EP1448504A2 - Isomere de clusianon et son utilisation - Google Patents

Isomere de clusianon et son utilisation

Info

Publication number
EP1448504A2
EP1448504A2 EP02803387A EP02803387A EP1448504A2 EP 1448504 A2 EP1448504 A2 EP 1448504A2 EP 02803387 A EP02803387 A EP 02803387A EP 02803387 A EP02803387 A EP 02803387A EP 1448504 A2 EP1448504 A2 EP 1448504A2
Authority
EP
European Patent Office
Prior art keywords
cancer
isomers
compound
general formula
hydrates
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Withdrawn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
EP02803387A
Other languages
German (de)
English (en)
Inventor
Siegfried Seeber
Ralf Axel Hilger
David Diaz-Carballo
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.)
Diagenics International Corp
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP1448504A2 publication Critical patent/EP1448504A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring

Definitions

  • telomeres The DNA segments at the ends of the chromosomes, the so-called telomeres, are responsible for this process of cell aging or senescence at the molecular level. They register, so to speak, how many replication cycles a cell population goes through and initiate senescence or the crisis from a certain point in time. This limits the ability of a cell population to grow without restriction. In most healthy human cells, telomeres shorten a little each time the cells divide when the chromosomes are replicated.
  • WO 00/74667 A2 proposes the use of telomerase inhibitors (for example AZT) in combination with an active ingredient which induces telomer destruction (for example paclitaxel) for cancer treatment.
  • telomerase inhibitors for example AZT
  • an active ingredient which induces telomer destruction for example paclitaxel
  • WO 99/65875 A1 and US Pat. No. 5,863,936 suggest the use of special heterobicyclic systems as telomerase inhibitors for the treatment of cancer.
  • Catechin derivatives as described in European patent application EP 0 938 897 AI, should also be able to be used as telomerase inhibitors for cancer treatment.
  • attempts are made to increase the tumor or other mechanisms at the molecular or cellular level.
  • alkylation reagents are often used, which ultimately induce direct damage to the DNA of the tumor or cancer cells via alkylation of the DNA (e.g. cyclophosphamide, Ifosfamide, carmustine, chlorambucil etc.).
  • substances are used for tumor or cancer therapy that interfere with the replication of the tumor or cancer cells by inhibiting topoisomerases (eg camptoceticin, 9-aminocamptothecin, irinotecan, topotecan, doxorubicin etc .) (see, for example, Clive Page et al., Integrated Pharmacology, Mosby, 1997).
  • the compound of general formula (I) can be present as constitutional isomers, in particular positional isomers (substitution isomers). This is known to those skilled in the art, and such compounds are also within the scope of the present invention.
  • the present invention also encompasses derivatives of the compound of the general formula (I) (for example ethers such as alkyl ethers such as methyl ether which can be obtained, for example, by alkylation of the tautomeric forms (I) or (I 1 ) ).
  • derivatives of the compound of the general formula (I) which are particularly preferred according to the invention are the pegylated derivatives, in particular the polyalkylene glycol ethers, preferably polyethylene glycol ether (PEG ether), of the tautomeric forms (I) and (I ").
  • PEG ether polyethylene glycol ether
  • the present invention also includes prodrugs and metabolites of the compound of general formula (I).
  • prodrugs are, in particular, those forms of the compound of the general formula (I) above which can themselves be biologically active or inactive, but which can be converted into the corresponding biologically active form (for example metabolically, solvolytically or in some other way).
  • the metabolites in particular are the products of the compound of the general formula (I) which result from the metabolism or which are converted in the metabolism.
  • the compound of the general formula (I) including its physiologically tolerable salts, hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites can consequently preferably be used in medicaments for the prophylaxis and / or treatment of diseases, preferably of tumor and cancer (cytostatics) and viral diseases (antivirals or antivirals).
  • diseases preferably of tumor and cancer (cytostatics) and viral diseases (antivirals or antivirals).
  • the active ingredient of the general formula (I) used according to the invention shows not only an anti-tumor effect, but also an anti-metastatic effect.
  • colon cancer colon cancer
  • breast cancer breast cancer
  • ovarian cancer uterine cancer
  • lung cancer Gastric cancer, liver cancer, pancreatic cancer, kidney cancer, Bla- cancer, prostate cancer, testicular cancer, bone cancer, skin cancer, Kaposi's sarcomas, brain tumors, myosarcomas, neuroblastomas (e.g. retinoblastomas), lymphomas and leukemias.
  • the present invention thus also relates to a pharmaceutical combination, in particular a cytostatic combination
  • the present invention also relates to a method for the prophylaxis and / or treatment of diseases of the human or animal body, in particular tumor or cancer diseases or viral diseases of all kinds, using the compound of the general formula (I) including its physiologically tolerable salts , Hydrates, isomers, in particular stereoisomers, tautomers and constitutional isomers, derivatives, prodrugs and metabolites in therapeutically effective doses or doses, if appropriate also in combination with other active substances, in particular chemotherapeutics (for example protein kinase inhibitors such as, for example, MAP kinase inhibitors ).
  • chemotherapeutics for example protein kinase inhibitors such as, for example, MAP kinase inhibitors.
  • the upper line corresponds to the concentration of methanol (%)
  • the middle line to the concentration of aqueous phase (%, ammonium formate 0.0 IM).
  • the concentration of acetonitrile (%) is kept constant at 5% (lower line).
  • HMBC Heteronuclear Multiple-Bond Correlation
  • Fig. Lc, ld and le are ⁇ -NMR spectra of the compound (I) (measurement frequency: 500 MHz, solvent: CD 3 OD).
  • the investigations to detect the degradation of the DNA by the substance (I) are carried out, for example, on human cells of a bronchial carcinoma (H460 WT) and a colorectal carcinoma (HT29 WT). DNA, isolated after treatment of the cells with substance (I) for different periods, is analyzed by gel electrophoresis.
  • H460 WT bronchial carcinoma
  • HT29 WT colorectal carcinoma
  • Tumor cells for example colon carcinoma cells (HCT8 WT) are co-incubated with the two active substances in different doses for 24 hours (FIG. 10).
  • 10 shows the coincubation experiment for cytotoxicity with substance (I) and a specific ERK1 / 2 inhibitor (MAP kinase inhibitor).
  • HCT8 WT cells were co-incubated. The points shown indicate the corresponding ratios (% of the respective IC 50 concentration) of the two active substances to one another.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un isomère de clusianon et son utilisation, en particulier comme principe actif pharmaceutique ou médical, en particulier dans la production de médicaments pour le traitement prophylactique et/ou thérapeutique (curatif) de maladies tumorales ou cancéreuses ainsi que de maladies virales. Le composé susmentionné peut être utilisé dans des cytostatiques et agents antiviraux (virostatiques). Ce composé agit, en particulier, comme inhibiteur de topoisomérases et de télomérases et comme régulateur dans la transduction de signal par les MAP kinases. Ce composé peut ainsi intervenir sur le plan cellulaire dans le mécanisme de prolifération de cellules tumorales ou cancéreuses et de virus.
EP02803387A 2001-11-21 2002-11-20 Isomere de clusianon et son utilisation Withdrawn EP1448504A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10157031 2001-11-21
DE10157031A DE10157031A1 (de) 2001-11-21 2001-11-21 Clusianonisomeres und seine Verwendung
PCT/EP2002/012968 WO2003043966A2 (fr) 2001-11-21 2002-11-20 Isomere de clusianon et son utilisation

