DE19838506C2 - Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation - Google Patents

Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation

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DE19838506C2
DE19838506C2 DE19838506A DE19838506A DE19838506C2 DE 19838506 C2 DE19838506 C2 DE 19838506C2 DE 19838506 A DE19838506 A DE 19838506A DE 19838506 A DE19838506 A DE 19838506A DE 19838506 C2 DE19838506 C2 DE 19838506C2
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cells
treatment
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compounds
malignant
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DE19838506A1 (en
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Thomas Beckers
Siavosh Mahboobi
Sabine Kuhr
Herwig Pongratz
Alfred Popp
Harald Hufsky
Frank-D Boehmer
Steffen Teller
Andreas Uecker
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Aeterna Zentaris GmbH
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Asta Medica GmbH
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Priority to KR1020007012248A priority patent/KR20010043288A/en
Priority to CNB998058033A priority patent/CN1151127C/en
Priority to ES99927711T priority patent/ES2190221T3/en
Priority to PCT/DE1999/001214 priority patent/WO1999057117A2/en
Priority to HU0102563A priority patent/HUP0102563A3/en
Priority to CA002496859A priority patent/CA2496859A1/en
Priority to SI9930233T priority patent/SI1109785T1/en
Priority to DE59903921T priority patent/DE59903921D1/en
Priority to BR9911017-2A priority patent/BR9911017A/en
Priority to SK1635-2000A priority patent/SK16352000A3/en
Priority to JP2000547087A priority patent/JP2002514572A/en
Priority to CA002330756A priority patent/CA2330756C/en
Priority to PL99346840A priority patent/PL346840A1/en
Priority to TR2000/03206T priority patent/TR200003206T2/en
Priority to AU44975/99A priority patent/AU752464B2/en
Priority to DK99927711T priority patent/DK1109785T3/en
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Priority to HK01109122A priority patent/HK1038354A1/en
Priority to US10/137,653 priority patent/US6812243B2/en
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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Description

Die Erfindung betrifft Tyrosinkinase-Inhibitoren vom Typ der Bis-indolyl- Verbindungen, diese enthaltende Arzneimittel und deren Verwendung zur Behandlung von malignen und anderen, auf pathologischen Zellproliferationen beruhenden Erkrankungen.The invention relates to tyrosine kinase inhibitors of the bis-indolyl type. Compounds, medicaments containing them and their use for Treatment of malignant and other, on pathological cell proliferation based diseases.

