EP2029125A2 - Composition pharmaceutique pour traiter des infections virales et/ou des maladies tumorales par inhibition du repliement et de la décomposition des protéines - Google Patents

Composition pharmaceutique pour traiter des infections virales et/ou des maladies tumorales par inhibition du repliement et de la décomposition des protéines

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Publication number
EP2029125A2
EP2029125A2 EP07765312A EP07765312A EP2029125A2 EP 2029125 A2 EP2029125 A2 EP 2029125A2 EP 07765312 A EP07765312 A EP 07765312A EP 07765312 A EP07765312 A EP 07765312A EP 2029125 A2 EP2029125 A2 EP 2029125A2
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EP
European Patent Office
Prior art keywords
chaperones
pharmaceutical composition
composition according
inhibitors
substances
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Withdrawn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
EP07765312A
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German (de)
English (en)
Inventor
Ulrich Schubert
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.)
Virologik GmbH
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Virologik GmbH
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Filing date
Publication date
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Publication of EP2029125A2 publication Critical patent/EP2029125A2/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • composition for the treatment of viral infections and / or tumors by inhibiting protein folding and protein degradation.
  • the invention relates to a pharmaceutical composition containing as active components at least one proteasome inhibitor and an inhibitor of protein folding enzymes. These agents are useful in the treatment of acute and chronic human and animal pathogenic virus infections. These include in particular pathogens of infectious diseases such as AIDS, hepatitis, hemorrhagic fever, SARS, smallpox, measles, polio or influenza.
  • the invention relates to agents which contain on the one hand as active ingredients inhibitors of protein folding. These include inhibitors of cellular folding enzymes (the enzymatic chaperones) as well as substances that interfere with the folding of proteins by chemical chaperones. On the other hand, these agents contain components that interfere with the ubiquitin-proteasome system, especially agents that inhibit the 26S proteasome.
  • Inhibitors of protein folding enzymes are known from WO 2005/063281 A2.
  • Proteasome inhibitors have been described both for the treatment of tumor diseases (for example US Pat. No. 6,083,903) and for the treatment of viral infections (WO 02/30455).
  • the invention had the object of providing novel pharmaceutical compositions for the treatment of viral infections and / or tumors.
  • a pharmaceutical composition which contains as active components at least one inhibitor of the ubiquitin-proteasome system and an inhibitor of protein folding enzymes or a method for influencing protein folding.
  • the inhibitor of protein folding enzymes is preferably at least one inhibitor of cellular chaperones or at least one chemical substance which directly affects protein folding (chemical anti-chaperone).
  • a method for influencing the protein folding is preferably the local hyperthermia.
  • a further preferred embodiment of the invention is that substances are used as inhibitors of cellular chaperones or chemical anti-chaperones, which
  • a) inhibit, regulate or otherwise affect the folding and proteolytic maturation of viral proteins and thereby inhibit the release and replication of viruses, especially pathogens such as AIDS, hepatitis, haemorrhagic fever, SARS, smallpox, measles, polio, herpesvirus infections or influenza , or b) interfere with the proliferation of degenerate cells, especially tumor cells, by driving them into programmed cell death by accumulation of misfolded proteins.
  • viruses especially pathogens such as AIDS, hepatitis, haemorrhagic fever, SARS, smallpox, measles, polio, herpesvirus infections or influenza
  • the pharmaceutical composition according to the invention is characterized in that as inhibitors of cellular chaperones or of chemical anti-chaperones substances are used which specifically influence the enzymatic activities of molecular folding enzymes of the host cells.
  • the cells of higher eukaryotes receive these inhibitors or substances and, after cell uptake, block the protein folding of virus structure peats and of proteins from tumor cells.
  • the inhibitors or substances may be administered in vivo in various forms, orally, intravenously, intramuscularly, subcutaneously or in encapsulated form with or without cell specificity-bearing alterations, due to the application of a particular application and / or dose regimen having low cytotoxicity , cause no or negligible side effects, have a relatively high metabolic half-life and a relatively low clearance rate in the organism.
  • composition according to the invention is further characterized in that are used as inhibitors of cellular chaperones or chemical anti-chaperones substances that are a) isolated in natural form from microorganisms or other natural sources, or b) by chemical modifications of natural substances or c) be prepared totally synthetically or d) be synthesized in vivo by gene therapy methods.
  • the inhibitors of cellular chaperones or the chemical anti-chaperones disrupt the highly organized processes of assembly and proteolytic maturation of virus structural proteins and thereby inhibit the release and production of infectious progeny viruses.
