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WO1984003042A1 - Procede pour la fabrication de preparations therapeutiques antineoplastiques - Google Patents

Procede pour la fabrication de preparations therapeutiques antineoplastiques Download PDF

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Publication number
WO1984003042A1
WO1984003042A1 PCT/EP1983/000031 EP8300031W WO8403042A1 WO 1984003042 A1 WO1984003042 A1 WO 1984003042A1 EP 8300031 W EP8300031 W EP 8300031W WO 8403042 A1 WO8403042 A1 WO 8403042A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
alkyl
titanium
hydrogen
bromine
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/EP1983/000031
Other languages
German (de)
English (en)
Inventor
Heimo J Keller
Bernhard Keppler
Uwe Krueger
Rudolf Linder
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
Priority to HU831172A priority Critical patent/HU199679B/hu
Priority to PCT/EP1983/000031 priority patent/WO1984003042A1/fr
Publication of WO1984003042A1 publication Critical patent/WO1984003042A1/fr
Priority to FI843745A priority patent/FI75171C/fi
Priority to NO844029A priority patent/NO844029L/no
Priority to DK481584A priority patent/DK481584A/da
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages

Definitions

  • the invention relates to a process for the preparation of preparations containing antineoplastic complex compounds.
  • Cisplatin known compound has proven to be an extremely potent anti-tumor agent, particularly in the treatment of testicular tumors, but also e.g. of ovarian tumors and small cell bronchial carcinomas.
  • a disadvantage of cisplatin is its relatively high toxicity. Its nephrotoxicity and its permanent hearing damage are particularly serious. Kidney and hearing damage is diagnosed with considerable frequency after the administration of a single therapeutic dose. In addition to the nephro- and haematotoxic effects, the long-term severe nausea and the associated nausea are particularly unpleasant for the patients.
  • EP-OS 49 486 di halogen bis (1, 3-di ketonato) tin, titanium, zirconium and hafnium compounds are described with antineoplastic activity.
  • R3 is hydrogen or phenyl
  • R4 C1-C18-alkyl, which can be substituted by hydroxy, C1-C3-alkylamine or alkali sulfonato groups, or C5-C8-cycloalkyl, which can be substituted by C1-C5-alkyl groups, hydroxy or alkali sulfonato groups,
  • X is fluorine, chlorine or bromine, m is 0 or 1, but not 0 if R1 is hydrogen
  • n is the number 0 or 1
  • a radical R4 contains an amino group, the hydrohalides of which have an interesting cytostatic activity with a favorable therapeutic range and are suitable for the treatment of cancerous diseases.
  • Hydrohalides are understood to mean hydrochlorides, hydrobromides and hydroiodides, with hydrochlorides being preferred.
  • An alkali sulfonato group is understood to mean an A-SOg radical, where A is an alkali metal. The sodium sulfonate residue is preferred.
  • C1-C3, C1-C4, C1-C5, C1-C8 or C1-C18 alkyl groups are straight-chain or branched alkyl groups with 1 to 3, 1 to 4, 1 to 5, 1 to 8 or 1 up to 18 carbon atoms.
  • AI kylreste with more than ten carbon atoms are preferably unbranched.
  • C1-C3-alkylamine is understood to mean mono- and di-C1-C3-alkylamine, with diethylamine being preferred.
  • C5-C8-cycloalkyl is to be understood as meaning cycloalkyls having five to eight ring carbon atoms, cyclohexyl being preferred.
  • the invention therefore relates to a process for the preparation of antineoplastic preparations, characterized in that
  • R4 is C1-C18-alkyl, which can be substituted by hydroxy, C1-C3-alkylamine or alkali sulfonato groups, or C5-C8-cycloalkyl, which can be substituted by C1-C5-alkyl groups, hydroxy or alkali sulfonato groups, with exclusion of moisture in one inert solvent with a diketone R1 (CH 2 ) m C (O) CHR3C (O) R2, wherein
  • R1 is hydrogen, C1-C8-alkyl or phenyl, which can be mono- or polysubstituted by fluorine, chlorine, bromine, nitro, C1-C4-alkyl, C1-C4-alkoxy or trifluoromethyl
  • R2 C1-C8-alkyl or phenyl, which can be mono- or polysubstituted by fluorine, chlorine, bromine, nitro, C1-C4-alkyl, C1-C4-alkoxy or trifluoromethyl
  • R3 is hydrogen or phenyl
  • m is the number 0 or 1, but not 0 if R1 is the Meaning hydrogen, implements, or
  • M, R1, R2, R3 and m have the meanings given above, and Z represents fluorine, chlorine, bromine or OR4, where R4 has the meanings given above, with an alcohol HOR4 or its
  • Alkaline alcoholate where R4 has the meanings given above, and brings an active ingredient thus obtained into a form suitable for pharmaceutical administration.
  • the preparations are prepared by processes known per se, the complex compounds 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 substance, the active substance content of these mixtures is 0.1 to 99.5, preferably 0.5 to 95 percent by weight of the total mixture.
  • the pharmaceutical preparations according to the invention if they are intended for application to humans, for example, can 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 (s) when administered parenterally in a daily dose of about 0.1 to about 5, preferably 1 to 3 mg / kg body weight, optionally in the form of several, preferably 1 to 3, individual doses Get the results you want.
