EP2137207A2 - Composés pharmaceutiquement actifs - Google Patents

Composés pharmaceutiquement actifs

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Publication number
EP2137207A2
EP2137207A2 EP08706741A EP08706741A EP2137207A2 EP 2137207 A2 EP2137207 A2 EP 2137207A2 EP 08706741 A EP08706741 A EP 08706741A EP 08706741 A EP08706741 A EP 08706741A EP 2137207 A2 EP2137207 A2 EP 2137207A2
Authority
EP
European Patent Office
Prior art keywords
peptide
acid
isoflavone
genistein
compound according
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Withdrawn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
EP08706741A
Other languages
German (de)
English (en)
Inventor
Herbert GÖRNE
Lutz MÜLLER-KUHRT
Christian Mang
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.)
Trojanon & Co KG GmbH
Original Assignee
Trojanon & Co KG GmbH
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 Trojanon & Co KG GmbH filed Critical Trojanon & Co KG GmbH
Publication of EP2137207A2 publication Critical patent/EP2137207A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to pharmaceutically active compounds of an isoflavone or isoflavone glycoside and, covalently linked thereto, an amino acid, a peptide or peptide derivative having 2 to 5 amino acids, as well as pharmaceutically acceptable salts or solvates of these compounds, as well as uses of such substances for the production of pharmaceutical compositions, in particular for the treatment of platelet aggregation and for tumor therapy.
  • Applications of the invention are therefore the medicine and the pharmaceutical industry.
  • Isoflavones sometimes also called isoflavonoids, form a group of mostly yellowish-colored plant dyes derived from isoflavone. In the context of this invention, the glycosides of the isoflavones are also counted.
  • the more known isoflavones include, in particular, isoflavone, daidzein, genistein, prunetin, biochanin A, orobol, santal, glycitein, pratense, formononetin, genistin, 6 "-O-malonylgenistin, 6" -O-acetylgenistin, daidzin, 6 "-O- Malonyldaidzin, 6 "-O-acetyldaidine, glycitin, ononine and sissotrine, and also genistin, daidzin, 6" -O-malonylglycitin and 6 "-O-acetylglycitin.
  • the malonyl glucosides of genistein make up the majority of isoflavones in soybeans.
  • the isoflavones are mainly present in their respective aglycone form genistein, daidzein and glycitein.
  • isoflavones are known to show estrogenic effects on grazing animals, for example. Other isoflavones are thought to have antioxidant activity in humans or other mammals, evidence of such an effect has not yet been achieved. It is also controversial whether and if so which isoflavones have an anti-carcinogenic, anti-atherogenic, anti-osteoporotic and / or hypolipidemic effect. In many cases, it has not hitherto been possible to reproduce the effects attributed to isoflavones by administering the pure isoflavone, if appropriate with customary pharmaceutical carriers and excipients.
  • genistein inhibits platelet aggregation by modulating intracellular metabolic processes: inhibition of tyrosine kinase in the metabolism of cyclooxygenase (5), modulation of cAMP by inhibition of phosphodiesterase (6), reduction of intracellular availability of peroxide as an important agent of phospholipase C and arachidonic acid metabolism (7, 8) ,
  • Genistein is an isoflavone derived from soy.
  • malignant cells such as those of hematopoietic tumors such as leukemias and lymphomas, melanomas and epithelial tumors such as mammary, lung, prostate and head and neck squamous cell carcinomas (7-5 )
  • the growth inhibitory activity of genistein is due to its antiproliferative and pro-apoptotic activity (6).
  • compositions isoflavones / short chain peptides superior inhibition of
  • Platelet aggregation or improved anti-tumor activity should be achieved. As far as possible, other areas of application of isoflavones should also be developed.
  • X is an isoflavone or isoflavone glycoside and Pep is an amino acid or a peptide or peptide derivative having 2 to 5 amino acids, and wherein there is a covalent bond between X and Pep or the linkage by a suitable linker system (such as ethylene glycol, ethanolamine, higher homologs thereof or the corresponding polyethylene glycol derivatives), as well as pharmaceutically acceptable salts or solvates of these compounds, which enhance the effects of the isoflavone component of the compound on organisms, especially mammals, or even develop biological effects in the first place.
