EP1448579A1

EP1448579A1 - Phospholipid derivatives of nucleosides as antitumoral medicaments

Info

Publication number: EP1448579A1
Application number: EP02803379A
Authority: EP
Inventors: Dieter Herrmann
Original assignee: Heidelberg Pharma Holding GmbH
Current assignee: Heidelberg Pharma Research GmbH
Priority date: 2001-11-21
Filing date: 2002-11-18
Publication date: 2004-08-25
Also published as: NZ533094A; CN1615314A; CA2468099A1; WO2003044035A1; US20050090659A1; AU2002356672A1; MXPA04004712A

Abstract

The invention relates to medicaments containing phospholipid derivatives preferably of unnatural nucleosides of general formula (I), wherein R1 represents an alkyl chain with 10-14 carbon atoms, R2 represents an alkyl chain with 8-12 carbon atoms, n represents a whole number from 0 to 2, R3 represents a hydroxy group, R4 and R5 represent hydrogen and B is a 5-fluorouracil. Said derivatives are used as antitumoral or antiproliferative active ingredients for the prophylaxis and/or curative, palliative or supportive treatment of tumor diseases or neoplasia such as carcinoma, sarcoma, lymphoma or leukemia, and also as monotherapeutic or monoprophylactic agents in free or fixed combination with other prophylactic or therapeutic modalities.

Description

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:

in the

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 , and 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. 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. The compounds are said to inhibit the multiplication of DNA or RNA viruses at the level of virus-specific DNA or RNA transcription.

From proc. Natl. Acad. Be. USA 83, 1911, 1986 and Nature 325, 773, 1987 it is known that the substances mentioned can suppress the multiplication of retroviruses by inhibiting the enzyme reverse transcriptase. Of particular therapeutic interest is the inhibitory effect of the compounds mentioned on HIV, the cause of the immune deficiency disease AIDS. EP 545 966 expressly points out that the compounds described develop their antiviral or antiretroviral activity without being cytotoxic in pharmacologically relevant doses.

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.

Surprisingly, it has now been found that some of the 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. B. Malignancies, neoplasias, carcinomas, sarcomas, or haematological tumor diseases, such as B. Leukaemias. 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. B. exercise the bone marrow or gastrointestinal tract.

The compounds according to the invention are those of the general formula I:

in the

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

B is an optionally modified or substituted nucleobase, and its physiologically tolerable salts of inorganic or organic acids including the various possible enantiomers, diastereomers or tautomers. 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:

a) OH H OH b) OH HH c) H OH H d) HH OH

In the general formula I Ri is preferably a straight chain C10 - C ₄ alkyl group. In particular, 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 Cβ-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.

Compounds of the general formula I in which R _{5 is} hydrogen are particularly preferred. These connections are not yet known by name.

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). These compounds are neither described in EP 545966 nor in WO 95/32984 and are accordingly new.

One way of preparing the compounds of the general formula I is described analogously in the patent EP 0 545 966 B1 and WO 95/32984, to which reference is hereby made.

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.

Of particular interest in this connection are the diastereomers of the general formulas IIa and IIb

in which 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.

Furthermore, 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

Formula I, in the

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 and

B stands for the 5-fluorouracil residue and their salts and all optically active forms and

Enantiomers.

Compounds of the general are particularly preferred as new substances

Formula I, in the

Ri is a dodecyl residue and

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 and

Enantiomers.