Publications (1)

Publication Number Publication Date
EP1448504A2 true EP1448504A2 (fr) 2004-08-25

Family

ID=7706391

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02803387A Withdrawn EP1448504A2 (fr) 2001-11-21 2002-11-20 Isomere de clusianon et son utilisation

Country Status (6)

Country Link
US (1) US7135501B2 (fr)
EP (1) EP1448504A2 (fr)
JP (1) JP2005509670A (fr)
AU (1) AU2002356679A1 (fr)
DE (1) DE10157031A1 (fr)
WO (1) WO2003043966A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6956061B2 (en) 2002-08-07 2005-10-18 Aventis Pharma Deutschland Gmbh Polyisoprenylbenzophenone derivatives, processes for their preparation and use thereof
DE10236262A1 (de) * 2002-08-07 2004-04-29 Aventis Pharma Deutschland Gmbh Polyisoprenyl-benzophenon-Derivate, Verfahren zu ihrer Herstellung und Verwendung desselben

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03043966A2 *

Also Published As

Publication number Publication date
WO2003043966A3 (fr) 2003-10-23
WO2003043966A2 (fr) 2003-05-30
JP2005509670A (ja) 2005-04-14
DE10157031A1 (de) 2003-06-05
AU2002356679A1 (en) 2003-06-10
US20050090562A1 (en) 2005-04-28
US7135501B2 (en) 2006-11-14
AU2002356679A8 (en) 2003-06-10

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