[go: up one dir, main page]

WO1986000804A1 - Compositions de ruthenium a effet inhibiteur de tumeurs - Google Patents

Compositions de ruthenium a effet inhibiteur de tumeurs Download PDF

Info

Publication number
WO1986000804A1
WO1986000804A1 PCT/EP1985/000368 EP8500368W WO8600804A1 WO 1986000804 A1 WO1986000804 A1 WO 1986000804A1 EP 8500368 W EP8500368 W EP 8500368W WO 8600804 A1 WO8600804 A1 WO 8600804A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
alkyl
phenyl
methyl
amino
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.)
Ceased
Application number
PCT/EP1985/000368
Other languages
German (de)
English (en)
Inventor
Heimo J. Keller
Bernhard Keppler
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of WO1986000804A1 publication Critical patent/WO1986000804A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0046—Ruthenium compounds
    • C07F15/0053—Ruthenium compounds without a metal-carbon linkage

Definitions

  • the invention relates to pharmaceutical preparations containing antineoplastic ruthenium compounds.
  • the complex compound cisOiammindichloroplatin (II) has proven itself as a potent anti-tumor agent.
  • compounds of the other platinum metals also show an inhibition of tumor growth (e.g. T. Giraldi et al., Cancer Res. HL 197732662-6).
  • L. J. Anghileri Z. Krebsforsch. 83M9751213-7) reports on a tumor-inhibiting effect of ruthenium red. 8ei M.J.Clarke, ACS Symp.Ser. 140 [1980] 157-180 the potential suitability of ruthenium complexes for cancer therapy is discussed.
  • B is a mono- or polynuclear, one or more nitrogen atom-containing basic heterocycle and X is chlorine or bromine, have an advantageous tumor-inhibiting activity with favorable toxicity. They are therefore suitable as a chemotherapeutic agent for the treatment of cancer. They are low-side effects chemotherapeutic agents for the treatment of tumors, for example ovarian tumors, breast tumors, Gastric tumors, prostate tumors, lung tumors, bladder tumors and in particular colorectal tumors and other malignant neoplasms are suitable. Accordingly, the compounds are useful for relieving the pain and suffering associated with cancer therapy, for inhibiting and regressing tumors, for alleviating symptoms and increasing life expectancy.
  • the invention therefore relates to pharmaceutical preparations containing these ruthenium complex compounds and their use for the preparation of pharmaceutical preparations, in particular those against cancer.
  • R1 ' is hydrogen, C 1 -C 4 alkyl or phenyl
  • B pyridine, which is substituted by C 1 -C 4 alkyl, hydroxy, amino, chlorine, formyl,
  • Ethoxycarbonyl, di-C 1 -C 4 alkylamino, diethylaminocarbonyl, ethoxycarbonylmethyl, hydroxyiminomethine, phenyl, benzyl, benzoyl, pyrrolidino, piperidino, pyrrol-1-yl or pyrrol-1-ylmethyl, or a ring can be substituted
  • Amino or phenyl preferably hydrogen or methyl, meaning tet, Y is nitrogen or CR4 ′′, where R4 ′′ is hydrogen, C 1 -C 4 -alkyl,
  • Amino or phenyl preferably hydrogen or methyl
  • Z is nitrogen or CR5 ", where R5" is hydrogen, C 1 -C 4 alkyl,
  • B '''pyridine which can be substituted by C 1 -C 4 alkyl, hydroxy, amino, chlorine, diethylamino, dimethylamino, hydroxyiminomethine, phenyl, pyrrolidino, piperidino or pyrrol-1-ylmethyl, preferably in the 4-position, one ring
  • R1 '' 'and R2 "' independently of one another are hydrogen or methyl or together pentamethylene
  • W is nitrogen or CR3 '", where R3''' is hydrogen or methyl
  • Y is nitrogen or CR4 '", where R4 "' is hydrogen or methyl
  • Z is nitrogen or CR5"'
  • R5' is hydrogen or methyl
  • A is a mono- or polynuclear basic heterocycle containing one or more nitrogen atoms, with the exception of pyridine and methyl-substituted pyridine and X being chlorine or bromine, are new and are therefore a further subject of the invention.
  • R1 ' is hydrogen, C 1 -C 4 alkyl or phenyl
  • Ethoxycarbonyl, di-C 1 -C 4 alkylamino, diethylaminocarbonyl, ethoxycarbonylmethyl, hydroxyiminomethine, phenyl, benzyl, benzoyl, pyrrolidino, piperidino, pyrrol-1-yl or pyrrol-1-ylmethyl may be substituted, with the exception of pyridine and methyl-substituted pyridine , or a ring
  • R1 is hydrogen, C 1 -C 4 alkyl or phenyl
  • R2 hydrogen, C 1 -C 4 alkyl, amino, phenyl or R1 and R2 together form a group - (CH 2 ) S -, where s is an integer from 4 to 8, W is nitrogen or CR3", where R3 "Hydrogen, C 1 -C 4 alkyl,
