DE202009007345U1 - New pharmaceuticals and pharmaceutical preparations - Google Patents
New pharmaceuticals and pharmaceutical preparations Download PDFInfo
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- DE202009007345U1 DE202009007345U1 DE202009007345U DE202009007345U DE202009007345U1 DE 202009007345 U1 DE202009007345 U1 DE 202009007345U1 DE 202009007345 U DE202009007345 U DE 202009007345U DE 202009007345 U DE202009007345 U DE 202009007345U DE 202009007345 U1 DE202009007345 U1 DE 202009007345U1
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- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Verbindung der allgemeinen Formel 
R1 ein Wasserstoff-, ein Fluor-, ein Chloratom oder eine Trifluormethylgruppe bedeutet,
R2 ein Wasserstoffatom oder eine C1-C4-Alkylgruppe, die unverzweigt oder verzweigt sein kann, bedeutet,
X eine direkte Bindung oder ein Sauerstoffatom bedeutet,
steht sowie ihre Salze mit physiologisch verträglichen Gegenionen.Compound of the general formula
R 1 represents a hydrogen, a fluorine, a chlorine atom or a trifluoromethyl group,
R 2 represents a hydrogen atom or a C 1 -C 4 -alkyl group which may be unbranched or branched,
X represents a direct bond or an oxygen atom,
and their salts with physiologically compatible counterions.
Description
Die vorliegende Gebrauchsmusteranmeldung betrifft neue Pharmazeutika, auf der Basis neuartiger Kinase-Inhibitoren.The this utility model application relates to new pharmaceuticals, based on novel kinase inhibitors.
Hintergrund und Stand der TechnikBackground and state of the art
Krebserkrankungen sind nach wie vor eine häufige Todesursache von Menschen in den Industrieländern. Allein in Deutschland werden jährlich ca. 395.000 neue Krebserkrankungen diagnostiziert. Die Heilungsrate liegt bei 30–60%. Trotz einer Reihe bekannter Medikamente zur Therapie von Krebs ist festzustellen, dass es eine Reihe von Tumore gibt, die nicht auf Therapeutika ansprechen. Daneben sind die bekannten Therapien durch eine Vielzahl von Nebenwirkungen gekennzeichnet.cancers are still a common cause of death of humans in the industrialized countries. Alone in Germany annually about 395,000 new cancers diagnosed. The cure rate is 30-60%. Despite a number of known drugs For the treatment of cancer is to be noted that there are a number of There are tumors that do not respond to therapeutics. Next to it are the known therapies characterized by a variety of side effects.
Es besteht daher Bedarf an weiteren Krebstherapeutika.It There is therefore a need for further cancer therapeutics.
Beschreibung der ErfindungDescription of the invention
Es
wurde nun gefunden, dass Verbindungen der allgemeinen Formel I 
R1 ein Wasserstoff-, ein Fluor-, ein Chloratom
oder eine Trifluormethylgruppe bedeutet,
R2 ein
Wasserstoffatom oder eine C1-C4-Alkylgruppe,
die unverzweigt oder verzweigt sein kann, bedeutet,
X eine
direkte Bindung oder ein Sauerstoffatom bedeutet,
steht sowie
ihre Salze mit physiologisch verträglichen Gegenionen,
überraschenderweise
hervorragende Eignung als Pharmazeutika, insbesondere als Krebstherapeutika
aufweisen. Diese sind dabei durch ein günstiges Wirkungs-/Nebenwirkungsprofil
gekennzeichnet.It has now been found that compounds of general formula I
R 1 represents a hydrogen, a fluorine, a chlorine atom or a trifluoromethyl group,
R 2 represents a hydrogen atom or a C 1 -C 4 -alkyl group which may be unbranched or branched,
X represents a direct bond or an oxygen atom,
and their salts with physiologically compatible counterions,
surprisingly excellent suitability as pharmaceuticals, especially as cancer therapeutics. These are characterized by a favorable effect / side effect profile.
Die Erfindung beruht auf der Erkenntnis, dass Verbindungen mit der -C-O-(C=O)-N-C oder der -C-O-(C=O)-N-O-C Gruppe einerseits kompetitiv mit natürlichen Liganden binden, aber andererseits nicht verstoffwechselt werden können. Die inhibitorische Wirkung wird also erheblich erhöht. Diese Erkenntnis liegt den in diesem Dokument beschriebenen Verbindungen zugrunde.The Invention is based on the finding that compounds with the -C-O- (C = O) -N-C or the -C-O- (C =O) -N-O-C group on the one hand competitively with natural Ligands bind, but on the other hand, can not be metabolized can. The inhibitory effect is so significant elevated. This finding is as described in this document Based on connections.
Detaillierte Beschreibung der Erfindung und bevorzugte AusführungsformenDetailed description of the invention and preferred embodiments
Bei den erfindungsgemäßen Verbindungen der allgemeinen Formel I handelt es sich um neuartig substituierte Verbindungen.at the compounds of the general Formula I is a novel substituted compound.
Der Rest R1 bedeutet ein Wasserstoffatom, ein Fluoratom, ein Chloratom oder eine Trifluormethylgruppe. Bevorzugt sind das Wasserstoffatom und das Fluoratom.The radical R 1 represents a hydrogen atom, a fluorine atom, a chlorine atom or a trifluoromethyl group. Preferred are the hydrogen atom and the fluorine atom.
