EP1912652A1 - TREATMENT OF TUMOURS WITH IKK-ß INHIBITORS - Google Patents

TREATMENT OF TUMOURS WITH IKK-ß INHIBITORS

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Publication number
EP1912652A1
EP1912652A1 EP06762748A EP06762748A EP1912652A1 EP 1912652 A1 EP1912652 A1 EP 1912652A1 EP 06762748 A EP06762748 A EP 06762748A EP 06762748 A EP06762748 A EP 06762748A EP 1912652 A1 EP1912652 A1 EP 1912652A1
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Prior art keywords
tumors
treatment
medicaments
compound
formula
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EP06762748A
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German (de)
French (fr)
Inventor
Olaf Weber
Karl Ziegelbauer
Thomas Krahn
Verena Vöhringer
Michael Schön
Margarete SCHÖN
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Bayer AG
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Bayer Healthcare AG
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the application relates to the use of an IKK-beta inhibitor by the preparation of medicaments for the treatment of tumors, as well as medicaments containing this DCK-beta inhibitor.
  • the treatment of tumors of the skin represents a large and, especially concerning the metastatic melanoma, unsatisfactorily solved medical problem.
  • epithelial skin tumors e.g. Basal cell carcinomas and spinozllular carcinomas including their pre-invasive precursors (actinic keratoses or carcinoma in situ).
  • the compound of formula (I) and / or its salts, hydrates and solvates thereby act apoptosis-inducing in the melanoma cell line A375, which is sensitive to various pro-apoptotic stimuli. If in cells which are sensitive to apoptosis in response to pro-apoptotic stimuli, caspases (enzymes which mediate intracellular apoptosis pathways) are blocked with the inhibitor zVAD, the apoptosis induced in these cells by stimulation with CH-I l is suppressed. In contrast, the addition of the compound of formula (I) and / or its salts, hydrates and solvates may re-induce apoptosis, indicating alternative routes of induction of apoptosis.
  • the compound of formula (I) and / or its salts, hydrates and solvates are useful for the treatment of skin tumors, e.g. Basaliomas, spinaliomas, melanomas, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumors and their precursors, in particular actinic keratoses and Bowen's disease, can be used.
  • skin tumors e.g. Basaliomas, spinaliomas, melanomas, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumors and their precursors, in particular actinic keratoses and Bowen's disease.
  • the treatment is preferably systemic and / or topical.
  • a systemic treatment the application of the drug can be made orally with tablets, juices, emulsions, capsules or other pharmaceutical preparations.
  • Systemic treatment may also be parenteral (intravenous, subcutaneous).
  • the topical treatment is carried out by applying the active ingredient in suitable formulations on the affected skin (skin lesion) or in the vicinity of the skin lesions to be treated.
  • the formulations used may be ointments, creams, powders, emulsions, solutions.
  • drug-impregnated patches or dressings may be used.
  • the systemic and / or topical treatment can be carried out according to different time schedules (one-time treatment up to several times a day over a defined period of time).
  • a further subject of the application are combinations of the compound of the formula (I) and / or its salts, hydrates and solvates, with at least one other active substance which can be used for the treatment of tumor diseases, in particular with dacarbacin (DTIC-DOME), doxorubicin ( Doxil), interferons (eg, interferon alfa-2b, intron A), imiquimod (Aldara, R-837, S-26308), resiquimod (R-848, S-28436), interleukin 2 (IL-2, proleukin, aldesleukin ), Retinoids, temozolomide and / or therapeutic melanoma vaccines (eg, prepared or synthetic antigens, or transfected cells) for the treatment of skin tumors.
  • DTIC-DOME dacarbacin
  • Doxil doxorubicin
  • interferons eg, interferon alfa-2b, intron A
  • imiquimod Aldara, R-8
  • Topical treatment of tumors of the genitourinary system e.g. by instillation of a solution or suspension of the compound of formula (I) or other suitable pharmaceutical preparations of the compound of formula (I) (e.g., emulsions, gels) is also possible.
  • a solution or suspension of the compound of formula (I) or other suitable pharmaceutical preparations of the compound of formula (I) e.g., emulsions, gels
  • TopCount Packard
  • A375 cells are plated in a density of 3x10 6 cells and Mel2a cells at a density of 3x10 3 cells in triplets in cell culture dishes and over the period indicated in Figures 3 to 5 with the compound of formula (I) or the corresponding controls, 0.5 ⁇ g / ml of anti-CD-95 (CH-I, Fa. Upstate), 6.6 ⁇ M zVAD (from R & D Systems). The addition takes place 30 minutes before the second substance. Thereafter, the detection of apoptosis with a Cell Death Detection ELISA PLUS (Roche Diagnostics) according to the manufacturer. A375 and Mel2a cells are established melanoma cell lines.
