WO1999051223A1 - Ansamycines benzoquinoides pour le traitement d'une crise ou d'un arret cardiaque - Google Patents

Ansamycines benzoquinoides pour le traitement d'une crise ou d'un arret cardiaque Download PDF

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Publication number
WO1999051223A1
WO1999051223A1 PCT/US1999/007242 US9907242W WO9951223A1 WO 1999051223 A1 WO1999051223 A1 WO 1999051223A1 US 9907242 W US9907242 W US 9907242W WO 9951223 A1 WO9951223 A1 WO 9951223A1
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cell
cells
geldanamycin
stroke
cardiac arrest
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PCT/US1999/007242
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English (en)
Inventor
Donald B. Defranco
Clifton W. Callaway
Christopher Lipinski
Nianqing Xiao
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University Of Pittsburgh Of The Commonwealth System Of Higher Education
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Priority to AU33785/99A priority Critical patent/AU3378599A/en
Publication of WO1999051223A1 publication Critical patent/WO1999051223A1/fr

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    • 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

Definitions

  • Oxidative stress is considered to be an important causative factor in the onset or progression of neurodegenerative diseases and may contribute to neuronal damage that results from cerebral ischemia (Coyle et al. (1993) Science 262:689 .
  • Reactive oxygen species (ROS) which are generated as by-products of many metabolic process including monoamine metabolism and arachidonic acid oxidation, may be the principal intracellular mediators of cell death in oxidatively stressed neuronal cells.
  • ROS reactive oxygen species
  • the damage to various macromolecules by chemical reactions with ROS can initiate an apoptotic program of cell death or lead to cell death by necrosis.
  • ROS Reactive oxygen species
  • HT22 has been developed that is particularly sensitive to glutamate-induced oxidative toxicity (Maher et al. (1997) J. Neurosci. 16:6394).
  • the cytotoxic effect of glutamate in HT22 cells is not due to excitotoxic effects of this stimulatory amino acid, as this cell line is devoid of ionotropic glutamate receptors.
  • glutamate-induced oxidative toxicity of HT22 cells is associated with an inhibition of cysteine transport which subsequently leads to depletion of intracellular glutathione levels and activation of neuronal 12-lipoxygenase.
  • the resulting ROS that are generated by arachidonic acid oxidation in these cells likely activate an apoptotic program of cell death by a number of different mechanisms (Lief al. (1997) Neuron 19:453).
  • Cell culture models such as HT22 cells, are well suited for studies designed to assess the effectiveness of pharmacological agents in preventing oxidative toxicity.
  • the list of agents that protect cultured neurons from this form of toxicity is quite extensive and includes growth factors, vitamin E, antioxidants, non-steroidal anti-inflammatory agents such as aspirin, and protein kinase inhibitors.
  • the different mechanisms of action of these neuroprotective compounds probably reflects the multitude of cellular processes that contribute to oxidative toxicity.
  • many compounds that provide protection against oxidative toxicity are only effective when given prior to the onset of oxidative stress, their clinical applicability is limited.
  • Conde et al. disclose that pretreatment of myogenic H9c2 cells and cardiomyocytes with herbimycin or geldanamycin resulted in overexpression of heat shock proteins and conferred protection against simulated ischemia.
  • the present invention by providing a method of preventing damage resulting from cardiac arrest or stroke in which the agent is administered following the onset of the damaging insult, has significant clinical applicability.
  • the present invention provides a method of inhibiting cell death induced by oxidative stress in a cell comprising contacting the cell with an cell-death- inhibiting effective amount of a composition comprising a benzoquinoid ansamycin.
  • a composition comprising a benzoquinoid ansamycin.
  • the cell is a neuronal cell and the benzoquinoid ansamycin is geldanamycin or herbimycin A.
  • the present invention further provides a method of reducing neurological injury resulting from cardiac arrest or stroke comprising administering to a patient suffering from cardiac arrest or stroke a composition comprising an effective amount of a benzoquinoid ansamycin.
  • a benzoquinoid ansamycin is geldanamycin or herbimycin A.
  • the present invention provides an article of manufacture comprising a packaging material and a pharmaceutical composition contained within the packaging material, wherein the pharmaceutical composition comprises a benzoquinoid ansamycin, and wherein the packaging material comprises a label that indicates that the composition can be used to reduce neurological injury resulting from cardiac arrest or stroke.
  • Fig. 1 is a graph depicting viability of cells treated with geldanamycin simultaneously with or subsequent to treatment with glutamate.