Die Aktivierung von Tyrosin-spezifischen Proteinkinasen ist ein Schlüsselereignis für die Stimulation der Teilung tierischer Zellen. Normalerweise erfolgt diese Stimulation durch exogene Faktoren, z. B. Wachstumsfaktoren, wenn die Proliferation eines bestimmten Zelltyps für die Gesamtfunktion eines Gewebes oder Organs erforderlich ist. In Tumoren ist die Zellproliferation ebenfalls mit der Aktivität von Tyrosinkinasen verknüpft. Häufig liegt in Tumorzellen jedoch eine aberrante Aktivität von Kinasen vor, welche durch Überexpression, konstitutiv aktive Kinase-Mutanten oder ektopische Aktivität von Wachstumsfaktoren verursacht ist. Der PDGF-Rezeptor ist einer der Wachstumsfaktoren mit Relevanz für menschliche Tumoren. PDGF stellt eines der Hauptmitogene im Serum dar und liegt in hohen Konzentrationen in Blutplättchen vor. Seine wichtigste Funktion im adulten Organismus ist die Wundheilung. Eine unerwünschte Aktivität des PDGF- Rezeptors ist an der Proliferation von verschiedenen Tumoren, z. B. Gliomen, Glioblastomen, Sarkomen, Mammakarzinomen, Ovarialkarzinomen und Kolonkarzinomen, beteiligt. Eine aberrante Aktivierung des PDGF/PDGF-Rezeptor- Systems nimmt auch eine Schlüsselstellung für pathologische Hyperproliferationen mesenchymaler Zellen im Kontext von Arteriosklerose, Restenose nach Ballon- Angioplasie, Arthritis und fibrotischen Erkrankungen ein. Unter verschiedenen Möglichkeiten, das Signal von Rezeptor-Tyrosinkinasen abzuschalten, ist die spezifische direkte Hemmung der Aktivität der Kinase am aussichtsreichsten.The activation of tyrosine-specific protein kinases is a key event for stimulating the division of animal cells. This is usually done Stimulation by exogenous factors, e.g. B. growth factors if the Proliferation of a particular cell type for the overall function of a tissue or Organ is required. In tumors, cell proliferation is also associated with that Linked activity of tyrosine kinases. However, there is often one in tumor cells aberrant activity of kinases, which is constitutive by overexpression active kinase mutants or ectopic activity of growth factors is caused. The PDGF receptor is one of the growth factors with relevance for human tumors. PDGF is one of the main mitogens in serum and is present in high concentrations in platelets. Its main function in adult organism is wound healing. An undesirable activity of the PDGF Receptor is involved in the proliferation of various tumors, e.g. B. gliomas, Glioblastomas, sarcomas, breast cancers, ovarian cancers and Colon carcinomas, involved. An aberrant activation of the PDGF / PDGF receptor Systems also holds a key position for pathological hyperproliferations mesenchymal cells in the context of arteriosclerosis, restenosis after balloon Angioplasia, arthritis and fibrotic diseases. Among different Ways to turn off the signal from receptor tyrosine kinases is that specific direct inhibition of kinase activity most promising.

Die Erfindung ist daher darauf gerichtet, Verbindungen zu schaffen, die als Inhibitoren von Tyrosinkinasen, insbesondere der PDGF-Rezeptor-Tyrosinkinasen, geeignet sind. Aus EP 0 537 532 A1, GB 330 332 und Chem. Abstr. 128 (1998), 61488y, sind Verbindungen vom Bisindol-Typ bekannt. Im Rahmen der vorliegenden Erfindung wurde eine Reihe von Verbindungen dieses oder ähnlichen Typs mit der allgemeinen Formel XI hergestellt:
The invention is therefore aimed at providing compounds which are suitable as inhibitors of tyrosine kinases, in particular of the PDGF receptor tyrosine kinases. From EP 0 537 532 A1, GB 330 332 and Chem. Abstr. 128 (1998), 61488y, compounds of the bisindole type are known. In the context of the present invention, a number of compounds of this or similar type with the general formula XI were prepared:

wobei R14 und R15 zusammen ein Sauerstoffatom bilden, R1 und R7 Wasserstoffatome bedeuten, A und B Stickstoffatome bedeuten sowie R3, R4, R5, R5, R8, R9, R10 und R11 gleich oder verschieden sind und jeweils ein Wasserstoffatom oder eine Alkyl-, Alkoxy-, Alkoxymethyl- oder Nitrogruppe oder ein Halogenatom bedeuten.wherein R 14 and R 15 together form an oxygen atom, R 1 and R 7 denote hydrogen atoms, A and B denote nitrogen atoms and R 3 , R 4 , R 5 , R 5 , R 8 , R 9 , R 10 and R 11 are the same or are different and each represents a hydrogen atom or an alkyl, alkoxy, alkoxymethyl or nitro group or a halogen atom.

In Chem. Abstract 128 (1998), 61488y, und Gazetta Chimica Italiana, LVII (1927), S. 177, wird die Verbindung Di-1H-indol-2-yl-methanon postuliert, ohne daß jeweils ein nachvollziehbares, zu der genannten Verbindung führendes Herstellungsverfahren angegeben wird.In Chem. Abstract 128 (1998), 61488y, and Gazetta Chimica Italiana, LVII (1927), P. 177, the compound di-1H-indol-2-yl-methanone is postulated without a comprehensible, leading to the named connection Manufacturing process is specified.

