EP1534666A1 - Compose pour la modulation du complexe enzyme de la glycolyse et/ou transaminase - Google Patents

Compose pour la modulation du complexe enzyme de la glycolyse et/ou transaminase

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Publication number
EP1534666A1
EP1534666A1 EP03794769A EP03794769A EP1534666A1 EP 1534666 A1 EP1534666 A1 EP 1534666A1 EP 03794769 A EP03794769 A EP 03794769A EP 03794769 A EP03794769 A EP 03794769A EP 1534666 A1 EP1534666 A1 EP 1534666A1
Authority
EP
European Patent Office
Prior art keywords
compound according
diseases
alkyl
different
same
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Withdrawn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
EP03794769A
Other languages
German (de)
English (en)
Inventor
Erich Eigenbrodt
Hans Scheefers
Sybille Mazurek
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
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Filing date
Publication date
Priority claimed from DE2002144080 external-priority patent/DE10244080A1/de
Application filed by ScheBo Biotech AG filed Critical ScheBo Biotech AG
Publication of EP1534666A1 publication Critical patent/EP1534666A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/24—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen

Definitions

  • the invention relates to compounds for modulating the glycolysis-enzyme and / or transaminase complex and consequently in particular to inhibiting the growth of cells and / or bacteria, pharmaceutical compositions containing such compounds and uses of such compounds for the production of pharmaceutical compositions for the treatment of various diseases.
  • Cancer is one of the leading causes of death these days and the number of cancer cases in industrialized countries is constantly increasing. This is mainly due to the fact that malignant tumors are a disease of old age and, thanks to the successful fight against infectious diseases, more people are reaching this age. Despite all the advances in the diagnostic and therapeutic fields, the prospects for a cure for the most common forms of internal cancer are rarely over 20%. A cancerous growth can currently be destroyed or inhibited in its growth. A regression of a tumor cell into a normal cell cannot yet be achieved. The main therapeutic measures, surgery and radiation, remove cancer cells from the organism. Also the currently used Che otherapeutika des Cancer, the cytostatics, only lead to the destruction or damage of tumor cells. The effect is so little specific in most cases that severe damage to healthy cells occurs at the same time.
  • tumor cells have a metabolism that differs from that of healthy cells, in particular glycolysis.
  • a change in the isoenzyme system involved in glycolysis and a change in the transport of NADH is typical for tumor cells.
  • Et al the activity of the enzymes of glycolysis is increased. This also allows high sales under the aerobic conditions typical of tumor cells.
  • E. Eigenbrodt et al. Biochemical an Molecular Aspects of Selected Cancers, Vol. 2, pp. 311 ff., 1994.
  • the present invention is based on the technical problem of specifying active substances which are able to modulate or inhibit the glycolysis-enzyme and transaminase complex, in particular the proliferation of
  • the invention teaches a compound according to formula I.
  • -Am represents an amino acid residue
  • q and r 0 or 1 and are identical or different
  • -O r - and / or -O q - can also be replaced by -S r - or -S -
  • - NR2.1R2.2 can be replaced by linear or branched -C1-C20 alkyl, or a physiologically acceptable salt of such a compound.
  • amino acid residue is defined in an amino acid as follows: NH 2 -CHAm-COOH.
  • Amino acid residues of the proteinogenic amino acids, especially the essential amino acids, are particularly suitable.
  • the various variants, such as L and D forms, are also included. The same applies in the case of (several) chiral centers.
  • R2 is at least simply present as -Am
  • -Am is preferably an essential amino acid residue
  • an R2 can be replaced by -Am.
  • Examples of compounds according to the invention are: NH 2 -0- (CH2) m -Rl, NH, -0- (CH 2 ) n -CO-Rl, NH 2 -0-CHHal- (CO) 0 -Rl, NH 2 - 0-CHHal-CH 2 - (CO) D -R1, NH 2 -0-CHHal- (CH 2 ) 2 - (CO) 0 -Rl, NH 2 -0-CHHal- (CH 2 ) 3 - (C0) o -Rl, NH 2 -0-CHHal- (CH 2 ) 4 - (C0) o -Rl, NH 2 -0-CO- (CH 2 ) n -CO-Rl, H 2 -C ⁇ CO- (CH 2 ) n -Rl, NH 2 -0- (CH 2 ) n -C0-Rl, NH 2 -0-CO- (CH 2 ) n -
  • R a -CN
  • Rl is as stated above, in particular -CN or -COOH, examples of such compounds are: NH 2 -0-CHAm-Rl, NH 2 -CHAm-0-Rl , NH 2 -0-CHAm-0-Rl, NH 2 -CHRl-0-Am, ⁇ m-0-CHNH 2 -0-Rl, NH 2 -0- (Am-O-CH-O-Rl).
  • NH 2 -0- or more -0- or on both sides of a -0- or more -0- there can be an immediate - (CH 2 ) X - interposed.
  • Substances according to the invention can, depending on the pH, be ionized in solution (for example as -C00 " in basic or as -NH 3 + in acid). Salts such as hydrochlorides etc. can also be formed.