  • Fig. 2 is a graph depicting viability of cells treated with geldanamycin or herbimycin A simultaneously with or subsequent to treatment with glutamate.
  • Fig. 3 is a graph depicting geldanamycin on glutamate-induced reduction in glutathione levels.
  • Fig. 4 is a graph of neurological deficit scores in rats treated with geldanamycin or control after asphyxial-induced cardiac arrest.
  • Figs. 5 A and B are Western blots demonstrating the induction of hsp70 and down-regulation of raf-1 in rat brain following intracranial injection of geldanamycin.
  • Fig. 6 is a graph depicting the accumulation of 17- allylaminogeldanamycin in mouse brain following intravenous administration.
  • the benzoquinoid ansamycins are compounds having a benzoquinone moiety, an ansa ring, and a carbamate noiety.
  • the benzoquinoid ansamycins may be represented by the general formula:
  • Geldanamycin and herbimycin A are commercially available. 5
  • the present invention provides a method of inhibiting cell death induced by oxidative stress in a cell comprising contacting a cell undergoing oxidative stress with a cell death-inhibiting effective amount of a composition comprising a benzoquinoid ansamycin.
  • Oxidative stress in a cell may result from various conditions characterized by an increased oxidative burden, including for example ischemia, reperfusion, sepsis, and acute inflammation.
  • the cell is a neuronal cell and oxidative stress results from cardiac arrest or stroke.
  • inhibition of cell death is defined as a statistically significant (P ⁇ 0.05) reduction in the number of cells undergoing cell death.
  • Cell death may be measured by methods known in the art, including for example DNA laddering, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assays, and DNA dye binding assays.
  • TUNEL terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling
  • DNA dye binding assays DNA dye binding assays.
  • characteristic nucleosome-sized cytoplasmic DNA indicates the presence of fragmented cytoplasmic DNA in the cytoplasm, and is used as a marker for cell death.
  • fluorescein-linked digoxigenin antibodies are used to detect the location of deoxyuridine residues that have been attached by terminal transferase to free 3' OH groups of DNA. Brightly fluorescing cells indicate the presence of fragmented DNA.
  • extranuclear staining with DNA-intercalating dye such as Hoechst 33258 is a marker for cell death.
  • the benzoquinoid ansamycin is geldanamycin or herbimycin A.
  • the terms geldanamycin and herbimycin A, as used herein, include analogues thereof that are capable of binding to hsp 90 and inhibiting cell death induced by oxidative stress.
  • Compositions useful in the present method preferably comprise a cell death-inhibiting effective amount of geldanamycin and a carrier.
  • a cell death-inhibiting effective amount is that amount that inhibits cell death by any of the above-described assays for cell death.
  • carrier as used herein includes any and all solvents, diluents, dispersion media, antibacterial and antifungal 6 agents, microcapsules, liposomes. cationic carriers, isotonic and absorption delaying agents, and the like.
  • a cell undergoing oxidative stress may be contacted with the composition of the invention by known methods including direct application to the cell, by intravenous, subcutaneous, intramuscular, intraperitoneal, and intraepidural injection, by topical administration, by inhalation, or by depot injections or erodible implants.
  • the cell is a neuronal cell, and the neuronal cell is contacted with the composition by direct application.
  • the cell is contacted with the composition after the onset of the oxidative stress, and preferably within about two hours of the onset of the oxidative stress.
  • the administration of a composition comprising a benzoquinoid ansamycin to a patient suffering from cardiac arrest or stroke results in a reduction in neurological injury associated with cardiac arrest or stroke.
  • the present invention provides a method of reducing neurological injury resulting from cardiac arrest or stroke comprising administering to a patient suffering from cardiac arrest or stroke a composition comprising an effective amount of a benzoquinoid ansamycin.
  • the benzoquinoid ansamycin is geldanamycin or herbimycin A.
  • An effective amount is defined herein as an amount effective to prevent or reduce neurological injury generally associated with cardiac arrest or stroke. Prevention or reduction of neurological injury may be assessed by scoring with standardized behavioral tests or by direct examination of brain histology post-mortem.
  • compositions preferably contain geldanamycin or herbimycin A and a carrier as defined above, and are administered by known routes as described above.
  • the composition is administered by intravenous infusion.
  • compositions of the present invention reduce neurological injury when administered after the onset of cardiac arrest or stroke.
  • the compositions are preferably administered within about two hours after the onset of cardiac arrest or 7 stroke, and more preferably within about one hour, and most preferably within about five minutes after the onset of cardiac arrest or stroke.