  • Amino or phenyl preferably hydrogen or methyl
  • Y is nitrogen or CR4 ", where R4" is hydrogen, C 1 -C 4 -alkyl
  • Amino or phenyl preferably hydrogen or methyl
  • Z is nitrogen or CR5 ", where R5" is hydrogen, C 1 -C 4 alkyl,
  • a '"pyridine which is substituted by C 2 -C 4 alkyl, hydroxy, amino, chlorine, diethylamino, dimethylamino, hydroxyiminomethine, phenyl, pyrrolidino, piperidino or pyrrol-1-ylmethyl, preferably in the 4-position, a ring in which
  • R1 "'and R2"' independently of one another are hydrogen or methyl or together pentamethylene, W nitrogen or CR3 “', where R3'" is hydrogen or methyl, Y is nitrogen or CR4 '", where R4'" is hydrogen or methyl, Z is nitrogen or CR5 '", where R5"' is hydrogen or methyl, but only one of the radicals R3 '", R4'" and R5 '"has a meaning other than hydrogen, and
  • the thioetherruthenium complex serving as the starting product is introduced in an inert solvent, such as, for example, toluene, and the heterocycle as such or dissolved in an inert solvent, preferably in the same solvent in which the starting product is dissolved, is added. It has proven advantageous to use a 5 to 20 times, preferably about 10 times, molar excess of the heterocycle.
  • the reaction takes place at room temperature or elevated temperature, expediently at the back river is being worked on. If the compound of the invention already precipitates out during the reaction, it is filtered off hot and the filter cake is washed out several times with hot solvent, preferably toluene. It can then be washed with hot n-hexane.
  • the polarity of the solvent is reduced by adding a non-polar solvent, such as, for example, n-heptane, n-hexane or n-pentane, until precipitation occurs.
  • a non-polar solvent such as, for example, n-heptane, n-hexane or n-pentane
  • the product obtained can be dissolved in an inert solvent, for example methylene chloride, for purification and precipitated again by carefully adding a non-polar solvent, for example petroleum ether or n-hexane.
  • a reduced temperature for example 0 to 10 ° C., preferably about 4 ° C.
  • the subsequent drying is carried out at reduced pressure, preferably about 10 to 150 Pa, in particular 70 Pa.
  • the temperature is chosen so that no decomposition reactions are observed.
  • the reactions are expediently carried out in carefully dried solvents with the exclusion of air and moisture.
  • heterocycles are known or are prepared by methods known per se.
  • 4- [2- (dimethyl- and diethylamino) ethyl] pyridine is prepared according to the method described by A.P. Phillips, J.Am. Chem. Soc. 78 [1956] 4441 and 4-methylmercaptopyridine according to the method described by A.King et al., J.Chem.Soc. 1939. 873 method specified.
  • C 1 -C 4 alkyl is straight-chain or branched, preferably straight-chain.
  • C 1 -C 4 alkylene is straight-chain or branched, for example methylene, ethylene, propylene, trimethylene and tetramethylene, with straight-chain being preferred.
  • the pharmaceutical preparations are produced by methods known per se, the compounds according to the invention being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredient, the active ingredient content of these mixtures is 0.1 to 99.5, preferably 0.5 to 95 percent by weight of the total mixture.
  • the active substances or the pharmaceutical preparations are used in any suitable formulation, provided that the formation or maintenance of sufficient active substance levels is ensured. This can be achieved, for example, by oral or parenteral administration in suitable doses.
  • the pharmaceutical preparation of the active ingredient is advantageously in the form of unit doses which are tailored to the desired administration.
  • a unit dose can be, for example, a tablet, a dragee, a capsule, a suppository or a measured volume of a powder, a granulate, a solution, an emulsion or a suspension.
  • unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or a multiple of a single therapeutic dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score line.
  • the pharmaceutical preparations according to the invention when in unit doses and for application e.g. are intended for humans, contain about 0.1 to 500 mg, advantageously 10 to 200 mg and in particular 50 to 150 mg of active ingredient.
  • the active ingredient or ingredients are administered orally in a daily dose of 0.1 to 5, preferably 1 to 3 mg / kg