  • a suitable linker system such as ethylene glycol, ethanolamine, higher homologs thereof or the corresponding polyethylene glycol derivatives
  • the constituent X of the compound I is formed from an isoflavone or isoflavone glycoside of a substance of the general formula (II) or from a pharmaceutically acceptable salt or solvate of such a substance:
  • radicals R 1, R 2, R 3, R 4, R 5 and R 6 may each independently be hydrogen, hydroxy, methoxy or glycoside (GIc), where one of the radicals 1-6 in the compound I is represented by the radical Pep (meaning see above ) is replaced.
  • Preferred linkages are R2 and R5.
  • glycoside in formula II has the general formula III
  • R is independently of R1, R2, R3, R4, R5 and R6 selected from the group consisting of hydrogen, acetyl and malonyl.
  • Particularly preferred compounds of the invention are those in which the constituent X is isoflavone, daidzein, genistein, prunetin, biochanin A, orobol, santal, glycitein, pratense, formononetin, genistin, 6 "-O-malonylgenistin, 6" -O-acetylgenistin, Daidzin, 6 "-O-malonyldaidzin, 6" -O-acetyldaidzin, glycitin, ononine or sissotrine is formed.
  • the constituent X contains two to three OH groups which are free or mixed wholly or partly with monosaccharides, incl.
  • acetic acid, malonic acid, cinnamic acid, coumaric acid, caffeic acid, ferulic acid acylated monosaccharides or disaccharides including in part with acetic acid, Malonic acid, cinnamic acid, coumaric acid, caffeic acid, ferulic acid, acylated disaccharides, methyl or sulfate are substituted.
  • X is formed from genistein, genistin, daidzein or daidzin, preferably genistein.
  • the ingredient Pep is formed from a dipeptide selected from the group of peptides having the sequences DD, EE, DE, ED; wherein D is aspartic acid and E is glutamic acid.
  • a dipeptide selected from the group of peptides having the sequences DD, EE, DE, ED; wherein D is aspartic acid and E is glutamic acid.
  • glutamic acid dipeptide (peptide of the sequence EE) is particularly preferred.
  • Glutamic acid dipeptide in conjunction with genistein could be a particularly striking
  • the ingredient Pep is formed from a peptide selected from the group of peptides having the sequences
  • D is aspartic acid and E is glutamic acid.
  • E glutamic acid
  • the covalent linkage between X and Pep can be formed within the compound according to the invention in any desired manner, preferably via a carbamate, ether or ester bond.
  • a carbamate, ether or ester bond has proven particularly useful when the peptide via its N-terminal amino group or via its C-terminal carboxyl group or the reduction obtainable by primary hydroxyl directly with a hydroxyl group of X, which is located at one of the positions R1-R6, to form a covalent carbamate, ether, or ester bond, or via a suitable linker system that combines both functionalities.
  • Suitable as a linker system are ethylene glycol, ethanolamine, higher homologs thereof or the corresponding polyethylene glycol derivatives.
  • the covalent linkage is formed via an amide, an ether or a carboxylic acid ester, preferably when the linkage via R 2 or R 5 is made by X.
  • the present invention further encompasses the use of these compounds or pharmaceutically acceptable salts or solvates thereof for the preparation of pharmaceutical compositions for the treatment and / or protection against medical indications of the human or other mammalian organism.
  • Preferred medical indications include the prophylaxis and therapy of thrombembolic diseases, cardiovascular diseases, vascular diseases and vascular anomalies, diseases associated with increased platelet count and / or platelet aggregation, metabolic diseases and cancers
  • Particularly preferred medical indications include prophylaxis and therapy of: hypertension, hypercholesterolemia, myocardial infarction and reinfarction, infarcts and reinfarts of other organs, stroke, pulmonary embolism, leg vein thrombosis, atherosclerotic vascular diseases, increased platelet count and or aggregation, diabetes mellitus, hyperhomocysteinemia, malignancies , and or or osteoporosis, as well as pre- and postoperative thrombosis prophylaxis,
  • the present invention further relates to the use of said compounds and drug combinations for the preparation of pharmaceutical compositions for the treatment and / or protection against medical indications of the human organism or of the organism of other mammals.
