WO2006133885A1 - Derives d'indole fusionnes tricycliques et leur utilisation en tant qu'inhibiteurs d'aurora kinase - Google Patents

Derives d'indole fusionnes tricycliques et leur utilisation en tant qu'inhibiteurs d'aurora kinase Download PDF

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WO2006133885A1
WO2006133885A1 PCT/EP2006/005633 EP2006005633W WO2006133885A1 WO 2006133885 A1 WO2006133885 A1 WO 2006133885A1 EP 2006005633 W EP2006005633 W EP 2006005633W WO 2006133885 A1 WO2006133885 A1 WO 2006133885A1
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formula
compound
compounds
alkyl
methyl
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PCT/EP2006/005633
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Guy Georges
Bernhard Goller
Hans-Willi Krell
Anja Limberg
Ulrike Reiff
Petra Rueger
Matthias Rueth
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F. Hoffmann-La Roche Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel tricyclic fused indole derivatives, to a process for their manufacture, pharmaceutical compositions containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents.
  • the serine/threonine kinase family includes members that control cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and regulation of the cell cycle.
  • Aurora kinases are a family of serine/threonine kinases that are believed to play a key role in the protein phosphorylation events that are essential for the completion of essential mitotic events.
  • the Aurora kinase family is made up of three key members: Aurora A, B and C (also known as Aurora-2, Aurora- 1 and
  • Aurora- 1 and Aurora-2 are described in US 6,207,401 of Sugen and in related patents and patent applications, e.g. EP 0 868 519 and EP 1 051 500.
  • Aurora A there is increasing evidence that it is a novel proto-oncogene.
  • Aurora A gene is amplified and transcript/protein is highly expressed in a majority of human tumor cell lines and primary colorectal, breast and other tumors. It has been shown that Aurora A overexpression leads to genetic instability shown by amplified centrosomes and significant increase in aneuploidy and transforms Ratl fibroblasts and mouse NIH3T3 cells in vitro. Aurora A-transformed NIH3T3 cells grow as tumors in nude mice (Bischoff, J.R., and Plowman, G.D., Trends Cell Biol.
  • Aurora A contributes to cancer phenotype by being involved in chromosome segregation and mitotic checkpoint control.
  • Aurora kinase by selective inhibitors is recognized to stop uncontrolled proliferation, re-establish mitotic checkpoint control and lead to apoptosis of tumor cells.
  • an Aurora inhibitor therefore slows tumor growth and induces regression (Harrington, E.A., et al., Nat. Med. 10 (2004) 262-267).
  • Low molecular weight inhibitors for protein kinases are widely known in the state of the art.
  • such inhibitors are based on i.e. quinazoline derivatives as claimed in the following patents and patent applications: WO 00/44728; WO 00/47212; WO 01/21594; WO 01/21595; WO 01/21596; WO 01/21597; WO 01/77085; WO 01/55116; WO 95/19169; WO 95/23141;
  • WO 2005/005414 relates to pyrazolyl-indole derivatives active as kinase inhibitors.
  • WO 2004/096792 relates to indole derivatives as KDR protein kinase inhibitors and WO 2003/024969 describes indole derivatives as tyrosine kinase inhibitors. Summary of the Invention
  • the present invention relates to tricyclic fused indole derivatives of formula I,
  • R 1 is hydrogen or alkyl
  • R 2 is hydrogen or alkyl
  • R 3 is hydrogen or alkyl; or alternatively R 2 and R 3 form together with the carbon atom to which they are attached a (C 5 -C 6 )cycloalkyl ring;
  • R 4 is hydrogen, alkyl, (C 3 -C 6 )cycloalkyl
  • the compounds according to this invention show activity as protein kinase inhibitors.
  • Many diseases are associated with abnormal cellular responses triggered by protein kinase mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
  • the compounds according to this invention in particular show activity as Aurora family kinase inhibitors, especially as Aurora A kinase inhibitors, and may therefore be useful for the treatment of diseases mediated by said kinase.
  • Aurora A inhibition leads to cell cycle arrest in the G2 phase of the cell cycle and exerts an antiproliferative effect in tumor cell lines.
