WO2002076993A1 - Tumor-inhibiting silicon compounds - Google Patents
Tumor-inhibiting silicon compounds Download PDFInfo
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- WO2002076993A1 WO2002076993A1 PCT/EP2002/003258 EP0203258W WO02076993A1 WO 2002076993 A1 WO2002076993 A1 WO 2002076993A1 EP 0203258 W EP0203258 W EP 0203258W WO 02076993 A1 WO02076993 A1 WO 02076993A1
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- compound
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- cycloalkyl
- cycloalkenyl
- alkenyl
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- 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
- A61K31/695—Silicon compounds
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- 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 System
- C07F7/02—Silicon compounds
- C07F7/025—Silicon compounds without C-silicon linkages
Definitions
- the present invention relates to silicon compounds and their use as medicaments for the prophylaxis and / or treatment of cancer.
- US-A-5 484 778 describes silicon phthalocyanines with amine ligands on the metal atom and their use for cancer treatment by photosensitization.
- antitumor agents which contain as active ingredient a mixture of organic compounds with amino and silyl groups, in which adriamycin is contained.
- the object of the present invention is to provide compounds for the treatment of cancer which are highly effective.
- z is an integer from 1 to 5;
- X is a halogen, pseudohalogen, the monovalent anion of a physiologically compatible inorganic acid, HC0 3 or R'COO, where R 'Ci - C 10 - aikyl, C 2 - C10 alkenyl, C 2 - C10 alkynyl, C 3 - C 10 cycloalkyl, C 3 - C 10 - cycloalkenyl, is a saturated or unsaturated heterocycle or aryl, which may each be substituted or unsubstituted;
- n is an integer from 1 to 3.
- z is an integer from 1 to 3, in particular 1;
- X is a halogen, pseudohalogen, HC0 3 or R'COO, in which R 'Ci - C 6 alkyl, C 2 - C 6 alkenyl, C 2 - C 6 alkynyl, C 3 - C 6 cycloalkyl, C 3 - C 6 - cycloalkenyl or aryl, each of which may be substituted or unsubstituted;
- n is an integer from 1 to 3, in particular 3.
- R d C ⁇ alkyl, C 2 - C 6 alkenyl, C 5 - C 6 cycloalkyl, C 5 - C 6 cycloalkenyl, aryl or hydrogen;
- X is a halogen or pseudohalogen
- n is an integer from 2 to 3.
- X is chlorine.
- z is very particularly preferably 1 and n is very particularly preferably 3.
- the compound of the general formula (I) is in the following form
- n moles of a compound of the general formula (III) are preferably reacted with about one mole of a compound of the general formula (II), where n has the meaning given above.
- the object of the present invention is achieved by a medicament which contains the compound according to the invention.
- the compound according to the invention can be used, inter alia, for the prophylaxis and / or treatment of cancer.
- the medicament according to the invention is administered primarily intravenously, but also intramuscularly, intraperitoneally, subcutaneously or orally. External application is also possible. Administration by intravenous injection or intravenous infusion is preferred.
- the medicament is produced by methods known per se, the compound according to the invention being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the medicament according to the invention contains pharmaceutical carriers in addition to the active substance, the active substance content of this mixture is 0.1 to 99.5, preferably 0.5 to 95% by weight of the total mixture.
- the medicament according to the invention can be 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 and its active ingredient content corresponds to a fraction or 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, for example in the form of a tablet with a notch.
- the pharmaceuticals according to the invention if they are in unit doses and for applications e.g. are intended for humans, contain about 0.1 to 500 mg, preferably 10 to 200 mg and in particular 50 to 150 mg of active ingredient.
- the active ingredient (s) are administered in a daily dose of 0.1 to 5, preferably 1 to 3 mg / kg of body weight, optionally in the form of several, preferably 1 to 3, single 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 medicament according to the invention can take place 1 to 4 times a day at fixed or varying times, e.g. 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 individuals to be treated, the type and severity of the disease, the type of preparation and administration of the medicinal products, 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 above-mentioned amount of active ingredient has to be exceeded. It may also be useful to administer the medication only once or several days apart.
- the determination of the required optimal dosage and type of application of the active ingredients can be done by any specialist on the basis of his specialist knowledge.
- the pharmaceuticals according to the invention generally consist of Compounds according to the invention and non-toxic, pharmaceutically acceptable pharmaceutical carriers which are used as admixtures or diluents, for example in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a bag or another container for the therapeutically active ingredient ,
- a carrier can serve, for example, as a mediator for the absorption of pharmaceuticals by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.