Compared to the previously known compounds, 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. Carmustin, Lomustin, Semustin, Nimustin, Fotemustin, Streptozotocin, Chlorozotocin), monofunctional and non-classical alkylating agents (e.g. Procarbazin, Dacarbazin, Hexamethylmelamin, Mitozolamidom, Temozolomid Adozelesin and its derivatives), platinum derivatives (e.g. cisplatin, carboplatin, ormaplatin, oxaliplatin, tetraplatin, nedaplatin, CI-973, DWA 2114R, JM 216, JM 335, bis- and trans-platinum derivatives), folic acid Antagonists or antifolates (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, Cytόsinarabinosid [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. vincristine [sulfate], vinblastine [sulfate], vindesine [sulfate], vinorelbine), AM-132, KW- 2170, rhizoxin, palmitoylrhizoxin, dolostatins (e.g. dolostatin 10), phomopsins, halchondrines, homohalichondrines, spongistatins, combrestatins, steganacin, taxanes (e.g. paclitaxel, docetaxel, baccatin III and their derivatives), topoisomerase inhibitor, such as inhibitor, such as inhibitor, such as inhibitor e.g. epipodophyllotoxins (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, rapamycins, deoxyspergualin and 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. 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. R-109339), phosphatase, adenosine deaminase, RNA polymerase, protein kinase C inhibitors (e.g. hexadecylphosphocholine, calphostin, gossipol , Quercetin, fisetin, staurosporins [e.g. midostaurin, 7-hydroxystaurosporin, KW-24Ö1J), Anti-angiogenesis agents or angiogenesis inhibitors (e.g. B. FMPA, TNP-470, anti-VEGFΛ / PF monoclonal antibody) or with 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. These 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. Examples of the latter compounds include buserelin (acetate), goserelin (acetate), leuprorelin (acetate), triptorelin (acetate). Examples of LHRH antagonists are Antide, Ramorelix, Cetrorelix, Teverelix, Abarelix and ORG 30850.

Examples of 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 5α-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. 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.

The following fluoropyrimidines or fluoropyrimidine formulations, individually or in free or fixed combination, are particularly suitable as combination partners of the compounds according to the invention:

UFT, a combination of uracil and tegafur (1- [2-tetrahydrofuranyl] -5- fluorouracil) in a fixed molar ratio of 4: 1,

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,

• Eniluracil (5-ethynyl-2,4 (1 H, 3H) pyrimidinedione), a potent and irreversible DPD inhibitor.

• Tegafur (1 [2-tetrahydrofuranyl] -5-fluorouracil)

• Capecitabine, enocitabine or galocitabine

By combining the compounds of the invention of formula I with uracil, Eniluracil, 3 ^{'-Ethynyluridin,} ^3' -Ethyny cytidine!, Fluoropyrimidines or DPD inhibitors or modulators, such as UFT, CDHP, CNDP etc., a further therapeutic advantage achieved in that the inhibition of DPD significantly increases the antitumor potency, the tolerance and the stability of the compounds according to the invention. The compounds of the formula I according to the invention 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. interleukins [IL] 1-18 [Edodekin], in particular IL 1, 2, 3, 6, 10, 11, 12), interferons (e.g. interferon α, ß, γ), tumor necrosis factors (e.g. TNF α, ß), TNF agonists (e.g. Sonermin) as well as transforming growth factors (e.g. TGF α, ß).

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).

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. In this context, 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). Further examples of 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. Examples of such therapy modalities are e.g. B. adoptive immunotherapy with cytotoxic effector cells such. B. lymphokine-activated killer cells (LAK), adherent LAK, large granular lymphocytes (LGL), natural killer cells (NK), tumor-infiltrating lymphocytes (TIL), dendritic cells or cytotoxic T-lymphocytes (CTL), and the transfer of genetically modified effector cells (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. Here, 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. Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. 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.

When compounds of formula I are combined with one or more further active ingredients, 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.

The following examples are intended to illustrate the invention without, however, restricting its scope.

example 1

Antitumor activity of δ-fluorine ^ '- deoxyuridine-S'-phosphoric acid-IS-dodecyl-thio-2-decyloxy) propyl ester (substance A) and 3'-azido-3'-deoxythymidine-5'-phosphoric acid (3-dodecylthio -2-decyloxy) propyl ester (substance B) im

MethA Fibrosarkommodell

The substances 5-fluoro-2'-deoxyuridine-5'-phosphoric acid- (3-dodecylthio-2-decyloxy) propyl ester (substance A) and 3'-azido-3'-deoxythymidine-5'-phosphoric acid- (3-dodecylthio-2-decyloxy) propyl ester (substance B) were among others in the murine methA fibrosar model in vivo for their antitumor or antiproliferative potency and effectiveness.