  • these substances regulate, disrupt or block the folding of viral proteins and / or tumor-specific proteins by disrupting the late processes of viral replication such as assembly, budding, proteolytic maturation and virus release.
  • the proteolytic processing of precursor proteins of the viral polyproteins is thereby disturbed.
  • the activity of viral proteases is blocked.
  • a further preferred embodiment of the invention is that are used as inhibitors of cellular chaperones or of chemical anti-chaperones substances that lase the activities of cellular proteases and / or enzymes, such as ligases, kinases, Hydro, glycosylation enzymes , Phosphatases, DNAses, RNAses, helicases and transferases that are involved in virus maturation.
  • the inhibitors of cellular chaperones according to the invention or the chemical anti-chaperones have a broad spectrum of activity and can therefore be used as novel broad-spectrum antivirals for the prevention and / or therapy of different viral infections.
  • the pharmaceutical composition is characterized in that are used as inhibitors of cellular chaperones or chemical anti-chaperones substances that block or inhibit cellular chaperones such as heat shock proteins (hsp) proteins, in particular the activities of the heat shock proteins Hsp27, Hsp30 , Hsp40, Hsp60, Hsp70, Hsp72, Hsp73, Hsp90, HsplO4 and Hsc70.
  • heat shock proteins Hsp27, Hsp30 , Hsp40, Hsp60, Hsp70, Hsp72, Hsp73, Hsp90, HsplO4 and Hsc70.
  • substances can be used which belong to the following substance classes and their derivatives: geldanamycin (inhibits Hsp90), radicicol (tyrosine kinase inhibitor, inhibits Hsp90), deoxyspergualin (inhibits Hsc70 and Hsp90), 4-PBA (4 Downregulation of protein and mRNA expression of Hsc70), herbimycin A (tyrosine kinase inhibitor with Hsp72 / 73 induction), epolactaene (inhibitor of Hsp60), scythe and reaper (inhibit Hsp70), artemisinin (inhibitor of Hsp90), CCT0180159 (as pyrazole inhibitor of Hsp90) and SNX-2112 (Hsp90 inhibitor), radanamycin (macrololidimer of radicicol and geldanamycin), novobiocin (Hsp90 inhibitor), quercetin (
  • Substances which regulate, disrupt or block the protein conformation and the folding of viral and / or tumor-specific proteins can be used as chemical anti-chaperones. These include, for example, substances such as glycerol, trimethylamine, betaine, trehalose or deuterated water (D 2 O).
  • substances can be used which are suitable for the treatment, therapy and inhibition of infections with different human pathogenic or animal-pathogenic viruses or substances which are used for the treatment, therapy and inhibition of infections with agents of chronic infectious diseases such as AIDS (HIV-I and HIV-2), hepatitis (HCV and HBV), the cause of the "Severe Acute Respiratory Syndrome” (SARS), the SARS-CoV (coronavirus), of poxviruses, of viral haemorrhagic fever (VHF) pathogens, as well as the Ebola virus as a member of the family Filoviridae; influenza-causing agents such as the influenza A virus.
  • agents of chronic infectious diseases such as AIDS (HIV-I and HIV-2), hepatitis (HCV and HBV), the cause of the "Severe Acute Respiratory Syndrome” (SARS), the SARS-CoV (coronavirus), of poxviruses, of viral haemorrhagic fever (VHF) pathogens, as well as the Ebol
  • the pharmaceutical composition according to the invention is further characterized in that the inhibitors of the UPS is at least one substance which a) especially in the form of proteasome inhibitors, the enzymatic activities of the complete 26S proteasome complex and the free, not with regulatory
  • Subunits assembled 2OS influenced catalytically active proteasome structure or b) specifically inhibits the action of ubiquitin ligases or c) specifically inhibits the action of ubiquitin hydrolases or d) specifically inhibits the action of ubiquitin-activating enzymes or e) specifically the mono- ubiquitinylation of proteins or f) specifically inhibits the poly-ubiquitinylation of proteins
  • proteasome inhibitors are taken up by higher eukaryotes and interact after cell uptake with the catalytic subunits of the proteasome and block all or some of the proteolytic activities of the proteasome - the trypsin, the chymotrypsin and / or the postglutamyl peptide hydrolyzing activities - irreversible or reversible within the 26S or the 2OS proteasome complex.
  • proteasome inhibitors used are substances which a) are isolated in natural form from microorganisms or other natural sources; or b) result from chemical modifications of natural substances; or c) produced totally synthetically; or d) be synthesized in vivo by gene therapy methods; or e) by genetic engineering in vitro or f) in microorganisms.