  • Aurora A inhibitors may be useful in the treatment of i.e. hyperproliferative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
  • Treatment of acute-myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST) is included.
  • Objects of the present invention are the compounds of formula I and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, their use as Aurora kinase inhibitors, the preparation of the above- mentioned compounds, pharmaceutical compositions containing them and their manufacture as well as the use of the above-mentioned compounds in treatment, control or prevention of illnesses, especially of illnesses and disorders as mentioned above like tumors or cancer (e.g. colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas) or in the manufacture of corresponding pharmaceutical compositions.
  • tumors or cancer e.g. colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas
  • cancer e.g. colorectal
  • alkyl as used herein means a saturated, straight-chain or branched-chain hydrocarbon containing 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n- butyl, 2-butyl, t-butyl, n-pentyl, 3-methyl-butyl, 2-methyl-butyl, n-hexyl, 3- methyl-pentyl, 2-ethyl-butyl, 3,3-dimethyl-butyl, 2,2-dimethyl-butyl or 2,3- dimethyl-butyl, preferably methyl, ethyl, n-propyl, isopropyl.
  • cycloalkyl means a monocyclic saturated hydrocarbon ring with 3 to 6 ring atoms.
  • saturated carbocyclic groups can be optionally substituted one or several times, preferably one to three times by alkyl, especially one to two times.
  • saturated carbocyclic groups are unsubstituted.
  • saturated carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 3-methyl-cyclopentyl, 3,3-dimethyl-cyclohexyl, 3-methyl-cyclohexyl,
  • the cycloalkyl ring which is formed by R 2 and R 3 together with the carbon atom to which they are attached is a cyclopentyl or cyclohexyl ring, preferably a cyclopentyl ring.
  • the compounds of formula I can exist in different tautomeric forms and in variable mixtures thereof. All tautomeric forms of the compounds of formula I and mixtures thereof are an objective of the invention.
  • the pyrazole ring of formula I can form two tautomeric forms as shown here below:
  • API+ refers to positive atmospheric pressure ionization mode
  • ESI+ refers to positive electrospray ionization mode
  • R 1 is alkyl
  • R 2 is alkyl
  • R 3 is alkyl
  • R 4 is hydrogen, alkyl or cyclopropyl.
  • R 1 is alkyl
  • R 2 is alkyl
  • R 3 is alkyl
  • R 4 is hydrogen or alkyl.
  • R 1 is alkyl
  • R 2 is alkyl
  • R 3 is alkyl
  • R 4 is alkyl
  • Such a compound is for example: l-Ethyl-3,3-dimethyl-6-(5-methyl-2H-pyrazol-3-yl)-3,5-dihydro-lH-pyrrolo[2,3- /]indol-2-one.
  • Another embodiment of the invention is a process for the preparation of the compounds of formula I, wherein
  • the compounds of formula I, or a pharmaceutically acceptable salt thereof, which are subject of the present invention may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I, or a pharmaceutically-acceptable salt thereof, are illustrated by the following representative scheme 1 and examples in which, unless otherwise stated, R 1 , R 2 , R 3 and R 4 have the significance given herein before.
  • Necessary starting materials are either commercially available or they may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying examples or in the literature cited below with respect to scheme 1. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • R 1 , R 2 R 3 and R 4 have the significance as given above for formula I and L represents a leaving group as e.g. iodine, bromine, chlorine, triflate and the like.
  • L 1 - (CH 2 ) 3 -L 2 or L ⁇ (CH 2 ) S -L 2 is used instead of R ! -L and R 2 -L and L 1 , L 2 are the same or different and represent a leaving group as e.g. iodine, bromine, chlorine, triflate and the like.
  • the dinitrile of formula II can be hydrolysed and cyclized under acidic conditions to give a 4H-isoquinoline-l,3-dione of formula III (see e.g. US 4,666,923A).
  • the subsequent Hofmann rearrangement in the presence of sodium hydroxide and bromine yields the ring contracted oxindole of formula IV (see e.g. US 4,666,923A).