MethA fibrosarcoma cells were propagated intraperitoneally (ip) as an ascitic tumor in female CB6Fι 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-Spezialdiätten 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.

To test the active substance, 1 × 10 ⁵ 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.

Table 1 Antitumor activity in the MethA fibrosar model

Dose of tumor volume (mm ³ ) ^a

Substance group (mg / kg / - application) day 21 day 28

1 control - 4,032 (-) 9,827 (-) (placebo ^b )

2 Substance A 3 1,649 * (59.1) 4,163 * (57.6)

3 Substance A 30 416 ** (89.7) 1,254 ** (87.2)

4 Substance A 100 357 ** (91.1) 762 ** (92.2)

2 substance B 3 3,998 (0.8) 10,228 (+4.1)

3 substance B 30 4.102 (+1.7) 9.963 (+1.4)

4 substance B 100 4,021 (0.3) 10,098 (+2.8)

Mediän; 10 animals per group; Percent inhibition based on the control values of group 1 in brackets (+ means increase) placebo: phosphate-buffered, physiological saline (PBS) * p <0.05, ** p 0.01; Mann-Whitney test

The results show that 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.

Example 2

Compatibility of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester (substance A) in vivo

Substance A was tested for tolerability in female NMRI mice. The animal husbandry conditions were the same as described under Example 1.

For this purpose, female NMRI mice, 6-8 weeks old (Charles River Laboratories, Sulzfeld, Germany), were treated orally by gavage with 1 or 1.5 g / kg of substance A. The following toxicity parameters were then determined:

• 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),

• Body weight

• 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

Control Substance A Substance A

Parameters (placebo ^b ) (1 g / kg) (1.5 g / kg)

Bone marrow cellularity 28.28 ± 0.99 28.48 ± 0.86 31.44 ± 1.51

(M / femur)

Blood values:

WBC (k / μl) 12.20 ± 0.66 14.34 ± 2.18 16.97 ± 6.05

RBC (M / μl) 9.24 ± 0.17 9.31 ± 0.23 8.34 ± 0.56

HB (g / l) 17.16 ± 0.31 17.85 ± 0.39 15.79 ± 0.92

HCT (%) 46.54 ± 0.97 47.93 ± 1.16 43.42 + 2.77

MCV (fl) 50.32 ± 0.51 51.50 ± 0.58 52.09 ± 0.81

MCH (pg) 18.62 ± 0.14 19.28 ± 0.22 19.09 ± 0.37

MCHC (g / dl) 36.91 ± 0.36 37.29 ± 0.44 36.53 ± 0.38

PLT (k / µl) 1115 ± 48 1153 + 41 1431 ± 172

Body weight (g) 29.7 ^C 28.7 ^C 27.9 °

Body weight:

Colon (g) 429 ± 17 373 ± 15 392 ± 29

Heart (g) 130 ± 3 133 ± 4 126 ± 9

Lungs (g) 218 ± 5 226 ± 9 206 ± 9

Liver (g) 1,597 ± 53 1,602 ± 42 1,739 ± 81

Kidneys (g) 380 ± 9 361 ± 17 351 ± 26

Spleen (g) 131 ± 12 125 ± 9 204 ± 26

Stomach (g) 226 ± 6 232 ± 7 232 ± 16

Intestine (g) 1,494 ± 73 1,622 ± 61 1,807 ± 112

Brain (g) 372 ± 21 399 ± 8 387 ± 18

Ovaries (g) 197 ± 18 183 + 17 203 ± 33

Mean ± SEM; 10 animals per group

Placebo: Phosphate-buffered, physiological saline (PBS) c median The data show that even very high doses of substance A, ie 1 or 1.5 g / kg body weight, do not cause any significant reduction in the above-mentioned tolerance parameters compared to those in the placebo (drinking water) -treated control group. These results demonstrate that substance A has no non-specific toxic properties in vivo even in very high doses. Even with a very high dose of substance A there is no bone marrow suppression, hematotoxicity or non-specific toxic organ intolerance.

In summary, 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.