  • the proteasome inhibitors are compounds which belong to the following substance classes: a) naturally occurring proteasome inhibitors:
  • Aclacinomycin A also referred to as Aclarubicin
  • modified peptide aldehydes such as N-carbobenzoxy-L-leucinyl-L-leucinyl-L-leucinal (also referred to as MG 132 or zLLL), its boric acid derivative MG232; N-carbobenzoxy-Leu-Leu-Nva-H (termed MGl 15; N-acetyl-leucinyl-L-leucinyl-L-norleucinal (referred to as LLnL), N-carbobenzoxy-Ile-Glu (OBut) -la-Leu -H (also referred to as PSI);
  • modified peptide aldehydes such as N-carbobenzoxy-L-leucinyl-L-leucinyl-L-leucinal (also referred to as MG 132 or zLLL), its boric acid derivative MG232; N-carbobenzoxy-Leu-Leu-Nva-H (termed
  • peptides which carry an ⁇ , ⁇ -epoxyketone C-terminal structure, furthermore vinylsulfones such as carbobenzoxy-L-leucinyl-L-leucinyl-L-leucine-vinyl-sulfone or 4-hydroxy-5-iodo-3-nitrophenylactetyl -L-leucinyl-L-leucinyl-L-leucine-vinylsulfone (NLVS);
  • glyoxal or boric acid radicals such as pyrazyl-CONH (CHPhe) CONH (CHisobutyl) B (OH) 2 ) as well as dipeptidyl-boric acid derivatives or
  • Pinacol esters such as benzyloxycarbonyl (Cbz) -Leu-Leu-boroLeu-Pinacol esters.
  • proteasome inhibitors the epoxyketones epoxomicin (epoxomycin, molecular formula: C28H86N4O7) and / or eponemycin (Eponemicin, molecular formula: C 20 H 36 N 2 O 5) or proteasome inhibitors from the PS series the compounds: a ) PS-519 as ⁇ -lactone as well as lactacystin derivative the compound IR- [IS, 4R, 5S]] - 1- (1-hydroxy-2-methylpropyl) -4-propyl-6-oxa-2-azabicyclo [3.2.0] heptane-3,7-dione -
  • PS-314 as peptidyl-boric acid derivative the compound N-pyrazinecarbonyl-L-phenylalanine-L-leucine-boric acid - molecular formula C1 9 H25BN4O4 - and / or c) PS-273 (morpholine-CONH- (CH-naphthyl) -CONH- (CH-isobutyl) -B (OH) 2 ) and its enantiomer PS-293 and / or d) the compound PS-296 (8-quinolyl -sulfonyl-CONH- (CH-Napthyl) -CONH (-CH-isobutyl) -B (OH) 2 ) and / or e) PS-303 (NH 2 (CH-Naphthyl) -CONH- (CH-isobutyl) - B (OH) 2 ) and / or f) PS
  • PS-383 pyridyl-CONH- (CH /? F-phenylalanine) -CONH- (CH-isobutyl) -B (OH) 2 ).
  • compositions described are useful as drugs or for the preparation of agents for the treatment of viral infections and / or tumor diseases.
  • CA carcinoma
  • AML - - Leukemia (AML, ALL, CML, CLL) - acute myeloid, chronic acute lymphocytic, chronic
  • the effect of these inhibitors for the treatment of Plasmazytomzellen of patients with multiple myeloma is used.
  • These B-cell tumors are characterized by an extremely high synthesis rate of immunoglobulins.
  • these plasmacytoma cells are particularly sensitive to the treatment with proteasome inhibitors. Therefore, proteasome inhibitors, especially in the form of boric acid peptides (trade name Velcade) are used successfully for the treatment of multiple myeloma.
  • a very narrow therapeutic window must be taken into account because the boundary between the therapeutic dose and the tolerable toxic dose is very narrow.
  • a further preferred embodiment of the invention relates to the antiviral effect in the combination of both active ingredients. It is known that proteasome inhibitors the
  • HIV human immunodeficiency virus
  • This embodiment of the invention is generally valid for all viral infections in which an ordered assembly of newly synthesized viral structure ports takes place.
  • Example 1 Hsp90 inhibitor 17-AAG shows no cytotoxicity in CEM cells up to a concentration of 10 mM.
  • CD4 + T lymphoid cells were seeded in a 96-well plate at a density of IxIO 4 cells per 100 ⁇ l.
