EP1448579A1 - Derives phospholipides de nucleosides utilises comme medicaments antitumoraux - Google Patents

Derives phospholipides de nucleosides utilises comme medicaments antitumoraux

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Publication number
EP1448579A1
EP1448579A1 EP02803379A EP02803379A EP1448579A1 EP 1448579 A1 EP1448579 A1 EP 1448579A1 EP 02803379 A EP02803379 A EP 02803379A EP 02803379 A EP02803379 A EP 02803379A EP 1448579 A1 EP1448579 A1 EP 1448579A1
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EP
European Patent Office
Prior art keywords
tumor
medicament according
fluorouracil
compounds
cells
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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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EP02803379A
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German (de)
English (en)
Inventor
Dieter Herrmann
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Heidelberg Pharma Research GmbH
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Heidelberg Pharma Holding GmbH
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Priority claimed from DE2001156910 external-priority patent/DE10156910A1/de
Priority claimed from DE2002109564 external-priority patent/DE10209564A1/de
Application filed by Heidelberg Pharma Holding GmbH filed Critical Heidelberg Pharma Holding GmbH
Publication of EP1448579A1 publication Critical patent/EP1448579A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • Phospholipid derivatives of nucleosides as anti-tumor drugs are Phospholipid derivatives of nucleosides as anti-tumor drugs
  • the present invention relates to medicaments which contain phospholipid derivatives, preferably non-natural nucleosides of the general formula I:
  • Ri represents an alkyl chain with 10-14 carbon atoms
  • R 2 represents an alkyl chain with 8-12 carbon atoms
  • n represents an integer value of 0, 1 or 2
  • R 3 represents a hydroxyl group
  • R 4 and R 5 represent hydrogen
  • B stands for 5-fluorouracil, as antitumor or antiproliferative active substances for prophylaxis and / or for curative, palhative or supportive treatment of tumor diseases or neoplasms, such as, for. B. carcinomas, sarcomas, lymphomas or leukemias.
  • the phospholipid derivatives of the general formula I can also be present in the form of their pharmacologically acceptable alkali or alkaline earth metal salts.
  • Phospholipid derivatives of nucleosides are known from patent EP 545 966 B1.
  • the compounds are described as antivirally active substances which are particularly suitable for the therapy and prophylaxis of infections which by DNA viruses, such as. B. the herpes simplex virus, the cytomegalovirus, Papova viruses, the varicella zoster virus or Epstein-Barr virus, or RNA viruses, such as. B. toga viruses or in particular retroviruses, such as. B. the oncoviruses HTLV-I and HTLV-II, as well as the lentiviruses, Visna and human immunodeficiency virus HIV-1 and HIV-2, are caused.
  • DNA viruses such as. B. the herpes simplex virus, the cytomegalovirus, Papova viruses, the varicella zoster virus or Epstein-Barr virus, or RNA viruses, such as. B. toga viruses or in particular retroviruses, such as. B. the oncoviruse
  • the above-mentioned patent also emphasizes that the compounds of the general formula I are particularly useful for treating the clinical manifestations of retroviral HIV infection in humans, such as persistent generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARG). and the clinical picture of AIDS.
  • PDL persistent generalized lymphadenopathy
  • ARG advanced stage of the AIDS-related complex
  • the compounds are said to inhibit the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription.
  • WO 95/32984 already describes lipid esters of nucleoside monophosphates with an antitumoral effect.
  • the compounds according to the invention differ from the structures claimed there by an altered substitution pattern on the C-2'-carbon atom of the sugar ring.
  • phospholipid derivatives of nucleosides which are known from EP 545 966 have further valuable pharmacological properties. These substances are particularly suitable for the prophylaxis and / or therapy of malignant tumors, such as.
  • the compounds of the present invention surprisingly have an antitumor or antiproliferative effect, but without non-specific toxic effects on other organ systems, such as, for example, in pharmacologically relevant doses.