  • the invention is based on the knowledge that in addition to classic metabolic diseases such as diabetes mellitus, obesity, other diseases such as cancer, autoimmune diseases and rheumatism are also caused by metabolic derangements. This explains the strong influence of diet on these diseases.
  • a direct measurable biochemical parameter for these metabolic derailments is the increase in pyruvate kinase type M2 (M2-PK), which increases in the blood of patients with all of the diseases mentioned above and below.
  • M2-PK pyruvate kinase type M2
  • the M2-PK detectable in the patient's blood comes from different cells: in cancer from tumor cells, in sepsis from immune cells, in rheumatism from immune and / or sinovial cells.
  • the tetrameric form of M2-PK is found in a highly ordered cytosolic complex, the glycolysis Enzyme complex.
  • the overactivation of oncoproteins leads to the migration of M2-PK from the complex and the typical changes in tumor metabolism.
  • the phosphoglyceromutase (PGM) leaves the complex and migrates to another enzyme complex in which cytosolic transaminases are associated (see Example 2). This complex is therefore called the transaminase complex.
  • the substrate of the PGM, glycerate-3-P is the precursor for the synthesis of the amino acids serine and gly- a. Both amino acids are essential for DNA and phoypholipid synthesis.
  • the invention further teaches the use of a compound according to the invention for the production of a pharmaceutical composition for the treatment of one or more diseases from the group consisting of "cancer, chronic inflammation, asthma, arthritis, osteoarthritis, chronic polyarthritis, rheumatic arthritis, inflammatory bowl disease, degenerative joint diseases, diseases of the rheumatic type with cartilage breakdown, sepsis, autoimmune diseases, type I diabetes, hashimotoid thyroiditis, autoimmune thrombitis, autoimmune thrombocytopenia "Inflammatory bowel diseases, Crohn's disease, uveitis, psoriasis, collagenosis, Goodpasture syndrome, diseases with impaired leukocyte adhesion, cachexia, diseases due to increased TNFalpha concentration, diabetes, obesity, bacterial infections, especially with resistant bacteria".
  • the term treatment also includes prophylaxis.
  • the invention further teaches a pharmaceutical composition, wherein a compound according to the invention is mixed with one or more physiologically compatible adjuvants and / or carriers and galenically for local or systemic administration, in particular orally, parenterally, for infusion or infusion into a target organ, for injection ( egi., im, intracapsular or intralumbal), is prepared for application in tooth pockets (space between the tooth root and gums).
  • a pharmaceutical composition wherein a compound according to the invention is mixed with one or more physiologically compatible adjuvants and / or carriers and galenically for local or systemic administration, in particular orally, parenterally, for infusion or infusion into a target organ, for injection ( egi., im, intracapsular or intralumbal), is prepared for application in tooth pockets (space between the tooth root and gums).
  • the invention teaches the use of a compound according to the invention for in vitro inhibition of the glycolysis-enzyme complex, in particular pyruvate kinase, asparaginase, serine dehydratases, transaminases, desaminases, and / or glutaminases.
  • transamination, oxidative deamination, hydrolytic deamination, and eliminating are blocked Deamination and reductive deamination.
  • alkyl includes linear and branched alkyl groups and cycloalkyl, optionally also cycloalkyl groups with linear or branched alkyl substituents.
  • aryl also includes aralkyl groups, where alkyl substituents can be alkyl or cycloalkyl.
  • compounds according to the invention are able to inhibit the aforementioned members of the glycolysis-enzyme complex.
  • the proliferation of cancer cells in therapeutically relevant concentrations can be inhibited. No cytotoxic effects are expected in the dose range in question.
  • the compounds according to the invention are also outstandingly suitable for the treatment and prophylaxis of the other diseases listed above.
  • the substances according to the invention are non-steroidal substances.
  • the inhibition of the glycolysis-enzyme and the transaminase complex includes in particular the inhibition of
  • substances according to the invention block, for example, the following reactions: i) threonine to glycine, ii) threonine to ⁇ -amino- ⁇ -ketobutyrate, iii) -amino- ⁇ -ketobutyrate to glycine, iv) see serine pyridoxal phosphate (PLP) Schiff Base to aminoacrylate, in particular the folic acid-dependent serine hydroxymethyltransferase, v) aminoacrylate to pyruvate (by shifting the equilibrium of the natural hydrolysis of the PLP Schiff base to the Schiff base), vi) transamination by means of PLP to synthesize an amino acid an oxo acid, especially the branched chain transaminase, the ⁇ -ketoglutarate, oxaloacetate, 3-hydroxypyruvate and glyoxalate transaminase, the glutamate dehydrogenase.
  • PLP serine pyridoxal