  • Figure 3 Detection of apoptosis in A375 melanoma cells.
  • Substance A induces dose-dependent apoptosis.
  • Positive control The antibody CH-I l stimulates Fas (CD-95) and induces apoptosis.
  • FIG. 4 Mel-2a cells are resistant to Fas stimulation (CD-95).
  • Substance A on the other hand, induced dose-dependent apoptosis in these cells, indicating a receptor-independent mechanism.
  • Figure 5 Inhibition of caspases with the inhibitor zVAD in apoptosis-sensitive (CH-I l) cells. The addition of A triggers the apoptosis inhibited by zVAD.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The application relates to the use of an IKK-beta inhibitor through production of medicaments for treating tumours, and to medicaments comprising the said IKK-beta inhibitor.

Description

Behandlung von Tumoren mit IKK-ß InhibitorenTreatment of tumors with IKK-ß inhibitors
Die Anmeldung betrifft die Verwendung eines IKK-beta Inhibitors durch Herstellung von Arzneimitteln zur Behandlung von Tumoren, sowie Arzneimittel enthaltend diesen DCK-beta Inhibitor.The application relates to the use of an IKK-beta inhibitor by the preparation of medicaments for the treatment of tumors, as well as medicaments containing this DCK-beta inhibitor.
Die Behandlung von Tumorerkrankungen der Haut stellt ein großes und, vor allem das metasta- sierende Melanom betreffend, unbefriedigend gelöstes medizinisches Problem dar.The treatment of tumors of the skin represents a large and, especially concerning the metastatic melanoma, unsatisfactorily solved medical problem.
Dabei sind die weitaus häufigsten Tumoren hellhäutiger Menschen epitheliale Hauttumoren, wie z.B. Basalzellkarzinome und spinozlluläre Karzinome einschließlich ihrer präinvasiven Vorstufen (aktinischen Keratosen bzw. Carcinoma in situ).The most common tumors of fair-skinned humans are epithelial skin tumors, e.g. Basal cell carcinomas and spinozllular carcinomas including their pre-invasive precursors (actinic keratoses or carcinoma in situ).
Während Basaliome und Spinaliome zusammen etwa 15 Prozent aller bösartigen Tumoren ausmachen, tritt das Melanom weit seltener auf. Nach Angaben der Dachdokumentation Krebs im Robert-Koch-Institut traten in Deutschland im Jahr 2000 knapp 11 500 Erkrankungen auf, in den USA lag die geschätzte Zahl der Neuerkrankungen im Jahre 2003 bei etwa 54 000. Die Prognose des metastasierenden Melanoms ist immer noch ungünstig und in der Regel besteht geringe Aussicht auf dauerhafte Heilung.While basaliomas and spinaliomas together account for about 15 percent of all malignant tumors, melanoma occurs much less frequently. According to the Dachdokumentation Krebs in the Robert Koch Institute, almost 11,500 illnesses occurred in Germany in the year 2000, in the USA the estimated number of new cases in 2003 was about 54,000. The prognosis of metastatic melanoma is still unfavorable and There is usually little chance of permanent cure.
Zu den wichtigsten Mechanismen, die für die Malignität von metastasierenden Hauttumoren verantwortlich sind, gehört die Resistenz gegenüber Apoptose (programmierter Zelltod).Among the major mechanisms responsible for the malignancy of metastatic skin tumors is resistance to apoptosis (programmed cell death).
Deshalb sind therapeutische Strategien bzw. Substanzen, die in Tumqrzejlen wieder Apoptose induzieren können, von hervorragender Bedeutung für erfolgreiche Therapien von Tumoren der Haut (l).Therefore, therapeutic strategies, or substances that can re-induce apoptosis in tumors, are of prime importance for successful therapies of tumors of the skin (1).
Aufgabe der Erfindung Untersuchungen war somit die Entwicklung eines neuen, bei tumorösen Hauterkrankungen wirksamen Therapeutikums, das nicht die Nachteile einer systemischen Chemotherapie (z.B. beträchtliche Nebenwirkungen, nur kurzzeitig andauernde klinische Besserung, oft nicht einfache Anwendung) aufweist und das in Krebszellen Apoptose induziert.OBJECT OF THE INVENTION Investigations have thus been the development of a new therapeutic agent for tumorous skin diseases, which does not have the drawbacks of systemic chemotherapy (for example considerable side effects, short-term clinical improvement, often not simple application) and induces apoptosis in cancer cells.
