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EP1368018A2 - Utilisation de phosphates de sucre, d'analogues de phosphates de sucre, d'acides amines et/ou d'analogues d'acides amines pour moduler le complexe glycolyse-enzyme, la navette malate/aspartate et/ou les transaminases - Google Patents

Utilisation de phosphates de sucre, d'analogues de phosphates de sucre, d'acides amines et/ou d'analogues d'acides amines pour moduler le complexe glycolyse-enzyme, la navette malate/aspartate et/ou les transaminases

Info

Publication number
EP1368018A2
EP1368018A2 EP02704608A EP02704608A EP1368018A2 EP 1368018 A2 EP1368018 A2 EP 1368018A2 EP 02704608 A EP02704608 A EP 02704608A EP 02704608 A EP02704608 A EP 02704608A EP 1368018 A2 EP1368018 A2 EP 1368018A2
Authority
EP
European Patent Office
Prior art keywords
glycolysis
amino acid
analogues
sugar phosphate
tumor
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Withdrawn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
EP02704608A
Other languages
German (de)
English (en)
Inventor
Erich Eigenbrodt
Sybille Mazurek
Helmut Grimm
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.)
ScheBo Biotech AG
Original Assignee
ScheBo Biotech 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 ScheBo Biotech AG filed Critical ScheBo Biotech AG
Priority to EP09075090A priority Critical patent/EP2090304A3/fr
Publication of EP1368018A2 publication Critical patent/EP1368018A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/70—Carbohydrates; Sugars; Derivatives 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/04—Immunostimulants
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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