Example 3

Preparation of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester

As described in WO 95/32984, 52 g of crude rac- (3-dodecylthio-2-decyloxy) propyl dihydrogenphosphate and 53.3 g of 2,4,6-triisopropylbenzenesulfonyl chloride in 600 ml abs. Pyridine stirred for one hour at room temperature under argon. Then 27.4 g of 3'-acetyl-2'-deoxy-5-fluorouridine were added and the mixture was stirred for a further 16 h.

100 ml of water were then added and the suspension was stirred for 10 minutes. The solvent was removed in vacuo, the residue was distilled twice with 200 ml of toluene each time and the remaining viscous oil was suspended in 700 ml of MTBE (methyl tertiary butyl ether). After heating to 40 ° C, sonicate the precipitate was filtered off in an ultrasonic bath and cooled to 20 ° C. and washed with 100 ml of MTBE.

The filtrate was extracted three times with 150 ml of 2N hydrochloric acid, the organic _. Phase evaporated and the residue dissolved in 400 ml of methanol. After adding 42 ml of 30% sodium methylate solution (pH = 11), briefly stirring and adding 5 ml of glacial acetic acid, the low boilers were distilled off in vacuo.

The residue was dissolved in 700 ml of MTBE and extracted twice with 100 ml of 2N hydrochloric acid. The organic phase was evaporated and redistilled with 100 ml of toluene.

In the residue, the title compound was in the form of a crude oil as the free acid.

Example 4

Preparation of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester, calcium salt

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 precipitate was filtered off, washed with acetone and dried in vacuo. Yield: 106 g of crude calcium salt.

Example 5

Chromatographic purification of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester

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 μm (column 50 mm 0, 200 mm length) with methanol / 0.04 M sodium acetate solution 80/20 as the eluent.

The product-containing fractions were combined and concentrated in vacuo to 30% of the original volume. With stirring, 20 g of calcium acetate in 40 ml of water were added dropwise and the suspension was stirred for 1 h. The precipitate was filtered off and dried in vacuo. Yield: 42.2 g calcium salt.

Example 6

Preparation of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester sodium salt

42.2 g of calcium salt were suspended in 400 ml of MTBE and 200 ml of 2N hydrochloric acid. The organic phase was separated, filtered through kieselguhr and evaporated in vacuo. The residue was redistilled twice with 100 ml of toluene and dissolved in 80 ml of toluene at 40 ° C. By adding 30% sodium methylate solution, the pH was adjusted to 7 with stirring and the solution was added dropwise at 1.4 ° C. in 1.4 liters of acetone.

After stirring for 1 h, the precipitate was filtered off, washed with acetone and dried in vacuo. Yield: 41.2 g, mp: 175 ° C (decomposition). Example 7

Preparation of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid - [(2R) - (3-dodecylthio-2-decyloxy)] propyl ester

Analogously to Examples 3 to 6, by using (R) - (3-dodecylthio-2-decyloxy) propyl dihydrogen phosphate, the conjugate 5-fluoro-2'-deoxyuridine-5'-phosphoric acid - [(2R) - (3 -dodecylthio-2-decyloxy)] propyl ester as the free acid, calcium salt and sodium salt.

In the thin-layer chromatogram, the identity could be verified in comparison to authentic samples.

Example 8

Preparation of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid - [(2S) - (3-dodecylthio-2-decyloxy)] propyl ester

Analogously to Examples 3 to 6, by using (S) - (3-dodecylthio-2-decyloxy) propyl dihydrogen phosphate, the conjugate 5-fluoro-2'-deoxyuridine-5'-phosphoric acid - [(2S) - (3 -dodecylthio-2-decyloxy)] propyl ester as the free acid, calcium salt and sodium salt.