  • To the medium (see Example 4a) were previously added appropriate amounts of 17-AAG to final concentrations of l ⁇ M; 10OnM; 1OnM; InM; 0.InM and 0.0 InM 17-AAG reach. After 30 hours incubation at 37 ° C and 5% CO 2 was added to 10 ⁇ l AlamarBlue TM (Invitrogen) and all batches were incubated for a further 4 hours at 37 ° C.
  • the measure of the vitality of the CEM cells (indicated in MTT CEM) under 17-AAG influence could be determined by measuring the color change of the medium by means of fluorescence measurement at 530/590 nm. All approaches were in triplicate.
  • Example 2 pNLenvl-transfected HeLaSS ⁇ cells show reduced Gag processing and increased Hsp70 expression in the cell fraction under 17-AAG influence in the virus fraction.
  • Example 4a / b For the biochemical analysis of the influence of 17-AAG on the kinetics of gag processing and virus release time kinetics were performed. The experimental details of cultivation, transfection, media change and time kinetics are given in Example 4a / b.
  • cultures of HeLaSS ⁇ cells were used, which were transfected with pNLenvl (Schubert et al, 1995).
  • 17-AAG-containing medium (10OnM 17-AAG), or inhibitor-free medium
  • the kinetics was started after distinct washing steps and aliquoting of the batches. Aliquots of cells were collected at each time point and separated by centrifugation into cell, virus and cell culture supernatant fractions.
  • the HIV proteins were separated by SDS-PAGE, transferred to PVDF membrane, and then visualized by X-ray on antibody-mediated chemo-luminescence.
  • Example 3 17-AAG, as well as the combination with PS341, inhibits virus replication of X4-tropic HI viruses in the HLAC model.
  • CEM cells were cultured in RPMI 1640 with 10% (v / v) fetal calf serum, 2 mM L-glutamine, 100 U ml-1 penicillin and 100 ⁇ g ml-1 streptomycin.
  • Heia cells were cultured in Dulbecco's modified Eagle's Medium (DMEM) with 10% fetal calf serum, 2 mM L-glutamine, 100 U ml-1 penicillin, and 100 ⁇ g / ml streptomycin.
  • DMEM Dulbecco's modified Eagle's Medium
  • Tonsillar cells were transfected into RPMI 1640 with 15% (v / v) fetal calf serum, 2 mM L-glutamine, 100 U ml-1 penicillin, 100 ⁇ g ml-1 streptomycin, 2.5 ⁇ g / ml fungizone, ImM sodium pyrovate, 1 % MEM non-essential amino acid solution and 50 ⁇ g / ml gentanamycin cultured ("tonsil medium").
  • Example 4b Transfection, change of media and kinetics Heia cells (ATCC CCL2) were transfected into OPTI-MEM by means of pNL ⁇ env-Lipofectamine 2000 mixture. After 8 hours of incubation in 37 ° C and 5% CO 2 , a change of media was performed. In one of the two batches a final concentration of 10OnM 17-AAG was added to the medium and incubated for a further 16 hours. After distinct washes in PBS, the respective times were aliquoted. At the appropriate time points, the cells were separated from the supernatant by centrifugation (5min, 5000rpm) and later lysed by CHAPS / DOC lysis (3min on ice).
  • VLP's in the supernatant were pelleted on a 20% sucrose pad (90 min; 14000 rpm) and, like the cell pellet lysates, separated by 10% SDS-PAGE, transferred to PVDF membrane by wet blot and placed in 10 % milk powder (in PBS-Tween 0.1%) blocked.
  • Detection of the HIV or cell-specific proteins was carried out via specific antibodies (against Hsp70, Hsp90, p24, PR55, ⁇ -actin). Through the reaction with secondary antibodies and their coupled chemo luminescence, the signals could be detected on X-ray films.
  • plasmid DNA from HIV-1 molecular DNA was transfected into HeLa cells using the calcium-phosphate precipitation method. These were confluent cultures of Heia cells (5x10 6 cells) with 25 ⁇ g plasmid DNA in calcium phosphate crystals, prepared by a method of Graham and van der Eb (1973), and then a glycerol shock according to Gorman et al. (1982). For the recovery of concentrated virus preparations, the cell culture supernatants were harvested two days after transfection. Subsequently, the cells and their components were separated by centrifugation (1.000 xg, 5 min, 4oC) and filtration (0.45 micron pore size).
  • Virus particles were pelleted by ultra-centrifugation (Beckman SW55 rotor, 1.5 hr, 35,000 rpm, 10oC) and subsequently resuspended in 1 ml of DMEM medium.