  • the present invention encompasses the use of at least one compound of the invention or pharmaceutically acceptable salts or solvates thereof as an adjunct to pharmaceutical compositions to improve the availability of drugs in these pharmaceutical compositions in mammals.
  • the present invention encompasses the use of the compounds according to the invention or pharmaceutically acceptable salts or solvates thereof as a food additive, as an additive for the protection of cells in fermenters or bioreactors, as pet food and as a plant protection agent.
  • Tumors such as leukemias and lymphomas, solid tumors such as melanoma, epithelial tumors such as mammary, lung, gastrointestinal, (eg pancreas), especially gastric and colon and prostate and head and neck
  • the present invention comprises methods for preparing the compound I. comprising the steps of: a) providing an active ingredient selected from the group consisting of isoflavone, daidzein, genistein, prunetin, biochanin A, orobol, santal, glycitein, pratense, formononetin, genistin, 6 "-O-malonylgenistin, 6" -O Acetylgenistine, daidzin, 6 "-O-malonyldaidzine, 6" -O-acetyldaidzine, glycitin, ononine and sissotrine, and / or a pharmaceutically acceptable solvate or salt of the active ingredient, wherein the active ingredient optionally has a protected side group, b) providing a peptide or peptide derivative of 2 to 5 amino acids in length or providing an amino acid and / or a solvate or salt of the peptide or amino acid, at least one of the amino acid
  • the preparation is carried out by means of a) 1. Preparation of a peptide of suitable length and sequence with at least one
  • the starting point of the invention is the surprising finding that the new compounds of the formula (I) are transported much more effectively into the cell via a cellular peptide transport system. This ensures that even lower concentrations of these compounds trigger physiological effects especially in the prevention, treatment and alleviation of human platelet aggregation and tumors and associated indications. Thus, much lower levels are required than when using the corresponding pure isoflavone or isoflavone glycoside.
  • the compound components X and Pep interact synergistically in an advantageous manner due to their covalent linkage.
  • synergy effects can occur with other active ingredients.
  • an active substance is understood as meaning a substance which, when administered to a mammal, in particular a human, can cause a pharmaceutically desired change in a physiological state of the treated mammal.
  • An active ingredient is understood in particular to mean the pharmaceutically active constituent of a drug, in particular also the active ingredient X of the compound according to the invention.
  • substances in their singular form are also referred to in the context of this invention, they also mean mixtures of several of the corresponding substances, unless otherwise stated.
  • the invention therefore also relates to those pharmaceutical compositions in which the active ingredient is a mixture of two or more compounds of the formula (I).
  • compounds according to the invention which are produced under an active ingredient and a peptide or covalently linked therefrom are also each pharmaceutically acceptable salts or solvates are counted.
  • peptides encompasses linear or branched peptides which can consist of both the 20 gene-coded amino acids and of unnaturally occurring alpha, beta and gamma amino acids.
  • a peptide derivative is understood as meaning a peptide which is represented in the main and / or in the side chain by at least one linear, cyclic or branched, halogenated or hydroxy or amine-substituted or unsubstituted, saturated or aliphatic alkyl, alkyl ether,
  • Alkylthioether, alkoxy, acyl or aryl radical is modified, wherein the radical contains between 1 and 20 carbon atoms.
  • the pharmaceutical or therapeutic effect achieved by the compound is also that of an antioxidant when the active ingredient X is formed from an isofiavon or an isoflavone glycoside.
  • the compound according to the invention makes it possible for the first time to achieve an antioxidant activity of an isoflavone previously suspected or only described at high concentrations at pharmaceutically acceptable concentrations of the active ingredient in the target cells of a treated mammal, especially a human.
  • a means is thus provided for the first time with which the hitherto only suspected beneficial effects of isoflavones and isoflavone glycosides can be reproducibly achieved.
  • Isoflavones, isoflavone glycosides and their pharmaceutically acceptable salts or solvates can thus be used for the first time in a pharmaceutical composition with peptides of precisely known, uniform and reproducible nature.
  • the amount of active ingredient and / or the amount of peptide each alone is insufficient to produce the pharmaceutical or therapeutic effect.