The enantiomerically pure (R) - (3-dodecylthio-2-decyloxy) propyl dihydrogen phosphate or (S) - (3-dodecylthio-2-decyloxy) propyl dihydrogen phosphate was prepared by separating the racemate via diastereomeric salts. Example 9

Combination of 5-fluoro-2'-deoxyuridine-5 ^, -phosphoric acid [2- (3'dodecylthio-2-decyloxy) propyl] ester sodium salt with cisplatin, doxorubicin, vincristine and camptothecin

The effect of combining substance A with cisplatin, doxorubicin, vincristine and camptothecin was tested in proliferation experiments. For this purpose, 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 μl of substance solution were placed in the first well and 25 μl were transferred to the next row, or 100 μl and 50 μl were transferred. 50 μl of cell suspension (5 × 10 ⁴ cells / ml, K562 cells, RPMI 1640 medium) were added and the plates were incubated for 24 to 78 hours at 37 ° C., 5% CO ₂ and 95% atmospheric humidity. Cells without substance and pure medium served as controls.

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. For this purpose, the cultures were incubated with 10 μl 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%.

The combination with doxorubicin resulted in a reduction in the IC 50 value for substance A of approximately 30% and for doxorubicin of approximately 50%.

The combination with vincristine resulted in a reduction of the IC ₅ o value for Compound A of about 60% and for vincristine by about 65%.

The combination with camptothecin resulted in a reduction in the IC 50 value for substance A of approximately 40% and for camptothecin of approximately 90%.

The tests prove that the combination can achieve a synergistic increase in effectiveness.

Example 10

(5-fluorouridine) -5'-phosphoric acid (3-dodecylsulfinyl-2-decyloxy) propyl ester

5g (5-fluorouridine) -5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester was suspended in 50 ml of glacial acetic acid and after addition of 5 ml 30%

Hydrogen peroxide stirred for 4 hours at room temperature.

Then the solvent was removed in a rotary evaporator and the

Residue by preparative column chromatography on RP 18 with

Methanol / 0.1 M acetate buffer purified as eluent.

The product-containing fractions were evaporated, the residue was stirred with acetone and the precipitate was filtered off with suction. After drying in

Vacuum drying cabinet at 40oC 4.5g of the sulfoxide were isolated.

214-216oC (decomposition), Rf = 0.27 (BuOAc / iPrOH / H2O / NH4OH

3/5/1/1),

31 P NMR: δ = 0.027ppm Example H

(5-fluorouridine) -5'-phosphoric acid (3-dodecylsulfonyl-2-decyloxy) propyl ester

10g (5-fluorouridine) -5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester were suspended in 100ml glacial acetic acid and after adding 25ml 30%

Hydrogen peroxide stirred at 50oC for 6 hours. Then another 13ml

Hydrogen peroxide added and stirred for a further 7 hours.

Then the solvent was removed in a rotary evaporator and the

Residue by preparative column chromatography on RP 18 with

Methanol / 0.1 M acetate buffer purified as eluent.

Vacuum drying cabinet at 40oC 8.5g of the sulfoxide were isolated.

Mp 204 - 207 ° C (decomposition),

Rf = 0.29 (BuOAc / iPrOH / H ₂ O / NH ₄ OH 3/5/1/1),

³¹ P NMR: δ = 0.073ppm

Example 12 Tablet formulation

1.50 kg of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecylthio-2-decyloxy) propyl ester calcium salt

1.42 kg of microcrystalline cellulose

1.84 kg lactose

0.04 kg polyvinyl pyrrolidone

0.20 kg magnesium stearate

are mixed dry, wet granulated with water, dried and pressed in a rotary press into tablets with a weight of 500 mg. Example 13 solution for injection

10.0 g of 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecyl-thio-2-decyloxy) propyl ester sodium salt are dissolved in 500 ml of physiological saline solution and filled into ampoules of 5 ml and sterilized. The solution can i.V. be applied.

Claims

claims

1. Compounds of the general formula

in which 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 hydroxy group

R ₄ and R _{5 are} hydrogen or, and

B 5-fluorouracil, which, after administration to humans, directly or indirectly is a phospholipid

Provide derivative of the general formula I or another antitumoral or antiproliferative active metabolite or residues thereof.

