fr
Priority to HU9904289A priority patent/HUP9904289A3/hu
Priority to BRPI9712930-5A priority patent/BR9712930A/pt
Priority to SK617-99A priority patent/SK61799A3/sk
Priority to NZ335977A priority patent/NZ335977A/xx
Priority to PL97333128A priority patent/PL333128A1/xx
Priority to JP52107198A priority patent/JP2001503752A/ja
Priority to IL12982697A priority patent/IL129826A0/xx
Publication of WO1998020013A1 publication Critical patent/WO1998020013A1/fr
Publication of WO1998020013A9 publication Critical patent/WO1998020013A9/fr
Priority to NO992209A priority patent/NO992209L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to new Knoevenagel condensation products, processes for their production and their use, in particular for pharmaceutical and analytical purposes. Furthermore, conjugates of the Knoevenagel condensates with biomolecules are disclosed.
  • the problem underlying the present invention was to provide new compounds which can be used in particular for pharmaceutical and analytical purposes.
  • This object is achieved by the synthesis of the compound (Z) -5'-O-phosphonopyridoxidenidhhodanin (3), which is a derivative of the vitamin B6 coenzyme pyridoxal-5'-phosphate (1).
  • Compound (3) is prepared by reacting (1) with the synthetic heterocyclic compound rhodanine (2) in a Knoevenagel condensation (cf. also Kesel et al., Tetrahedron 52 (1 8.1 1 .1 996), 14787-14800).
  • Compound 3 is named (Z) -5 - [[5-hydroxy-6-methyl-3- [(phosphonooxy) methyl] -4-pyridinyl] methylene] -2-thioxo-4-thiazolidinone.
  • the rhodanine portion of this molecule is able to bind to biomolecules such as single-stranded nucleic acids.
  • the charged phosphate group ensures good water solubility.
  • Compound 3 is subject to a (Z / E) stereoisomerism to form the (E) isomer 4. This cis / trans rearrangement is triggered, for example, by UV radiation with the wavelengths 254 nm and / or 366 nm.
  • red 3-pyridinolate 5 in the form of a free acid, e.g. in pyridine or dimethyl sulfoxide (DMSO).
  • the yellow compound 3 forms a deep red monosodium salt, the structure of which could be elucidated by X-ray structure analysis. It was crystallized as hemiheptadecahydrate (8.5 hydrate) and is present as (Z) - stereoisomer 6. When exposed to UV radiation, the monosodium salt 6 is also subject to the cis / trans rearrangement to the red (E) stereoisomer 7.
  • Derivatives of compound 3 can be obtained by reaction with C 12 -C 18 fatty acid chlorides on the OH group.
  • the present invention further relates to compounds of the general formula (8).
  • X 1 , X 2 and X 3 are each independently selected from O, S and NR 5 ;
  • R ⁇ R 2 , R 3 , R 4 and R 5 are each independently selected from any substituent;
  • R 6 is selected from optionally substituted hydrocarbon radicals and O and n is 0 or 1; and salts, for example salts with alkali metal, alkaline earth metal or ammonium ions, hydrates and stereoisomers thereof, with the proviso that the compound is not pyridoxylidene rhodanine.
  • X 1 is preferably O.
  • X 2 is preferably NR 5 , where R 5 is hydrogen or CC 4 alkyl and particularly preferably hydrogen.
  • X 3 is preferably S.
  • Y is preferably S.
  • Z is preferably CR 5 , where R 5 is hydrogen or C r C 4 alkyl and particularly preferably hydrogen.
  • the substituents R 1 to R 4 can in themselves be any substituents provided that they are compatible with the overall structure.
  • R 1 and R 2 or / and R 3 and R 4 can be bridged.
  • the substituents R 1 to R 4 are hydrogen, halogen, hydroxyl, amine and optionally substituted alkyl radicals, for example C to C 6 alkyl, aminoalkyl, hydroxyalkyl, alkoxy etc.
  • at least one of the substituents R to R 4 contains a sub physiologically negatively charged group, for example an acid group such as phosphate, carboxylate, sulfonate etc.
  • the compounds of the general formula (8) are particularly preferably the (Z) -5-O-phosphonopyridoxylidene rhodanine (3), and salts, hydrates and stereoisomers thereof.
  • the present invention further provides a process for the preparation of a compound of the general formula (8), characterized in that a compound of the formula (9)
  • REPLACEMENT BUTT (RULE 26) wherein X 1 , X 2 , X 3 , Y, Z, R 1 -R 5 and R 6 are as defined for the compounds 8.
  • the reaction is preferably carried out in an essentially equimolar ratio of 9 to 10 in a suitable solvent or solvent mixture.
  • the temperature is preferably from room temperature to the reflux temperature of the solvent.
  • the compounds of general formula (8) surprisingly have pharmaceutical activity.
  • the invention thus furthermore relates to a pharmaceutical composition which contains as active ingredient a compound as stated above (preferably without taking into account the disclaimer in claim 1) and, if appropriate, pharmaceutically customary additives, auxiliaries, carriers and diluents.
  • a first important application of the compounds according to the invention is the treatment of infectious diseases, for example viral infections, parasitic diseases, fungal diseases or bacterial diseases.
  • infectious diseases for example viral infections, parasitic diseases, fungal diseases or bacterial diseases.