Die Aufgabe, die der Erfindung zugrundeliegt, wird erfindungsgemäß durch Verbindungen gelöst, die in Anspruch 1 definiert sind.The object on which the invention is based is achieved according to the invention by Solved compounds that are defined in claim 1.

Die Verbindungen der Formel XI sind nach dem folgenden Schema herstellbar:
The compounds of the formula XI can be prepared according to the following scheme:

Die folgenden Beispiele erläutern die Erfindung, ohne sie zu beschränken.The following examples illustrate the invention without restricting it.

Beispiel 1example 1 Bis(N-phenylsulfonylindol-2-yl)methan-1-onBis (N-phenylsulfonylindol-2-yl) methan-1-one

Die Lösung von 20.00 g (36.9 mmol) Bis(N-phenylsulfonylindol-2-yl)-1-methanol in 200 ml absol. DMF wird auf 0°C gekühlt. Nach Zugabe von 90.4 g Pyridiniumdichromat (PDC) wird 20 h bei Raumtemp. gerührt. Zur Aufarbeitung werden 700 ml H2O und 700 ml CH2Cl2 zugegeben. Die wäßr. Phase wird mit 2 × 200 ml CH2Cl2 extrahiert. Die vereinigten org. Extrakte werden mit 500 ml H2O gewaschen. Nach Abziehen des Lösungsmittels i. Vak. und Zugabe von CH2Cl2 fällt das Produkt aus: farblose Kristalle, Ausb. 15.0 g (75%). Schmp.: 244°C (MeOH/Ether)The solution of 20.00 g (36.9 mmol) bis (N-phenylsulfonylindol-2-yl) -1-methanol in 200 ml absolute. DMF is cooled to 0 ° C. After adding 90.4 g of pyridinium dichromate (PDC) for 20 h at room temperature. touched. For working up, 700 ml of H 2 O and 700 ml of CH 2 Cl 2 are added. The aq. Phase is extracted with 2 × 200 ml CH 2 Cl 2 . The united org. Extracts are washed with 500 ml H 2 O. After removing the solvent i. Vac. and adding CH 2 Cl 2 , the product precipitates: colorless crystals, yield. 15.0 g (75%). Mp: 244 ° C (MeOH / ether)

Analog wurden hergestellt:The following were produced analogously:

Beispiel 2Example 2 (5-Methoxy-N-phenylsulfonylindol-2-yl)-(N-phenylsulfonylindol-2-yl)methan-1-on(5-methoxy-N-phenylsulfonylindol-2-yl) - (N-phenylsulfonylindol-2-yl) methan-1-one

Schmp. 205°C (MeOH)Mp 205 ° C (MeOH)

Beispiel 3Example 3 Bis(5-methoxy-N-phenylsulfonylindol-2-yl)-1-methanonBis (5-methoxy-N-phenylsulfonylindol-2-yl) -1-methanone