  • the virus preparations were sterilized by filtration (0.45 .mu.m pore size) and portioned frozen (-80 0 C).
  • Single virus preparations were standardized by determination of reverse transcriptase activity using a previously described assay (Willey et al, 1988) using [32 P] -TTP incorporation into an oligo (dT) -poly (A) template.
  • Example 4d HLAC model (extraction, infection, kinetics)
  • the tonsil tissue was washed in PBS, cleaned by scalpels of blood clots and divided into 1-mm pieces. Single cells were obtained by mechanical squeezing through a filter mesh. After centrifugation of the isolated cells (5 min, 1200rpm), the cells were counted, seeded in 96-well plates and incubated overnight at 37 ° C and 5% CO 2 . The infection of the cells was carried out by addition of 10ng X4-tropher HIV stocks with simultaneous application of the corresponding inhibitor concentrations. The following day, 50 .mu.l of supernatant were taken ( "1 dpi") and stored at -80 0 C. The cells were then centrifuged (5 min, 1200 rpm)...
  • FIG. 1 is a diagrammatic representation of FIG. 1:
  • the Hsp90 inhibitor 17-AAG shows up to a concentration of 1OnM no cytotoxicity in CEM cells.
  • CD4 + T lymphoid cells CEM cells
  • AlamarBlue TM Invitrogen
  • FIG. 2 is a diagrammatic representation of FIG. 1
  • HeLaSS ⁇ cells transf ⁇ instance with subgenomic HIV-I expression vector pNLenvl show under 17-AAG influence in the virus fraction reduced Gag processing and increased Hsp70 expression in the cell fraction.
  • FIG. 3 is a diagrammatic representation of FIG. 3
  • Tonsil B (B) also showed no effect on X4-tropic HIV replication when incubated with InM PS341 or InM 17-AAG. In contrast to tonsil A, a significant reduction in virus replication could be detected in tonsil B even with the addition of 1OnM 17-AAG. In any combination of proteasome inhibitor PS341 with Hsp90 inhibitor 17-AAG, no viral replication could be detected.

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  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Oncology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne une composition pharmaceutique comportant comme agents actifs au moins un inhibiteur du protéasome et un inhibiteur d'enzymes de repliement des protéines. Ces substances sont adaptées au traitement d'infections aiguës et chroniques à virus pathogènes chez l'homme et l'animal.
EP07765312A 2006-06-01 2007-06-01 Composition pharmaceutique pour traiter des infections virales et/ou des maladies tumorales par inhibition du repliement et de la décomposition des protéines Withdrawn EP2029125A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006026464A DE102006026464A1 (de) 2006-06-01 2006-06-01 Pharmazeutische Zusammensetzung zur Behandlung von Virusinfektionen und / oder Tumorerkrankungen durch Inhibition der Proteinfaltung und des Proteinabbaus
PCT/EP2007/055425 WO2007138116A2 (fr) 2006-06-01 2007-06-01 Composition pharmaceutique pour traiter des infections virales et/ou des maladies tumorales par inhibition du repliement et de la décomposition des protéines

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EP2029125A2 true EP2029125A2 (fr) 2009-03-04

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US (1) US20090156473A1 (fr)
EP (1) EP2029125A2 (fr)
JP (1) JP2009538881A (fr)
KR (1) KR20090048403A (fr)
CN (1) CN101453998A (fr)
AU (1) AU2007267082A1 (fr)
BR (1) BRPI0712459A2 (fr)
CA (1) CA2654276A1 (fr)
DE (1) DE102006026464A1 (fr)
IL (1) IL195611A0 (fr)
MX (1) MX2008015259A (fr)
NO (1) NO20085243L (fr)
RU (1) RU2008152796A (fr)
WO (1) WO2007138116A2 (fr)
ZA (1) ZA200810531B (fr)

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US20090156473A1 (en) 2009-06-18
WO2007138116A2 (fr) 2007-12-06
MX2008015259A (es) 2009-03-26
KR20090048403A (ko) 2009-05-13
DE102006026464A1 (de) 2007-12-06
RU2008152796A (ru) 2010-07-20
NO20085243L (no) 2009-02-27
CN101453998A (zh) 2009-06-10
BRPI0712459A2 (pt) 2012-07-31
WO2007138116A3 (fr) 2008-05-08
AU2007267082A1 (en) 2007-12-06
JP2009538881A (ja) 2009-11-12
ZA200810531B (en) 2009-11-25
CA2654276A1 (fr) 2007-12-06
IL195611A0 (en) 2009-09-01

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