  • compounds of formula IV can be synthesized by alkylation of commercially available l,3-dihydro-indol-2-one with R 2 -L and R 3 -L as described in
  • the precursor of formula IX of the Fischer indole synthesis (step 8) can be obtained from amine VII by diazotization with nitrous acid, reduction to the hydrazine with tin dichloride under acidic conditions and formation of the hydrazone with methyl ketone VIII.
  • the [3,3] -rearrangement of hydrazones of formula IX in step 8 takes place under acid catalysis, typically using polyphosphoric acid (PPA), to give the desired indole I.
  • PPA polyphosphoric acid
  • Methylketones of formula VIII are either commercially available or they can be synthesized by standard procedures of organic chemistry, e.g. by addition of methyl magnesium halogenide (e.g. iodide) to the N-methoxy-N- methyl amides of lH-pyrazole-3-carboxylic acid (Weinreb amides).
  • methyl magnesium halogenide e.g. iodide
  • Weinreb amides e.g. iodide
  • the lH-pyrazole-3-carboxylic acid ester can be directly converted to the methyl ketones of formula VIII with methyl magnesium iodide according to e.g. Kikkawa, L, and Yorifuji, T., Synthesis (1980) 877 - 880.
  • compositions containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of the present invention and/or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more pharmaceutically acceptable carriers.
  • the compounds of the present invention as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses. Based on their Aurora tyrosine kinase inhibition and their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer in humans or animals and for the production of corresponding pharmaceutical compositions.
  • the dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
  • An embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, together with pharmaceutically acceptable excipients.
  • Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable adjuvants for the treatment of diseases mediated by an inappropriate activation of Aurora family tyrosine kinases.
  • Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, for the inhibition of tumor growth.
  • Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, for the inhibition of tumor growth.
  • Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable adjuvants for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
  • Another embodiment of the invention is a pharmaceutical composition containing one or more compounds of formula I as active ingredients together with pharmaceutically acceptable adjuvants for the treatment of acute-myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
  • AML acute-myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • GIST gastrointestinal stromal tumor
  • Another embodiment of the invention is the use of one or more compounds of formula I for the manufacture of pharmaceutical compositions for the treatment of diseases mediated by an inappropriate activation of Aurora family tyrosine kinases.
  • Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the inhibition of tumor growth.
  • Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding pharmaceutical compositions for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or renal cancers, leukemias or lymphomas.
  • Another embodiment of the invention is the use of a compound according to formula I, for the treatment of acute-myelogenous leukemia (AML, acute lymphocytic leukemia (ALL) and gastrointestinal stromal tumor (GIST).
  • AML acute-myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • GIST gastrointestinal stromal tumor
  • Another embodiment of the invention is the use of the compounds of formula I as Aurora A tyrosine kinase inhibitors.
  • Another embodiment of the invention is the use of the compounds of formula I as anti-proliferating agents.
  • Another embodiment of the invention is the use of one or more compounds of formula I for the treatment of cancer.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids.
  • Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like.
  • the chemical modification of a pharmaceutical compound (i.e. a drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See e.g.
  • the compounds of formula I can contain one or several chiral centers and can then be present in a racemic or in an optically active form.
  • the racemates can be separated according to known methods into the enantiomers. For instance, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L- camphorsulfonic acid.
  • separation of the enantiomers can also be achieved by using chromatography on chiral HPLC-phases (HPLC: High
  • the compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that said compounds show activity as inhibitors of the Aurora kinase family and also show anti-proliferative activity. Consequently the compounds of the present invention are useful in the therapy and/or prevention of illnesses with known over-expression of kinases of the Aurora family preferably Aurora A, especially in the therapy and / or prevention of illnesses mentioned above.
  • the activity of the present compounds as inhibitors of the Aurora kinase family and anti-proliferative agents is demonstrated by the following biological assays:
  • Aurora A is a serine threonine kinase involved in spindle assembly and chromosome segregation.
  • the assay is a typically ELISA-type assay where biotinylated substrate (PKB-GSK2) is phosphorylated. Phosphorylation is detected by peroxidase (POD) labelled polyclonal antibody (PAK ⁇ M-Ig>S-IgG-POD) and phosphopeptide monoclonal antibody (Mab) (MAK ⁇ P-GSK>M-27E5-IgG).