- Tablets dragees 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; Binder, z; B. 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 designed in such a way that it causes a delayed dissolution and absorption of the pharmaceutical preparation in the gastrointestinal tract, so that, for example, better tolerance, protaction 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 can 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, heptadecaethyleneoxycatanol, polyoxyethylene sorbitol 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
- Dispersing and wetting agents e.g. Polyoxy
- Oily suspensions can contain, for example, peanut, olive, sesame, coconut or paraffin oil and thickeners, such as beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
- Water-dispersible powders and granules may contain the compound of the invention 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, such as Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
- emulsifiers such as Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
- Aqueous solutions can contain preservatives, e.g. Methyl or propyl hydroxybenzoates; Thickener; Flavoring agents; Sweeteners, e.g. Contain sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavorings and colorings.
- preservatives e.g. Methyl or propyl hydroxybenzoates
- Thickener e.g. Methyl or propyl hydroxybenzoates
- Flavoring agents e.g. Contain sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavorings and colorings.
- Sterile injectable, aqueous solutions, isotonic saline solutions or other solutions are used for parenteral use of the medicinal substances.
- KP 404 is produced by reacting silicon tetrachloride (SiCI 4 ) with tropolone in chloroform (CHCI 3 ).
- SiCI 4 silicon tetrachloride
- CHCI 3 chloroform
- 3 3.17 g (26.0 mmol) of tropolone are dissolved in 42.6 ml of CHCI 3 per ml (8.7 mmol) of SiCI 4 used, and the SiCI 4 is then added rapidly.
- the precipitated product is refluxed in a strong stream of nitrogen until no further HCl escapes (approx. 3 h), suction filtered and washed with warm CHCI 3 .
- EKVX non-small cell bronchial carcinoma line
- UACC-62 melanoma cell line
- Above-average activity was also observed in individual colon carcinoma and leukemia cell lines.
Abstract
The invention relates to a compound of general formula (I), wherein R represents C1-C15-alkyl, C2-C15-alkenyl, C2-C15-alkinyl, C3-C16-cycloalkyl, C3-C16-cycloalkenyl, aryl or a saturated or unsaturated heterocycle that may in turn be substituted or unsubstituted, or hydrogen; z is a whole number from 1 to 5; X represents halogen, pseudo halogen, the monovalent anion of a physiologically acceptable inorganic acid, HCO3 or R'COO, wherein R' C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkinyl, C3-C10-cycloalkyl, C3-C10-cycloalkenyl may represent a saturated or unsaturated heterocycle or aryl that may in turn be substituted or unsubstituted and n is a whole number from 1 to 3. The invention also relates to the production of said compounds and to their use in the prophylaxis and/or treatment, among other things, of cancer diseases.
Description
Tumorhemmende Siliciumverbindungen Anti-tumor silicon compounds
Die vorliegende Erfindung betrifft Siliciumverbindungen und deren Verwendung als Arzneimittel zur Prophylaxe und/oder Behandlung von Krebserkrankungen.The present invention relates to silicon compounds and their use as medicaments for the prophylaxis and / or treatment of cancer.
In der US-A-4 278 666 werden (Trihydrocarbylsilylmethyloxyimino)alkane und deren Verwendung zur Behandlung von Tumorerkrankungen beschrieben.US Pat. No. 4,278,666 describes (trihydrocarbylsilylmethyloxyimino) alkanes and their use for the treatment of tumor diseases.
Die US-A-5 484 778 beschreibt Silicium-Phthalocyanine mit Amin-Liganden am Metallatom sowie deren Verwendung zur Krebsbehandlung durch Photosensibilisierung.US-A-5 484 778 describes silicon phthalocyanines with amine ligands on the metal atom and their use for cancer treatment by photosensitization.
In der US-A-5 910485 werden Antitumormittel offenbart, die als Wirkstoff eine Mischung organischer Verbindungen mit Amino- und Silyl-Gruppen enthalten, in der Adriamycin enthalten ist.In US-A-5 910485 antitumor agents are disclosed which contain as active ingredient a mixture of organic compounds with amino and silyl groups, in which adriamycin is contained.
Aufgabe der vorliegenden Erfindung ist es, Verbindungen zur Behandlung von Krebserkrankungen zur Verfügung zu stellen, die eine hohe Wirksamkeit aufweisen.The object of the present invention is to provide compounds for the treatment of cancer which are highly effective.