  • Ri represents an alkyl chain with 10-14 carbon atoms
  • R 2 represents an alkyl chain with 8-12 carbon atoms
  • n represents an integer value of 0, 1 or 2
  • R 3 , R and R 5 independently of one another represent hydrogen or a hydroxyl group , with the proviso that R 3 and R 4 are not simultaneously hydroxyl groups and
  • the nucleo base in general formula I is preferably gytosin, adenine, thymine, guanine, 5-fluorouracil, 5-bromouracil, 5-ethynyluracil, 5-propenyluracil, 5-trifluoromethyluracil, 2-amino-6-chloropurine, 2-chloroadenine , 2-fluoroadenine, 2,6-diaminopurine, 2-bromadenine, 6-mercaptopurine or 6-methyl mercaptopurine.
  • Non-natural and especially halogenated nucleobases are preferred.
  • the purine bases are preferably linked to the sugar via the Ng nitrogen, the pyrimidine bases via the Ni nitrogen.
  • Preferred sugars have the following combinations of the radicals R 3 , R 4 and R5:
  • Ri is preferably a straight chain C10 - C 4 alkyl group.
  • Ri represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group.
  • the undecyl and dodecyl radicals are particularly preferred for Ri.
  • R 2 preferably denotes a straight-chain C ⁇ -C 2 alkyl group, in particular an octyl, nonyl, decyl, undecyl or dodecyl group.
  • the decyl and undecyl radicals are particularly preferred for R 2 .
  • the sulfur characterized by different oxidation states with n equal to 0, 1 or 2 is a thioether, a sulfoxide or a sulfone. Thioethers and sulfoxides are particularly preferred.
  • Preferred salts of the compounds of general formula I are alkali and alkaline earth salts. Sodium, calcium and magnesium salts are particularly preferred.
  • the compound 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylmercapto-2-decyloxy) propyl ester and its sulfoxide and sulfone derivative are very particularly preferred (Ri is dodecyl, R 2 is decyl, R4 / R 5 is hydrogen, R 3 is hydroxy, n is 0, 1 or 2 and B is 5-fluorouracil).
  • Ri dodecyl
  • R 2 is decyl
  • R4 / R 5 is hydrogen
  • R 3 is hydroxy
  • n 0, 1 or 2
  • B is 5-fluorouracil
  • the compounds according to the invention Compared to chemotherapeutic agents previously used for the treatment of malignant neoplasms or tumors, the compounds according to the invention have a higher pharmacological-medical potency, a better effectiveness and / or a significantly lower toxicity and thus a greater therapeutic range in vivo.
  • the compounds of the general formula I are distinguished clinically and practically by the advantage that the administration of medicaments containing these compounds can be carried out continuously over a relatively long period of time. Discontinuation or intermittent administration, which is very common with the cytostatics or chemotherapeutics used in current drug tumor therapy or is often absolutely necessary due to significant, undesirable side effects, can result in the application of drugs that Contain compounds of general formula I as antitumor agents, avoided. Because of the good tolerance of the compounds of general formula I according to the invention, continuous enteral or parenteral administration of these substances is made possible in the first place.
  • the compounds of general formula I contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are also the subject of the present invention.
  • R 1, R 2 , n, R 3 , R 4 , R 5 and B have the meaning given above for the general formula I and which may optionally be present in the form of their salts.
  • the tautomers of the compounds according to the invention and their physiologically tolerable salts of inorganic and organic acids or bases are also included in the present invention. They also show selective anti-tumor or anti-proliferative properties.
  • the present invention also relates to new general substances
  • Ri is an alkyl radical with 10-14 C atoms and R 2 is an alkyl radical with 8-12 C atoms, n can be 0, 1 or 2,
  • R 4 and R 5 represent hydrogen
  • R 3 represents a hydroxy group
  • Ri is a dodecyl residue
  • R 2 is a decyl radical, n can be 0, 1 or 2,
  • R 4 and R 5 represent hydrogen
  • R 3 represents a hydroxy group
  • the new substances show an antitumor or antiproliferative effect at considerably lower doses, or have a substantially greater therapeutic range in vitro or in vivo.