  • compositions are generally known in the art and reference can conveniently be made to Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pennsylvania.
  • Formulation of benzoquinoid ansamycins for use in present methods must be stable under the conditions of manufacture and storage and must also be preserved against the contaminating action of microorganisms such as bacteria and fungi. Prevention against microorganism contamination can be achieved through the addition of various antibacterial and antifungal agents.
  • benzoquinoid ansamycins suitable for administration include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and may be fluid to the extent that easy syringability exists.
  • Typical carriers include a solvent or dispersion medium containing, for example, water buffered aqueous solutions (i.e., biocompatible buffers), ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants, or vegetable oils.
  • Sterilization can be accomplished by an art- recognized technique, including but not limited to filtration or addition of antibacterial or antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid or thimerosal. Further, isotonic agents such as sugars or sodium chloride may be incorporated in the subject compositions.
  • antibacterial or antifungal agents for example, paraben, chlorobutanol, phenol, sorbic acid or thimerosal.
  • isotonic agents such as sugars or sodium chloride may be incorporated in the subject compositions.
  • sterile injectable solutions containing the subject compounds is accomplished by incorporating these compounds in the required amount in the appropriate solvent with various ingredients enumerated above, as required, followed by sterilization, preferably filter sterilization. To obtain a sterile powder, the above solutions are vacuum-dried or freeze-dried as necessary.
  • the subject compounds are thus compounded for convenient and effective administration in pharmaceutically effective amounts with a suitable pharmaceutically acceptable carrier and/or diluent in a therapeutically effective dose.
  • the term "pharmaceutically acceptable carrier and/or diluent'" includes any and all solvents, dispersion media, antibacterial and antifungal agents, microcapsules, liposomes, cationic lipid carriers, isotonic and absorption delaying agents and the like which are not incompatible with the active ingredients.
  • the use of such media and agents for pharmaceutical active substances is well known in the art.
  • Supplementary active ingredients may also be incorporated into the compositions and used in the methods of present invention.
  • the precise therapeutically effective amount of the benzoquinoid ansamycin to be used in the methods of this invention applied to humans can be determined by the ordinary skilled artisan with consideration of individual differences in age, weight, extent of disease and condition of the patient. It can generally be stated that the pharmaceutical preparation of the present invention should be preferably administered in an amount of at least about 1 mg kg per infusion dose, and more preferably in an amount up to about 10 mg/kg per dose, or at a dose that achieves a serum concentration of at least about 0.1 ⁇ g/ml.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly depend upon the unique characteristics of the active material, and the limitations inherent in the art of compounding such an active material for the treatment of neurological injury resulting from cardiac arrest or stroke.
  • the principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinabove disclosed.
  • a suitable pharmaceutically acceptable carrier in dosage unit form as hereinabove disclosed.
  • the dosages are determined by reference to the usual dose and manner of administration of the ingredients.
  • the present invention further provides an article of manufacture comprising a packaging material and a pharmaceutical composition contained within the packaging material, wherein the pharmaceutical composition comprises a benzoquinoid ansamycin, and wherein the packaging material comprises a label that indicates that the composition can be used to reduce neurological injury resulting from cardiac arrest or stroke.
  • the benzoquinoid ansamycin is geldanamycin or herbimycin A.
  • the pharmaceutical compositions may be prepared as described hereinabove.
  • the packaging material may comprise glass, plastic, metal, or any other suitable inert material that does not react with any of the ingredients contained therein.
  • HT22 hippocampal cell line obtained from Dr. David Schubert, The Salk Institute for Biological Studies, LaJolla, CA 92037
  • DMEM Dulbecco's minimum essential medium
  • GA 0.1 ⁇ g/ml geldanamycin
  • hsp70 by GA in HT22 cells was as effective as a 60 minute 42 °C heat shock.
  • this compound does not generally up-regulate the expression of all members of the heat shock protein family.
  • GA treatment in other cultured cells typically leads to the selective degradation of hsp90-associated signaling molecules.