Diese Aufgabe wird gelöst durch eine Verbindung der allgemeinen Formel (I)This object is achieved by a compound of the general formula (I)
R Ci -Ci5 -Alkyl, C2 -C15 -Alkenyl, C2 -C15 -Alkinyl, C3 -Cι6 -Cycloalkyl, C3 - Ciβ -Cycloalkenyl, Aryl oder ein gesättigter oder ungesättigter Heterocyclus, die jeweils substituiert oder unsubstituiert sein können, oder Wasserstoff ist;R Ci -Ci5 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl, C 3 -Cι 6 cycloalkyl, C 3 - Ciβ cycloalkenyl, aryl or a saturated or unsaturated heterocycle, each substituted or may be unsubstituted or is hydrogen;
z eine ganze Zahl von 1 bis 5 ist;
X ein Halogen, Pseudohalogen, das einwertige Anion einer physiologisch verträglichen anorganischen Säure, HC03 oder R'COO, worin R' Ci - C10 - Aikyl, C2 - C10 -Alkenyl, C2 - C10 -Alkinyl, C3 - C10 -Cycloalkyl, C3 - C10 - Cycloalkenyl, ein gesättigter oder ungesättigter Heterocyclus oder Aryl, die jeweils substituiert oder unsubstituiert sein können, ist;z is an integer from 1 to 5; X is a halogen, pseudohalogen, the monovalent anion of a physiologically compatible inorganic acid, HC0 3 or R'COO, where R 'Ci - C 10 - aikyl, C 2 - C10 alkenyl, C 2 - C10 alkynyl, C 3 - C 10 cycloalkyl, C 3 - C 10 - cycloalkenyl, is a saturated or unsaturated heterocycle or aryl, which may each be substituted or unsubstituted;
n eine ganze Zahl von 1 bis 3 ist.n is an integer from 1 to 3.
In einer bevorzugten Ausführungsform istIn a preferred embodiment
R Ci - C10 -Alkyl, C2 - C10 -Alkenyl, C2 - C10 -Alkinyl, C3 - C« -Cycloalkyl, C3 - C10 -Cycloalkenyl, Aryl oder Wasserstoff, insbesondere C3 - C6 - Cycloalkyl;R Ci - C10 alkyl, C 2 - C 10 alkenyl, C 2 - C 10 alkynyl, C 3 - C "cycloalkyl, C 3 - C 10 cycloalkenyl, aryl or hydrogen, in particular C 3 - C 6 - cycloalkyl;
z eine ganze Zahl von 1 bis 3, insbesondere 1 ;z is an integer from 1 to 3, in particular 1;
X ein Halogen, Pseudohalogen, HC03 oder R'COO, worin R' Ci - C6 -Alkyl, C2 - C6 -Alkenyl, C2 - C6 -Alkinyl, C3 - C6 -Cycloalkyl, C3 - C6 - Cycloalkenyl oder Aryl, die jeweils substituiert oder unsubstituiert sein können;X is a halogen, pseudohalogen, HC0 3 or R'COO, in which R 'Ci - C 6 alkyl, C 2 - C 6 alkenyl, C 2 - C 6 alkynyl, C 3 - C 6 cycloalkyl, C 3 - C 6 - cycloalkenyl or aryl, each of which may be substituted or unsubstituted;
n eine ganze Zahl von 1 bis 3, insbesondere 3.n is an integer from 1 to 3, in particular 3.
In einer besonders bevorzugten Ausführungsform istIn a particularly preferred embodiment
R d - Cβ -Alkyl, C2 - C6 -Alkenyl, C5 - C6 -Cycloalkyl, C5 - C6 - Cycloalkenyl, Aryl oder Wasserstoff;R d - Cβ alkyl, C 2 - C 6 alkenyl, C 5 - C 6 cycloalkyl, C 5 - C 6 cycloalkenyl, aryl or hydrogen;
z 1 oder 2;z 1 or 2;
X ein Halogen oder Pseudohalogen;X is a halogen or pseudohalogen;
n eine ganze Zahl von 2 bis 3.n is an integer from 2 to 3.
In einer ganz besonders bevorzugten Ausführungsform ist X Chlor. Weiterhin ist z ganz besonders bevorzugt 1 und n ganz besonders bevorzugt 3.
In einer bevorzugten Ausführungsform liegt die Verbindung der allgemeinen Formel (I) in folgender Form vorIn a very particularly preferred embodiment, X is chlorine. Furthermore, z is very particularly preferably 1 and n is very particularly preferably 3. In a preferred embodiment, the compound of the general formula (I) is in the following form
SiX n x H2OSiX n x H2O
wobei R, X, n und z die vorstehende Bedeutung haben.where R, X, n and z have the above meaning.