  • Hydrogen peroxide is a triggering or at least promoting factor in the emergence of numerous
  • Isoflavone compositions particularly in humans, have failed to reduce the availability of hydrogen peroxide and to eliminate its disease-promoting or disease-causing effects. In particular, it has not been reproducibly succeeded by administering the isoflavones and isoflavone glycosides
  • the compound of the invention provides a remedy for the first time.
  • a compound of the invention of one of the previously described types which is adapted to inhibit platelet aggregation Prevention and / or treatment of hypertension, hypercholesterolemia, hyperhomocysteinemia, diabetes mellitus, myocardial infarction, stroke, atherosclerotic vascular disease, malignancies, and osteoporosis.
  • compounds according to the invention are present in an amount which is sufficient to bring about an inhibition of platelet aggregation when administered to a mammal, in particular a human.
  • Such an effect has not been reproducibly achieved, especially when administering daidzein, daidzin, genistein and / or genistin, if appropriate with customary pharmaceutical auxiliaries and carriers, using physiologically acceptable concentrations of the named active ingredient or of the active substances mentioned.
  • the pharmaceutical composition according to the invention is therefore advantageously suitable as a substitute for conventional acetylsalicylic acid and / or clopidogrel-containing pharmaceutical compositions.
  • the pharmaceutical according to the invention is therefore advantageously suitable as a substitute for conventional acetylsalicylic acid and / or clopidogrel-containing pharmaceutical compositions.
  • compositions make it possible, without the known side effects of conventional pharmaceutical compositions with acetylsalicylic acid and / or clopidogrel-based active ingredients, to achieve a desired therapeutic effect, in particular to inhibit platelet aggregation in the blood of a treated human or other mammal.
  • compositions according to the invention which are particularly suitable for inhibiting platelet aggregation in a mammal such as, for example, humans.
  • the undesirable side effects occurring in connection with the use of conventional acetylsalicylic acid and / or clopidogrel-based antiplatelet agents as well as treatment failure can be avoided or at least reduced.
  • the therapeutic efficacy may include or consist of an antioxidant effect, in particular the lowering of the availability of hydrogen peroxide in a mammal, and particularly preferably the inhibition of platelet aggregation.
  • the pharmaceutical preparation according to the invention is preferably prepared for oral or parenteral administration.
  • the pharmaceutical composition according to the invention can be present in particular in the form of a tablet, dragee, juice or other solution.
  • Composition may preferably be as pharmaceutically acceptable carrier and
  • Excipients contain water and glucose. Further suitable auxiliaries and carriers are taken from the expert in the publication by Fiedler, H.P., Encyclopedia of adjuvants for pharmacy, cosmetics and adjacent fields, 4th edition, Aulendorf: ECV Editio Kantor-Verlag, 1996.
  • composition according to the invention is preferably formulated as a solid or liquid dosage form, in particular powders, powders, granules, tablets, in particular film-coated tablets, pastilles, sachets, cachets, dragees, capsules, ointments, creams, hydrogels, pastes, patches, solutions, emulsions, in particular of Oil-in-water type, suspensions such as lotions, injection and infusion preparations.
  • the pharmaceutical preparation according to the invention contains the compound optionally in particularly selected amounts. Usually, a preparation according to the invention will also contain iron in the previously known, optionally preparation-dependent amounts. If the pharmaceutical composition according to the invention contains the compound according to the invention as an active ingredient, the amount thereof is at least 1 mg per administration unit (for example per tablet) and preferably up to 500 mg per administration unit.
  • compositions according to the invention contain a total of
  • the concentration of the compound according to the invention is at least 0.1 mg / ml and preferably up to 100 mg / ml, more preferably 10 to 50 mg / ml.
  • Example 1 Anti-tumor Efficiency of Glu-Glu Genistein
  • the novel derivative Glu-Glu-Genistein can be transported much more effectively into the cell by means of the two glutamic acid residues via a cellular peptide transport system. It is therefore to be expected that even lower concentrations of Glu-Glu-Genistein can trigger physiological effects such as an induction of apoptosis (physiological cell death).
  • Cutaneous squamous cell carcinoma SCC-12, SCC-13
  • the cells are pre-cultivated for 2-3 weeks until a uniform growth (logarithmic phase) is established.