  • Body weight optionally in the form of several, preferably 1 to 3, individual doses to achieve the desired results.
  • a single dose contains the active ingredient (s) in amounts of 0.1 to 5, preferably 1 to 3 mg / kg body weight. Similar doses can be used in oral treatment.
  • the therapeutic administration of the pharmaceutical preparation can take place 1 to 4 times a day at fixed or varying times, eg before meals and / or in the evening. However, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individual to be treated, the type and severity of the disease, the type of preparation and the application of the pharmaceutical preparation, and the period or Interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the amount of active ingredient mentioned above must be exceeded. It may also prove expedient to administer the pharmaceutical preparation only once or at intervals of several days.
  • the optimum dosage and type of application of the active ingredients required in each case can be determined by any specialist on the basis of his or her specialist knowledge.
  • the pharmaceutical preparations generally consist of the active compounds according to the invention and non-toxic, pharmaceutically acceptable medicament carriers which are used as admixtures or diluents in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a sachet or another container, for the therapeutically active ingredient.
  • a carrier can e.g. serve as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener, as a taste corrector, as a colorant or as a preservative.
  • Tablets, dragees, hard and soft capsules e.g. come from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
  • Tablets can contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, for example corn starch or alginates; Binders, for example starch, gelatin or acacia; and lubricants, for example aluminum or magnesium stearate, talc or silicone oil. They can also be provided with a coating, which can also be such that it delays the dissolution and absorption of the pharmaceutical preparation in the gastrointestinal tract causes, so that, for example, better tolerance, protracting or retardation is achieved.
  • Gelatin capsules can contain the drug mixed with a solid, for example calcium carbonate or kaolin, or an oily, for example olive, peanut or paraffin oil, diluent.
  • Aqueous suspensions may include suspending agents, e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth or acacia; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
  • suspending agents e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth or acacia
  • oily suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickeners such as e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
  • Water dispersible powders and granules can be admixed with the drugs in admixture with dispersing, wetting and suspending agents e.g. the above, as well as with sweeteners, flavorings and colorants.
  • Emulsions can e.g. Olive, peanut or paraffin oil in addition to emulsifiers, e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
  • emulsifiers e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
  • sterile injectable if necessary short-term, aqueous suspensions, isotonic salt solutions or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents, for example propylene or butylene glycol, and / or solubilizers, for example Tweene ® , Cremophore ⁇ are used or polyvinyl pyrrolidone.
  • hydrophilic polymers such as polyvinylpyrrolidone (PVP) or polyoxyethylene sorbitan (Tween ®) or, especially, glycerol Polyethylenglycolricinoleat (Cremophor ® EL) and after removal of the solvent or residues remaining to be administered as aqueous solutions.
  • PVP polyvinylpyrrolidone
  • Tween ® polyoxyethylene sorbitan
  • glycerol Polyethylenglycolricinoleat Remophor ® EL
  • suitable organic solvents are chloroform or methylene chloride, which are made anhydrous in the usual way before use. It has proven to be expedient to use the hydrophilic polymers in a 5- to 50-, preferably 10- to 35-fold, excess by weight over the complex compound.
  • the aqueous solutions of the coprecipitates are prepared by treating the coprecipitates with water.
  • PVP co-precipitates usually go into solution at room temperature.