Es wurde nun überraschenderweise gefunden, dass die Verbindung der Formel (I) It has now surprisingly been found that the compound of the formula (I)
und/oder deren Salze, Hydrate und Solvate, welche potente, kompetative und selektive Inhibitoren der UCK-beta Kinase sind, zur Behandlung von Tumoren und ihrer Vorstufen eingesetzt werden können. Bevorzugt ist das Hydrochlorid der Verbindung der Formel (I).and / or their salts, hydrates and solvates, which are potent, competitive and selective inhibitors of UCK-beta kinase, can be used to treat tumors and their precursors. Preferably, the hydrochloride of the compound of formula (I).
Die Verbindung der Formel (I) und/oder deren Salze, Hydrate und Solvate, wirken dabei apoptose- induzierend in der Melanom-Zelllinie A375, die empfindlich auf verschiedene pro-apoptotische Stimuli reagiert. Werden in A375 Zellen, die gegenüber pro-apoptotischen Stimuli empfindlich mit Apoptose reagieren, Caspasen (Enzyme, die intrazelluläre Signalwege der Apoptose vermitteln) mit dem Inhibitor zVAD blockiert, wird die in diesen Zellen durch Stimulation mit CH-I l induzierte Apoptose unterdrückt. Dagegen vermag die Zugabe der Verbindung der Formel (I) und/oder deren Salze, Hydrate und Solvate, die Apoptose wieder auszulösen, was auf alternative Wege der Induktion von Apoptose hinweist.The compound of formula (I) and / or its salts, hydrates and solvates, thereby act apoptosis-inducing in the melanoma cell line A375, which is sensitive to various pro-apoptotic stimuli. If in cells which are sensitive to apoptosis in response to pro-apoptotic stimuli, caspases (enzymes which mediate intracellular apoptosis pathways) are blocked with the inhibitor zVAD, the apoptosis induced in these cells by stimulation with CH-I l is suppressed. In contrast, the addition of the compound of formula (I) and / or its salts, hydrates and solvates may re-induce apoptosis, indicating alternative routes of induction of apoptosis.
Insbesondere wurde gefunden, dass die Verbindung der Formel (I) und/oder deren Salze, Hydrate und Solvate, zur Behandlung von Hauttumoren wie z.B. Basaliome, Spinaliome, Melanome, kutane Manifestationen von T-Zell-Lymphomen, kutane Metastasen anderer Tumore und ihrer Vorstufen, wie insbesondere aktinische Keratosen und Morbus Bowen, eingesetzt werden kann.In particular, it has been found that the compound of formula (I) and / or its salts, hydrates and solvates are useful for the treatment of skin tumors, e.g. Basaliomas, spinaliomas, melanomas, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumors and their precursors, in particular actinic keratoses and Bowen's disease, can be used.
Die Behandlung erfolgt vorzugsweise systemisch und/oder topisch. Bei einer systemischen Behandlung kann die Applikation des Wirkstoffes oral mit Tabletten, Säften, Emulsionen, Kapseln oder anderen pharmazeutischen Zubereitungen erfolgen. Eine systemische Behandlung kann auch parenteral (intravenös, subkutan) erfolgen. Die topische Behandlung erfolgt durch Auftragen des Wirkstoffes in geeigneten Formulierungen auf die befallene Haut (Hautläsion) oder in die Nähe der zu behandelnden Hautläsionen. Die verwendeten Formulierungen können Salben, Cremes, Puder, Emulsionen, Lösungen sein. Darüber hinaus können mit Wirkstoff imprägnierte Pflaster oder Verbände verwendet werden. Die systemische und/oder topische Behandlung kann nach verschiedenen zeitlichen Schemata erfolgen (einmalige Behandlung bis zu mehrfach täglich über einen festgelegten Zeitraum).The treatment is preferably systemic and / or topical. In a systemic treatment, the application of the drug can be made orally with tablets, juices, emulsions, capsules or other pharmaceutical preparations. Systemic treatment may also be parenteral (intravenous, subcutaneous). The topical treatment is carried out by applying the active ingredient in suitable formulations on the affected skin (skin lesion) or in the vicinity of the skin lesions to be treated. The formulations used may be ointments, creams, powders, emulsions, solutions. In addition, drug-impregnated patches or dressings may be used. The systemic and / or topical treatment can be carried out according to different time schedules (one-time treatment up to several times a day over a defined period of time).
