EP1536789A1 - Arzneimittel enthaltend disorale und ihre derivate und deren anwendung zur behandlung gutartiger und bösartiger tumorerkrankngen - Google Patents

Arzneimittel enthaltend disorale und ihre derivate und deren anwendung zur behandlung gutartiger und bösartiger tumorerkrankngen

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Publication number
EP1536789A1
EP1536789A1 EP03794920A EP03794920A EP1536789A1 EP 1536789 A1 EP1536789 A1 EP 1536789A1 EP 03794920 A EP03794920 A EP 03794920A EP 03794920 A EP03794920 A EP 03794920A EP 1536789 A1 EP1536789 A1 EP 1536789A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
disorazole
cancer
treatment
medicament
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.)
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Application number
EP03794920A
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German (de)
English (en)
French (fr)
Inventor
Herbert Irschik
Rolf Jansen
Florenz Sasse
Silke Baasner
Peter Schmidt
Eckhard Günther
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.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris AG
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Publication of EP1536789A1 publication Critical patent/EP1536789A1/de
Withdrawn legal-status Critical Current

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Definitions

  • tumors are a fundamental disease of higher organisms in the plant, animal and human kingdoms.
  • the generally recognized multi-step model of cancer development assumes that the accumulation of several mutations in a single cell changes their proliferation and differentiation behavior in such a way that a malignant state with metastasis is ultimately achieved via benign intermediates.
  • the term cancer or tumor hides a clinical picture with more than 200 different individual diseases. Tumor diseases can be benign or malignant.
  • the main tumors are those of the lungs, breast, stomach, cervix, prostate, head and neck, colon and rectum, liver and blood system.
  • the present invention relates to disorazoles - with the exception of disorazole A1 - and derivatives of disorazoles, and to their use as medicaments, in particular for the treatment of benign and malignant tumors in humans and mammals.
  • disorazoles E1 and D1 in particular have an outstanding cytotoxic effect on various human tumor cell lines.
  • the division of ovarian cancer, prostate cancer, glioblastoma, lung cancer and breast cancer cells is among others inhibited.
  • the effect of the disorazoles E1 and D1 is dependent on the cell cycle, even in nanomolar concentrations the cell cycle is stopped in the G2 / M phase and the cancer cells are driven into apoptosis. It was also possible to show that the antiproliferative effect of the claimed disorazoles is based, inter alia, on an effective inhibition of tubulin polymerization.
  • Disorazole E1 is especially active against cell lines resistant to paclitaxel and vindesin. It could be shown according to the invention that disorazole E1 is highly potent in terms of its biological action and can therefore be used as an active ingredient in a medicament for combating cancer.
  • disorazole A1 is unsuitable for use as a cytostatic (G. Hoefle, Annual Report 1999/2000 of the Society for Biotechnological Research GBF, p. 103).
  • Natural products are an important source for new lead structures in pharmaceutical research and are in part also directly suitable for the development of a new drug (Y.-Z. Shu, J. Nat. Prod., 1998. 61, 1053-1071). It is known that many natural products have strong cytotoxic effects (V. J. Ram, S. Kumari, DNP, 2001, 14 (8), 465-482).
  • Disorazole A1 has been reported to have an antiproliferative effect in cellular models (H. Irschik, R. Jansen, K. Gerth, G. Höfle, H. Reichenbach, J. Antibiot. 1995.
  • the compounds according to the invention are suitable, without being restricted to being used as medicaments for the treatment of benign and malignant tumor diseases or other antiproliferative diseases in humans and animals.
  • the compounds according to the invention are suitable for combating all diseases which are based on the uncontrolled and rapid division of cells and thereby cause pathological conditions.
  • the compounds according to the invention as a single substance or in combination with other cytotoxic substances, for example cisplatin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate and in particular in combination with inhibitors of signal transduction, such as Herceptin, Glivec or Iressa, are not limited to this , are used.
  • cytotoxic substances for example cisplatin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate and in particular in combination with inhibitors of signal transduction, such as Herceptin, Glivec or Iressa, are not limited to this , are used.