  • the cells are seeded in 6-well dishes (in each case 200,000 cells per well). The treatment takes place after 24 hours.
  • Apoptosis 24 hours before sowing, the cells get fresh growth medium.
  • the cells are seeded to the determined conditions in 6-well dishes (i.d.R .: 200,000 cells per well). After 24 hours the treatment is carried out. Used concentrations and treatment times depend on the results of the preliminary experiments. Growth and effects are monitored and recorded microscopically at least once a day. After the incubation period, the 6-well dishes are centrifuged and the cell pellet is lysed. Using anti-histone and anti-DNA antibodies, a sandwich ELISA is carried out, which allows a statement about the extent of DNA fragmentation (Cell Death Detection ELISA, Roche). Apoptosis is presented in relative terms relative to untreated controls.
  • the cells receive fresh growth medium 24 hours before sowing. The cells are seeded in 6-well dishes to the determined conditions (i.d.R. ': 200,000 cells per well). After 24 hours the treatment is carried out. Used concentrations and treatment times depend on the results of the preliminary experiments. Growth and effects are monitored microscopically and recorded at least once a day. After the incubation period, the cell culture supernatant is harvested. In this, the activity of the lactate dehydrogenase is determined by an enzymatic detection method (LDH release assay, Fa. Roche). Cytotoxicity is presented in relative terms relative to untreated controls.
  • LDH release assay Fa. Roche
  • Proliferation Assay 24 hours before sowing, the cells get fresh growth medium. The cells are seeded in low density in 6-well dishes (usually: 50,000 cells per well). After 24 hours the treatment is carried out. The cell proliferation determinations are made at times 0, 1, 2, 3, 5, 7 days after treatment. To determine the cell number, the adherent cells are fixed and stained with crystal violet. The intensity of the coloring is determined photometrically. The cell proliferation is shown in growth curves.
  • a platelet aggregation superior to the genistein can be achieved due to improved intracellular availability. This is done via a coupling to the dipeptide GIu-GIu, so that Gen-Glu-Glu iS a peptidomimetic via specific oligopeptide transporters of the platelet membrane is increasingly transported to intracellular.
  • Platelet rich plasma is spiked with genistein dissolved in DMSO in different concentrations: 0, 25, 50, 100, 200 ⁇ M. Subsequently, measurement of collagen induced aggregation by means of
  • Genistein 1 in DCM are added 4.9 ml (2 eq.) Of pyridine and 13.05 g (60.7 mmol, 2.1 eq.) Of di-tert-butyl dicarbonate and the mixture is stirred at room temperature for 30 min touched. The solvent is stripped off, the oily residue is coevaporated twice with toluene. The resulting solid is dried under high vacuum.
  • reaction mixture is diluted with ethyl acetate and washed three times with water, then the organic phase is dried over sodium sulfate and concentrated in water
  • Genistein-Glu-Glu linked ether coupling N-terminal, methyl group as link, binding via the OH group in C 5 position of the genistein, in the following L2
  • Genistein-Glu-Glu ether coupling C-terminal via the OH group in C 5 position of the genistein, in the following A2
  • Genistein-Glu linker ether coupling N-terminal, binding via the OH group in position C 5 , in the following L1
  • Genistein-Glu ether coupling C-terminal, binding via the OH group in C 5 position of the genistein, in the following A1 • native genistein
  • the substances used are genistein, Glu-Glu 1 DMSO, Ala-Ala from the Fma Sigma-Aldrich, Kunststoff.
  • the measurement was performed using the Platelet Aggregation Profiler model PAP-8E from Bio / Data Corporation, an 8-channel aggregometer with computer-aided digital curve generation. preanalytics
  • the whole blood thus obtained is centrifuged at 1500 rpm for 10 minutes.
  • the platelet-rich plasma (PRP) so obtained is allowed to rest for 45 minutes at room temperature.
  • platelet-poor plasma is obtained from the same sample by means of customary centrifuging in order to generate the respective blank values.
  • For the measurement cuvettes are used with 0.25ml filling volume.