Definitions

  • sugar phosphates Use of sugar phosphates, sugar phosphate analogs, amino acids and / or amino acid analogs for modulating the glycolysis-enzyme complex, the malate aspartate shuttle and / or the transaminases.
  • the invention relates to uses of sugar phosphates, sugar phosphate analogs, amino acids and / or amino acid analogs for modulating metabolic processes.
  • Tumor therapies that act specifically on the tumor tissue and have comparatively few side effects.
  • the tumor growth is selectively inhibited and / or apoptosis of tumor cells is initiated.
  • PK Pyruvate kinase
  • M2-PK is the embryonic form and replaces all other forms in proliferating cells and tumor cells (see GEJ Staal et al., Biochemical and Molecular Aspects of Selected Cancers, TG Pretlow et al., Eds., Academic Press Inc., San Diego, 1, pages
  • Rat M2-PK protein consists of 530 amino acids and differs only in one residue from human M2-PK (see T. Noguchi et al., J. Biol. Chem., 261, pages 13807 -
  • M2-PK is a glycolytic enzyme, which can be present in a highly active tetrameric and a less active dimeric form. Only that highly active tetrameric form is associated in the glycolysis-enzyme complex.
  • the glycolysis-enzyme complex is an association of glycolysis enzymes, NDPK, adenylate kinase, RNA, A-raf and components of the protein kinase cascade. The transition between the two forms of M2-PK ultimately regulates the glycolytic conversion in tumor cells (see S. Mazurek et al .: J. Cell. Physiol.
  • M2-PK The activity of M2-PK thus controls the transit of the glycolytic path. If the M2-PK is in the dimeric form, the glucose carbon atoms are introduced into branching synthesis processes. If the M2-PK is present as a tetrameric form and associated in the glycolysis-enzyme complex, the glucose is converted very effectively to pyruvate and lactate with energy generation.
  • M2-PK allows cells to survive in conditions with low oxygen levels, since oxidative phosphorylization is not required for the production of ATP by PK. In general, an increased amount of M2-PK is found in malignant tumors and in the blood of tumor patients.
  • Transaminases are enzymes that transfer amino groups from 2-amino acids to 2-keto acids during the transformation. It is a subset of the transferases.
  • the prosthetic group is pyridoxal phosphate. Inhibition of transaminases leads to an increase in amino acids. From the literature reference E. Eigenbrodt et al. , Biochemical on Molecular Aspects of Selected Cancers, Vol. 2, p. 311 ff., 1994, it is known that aminooxyacetate and cycloserine can inhibit glutamate pyruvate transaminase and inhibit cell proliferation. Technical problem of the invention.
  • the present invention is based on the technical problem of specifying active substances which are able to inhibit the proliferation of cancer cells and thus the growth of neoplastic tumors and excessive defense reactions of the body, such as e.g. to inhibit septic shock, autoimmune diseases, graft rejection and acute and chronic inflammatory reactions, with only minor to no cytotoxicity to normal cells of the blood, the immune system and normal tissue cells.
  • the invention teaches the use of a substance selected from the group consisting of "amino acids, amino acid analogs, sugar phosphates, sugar phosphate analogs and mixtures of such substances" for the production of a pharmaceutical composition for the treatment of tumors and / or for immunosuppression and / or sepsis by modulating the association of the amino acids, amino acid analogs, sugar phosphates, sugar phosphate analogs and mixtures of such substances" for the production of a pharmaceutical composition for the treatment of tumors and / or for immunosuppression and / or sepsis by modulating the association of the
  • Glycolysis-enzyme complex / M2-PK and / or by inhibiting transaminases and / or by breaking the binding of the (itochondral) malate dehydrogenase to p36.
  • the invention is based initially on the knowledge that the ratio of tetrameric and dimeric M2-PK in tumor cells is approximately 50:50. It was then recognized that a change in this ratio, thus a shift to one of the two forms for which tumor therapy is suitable. It has been found that when tetramerization of M2-PK is complete, nucleic acid synthesis and consequently proliferation are inhibited. With complete dimerization, on the other hand, there is an inhibition of energy production from glucose with the result of apoptosis, an equally positive therapeutic effect. Surprisingly, both effects can be used for tumor therapy. No cytotoxic effects are to be expected since this metabolic state is tumor-specific.
  • the NAD-dependent cytosolic glycerol 3-phosphate dehydrogenase disappears when the tumor develops.
  • Malate-aspartate shuttles are the precursor of the mitochondrial malate dehydrogenase, which is held in the cytosol by binding to the phosphoprotein p36.
  • the binding of the mitochondrial malate dehydrogenase to p36 in the cytosol can be broken down by amino acids and by sugar phosphates and analogues.
  • analogs denotes compounds which can be derived structurally from natural amino acids or sugars, ie which are different from them7 " ⁇ but which have the same or an even stronger modulation of the glycolysis-enzyme complex / M2-PK association, a transaminase Inhibition and / or dissolution of the p36-malate dehydrogenase binding act as the underlying natural substance ..