Der Rest R2 bedeutet ein Wasserstoffatom oder eine C1-C4-Alkylgruppe, die unverzweigt oder verzweigt sein kann, nämlich eine Methyl-, eine Ethyl-, eine n-Propyl-, eine iso-Propyl, eine n-Butyl, eine iso-Butyl oder eine tert-Butyl-gruppe. Eine Methylgruppe ist dabei bevorzugt.The radical R 2 denotes a hydrogen atom or a C 1 -C 4 -alkyl group which may be unbranched or branched, namely a methyl, an ethyl, an n- propyl, an iso- propyl, a n- butyl, a iso- butyl or a tert-butyl group. A methyl group is preferred.
Die Gruppe X bedeutet eine direkte Bindung oder ein Sauerstoffatom.The Group X represents a direct bond or an oxygen atom.
Die erfindungsgemäßen Verbindungen können durch das Vorhandensein von Asymmetriezentren als Stereoisomere vorliegen. Gegenstand der vorliegenden Erfindung sind alle möglichen Stereoisomere sowohl als Racemate, als auch in enantiomerenreiner Form. Der Begriff Stereoisomere umfaßt auch alle möglichen Diastereomere und Regioisomere und Tautomere (z. B. Keto-Enol-Tautomere), in denen die erfindungsgemäßen Verbindungen vorliegen können, die damit ebenfalls Gegenstand der Erfindung sind.The compounds of the invention may exist as stereoisomers due to the presence of asymmetric centers. The present invention relates to all possible stereoisomers both as racemates, as well as in enantiomerically pure form. The term stereoisomers also includes all possible diastereomers and regioisomers and tautomers (eg, keto-enol tautomers) in which the present invention Compounds may be present, which are thus also the subject of the invention.
Besonders
bevorzugte Ausführungsformen der allgemeinen Formel I sind
nachfolgend abgebildet: 
Verwendungenuses
Die Verbindungen der allgemeinen Formel I sind als Arzneimittel geignet. Besonders geeignet sind sie zur Behandlung von Krebserkrankungen. Dabei kommen sie insbesondere zur Behandlung von hämatologischen oder soliden Tumoren in Betracht, wie z. B. non-Hodgkin Tumoren, von hepatozellulären Karzinomen oder von T-Zell Lypmhomen.The Compounds of general formula I are suitable as medicaments. They are particularly suitable for the treatment of cancer. They come in particular for the treatment of hematological or solid tumors, such. Non-Hodgkin's tumors, of hepatocellular carcinomas or of T-cell lypmhomas.
Die Wirkung der erfindungsgemäßen Verbindungen als Krebstherapeutika ist möglicherweise auf ihre Eignung zur Inhibierung der RAF-Kinase und der VEGF- Kinase zurückzuführen.The Effect of the compounds of the invention as Cancer therapeutics may be appropriate to their suitability Attributed to inhibition of RAF kinase and VEGF kinase.
Die Eignung als Krebstherapeutika ist weiterhin auf die Wirkung dieser Verbindungen auf die Modulation des Zellzyklus, die Modulation der Zelldifferenzierung, der Apoptose und der Angiogenese zurückzuführen.The Suitability as cancer therapeutics is still on the effect of these Compounds on the modulation of the cell cycle, the modulation of Cell differentiation, apoptosis and angiogenesis.
Die Verbindungen der allgemeinen Formel I führen zu einer dosis-abhängigen Hemmung der Koloniebildung im Kolonieassay der Fa. Oncotest (Freiburg). IC50-Werte in 25 verschiedenen Zellkulturlinien (darunter MCF-7, HT-29, BxPC-3, MDA-MB-453, NK1) lagen im Allgemeinen zwischen 4 und 40 μM. Eine herausragend hohe Selektivität wurde beim kleinzelligen Lungenkarzinom (LXFS650) gefunden, gefolgt vom Nierenkarzinommodell (RXF 1393).The compounds of the general formula I lead to a dose-dependent inhibition of colony formation in the colony assay of the company Oncotest (Freiburg). IC 50 values in 25 different cell culture lines (including MCF-7, HT-29, BxPC-3, MDA-MB-453, NK1) were generally between 4 and 40 μM. An outstanding high selectivity was found in small cell lung carcinoma (LXFS650) followed by renal carcinoma model (RXF 1393).