Schmp.: 190-191°CMp: 190-191 ° C

Beispiel 4Example 4 Bisindol-2-ylmethan-1-onBisindol-2-ylmethan-1-one

10.0 g (18.5 mmol) Bis(N-phenylsulfonylindol-2-yl)methan-1-on werden in 380 ml 99 proz. EtOH gelöst. Nach Zugabe von 210 ml 10 proz. NaOH wird die Lösung 20 h unter Rückfluß erhitzt. Zur Aufarbeitung wird das EtOH abgezogen, 500 ml ges. NaCl-Lösung und 500 ml CH2Cl2 werden zugefügt und die Phasen getrennt. Die wäßr. Phase wird mit 2 × 200 ml CH2Cl2 extrahiert, die vereinigten org. Extrakte werden über Na2SO4 getrocknet und i. Vak. eingeengt. Das Bisindol fällt als Rohprodukt aus und kann aus CH2Cl2 umkristallisiert werden, gelbe Kristalle, Ausb. 4.5 g (93%). Schmp.: 272-273°C (CH2Cl2)10.0 g (18.5 mmol) of bis (N-phenylsulfonylindol-2-yl) methan-1-one are dissolved in 380 ml of 99 percent. EtOH solved. After adding 210 ml 10 percent. NaOH, the solution is heated under reflux for 20 h. For working up, the EtOH is drawn off, 500 ml sat. NaCl solution and 500 ml CH 2 Cl 2 are added and the phases are separated. The aq. Phase is extracted with 2 × 200 ml CH 2 Cl 2 , the combined org. Extracts are dried over Na 2 SO 4 and i. Vac. constricted. The bisindole precipitates as a crude product and can be recrystallized from CH 2 Cl 2 , yellow crystals, yield. 4.5 g (93%). Mp: 272-273 ° C (CH 2 Cl 2 )

Analog wurden hergestellt:The following were produced analogously:

Beispiel 5Example 5 (5-Methoxyindol-2-yl)-(indol-2-yl)methan-1-on(5-methoxyindol-2-yl) - (indol-2-yl) methan-1-one

Schmp.: 233-235°C (MeOH) Mp: 233-235 ° C (MeOH)  

Beispiel 6Example 6 Bis(5-methoxyindol-2-yl)-1-methanonBis (5-methoxyindol-2-yl) -1-methanone

Schmp.: 202-204°CMp: 202-204 ° C

Beispiel 7Example 7 Dibenzothiophen-2-yl-1-methanonDibenzothiophene-2-yl-1-methanone

Schmp.: 161°CMp: 161 ° C

Beispiel 8Example 8 5-Methoxy-1-phenylsulfonyl-3-indolyl(1-phenylsulfonyl-2-indolyl)-1-methanon5-methoxy-1-phenylsulfonyl-3-indolyl (1-phenylsulfonyl-2-indolyl) -1-methanone

Schmp.: 114-116°CMp: 114-116 ° C

Beispiel 9Example 9 (1H-Indol-2-yl)-(1-H-indol-3-yl)-1-methanon(1H-Indol-2-yl) - (1-H-indol-3-yl) -1-methanone

Schmp.: 260-261°C (MeOH)Mp: 260-261 ° C (MeOH)

Beispiel 10Example 10 Test zur Messung der Hemmung der PDGF-abhängigen Tyrosinphosphorylierung für die Verbindungen nach Beispiel 4, 5 und 6Test to measure the inhibition of PDGF-dependent tyrosine phosphorylation for the compounds according to Examples 4, 5 and 6