Die Aufgabe wird weiterhin durch ein Verfahren zum Herstellen einer Verbindung der allgemeinen Formel (I) gelöst. Darin wird eine Verbindung der allgemeinen Formel (II)The object is further achieved by a process for the preparation of a compound of the general formula (I). A compound of the general formula (II)
SiX4 (II)SiX4 (II)
worin X wie vorstehend definiert ist,where X is as defined above,
mit einer Verbindung der allgemeinen Formel (III)with a compound of the general formula (III)
worin R und z wie vorstehend definiert sind,where R and z are as defined above,
umgesetzt.implemented.
Dabei werden vorzugsweise etwa n Mol einer Verbindung der allgemeinen Formel (III) mit etwa einem Mol einer Verbindung der allgemeinen Formel (II) umgesetzt, wobei n die vorstehend genannte Bedeutung hat.
Ferner wird die Aufgabe der vorliegenden Erfindung durch ein Arzneimittel gelöst, das die erfindungsgemäße Verbindung enthält. Die erfindungsgemäße Verbindung kann unter anderem zur Prophylaxe und/oder Behandlung von Krebserkrankungen eingesetzt werden.About n moles of a compound of the general formula (III) are preferably reacted with about one mole of a compound of the general formula (II), where n has the meaning given above. Furthermore, the object of the present invention is achieved by a medicament which contains the compound according to the invention. The compound according to the invention can be used, inter alia, for the prophylaxis and / or treatment of cancer.
Im folgenden wird das Arzneimittel, enthaltend eine erfindungsgemäße Verbindung, genauer beschrieben.The medicament containing a compound according to the invention is described in more detail below.
Das erfindungsgemäße Arzneimittel wird vor allem intravenös, aber auch intramuskulär, intraperitoneal, subkutan oder peroral verabreicht. Auch eine äußerliche Applikation ist möglich. Bevorzugt ist die Verabreichung durch intravenöse Injektion oder intravenöse Infusion.The medicament according to the invention is administered primarily intravenously, but also intramuscularly, intraperitoneally, subcutaneously or orally. External application is also possible. Administration by intravenous injection or intravenous infusion is preferred.
Das Arzneimittel wird nach an sich bekannten Verfahren hergestellt, wobei die erfindungsgemäße Verbindung als solche oder gegebenenfalls in Kombination mit geeigneten pharmazeutischen Trägerstoffen eingesetzt wird. Enthält das erfindungsgemäße Arzneimittel neben dem Wirkstoff pharmazeutische Trägerstoffe, beträgt der Wirkstoffgehalt dieser Mischung 0,1 bis 99,5, vorzugsweise 0,5 bis 95 Gew.- % der Gesamtmischung.The medicament is produced by methods known per se, the compound according to the invention being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the medicament according to the invention contains pharmaceutical carriers in addition to the active substance, the active substance content of this mixture is 0.1 to 99.5, preferably 0.5 to 95% by weight of the total mixture.
Das erfindungsgemäße Arzneimittel kann in jeder geeigneten Formulierung angewandt werden unter der Voraussetzung, dass die Ausbildung bzw. Aufrechterhaltung von ausreichenden Wirkstoffpegeln gewährleistet ist. Das kann beispielsweise durch orale oder parenterale Gabe in geeigneten Dosen erreicht werden. Vorteilhafterweise liegt die pharmazeutische Zubereitung des Wirkstoffs in Form von Einheitsdosen vor, die auf die gewünschte Verabreichung abgestimmt sind. Eine Einheitsdosis kann zum Beispiel eine Tablette, ein Dragee, eine Kapsel, ein Suppositorium oder eine gemessene Volumenmenge eines Pulvers, eines Granulates, einer Lösung, einer Emulsion oder einer Suspension sein.The medicament according to the invention can be 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.
Unter "Einheitsdosis" im Sinne der vorliegenden Erfindung wird eine physikalisch bestimmte Einheit verstanden, die eine individuelle Menge des aktiven Bestandteils in Kombination mit einem pharmazeutischen Trägerstoff enthält und deren Wirkstoffgehalt
einem Bruchteil oder Vielfachen einer therapeutischen Einzeldosis entspricht. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben, einer drittel oder einer viertel Tagesdosis entspricht. Wenn für eine einzelne therapeutische Verabreichung nur ein Bruchteil, wie die Hälfte oder ein Viertel der Einheitsdosis benötigt wird, ist die Einheitsdosis vorteilhafterweise teilbar, z.B. in Form einer Tablette mit Bruchkerbe.For the purposes of the present invention, “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 and its active ingredient content corresponds to a fraction or 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, for example in the form of a tablet with a notch.