  • a single dose contains the active ingredient (s) in amounts of about 0.1 to about 5, preferably 1 to 3 mg / kg body weight. Similar doses can be used in oral treatment. 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 above-mentioned amount of active ingredient must be exceeded.
  • the treatment with the medicaments according to the invention can be combined with the administration of other cytostatics with different activity spectra. It can also be expedient to carry out the treatment on the principle of cyclic cytostatic therapy. A break is taken after each treatment. It makes use of the experience that healthy tissue in most organs regenerates faster than malignant tissue.
  • the preparations produced according to the invention are administered primarily intravenously, but also intramuscularly, intraperitoneally, subcutaneously, rectally or orally. External application is also possible. Administration by intravenous injection or intravenous infusion is preferred.
  • the pharmaceutical preparations generally consist of the complex compounds and the non-toxic, pharmaceutically acceptable medicament carriers known to the person skilled in the art, which as an admixture or diluent in solid, semi-solid or liquid form or as a coating agent, for example in the form of a capsule, a table cover, a sachet or another container for which the therapeutically active ingredient is used.
  • Sterile injectable 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 are used for the parenteral use of the medicinal substances. eg Tweene ® , Cremophore ® or polyvinyl pyrrolidone.
  • hydrophilic polymers such as polyvinyl pyrrolidones (PVP), or polyoxyethylene sorbitan fatty esters (Tween ®) or, especially, glycerol Polyethylenglykolricinoleat (Cremophor ® EL) and after removal of the or the residual solvent to be administered as aqueous solutions.
  • PVP polyvinyl pyrrolidones
  • Tween ® polyoxyethylene sorbitan fatty esters
  • glycerol Polyethylenglykolricinoleat Remophor ® EL
  • suitable organic solvents are chloroform or methylene chloride. in question, 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 co-precipitates are prepared by treating the co-precipitates with water.
  • PVP co-precipitates usually go into solution at room temperature.
  • Coprecipitates with polyoxyethylene sorbitan fatty acid esters or glycerol-polyethylene glycol ricinooleate 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.
  • M, R1, R2, R3, R4, X, m and n have the meanings given above, and, if a radical R4 contains an amino group, its hydrohalides, dissolved in an inert organic solvent together with a likewise dissolved hydrophilic polymer to dryness concentrated and the coprecipitate obtained prepared as an aqueous solution.
  • the metal complexes are prepared either by reacting the corresponding metal tetraalcoholate with the corresponding diketone in a molar ratio of 1: 2 [A.Yamamoto, S.Kambara, J.Am.Chem.Soc. 79, 4344 (1957)] or by reacting the corresponding dihalobis
  • a base When reacting a dihalobis (diketonato) metal (IV) complex with an alcohol, it is advantageous to work in the presence of a base.
  • Ammonia which is passed through the reaction mixture is advantageously used as the base.
  • the ammonium haiogenide formed is only slightly soluble in the solvents used and can be separated off by filtration and / or centrifugation. Residues of the ammonium halide can be removed from the end product by sublimation in a high vacuum.
  • the alcoholato groups of the alcoholato-diketone atom metal (IV) complexes can be exchanged for other alcoholato groups [UBSaxena et al., J.Chem.Soc. A 1970, 904; D, M, Puri, RCMehrotra, J.Indian Chem. Soc. 39; 499 (1962)].
  • the alcoholato-diketone atom metal (IV), the alcoholato groups of which are to be exchanged, is heated as such or in a suitable solvent together with an alcohol, which is preferably used in excess.
  • This method is particularly suitable for replacing a low alcoholate anion with the alcoholate anion of a higher alcohol.
  • the exchange can be promoted by distilling off the alcohol released as an azeotrope is gated.
  • the reactions are expediently carried out in a dry protective gas atmosphere, preferably nitrogen atmosphere, and using anhydrous starting materials and, if appropriate, carefully dried solvents.
  • the reactions are carried out either without a solvent or in inert solvents, such as, for example, benzene, n-hexane, diethyl ether, methylene chloride or chloroform. It is possible to work without a solvent especially if at least one of the reactants is present as a liquid. If one of the reactants is insoluble in the solvent used, it is presented as a suspension in this solvent and the soluble reactant is added dropwise in solution.
  • solvents such as, for example, benzene, n-hexane, diethyl ether, methylene chloride or chloroform.
  • reaction products are precipitated from the reaction solution either by concentrating and / or cooling and / or by adding precipitating solvents, in particular hexane and petroleum ether.