Die Erfindung lehrt daher die Verwendung einer erfindungsgemäßen Verbindung zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung einer oder mehrerer Erkrankungen aus der Gruppe bestehend aus „Krebs, wie Leberkrebs, Lungenkrebs, Leukämie, Nierenkrebs, Eierstockkrebs, Sarkome, Meningiom, Darmkrebs, Lymphknotenkrebs, Hirntumore, Brustkrebs, Pankreaskrebs, Prostatakrebs, Hautkrebs/Melanome, Magen- und Speiseröhrenkrebs, T-Zell-Lymphome, CTLC, aber auch chronische Entzündungen, Asthma, Allergie, Rhinitis, Uveitis, Urticaria, Arthritis, Osteaoarthritis, chronische Polyarthritis, rheumatoide Arthritis, Inflammatory bowel disease, degenerative Gelenkserkrankungen, Erkrankungen des rheumatischen Formenkreises mit Knorpelabbau, Sepsis, Autoimmunerkrankungen, Typ I Diabetes, Hashimoto-Thyreoiditis, Autoimmunthrombozytopenie, Multiple Sklerose, Myasthenia gravis, chronisch entzündliche Darmerkrankungen, Morbus Crohn, Uveitis, Psoriasis, atopische Dermatitits, Kollagenosen, Goodpasture-Syndrom, Erkrankungen mit gestörter Leukozyten-Adhäsion, Cachexie, Erkrankungen durch erhöhte TNFalpha Konzentration, Diabetes, Adipositas, bakterielle Infektionen, insbesondere mit resistenten Bakterien, Herzinsuffizienz und der Chronic Cardiac Failure (CCF)”. Der Begriff der Behandlung umfasst auch die Prophylaxe. Besonders geeignet sind die Verbindungen der allgemeinen Formel I zur Therapie von neoplastischen Erkrankungen.The Invention therefore teaches the use of an inventive Compound for the preparation of a pharmaceutical composition for the treatment of one or more diseases from the group cancer, such as liver cancer, lung cancer, leukemia, Kidney cancer, ovarian cancer, sarcoma, meningioma, colorectal cancer, lymph node cancer, Brain tumors, breast cancer, pancreatic cancer, prostate cancer, skin cancer / melanoma, Gastric and esophageal cancer, T-cell lymphoma, CTLC, but also chronic inflammation, asthma, allergy, rhinitis, Uveitis, urticaria, arthritis, osteoarthritis, chronic polyarthritis, Rheumatoid arthritis, Inflammatory bowel disease, degenerative Joint diseases, diseases of the rheumatic type with cartilage degradation, sepsis, autoimmune diseases, type I diabetes, Hashimoto's thyroiditis, autoimmune thrombocytopenia, multiple sclerosis, Myasthenia gravis, chronic inflammatory bowel disease, Crohn's disease, uveitis, psoriasis, atopic dermatitis, collagenosis, Goodpasture syndrome, disorders with impaired leucocyte adhesion, Cachexia, diseases due to increased TNFalpha concentration, diabetes, Obesity, bacterial infections, especially with resistant Bacteria, Heart Failure and the Chronic Cardiac Failure (CCF) ". The term treatment also includes prophylaxis. Especially the compounds of general formula I are suitable for therapy of neoplastic diseases.
Formulierungenformulations
Die vorliegende Erfindung lehrt eine pharmazeutische Zusammensetzung enthaltend mindestens eine erfindungsgemäße Verbindung. Optional können ein oder mehrere physiologisch verträgliche Hilfsstoffe und/oder Trägerstoffe mit der Verbindung gemischt und die Mischung galenisch zur lokalen oder systemischen Gabe, insbesondere oral, parenteral, zur Infusion, zur Injektion hergerichtet sein. Die Auswahl der Zusatz- und/oder Hilfsstoffe wird von der gewählten Darreichungsform abhängen. Die galenische Herrichtung der erfindungsgemäßen pharmazeutischen Zusammensetzung erfolgt in fachüblicher Weise. Aminogruppenhaltige verbindungen können auch in Form eines Ammoniumsalzes vorliegen, z. B. als Chlorid, Bromid, Mesylat, Tosylat, Oxalat, Orotat, Maleat, Fumarat oder als Tartrat. Geeignete feste oder flüssige galenische Zubereitungsformen sind beispielsweise Granulate, Pulver, Dragees, Tabletten, Mikrokapseln, Suppositorien, Sirupe, Säfte, Suspensionen, Emulsionen, Tropfen oder Lösungen zur Injektion (i. v., i. p., i. m., s. c.) oder Vernebelung (Aerosole), Zubereitungsformen zur Trockenpulverinhalation, transdermale Systeme sowie Präparate mit retardierter Wirkstofffreigabe, bei deren Herstellung übliche Hilfsmittel wie Trägerstoffe, Spreng-, Binde-, Überzugs-, Quellungs-, Gleit- oder Schmiermittel, Geschmacksstoffe, Süßungsmittel und Lösungsvermittler Verwendung finden. Als Hilfsstoffe seien beispielsweise Magnesiumkarbonat, Titandioxyd, Laktose, Mannit und andere Zucker, Talkum, Milcheiweiß, Gelatine, Stärke, Zellulose und ihre Derivate, tierische und pflanzliche Öle wie Lebertran, Sonnenblumen-, Erdnuss- oder Sesamöl, Polyethylenglykole und Lösungsmittel wie etwa steriles Wasser und ein- oder mehrwertige Alkohole, beispielsweise Glyzerin genannt.The The present invention teaches a pharmaceutical composition containing at least one compound of the invention. Optionally, one or more physiologically acceptable Adjuvants and / or carriers mixed with the compound and the mixture is galenic for local or systemic administration, in particular oral, parenteral, for infusion, for injection. The choice of additives and / or auxiliaries is chosen by the selected Depend on dosage form. The galenic preparation of the inventive pharmaceutical composition takes place in the usual way. Amino-containing compounds may also be in the form of an ammonium salt, for. As chloride, bromide, mesylate, tosylate, oxalate, orotate, maleate, Fumarate or as tartrate. Suitable solid or liquid galenic preparations are, for example, granules, powders, Dragees, tablets, microcapsules, suppositories, syrups, juices, suspensions, Emulsions, drops or solutions for injection (i. i. p., i. m., s. c.) Or nebulization (aerosols), Formulations for dry powder inhalation, transdermal systems and preparations with retarded release of active ingredient, in their preparation usual Aids such as carriers, blasting, binding, coating, Swelling, lubricants or lubricants, flavorings, sweeteners and solubilizers use. As auxiliaries For example, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, Cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and on or Polyhydric alcohols, for example, called glycerol.