  • the compounds of the present invention or their pharmaceutical preparations can also be used in free or fixed combination with other suitable medicaments or active substances for prophylaxis and / or for curative, palliative or supportive treatment of tumor diseases or neoplasias.
  • Examples of these other drugs include e.g. B. other cytostatics or chemotherapy drugs that are used for the prophylaxis and / or therapy of tumor be used.
  • This group includes, for example, nitrogen mustard derivatives (e.g. cyclophosphamide, ifosfamide, trofosfamide, mafosfamide, chlorambucil, melphalan), aziridines and epoxides (e.g. thiotepa, triethylene melamine, trenimony, treosulfan), alkyl alkane -Sulfonates (e.g. Busulfan), nitrosoureas (e.g.
  • methotrexate trimetrexate, Tomudex, edatrexate, lometrexol
  • purine and purine nucleoside analogs (6-mercaptopurine, 6-thioguanine, pentostatin), pyrimidine and pyrimidine nucleoside analogs (e.g.
  • 5-fluorouracil 5-fluorouridine, 5-fluorodeoxyuridine, F torafur, Carmofur, Tegafur, Tegafur-Gimestat-Otastat, Capecitabine, Enocitabine, Galocitabine, Doxifluridine, Cyt ⁇ sinarabinosid [Ara-C], Azacitidin [Aza-C], CI-F-AraA, Peldesin, Gemcitabin and its derivatives) related intercalating compounds (e.g. B.
  • doxorubicin and its morpholino derivatives daunorübicin, epirubicin, idarubicin, pirarubicin, aclarubicin, amrubicin, MX-2, mitoxantrone, losoxantrone, amsacrine and pyrazoloacridine), antibiotic cytostatics or peer chemotherapy drugs , Actinomycin D, mithramycin, clecarmycin, FK-317), microtubule inhibitors such as vinca alkaloids (e.g.
  • etoposide, etoposide phosphate, teniposide) J 1070088, TOP-53 or camptothecin and its analogues e.g. 9-amino-camptothecin, topotecan, irinotecan, exatecan, CPT-11
  • L- Asparaginase sparfosate, hydroxyurea, mitotane, epothilone and deoxyepot hilone and its derivatives, fludarabine, fludarabine phosphate, 2-chlorodeoxyadenosine, 2'-deoxycoformycin, homoharringtonine, sumarin, anti-tumor immunosuppressive drugs, such as. B.
  • cyclosporins e.g. cortisol, cortisone, prednisone, prednisolone, para-, ß-, dexamethasone.
  • corticoids e.g. cortisol, cortisone, prednisone, prednisolone, para-, ß-, dexamethasone.
  • the compounds of the present invention and their pharmaceutical preparations can also be used in free or fixed combination with tyrosine kinase inhibitors (e.g. SU-5416, KT-8391, KT-5555), famesyl transferase inhibitors (e.g. BMS- 214662, ER-51785, R 115777), thymidylate synthase inhibitors (z. B. 2 '-deoxy-2' -fluoro-4 '-thioarabinosylcytosin, raltitrexed, TK-117, TAS 102, TAS 103) DNA Polymerase inhibitors (e.g.
  • tyrosine kinase inhibitors e.g. SU-5416, KT-8391, KT-5555
  • famesyl transferase inhibitors e.g. BMS- 214662, ER-51785, R 115777
  • thymidylate synthase inhibitors z. B.
  • cytosine 1- (2-deoxy-2-methylene-D-erythropentofuranosyl) cytosine [DMDC, Y-26436], CS-682), histone deacylase inhibitors (e.g. MS -275), metalloproteinase inhibitors (e.g. Marimastat, Batimastat, CGS-27023A, MMI-166, S-3304), P-glycoprotein inhibitors (e.g. Valspodar, MS-209, PAK-104P, LY -335979), cyclooxygenase-2 inhibitors (e.g.