  • Coprecipitates with polyoxyethylene sorbitan fatty acid esters or glycerol-polyoxyethylene glycol ricinoleate can advantageously be brought into solution if the coprecipitate and the water are heated to 25 ° to 60 ° C., preferably 30 ° to 40 ° C., before being combined. With the addition of propylene or butylene glycol, the dissolution can also take place at room temperature.
  • Coprecipitates obtained from the complex compounds and hydrophilic polymers, processes for producing these coprecipitates, and aqueous solutions containing these coprecipitates are further objects of the present invention.
  • the active compounds can also be formulated in microencapsulated form with one or more of the stated carriers or additives.
  • the reaction mixture is then refluxed for about one to several hours.
  • the progress of the reaction can be followed by the progressive brightening of the deep red color resulting from the dissolved thioether complex. If the complex compound according to the invention precipitates out during the reaction, it is filtered off hot and the filter cake is washed several times with hot toluene and then with hot n-hexane. If the complex does not precipitate out or is incomplete, the polarity of the reaction mixture is reduced by adding n-heptane, n- ⁇ e ⁇ an or n-pentane until precipitation occurs.
  • Recrystallization can take place from a suitable solvent by carefully lowering the polarity of the solvents. Crystallization takes place at an ambient temperature of 4 ° C (refrigerator). The subsequent drying takes place at a pressure of 70 Pa (0.5 Torr), unless otherwise stated.
  • the ligand is added dissolved in 40 ml of toluene. Response time 22 hours. Precipitation by adding n-heptane. Fall over from methylene chloride by adding n-heptane until permanent turbidity. At 4 ° C, shiny bronze plates separate after several days. Drying at 70 ° C. Yield: 0.12 g (20% of theory). Mp: 235-237 ° C.
  • the red-violet complex is obtained by removing the acetone. Drying at 80 ° C.
  • Reaction mixture by adding about 200 ml of n-heptane. Reprecipitation from methylene chloride, by adding n-pentane until permanent turbidity. After several days at 4 ° C, purple, felt-like crystals precipitate.
  • mice Approximately 4 week old 18 to 20 g female BDF f mice are transferred approximately 2x10 5 or 10 6 P 388 leukemia cells in 0.2 ml of physiological saline intraperitoneally (ip). The leukemia is kept in passage on DBA / 2 mice. The leukemia cells are taken from freshly killed animals immediately before the transplant. The animals are randomized at the top vaccination. 3 to 6 mice are used per dose. The number of control groups (untreated animals) is chosen so that it corresponds approximately to the square number of the total number of groups in more extensive experiments.
  • the substances are as xx ⁇ rige solutions necessary injected intraperitoneally appropriate with the aid of L ⁇ sungsvermittschreib, for example, Tween ® (polyoxyethylene derivatives of sorbitan esters), first 24 hours after transplantation.
  • the experimental conditions correspond to the P 388 leukemia model of the US National Cancer Institute (NCP. (Methods of Development of New Anticancer Drugs, NCI Monography 45, US Department of Health, Education and Wellfare, Public Health Service, March 1977, page 147).
  • the following table summarizes results from the tumor model described under point A.
  • the stated dose was applied once at the beginning of the experiment (day 1) or on days 1, 5 and 9 as indicated.
  • the T / C factor expressed as a percentage, means the percentage increase in the median survival time of the treated animals compared to the median survival time of the untreated control animals.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Les compositions ayant la formule générale (I) B3RuX3, dans laquelle B représente un hétérocycle basique mononucléaire ou polynucléaire contenant un ou plusieurs atomes d'azote et X représente du chlore ou du brome, présentent un effet inhibiteur de tumeurs et peuvent ainsi être utilisées en chimiothérapie pour le traitement du cancer.
PCT/EP1985/000368 1984-07-24 1985-07-24 Compositions de ruthenium a effet inhibiteur de tumeurs Ceased WO1986000804A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CH03592/84-0 1984-07-24
CH03595/84-6 1984-07-24
CH359584 1984-07-24
CH359284 1984-07-24
CH02908/85-3 1985-07-04
CH290885 1985-07-04