  • viral infections in particular those viral infections which are caused by enveloped viruses, such as hepadnaviruses, herpes viruses or retroviruses, e.g. HIV.
  • enveloped viruses such as hepadnaviruses, herpes viruses or retroviruses, e.g. HIV.
  • the compounds according to the invention have also proven suitable for the treatment of diseases which are caused by other viruses, such as, for example, influenza or papilloma viruses.
  • the compounds according to the invention have proven to be very suitable for controlling parasites such as, for example, Leishmania, Plasmodia or Trypanosomes.
  • the compounds are most preferably used in HIV therapy, for example in combination therapy with other agents such as AZT or DDI.
  • the compounds according to the invention are also used to combat tumor diseases, for example leukemia, in particular T-cell leukemia, or skin tumors such as malignant tumors.
  • tumor diseases for example leukemia, in particular T-cell leukemia, or skin tumors such as malignant
  • the compounds 8 also have immunomodulatory effects and are therefore suitable, for example, for the treatment of autoimmune diseases such as, for example, multiple sclerosis, Alzheimer's disease, lupus erythematosus, myasthenia gravis, chronic arthritis, type I diabetes, etc. and various neurodegenerative diseases.
  • autoimmune diseases such as, for example, multiple sclerosis, Alzheimer's disease, lupus erythematosus, myasthenia gravis, chronic arthritis, type I diabetes, etc. and various neurodegenerative diseases.
  • the compounds 8 are suitable for the treatment of diseases which exist in connection with disorders of the vitamin B metabolism, e.g. as a vitamin B6 antagonist.
  • the compounds of the invention act as effectors, e.g. Activators, inhibitors or modifiers, on enzymatic reactions of the caspase system, and in particular as inhibitors of nitrogen monoxide synthases.
  • compounds 8 can influence the secretion of TNF ⁇ in T lymphocytes. They are also able to bind to the cellular CD38 receptor, thereby inhibiting the binding of HIV gp41. In this way, the signal transmission path is decoupled from CD38, which leads to an inhibition of syncytia formation, NO release, T cell death by apoptosis, and single cell lysis.
  • the compounds according to the invention can be used as such for therapeutic purposes. However, they can also be used as chelates with polyvalent metal ions or as noncovalent and / or covalent conjugates with biomolecules, for example nucleic acids, proteins, lipids, fatty acids etc.
  • the pharmaceutical compositions according to the invention can be in any form, for example as creams, ointments, injectable or orally administrable liquids, liposomal formulations, tablets, dragées, capsules etc.
  • the application can be, for example, locally or systemically, topically, orally or by injection.
  • the dosage can be varied within a wide range, for example from 0.01 ⁇ g to 1 mg per kg of body weight, depending on the type of disease and application.
  • the compounds according to the invention are also suitable as detection reagents.
  • they can be used in the form of radioactive, for example with 3 H, 14 C, 32 P or 35 S-labeled derivatives.
  • use in unlabelled form is preferred, since its strong coloring or fluorescent properties make it easy to detect in biological systems.
  • the compounds according to the invention are therefore suitable for the detection of biomolecules, for example in diagnostic analysis methods, for example for the detection of single-stranded nucleic acids.
  • the compounds are also suitable for structure elucidation, for example for sequencing proteins or nucleic acids.
  • the compounds according to the invention can also be used for electrochromic applications, e.g. can be used as molecular digital switch substances or indicators for pH value, temperature and solvent.
  • the compounds or derivatives thereof according to the invention are suitable as absorbers for ions, organic substances etc. or due to their intense colors and reversible color changes for decorative applications.
  • the alkaline earth metal salts for example Mg or Ca salts of the compounds, which are in the form of gels.
  • nanotechnology where, for example, individual fluorescent dye molecules and biomolecule derivatives excited with laser systems are detected and detected by sensitive detection systems, for example CCD cameras or avalanche detectors and optical techniques on thin-layer plates, in membranes, cells, drops, capillaries, etc. can be located.
  • sensitive detection systems for example CCD cameras or avalanche detectors and optical techniques on thin-layer plates, in membranes, cells, drops, capillaries, etc.
  • Further possibilities for single-molecule localization are optical scanning near-field microscopy on mini chips, confocal microscopy in polyacrylamide gels, for example 2-dimensional or multidimensional gel electophoresis of nucleic acids.
  • the present invention also relates to derivatives of the compounds (8) which result from hydrolytic degradation and have, for example, the general formulas 11, 12 or 13:
  • Fig. 1 the protection of cells against HIV infection mediated by compound (3).