  • phosphatase adenosine deaminase
  • RNA polymerase protein kinase C inhibitors
  • protein kinase C inhibitors e.g. hexadecylphosphocholine, calphostin, gossipol , Quercetin, fisetin, staurosporins [e.g. midostaurin, 7-hydroxystaurosporin, KW-24 ⁇ 1J
  • Anti-angiogenesis agents or angiogenesis inhibitors e.g. B. FMPA, TNP-470, anti-VEGF ⁇ / PF monoclonal antibody
  • apoptosis agonists / inducers e.g. AOP 99.0001, Irofulven, NCO-700, T 215, TAC-101 for prophylaxis and / or Treatment of tumor diseases or neoplasia can be used.
  • the compounds of the formula I according to the invention can also be used in free or fixed combination for the prophylaxis and / or therapy of tumor diseases or neoplasias together with hormones or anti-hormones related to oncological prophylaxis and / or therapy.
  • hormones or anti-hormones related to oncological prophylaxis and / or therapy.
  • hormones or anti-hormones related to oncological prophylaxis and / or therapy.
  • hormones or anti-hormones related to oncological prophylaxis and / or therapy include, for example, androgens, estrogens, progestogens, antiandrogens, antiestrogens and antigestagens as well as inhibitors of the releasing hormones, such as LHRH (luteinizing hormone-releasing hormone), their analogs, Antagonists and superagonists.
  • LHRH leuprorelin
  • Examples of LHRH antagonists are Antide, Ramorelix, Cetrorelix, Tevere
  • hormone agonists that can be combined with the compounds according to the invention are e.g. B. the estrogen derivatives fosfestrol, chlorotrianisen, ethynyl estradiol, diethylstilbestrol, polyestradiol phosphate and the progestogen analogues medroxyprogesterone acetate, megestrol acetate and fluoxymesterone.
  • the compounds of formula I according to the invention can also be used in free or fixed combination for the prophylaxis and / or therapy of tumor diseases or neoplasias together with 5 ⁇ -reductase inhibitors (e.g. epristeride, finasteride, turosteride, LV 654066), steroidal and non-steroidal antiandrogens (e.g. cyproterone acetate, flutamide, BMOT, anandron [RU 23908], Faslodex, Casodex [ICI 176334], WIN 49596), non-steroidal anti-estrogens (e.g.
  • 5 ⁇ -reductase inhibitors e.g. epristeride, finasteride, turosteride, LV 654066
  • steroidal and non-steroidal antiandrogens e.g. cyproterone acetate, flutamide, BMOT, anandron [RU 23908], Fas
  • tamoxifen diethylstilbestrol, clomiphene, nafoxidine, MER-25, droloxifene, Toremifene, zindoxifene, tetramethyl-HES, LY 117018) and together with anti-estrogens, such as. B. ICI 164384, ZK 119010, ICI 182780, RU 58668. Examples of antigenic combination partners are mifepristone (RU 486) and onapristone (ZK 98.299).
  • Aromatase inhibitors such as, for. B. aminoglutethimide, rogletimide, letrozole, also steroidal aromatase inhibitors, such as. B. exemestane, formestan, minamestane, atamestane, MDL 18962, ORG 30958, and non-steroidal aromatase inhibitors, such as. B. Fadrozole, Vorozole, Anastrozole, CGS-20267.
  • the compounds of the formula I according to the invention can be used in particular in free or fixed combination with uracil, eniluracil, 3'-ethynyluridine, 3'-ethynylcytidine, Fluoropyrimidines (e.g. (E) -2'-deoxy-2 ' - (fluoromethylene) cytidine, MDL-101731) and / or dihydropyrimidine dehydrogenase (DPD) inhibitors for the prophylaxis and / or treatment of tumor diseases or neoplasms, such as B. colorectal, breast, ovarian, prostate, pancreatic or lung carcinoma can be used.