  • the 1,3-diketones are known or can be prepared by methods known per se. For example, they can be obtained by ester condensation of the corresponding aryl methyl ketone with ethyl acetate or the corresponding aryl acetic acid ethyl ester with sodium amide as the condensing agent (JTAdams, CR Hauser, J.Amer.Chem.Soc. 66, 1220 [1944]). It is also possible to obtain the 1,3-diketones by adding the corresponding aryl methyl ketone, dissolved in ethyl acetate, to a suspension of sodium in benzene or toluene (DW Brown, SF Dyke, M. Sainsbury, G. Hardy, J.
  • a solution of the coprecipitate in physiological saline is prepared particularly advantageously by injecting the coprecipitate, which has been preheated in a syringe to 40 ° C., into a physiological saline solution (0.9% aqueous sodium chloride solution) which has also been preheated to 40 ° C.
  • mice Approximately 6 week old 18 to 20 g NMRI female mice are each transferred approximately 10 sarcoma 180 tumor cells intraperitoneally (ip) in 0.2 ml of physiological saline. The tumor is kept in passage on the same mouse strain. The tumor cells are taken from freshly killed animals immediately before the transplant. When vaccinated, the animals are randomized. 6 mice are used per dose. The number of control groups (untreated animals) is chosen so that it corresponds approximately to the number of squares from the total number of groups. The substances are injected intraperitoneally as suspensions in typical solubilizers, such as Tween ® (polyoxyethylene derivatives of sorbitan esters), 24 hours after the transplantation.
  • solubilizers such as Tween ® (polyoxyethylene derivatives of sorbitan esters)
  • NMRI mice as under 1. are each subcutaneously (approx. 20 ⁇ 10 sarcoma 180 tumor cells in 0.2 ml of physiological saline solution (s.c.)). Therapy is started with a median tumor weight of 0.5 g, which is reached after about 8 days under the given test conditions.
  • the metal complexes are administered as co-precipitate solutions in physiological saline twice a week into the tail vein.
  • the tumor weight is estimated during the experiment in the usual way by palpating and comparing it with standardized kneading balls.
  • NMRI mice as under 1. are transferred intraperitoneally on day 0 of 10 Ehrlich ascites tumor cells in 0.2 ml of physiological saline.
  • the metal complexes are administered intraperitoneally as solutions of coprecipites in physiological saline.
  • the animals are sacrificed and the Ehrlich ascites tumor cells are counted. Three animals are used per group.
  • Results from the sarcoma 180 tumor model described under point A 1 are summarized in Table I below.
  • the indicated dose was applied once at the beginning of the experiment as indicated.
  • the factor T / C given in percent means the percentage increase in the median survival time of the treated animals compared to the median survival time of the untreated control animals.
  • the experiment is stopped as soon as the median survival time T / C of the treated animals has reached 300% of the median survival time of the untreated animals.
  • the comparative compound cisplatin has a therapeutic effect in a dose range of approximately 8 to 10 mg / kg and the animals are largely cured.
  • the median survival time of the animals treated with cisplatin already becomes smaller at a dose of about 20 mg / kg than that of the untreated control animals.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Les composés complexes de formule (I) dans laquelle M est le titane, le zirconium ou l'hafnium, R1 représente l'hydrogène, alkyl en C1-C8 ou phényl, pouvant être substitué une ou plusieurs fois par le fluor, le chlore, le brome, un groupe nitro, alcoxy en C1-C4 ou trifluorométhyl, R2 est alkyl en C1-C8 ou phényl, pouvant être substitué une ou plusieurs fois par le fluor, le chlore, le brome, un groupe nitro, alkyl en C1-C4, alcoxy en C1-C4 ou trifluorométhyl, R3 est l'hydrogène ou phényl, R4 est alkyl en C1-C18, substitué ou non par hydroxy, alkylamine en C1-C3 ou des groupes sulfonates alcalins ou cycloalkyle en C5-C8, substitué ou non par des groupes alkyles en C1-C5, hydroxy ou sulfonates alcalins. X est le fluor, le chlore ou le brome, m est 0 ou 1 mais n'est pas 0 lorsque R1 représente l'hydrogène et n est 0 ou 1, et pour autant que le reste R4 renferme un groupe amino, leurs hydrohalogénures montrent une bonne activité cytostatique avec faible toxicité.
PCT/EP1983/000031 1983-02-09 1983-02-09 Procede pour la fabrication de preparations therapeutiques antineoplastiques Ceased WO1984003042A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
HU831172A HU199679B (en) 1983-02-09 1983-02-09 Process for producing new complex compounds and antineoplastic compositions containing them
PCT/EP1983/000031 WO1984003042A1 (fr) 1983-02-09 1983-02-09 Procede pour la fabrication de preparations therapeutiques antineoplastiques
FI843745A FI75171C (fi) 1983-02-09 1984-09-24 Foerfarande foer framstaellning av vid behandling av kancersjukdomar anvaendbara samutfaellningar.
NO844029A NO844029L (no) 1983-02-09 1984-10-08 Fremgangsmaate ved fremstilling av antineoplastisk virkende preparater
DK481584A DK481584A (da) 1983-02-09 1984-10-08 Fremgangsmaade til fremstilling af antineoplastisk virkende praeparater