2. Compounds according to claim 1, wherein Ri is a dodecyl radical and R _{2 is} a decyl radical.

3. 5-fluoro-2'-deoxyuridine-5'-phosphoric acid (3-dodecyl-thio-2-decyloxy) propyl ester and its salts, stereoisomers or tautomers as well as all optically active forms and mixtures of enantiomers. Compounds of the general formula IIa or IIb,

in which

Ri is a dodecyl residue and

R _{2 is} a decyl radical, n can be equal to 0.1 or 2,

R and R _{5 represent} hydrogen,

R _{3 represents} a hydroxy group and

B represents the 5-fluorouracil radical, and their salts.

5. Use of a compound according to claims 1-4 for prophylaxis and / or for curative, palhative or supportive treatment of tumor diseases or neoplasias.

6. Use according to claim 5, wherein the tumor disease or neoplasia is a carcinoma, in particular a colorectal, breast, ovarian, prostate, lung or pancreatic carcinoma, sarcoma, lymphoma or leukemia.

, Medicaments for the prophylaxis and / or therapy of tumor diseases or haematological neoplasias containing compounds of the general formula I,

in the

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 hydroxy group,

R ₄ and Rs represent hydrogen, and

B is 5-fluorouracil, or their physiologically tolerable salts, stereoisomers or tautomers as an active ingredient.

8. Medicament according to claim 7, wherein R-ι represents a straight-chain C ₁₀ -C ₁₄ alkyl group.

9. Medicament according to claim 7 or 8, wherein Ri represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group.

10. Medicament according to one of claims 7 to 9, wherein R _{2 is} a straight-chain Cβ-Cι ₂ alkyl group.

11. Medicament according to claim 10, wherein R _{2 is} an octyl, nonyl, decyl, undecyl or dodecyl group.

12. Medicament according to claim 7, wherein R 1 is undecyl or dodecyl and R _{2 is} decyl or undecyl.

13. Medicament according to one of claims 7 to 12, wherein n is 0 or 1.

14. Medicament according to one of claims 7 to 13, characterized in that one or more further active ingredients for prophylaxis and / or for curative, palhative or supportive treatment of tumor diseases or neoplasias, if desired in two or more separate administration forms, are contained.

15. Medicament according to claim 14, characterized in that the further active substance or the further active substances is or are selected from:

Nitrogen mustard derivatives, e.g. B. Cyclophosphamide

Aziridines or epoxides, e.g. B. Thiotepa

Alkyl alkane sulfonates, e.g. B. Busulfan

Nitrosohams, e.g. B. Carmustin

Monofunctional or non-classical alkylating agents, e.g. B. procarbazine,

adozelesin

Platinum derivatives, e.g. B. cisplatin, carboplatin

Folic acid antagonists or antifolates, e.g. B. Methotrexate

Purine or purine nucleoside analogs, e.g. B. 6-mercaptopurine,

pentostatin • Pyrimidine or pyrimidine nucleoside analogs, e.g. B. 5-fluorouracil, 5-fluorouridine, 5-fluorodeoxyuridine, capecitabine, tegafur, carmofur, ftorafur

Anthracyclines or chemically related intercalating compounds, e.g. B. doxorubicin or its morpholino derivatives, MX-2

• Antibiotic cytostatics or chemotherapy drugs, e.g. B. Bleomycin

• Microtubulus (eg Vinca alkaloids, taxanes) -, topoisomerase (eg epipodophyllotoxins) -, phosphatase, tyrosine kinase, thymidylate synthase -, DNA or RNA polymerase, histone deacylase, metalloproteinase (e.g. Marimastat), protein kinase C (e.g. staurosporins), P-glycoprotein, cyclooxygenase-2, adenosine desaminase, famesyltransferase or angiogenesis inhibitors

Apoptosis agonists or inducers (eg AOP 99.0001)

Corticoids, e.g. B. Cortisone, Prednisone

16. Medicament according to claim 14, characterized in that the further active substance or substances is selected from: hormones (for example androgens, estrogens, gestagens); Anti-hormones (e.g. anti-androgens, anti-estrogens [e.g. tamoxifen, toremifene], anti-progestogens); Inhibitors of releasing hormones, their analogs, antagonists or superagonists (e.g. buserelin, leuprorelin); Aromatase (e.g. aminoglutethimide); or 5α-reductase inhibitors.