  • uracil e.g. (E) -2'-deoxy-2 ' - (fluoromethylene) cytidine, MDL-101731
  • DPD dihydropyrimidine dehydrogenase
  • fluoropyrimidines or fluoropyrimidine formulations are particularly suitable as combination partners of the compounds according to the invention:
  • S-1 (BMS 247617), a combination consisting of tegafur and two 5-fluorouracil modulators, namely CDHP (chloro-2,4-dihydroxypyrimidine, a potent DPD inhibitor) and potassium oxonate,
  • BOF-A2 (Emitefur), a drug consisting of 1-ethoxymethyl-5-fluorouracil (EM-FU) and 3-cyano-2,6-dihydroxypyridine (CNDP), a potent DPD inhibitor,
  • the compounds of the invention of formula I can furthermore be used in free or fixed combination together with cytokines or cytokine receptor agonists or antagonists in the prophylaxis and / or therapy of tumor diseases or neoplasias. Interleukins (e.g.
  • interferons e.g. interferon ⁇ , ß, ⁇
  • tumor necrosis factors e.g. TNF ⁇ , ß
  • TNF agonists e.g. Sonermin
  • TGF ⁇ , ß transforming growth factors
  • Hematopoietic growth factors are also suitable for combination therapy with the compounds according to the invention. Examples of this are e.g. B. Erythropoietin, thrombopoietin, granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage-colony-stimulating factor (GM-CSF) and macrophage-colony-stimulating factor (M-CSF).
  • G-CSF granulocyte-colony-stimulating factor
  • GM-CSF granulocyte-macrophage-colony-stimulating factor
  • M-CSF macrophage-colony-stimulating factor
  • the compounds of the formula I according to the invention are suitable on account of their high antitumor potency and, at the same time, very good tolerance for the prophylaxis and / or therapy of tumor diseases or neoplasia in combination with specific or non-specific, active or with humoral or cellular passive immunotherapy modalities.
  • Examples of specific, active immunotherapies are e.g. B. the injection or application of irradiated tumor cells or tumor-associated antigens or immunization with genetically modified tumor cells, for. B. with cytokine gene transfectants, or with virus-infected tumor cells.
  • non-specific, active immunotherapies include, for example, the application of immunostimulating or modulating substances, such as, for. B. BCG, Iscador, Ok-432, Levamisole, Ubenimex, Lentinam, Bestatin, MER, MTP-PE.
  • Passive, humoral immunotherapies in which the compounds of the formula I according to the invention can be used in the prophylaxis and / or therapy of tumor diseases or neoplasias are, for example, the injection or application of murine, human or humanized monoclonal antibodies or of immune conjugates, e.g. B. radioisotope, cytostatics or toxin-coupled (immunotoxins) monoclonal antibodies (e.g. gentuzumab, edrecolomab, trastuzumab, rituximab, lintuzumab, ACA-11, V-10500, anti-HM1.24 MAß, C225).
  • B. radioisotope, cytostatics or toxin-coupled (immunotoxins) monoclonal antibodies e.g. gentuzumab, edrecolomab, trastuzumab, rituximab, lintuzumab,
  • passive, humoral immunotherapies are genetically modified monoclonal antibodies, bispecific antibodies or immunoglobulin T cell receptor chimeras.
  • the compounds of the formula I according to the invention can furthermore be used in combination with passive, cellular immunotherapies in the prophylaxis and / or therapy of tumor diseases or neoplasias.
  • therapy modalities are e.g. B. adoptive immunotherapy with cytotoxic effector cells such.
  • LAK lymphokine-activated killer cells
  • LGL large granular lymphocytes
  • NK natural killer cells
  • TIL tumor-infiltrating lymphocytes
  • CTL cytotoxic T-lymphocytes
  • gene therapy e.g. adenoviral-p53
  • the compounds of formula I according to the invention also show valuable pharmacological properties in combination with radiotherapy. Due to their high antitumor potency, combined with radiotherapy in the treatment of tumor diseases or neoplasia, synergistic antitumor or antiproliferative effects occur. On the other hand, the known, non-specific cytotoxic side effects of radiotherapy on rapidly proliferating cells, such as. B. bone marrow cells or mucosal cells of the gastrointestinal tract, due to the excellent organ / tissue tolerance of the compounds of formula I according to the invention when combining these substances with radiotherapy, and thus the therapeutic range of the combination therapy is significantly increased.