Eine erfindungsgemäße pharmazeutische Zusammensetzung ist dadurch herstellbar, dass mindestens eine erfindungsgemäß verwendete Substanzkombination in definierter Dosis mit einem pharmazeutisch geeigneten und physiologisch verträglichen Träger und ggf. weiteren geeigneten Wirk-, Zusatz- oder Hilfsstoffen mit definierter Dosis gemischt und zu der gewünschten Darreichungsform hergerichtet ist.A inventive pharmaceutical composition is producible by at least one used according to the invention Substance combination in a defined dose with a pharmaceutically suitable and physiologically acceptable carriers and optionally other suitable active ingredients, additives or excipients with defined Dose mixed and to the desired dosage form is prepared.
Als Verdünnungsmittel kommen Polyglykole, Ethanol, Wasser und Pufferlösungen in Frage. Geeignete Puffersubstanzen sind beispielsweise N,N-Dibenzylethylendiamin, Diethanolamin, Ethylendiamin, N-Methylglukamin, N-Benzylphenethylamin, Diethylamin, Phosphat, Natriumbikarbonat und Natriumkarbonat. Es kann aber auch ohne Verdünnungsmittel gearbeitet werden.When Diluents include polyglycols, ethanol, water and Buffer solutions in question. Suitable buffer substances are for example N, N-dibenzylethylenediamine, diethanolamine, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, diethylamine, phosphate, Sodium bicarbonate and sodium carbonate. But it can also be without a diluent to be worked.
Vorzugsweise wird die pharmazeutische Zusammensetzung in Dosierungseinheiten herstellt und verabreicht, wobei jede Einheit als aktiven Bestandteil eine definierte Dosis der erfindungsgemäßen Verbindung gemäß Formel I enthält. Bei festen Dosierungseinheiten wie Tabletten, Kapseln, Dragees oder Suppositorien kann diese Dosis 0,1–1.000 mg, bevorzugt 10–50 mg, und bei Injektionslösungen in Ampullenform 0,01–1.000 mg, vorzugsweise 10–40 mg, betragen.Preferably the pharmaceutical composition is in dosage units and administered, each unit as an active ingredient a defined dose of the compound of the invention according to formula I contains. For solid dosage units such as tablets, Capsules, dragees or suppositories can dose this 0.1-1000 mg, preferably 10-50 mg, and for injection solutions in the form of ampoules 0.01-1000 mg, preferably 10-40 mg.
Für die klinische Anwendung ist die Herstellung von Infusionslösungen eine weitere bevorzugte Ausführungsform.For the clinical application is the production of infusion solutions another preferred embodiment.
Für die Behandlung eines Erwachsenen, 50–100 kg schweren, beispielsweise 70 kg schweren, Patienten sind beispielsweise Tagesdosen von 0,1–1.000 mg Wirkstoff, vorzugsweise 10–50 mg, indiziert. Unter Umständen können jedoch auch höhere oder niedrigere Tagesdosen angebracht sein. Die Verabreichung der Tagesdosis kann sowohl durch Einmalgabe in Form einer einzelnen Dosierungseinheit oder aber mehrerer kleinerer Dosierungseinheiten als auch durch Mehrfachgabe unterteilter Dosen in bestimmten Intervallen erfolgen.For example, for the treatment of an adult, patients weighing 50-100 kg, for example 70 kg, daily doses of 0.1-1,000 mg active substance, preferably 10-50 mg, are indicated. However, higher or lower daily doses may be appropriate. The administration of the Daily dose can be done by single dose in the form of a single dosage unit or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
Die erfindungsgemäßen Zubereitungen können beispielsweise wie folgt hergestellt werden:The Preparations according to the invention can For example, be prepared as follows:
Dragees (mit 75 mg Wirksubstanz)Dragees (with 75 mg active substance)
1 Drageekern enthält:
- • Wirksubstanz 75,0 mg
- • Calciumphosphat 93,0 mg
- • Maisstärke 35,5 mg
- • Polyvinylpyrrolidon 10,0 mg
- • Hydroxypropylmethylcellulose 15,0 mg
- • Magnesiumstearat 1,5 mg
- • Active substance 75.0 mg
- • Calcium phosphate 93.0 mg
- • corn starch 35.5 mg
- Polyvinylpyrrolidone 10.0 mg
- • hydroxypropylmethylcellulose 15.0 mg
- • Magnesium stearate 1.5 mg
Herstellung:production:
Die
Wirksubstanz wird mit Calciumphosphat, Maisstärke, Polyvinylpyrrolidon,
Hydroxypropylmethylcellulose und der Hälfte der angegebenen
Menge Magnesium stearat gemischt. Auf einer Tablettiermaschine werden
Preßlinge mit einem Durchmesser von ca. 13 mm hergestellt,
diese werden auf einer geeigneten Maschine durch ein Sieb mit 1,5
mm – Maschenweite gerieben und mit der restlichen Menge
Magnesiumstearat vermischt. Dieses Granulat wird auf einer Tablettiermaschine
zu Tabletten mit der gewünschten Form gepreßt.