  • genistein and the peptides used for use AIa-AIa and Glu-Glu are prepared in a ratio of 1 mg to 1 ml stock solutions, genistein and the investigated coupling products in DMSO, Glu-Glu and Ala-Ala in H 2 O.
  • the aggregation-inhibiting effect of native genistein was determined: The reference (no addition) resulted in an aggregation of 90%, corresponding also to the preliminary test. After addition of genistein 50 ⁇ M resulted an aggregation of 82% of the platelets, with the addition of genistein 100 ⁇ M an aggregation of 50% and at a concentration of 200 ⁇ M an almost complete inhibition of platelet aggregation.

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Abstract

L'invention concerne des composés pharmaceutiquement actifs comprenant une isoflavone ou un glycoside d'isoflavone, et un aminoacide, un peptide ou un dérivé de peptide de 2 à 5 aminoacides lié par covalence avec le glycoside d'isoflavone, ainsi que des sels ou des solvates pharmaceutiquement acceptables de ces composés. L'invention concerne en outre des utilisations de tels produits pour la fabrication de compositions pharmaceutiques, en particulier pour le traitement de l'agrégation de thrombocytes et pour le traitement de tumeurs. Les domaines d'application de l'invention sont en conséquence la médecine et l'industrie pharmaceutique. Les composés selon l'invention répondent à la formule générale (I) X-Pep, dans laquelle X désigne une isoflavone ou un glycoside d'isoflavone, et Pep désigne un aminoacide ou un peptide ou un dérivé peptidique de 2 à 5 aminoacides, X et Pep étant liés par covalence ou par un système de linker.
EP08706741A 2007-01-10 2008-01-10 Composés pharmaceutiquement actifs Withdrawn EP2137207A2 (fr)

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WO2009012109A2 (fr) 2007-07-13 2009-01-22 Emory University Composes contenant de la cyanine utiles dans l'imagerie et le traitement du cancer
US8903842B2 (en) 2007-10-26 2014-12-02 Microsoft Corporation Metadata driven reporting and editing of databases
JP5641466B2 (ja) * 2008-07-26 2014-12-17 国立大学法人九州工業大学 ペプチドの製造方法
WO2010134226A1 (fr) * 2009-05-20 2010-11-25 学校法人日本大学 Création d'un motif structural comprenant un acide aminé acide, apte à stabiliser une protéine dans des cellules, et applicable à une protéinothérapie, à l'ajustement de la différenciation/indifférenciation d'une cellule et à une thérapie par anticorps
EP2736506B1 (fr) * 2011-07-26 2018-09-05 University Of Southern California Inhibiteurs de monoamine oxydase et procédés pour le traitement et le diagnostic du cancer de la prostate
US9675620B2 (en) 2011-07-26 2017-06-13 University Of Southern California MAO inhibitors and their conjugates as therapeutics for the treatment of brain cancer
KR101719015B1 (ko) * 2012-07-25 2017-03-23 상지대학교산학협력단 프루네틴을 유효성분으로 함유하는 비만 또는 대사성 질환의 예방 또는 치료용 약학적 조성물
CN106146450B (zh) * 2015-04-20 2019-02-15 南京华迈生物医药科技有限公司 刺芒柄花素衍生物、其制备方法和医药用途
CN105085624B (zh) * 2015-09-21 2018-07-10 北京海木集团有限公司 光滑爪蟾皮肤抗菌肽及其制备方法与用途
CN106336438B (zh) * 2016-08-24 2018-11-23 南京中医药大学 一种琥珀酰芒柄花苷及其在制备心血管疾病药物方面的应用
JP6923100B1 (ja) * 2021-06-03 2021-08-18 株式会社ナボカルコスメティックス 新規イソフラボン化合物
WO2023282755A1 (fr) * 2021-07-09 2023-01-12 Latkovic Filip Médicament contre le virus du sras-cov-2 à base d'oligopeptides d'aspartate-glutamate synthétiques
KR20240086940A (ko) * 2022-12-09 2024-06-19 (주)케어젠 연골 재생용 펩타이드 및 이의 용도

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DE102007002386A1 (de) 2008-07-17
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AU2008204631A1 (en) 2008-07-17
CA2675029A1 (fr) 2008-07-17

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