Die erfindungsgemäßen Arzneimittel können, wenn sie in Einheitsdosen vorliegen und für Applikationen z.B. am Menschen bestimmt sind, etwa 0,1 bis 500 mg, bevorzugt 10 bis 200 mg und insbesondere 50 bis 150 mg Wirkstoff enthalten.The pharmaceuticals according to the invention, if they are in unit doses and for applications e.g. are intended for humans, contain about 0.1 to 500 mg, preferably 10 to 200 mg and in particular 50 to 150 mg of active ingredient.
Im allgemeinen werden in der Humanmedizin der oder die Wirkstoffe in einer Tagesdosis von 0,1 bis 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht, gegebenenfalls in Form mehrerer, vorzugsweise 1 bis 3 Einzelgaben zur Erzielung der gewünschten Ergebnisse verabreicht. Eine Einzelgabe enthält den oder die Wirkstoffe in Mengen von 0,1 bis 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht. Bei einer oralen Behandlung können ähnliche Dosierungen zur Anwendung kommen.In general, in human medicine the active ingredient (s) are administered in a daily dose of 0.1 to 5, preferably 1 to 3 mg / kg of body weight, optionally in the form of several, preferably 1 to 3, single 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.
Die therapeutische Verabreichung des erfindungsgemäßen Arzneimittels kann 1 bis 4 mal am Tage zu festgelegten oder variierenden Zeitpunkten erfolgen, z.B. jeweils vor den Mahlzeiten . und/oder am Abend. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art, dem Körpergewicht und dem Alter der zu behandelnden Individuen, der Art und Schwere der Erkrankung, der Art der Zubereitung und der Applikation der Arzneimittel sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der oben genannten Menge Wirkstoff auszukommen, während in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muss. Es kann sich auch als zweckmäßig erweisen, die Arzneimittel nur einmalig oder im Abstand von mehreren Tagen zu verabreichen.The therapeutic administration of the medicament according to the invention can take place 1 to 4 times a day at fixed or varying times, e.g. 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 individuals to be treated, the type and severity of the disease, the type of preparation and administration of the medicinal products, 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 above-mentioned amount of active ingredient has to be exceeded. It may also be useful to administer the medication only once or several days apart.
Die Festlegung der erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens erfolgen.The determination of the required optimal dosage and type of application of the active ingredients can be done by any specialist on the basis of his specialist knowledge.
Die erfindungsgemäßen Arzneimittel bestehen in der Regel aus den
erfindungsgemäßen Verbindungen und nichttoxischen, pharmazeutisch verträglichen Arzneimittelträgern, die als Zumischung oder Verdünnungsmittel, beispielsweise in fester, halbfester oder flüssiger Form oder als Umhüllungsmittel, beispielsweise in Form einer Kapsel, eines Tablettenüberzugs, eines Beutels oder eines anderen Behältnisses für den therapeutisch aktiven Bestandteil in Anwendung kommen. Ein Trägerstoff kann z.B. als Vermittler für die Arzneimittelaufnahme durch den Körper, als Formulierungshilfsmittel, als Süßungsmittel, als Geschmackskorrigens, als Farbstoff oder als Konservierungsmittel dienen.The pharmaceuticals according to the invention generally consist of Compounds according to the invention and non-toxic, pharmaceutically acceptable pharmaceutical carriers which are used as admixtures or diluents, for example in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a bag or another container for the therapeutically active ingredient , A carrier can serve, for example, as a mediator for the absorption of pharmaceuticals by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.