Publications (1)

Publication Number Publication Date
WO1986000804A1 true WO1986000804A1 (fr) 1986-02-13

Family

ID=27174011

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1985/000368 Ceased WO1986000804A1 (fr) 1984-07-24 1985-07-24 Compositions de ruthenium a effet inhibiteur de tumeurs

Country Status (2)

Country Link
EP (1) EP0188585A1 (fr)
WO (1) WO1986000804A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005814A1 (fr) * 1993-08-25 1995-03-02 Johnson Matthey Public Limited Company Compositions pharmaceutiques comprenant des complexes metalliques
WO1996013510A1 (fr) * 1994-10-28 1996-05-09 Procept, Inc. Complexes de ruthenium et leur utilisation comme immunosuppresseurs
US5708022A (en) * 1994-10-28 1998-01-13 Procept, Inc. Method for inhibiting immune response
US6750251B2 (en) 1999-10-27 2004-06-15 The University Court, The University Of Edinburgh (Uk) Half-sandwich ruthenium (II) compounds comprising nitrogen containing ligands for treatment of cancer
US6936634B2 (en) 2000-06-30 2005-08-30 The University Court, The University Of Edinburgh (Uk) Ruthenium (II) compounds for use in the therapy of cancer

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
American Chemical Society Symposium Series, Volume 140, 1980, Editor M.J. Comstock (US) M.J. CLARKE: "The Potential of Ruthenium in Anticancer Pharmaceuticals", pages 157-180, see page 174, paragraph 2 to page 178, paragraph 1 (cited in the application) *
Collection of Czechoslovak Chemical Communications, Volume 26, No. 5, Prague (CS) F. KRALIK et al.: "Komplexverbindungen des Rutheniums mit Funfzahligen Heterocyclischen Basen II. Reaktionen des Ruthenium (III)- Chlorids mit Pyrazol und Imidazol", pages 1298-1304, see page 1300, paragraph 1 *
J. Chem. Soc. (A) 1967 J. LEWIS et al.: "The Preparation, Infared Spectra, and Magnetic Properties of some Ruthenium (II), Ruthenium (III), and Osmium (III) Complexes", pages 366-70, see page 1370 paragraphs g to 1 (cited in the application) *
Transition Metal Chemie, Volume 4, No. 2, Verlag Chemie, GmbH Weinhein (DE) S.A.A. ZAIDI et al.: "Studies on Ruthenium (III), Rhodium (III) and Iridium (III) Complexes of Indazoles", pages 133-136, see page 133, "Summary", "Introduction" and table 1 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005814A1 (fr) * 1993-08-25 1995-03-02 Johnson Matthey Public Limited Company Compositions pharmaceutiques comprenant des complexes metalliques
AU698785B2 (en) * 1993-08-25 1998-11-05 Anormed Inc. Pharmaceutical compositions comprising metal complexes
KR100331978B1 (ko) * 1993-08-25 2002-09-26 아노메드 인코포레이티드 금속착체를포함하는의약조성물
WO1996013510A1 (fr) * 1994-10-28 1996-05-09 Procept, Inc. Complexes de ruthenium et leur utilisation comme immunosuppresseurs
US5708022A (en) * 1994-10-28 1998-01-13 Procept, Inc. Method for inhibiting immune response
US6750251B2 (en) 1999-10-27 2004-06-15 The University Court, The University Of Edinburgh (Uk) Half-sandwich ruthenium (II) compounds comprising nitrogen containing ligands for treatment of cancer
US6979681B2 (en) 1999-10-27 2005-12-27 University Court, The University Of Edinburgh Half-sandwich ruthenium (II) compounds comprising nitrogen containing ligands for treatment of cancer
US6936634B2 (en) 2000-06-30 2005-08-30 The University Court, The University Of Edinburgh (Uk) Ruthenium (II) compounds for use in the therapy of cancer