Bevorzugt ist die topische Behandlung von Tumoren des Auges und Metastasen anderer Tumoren am Auge sowie von Tumoren des Ohres (und Metastasen anderer Tumoren am Ohr) und von Tumoren der äußeren Genitalien (und Metastasen anderer Tumoren an den äußeren Genitalien) Dies schließt Tumoren, die durch Virusinfektionen hervorgerufen werden (z.B. durch Infektion mit unterschiedlichen Typen des humanen Papillomvirus hervorgerufene Genitalwarzen, Kaposisar- kome der Haut und Schleimhaut, Epidermodysplasia verucciformis oder andere neoplastischen Veränderungen) ein.Preference is given to the topical treatment of tumors of the eye and metastases of other tumors on the eye as well as of tumors of the ear (and metastases of other tumors on the ear) and of Tumors of the external genitalia (and metastases of other tumors on the external genitalia). This includes tumors caused by viral infections (eg genital warts caused by infection with different types of human papilloma virus, skin and mucous capillary cavities, epidermodysplasia verucciformis or other neoplastic changes ) one.
Ein weiterer Gegenstand der Anmeldung sind Kombinationen der Verbindung der Formel (I) und/oder deren Salze, Hydrate und Solvate, mit mindestens einem anderen Wirkstoff, der zur Behandlung von Tumorerkrankungen eingesetzt werden kann, insbesondere mit Dacarbacin (DTIC-DOME), Doxorubicin (Doxil), Interferonen (z.B. Interferon alfa-2b, Intron-A), Imiquimod (Aldara, R-837, S-26308), Resiquimod (R-848, S-28436), Interleukin 2 (IL-2, Proleukin, Aldesleukin), Retinoiden, Temozolomid und/oder therapeutischen Melanom-Vakzinen (z.B. präparierte oder synthetische Antigene, oder transfizierte Zellen), zur Behandlung von Tumorerkrankungen der Haut.A further subject of the application are combinations of the compound of the formula (I) and / or its salts, hydrates and solvates, with at least one other active substance which can be used for the treatment of tumor diseases, in particular with dacarbacin (DTIC-DOME), doxorubicin ( Doxil), interferons (eg, interferon alfa-2b, intron A), imiquimod (Aldara, R-837, S-26308), resiquimod (R-848, S-28436), interleukin 2 (IL-2, proleukin, aldesleukin ), Retinoids, temozolomide and / or therapeutic melanoma vaccines (eg, prepared or synthetic antigens, or transfected cells) for the treatment of skin tumors.
Eine kombinierte Behandlung der Verbindung der Formel (I) und/oder deren Salze, Hydrate und " ""Solvate, mit "Radiotherapien; Bestrahlungstherapie mit sichtbarem Licht, ionisierender Strahlung,- UV-Strahlung, photodynamischer Therapie ist ebenfalls bevorzugt.A combined treatment of the compound of formula (I) and / or its salts, hydrates and "" solvates, with " radiotherapies; Irradiation therapy with visible light, ionizing radiation, UV radiation, photodynamic therapy is also preferred.
Eine topische Behandlung von Tumoren des Urogenitalsystems z.B. durch Instillation einer Lösung oder einer Suspension der Verbindung der Formel(I) oder anderen geeigneten pharmazeutischen Zubereitungen der Verbindung der Formel (I) (z.B. Emulsionen, Gelen) ist ebenfalls möglich.Topical treatment of tumors of the genitourinary system e.g. by instillation of a solution or suspension of the compound of formula (I) or other suitable pharmaceutical preparations of the compound of formula (I) (e.g., emulsions, gels) is also possible.
Die nachfolgenden Beispiele dienen zur Verdeutlichung der Erfindung. The following examples serve to illustrate the invention.