  • Fig.2 a schematic representation of hydrolysis by-products that arise during the synthesis of compound (3)
  • REPLACEMENT BUTT (RULE 26) The mixture is boiled on a water bath with stirring under reflux. The pyridoxal-5'-phosphate monohydrate now slowly goes into solution and an initially yellow, then orange, then red suspension is formed. After boiling for 20 minutes, 1 50 ml of water are added through the cooler because the suspension begins to belch. The mixture is heated for a further 10 min, during which the red reaction product precipitates and leads to belching. Then refrigerate in the freezer at a temperature of - 18 ° C for no more than 2 hours.
  • the orange product is filtered off, transferred with the mother liquor and with 100 ml of ice-cold abs. Washed ethanol. Vacuum drying in a desiccator over anhydrous calcium chloride; Yield: 9.85 g of orange-yellow crude product (Z) -5 - [[5-hydroxy-6-methyl-3- [phosphonooxy) methyl] -4-pyridinyl] - methylene] -2-thioxo-4-thiazolidinone.
  • the product contains educts, by-products and, despite vacuum drying, ethanol and water.
  • the analysis of compound 3 comprises 1 H-NMR spectroscopy, 13 C-NMR spectroscopy, 31 P-NMR spectroscopy, RP-18 HPLC, fast atom bombardment mass spectrometry (FAB MS), IR spectroscopy, UV spectrophotometry and fluorescence spectrophotometry. Typical analytical data of compound 3 follow.
  • Compounds 3 and 6 can be used in radiolabelled form, for example labeled with 3 H, 14 C, 32 P or 35 S, as probes for the detection of single-stranded nucleic acids.
  • the substances 3/6 can also be used for the fluorescence detection of single-stranded DNA.
  • the (E) stereoisomer 4 fluoresces in DSMO, the (Z) stereoisomer in water significantly less.
  • the (E) stereoisomer 4 is bound to single-stranded DNA, single-stranded DNA can be detected when fluorescence occurs after extraction with DMSO.
  • the wavelength used for excitation is in the range from 420 to 500 nm, the emission in DMSO or pyridine is 575 nm.
  • Substance 6 inhibits the neuronal, endothelial and immunologically / - inducible isoforms of nitrogen monoxide synthase (NOS).
  • the inhibition constant (IC 50 ) for nNOS is 61.25 ⁇ M.
  • the inhibition constant (IC 50 ) is 50 ⁇ M.
  • Substance 3 can be used in radioactively labeled or unlabelled form for the two-dimensional electrophoretic separation of single-stranded nucleic acids. In the first dimension there can be a separation according to the charge and in the second dimension a separation according to the molecular size. Compound 3 can be associatively or covalently coupled to the nucleic acid.
  • Substance 3 and derivatives thereof are effective as therapeutic agents, in particular for influencing the propagation processes of infectious agents, e.g. from those that occur in the host with intermediates as single-stranded DNA, such as retroviruses, herpes viruses or hepatoviruses.
  • Myeloid HUT78 cells are exposed to HIV infection in the absence or in the presence of 1, 87 mM or 0, 1 87 mM compound 3.
  • the HIV detection is carried out by photometric determination of the p24 antigen. From Figure 1 it can be seen that no p24 was detectable in the cells treated according to the invention, whereas in the control the p24 test was positive from the seventh day.
  • Total remission is found a few hours after local application to the affected skin.
  • a patient (51 years, male) with virus flu is orally treated with a few drops of an H 2 O / DMSO solution of compound 3 (approx. 1 ⁇ g / ml). The disease symptoms disappeared overnight.
  • the (Z / E) stereoisomerism of compound 3 occurs depending on the temperature (thermochromism) and depending on the solvent (solvatochromism). 3 can therefore be used as a temperature indicator and / or solvent indicator.
  • the (Z / E) stereoisomerism of compounds 3 and 4 occurs depending on the application of an electric field (electrochromism). Therefore 3 can be used as a digital switching element due to the different fluorescence spectroscopic properties compared to 4 e.g. when excited by laser light with a wavelength of 480 nm. Thereby, after applying an electric field to 3, rearrangement in 4 occurs and thus fluorescence emission up to 575 nm after excitation at 480 nm.
  • Compound 3 can act in metabolism as an antagonist of the coenzyme pyridoxal-5'-phosphate by binding to the enzymes which require this coenzyme and therefore have tumor-inhibiting properties. - 1 7 -
  • Compound 3 can be used for the proliferation control / chemotherapy / cytostatic therapy of malignant tumors in local application to skin tumors (malignant melanoma, Karposi sarcoma), possibly in combination with UV radiation, and / or for the proliferation control of other skin diseases with an increased cell division rate (e.g. Psoriaris) can be used.
  • the binding of compound 3 to replication-active single-stranded DNA regions can be photochemically fixed by UV radiation and leads to locally limited cytotoxicity.
  • Compound 3 due to its coloring and fluorescent properties, as well as its ability to couple to biomolecules, e.g. Proteins are used for structure elucidation, e.g. for amino acid sequence determination of proteins or for DNA sequencing.