Swiss 3T3-Zellen werden für 1 Woche unter Standardbedingungen (DMEM mit Glutamin, 4 g Glukose/I, 10% FKS Antibiotika, 5-7,5% CO2) kultiviert und sind am Ende der Kulturperiode konfluent und nicht mehr proliferierend. Das Medium wird durch serumfreies DMEM ersetzt und die Zellen werden mit den erfindungsgemäßen Verbindungen oder in Kontrollversuchen mit DMSO (Endkonzentration 0,1-1%) für 2 h bei 37°C inkubiert. Die Zellen werden dann durch Zugabe von PDGF-BB zu einer Endkonzentration von 100 ng/ml für 5 min bei Raumtemperatur stimuliert, in Kontrollen erfolgt Zugabe des entsprechenden Lösemittels. Dann erfolgt zweimaliges Waschen der Zellen mit eiskalter PBS und Lyse der Zellen in einem Triton X-100- haltigen Lysispuffer (Zusammensetzung und Verfahren wie in Selective platelet­ derived growth factor receptor kinase blockers reverse sis-transformation M. Kovalenko, A. Gazit, A. Böhmer, C. Rorsman, L. Rönnstrand, C. H. Heldin, J. Waltenberger, F. D. Böhmer, A. Levitzki (1994) Cancer Res. 54, 6106-6114 beschrieben). Die Lysate werden zentrifugiert und die Eiweißkonzentration wird bestimmt. 10 µg Lysatprotein werden direkt auf Nitrozellulose-Membranen aufgetragen (Dot-Blot-Apparatur oder entsprechende Multiwellplatten mit Nitrozellulose-Boden).Swiss 3T3 cells are cultivated for 1 week under standard conditions (DMEM with glutamine, 4 g glucose / I, 10% FCS antibiotics, 5-7.5% CO 2 ) and are confluent at the end of the culture period and no longer proliferating. The medium is replaced by serum-free DMEM and the cells are incubated with the compounds according to the invention or in control experiments with DMSO (final concentration 0.1-1%) for 2 h at 37 ° C. The cells are then stimulated by adding PDGF-BB to a final concentration of 100 ng / ml for 5 min at room temperature, in controls the appropriate solvent is added. Then the cells are washed twice with ice-cold PBS and the cells are lysed in a Triton X-100-containing lysis buffer (composition and method as in Selective platelet derived growth factor receptor kinase blockers reverse sis-transformation M. Kovalenko, A. Gazit, A. Böhmer, C. Rorsman, L. Rönnstrand, CH Heldin, J. Waltenberger, FD Böhmer, A. Levitzki (1994) Cancer Res. 54, 6106-6114). The lysates are centrifuged and the protein concentration is determined. 10 µg of lysate protein are applied directly to nitrocellulose membranes (dot blot apparatus or corresponding multiwell plates with a nitrocellulose base).

Der Nachweis der Tyrosinphosphorylierung erfolgt mit Antiphosphosphotyrosin- Antikörpern nach Standardverfahren. Typischerweise wird ein monoklonaler Antiphosphotyrosin-Antikörper, konjugiert mit Meerrettich-Peroxidase (POD) und Detektion der POD-Aktivität mittels Chemiluminiszenz-Nachweis verwendet. Die Quantifizierung erfolgt entweder über Grauwertanalysen von zur Luminiszenz- Detektion verwendeten Filmen oder direkt mit einem Luminometer. Üblicherweise resultiert die PDGF-Stimulation der Zellen in einer 3-10-fachen Verstärkung des Signals.The detection of tyrosine phosphorylation is carried out with antiphosphosphotyrosine Antibodies following standard procedures. Typically a monoclonal Antiphosphotyrosine antibody conjugated to horseradish peroxidase (POD) and Detection of POD activity by means of chemiluminescence detection used. The Quantification takes place either via gray value analyzes from to luminance Detection used films or directly with a luminometer. Usually PDGF stimulation of the cells results in a 3-10-fold amplification of the Signal.

Die Verbindungen wurden primär zweifach in der Endkonzentration 10 µg/ml eingesetzt. Bei aktiven Verbindungen erfolgte eine Titration in den Stufen 30 µM, 10 µM, 3 µM, 1 µM, 0,3 µM und 0,1 µM als Doppelbestimmung. Die Ergebnisse sind in der Tabelle 1 gezeigt.The compounds became primary twice in the final concentration 10 µg / ml used. Active compounds were titrated to levels 30 µM, 10 µM, 3 µM, 1 µM, 0.3 µM and 0.1 µM as double determination. The results are in shown in Table 1.

Tabelle 1 Table 1

Der qualitative Nachweis der Effekte auf die Tyrosinphosphorylierung des PDGF- Rezeptors und zellulärer Substrate erfolgt durch Analyse der Zell-Lysate mittels Polyakrylamidgelelktrophorese und Immunoblotting mit Anti- Phosphotyrosinantikörpern nach Standardverfahren. Qualitative evidence of the effects on tyrosine phosphorylation of PDGF Receptor and cellular substrates is done by analyzing the cell lysates using Polyacrylamide gel electrophoresis and immunoblotting with anti Phosphotyrosine antibodies according to standard procedures.  