  • PDB-GSK2 biotinylated substrate
  • Phosphorylation is detected by peroxidase (POD) labelled polyclonal antibody (PAK ⁇ M-Ig>S-IgG-POD) and phosphopeptide monoclonal antibody (Mab) (MAK ⁇ P-GSK>M-27E5-IgG).
  • POD peroxidase
  • Mob phosphopeptid
  • Antibody stock solution l,85mg/ml, diluted in
  • ABTS tablets dissolve one ABTS tablet in 50 ml of working solution
  • This assay is performed in 96-well format for IC 50 determination with 5 samples (each with 8 concentrations by twofold testing ), 100 ⁇ l incubation volume and the following plate layout:
  • Sample preparation add 24 ⁇ l per well samples (descending sequence ) diluted in kinase buffer to assay plate ( final cone, for DMSO 1%).
  • Negative control without ATP.
  • a viability assay was performed using the CellTiter-Glo® Luminescent Cell Viability Assay (see Promega Corporation's Technical Bulletin No. 288, pp. 1-11 [revised 2/04] which is hereby incorporated by reference in its entirety).
  • This assay is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells.
  • the assay is designed for use with multiwell formats, making it ideal for automated high-throughput screening (HTS), cell proliferation and cytotoxicity assays.
  • the homogeneous assay procedure involves adding a single reagent (containing luciferase, luciferan substrate, and buffer) directly to cells cultured in serum- supplemented medium. Cell washing, removal of medium and multiple pipetting steps are not required.
  • the system detects as few as 15 cells/well in a 384- well format in 10 minutes after adding reagent and mixing.
  • the homogeneous "add-mix-measure" format results in cell lysis and generation of a luminescent signal proportional to the amount of ATP present.
  • ATP is directly proportional to the number of cells present in culture.
  • the above- referenced assay generates a "glow-type" luminescent signal, produced by the luciferase reaction, which has a half-life generally greater than five hours, depending on cell type and medium used.
  • the extended half-life eliminates the need to use reagent injectors and provides flexibility for continuous or batch mode processing of multiple plates.
  • the unique homogeneous format avoids errors that may be introduced by other ATP measurement methods that require multiple steps.
  • HCT 116 cells human colon carcinoma , ATCC-No. CCl-247 were cultivated in RPMI 1640 medium with GlutaMAXTM I (cell culture media that contains L-Alanyl- L-Glutamine [a stabilized a form/source of L-Glutamine] from Invitrogen, Cat-No.
  • FCS 2,5 % Fetal Calf Serum
  • FBS 2,5 % Fetal Calf Serum
  • penicillin/ lOO ⁇ g/ml streptomycin Pen/Strep from Invitrogen Cat. No. 15140.
  • penicillin/ lOO ⁇ g/ml streptomycin Pen/Strep from Invitrogen Cat. No. 15140.
  • the viability assay was done according to the instructions of the manufacturer. In brief: the cell-plate was equilibrated to room temperature for approximately 30 minutes and then reagent (containing luciferase, luciferan substrate, and buffer) was added. The contents were carefully mixed for 15 minutes to induce cell lysis. After 45 minutes the luminescent signal was measured in Victor
  • RPMI 1640 with cell culture media containing L-Alanyl-L- Glutamine [GlutaMAXTM I (Invitrogen, Cat-No. 61870), 5 % FCS (Sigma
  • HCTl 16 (ATCC-No. CCl-247): 1000 cells in 60 ⁇ l per well of 384 well plate
  • a serial dilution with dilution steps of 1:3 was followed according to the procedure (a -e) as described here below: a) for the second highest concentration add 10 ⁇ l of 10 mM stock solution of compound to 20 ⁇ l dimethylsulfoxide (DMSO) b) dilute 8x 1:3 (always 10 ⁇ l to 20 ⁇ l DMSO) in this DMSO dilution row (results in 9 wells with concentrations from 3333,3 ⁇ M to 0.51 ⁇ M) c) dilute each concentration 1: 47,6 (3,5 ⁇ l compound dilution to 163 ⁇ l media) e) add 10 ⁇ l of every concentration to 60 ⁇ l media in the cell plate resulting in final concentration of DMSO : 0.3 % in every well and resulting in 10 final concentration of compounds ranging from 30 ⁇ M to 0.0015 ⁇ M.