Abstract

L'invention concerne de nouveaux produits de condensation de Knoevenagel, leur procédé de production et leur utilisation, notamment à des fins pharmaceutiques et analytiques. On décrit en outre des conjugués des condensats de Knoevenagel avec des biomolécules. Un produit caractéristique de l'invention est illustré par le composé de formule (3).
PCT/EP1997/006184 1996-11-07 1997-11-07 Nouveaux produits de condensation de knoevenagel, leur procede de production et leur utilisation WO1998020013A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
SK617-99A SK61799A3 (en) 1996-11-07 1997-11-07 New knoevenagel condensation products, method for their production and their use
CA002270973A CA2270973A1 (fr) 1996-11-07 1997-11-07 Nouveaux produits de condensation de knoevenagel, leur procede de production et leur utilisation
EP97951145A EP0937089A1 (fr) 1996-11-07 1997-11-07 Nouveaux produits de condensation de knoevenagel, leur procede de production et leur utilisation
HU9904289A HUP9904289A3 (en) 1996-11-07 1997-11-07 Pyridines substituted by heterocyclic groups, method for their production and pharmaceutical compositions containing the same
BRPI9712930-5A BR9712930A (pt) 1996-11-07 1997-11-07 produtos de condensação de knoevenagel, processos para a sua preparação e aplicação
AU54798/98A AU728345B2 (en) 1996-11-07 1997-11-07 New knoevenagel condensation products, method for their production and their use
NZ335977A NZ335977A (en) 1996-11-07 1997-11-07 Pyridine derivatives which are knoevenagel condensation products
IL12982697A IL129826A0 (en) 1996-11-07 1997-11-07 New knoevenagel condensation products method for their production and their use
JP52107198A JP2001503752A (ja) 1996-11-07 1997-11-07 新規クネベナゲル縮合生成物、その製法及びその使用
PL97333128A PL333128A1 (en) 1996-11-07 1997-11-07 New products of knoevenagel's condensation, method of manufacturing of them and their applications
NO992209A NO992209L (no) 1996-11-07 1999-05-06 Nye Knoevenagel-kondensasjonsprodukter, fremgangsmÕte for deres fremstilling samt anvendelse derav

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19645974.5 1996-11-07
DE19645974A DE19645974C1 (de) 1996-11-07 1996-11-07 (Z)-5-[[3-Hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridinyl]methylen]-2-thioxo-4- thiazolidinon, Verfahren zu dessen Herstellung und Verwendung

Publications (2)

Publication Number Publication Date
WO1998020013A1 true WO1998020013A1 (fr) 1998-05-14
WO1998020013A9 WO1998020013A9 (fr) 1998-07-02

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PCT/EP1997/006184 WO1998020013A1 (fr) 1996-11-07 1997-11-07 Nouveaux produits de condensation de knoevenagel, leur procede de production et leur utilisation

Country Status (17)