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1983/000031 WO1984003042A1 (fr) 1983-02-09 1983-02-09 Procede pour la fabrication de preparations therapeutiques antineoplastiques

Publications (1)

Publication Number Publication Date
WO1984003042A1 true WO1984003042A1 (fr) 1984-08-16

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PCT/EP1983/000031 Ceased WO1984003042A1 (fr) 1983-02-09 1983-02-09 Procede pour la fabrication de preparations therapeutiques antineoplastiques

Country Status (5)

Country Link
DK (1) DK481584A (fr)
FI (1) FI75171C (fr)
HU (1) HU199679B (fr)
NO (1) NO844029L (fr)
WO (1) WO1984003042A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2344820B (en) * 1997-05-14 2002-05-08 Secr Defence Chemical vapour deposition precursors
WO2003014134A1 (fr) * 2001-08-07 2003-02-20 Inorgtech Limited Precurseurs pour depot chimique en phase vapeur a partir de precurseur organometalliques
US6562990B1 (en) 2002-07-03 2003-05-13 E. I. Du Pont De Nemours And Company Titanium chelates and processes therefor
EP2322690A2 (fr) 2009-10-23 2011-05-18 Air Products And Chemicals, Inc. Précurseurs métalliques du groupe 4 et films contenant du métal
EP2322530A2 (fr) 2009-10-23 2011-05-18 Air Products And Chemicals, Inc. Précurseurs métalliques du groupe 4 et films contenant du métal
US8471049B2 (en) 2008-12-10 2013-06-25 Air Product And Chemicals, Inc. Precursors for depositing group 4 metal-containing films
CN116262764A (zh) * 2021-12-14 2023-06-16 蔡易州 新型钛催化剂、其用途以及聚酯树酯的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0073502A1 (fr) * 1981-09-02 1983-03-09 Byk Gulden Lomberg Chemische Fabrik GmbH Complexes de métaux ayant une action néoplastique et médicaments les contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0073502A1 (fr) * 1981-09-02 1983-03-09 Byk Gulden Lomberg Chemische Fabrik GmbH Complexes de métaux ayant une action néoplastique et médicaments les contenant

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2344820B (en) * 1997-05-14 2002-05-08 Secr Defence Chemical vapour deposition precursors
WO2003014134A1 (fr) * 2001-08-07 2003-02-20 Inorgtech Limited Precurseurs pour depot chimique en phase vapeur a partir de precurseur organometalliques
US6562990B1 (en) 2002-07-03 2003-05-13 E. I. Du Pont De Nemours And Company Titanium chelates and processes therefor
US8471049B2 (en) 2008-12-10 2013-06-25 Air Product And Chemicals, Inc. Precursors for depositing group 4 metal-containing films
EP2322690A2 (fr) 2009-10-23 2011-05-18 Air Products And Chemicals, Inc. Précurseurs métalliques du groupe 4 et films contenant du métal
EP2322530A2 (fr) 2009-10-23 2011-05-18 Air Products And Chemicals, Inc. Précurseurs métalliques du groupe 4 et films contenant du métal
US8952188B2 (en) 2009-10-23 2015-02-10 Air Products And Chemicals, Inc. Group 4 metal precursors for metal-containing films
CN116262764A (zh) * 2021-12-14 2023-06-16 蔡易州 新型钛催化剂、其用途以及聚酯树酯的制备方法

Also Published As

Publication number Publication date
FI843745A0 (fi) 1984-09-24
HUT33968A (en) 1985-01-28
HU199679B (en) 1990-03-28
NO844029L (no) 1984-10-08
DK481584D0 (da) 1984-10-08
DK481584A (da) 1984-10-08
FI75171C (fi) 1988-05-09
FI843745L (fi) 1984-09-24
FI75171B (fi) 1988-01-29

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