Weiterhin wurden die erfindungsgemäßen Verbindungen in vitro mit isolierten Plasmamembranen von Swiss 3T3 Zellen und mit aus überexprimierenden Zellen gereinigtem PDGF-Rezeptor untersucht, in intakten A431-Zellen (und teilweise auch in Swiss 3T3 Plasmamembranen) auf eine mögliche Hemmung der EGF Rezeptortyrosinkinase getestet und auf Hemmung rekombinanter Src-Kinase getestet. Die Ergebnisse sind in Tabelle 2 gezeigt.Furthermore, the compounds according to the invention were isolated in vitro Plasma membranes from Swiss 3T3 cells and with from overexpressing cells purified PDGF receptor examined in intact A431 cells (and partially also in Swiss 3T3 plasma membranes) for a possible inhibition of EGF Receptor tyrosine kinase tested and for inhibition of recombinant Src kinase tested. The results are shown in Table 2.

DNA-Synthese-Tests in Swiss 3T3-Zellen, die mit unterschiedlichen Wachstumsfaktoren stimuliert werden, sind geeignet, selektive antiproliferative Wirkungen von Rezeptor-Tyrosinkinasehemmstoffen zu charakterisieren. Die Verbindungen wurden hinsichtlich ihrer Wirkung auf die durch PDGF-BB, bFGF, FCS und die Kombination von EGF und Insulin in diesen Zellen stimulierte DNA- Synthese untersucht. Diese Stimulantien sind annähernd equipotent und erhöhen die DNA-Synthese in vorher Wachstums-arretierten Swiss 3T3-Zellen auf das 5-20- fache. Die Dosis-Abhängigkeiten der ensprechenden Versuche sowie die erhaltenen IC50-Werte sind ebenfalls in Tabelle 2 dargestellt.DNA synthesis tests in Swiss 3T3 cells with different Growth factors that are stimulated are apt to be selective antiproliferative Characterize effects of receptor tyrosine kinase inhibitors. The Compounds were evaluated for their effect on those by PDGF-BB, bFGF, FCS and the combination of EGF and insulin in these cells stimulated DNA Synthesis examined. These stimulants are approximately equipotent and increase DNA synthesis in previously growth-locked Swiss 3T3 cells on the 5-20 fold. The dose dependencies of the corresponding experiments as well as the IC50 values obtained are also shown in Table 2.

Weiterhin wurden die Verbindungen auf eine mögliche anti-transformierende Wirkung unter Verwendung von sis-transformierten NIH3T3-Zellen untersucht. In diesen Zellen wird ein u. a. durch irreguläres mehrschichtiges Wachstum und Koloniebildung in Weichagar gekennzeichneter transformierter Phänotyp durch Expression von PDGF-BB und permanente Aktivierung der endogenen PDGF- Rezeptoren aufrecht erhalten. Die erhaltenen IC50-Werte sind ebenfalls in Tabelle 2 dargestellt.Furthermore, the compounds were shown to be a possible anti-transforming Effect investigated using sis-transformed NIH3T3 cells. In these cells a u. a. through irregular multilayered growth and Colony formation in soft agar characterized by transformed phenotype Expression of PDGF-BB and permanent activation of endogenous PDGF- Maintain receptors. The IC50 values obtained are also in table 2 shown.