  • hsp70 was not induced in HT22 cells which were subjected to oxidative stress as a result of treatment with 5 mM glutamate. This oxidative stress in HT22 cells ultimately culminates in cell death. Since GA treatment was still able to induce hsp70 in the presence of 5 mM glutamate, the pathway leading to hsp70 induction in HT22 cells was not immobilized by oxidative glutamate toxicity. This example demonstrates that hsp70 levels are induced by GA, and that GA-induced hsp70 levels are maintained in the presence of 5 mM glutamate for up to 12 hours in HT22 cells.
  • Example 2 Geldanamycin Protects HT22 Cells from Glutamate-induced Cytotoxicity HT22 cells were seeded on 60 mm tissue culture dishes at 300,000 cells per dish and grown overnight. Cells were then incubated in the presence of 5 mM glutamate for 20 hours.
  • Geldanamycin (0.1 ⁇ g/ml) was added either at the same time, or 1 , 2 or 6 hours after the addition of glutamate.
  • Phase contrast images demonstrated that treatment of HT22 cells with 0.1 ⁇ g/ml GA led to protection from glutamate-induced oxidative toxicity. After 24 hours of glutamate treatment, extensive cell death was visible both by inspection of HT22 cell cultures under light microscopy and as assessed by trypan blue staining.
  • HT22 cells were seeded on 96-well plates at 5,000 cells per well and grown for 12 hours. Cells were then treated with 2mM, 5mM or lOmM concentrations of glutamate.
  • G Geldanamycin
  • Herb herbimycin A
  • Fig. 2 determinations ⁇ S.D. Similar results were obtained in a replicate experiment. Cell viability was expressed relative to control cells treated with GA or Herb alone. As shown in Figure 1, 0.1 ⁇ g/ml GA provided effective protection in HT22 cells against cytotoxic effects observed in the presence of 2 and 5mM glutamate. GA still protected HT22 cells from toxicity that resulted from a 10 mM glutamate treatment, but it was less effective at this higher dose of glutamate. Herbimycin A, another benzoquinoid ansamycin closely related to GA, also protected HT22 cells from the glutamate-induced oxidative toxicity (Fig. 2).
  • GA retained its capacity to protect HT22 cells from oxidative stress, even if given after the addition of glutamate.
  • the ability of GA, given following glutamate treatment, to protect HT22 cells from glutamate-induced oxidative toxicity diminished over time but was still apparent 6 hours after cells were initially exposed to 2 or 5 mM glutamate (Fig. 1).
  • GA-induction of hsp70 can be associated with protection against cell death in HT22 12 cells, even if hsp70 induction follows the initiation of glutamate-induced oxidative toxicity.
  • GSH Cellular glutathione
  • HT22 cells were seeded onto 96-well plates at 20,000 cells per well and grown overnight. Cells were then treated with 5 mM glutamate (Glu) and/or 0.1 ⁇ g/ml geldanamycin (GA) for 2, 4, 6 or 8 hours. Monochlorobimane was added to 40 ⁇ M and following an additional 30 minutes of incubation, fluorescence at 460 nm in response to excitation at 395 nm was measured using a Perkin Elmer fluorescence plate reader. Values represent the average of triplicate experiments ⁇ S.D.
  • oxidative glutamate toxicity in HT22 cells has the characteristics of programmed cell death, the present example was performed to determine whether the protective effects of GA result from a disruption in the apoptotic program.
  • HT22 cells were treated with 5 mM glutamate (Glu) for 20 hours.
  • 0.1 ⁇ g/ml geldanamycin (GA) was added either at the same time as glutamate, or 1 , 2 or 6 hours after the addition of glutamate.
  • Genomic DNA was prepared as described by Ausubel et al.; eds, Current Protocols in Molecular Biology. Vol. 2 John Wiley and Sons, Inc., Boston, 1994.
  • icv injection as follows. Rats were stereotaxically fitted with 4mm x 22 gauge guide cannulae directed at the lateral ventricle (AP-2.0, ML+2.0). Three days later, geldanamycin (20 ⁇ g in 10 ml of dimethyl sulfoxide (DMSO)) or DMSO vehicle was injected over 60 seconds. The injector was removed and replaced with a stylet. At 12 or 24 hours after injection, hippocampi were isolated from which whole cell extracts were prepared and subjected to Western blot analysis to visualize raf-1 and actin, or hsp70. Negative and positive control protein samples for hsp70 were prepared from untreated or heat shocked HT22 cells.
  • DMSO dimethyl sulfoxide
  • 17-allylaminogeldanamycin (60mg/kg) was administered to CD2F1 mice by intravenous (iv) injection. Brain levels of 17-AAG were determined at various time points after administration. As shown in the graph at Figure 6, 17- AAG accumulated in brain tissue within minutes following iv injection of 60mg/kg. 17-AAG levels remained fairly constant over the first few hours after iv injection, but then declined over the next 16-18 hours to approximately 10% of peak values.
  • 17-AAG levels in brain are comparable to the levels used in cell culture (i.e., 0.1 ⁇ g/ml) to bring about desired biochemical effects and protection from oxidative toxicity.
  • the rats were extubated and returned to cages for behavioral observation.
  • the neurological deficit scores consist of five components: consciousness and respiration, cranial nerve function, motor function, sensory function, and coordination.