Zur oralen Anwendung können z.B. Tabletten Dragees, harte und weiche Kapseln, z.B. aus Gelatine, dispergierbare Pulver, Granulate, wässrige und ölige Suspensionen, Emulsionen, Lösungen oder Sirupe kommen.For oral use e.g. Tablets dragees, hard and soft capsules, e.g. come from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
Tabletten können inerte Verdünnungsmittel, z.B. Calciumcarbonat, Calciumphosphat, Natriumphosphat oder Laktose; Granulierungs- und Verteilungsmittel, z.B. Maisstärke oder Alginate; Bindemittel, z;B. Stärke, Gelatine oder Akaziengummi; und Gleitmittel, z.B. Aluminium- oder Magnesiumstearat, Talkum oder Silikonöl, enthalten. Sie können zusätzlich mit einem Überzug versehen sein, der auch so beschaffen sein kann, dass er eine verzögerte Auflösung und Resorption der Arzneimittelzubereitung im Gastrointestinaltrakt bewirkt, so dass z.B. eine bessere Verträglichkeit, Protahierung oder Retardierung erreicht wird. Gelatinekapseln können den Arzneistoff vermischt mit einem festen, z.B. Calciumcarbonat oder Kaolin, oder einem öligen, z.B. Oliven-, Erdnuss-, oder Paraffinöl, Verdünnungsmittel enthalten.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; Binder, z; B. 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 designed in such a way that it causes a delayed dissolution and absorption of the pharmaceutical preparation in the gastrointestinal tract, so that, for example, better tolerance, protaction 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.
Wässrige Suspensionen können Suspendiermittel, z.B. Natriumcarboxymethylcellulose, Methylcellulose, Hydroxypropylcellulose, Natriumalginat, Polyvinylpyrrolidon, Traganthgummi oder Akaziengummi; Dispergier- und Benetzungsmittel, z.B. Polyoxyethylenstearat, Heptadecaethylenoxycatanol, Polyoxyethylensorbitolmonooleat oder Lecithin; Konservierungsmittel, z.B. Methyl- oder Propylhydroxybenzoate; Geschmacksmittel; Süßungsmittel, z.B. Saccharose, Laktose, Natriumcyclamat, Dextrose, Invertzuckersirup, enthalten.Aqueous suspensions can 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, heptadecaethyleneoxycatanol, polyoxyethylene sorbitol monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxybenzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
Ölige Suspensionen können z.B. Erdnuss-, Oliven-, Sesam-, Kokos- oder Paraffinöl und Verdickungsmittel, wie z.B. Bienenwachs, Hartparaffin oder Cetylalkohol, enthalten;
ferner Süßungsmittel, Geschmacksmittel und Antioxidantien.Oily suspensions can contain, for example, peanut, olive, sesame, coconut or paraffin oil and thickeners, such as beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
In Wasser dispergierbare Pulver und Granulate können die erfindungsgemäße Verbindung in Mischung mit Dispergier-, Benetzungs- und Suspendiermitteln, z.B. den oben genannten, sowie mit Süßungsmitteln, Geschmacksmitteln und Farbstoffen enthalten.Water-dispersible powders and granules may contain the compound of the invention in admixture with dispersing, wetting and suspending agents, e.g. the above, as well as with sweeteners, flavorings and colorants.
Emulsionen können z.B. Oliven-, Erdnuss-, oder Paraffinöl neben Emulgiermitteln, wie z.B. Akaziengummi, Traganthgummi, Phosphatiden, Sorbitanmonooleat, Polyoxyethylensorbitanmonooleat, und Süßungs- und Geschmacksmittel enthalten.Emulsions can e.g. Olive, peanut, or paraffin oil in addition to emulsifiers, such as Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
Wässrige Lösungen können Konservierungsmittel, z.B. Methyl- oder Propylhydroxybenzoate; Verdickungsmittel; Geschmacksmittel; Süßungsmittel, z.B. Saccharose, Laktose, Natriumcyclamat, Dextrose, Invertzuckersirup, sowie Geschmacksmittel und Farbstoffe enthalten.Aqueous solutions can contain preservatives, e.g. Methyl or propyl hydroxybenzoates; Thickener; Flavoring agents; Sweeteners, e.g. Contain sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup, as well as flavorings and colorings.
Zur parenteralen Anwendung der Arzneistoffe dienen steril injizierbare, wässrige Lösungen, isotonische Salzlösungen oder sonstige Lösungen.Sterile injectable, aqueous solutions, isotonic saline solutions or other solutions are used for parenteral use of the medicinal substances.
Die folgenden Beispiele erläutern die Erfindung.The following examples illustrate the invention.