Demnach wurden Wirkungen auf die PDGF-Rezeptorkinase durch die Verbindungen in folgenden Tests gefunden:
Accordingly, effects on the PDGF receptor kinase by the compounds were found in the following tests:

  • - PDGF-Rezeptor-Autophosphorylierung in intakten Swiss 3T3-Zellen- PDGF receptor autophosphorylation in intact Swiss 3T3 cells
  • - PDGF-Rezeptor-Autophosphorylierung in isolierten Membranen von Swiss 3T3- Fibroblasten- PDGF receptor autophosphorylation in isolated membranes from Swiss 3T3 Fibroblasts
  • - PDGF-Rezeptor-Autophosphorylierung in gereinigten Rezeptorpräparaten- PDGF receptor autophosphorylation in purified receptor preparations

Keine Wirkungen wurden in analogen Tests mit der Rezeptor-Tyrosinkinase für den Epidermalen Wachstumsfaktor sowie mit der cytosolischen Tyrosinkinase Src bis zu einer Konzentration von von 30 µM beobachtet. Damit weisen die Verbindungen Spezifität für die Hemmung der PDGF-Rezptor-Tyrosinkinase gegenüber anderen Tyrosinkinasen auf.No effects were seen in analog tests with the receptor tyrosine kinase for the  Epidermal growth factor as well as with the cytosolic tyrosine kinase Src up to a concentration of 30 µM was observed. So the connections point Specificity for the inhibition of PDGF receptor tyrosine kinase compared to others Tyrosine kinases.

Tabelle 2 Table 2

Claims (8)

1. Verbindungen mit der allgemeinen Formel XI
worin A und B Stickstoffatome und R1 und R7 Wasserstofftatome bedeuten, R14 und R15 zusammen ein Sauerstoffatom bilden und R3, R4, R5, R6, R8, R9, R10 und R11 gleich oder verschieden sind und jeweils ein Wasserstoffatom, eine Alkyl-, Alkoxy, Alkoxymethyl, Nitrogruppe oder ein Halogenatom bedeuten.1. Compounds with the general formula XI
wherein A and B are nitrogen atoms and R 1 and R 7 are hydrogen atoms, R 14 and R 15 together form an oxygen atom and R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 and R 11 are the same or different are each a hydrogen atom, an alkyl, alkoxy, alkoxymethyl, nitro group or a halogen atom. 2. Bis(indol-2-yl)-methan-1-on.2. bis (indol-2-yl) methan-1-one. 3. (5-Methoxyindol-2-yl)-(indol-2-yl)methan-1-on.3. (5-methoxyindol-2-yl) - (indol-2-yl) methan-1-one. 4. Bis(5-methoxyindol-2-yl)-1-methanon.4. bis (5-methoxyindol-2-yl) -1-methanone. 5. Arzneimittel, enthaltend eine Verbindung nach einem der Ansprüche 1 bis 4.5. Medicament containing a compound according to any one of claims 1 to 4. 6. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 4 als Inhibitor einer Tyrosinkinase.6. Use of a compound according to any one of claims 1 to 4 as an inhibitor a tyrosine kinase. 7. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 4 als Inhibitor einer PDGF-Rezeptor-Tyrosinkinase. 7. Use of a compound according to any one of claims 1 to 4 as an inhibitor a PDGF receptor tyrosine kinase.   8. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 4 zur Behandlung von Tumoren, Arteriosklerose, Restenose nach Ballon-Angioplasie, Arthritis und fibrotischen Erkrankungen.8. Use of a compound according to one of claims 1 to 4 for Treatment of tumors, arteriosclerosis, restenosis after balloon angioplasia, Arthritis and fibrotic diseases.
DE19838506A 1998-05-04 1998-08-25 Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation Expired - Fee Related DE19838506C2 (en)