Kerngewicht:
230 mg
Stempel: 9 mm, gewölbtThe active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On a tableting machine compacts are produced with a diameter of about 13 mm, these are ground on a suitable machine through a sieve with 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.
Core weight: 230 mg
Stamp: 9 mm, curved
Die so hergestellten Drageekerne werden mit einem Film überzogen, der im wesentlichen aus Hydroxypropylmethylcellulose besteht. Die fertigen Filmdragees werden mit Bienenwachs geglänzt. Drageegewicht: 245 mg.The coated dragee cores are coated with a film, which consists essentially of hydroxypropylmethylcellulose. The finished film dragees are shone with beeswax. Dragee weight: 245 mg.
Tabletten (mit 100 mg Wirksubstanz)Tablets (with 100 mg active substance)
Zusammensetzung: 1 Tablette enthält:
- • Wirksubstanz 100,0 mg
- • Milchzucker 80,0 mg
- • Maisstärke 34,0 mg
- • Polyvinylpyrrolidon 4,0 mg
- • Magnesiumstearat 2,0 mg
- • Active substance 100.0 mg
- • lactose 80.0 mg
- • corn starch 34.0 mg
- • Polyvinylpyrrolidone 4.0 mg
- • Magnesium stearate 2.0 mg
Herstellungverfahren:Production process:
Wirkstoff,
Milchzucker und Stärke werden gemischt und mit einer wäßrigen
Lösung des Polyvinylpyrrolidons gleichmäßig
befeuchtet. Nach Siebung der feuchten Masse (2,0 mm-Maschenweite)
und Trocknen im Hordentrockenschrank bei 50°C wird erneut
gesiebt (1,5 mm-Maschenweite) und das Schmiermittel zugemischt.
Die preßfertige Mischung wird zu Tabletten verarbeitet.
Tablettengewicht:
220 mg Active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a rack oven at 50 ° C is again sieved (1.5 mm mesh) and the lubricant mixed. The ready-to-use mixture is processed into tablets.
Tablet weight: 220 mg
Tabletten (mit 150 mg Wirksubstanz)Tablets (with 150 mg active substance)
Zusammensetzung:Composition:
1 Tablette enthält:
- • Wirksubstanz 150,0 mg
- • Milchzucker pulv. 89,0 mg
- • Maisstärke 40,0 mg
- • Kolloide Kieselgelsäure 10,0 mg
- • Polyvinylpyrrolidon 10,0 mg
- • Magnesiumstearat 1,0 mg
- • Active substance 150.0 mg
- • lactose powdered 89.0 mg
- • corn starch 40.0 mg
- Colloidal silicic acid 10.0 mg
- Polyvinylpyrrolidone 10.0 mg
- • Magnesium stearate 1.0 mg
Herstellung:production:
Die mit Milchzucker, Maisstärke und Kieselsäure gemischte Wirksubstanz wird mit einer 20%igen wäßrigen Polyvinylpyrrolidonlösung befeuchtet und durch ein Sieb mit 1,5 mm-Maschenweite geschlagen.The mixed with lactose, cornstarch and silicic acid Active substance is mixed with a 20% aqueous solution of polyvinylpyrrolidone moistened and beaten through a sieve with 1.5 mm mesh size.
Das
bei 45°C getrocknete Granulat wird nochmals durch dasselbe
Sieb gerieben und mit der angegebenen Menge Magnesiumstearat gemischt.
Aus der Mischung werden Tabletten gepreßt.
Tablettengewicht:
300 mgThe granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. From the mixture tablets are pressed.
Tablet weight: 300 mg
Hartgelatine-Kapseln (mit 150 mg Wirksubstanz)Hard gelatine capsules (with 150 mg active substance)
1 Kapsel enthält:
- • Wirkstoff 150,0 mg
- • Maisstärke getr. ca. 180,0 mg
- • Milchzucker pulv. ca. 87,0 mg
- • Magnesiumstearat 3,0 mg ca. 420,0 mg
- • Active ingredient 150.0 mg
- • corn starch drink. about 180.0 mg
- • lactose powder approx. 87.0 mg
- • Magnesium stearate 3.0 mg approx. 420.0 mg
Herstellung:production:
Der Wirkstoff wird mit den Hilfsstoffen vermengt, durch ein Sieb von 0,75 mm-Maschenweite gegeben und in einem geeigneten Gerät homogen gemischt.Of the Active substance is mixed with the excipients, through a sieve of 0.75 mm mesh size and in a suitable device homogeneously mixed.
Die
Endmischung wird in Hartgelatine-Kapseln der Größe
1 abgefüllt.
Kapselfüllung: ca. 320 mgThe final mixture is filled into size 1 hard gelatin capsules.
Capsule filling: approx. 320 mg
Suppositorien (mit 150 mg Wirksubstanz)Suppositories (with 150 mg active substance)
1 Zäpfchen enthält:
- • Wirkstoff 150,0 mg
- • Polyethylenglykol 1500 550,0 mg
- • Polyethylenglykol 6000 460,0 mg
- • Polyoxyethylensorbitanmonostearat 840 mg
- • Active ingredient 150.0 mg
- • Polyethylene glycol 1500 550.0 mg
- • polyethylene glycol 6000 460.0 mg
- • Polyoxyethylene sorbitan monostearate 840 mg
Herstellung:production:
Nach dem Aufschmelzen der Suppositorienmasse wird der Wirkstoff darin homogen verteilt und die Schmelze in vorgekühlte Formen gegossen.To the melting of the suppository mass becomes the active ingredient therein homogeneously distributed and the melt in pre-cooled molds cast.