  • the compounds according to the invention can be administered as liquid pharmaceutical forms. This is done in the most suitable manner in the form of solutions or suspensions.
  • the compounds according to the invention can preferably be injected into an artery, intra-arterially; into a vein, intravenously as an injection or infusion; into the skin, intracutaneously as an injection; under the skin, subcutaneously as an injection; into the muscle, intramuscularly as an injection; into the abdominal cavity, intraperitoneally as an injection or infusion.
  • the compounds of general formula I according to the invention have at least one asymmetry center, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers, both in substance and also as pharmaceutically acceptable salts of these compounds.
  • the mixtures can be present in any mixing ratio of the stereoisomers. If possible, the configuration of each of the double bonds in the compounds according to the invention can be E or Z, independently of one another.
  • the compounds of the invention may be in the form of the tautomers.
  • the invention relates to compounds of the general formula I:
  • Alkylaminothiocarbonyl (Ci-C ⁇ J-alkyl-carbonyl or (CC ö ) - alkoxycarbonyl- (-C-Ce) -alkyl,
  • substitution of the alkyl radical with F, Cl, Br, I, CN, NH 2 , NH- (CC 20 ) -alkyl, NH- (C 3 -C 12 ) -cycloalkyl, OH, O- (CC 20 ) -alkyl can be carried out simply or on the same or different atoms several times with the same or different substituents, and the substitution of an aryl radical with F, Cl, Br.
  • X, Y in each case individually, independently of one another or together, oxygen, sulfur, two vicinal hydroxyl groups, two vicinal methoxy groups, are part of a double bond,
  • aryl means aromatic hydrocarbons, including phenyls, naphthyls and anthracenyls.
  • the radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different.
  • the heterocycle can also Be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • the heteroaryl radical is selected from the group, the pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenazinyl, phenothiazinyl.
  • Base R Alk, OAIk
  • R alk, alkylaryl
  • the corresponding disorazole of the general formula I with a corresponding alkylation halide or alkylaryl halide and a suitable base preferably triethylamine, pyridine, an alcoholate , Sodium hydride or potassium carbonate, are reacted in a suitable solvent, for example dichloromethane, diethyl ether, acetonitrile, / V / V-dimethylformamide between 0 and 100 ° C. (J. Org. Chem. 1971, 36, 284-294).
  • a suitable base preferably triethylamine, pyridine, sodium hydride, one Alcoholate, NaOH in water or potassium carbonate and in a suitable solvent, for example dichloromethane, diethyl ether, acetonitrile, NN-dimethylformamide or solvent mixtures such as dioxan
  • the corresponding disorazole of general formula I with corresponding alkylcarboxylic acid chlorides, alkylcarboxylic acid anhydrides or chloroformates in the presence of a suitable base, preferably triethylamine, pyridine, sodium hydride , an alcoholate, NaOH in water or potassium carbonate and in a suitable solvent, for example dichloromethane, diethyl ether, acetonitrile, NN-dimethylformamide or solvent mixtures such as dioxane-water or THF-water mixtures at a temperature between 0 and 100 ° C. (J.Org. Chem. 1957, 22, 1551; Synth. Commun. 1997, 27, 2777; J.Org. Chem. 1961, 24, 774).
  • Disorazoles such as, for example, disorazole E1 are preferably used as an active ingredient in a finished medicament for the treatment of malignant tumor diseases such as breast cancer, lung cancer, ovarian cancer, skin cancer, prostate cancer, colon cancer, kidney cell cancer, liver cancer, pancreatic cancer and cancer of the brain.
  • malignant tumor diseases such as breast cancer, lung cancer, ovarian cancer, skin cancer, prostate cancer, colon cancer, kidney cell cancer, liver cancer, pancreatic cancer and cancer of the brain.
  • the active ingredient is present as a lyophilisate together with auxiliary substances known to the person skilled in the art in an injection bottle and is dissolved with physiological saline solution before use, then diluted in an injection bag and administered to the patient with a cannula into the vein.
  • the dosage is between 0.1 mg and 100 mg of active ingredient per m 2 .
  • the duration of the infusion depends on the objective criteria of the disease.
  • disorazoles such as disorazole E1 as an active ingredient in a finished drug for the treatment of inflammatory diseases.
