WO2002076993A1 - Composes de silicium d'inhibition tumorale - Google Patents

Composes de silicium d'inhibition tumorale Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
compound
general formula
cycloalkyl
cycloalkenyl
alkenyl
Prior art date
Application number
PCT/EP2002/003258
Other languages
German (de)
English (en)
Inventor
Bernhard Keppler
Original Assignee
Faustus Forschungs Cie. Translational Cancer Research 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 Faustus Forschungs Cie. Translational Cancer Research Gmbh filed Critical Faustus Forschungs Cie. Translational Cancer Research Gmbh
Publication of WO2002076993A1 publication Critical patent/WO2002076993A1/fr

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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
    • A61K31/695—Silicon 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
    • C07F7/02—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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule générale (I) dans laquelle: R est alkyle en C1-C15, alcényle en C2-C15, alcynyle en C2-C15, cycloalkyle en C3-C16, cycloalcényle en C3-C16, aryle ou un hétérocycle saturé ou insaturé, qui peuvent être substitués ou non substitués, ou hydrogène; z est un nombre entier de 1 à 5; X est un halogène, un pseudohalogène, l'anion monovalent d'un acide inorganique toléré d'un point de vue physiologique, HCO3 ou R'COO, où R' est alkyle en C1-C10, alcényle en C2-C10, alcynyle en C2-C10, cycloalkyle en C3-C10, cycloalcényle en C3-C10, un hétérocycle saturé ou insaturé ou aryle, qui peuvent être substitués ou non substitués; n est un nombre entier de 1 à 3. Cette invention concerne également un procédé permettant la préparation dudit composé et son utilisation pour la prévention et/ou le traitement entre autres de maladies cancéreuses.
PCT/EP2002/003258 2001-03-23 2002-03-22 Composes de silicium d'inhibition tumorale WO2002076993A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10114222.6 2001-03-23
DE2001114222 DE10114222C1 (de) 2001-03-23 2001-03-23 Tumorhemmende Siliciumverbindungen, Verfahren zu ihrer Herstellung und deren Verwendung

Publications (1)

Publication Number Publication Date
WO2002076993A1 true WO2002076993A1 (fr) 2002-10-03

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Country Status (2)

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DE (1) DE10114222C1 (fr)
WO (1) WO2002076993A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102012103097A1 (de) 2012-04-11 2013-10-17 Fluoron Gmbh Färbemittel zum Einfärben einer ophthalmischen Membran
CN110256504A (zh) * 2019-07-26 2019-09-20 广西师范大学 环庚三烯酚酮与8-羟基喹啉混配铂配合物及其制备方法和应用
CN110330533A (zh) * 2019-07-26 2019-10-15 广西师范大学 2-甲基-8-羟基喹啉与托酚酮混配铂配合物及其制备方法和应用
CN110357926A (zh) * 2019-07-26 2019-10-22 广西师范大学 环庚三烯酚酮与邻菲啰啉混配锰配合物及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0016375A2 (fr) * 1979-03-12 1980-10-01 Shin-Etsu Chemical Co., Ltd. Composés d'oxime contenant du silicium, procédé pour leur préparation et agents anti-tumeur les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0016375A2 (fr) * 1979-03-12 1980-10-01 Shin-Etsu Chemical Co., Ltd. Composés d'oxime contenant du silicium, procédé pour leur préparation et agents anti-tumeur les contenant
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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102012103097A1 (de) 2012-04-11 2013-10-17 Fluoron Gmbh Färbemittel zum Einfärben einer ophthalmischen Membran
CN110256504A (zh) * 2019-07-26 2019-09-20 广西师范大学 环庚三烯酚酮与8-羟基喹啉混配铂配合物及其制备方法和应用
CN110330533A (zh) * 2019-07-26 2019-10-15 广西师范大学 2-甲基-8-羟基喹啉与托酚酮混配铂配合物及其制备方法和应用
CN110357926A (zh) * 2019-07-26 2019-10-22 广西师范大学 环庚三烯酚酮与邻菲啰啉混配锰配合物及其制备方法和应用
CN110256504B (zh) * 2019-07-26 2021-05-18 广西师范大学 环庚三烯酚酮与8-羟基喹啉混配铂配合物及其制备方法和应用
CN110330533B (zh) * 2019-07-26 2021-05-28 广西师范大学 2-甲基-8-羟基喹啉与托酚酮混配铂配合物及其制备方法和应用

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Publication number Publication date
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