Suspension (mit 50 mg Wirksubstanz)Suspension (with 50 mg active substance)
100 ml Suspension enthalten:
- • Wirkstoff 1,00 g
- • Carboxymethylcellulose-Na-Salz 0,10 g
- • p-Hydroxybenzoesäuremethylester 0,05 g
- • p-Hydroxybenzoesäurepropylester 0,01 g
- • Rohrzucker 10,00 g
- • Glycerin 5,00 g
- • Sorbitlösung 70%ig 20,00 g
- • Aroma 0,30 g
- • Wasser dest. ad 100 ml
- • Active ingredient 1.00 g
- Carboxymethylcellulose Na salt 0.10 g
- P-Hydroxybenzoic acid methyl ester 0.05 g
- P-hydroxybenzoic acid propyl ester 0.01 g
- • cane sugar 10.00 g
- • Glycerine 5.00 g
- • Sorbitol solution 70% 20.00 g
- • Aroma 0.30 g
- • dist. Water. ad 100 ml
Herstellung:production:
Dest. Wasser wird auf 70°C erhitzt. Hierin wird unter Rühren p-Hydroxybenzoesäuremethylester und -propylester sowie Glycerin und Carboxymethylcellulose-Natriumsalz gelöst. Es wird auf Raumtemperatur abgekühlt und unter Rühren der Wirkstoff zugegeben und homogen dispergiert. Nach Zugabe und Lösen des Zuckers, der Sorbitlösung und des Aromas wird die Suspension zur Entlüftung unter Rühren evakuiert.Least. Water is heated to 70 ° C. Herein is stirring p-hydroxybenzoic acid methyl ester and propyl ester and Glycerol and carboxymethylcellulose sodium salt dissolved. It is cooled to room temperature and stirred the active ingredient added and dispersed homogeneously. After adding and Dissolve the sugar, the sorbitol solution and the aroma The suspension is for deaeration with stirring evacuated.
5 ml Suspension enthalten 50 mg Wirkstoff.5 ml of suspension contain 50 mg of active ingredient.
Ampullen (mit 10 mg Wirksubstanz)Ampoules (with 10 mg active substance)
Zusammensetzung:Composition:
- • Wirkstoff 10,0 mg• Active ingredient 10.0 mg
- • 0,01 n Salzsäure s. q.• 0.01 n hydrochloric acid s. q.
- • Aqua bidest ad 2,0 ml• Aqua bidest ad 2.0 ml
Herstellung:production:
Die Wirksubstanz wird in der erforderlichen Menge 0,01 n HCl gelöst, mit Kochsalz isotonisch gestellt, sterilfiltriert und in 2 ml Ampullen abgefüllt.The Active substance is dissolved in the required amount of 0.01N HCl, isotonic with saline, sterile filtered and in 2 ml ampoules bottled.
Ampullen (mit 50 mg Wirksubstanz)Ampoules (with 50 mg active substance)
Zusammensetzung:Composition:
- • Wirkstoff 50,0 mg• Active ingredient 50.0 mg
- • 0,01 n Salzsäure s. q.• 0.01 n hydrochloric acid s. q.
- • Aqua bidest ad 10,0 ml• Aqua bidest ad 10.0 ml
Herstellung:production:
Die Wirksubstanz wird in der erforderlichen Menge 0,01 n HCl gelöst, mit Kochsalz isotonisch gestellt, sterilfiltriert und in 10 ml Ampullen abgefüllt.The Active substance is dissolved in the required amount of 0.01N HCl, isotonic with saline, sterile filtered and in 10 ml ampoules bottled.
Entsprechende Formulierungen sind für die unten genannten Verbindungen der alternativen Ausführungsformen der Formeln VII–XXVI herstellbar.Appropriate Formulations are for the compounds listed below the alternative embodiments of the formulas VII-XXVI produced.