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Abstract

L'invention concerne un procédé permettant d'inhiber dans une cellule la dégénérescence neuronale induite par le dommage oxydatif. Le procédé consiste à placer ladite cellule au contact d'une composition contenant une ansamycine benzoquinoïde. L'invention concerne en outre un procédé pouvant réduire une altération neurologique résultant d'une crise ou d'un arrêt cardiaque. Le procédé consiste à administrer à un patient une composition contenant une ansamycine benzoquinoïde.
PCT/US1999/007242 1998-04-03 1999-04-01 Ansamycines benzoquinoides pour le traitement d'une crise ou d'un arret cardiaque WO1999051223A1 (fr)

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US60/080,605 1998-04-03

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Cited By (17)

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EP1200078A1 (fr) * 1999-07-09 2002-05-02 Oregon Health & Science University Compositions et procedes activant la regeneration nerveuse
WO2005063714A1 (fr) 2003-12-23 2005-07-14 Infinity Pharmaceuticals, Inc Analogues d'ansamycines contenant de la benzoquinone pour le traitement du cancer
WO2006039977A1 (fr) 2004-10-08 2006-04-20 Merck Patent Gmbh 3-(2-hydroxyphenyl)-pyrazoles et leur utilisation en tant que modulateurs de hsp90
WO2006092202A1 (fr) 2005-03-02 2006-09-08 Merck Patent Gmbh Derives de thienopyridine et leur utilisation comme modulateurs de la hsp90
US7129244B2 (en) 2003-09-18 2006-10-31 Conforma Therapeutics Corporation Triazolopyrimidines and related analogs as HSP90-inhibitors
US7241890B2 (en) 2001-10-30 2007-07-10 Conforma Therapeutics Corporation Purine analogs having HSP90-inhibiting activity
WO2007138994A1 (fr) 2006-05-26 2007-12-06 Chugai Seiyaku Kabushiki Kaisha Inhibiteur de la hsp90
DE102007002715A1 (de) 2007-01-18 2008-07-24 Merck Patent Gmbh Triazolderivat
US7465718B2 (en) 2002-02-08 2008-12-16 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
DE102007028521A1 (de) 2007-06-21 2008-12-24 Merck Patent Gmbh Indazolamidderivate
DE102007032739A1 (de) 2007-07-13 2009-01-15 Merck Patent Gmbh Chinazolinamidderivate
DE102007041116A1 (de) 2007-08-30 2009-03-05 Merck Patent Gmbh 1,3-Dihydro-isoindolderivate
DE102008061214A1 (de) 2008-12-09 2010-06-10 Merck Patent Gmbh Chinazolinamidderivate
DE102009054302A1 (de) 2009-11-23 2011-05-26 Merck Patent Gmbh Chinazolinderivate
US8093229B2 (en) 2005-03-30 2012-01-10 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
DE102010046837A1 (de) 2010-09-29 2012-03-29 Merck Patent Gmbh Phenylchinazolinderivate
US8362236B2 (en) 2007-03-01 2013-01-29 Chugai Seiyaku Kabushiki Kaisha Macrocyclic compound