  • An analog can in particular be a derivative, ie a naturally present group or an H atom can be replaced by another, non-naturally occurring group
  • This applies to both side chains and the core structure for example the carboxyl group of an amino acid can be replaced by a cyanide group, in the case of sugar phosphates one or several phosphate groups can be replaced by one cyanide group.
  • Amino acid analogs are in particular also the precursors of the amino acids, the ⁇ -keto acids, and those ⁇ -keto acids in which the -COOH group is replaced by a cyanide group (-CN).
  • a pharmaceutical composition according to the invention can contain several different compounds used according to the invention.
  • a pharmaceutical composition according to the invention can additionally contain an active ingredient different from an active ingredient used according to the invention. Then it is a combination product.
  • the various active ingredients used can be prepared in a single dosage form, i.e. the active ingredients are mixed in the dosage form.
  • the substance is selected from the group consisting of "serine, cyberin, valine, leucine, isoleucine, proline, methionine, cysteine, aminoisobutyrate, aminooxyacetate, Chba,
  • the S substance is preferably selected from the
  • Rl -NR4R5 or an amino acid residue, optionally derivatized
  • Stof- '' fen typically (if necessary to give 2- or ⁇ -oxonitriles or Ke toklaren 'esterified). These substances are highly effective amino acid analogs.
  • heterocyclic groups are: furanyl, thiophenyl, pyrrolyl, isopyrrolyl, 3-isopyrrolyl, pyrazolyl, 2-isoimidazolyl, triazolyl, oxazolyl, isoaxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidi- nylyl, pyrazazinyl, pyridazinyl Indenyl, benzofurnyl, benzothiofuranyl, indolyl, isoindazolyl, benzoxazolyl, where the groups mentioned can be partially hydrogenated.
  • Suitable counterions for ionic compounds according to formula I are, for example, Na + , K + , Li + , and / or cyclohexylammonium.
  • the medicaments produced with the compounds used according to the invention can be administered orally, intramuscularly, peri-articularly, intra-articularly, intravenously, intraperitoneally, subcutaneously or rectally.
  • intravenous administration is particularly preferred, especially in the case of Chba, aminooxyacetate
  • the invention further teaches a process for the preparation of a medicament, which is characterized in that at least one compound used in accordance with the invention is mixed with a pharmaceutically suitable and physiologically tolerable carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries and is prepared to give the desired dosage form.
  • Suitable solid or liquid galenical forms of preparation are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, as well as preparations with protracted active ingredient release, and conventional auxiliaries in their preparation such as carriers, explosives, binders, coating agents, swelling agents, lubricants or lubricants, flavoring agents, sweeteners and solubilizers are used. ; Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, • gelatin, starch, cellulose and its derivatives, animal and vegetable oils. Such as cod liver oil, .. sunflower, peanut-
  • polyethylene glycols and solvents such as sterile water and mono- or polyhydric alcohols e.g. Called glycerin.
  • the medicaments are preferably produced and administered in dosage units, each unit containing as active ingredient a certain dose of the compound according to the invention according to formula I.
  • this dose can be 1 to 5000 mg, 5 preferably 50 to 1000 mg, and for injection solutions in ampoule form 1 to 5000 mg, preferably 50 to 2000 mg, for intramuscular injection or 1 to 100 mol, preferably 10 to 100 mmol , with intraperitoneal injection.
  • Appropriate doses can be used, but preferably reduced by a factor of 0.5 to 0.1.
  • daily doses For the treatment of an adult patient weighing 50 to 100 kg, for example 70 kg, daily doses of 20 to 5000 mg of active ingredient, preferably 500 to 3000 mg, are indicated. Under certain circumstances, however, higher or lower daily doses may also be appropriate.
  • the daily dose can be administered either as a single dose in the form of a single dosage unit or else several smaller dosage units, or by
  • the immu ompetent adult rat used by i .v. -Infusion is being treated. This is a model more similar to human therapy than the non-immunocompetent nude mouse that is commonly used.
  • the animal experiments were approved in accordance with Section 8 (1) of the German Animal Welfare Act and were carried out in accordance with the recommendations of the Veterinary Association for Animal Welfare.
  • Male inbred rats Male inbred rats (Sprague-Dawley, 200-250 g, Charles River, Sulzfeld, Germany) were used as tumor recipients.
  • Novikoff hepatoma was used as tumor cells. Among several experimentally generated tumors tested, the Novikoff hepatoma best meets the requirements of a solid tumor that shows all signs of malignancy and is morphologically similar to hepatocellular carcinoma in humans. Novikoff hepatoma was induced by Alex B. Novikoff in 1951 by feeding a diet with 0.06% 4-dimethylazobenzene (buttery yellow) to female Sprague-Dawley rats [Novikoff B. A transplantatble rat liver tumor induced by 4-dimethylaminoazobenzene. Cancer Res 1951; 17: 1010].