Im Rahmen von pharmazeutischen Zusammensetzungen können erfindungsgemäße Verbindungen mit anderen, per se bekannten Wirkstoffen kombiniert werden. Hierfür kommen beispielsweise in Frage: Aldesleukin, Amifostine, Atrasentan, Bevacizumab, Bexaroten, Bortezomib, Capecitabine, Carboplatin, Chlorambucil, Cisplatin, Cladribine, Cyclophosphamid, Cytamid, Dacarbazin, Docetaxel, Droloxifene, Edrecolomab, Epothilone, Erlotinib, Etoposide, Exemestane, Flavopiridol, Fludarabine, Fluorouracil, Formestane, Fulvestrant, Gefitinib, Gemcitabine, Idarubicin, Irinotecan, Ixabepilone, Lonafarnib, Miltefosine, Mitomycin, Neovastat, Oxaliplatin, Paclitaxel, Pemetrexed, Porfimer, Rapamycin, Rituximab, Sorafenib, Tegafur, Temozolomide, Tipifarnib, Topotecan, Trimetrexate, Vorozole, Vinblastine, und Mischungen von zwei oder mehreren solcher Wirkstoffe. Dabei kann die erfindungsgemäße Verbindung in Rahmen einer einzigen galenischen Herrichtung mit der Wirksubstanz gemischt sein. Es ist aber auch möglich, dass die pharmazeutische Zusammensetzung aus zwei (oder mehr) verschiedenen galenischen Herrichtungen besteht, wobei in einer ersten Herrichtung die erfindungsgemäße Verbindung und in einer zweiten Herrichtung der Wirkstoff enthalten sind. Dabei kann im Rahmen der ersten Herrichtung auch ein von dem Wirkstoff der zweiten Herrichtung verschiedener Wirkstoff eingerichtet sein.in the Frameworks of pharmaceutical compositions can be used according to the invention Compounds combined with other drugs known per se become. For example: Aldesleukin, Amifostine, atrasentan, bevacizumab, bexarotene, bortezomib, capecitabine, Carboplatin, chlorambucil, cisplatin, cladribine, cyclophosphamide, Cytamid, dacarbazine, docetaxel, droloxifene, edrecolomab, epothilone, Erlotinib, etoposide, exemestane, flavopiridol, fludarabine, fluorouracil, Formestane, fulvestrant, gefitinib, gemcitabine, idarubicin, irinotecan, Ixabepilone, Lonafarnib, Miltefosine, Mitomycin, Neovastat, Oxaliplatin, Paclitaxel, pemetrexed, porfimer, rapamycin, rituximab, sorafenib, Tegafur, temozolomide, tipifarnib, topotecan, trimetrexate, vorozole, Vinblastine, and mixtures of two or more such agents. In this case, the compound of the invention in Frame of a single galenic preparation with the active substance be mixed. But it is also possible that the pharmaceutical Composition of two (or more) different galenic preparations consists, wherein in a first preparation, the inventive Compound and included in a second preparation of the active ingredient are. It can in the context of the first preparation also one of the Active ingredient of the second preparation of various active ingredient be.
Herstellungsverfahrenproduction method
Die Herstellung der weiteren erfindungsgemäßen Verbindungen der allgemeinen Formel I erfolgt über die dem Fachmann bekannten Verfahren der organischen Chemie, wobei die Einführung der C-O-N-C Gruppe bevorzugt (aber nicht ausschließlich) durch Umsetzung mit tert.-Butyl-dimethylsilylhydroxylamin (oder dessen Analoga) verläuft.The Preparation of the other compounds of the invention the general formula I is carried out by those skilled in the art known methods of organic chemistry, the introduction of the C-O-N-C group preferred (but not exclusive) by reaction with tert-butyl-dimethylsilylhydroxylamine (or its analogs) runs.
Ausgehend von dieser Vorschrift kann der Fachmann auf dem Gebiet der organischen Chemie die Derivate der allgemeinen Formel I (sowie der weiter unten genannten alternativen Ausführungsformen) in einfacher Weise herstellen.outgoing of this provision, the expert in the field of organic Chemistry the derivatives of the general formula I (as well as the below mentioned alternative embodiments) in simpler Make way.
Die Verwendbarkeit der erfindungsgemäßen Verbindungen in der Therapie von Krebs kann wie folgt untersucht werden:The Usability of the compounds of the invention in the therapy of cancer can be studied as follows:
Proliferationsassayproliferation assay
Kultivierte humane Tumorzellen, beispielsweise hormonunabhängige menschliche Mammakarzinomzellen, MCF7, menschliche nicht-kleinzellige Lungenkarzinomzellen, z. B. DU145, hormonunabhängige menschliche Prostatakarzinomzellen, z. B. ATCC HTB-81 oder MaTu-MDR, können in einer Dichte von ca. 5.000 Zellen pro Messpunkt in 96-Loch Multititerplatten in 200 μl des entsprechenden Wachstumsmediums vorbereitet werden. Nach 24 Stunden können die Zellen einer Platte mit Kristallviolett gefärbt werden, während das Medium der anderen Platten durch frisches Kulturmedium, dem die Testsubstanzen in verschiedenen Konzentrationen (0 μMol, sowie im Bereich 0,01–30 μMol) zugesetzt werden, ersetzt werden. Die Zellen können dann für vier Tage in Anwesenheit der Testsubstanzen inkubiert werden. Die Zellproliferation kann durch Färbung der Zellen mit Kristallviolett bestimmt werden.cultivated human tumor cells, for example hormone-independent human Breast carcinoma cells, MCF7, human non-small cell lung carcinoma cells, z. DU145, hormone independent human prostate carcinoma cells, z. ATCC HTB-81 or MaTu-MDR, can be in one density of about 5,000 cells per measurement point in 96-well multi-well plates prepared in 200 μl of the appropriate growth medium become. After 24 hours, the cells of a plate be colored with crystal violet, while the Medium of the other plates by fresh culture medium, which the Test substances in different concentrations (0 μmol, and in the range 0.01-30 μmol), be replaced. The cells can then be left for four Days are incubated in the presence of the test substances. Cell proliferation can be determined by staining the cells with crystal violet become.
XTT-Test auf mitochondriale Aktivität lebender Zeile.XTT test for mitochondrial activity living line.