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DE19838506A DE19838506C2 (en) 1998-05-04 1998-08-25 Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation
TR2000/03206T TR200003206T2 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant diseases and other diseases caused by pathological cell proliferation.
KR1020007012248A KR20010043288A (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
CNB998058033A CN1151127C (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
ES99927711T ES2190221T3 (en) 1998-05-04 1999-04-22 DERIVATIVES OF INDOL AND ITS USE FOR THE TREATMENT OF MALIGNAL AND OTHER DISEASES, BASED ON PATHOLOGICAL CELL PROLIFERATIONS.
PCT/DE1999/001214 WO1999057117A2 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
AU44975/99A AU752464B2 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
CA002496859A CA2496859A1 (en) 1998-05-04 1999-04-22 Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation
SI9930233T SI1109785T1 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
AT99927711T ATE230394T1 (en) 1998-05-04 1999-04-22 INDOLE DERIVATIVES AND THE USE THEREOF FOR THE TREATMENT OF MALIGNANTS AND OTHER DISEASES BASED ON PATHOLOGICAL CELL PROLIFERATIONS
BR9911017-2A BR9911017A (en) 1998-05-04 1999-04-22 Indole derivatives and their use for the treatment of malignant and other diseases, which are based on the proliferation of pathological cells
SK1635-2000A SK16352000A3 (en) 1998-05-04 1999-04-22 Indole derivatives, process for the preparation thereof, their use for the medicaments comprising said compounds
JP2000547087A JP2002514572A (en) 1998-05-04 1999-04-22 Indole derivatives and their use for treating malignant diseases and other diseases based on pathological cell proliferation
CA002330756A CA2330756C (en) 1998-05-04 1999-04-22 Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation
IL13905699A IL139056A0 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
PL99346840A PL346840A1 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
HU0102563A HUP0102563A3 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
DK99927711T DK1109785T3 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
CZ20003960A CZ20003960A3 (en) 1998-05-04 1999-04-22 Indole derivatives and their use for treating malignant and other diseases induced by pathological proliferation of cells
EP99927711A EP1109785B1 (en) 1998-05-04 1999-04-22 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
DE59903921T DE59903921D1 (en) 1998-05-04 1999-04-22 INDOLDER DERIVATIVES AND THE USE THEREOF FOR TREATING MALIGNAS AND OTHER DISEASES BASED ON PATHOLOGICAL CELL PROLIFERATIONS
US09/305,115 US6407102B1 (en) 1998-05-04 1999-05-04 Indole derivatives and their use for the treatment of malignant and other diseases based on pathological cell proliferation
ARP990102079A AR018600A1 (en) 1998-05-04 1999-05-04 DERIVATIVES OF INDOL; ITS USE FOR THE PREPARATION OF COMPOSITIONS FOR THE TREATMENT OF MALIGNAL DISEASES, DUE TO THE PROLIFERATION PATOLOGICADE CELLS; PROCEDURE TO PREPARE SUCH DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
NZ507735A NZ507735A (en) 1998-05-04 2000-10-24 Indole derivatives useful for treating malignant and other diseases caused by pathological cell proliferation
NO20005448A NO317261B1 (en) 1998-05-04 2000-10-27 Indole derivatives and their use in the treatment of malignant and other diseases based on pathological cell proliferation
BG104996A BG104996A (en) 1998-05-04 2000-11-28 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation
HK01109122A HK1038354A1 (en) 1998-05-04 2001-12-27 Indole derivatives and their use in the treatment of malignant and other diseases caused by pathological cell proliferation.
US10/137,653 US6812243B2 (en) 1998-05-04 2002-05-03 Indole derivatives and their use for the treatment of malignant and other diseases based on pathological proliferation

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GB330332A (en) * 1929-03-26 1930-06-12 Ici Ltd Improvements in the manufacture of indoles
EP0537532A1 (en) * 1991-10-07 1993-04-21 Nisshin Flour Milling Co., Ltd. 2,2'-Alkylenediindole derivatives, process for their production, medicines containing them and their use as anti-ulcer agents

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Publication number Priority date Publication date Assignee Title
GB330332A (en) * 1929-03-26 1930-06-12 Ici Ltd Improvements in the manufacture of indoles
EP0537532A1 (en) * 1991-10-07 1993-04-21 Nisshin Flour Milling Co., Ltd. 2,2'-Alkylenediindole derivatives, process for their production, medicines containing them and their use as anti-ulcer agents

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Gazzetta Chim. Ital. LVII(1927), S. 477 *

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