Beispiel 1example 1
Synthese von Chlorotristropolonatosilicium IV (KP 404)Synthesis of chlorotristropolonatosilicon IV (KP 404)
Beispiel 2Example 2
Tumorhemmende Aktivität von KP 404Anti-tumor activity of KP 404
Im 48 h-Sulforhodamin B-Assay an über 50 humanen Tumorzellinien wurde eine gute Wirksamkeit mit folgenden Kennwerten festgestellt:In the 48 h sulforhodamine B assay on over 50 human tumor cell lines, good efficacy was found with the following parameters:
mittler l≤o; 16,2 μmoJ/ϊ ^ ■* 7,21 μg/m ^ * ^ middle l≤o; 16.2 μmoJ / ϊ ^ ■ * 7.21 μg / m ^ * ^
, '^ \ mittler TGI: \ 57,5 μmoϊ/ϊ ^ 25,6 μg/ml :, mittlere LCS0: 95,5, "μmol/1 ;„ - ^ 42,3 μg/ml . * " - -, '^ \ Mid TGI: \ 57.5 μmoϊ / ϊ ^ 25.6 μ g / ml: LC S0 average: 95.5, "mol / 1;" - ^ 42.3 ug / ml * "-. -
Die stärkste Wirksamkeit wurde an einer nicht-kleinzelligen Bronchialkarzinomlinie (EKVX) und an einer Melanom-Zellinie (UACC-62) beobachtet. Überdurchschnittliche Aktivitäten wurden weiters an einzelnen Kolonkarzinom- und Leukämie-Zellinien beobachtet.
The greatest effectiveness was observed on a non-small cell bronchial carcinoma line (EKVX) and on a melanoma cell line (UACC-62). Above-average activity was also observed in individual colon carcinoma and leukemia cell lines.
Claims
Ansprüche:Expectations:
1. Verbindung der allgemeinen Formel (I)1. Compound of the general formula (I)
woπnembedded image in which
R Ci - C15 Alkyl, C2 - C15 -Alkenyl, C2 - C« -Alkinyl, C3 - Ciβ -Cycloalkyl, C3 - Cιe -Cycloalkenyl, Aryl oder ein gesättigter oder ungesättigter Heterocyclus, die jeweils substituiert oder unsubstituiert sein können, oder Wasserstoff ist;R Ci - C15 alkyl, C 2 - C15 alkenyl, C 2 - C «alkynyl, C 3 - Ciβ-cycloalkyl, C 3 - Cιe cycloalkenyl, aryl or a saturated or unsaturated heterocycle, which can each be substituted or unsubstituted , or is hydrogen;
z eine ganze Zahl von 1 bis 5 ist;z is an integer from 1 to 5;
X ein Halogen, Pseudohalogen, das einwertige Anion einer physiologisch verträglichen anorganischen Säure, HC03 oder R'COO, worin R' Ci - C10 - Alkyl, C2 - C10 -Alkenyl, C2 - C10 -Alkinyl, C3 - C«> -Cycloalkyl, C3 - C10 - Cycloalkenyl, ein gesättigter oder ungesättigter Heterocyclus oder Aryl, die jeweils substituiert oder unsubstituiert sein können, ist;X is a halogen, pseudohalogen, the monovalent anion of a physiologically compatible inorganic acid, HC0 3 or R'COO, where R 'Ci - C 10 alkyl, C 2 - C10 alkenyl, C 2 - C10 alkynyl, C 3 - C Is cycloalkyl, C 3 -C 10 cycloalkenyl, a saturated or unsaturated heterocycle or aryl, each of which may be substituted or unsubstituted;
n eine ganze Zahl von 1 bis 3 ist.n is an integer from 1 to 3.
Verbindung nach Anspruch 1 , worin X Chlor ist.A compound according to claim 1, wherein X is chlorine.
3. Verbindung nach Anspruch 1 oder 2, worin n 3 ist.
3. A compound according to claim 1 or 2, wherein n is 3.
4. Verfahren zum Herstellen einer Verbindung der allgemeinen Formel (I) nach einem der Ansprüche 1 bis 3, wobei eine Verbindung der allgemeinen Formel (II)
4. A process for producing a compound of the general formula (I) according to any one of claims 1 to 3, wherein a compound of the general formula (II)
worin X wie in Anspruch 1 definiert ist, mit einer Verbindung der allgemeinen Formel (III)wherein X is as defined in claim 1, with a compound of general formula (III)
worin R und z wie in Anspruch 1 definiert sind, umgesetzt wird.wherein R and z are as defined in claim 1 is implemented.
5. Arzneimittel, enthaltend mindestens eine Verbindung der allgemeinen Formel (I) nach einem der Ansprüche 1 bis 3.5. Medicament containing at least one compound of general formula (I) according to one of claims 1 to 3.
6. Verwendung einer Verbindung der allgemeinen Formel (I) nach mindestens einem der Ansprüche 1 bis 3 zur Prophylaxe und/oder Behandlung von Krebserkrankungen.6. Use of a compound of general formula (I) according to at least one of claims 1 to 3 for the prophylaxis and / or treatment of cancer.