  • inflammatory respiratory diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammation mediated by eosinophils such as eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticitis, ulcer and proliferative skin diseases such as psoriasis and keratosis.
  • inflammatory respiratory diseases such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammation mediated by eosinophils such as eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticitis, ulcer and proliferative skin diseases
  • disorazoles such as disorazole E1 as an active ingredient in a finished drug with an immunomodulatory effect for the treatment of immune and autoimmune diseases.
  • diseases can include, for example, joint inflammation such as arthritis and rheumatoid arthritis and other arthritic diseases such as rheumatoid spondylitis and osteoarthritis.
  • disorazoles such as, for example, disorazole E1 as an active ingredient in a finished medicinal product, which can be used to treat infections such as viral infections and parasite infections, for example to treat malaria, infection-related fever, infection-related muscle pain, HIV infections (AIDS) and cachexia.
  • infections such as viral infections and parasite infections, for example to treat malaria, infection-related fever, infection-related muscle pain, HIV infections (AIDS) and cachexia.
  • Parenteral, transdermal, topical, inhalative and intranasal preparations are preferred for the application of the compounds according to the invention.
  • the preparation, filling and sealing of the preparations takes place under the usual antimicrobial and aseptic conditions.
  • the pharmaceutical forms optionally contain auxiliaries, such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, puffers, salt formers, preservatives, antioxidants, colorants, flavorings and
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, puffers, salt formers, preservatives, antioxidants, colorants, flavorings and
  • the medicaments according to the invention can be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or plaster; through the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonary or by inhalation as aerosol or inhalation; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, Lamellae or eyewash; into an artery, intraarterially as an injection; into a vein, intravenously as an injection or infusion, paravenously as an injection or infusion; into the skin, intracutaneously as an injection or implant; under the skin, subcutaneously as an injection or implant; in the muscle, intramuscularly as an injection or implant; into the abdominal cavity, intraperitoneally as an injection or infusion.
  • the compounds of general formula I according to the invention can be used as a single substance or in combination with other cytotoxic substances, e.g. Paclitaxel, docetaxel, vincristine, vindesine, cisplatin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate or in combination with immunomodulators or antibodies and in particular in combination with signal transduction inhibitors, e.g. Herceptin, Glivec or Iressa can be used.
  • cytotoxic substances e.g. Paclitaxel, docetaxel, vincristine, vindesine, cisplatin, carboplatin, doxorubicin, ifosfamide, cyclophosphamide, 5-FU, methotrexate or in combination with immunomodulators or antibodies and in particular in combination with signal transduction inhibitors, e.g. Herceptin, Glivec or Iressa can be used.
  • Preparations for parenteral administration of disorazoles such as, for example, disorazole E1 can be administered in separate dosage unit forms, e.g. There are ampoules or vials. Solutions of the active ingredient are preferably used, preferably aqueous solutions and especially isotonic solutions or suspensions. These injection forms can be made available as ready-to-use preparations or can be prepared with the desired solvent or suspending agent just before use by mixing the active compound, for example the lyophilisate, optionally with other solid carriers.
  • disorazoles such as, for example, disorazole E1
  • aqueous or oily solutions or as aqueous or oily suspensions. They can also be in the form of lyophilisates which are prepared with the appropriate solvent or suspending agent before use.
  • Biological effects of the compounds according to the invention can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be in the form of lyophilisates which are prepared with the appropriate solvent or suspending agent before use.
  • the compounds of the invention were tested for their anti-proliferative activity in a proliferation test on established tumor cell lines (D.A. Scuderio et al. Cancer Res. 1988, 48, 4827-4833).
  • the test used determines the cellular dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number.