  • This liver tumor which grows both as an ascitic tumor and as a solid tumor, shows the typical malignancy criteria such as hyperchromasia, polymorphism, increased mitotic rate and a shifted core-plasma relation in favor of the core.
  • malignancy criteria such as hyperchromasia, polymorphism, increased mitotic rate and a shifted core-plasma relation in favor of the core.
  • the chromate scaffold appears irregularly and the nuclei are lobed, round or oval. 5
  • the Novikoff hepatoma cells were made available by the German Cancer Research Center in Heidelberg. The cells were taken up in Hank 's solution and sterile for passaging a Sprague-Dawley rat
  • the freezing medium consisted of 40% Dulbecco's, 40% FKS and 20% 5 DMSO.
  • the cells were prepared for application as follows: after thawing, the pellet in a Falcon tube was mixed with 50 ml of a medium preheated to 37 ° C (Dulbecco's + 40% FKS) and for five
  • the pellet was filled with HBSS, 100 microliters removed with an Eppendorf pipette and counted in a Neubauer counting chamber to determine the number of vital cells after vital staining with erythrosin (BioMed, Kunststoff, Germany). After centrifugation and decantation, the cell suspension was diluted with HBSS until the suspension contained 5 ⁇ 10 6 vital cells per ml. 1 ml of this suspension was taken up in an insulin syringe and the rat was injected subcutaneously on the back.
  • a shaved skin fold of the animal anesthetized with ether and disinfected with 70% alcohol was lifted and pierced longitudinally from caudal to cranial with a No. 14 cannula and the tumor cells were injected subcutaneously.
  • the infusion of the test animals with substances according to the invention started as soon as the tumor reached a volume of 1 ml.
  • the tumor size was determined by CT-assisted volumimetry.
  • the rats were given 0.315 mg fentanyl citrate / kg body weight i.m. (Hypnorm®,
  • a silicone tube (Silastic R 0.012 inch x 0.025 inch, No. 602-105 HH 061999, Dow Corning Corp. , -Midland, Mich., USA) with the help of chloroform on the end of a 5 cm long spiral piece of PE 10 (polyethylene) catheter (Clay Adams, Parsippany, NJ, USA). , The opposite end was fused with a 30 cm long piece of ..PE 20 catheter. The silicone piece was inserted into the left jugular vein of the recipient and secured with a ligature as previously described [Weeks JR. Long term intravenous infusion. In: Meyers RD (ed.) Methods in Psychobiology, Academic Press 1972; 2: 155].
  • the spiral portion of the catheter came to rest in the subcutaneous tissue and provided the extra length necessary to avoid catheter dislocation when the animal was moving its head.
  • the other end was passed out through the skin of the back, protected in a metal spiral hose, which was attached to the animal via a " bodice, and connected to an infusion pump, which enabled a body weight-adapted continuous infusion.
  • the animals were in one during the infusion metabolic cage.
  • Figure 1 shows the results obtained. While the control animals had a tumor of considerable size, a significant inhibition of tumor growth was found with Chba or A ⁇ -inonxyacetat. At the start of treatment with a relatively small tumor size, virtually complete inhibition of tumor growth, even apoptosis, was observed.
  • Example 4 • dose dependency, the inhibition of proliferation.
  • Novikoff hepatoma cells were cultivated in the usual way for the measurements.
  • the control group received solvents without active substance.
  • the other groups received different doses of the respective compound.
  • the cell density was determined in the usual way.
  • FIG. 2 shows the dose dependency of the cell densities obtained for aminooxyacetate, in FIG. 3 for Chba, in FIG. 4 for glycerate 2, 3-bisphosphate and in FIG. 5 for fructose-1, 6-bis-phosphate. A practically complete inhibition can be seen in all cases, at least at higher doses.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'une substance sélectionnée dans le groupe comprenant des acides aminés, des analogues d'acides aminés, des phosphates de sucre, des analogues de phosphates de sucre et des mélanges de ces substances, pour réaliser une préparation pharmaceutique destinée au traitement de tumeurs et/ou de la suppression immunitaire et/ou de la spesie, par modulation de l'association du complexe glycolyse-enzyme/M2-PK et/ou par inhibition de transaminases et/ou par suppression de la liaison entre la malate déshydrogénase et p36.
EP02704608A 2001-03-13 2002-01-17 Utilisation de phosphates de sucre, d'analogues de phosphates de sucre, d'acides amines et/ou d'analogues d'acides amines pour moduler le complexe glycolyse-enzyme, la navette malate/aspartate et/ou les transaminases Withdrawn EP1368018A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09075090A EP2090304A3 (fr) 2001-03-13 2002-01-17 Utilisation de phosphates de sucre, de phosphates de sucre analogues, d'aminoacides et/ou d'aminoacides analogues en vue de la modulation du complexe glucose-enzyme, du Malate Aspartate Shuttle et/ou des transaminases