1. IKK-beta- Kinase- Assay:1. IKK Beta Kinase Assay:
1. IKK-beta-Kinase- Assay:1. IKK beta kinase assay:
Die Kinaseaktivität humaner IKK-beta (7 nM) wird bei unterschiedlichen Konzentrationen [Y33P]ATP und GST-IκBα (1-54) Substrat in Gegenwart der Verbindung der Formel (I) = Substanz A gemessen. Dabei werden fixe Konzentrationen von 2 μM GST-IκBα (1-54) (Abbildung 3 A) bzw. 5 μM ATP (Abbildung 3 B) gewählt. Es wird 30 Minuten bei 25 0C inkubuiert, die Reaktion wird anschließend durch Zugabe von EDTA abgestoppt. Mit TCA wird die Reaktion in einer Filterplatte präzipitiert, Microscint PS (Packard) wird zugegeben und die Menge von in GST-IκBα (1-54) inkorporiertes 33P mit einem TopCount (Packard) bestimmt.The kinase activity of human IKK-beta (7 nM) is measured at different concentrations [Y 33 P] ATP and GST-IκBα (1-54) substrate in the presence of the compound of formula (I) = substance A. Fixed concentrations of 2 μM GST-IκBα (1-54) (Figure 3 A) and 5 μM ATP (Figure 3 B) are chosen. It is incubated for 30 minutes at 25 0 C, the reaction is then stopped by addition of EDTA. With TCA, the reaction is precipitated in a filter plate, Microscint PS (Packard) is added and the amount of 33 P incorporated in GST-IκBα (1-54) is determined with a TopCount (Packard).
2. Messung von Apoptoseaktivität in Melanom-Zelllinien2. Measurement of apoptosis activity in melanoma cell lines
A375 Zellen werden in einer Dichte von 3x106 Zellen und Mel2a Zellen in einer Dichte von 3x103 Zellen in Tripletts in Zellkulturschalen ausplattiert und über den in den Abbildungen 3 bis 5 angegebenen Zeitraum mit der Verbindung der Formel (I) oder den entsprechenden Kontrollen, 0.5μg/ml anti-CD-95 (CH-I l, Fa. Upstate), 6.6 μM zVAD (Fa. R&D Systems) inkubiert. Die Zugabe erfolgt 30 Minuten vor der Zweitsubstanz. Danach erfolgt der Apoptosenachweis mit einem Cell Death Detection ELISAPLUS (Fa. Roche Diagnostics) entsprechend den Herstellerangaben. A375 und Mel2a Zellen sind etablierte Melanomzelllinien. A375 cells are plated in a density of 3x10 6 cells and Mel2a cells at a density of 3x10 3 cells in triplets in cell culture dishes and over the period indicated in Figures 3 to 5 with the compound of formula (I) or the corresponding controls, 0.5 μg / ml of anti-CD-95 (CH-I, Fa. Upstate), 6.6 μM zVAD (from R & D Systems). The addition takes place 30 minutes before the second substance. Thereafter, the detection of apoptosis with a Cell Death Detection ELISA PLUS (Roche Diagnostics) according to the manufacturer. A375 and Mel2a cells are established melanoma cell lines.
Apoptoseassay an Melanomzelllinie A375 nach 24h InkubationApoptosis assay on melanoma cell line A375 after 24 h incubation
Kontr. 0,1% 57,88 28,94 13,89 5,78 1,38 0,138 0,00552 CH 110.1% 57.88 28.94 13.89 5.78 1.38 0.138 0.00552 CH 11
DMSODMSO
Bay 65-5811 Konzentration im Inkubatioπsmedium [μM]Bay 65-5811 Concentration in Incubation Medium [μM]
Abbildung 3: Nachweis von Apoptose in A375 Melanomzellen. Substanz A induziert dosisabhängig Apoptose. Positivkontrolle: Der Antikörper CH-I l stimuliert Fas (CD-95) und induziert damit Apoptose. Figure 3: Detection of apoptosis in A375 melanoma cells. Substance A induces dose-dependent apoptosis. Positive control: The antibody CH-I l stimulates Fas (CD-95) and induces apoptosis.
Apoptoseassay an Melanomzellline Mel2a nach 24h InkubationApoptosis assay on melanoma cell line Mel2a after 24h incubation
Kontr. 0,1% 0,2% 57,88 28,94 13,89 5,78 1,38 0,138 0,00552 CH 110.1% 0.2% 57.88 28.94 13.89 5.78 1.38 0.138 0.00552 CH 11
DMSO DMSODMSO DMSO
Bay 65-5811 Konzentration im Inkubationsmedium [μM]Bay 65-5811 concentration in incubation medium [μM]
Abbildung 4: Mel-2a Zellen sind resistent gegen Stimulation von Fas (CD-95). Substanz A dagegen löste in diesen Zellen dosisabhängig Apoptose aus, was auf einen rezeptor-unabhängigen Mechanismus hindeutet. Figure 4: Mel-2a cells are resistant to Fas stimulation (CD-95). Substance A, on the other hand, induced dose-dependent apoptosis in these cells, indicating a receptor-independent mechanism.