  • DMSO dimethylsulfoxide
  • the compounds according to this invention and their pharmaceutically acceptable salts can be used as pharmaceutical compositions, e.g. in the form of pharmaceutical compositions.
  • the pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, drag ⁇ es, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • compositions can be obtained by processing the compounds according to this invention with pharmaceutically acceptable, inorganic or organic carriers.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or it's salts and the like can be used, for example, as such carriers for tablets, coated tablets, drag ⁇ es and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • compositions comprise e.g. the following:
  • the resulting brown oil (22.8Og, 96%) is a 85:15 mixture of the isomers 2-benzyl-5- methyl-2H-pyrazole-3-carboxylic acid ethyl ester and l-benzyl-5-methyl-lH- pyrazole-3-carboxylic acid ethyl ester.
  • Triethylamine (9.8 g, 97.3 mmol) and methyl magnesium iodide (32.4 ml, 3M in diethyl ether) were dissolved in toluene (30 ml) and cooled to 0 0 C.
  • a solution of ethyl-S-methylpyrazol-S-carboxylate (5g, 32.4 mmol) in toluene (20 ml) was added dropwise while the temperature was kept below 10 0 C. After warming to room temperature the mixture was stirred for 2 h. The resulting solution was cooled to
  • Polyphosphoric acid (20.00 g, 204.1 mmol) was warmed to 80 0 C and l-ethyl-3,3- dimethyl-5- ⁇ N'-[l-(5-methyl-2H-pyrazol-3-yl)-ethylidene]-hydrazino ⁇ -l,3- dihydro-indol-2-one (0.90 g, 2.77 mmol) was added in portions. The mixture was stirred for 2 hours at 80 0 C. It was quenched with ice water (50 ml) and pH was adjusted to 7 - 8 by adding aqueous ammonia. The crude product was isolated by suction and washed with water. The solid was dried and purified by HPL chromatography.

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Abstract

L'invention concerne des composés de formule (I), leurs sels pharmaceutiquement acceptables, leurs formes énantiomères, les diastéréoisomères et racémates, la préparation des composés précités, les compositions pharmaceutiques les contenant et leur préparation, ainsi que l'utilisation des composés précités pour enrayer ou prévenir des maladies, notamment le cancer.
PCT/EP2006/005633 2005-06-15 2006-06-13 Derives d'indole fusionnes tricycliques et leur utilisation en tant qu'inhibiteurs d'aurora kinase WO2006133885A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022102A2 (fr) * 2005-08-12 2007-02-22 Genentech, Inc. Inhibiteurs pentatycliques des kinases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040242559A1 (en) * 2003-04-25 2004-12-02 Aventis Pharma S.A. Novel indole derivatives, preparation thereof as medicinal products and pharmaceutical compositions, and especially as KDR inhibitors
WO2005005414A2 (fr) * 2003-07-08 2005-01-20 Pharmacia Italia S.P.A. Derives de pyrazolyl-indole actifs en tant qu'inhibiteurs de kinase, procede de preparation correspondant et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040242559A1 (en) * 2003-04-25 2004-12-02 Aventis Pharma S.A. Novel indole derivatives, preparation thereof as medicinal products and pharmaceutical compositions, and especially as KDR inhibitors
WO2005005414A2 (fr) * 2003-07-08 2005-01-20 Pharmacia Italia S.P.A. Derives de pyrazolyl-indole actifs en tant qu'inhibiteurs de kinase, procede de preparation correspondant et compositions pharmaceutiques les contenant

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022102A2 (fr) * 2005-08-12 2007-02-22 Genentech, Inc. Inhibiteurs pentatycliques des kinases
WO2007022102A3 (fr) * 2005-08-12 2007-05-10 Genentech Inc Inhibiteurs pentatycliques des kinases
US7749994B2 (en) 2005-08-12 2010-07-06 Genentech, Inc. Pentacyclic kinase inhibitors

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