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EP1200078A1 (fr) * 1999-07-09 2002-05-02 Oregon Health & Science University Compositions et procedes activant la regeneration nerveuse
EP1200078A4 (fr) * 1999-07-09 2004-06-30 Univ Oregon Health & Science Compositions et procedes activant la regeneration nerveuse
EP2336133A1 (fr) 2001-10-30 2011-06-22 Conforma Therapeutics Corporation Analogues de purine présentant une activité inhibitrice de HSP90
US7241890B2 (en) 2001-10-30 2007-07-10 Conforma Therapeutics Corporation Purine analogs having HSP90-inhibiting activity
US7465718B2 (en) 2002-02-08 2008-12-16 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
US7138401B2 (en) 2003-09-18 2006-11-21 Conforma Therapeutics Corporation 2-aminopurine analogs having HSP90-inhibiting activity
EP2145888A1 (fr) 2003-09-18 2010-01-20 Conforma Therapeutics Corporation Dérivés de déazapurine en tant qu'inhibiteurs de l'HSP90
US7129244B2 (en) 2003-09-18 2006-10-31 Conforma Therapeutics Corporation Triazolopyrimidines and related analogs as HSP90-inhibitors
US7148228B2 (en) 2003-09-18 2006-12-12 Conforma Therapeutics Corporation Pyrazolopyrimidines and related analogs as HSP90-inhibitors
US7138402B2 (en) 2003-09-18 2006-11-21 Conforma Therapeutics Corporation Pyrrolopyrimidines and related analogs as HSP90-inhibitors
EP2492261A1 (fr) 2003-12-23 2012-08-29 Infinity Discovery, Inc. Analogues d'ansamycines contenant de la benzoquinone pour le traitement du cancer
WO2005063714A1 (fr) 2003-12-23 2005-07-14 Infinity Pharmaceuticals, Inc Analogues d'ansamycines contenant de la benzoquinone pour le traitement du cancer
WO2006039977A1 (fr) 2004-10-08 2006-04-20 Merck Patent Gmbh 3-(2-hydroxyphenyl)-pyrazoles et leur utilisation en tant que modulateurs de hsp90
WO2006092202A1 (fr) 2005-03-02 2006-09-08 Merck Patent Gmbh Derives de thienopyridine et leur utilisation comme modulateurs de la hsp90
US8093229B2 (en) 2005-03-30 2012-01-10 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
WO2007138994A1 (fr) 2006-05-26 2007-12-06 Chugai Seiyaku Kabushiki Kaisha Inhibiteur de la hsp90
US8193351B2 (en) 2006-05-26 2012-06-05 Chugai Seiyaku Kabushiki Kaisha HSP90 inhibitor
DE102007002715A1 (de) 2007-01-18 2008-07-24 Merck Patent Gmbh Triazolderivat
WO2008086857A1 (fr) 2007-01-18 2008-07-24 Merck Patent Gmbh Dérivé de triazole comme inhibiteur de hsp90
US8362236B2 (en) 2007-03-01 2013-01-29 Chugai Seiyaku Kabushiki Kaisha Macrocyclic compound
DE102007028521A1 (de) 2007-06-21 2008-12-24 Merck Patent Gmbh Indazolamidderivate
DE102007032739A1 (de) 2007-07-13 2009-01-15 Merck Patent Gmbh Chinazolinamidderivate
DE102007041116A1 (de) 2007-08-30 2009-03-05 Merck Patent Gmbh 1,3-Dihydro-isoindolderivate
DE102008061214A1 (de) 2008-12-09 2010-06-10 Merck Patent Gmbh Chinazolinamidderivate
DE102009054302A1 (de) 2009-11-23 2011-05-26 Merck Patent Gmbh Chinazolinderivate
WO2011060873A1 (fr) 2009-11-23 2011-05-26 Merck Patent Gmbh Dérivés de quinazoline
DE102010046837A1 (de) 2010-09-29 2012-03-29 Merck Patent Gmbh Phenylchinazolinderivate
WO2012041435A1 (fr) 2010-09-29 2012-04-05 Merck Patent Gmbh Dérivés de phénylquinazoline

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