  • the medicaments according to the invention containing compounds according to the invention of the formula I for the prophylaxis and / or therapy of tumor diseases or neoplasias, can be administered enterally or parenterally in liquid or solid form.
  • the usual forms of application come into question, such as tablets, capsules, dragees, syrups, solutions, sprays or suspensions.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers.
  • additives are e.g. B.
  • Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids, such as. B. stearic acid, gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers, such as polyethylene glycols etc.
  • Preparations suitable for oral applications can, if desired, contain flavoring or sweetening agents.
  • the dosage can depend on various factors, such as the mode of administration, species, age or individual condition.
  • the compounds according to the invention are usually administered in doses of 0.1-100 mg per kg body weight per day, preferably 0.2-80 mg per kg body weight per day. It is preferred to distribute the daily dose over 2 to 5 applications, with 1 to 2 tablets or ampoules with an active substance content of 0.5 to 500 mg being administered with each application.
  • the tablets can also be delayed, which reduces the number of applications per day to 1-3.
  • the active substance content of the retarded tablets can be 2 - 1000 mg.
  • the active ingredient can also be administered by 1-3 parenteral applications or administered by continuous infusion, the amounts of 5 - 1000 mg per day are usually sufficient.
  • the active ingredients can either be in a fixed combination in the same application form, e.g. Tablet or ampoule, or in one or more different application forms can be provided. The latter is necessary if the active ingredients to be combined e.g. are not compatible with each other, e.g. because there are reactions during storage. Of course, even when three or more active ingredients are combined, they can all be produced in a fixed combination in one application form or else in two or more application forms and applied in a free combination.
  • MethA fibrosarcoma cells were propagated intraperitoneally (ip) as an ascitic tumor in female CB6F ⁇ mice (Charles River Laboratories, Sulzfeld, Germany). The animals were kept in Macrolon Cages kept under laminar flow conditions at 23 ⁇ 1 ° C room temperature, 55 ⁇ 15% relative humidity and a 12 h light-dark rhythm. The mice were fed a standard diet (Ssniff-Spezialdiuschten GmbH, Soest / Westphalia, Germany) and had free access to drinking water. Before inclusion in the respective experiment, the animals were acclimatized for at least 14 days. They have been routinely screened for infection by murine viruses.
  • MethA fibrosarcoma cells per mouse were subcutaneously (sc) inoculated into female CB6Fr mice, 6-8 weeks old.
  • the tumor growth in mice of the control group as well as in animals of the substance-treated groups was regularly monitored at weekly intervals by measuring the two mutually perpendicular tumor diameters, as in Hermann DBJ, Pahlke W., Opitz H.-G. and Bicker U., Cancer Treatment Reviews, 17, 247-252, 1990.
  • the test substances were tested in a dose-dependent manner and administered ip once a week in phosphate-buffered physiological saline (PBS). Animals in the control group were treated with placebo (PBS).
  • Table 1 shows the effect of substances A and B on tumor growth in the MethA fibrosar model in vivo. Tumor volumes on day 21 and 28 after tumor cell inoculation are given as medians from 10 animals per test group.
  • Substance group (mg / kg / - application) day 21 day 28
  • substance A according to the invention surprisingly significantly inhibits tumor growth, depending on dose and time, i.e. has an antitumoral or antiproliferative effect.
  • Substance B (example 1a from EP 545966) shows no anti-tumor or anti-proliferative properties.
  • Substance A was tested for tolerability in female NMRI mice.
  • the animal husbandry conditions were the same as described under Example 1.