Apoptoseassay an Melanomzelllinie A375 nach 12h InkubationApoptosis assay on melanoma cell line A375 after 12 h incubation
Kontr. DMSO 0,2% Z-VAD CHIl Z-VAO+CH11 Z-VAD+28,94 28,94DMSO 0.2% Z-VAD CHIl Z-VAO + CH11 Z-VAD + 28.94 28.94
Bay 65-5811 Konzentration im Inkubatk>πsmeflium[μM]Bay 65-5811 concentration in incubate> πsmeflium [μM]
Abbildung 5: Inhibition von Caspasen mit dem Inhibitor zVAD in apoptosesensitiven (CH-I l) Zellen. Die Zugabe von A löst die Apoptose, die durch zVAD inhibiert wird, wieder aus. Figure 5: Inhibition of caspases with the inhibitor zVAD in apoptosis-sensitive (CH-I l) cells. The addition of A triggers the apoptosis inhibited by zVAD.

Claims

Patentansprüche claims
1. Verwendung der Verbindung der Formel (I)1. Use of the compound of the formula (I)
und/oder deren Salze, Hydrate und Solvate, zur Herstellung von Arzneimitteln zur Behand- lung von Tumoren und ihrer Vorstufen.and / or their salts, hydrates and solvates, for the preparation of medicaments for the treatment of tumors and their precursors.
2. Verwendung gemäß Anspruch 1, zur Behandlung von Hauttumoren und ihrer Vorstufen.2. Use according to claim 1, for the treatment of skin tumors and their precursors.
3. Verwendung gemäß Anspruch 1, zur Herstellung von systemischen Arzneimitteln.3. Use according to claim 1, for the preparation of systemic medicaments.
4. Verwendung gemäß Anspruch 1 , zur Herstellung von topischen Arzneimitteln.4. Use according to claim 1, for the preparation of topical medicaments.
5. Verwendung gemäß Anspruch 1, zur Herstellung von Arzneimitteln zur topischen Behand- lung von Tumoren des Auges und Metastasen anderer Tumoren am Auge, von Tumoren des Ohres und Metastasen anderer Tumoren am Ohr, von Tumoren der äußeren Genitalien und Metastasen anderer Tumoren an den äußeren Genitalien.5. Use according to claim 1, for the preparation of medicaments for the topical treatment of tumors of the eye and metastases of other tumors on the eye, of tumors of the ear and metastases of other tumors on the ear, of tumors of the outer genitalia and metastases of other tumors on the outer Genitals.
6. Arzneimittel zur Behandlung von Tumoren und ihrer Vorstufen enthaltend eine Verbindung der Formel (I)6. Medicaments for the treatment of tumors and their precursors containing a compound of the formula (I)
und/oder deren Salze, Hydrate und Solvate.and / or their salts, hydrates and solvates.
7. Arzneimittel zur Behandlung von Tumoren der Haut und ihrer Vorstufen enthaltend eine7. Medicaments for the treatment of tumors of the skin and their precursors containing a
Verbindung der Formel (I) Compound of the formula (I)
und/oder deren Salze, Hydrate und Solvate.and / or their salts, hydrates and solvates.
8. Arzneimittel enthaltend eine Verbindung der Formel (I) und/oder deren Salze, Hydrate und Solvate, in Kombination mit mindestens einem anderen Wirkstoff der zur Behandlung von Tumorerkrankungen eingesetzt werden kann. 8. Medicaments containing a compound of formula (I) and / or their salts, hydrates and solvates, in combination with at least one other active substance which can be used for the treatment of tumor diseases.
EP06762748A 2005-08-04 2006-07-21 TREATMENT OF TUMOURS WITH IKK-ß INHIBITORS Withdrawn EP1912652A1 (en)

Applications Claiming Priority (2)

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DE102005036655A DE102005036655A1 (en) 2005-08-04 2005-08-04 Treatment of tumors with IKK-ß inhibitors
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JP4272338B2 (en) * 2000-09-22 2009-06-03 バイエル アクチェンゲゼルシャフト Pyridine derivatives
JP2003277383A (en) * 2002-03-14 2003-10-02 Bayer Ag Optically active pyridine derivative and medicine containing the same

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