  • Amino acids inhibited It is important to release NH 2 -OH or CH3-OH (-H at C or N, possibly replaced by other radicals, for example alkyl) by glutaminase, arginase, asparaginase or serine hydroxymethyltransferase. This leads to an increased specificity, since a characteristic of tumor cells is a high glutaminase and serine hydroxymethyltransferase activity.
  • NH 2 -OH (hydroxylamine, HA) can be phosphorylated by the high pyruvate kinase activities instead of the -OH of the phosphate (for example the ADP). This leads to the decoupling of the pyruvate kinase reaction in tumor cells. Therefore, in general, the invention also includes all natural metabolites of the Substances according to the invention, in particular of amino oxyacetate, ie fragments of these substances.
  • the cytosolic isoforms of the glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), glutamate dehydrogenase (GIDH) and malate dehydrogenase (MDH) are associated in the transaminase complex.
  • the 'GOT and MDH are components of the malate-aspartate shuttle, which transports the hydrogen produced in the cytosol to the mitochondria.
  • NAD + is recycled for the cytosolic glyceraldehyde 3-phosphate dehydrogenase reaction.
  • the malate-aspartate shuttle is part of glutaminolysis. For an active malate-aspartate shuttle, this is in addition to the GOT
  • Presence of the p36 bound form of MDH is important, as shown in Example 3.
  • a pharmaceutical composition according to the invention can contain several different compounds falling under the above definitions.
  • a pharmaceutical composition according to the invention can additionally contain an active ingredient different from the compound of the formula I. Then it is a combination product.
  • the various active ingredients used can be prepared in a single dosage form, ie the active ingredients are mixed in the dosage form. However, it is also possible to prepare the different active substances in spatially separate dosage forms of the same or different types.
  • Counter ions for ionic compounds according to formula I are Na + , K +, Li +, cyclohexylammmonium, or basic amino acids (eg lysine, argini, ornithine, glutamine).
  • the medicaments produced with the compounds according to the invention can be administered orally, intramuscularly, peri-articularly, intra-articularly, intravenously, intraperitoneally, subcutaneously or rectally.
  • the invention also relates to processes for the production of medicaments which are characterized in that at least one compound of the formula I is brought into a suitable dosage form with a pharmaceutically suitable and physiologically tolerable carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries.
  • Forms of preparation are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and preparations with a protracted active ingredient release, which are customary in their preparation
  • Auxiliaries such as carriers, explosives, binders, coating agents, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used.
  • the medicaments are preferably produced and administered in dosage units, each unit containing as active ingredient a defined dose of the compound of the formula I according to the invention.
  • this dose can be 1 to 1000 mg, preferably 50 to 300 mg, and in the case of injection solutions in ampoule form 0.3 to 300 mg, preferably 10 to 100 mg.
  • daily doses of 20 to 1000 mg of active ingredient, preferably 100 to 500 mg, are indicated, for example. Under certain circumstances, however, higher or lower daily doses may also be appropriate.
  • the daily dose can be administered either by single administration in the form of a single dosage unit or else several smaller dosage units, or by multiple administration of divided doses at certain intervals.
  • Example 1 Quantification of the effectiveness of a compound according to the invention Novikoff hepatoma cells that can be used are available from the tumor bank of the German Cancer Research Center, Heidelberg, (Cancer Research 1951, 17, 1010). 100,000 cells are sown per 25 cm 2 cultivation bottle. A substance according to the invention, dissolved in a solvent suitable for use in cell cultures such as water, dilute ethanol, dimethyl sulfoxide or the like, is added to the culture medium in increasing concentration, for example in the concentration range from 80 ⁇ m to 5000 ⁇ m or from 100 ⁇ m to 300 ⁇ m. After four days of cultivation, the number of cells per bottle is counted. In comparison to the control sample (without the addition of a compound according to the invention or with the alternative addition of a reference compound), one can see the extent and the dose dependency of an inhibition of proliferation of the compound used.
  • a solvent suitable for use in cell cultures such as water, dilute ethanol, dimethyl sulfoxide or the like
  • FIG. 1 a shows an isoelectric focusing of a tumor cell extract (MCF-7 cells). It can be seen that PGM leaves the glycolysis-enzyme complex and migrates into a complex associated with the cytosolic transaminases, the transaminase complex.
  • the transaminase complex is composed as follows: cytosolic