  • Blood values including white blood cell concentration (WBC), red blood cell concentration (RBC), hemoglobin (HB), hematocrit (HCT), thrombocyte concentration (PLT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC),
  • Bone marrow cellularity i.e. Number of bone marrow cells per femur (M / femur),
  • Organ weights including weights of colon, heart, brain, intestine, lungs, liver, stomach, spleen, kidneys, ovaries.
  • Table 2 shows the results of these experiments.
  • Table 2 Compatibility of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester (substance A) in vivo a
  • Placebo Phosphate-buffered, physiological saline (PBS) c median
  • PBS physiological saline
  • the results from Examples 1 and 2 show that the compounds of the general formula I according to the invention have surprisingly very good antitumoral or antiproliferative activity in vivo, but without non-specific toxic properties, such as e.g. Bone marrow suppression, hematotoxicity or organ toxicity.
  • Other compounds described in EP 545 966 that do not fall under Formula I do not show these pharmacological properties.
  • the crude product of the last reaction was dissolved in 1 l of acetone at 50 ° C.
  • the calcium salt could be precipitated by slowly adding 30 g of calcium acetate in 75 ml of water while stirring and cooling to room temperature over 1 hour.
  • the calcium salt of the last reaction was suspended in 600 ml MTBE and 200 ml 2N hydrochloric acid. The organic phase was separated and in vacuo evaporated. Yield: 67.4 g.
  • the crude product was dissolved in 140 ml of methanol at 40 ° C., and 36 ml of triethylamine and 20 ml of water were added.
  • the product was purified in portions by preparative HPLC on LiChroprep RP18, 25-40 ⁇ m (column 50 mm 0, 200 mm length) with methanol / 0.04 M sodium acetate solution 80/20 as the eluent.
  • the identity could be verified in comparison to authentic samples.
  • the identity could be verified in comparison to authentic samples.
  • substance A was dissolved in a stock concentration of 1 mg / ml in medium.
  • the other substances were also dissolved in water or DMSO (dimethyl sulfoxide) in a stock concentration of 1 mg / ml.
  • the test series were carried out in 96-well plates. For each series of titrations, either 75 ⁇ l of substance solution were placed in the first well and 25 ⁇ l were transferred to the next row, or 100 ⁇ l and 50 ⁇ l were transferred.
  • the in vitro activity of the test substances was determined colorimetrically on the basis of the cleavage of the tetrazolium salt WST-1, Röche Molecular Biochemicals, Mannheim, DE.
  • WST-1 tetrazolium salt
  • Röche Molecular Biochemicals Mannheim, DE.
  • the cultures were incubated with 10 ⁇ l WST for 4 hours. The plates were then shaken gently for 10 minutes. The optical density was measured with an ELISA reader (Spectra MAX 340 P c, Molecular Devices, Ismaning, DE) at wavelengths from 440 to 650 nm.
  • the IC 50 value for the individual substances was determined in each case. In the combination, one of the substances was used in a concentration that just did not show any antiproliferative activity, and the IC 50 value for the combination was determined after the addition of the second substance. The combination with cisplatin resulted in a reduction of the IC 50 value for substance A by 25% and for cisplatin by 50%.
  • camptothecin resulted in a reduction in the IC 50 value for substance A of approximately 40% and for camptothecin of approximately 90%.
  • Vacuum drying cabinet at 40oC 4.5g of the sulfoxide were isolated.
  • Vacuum drying cabinet at 40oC 8.5g of the sulfoxide were isolated.

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Abstract

L'invention concerne des médicaments contenant des dérivés phospholipides de préférence de nucléosides non naturels correspondant à la formule générale (I), dans laquelle R1 représente une chaîne alkyle comportant 10-14 atomes de carbone ; R2 représente une chaîne alkyle comportant 8-12 atomes de carbone ; n représente un nombre entier pouvant aller de 0 à 2 ; R3 représente un groupe hydroxy ; R4 et R5 représentent hydrogène et B représente 5-fluoroacil. Ces dérivés sont utilisés comme principes actifs antitumoraux ou antiprolifératifs pour la prophylaxie et/ou le traitement curatif, palliatif ou de soutien de maladies tumorales ou de néoplasies, par exemple, les carcinomes, les sarcomes ou les leucémies, et également comme agents monothérapeutiques ou monoprophylactiques tant en association libre qu'en association fixe avec d'autres modalités de prophylaxie ou de thérapie.