  • the cell lines used as examples are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the ovarian adenocarcinoma cell line SKOV-3 (ATCC HTB77), the human glioblastoma cell line SF-268 (NCI 503138) and the lung carcinoma cell line NCI -H460 (NCI 503473) and the human colon adenocarcinoma cell line RKOP27.
  • Table 1 shows the cytotoxic or growth-inhibiting activity of the compounds described and of reference compounds. The results show a very potent inhibition of the proliferation of selected tumor cell lines by the substances according to the invention.
  • Disorazole E1 0.00005 0.000016 0.00012 0.00003 0.00006
  • Disorazole D1 0.00015 0.0001 0.00022 0.00015 0.0003
  • Disorazole A1 0.00015 0.0002 0.00027 0.00015 0.00025
  • the substances according to the invention were investigated against multi-drug-resistant cell lines (MDR) in comparison to the non-resistant wild-type cell lines.
  • MDR multi-drug-resistant cell lines
  • the cell lines examined are the acute myeloid leukemia cell line LT12 and the resistant line LT12 / mdr.
  • the murine P388 cell line methyl-cholanthrene-induced lymphoid neoplasm
  • the doxorubicin-resistant P388 were used as test systems.
  • Table 2 Inhibitory effects of disorazole E1 and reference substances in the XTT proliferation test on non-resistant and resistant tumor cell lines.
  • Disorazole E1 shows a very potent inhibitory effect on all cell lines tested, while the classic tubulin inhibitors such as paclitaxel or vincristine show a strongly reduced effect and cross-resistance on the MDR1 cell lines.
  • the cell cycle involves the development of the cell from one cell generation to the next.
  • the cell During the resting phase (G0) and pre-synthetic phase (G1) the cell has a diploid set of chromosomes (2c).
  • the amount of DNA is increased by replication.
  • the S phase ends when the premitotic phase (G2M) is reached, in which the cell has a reduplicated chromosome population (4c) and doubled DNA content.
  • G2M premitotic phase
  • M mitosis phase
  • the reduplicated chromosomes are evenly divided into two daughter cells, which then each show a diploid DNA content and are in the G01 phase, so that the cell cycle can start again.
  • KB / HeLa cells were treated with the test substances in different concentrations (0.1-1000 nM) for 24 hours at 37 ° C.
  • the percentage of cells locked in the G2 / M phase of the cell cycle after treatment with reference or selected test substances is as follows
  • Example EC 50 in [nM] (50% cells in G2 / M)
  • Cells can be locked in the G2 / M phase.
  • the compounds according to the invention have the highest activities compared to the reference compounds.
  • Disorazole E1 in particular inhibits the cell cycle in the G2 / M phase in extremely low concentrations.
  • Disorazole E1 (D-42805): 0.25mg / kg; i.V .: day 0, 7; 8 dead (day
  • Disorazole E1 (D-42805): 0.1mg / kg; IV: day 0.7, 14; no deaths
  • Disorazole E1 (D-42805): 0.05mg / kg; i.v .: day 0,7,14; no deaths
  • disorazole E1 was tested for mutagenicity in a fluctuation assay against mutant strains TA98 and TA100 of the bacterium Salmonella typhimurium at three concentrations (2.5; 5 and 10 ⁇ M).
  • the mutagenicity studies were also carried out in the presence of the rat liver enzyme S9. The results are summarized in Table 5 below:
  • Disorazole E1 shows under the described assay conditions in the above. Concentrations no effects, it is therefore AMES test inactive.
  • Disorazole E1 1 119.6 95.9
  • HepG2 human hepatocellular carcinoma cells

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EP03794920A 2002-08-24 2003-08-22 Arzneimittel enthaltend disorale und ihre derivate und deren anwendung zur behandlung gutartiger und bösartiger tumorerkrankngen Withdrawn EP1536789A1 (de)

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BRPI0716190A2 (pt) * 2006-09-06 2013-11-12 Aeterna Zentaris Gmbh Conjugados de disorazóis e seus derivados com móleculas de ligação celular, derivados de disorazol, processos para fabricação e uso dos mesmos
EP1900742A1 (en) 2006-09-07 2008-03-19 AEterna Zentaris GmbH Conjugates of disorazoles and their derivatives with cell-binding molecules, novel disorazole derivatives, processes of manufacturing and uses thereof
WO2018237178A1 (en) * 2017-06-22 2018-12-27 William Marsh Rice University Synthesis of disorazoles and analogs thereof as potent anticancer agents

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ZA200501196B (en) 2005-10-26
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WO2004024149A1 (de) 2004-03-25
AR042617A1 (es) 2005-06-29
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PL376407A1 (en) 2005-12-27
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