  • Glutamate oxaloacetate transaminase Glutamate oxaloacetate transaminase
  • MDH c-malate dehydrogenase
  • PGM phosphoglyceromutase
  • Glutamate oxaloacetate transaminase Glutamate oxaloacetate transaminase
  • MDH c-malate dehydrogenase
  • PGM phosphoglyceromutase
  • GGT Glutamate pyruvate transaminase
  • GTT Glutamate pyruvate transaminase
  • GIDH c-glutamate hydroxypyruvate transaminase
  • GIDH c-glutamate dehydrogenase
  • the PGM and the nucleotide diphosphate kinase (NDPK) can be used in both Transaminase- as well as be associated in the glycolysis-enzyme complex.
  • FIG. 1b shows the effect of aminooxyacetate (AOA) and hydroxylamine (HA) on the activity of the cytosolic and mitochondrial isoenzyme of the GOT in vitro.
  • the GOT isoenzymes were separated by isoelectric focusing. It can be seen that aminooxyacetate, in particular the cytosolic isoenzyme and hydroxylamine, inhibit both GOT isoenzymes.
  • the inhibition of the GOT leads to an inhibition of the malate-aspartate shuttle. As a result, NAD cannot be recycled and glycolysis is inhibited at the GAPDH level.
  • the invention further teaches the use of N- (4'-trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide (C 12 H 9 F 3 N 2 0 2 ; MW 270.2, see also FIG. 2a) and / or its natural one active metabolites A 77 1726 according to Figure 2b for the preparation of a pharmaceutical composition for the treatment of
  • the benzene ring can in general be substituted with -CHal3 or -0-CHal3 or -Hai at any point, once, twice, three times, four times or five times.
  • the pharmaceutical composition according to the invention is particularly suitable for the treatment of large tumors, ie from 0.1 to 1 cm 3 tumor size.
  • An inventive The pharmaceutical composition is prepared, for example, for oral administration, for example with the following auxiliaries and carriers: colloidal Si0 2 , crospovidone, hydroypropylmethyl cellulose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, starch, talc, Ti0 2 , and / or yellow iron oxide.
  • the dosage is 1 to 50 mg daily, preferably 10 to 30 mg. It may be advisable to initially administer a starting dose of 20 to 500 mg, in particular 50 to 150 mg, for the first 1 to 10 days, in particular the first 1 to 3 days.
  • the substance mentioned at the outset is reacted with one or more sugar phosphates, for example fructose-1, 6-bisphosphate, glycerate-2, 3-bisphosphate, glycerate-3-phosphate, ribose-1, 5-bisphosphate, ribulose- 1, 5-bisphosphate, combined, the combination of substances can be mixed in a dosage form, for example tablets.
  • sugar phosphates for example fructose-1, 6-bisphosphate, glycerate-2, 3-bisphosphate, glycerate-3-phosphate, ribose-1, 5-bisphosphate, ribulose- 1, 5-bisphosphate, combined
  • the combination of substances can be mixed in a dosage form, for example tablets.
  • Sugar phosphate can be administered in a dosage of 20 to 5000 mg per day, for example 100 to 500 mg.
  • AOA is particularly effective on small tumors ( ⁇ 0.1 to 1 cm 3 ) or prevents their formation, in particular the formation of metastases, while compounds of the formulas 10 or 11, if appropriate in combination with sugar phosphate, are effective against the large tumors , The reason for this is the different metabolism in small and large tumors.
  • the above statements on combinations apply analogously.
  • Substances according to the invention can furthermore be used for producing a pharmaceutical composition for the treatment of heart failure or chronic cardiac failure (CCF).
  • CCF chronic cardiac failure
  • This aspect of the invention is based on the knowledge that alternative energy-generating biochemical processes are modulated with the substances according to the invention and thus it is also possible, as it were, to create replacement paths for the above-mentioned poorly functioning processes, for example by activating the serolysis or Glutaminolysis or with substances according to the invention to shift the existing dynamic balance between glycolysis on the one hand and glutaminolysis on the other hand in favor of glycolysis with simultaneous administration of oxygen (increase in the oxygen partial pressure in the blood, for example by ventilation).
  • the administration of anti-inflammatory substances according to the invention the threatening life-threatening acidosis (due to lactate formation) can be avoided.
  • the substances according to the invention intervene directly in the energy metabolism and improve it. As a result, side effects are comparatively minor.
  • the invention therefore furthermore teaches the use of a test system which detects tumor M2-PK for producing a diagnostic agent for in vitro diagnosis of heart failure, in particular also of the degree or the associated inflammatory processes.
  • any known test systems can be used which detect tumor M2-PK, for example immunological test systems with antibodies.
  • test systems known per se can also be used which detect tumor M2-PK as tumor metabolism markers, for example monoclonal antibodies specific therefor.