Prinzip der Methode:Principle of the method:
Beim XTT-Test wird das gelbe Tetrazoliumsalz XTT (Natrium 3'-[1-(phenylaminocarbonyl)-3,4tetrazolium]-bis(methoxy-6-nitro)benzolsulfonsäure) durch metabolisch aktive Zellen in orange farbenes Formazan umgewandelt (Abspaltung des Tetrazolium-Ringes des XTT). Die Bioreduktion des XTT wird durch den Zusatz von PMS (electron coupling phenazine methosulfate) potentiert. Die Farbintensität korreliert mit den mitochondrialen Dehydrogenase-Aktivitäten und der Anzahl lebender Zellen. Die Quantifizierung der Farbintensität erfolgt spektralphotometrisch mit Hilfe eines ELISA Readers.At the XTT test is the yellow tetrazolium salt XTT (sodium 3 '- [1- (phenylaminocarbonyl) -3,4tetrazolium] bis (methoxy-6-nitro) benzenesulfonic acid) converted into orange colored formazan by metabolically active cells (Cleavage of the tetrazolium ring of the XTT). The bioreduction of the XTT is enhanced by the addition of PMS (electron coupling phenazine methosulfate) potentiated. The color intensity correlates with the mitochondrial Dehydrogenase activities and the number of living cells. The quantification of the color intensity is carried out spectrophotometrically with the help of an ELISA reader.
Etablierung bei ScheBo BiotechEstablishment at ScheBo Biotech
Bei der Etablierung des Verfahrens wurde für jede Zelllinien die optimale Ausgangszellzahl pro well für eine ideale Messung der optischen Dichte ermittelt werden. Zusätzlich wurden für jede Zelllinie Korrelationskurven zwischen der OD und der zugrundeliegenden Zellzahl erstellt. Weiterhin wurde für jede Zelllinie der optimale Zeitpunkt der Substanzzugabe und der Kultivierungszeit ermittelt (siehe Durchführung).at The establishment of the procedure was for each cell lines the optimal starting cell number per well for an ideal Measurement of the optical density can be determined. additionally were for each cell line correlation curves between the OD and the underlying cell number created. Was continued for each cell line the optimal time of substance addition and the cultivation time (see implementation).
Durchführungexecution
In Abhängigkeit von der Zelllinie werden zum Zweitpunkt t0 zwischen 500 und 5000 Zellen in 100 μl Nährmedium pro well einer 96-well-Platte auspassagiert.In Dependence on the cell line becomes the second point t0 between 500 and 5000 cells in 100 μl of nutrient medium per well of a 96-well plate auspassagiert.
Es werden 50 μl Substanz bzw. in den Kontrolle 50 μl Lösungsmittel zugesetzt.It 50 μl of substance or in the control 50 μl Solvent added.
Nach 4 (NK, MCF-7, BxPC-3, WI-38) bzw. nach 6 (MDA-MB-453, HT 29, KB-V1) Kultivierungstagen im Brutschrank werden 75 μl der frisch vorbereiteten XTT-Lösung (1 mg/ml XTT, 0.383 mg/ml PMS: im Verhältnis 1:50) zugesetzt.To 4 (NK, MCF-7, BxPC-3, WI-38) or according to 6 (MDA-MB-453, HT 29, KB-V1) Cultivation days in the incubator are 75 .mu.l fresh prepared XTT solution (1 mg / ml XTT, 0.383 mg / ml PMS: in the ratio 1:50).
Nach einer Inkubationszeit von 3 h im Brutschrank bei 37°C werden die ODs im ELISA Reader bei einer Wellenlänge von 450 nm (Referenz-Wellenlänge 620 nm) gemessen.
- Literatur:
Scudiero, D. et al.: Cancer Res. (1988), 48: 4827–4833
- Literature:
Scudiero, D. et al .: Cancer Res. (1988), 48: 4827-4833
ZITATE ENTHALTEN IN DER BESCHREIBUNGQUOTES INCLUDE IN THE DESCRIPTION
Diese Liste der vom Anmelder aufgeführten Dokumente wurde automatisiert erzeugt und ist ausschließlich zur besseren Information des Lesers aufgenommen. Die Liste ist nicht Bestandteil der deutschen Patent- bzw. Gebrauchsmusteranmeldung. Das DPMA übernimmt keinerlei Haftung für etwaige Fehler oder Auslassungen.This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.
Zitierte Nicht-PatentliteraturCited non-patent literature
- - Scudiero, D. et al.: Cancer Res. (1988), 48: 4827–4833 [0053] Scudiero, D. et al .: Cancer Res. (1988), 48: 4827-4833 [0053]
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011093524A1 (en) * | 2010-01-29 | 2011-08-04 | Otsuka Pharmaceutical Co., Ltd. | Di - substituted pyridine derivatives as anticancers |
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| Title |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011093524A1 (en) * | 2010-01-29 | 2011-08-04 | Otsuka Pharmaceutical Co., Ltd. | Di - substituted pyridine derivatives as anticancers |
| CN102791690A (en) * | 2010-01-29 | 2012-11-21 | 大塚制药株式会社 | Di-substituted pyridine derivatives as anticancers |
| US8722663B2 (en) | 2010-01-29 | 2014-05-13 | Otsuka Pharmaceutical Co., Ltd. | Di-substituted pyridine derivatives as anticancers |
| CN102791690B (en) * | 2010-01-29 | 2015-12-02 | 大塚制药株式会社 | As the disubstituted pyridines derivative of anticarcinogen |
| EA026042B1 (en) * | 2010-01-29 | 2017-02-28 | Оцука Фармасьютикал Ко., Лтд. | Disubstituted pyridine derivatives as anticancers |
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