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10112926A DE10112926B4 (de) 2001-03-13 2001-03-13 Verwendung von Aminooxyacetat zur Tumorbehandlung
DE10112926 2001-03-13
PCT/DE2002/000212 WO2002072077A2 (fr) 2001-03-13 2002-01-17 Utilisation de phosphates de sucre, d'analogues de phosphates de sucre, d'acides amines et/ou d'analogues d'acides amines pour moduler le complexe glycolyse-enzyme, la navette malate/aspartate et/ou les transaminases

Related Child Applications (1)

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EP09075090A Division EP2090304A3 (fr) 2001-03-13 2002-01-17 Utilisation de phosphates de sucre, de phosphates de sucre analogues, d'aminoacides et/ou d'aminoacides analogues en vue de la modulation du complexe glucose-enzyme, du Malate Aspartate Shuttle et/ou des transaminases

Publications (1)

Publication Number Publication Date
EP1368018A2 true EP1368018A2 (fr) 2003-12-10

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EP02704608A Withdrawn EP1368018A2 (fr) 2001-03-13 2002-01-17 Utilisation de phosphates de sucre, d'analogues de phosphates de sucre, d'acides amines et/ou d'analogues d'acides amines pour moduler le complexe glycolyse-enzyme, la navette malate/aspartate et/ou les transaminases
EP09075090A Withdrawn EP2090304A3 (fr) 2001-03-13 2002-01-17 Utilisation de phosphates de sucre, de phosphates de sucre analogues, d'aminoacides et/ou d'aminoacides analogues en vue de la modulation du complexe glucose-enzyme, du Malate Aspartate Shuttle et/ou des transaminases

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Country Status (7)

Country Link
US (2) US20040235755A1 (fr)
EP (2) EP1368018A2 (fr)
JP (1) JP2004524326A (fr)
AU (1) AU2002238390A1 (fr)
CA (1) CA2457192A1 (fr)
DE (2) DE10112926B4 (fr)
WO (1) WO2002072077A2 (fr)

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DE10112925A1 (de) * 2001-03-13 2002-10-02 Erich Eigenbrodt Verwendung von Zuckerphosphaten, Zuckerphosphatanalogen, Aminosäuren, Aminosäureanalogen zur Modulation von Transaminasen und/oder der Assoziation p36/Malat Dehydrogenase
AU2003266272A1 (en) * 2002-08-12 2004-03-03 Amynon Bio Tech Gmbh Peptide modulators of tumour specific pyruvate kinase subtype m2 (m2-pk)
DE10357301A1 (de) * 2003-12-05 2005-07-07 Schebo Biotech Ag Verbindungen zur Modulation des Glykolyse-Enzym- und/oder Transaminase-Komplexes
EP1595957A1 (fr) * 2004-05-12 2005-11-16 Erich Eigenbrodt Phosphoglycerate mutases et produits enzymatiques
WO2006024492A2 (fr) * 2004-08-30 2006-03-09 Interstitial Therapeutics Implant medical comprenant des inhibiteurs de la synthese atp
EP1966608A1 (fr) * 2005-12-21 2008-09-10 Roche Diagnostics GmbH Méthode d'evaluation du cancer colorectal par mesure de l'hemoglobine et de la pyruvate-kinase m2 dans un echantillon de selles
US8877791B2 (en) 2006-08-04 2014-11-04 Beth Israel Deaconess Medical Center, Inc. Inhibitors of pyruvate kinase and methods of treating disease
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ES2659327T3 (es) * 2009-01-14 2018-03-14 Novigo GmbH & Co. KG Agente para la prevención y el tratamiento de pitiriasis versicolor
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WO2002072077A2 (fr) 2002-09-19
DE10112926B4 (de) 2005-11-10
US20040235755A1 (en) 2004-11-25
EP2090304A3 (fr) 2010-07-21
JP2004524326A (ja) 2004-08-12
EP2090304A2 (fr) 2009-08-19
US20090163591A1 (en) 2009-06-25
WO2002072077A3 (fr) 2002-12-27
DE10112926A1 (de) 2002-10-02
CA2457192A1 (fr) 2003-09-19
AU2002238390A1 (en) 2002-09-24

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