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Abstract

L'invention concerne des composés pour la modulation du complexe enzyme de la glycolyse et du complexe transaminase, des compositions pharmaceutiques contenant de tels composés, ainsi que l'utilisation de tels composés dans la production de compositions pharmaceutiques destinées au traitement de différents maladies.
EP03794769A 2002-09-06 2003-07-07 Compose pour la modulation du complexe enzyme de la glycolyse et/ou transaminase Withdrawn EP1534666A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DE2002144080 DE10244080A1 (de) 2002-09-06 2002-09-06 Verbindungen zur Modulation des Glykolyse-Enzym- und/oder Transaminase-Komplexes
DE10244080 2002-09-06
DE10242445 2002-09-11
DE10242445 2002-09-11
DE10244299 2002-09-23
DE10244299 2002-09-23
PCT/DE2003/002344 WO2004024676A1 (fr) 2002-09-06 2003-07-07 Compose pour la modulation du complexe enzyme de la glycolyse et/ou transaminase

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EP1534666A1 true EP1534666A1 (fr) 2005-06-01

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EP03794769A Withdrawn EP1534666A1 (fr) 2002-09-06 2003-07-07 Compose pour la modulation du complexe enzyme de la glycolyse et/ou transaminase

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US (2) US7223784B2 (fr)
EP (1) EP1534666A1 (fr)
JP (1) JP2005538165A (fr)
AU (1) AU2003258454A1 (fr)
CA (1) CA2498045A1 (fr)
WO (1) WO2004024676A1 (fr)

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AU2003258454A1 (en) 2004-04-30
US20070238781A1 (en) 2007-10-11
CA2498045A1 (fr) 2004-03-25
US7223784B2 (en) 2007-05-29
WO2004024676A1 (fr) 2004-03-25
US20040147587A1 (en) 2004-07-29

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