7. Verwendung einer Verbindung der allgemeinen Formel (I) nach mindestens einem der Ansprüche 1 bis 3 zur Herstellung eines Medikaments zur Prophylaxe und/oder Behandlung von Krebserkrankungen.
7. Use of a compound of general formula (I) according to at least one of claims 1 to 3 for the manufacture of a medicament for the prophylaxis and / or treatment of cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2001114222 DE10114222C1 (en) | 2001-03-23 | 2001-03-23 | Tropolonato-silicon derivatives useful for the prevention and treatment of cancers |
| DE10114222.6 | 2001-03-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002076993A1 true WO2002076993A1 (en) | 2002-10-03 |
Family
ID=7678677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2002/003258 WO2002076993A1 (en) | 2001-03-23 | 2002-03-22 | Tumor-inhibiting silicon compounds |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE10114222C1 (en) |
| WO (1) | WO2002076993A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102012103097A1 (en) | 2012-04-11 | 2013-10-17 | Fluoron Gmbh | Dye useful in kit and medical device used during e.g. cataract surgery for staining e.g. inner ophthalmic membrane, posterior/anterior lens capsule and cornea, and removing ophthalmic membrane, comprises Acid Violet 17 and carrier |
| CN110256504A (en) * | 2019-07-26 | 2019-09-20 | 广西师范大学 | Tropolone and 8-hydroxyquinoline mixture platinum complex and its preparation method and application |
| CN110330533A (en) * | 2019-07-26 | 2019-10-15 | 广西师范大学 | 2- methyl -8-hydroxyquinoline and tropolone mixture platinum complex and its preparation method and application |
| CN110357926A (en) * | 2019-07-26 | 2019-10-22 | 广西师范大学 | Tropolone and phenanthroline mixture manganese complex and its preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0016375A2 (en) * | 1979-03-12 | 1980-10-01 | Shin-Etsu Chemical Co., Ltd. | Novel silicon-containing oxime compounds, a method for their preparation, and anti-tumor agents containing the same |
-
2001
- 2001-03-23 DE DE2001114222 patent/DE10114222C1/en not_active Expired - Fee Related
-
2002
- 2002-03-22 WO PCT/EP2002/003258 patent/WO2002076993A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0016375A2 (en) * | 1979-03-12 | 1980-10-01 | Shin-Etsu Chemical Co., Ltd. | Novel silicon-containing oxime compounds, a method for their preparation, and anti-tumor agents containing the same |
| US4278666A (en) * | 1979-03-12 | 1981-07-14 | Shin-Etsu Chemical Co., Ltd. | Novel organosilicon compounds and anti-transplanted tumor agents containing the same |
Non-Patent Citations (2)
| Title |
|---|
| MUETTERTIES, E.L.; WRIGHT, C.M., J. AM. CHEM. SOC., vol. 86, no. 22, 1964, pages 5132 - 5137, XP002206670 * |
| PEGGS, A.; BOWEN, H., PHYTOCHEMISTRY, vol. 23, no. 8, 1984, pages 1788 - 1789, XP002206669 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102012103097A1 (en) | 2012-04-11 | 2013-10-17 | Fluoron Gmbh | Dye useful in kit and medical device used during e.g. cataract surgery for staining e.g. inner ophthalmic membrane, posterior/anterior lens capsule and cornea, and removing ophthalmic membrane, comprises Acid Violet 17 and carrier |
| CN110256504A (en) * | 2019-07-26 | 2019-09-20 | 广西师范大学 | Tropolone and 8-hydroxyquinoline mixture platinum complex and its preparation method and application |
| CN110330533A (en) * | 2019-07-26 | 2019-10-15 | 广西师范大学 | 2- methyl -8-hydroxyquinoline and tropolone mixture platinum complex and its preparation method and application |
| CN110357926A (en) * | 2019-07-26 | 2019-10-22 | 广西师范大学 | Tropolone and phenanthroline mixture manganese complex and its preparation method and application |
| CN110256504B (en) * | 2019-07-26 | 2021-05-18 | 广西师范大学 | Tropolone and 8-hydroxyquinoline mixed platinum complex and preparation method and application thereof |
| CN110330533B (en) * | 2019-07-26 | 2021-05-28 | 广西师范大学 | 2-methyl-8-hydroxyquinoline and tropolone mixed platinum complex and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE10114222C1 (en) | 2002-05-16 |
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