Also Published As

Publication number Publication date
EP0188585A1 (fr) 1986-07-30

Similar Documents

Publication Publication Date Title
DE60006810T2 (de) Dicarboxylato-diamin-platin-derivate und zusammensetzungen die diese als antitumormittel enthalten
EP0191096B1 (fr) Compositions de ruthenium a effet inhibiteur de tumeurs
EP0153636B1 (fr) Sels de métallicénium et leur utilisation comme cytostatiques dans le traitement du cancer
DE10202468A1 (de) Pteridinderivate, Verfahren zu deren Herstellung und ihre Verwendung
EP0202673B1 (fr) Complexes de Titanocène à activité cytostatique
WO1986000804A1 (fr) Compositions de ruthenium a effet inhibiteur de tumeurs
EP0073502B1 (fr) Complexes de métaux ayant une action néoplastique et médicaments les contenant
DE60012750T2 (de) Neue xanthon derivate, deren herstellung und verwendung als arzneimittel
EP0835112B1 (fr) Preparations medicamenteuses contenant des complexes de ruthenium (iii) a action antitumorale
EP0049486B1 (fr) Complexes métalliques pour utilisation dans le traitement du cancer
DE3149710A1 (de) Heterocyclische verbindungen, verfahren zu ihrer herstellung, ihre verwendung und sie enthaltende pharmazeutische zubereitungen
DE1963317A1 (de) Chemische Verfahren und Produkte
EP1678189A2 (fr) Procedure pour la preparation des sels et derivees de trans- et cis-diammoniumdichlorodihydroxyplatine et leur usage pour la preparation des agents pharmaceutique
WO1984003042A1 (fr) Procede pour la fabrication de preparations therapeutiques antineoplastiques
DE19510229A1 (de) Antimikrobiell und antineoplastisch wirkende Bismutverbindungen mit Tropolon-, Thiosemicarbazon- und Dithiocarbazonsäureesterverbindungen und diese enthaltende Arzneimittel
DE10138561B4 (de) Tumorhemmende Cerverbindungen sowie deren Verwendung
DE60004826T2 (de) Dimere ruthenium komplexe für antimetastatische und antineoplastische arzneimittel
DE10116527C2 (de) Tumorhemmende Galliumverbindungen, deren Verwendung als Arzneimittel sowie ein Arzneimittel, diese enthaltend
DE10226592A1 (de) Tumorhemmende Platin(II)-oxalato-Komplexe
DE69219588T2 (de) Oxaza substituierte phosphine
WO2002076993A1 (fr) Composes de silicium d'inhibition tumorale
DE19701692A1 (de) Antineoplastisch wirkende Metallkomplexe und diese enthaltende Arzneimittel
EP1414830A1 (fr) Composes de lanthane inhibiteurs de tumeurs
DE10114106C1 (de) Tumorhemmende Siliciumverbindungen, Verfahren zu ihrer Herstellung und deren Verwendung als Arzneimittel
AT503733A1 (de) Halbsandwich ruthenium(ii)- und osmium(ii) komplexverbindungen, verfahren zu ihrer herstellung und deren verwendung bei der bekämpfung von tumorerkrankungen

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): JP US

AL Designated countries for regional patents

Designated state(s): AT BE CH DE FR GB IT LU NL SE