EP02803379A 2001-11-21 2002-11-18 Derives phospholipides de nucleosides utilises comme medicaments antitumoraux Withdrawn EP1448579A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE2001156910 DE10156910A1 (de) 2001-11-21 2001-11-21 Phospholipid-Derivate von Nucleosiden als antitumorale Arzneimittel
DE10156910 2001-11-21
DE10209564 2002-03-04
DE2002109564 DE10209564A1 (de) 2002-03-04 2002-03-04 Phospholipid-Derivate von Nucleosiden als antitumorale Arzneimittel
PCT/EP2002/012908 WO2003044035A1 (fr) 2001-11-21 2002-11-18 Derives phospholipides de nucleosides utilises comme medicaments antitumoraux

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EP1448579A1 true EP1448579A1 (fr) 2004-08-25

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US (1) US20050090659A1 (fr)
EP (1) EP1448579A1 (fr)
CN (1) CN1615314A (fr)
AU (1) AU2002356672A1 (fr)
CA (1) CA2468099A1 (fr)
MX (1) MXPA04004712A (fr)
NZ (1) NZ533094A (fr)
WO (1) WO2003044035A1 (fr)

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AU2002356672A1 (en) * 2001-11-21 2003-06-10 Ganymed 256 Vermogensverwaltungs Gmbh Phospholipid derivitives of nucleosides as antitumoral medicaments
DK1874821T3 (da) 2005-04-26 2013-07-08 Trion Pharma Gmbh Kombination af antistoffer med glykokortikoider til behandling af kræft
NO324263B1 (no) 2005-12-08 2007-09-17 Clavis Pharma Asa Kjemiske forbindelser, anvendelse derav ved behandling av kreft, samt farmasoytiske preparater som omfatter slike forbindelser
US7378401B2 (en) * 2006-07-14 2008-05-27 Heidelberg Pharma Gmbh Use of Fosfluridine Tidoxil (FT) for the treatment of intraepithelial proliferative diseases
MX2010003002A (es) 2007-09-26 2010-07-05 Sinai School Medicine Analogos de azacitidina y sus usos.
CN101485887B (zh) * 2008-01-17 2011-06-29 中国人民解放军第二军医大学 5-氟尿嘧啶-sn2-磷脂酰胆碱共聚物及其制备方法和用途

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JPS61152694A (ja) * 1984-12-27 1986-07-11 Toyama Chem Co Ltd 新規な５−フルオロ−２′−デオキシウリジン−５′−ホスフエ−ト誘導体およびその塩
DE3906952A1 (de) * 1989-03-04 1990-09-06 Boehringer Mannheim Gmbh (3-(c(pfeil abwaerts)1(pfeil abwaerts)(pfeil abwaerts)6(pfeil abwaerts)-c(pfeil abwaerts)1(pfeil abwaerts)(pfeil abwaerts)8(pfeil abwaerts))alkansulfinyl- und sulfonyl-2-methoxymethyl-propyl)-(2-trimethylammonio-ethyl) phosphate, verfahren zu deren herstellung diese verbindungen enthaltende arzneimittel
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AU2002356672A1 (en) * 2001-11-21 2003-06-10 Ganymed 256 Vermogensverwaltungs Gmbh Phospholipid derivitives of nucleosides as antitumoral medicaments

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US20050090659A1 (en) 2005-04-28
CN1615314A (zh) 2005-05-11
MXPA04004712A (es) 2005-06-20
NZ533094A (en) 2006-01-27
AU2002356672A1 (en) 2003-06-10
CA2468099A1 (fr) 2003-05-30
WO2003044035A1 (fr) 2003-05-30

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