17. Medicament according to claim 14, characterized in that the further active substance or substances is selected from: uracil, 3'-ethylnyluridine, 3 ^' -ethynylcytidine, tegafur (1- [2-tetrahydrofuranyl] -5- fluorouracil ), Fluoropyrimidines, dihydropyrimidine dehydrogenase (DPD) inhibitors (e.g. chloro-2,4-dihydroxypyrimidine, 3-cyano-2,6-dihydroxy-pyrimidine, 5-ethynyl-2,4 (1 H, 3H) -pyrimidinedione).

8. Medicament according to claim 14, characterized in that the further active substance or substances is selected or are among the following dihydropyrimidine dehydrogenase (DPD) inhibitors or inhibitor formulations:

S-1 (BMS 247617), a combination consisting of tegafur and the two 5-fluorouracil modulators CDHF (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-dihydroxypyrimidine (CNDP), a potent DPD inhibitor,

• Tegafur / 1- [2-tetrahydrofuranyl] -5-fluorouracil

19. Medicament according to claim 14, characterized in that the further active substance or substances is selected or are cytokines, such as. B. interleukins, interferons, tumor necrosis factors or transforming growth factors.

20. Medicament according to claim 14, characterized in that the further active ingredient or the other active ingredients is selected or are among haematopoietic growth factors, such as. B. erythropoietin, thrombopoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF).

21. Medicament according to one of claims 7 to 13, characterized in that agents for active, specific immunotherapy (z. B. application of irradiated tumor cells, tumor-associated antigens, virus-infected or genetically modified tumor cells [e.g. B. cytokine gene transfectants]) or for non-specific immunotherapy (e.g. application of immunostimulating or modulating agents (e.g. BCG, Iscador, Levamisole, Ubenimex, Bestatin, Ok-432), or for passive, humoral immunotherapy (eg application of murine, human, humanized or bispecific monoclonal antibodies, [eg C225] immune conjugates [eg radioisotope, cytostatics or toxin-coupled monoclonal antibodies or immunotoxins], immunoglobulin T cell - Chimeras) or for cellular immunotherapy (e.g. adoptive immunotherapy with cytotoxic effector cells [e.g. lymphokine-activated or natural killer cells, tumor-infiltrating lymphocytes, cytotoxic T-lymphocytes], transfer of genetically modified effector cells [gene therapy]) with compounds of the formula I be combined.

22. A method for the treatment of tumors, characterized in that a medicament according to at least one of claims 7 to 13 is used.

23. The method according to claim 22, wherein the medicaments are used in combination with specific or non-specific, active or with humoral or cellular passive immunotherapy modalities.

24. The method according to claim 23, wherein the specific, active immunotherapies are selected from 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.

25. The method according to claim 23, wherein the non-specific, active immunotherapies are selected with the application of immune stimulating or modulating substances, such as. B. BCG, Iscador, Ok-432, Levamisole, Ubenimex, Lentinam, Bestatin, MER, MTP-PE.

26. The method according to claim 23, wherein the passive, humoral immunotherapies are selected from the injection or application of murine, human or humanized monoclonal antibodies or immune conjugates, for. B. radioisotope, cytostatics or toxin-coupled (immunotoxins) monoclonal antibodies (e.g. gentuzumab, edrecolomab, trastuzumab, rituximab, lintuzumab, ACA-11, V-10500, anti-HM1.24 MAB, C225) or genetic altered monoclonal antibodies, bispecific antibodies or immunoglobulin T cell receptor chimeras.

27. The method according to claim 23, wherein the passive, cellular immunotherapies are selected from adoptive immunotherapies with cytotoxic effector cells, such as. B. lymphokine-activated killer cells (LAK), adherent LAK, large granular lymphocytes (LGL), natural killer cells (NK), tumor-infiltrating lymphocytes (TIL), dendritic cells or cytotoxic T-lymphocytes (CTL), and the transfer of genetically modified effector cells (gene therapy) , e.g.; Adenoviral-p53).

28. The method according to claim 22, wherein the medicaments are used in combination with radiotherapy.