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EP (1) EP0937089A1 (fr)
JP (1) JP2001503752A (fr)
KR (1) KR20000053141A (fr)
CN (1) CN1236369A (fr)
AU (1) AU728345B2 (fr)
BR (1) BR9712930A (fr)
CA (1) CA2270973A1 (fr)
CZ (1) CZ160999A3 (fr)
DE (1) DE19645974C1 (fr)
HU (1) HUP9904289A3 (fr)
IL (1) IL129826A0 (fr)
NO (1) NO992209L (fr)
NZ (1) NZ335977A (fr)
PL (1) PL333128A1 (fr)
SK (1) SK61799A3 (fr)
TR (1) TR199901733T2 (fr)
WO (1) WO1998020013A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999057124A1 (fr) * 1998-05-04 1999-11-11 Andreas Johannes Kesel Condensats knoevenagel monomeres, oligomeres et polymeres
WO2000066599A1 (fr) * 1999-04-30 2000-11-09 Oberthuer Walter Analogues de la vitamine b6 a effet antioxydant
EP1128832A1 (fr) * 1998-08-21 2001-09-05 Viropharma Incorporated Composes, compositions et procedes pour traiter des infections virales et les maladies qui y sont liees
WO2003034137A2 (fr) * 2001-10-16 2003-04-24 Hewlett-Packard Company Dispositif de lecture electronique portable
WO2003034136A2 (fr) * 2001-10-16 2003-04-24 Hewlett-Packard Company Affichage haute resolution

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012124A1 (fr) * 1991-12-19 1993-06-24 Ab Astra Benzimidazoles substitues et procede de preparation et d'utilisation de ces derniers
EP0636630A1 (fr) * 1993-07-30 1995-02-01 ZAMBON GROUP S.p.A. Dérivés du propanamide substitués sur l'azote par un groupe n-hétéroaryle, utiles dans le traitement des maladies cardiovasculaires
EP0693496A1 (fr) * 1994-07-19 1996-01-24 Roussel Uclaf Nouvelles céphalosporines comportant en position 7 un radical benzyloxyimino substitué, leur procédé de préparation, leur application comme médicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012124A1 (fr) * 1991-12-19 1993-06-24 Ab Astra Benzimidazoles substitues et procede de preparation et d'utilisation de ces derniers
EP0636630A1 (fr) * 1993-07-30 1995-02-01 ZAMBON GROUP S.p.A. Dérivés du propanamide substitués sur l'azote par un groupe n-hétéroaryle, utiles dans le traitement des maladies cardiovasculaires
EP0693496A1 (fr) * 1994-07-19 1996-01-24 Roussel Uclaf Nouvelles céphalosporines comportant en position 7 un radical benzyloxyimino substitué, leur procédé de préparation, leur application comme médicaments

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999057124A1 (fr) * 1998-05-04 1999-11-11 Andreas Johannes Kesel Condensats knoevenagel monomeres, oligomeres et polymeres
US6369042B1 (en) 1998-05-04 2002-04-09 Oberthuer Walter Antioxidative vitamin B6 analogs
EP1128832A1 (fr) * 1998-08-21 2001-09-05 Viropharma Incorporated Composes, compositions et procedes pour traiter des infections virales et les maladies qui y sont liees
EP1128832A4 (fr) * 1998-08-21 2003-03-05 Viropharma Inc Composes, compositions et procedes pour traiter des infections virales et les maladies qui y sont liees
WO2000066599A1 (fr) * 1999-04-30 2000-11-09 Oberthuer Walter Analogues de la vitamine b6 a effet antioxydant
WO2003034137A2 (fr) * 2001-10-16 2003-04-24 Hewlett-Packard Company Dispositif de lecture electronique portable
WO2003034136A2 (fr) * 2001-10-16 2003-04-24 Hewlett-Packard Company Affichage haute resolution
WO2003034137A3 (fr) * 2001-10-16 2003-11-27 Hewlett Packard Co Dispositif de lecture electronique portable
WO2003034136A3 (fr) * 2001-10-16 2004-03-11 Hewlett Packard Co Affichage haute resolution
US6940497B2 (en) 2001-10-16 2005-09-06 Hewlett-Packard Development Company, L.P. Portable electronic reading apparatus

Also Published As

Publication number Publication date
NO992209L (no) 1999-07-01
DE19645974C1 (de) 1998-08-13
JP2001503752A (ja) 2001-03-21
CA2270973A1 (fr) 1998-05-14
KR20000053141A (ko) 2000-08-25
EP0937089A1 (fr) 1999-08-25
HUP9904289A3 (en) 2001-08-28
NZ335977A (en) 2000-12-22
NO992209D0 (no) 1999-05-06
AU728345B2 (en) 2001-01-04
BR9712930A (pt) 2006-04-18
SK61799A3 (en) 2000-01-18
PL333128A1 (en) 1999-11-22
CZ160999A3 (cs) 1999-09-15
HUP9904289A2 (hu) 2001-04-28
IL129826A0 (en) 2000-02-29
CN1236369A (zh) 1999-11-24
AU5479898A (en) 1998-05-29
TR199901733T2 (xx) 1999-09-21

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