WO2006021548A1 - Dihydropteridinone, verfahren zu deren herstellung und deren verwendung als arzneimittel - Google Patents
Dihydropteridinone, verfahren zu deren herstellung und deren verwendung als arzneimittel Download PDFInfo
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- WO2006021548A1 WO2006021548A1 PCT/EP2005/054099 EP2005054099W WO2006021548A1 WO 2006021548 A1 WO2006021548 A1 WO 2006021548A1 EP 2005054099 W EP2005054099 W EP 2005054099W WO 2006021548 A1 WO2006021548 A1 WO 2006021548A1
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- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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Definitions
- the present invention relates to novel dihydropteridinones of the general formula (1)
- radicals R 1 to R 5 , R a to R c , W, Q 1 and Q 2 have the meanings mentioned in the claims and the description, their isomers, processes for preparing these dihydropteridinones and their use as medicaments.
- Pteridinone derivatives are known as active ingredients with antiproliferative action from the prior art.
- WO 01/019825 and WO 03/020722 describe the use of pteridinone derivatives for the treatment of tumor diseases.
- Tumor cells partially or completely elude regulation and control by the organism and are characterized by uncontrolled growth. This is based on
- cyclin-dependent kinases CDK's
- Aurora B is described as having an essential function in entering mitosis. Aurora B phosphorylates histone H3 on SerlO and thus initiates chromosome condensation (Hsu et al., 2000, Cell 102: 279-91).
- a specific cell cycle arrest in the G2 / M phase can also be triggered, for example, by inhibition of specific phosphatases such as, for example, Cdc25C (Russell and Nurse 1986, Cell 45: 145-53).
- Yeasts with defective Cdc25 gene arrest in the G2 phase while overexpression of Cdc25 leads to premature entry into the mitotic phase (Russell and Nurse 1987, Cell 49: 559-67). Furthermore, arrest in the G2 / M phase may also be due to inhibition of certain motor proteins, the so-called kinesins such as Eg5 (Mayer et al., 1999, Science 286: 971-4), or microtubule stabilizing or destabilizing agents (eg, colchicine, Taxol, etoposide, vinblastine, vincristine) (Schiff and Horwitz 1980, Proc Natl Acad Sci. USA 77: 1561-5).
- Eg5 Mayer et al., 1999, Science 286: 971-4
- microtubule stabilizing or destabilizing agents eg, colchicine, Taxol, etoposide, vinblastine, vincristine
- polo-like kinases In addition to cyclin-dependent and Aurora kinases, the so-called polo-like kinases, a small family of serine / threonine kinases, play an important role in the regulation of the eukaryotic cell cycle. So far, the polo-like kinases PLK-I, PLK-2, PLK-3 and PLK-4 have been described in the literature. Especially for PLK-I a central role in the regulation of the mitosis phase has been shown. PLK-I is responsible for the maturation of the centrosomes, for the activation of the phosphatase Cdc25C, and for the activation of the anaphase Promoting Complex (Glover et al., 1998, Genes Dev.
- compounds of the general formula (I) in which the radicals R 1 to R 5 , R a to R c , W, Q 1 and Q 2 have the meanings mentioned below are inhibitors of specific cell cycle kinases, in particular the polyols. like kinases, act. These compounds exhibit antiproliferative activity by arresting cells in the mitosis phase of the cell cycle before initiating the programmed cell death in the arrested cells.
- the compounds of the present invention can be used to treat diseases related to the activity of specific cell cycle kinases and characterized by excessive or abnormal cell proliferation.
- the present invention therefore relates to compounds of the general formula (1)
- R 1 , R 2 are each independently hydrogen or optionally mono- or polysubstituted C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or R 1 and R 2 together represent a saturated or partially unsaturated 2-5-membered Form an alkyl bridge in which a -CH 2 group can be replaced by O, S, -NR 8 or a -CH group by N;
- R 4 is a radical selected from the group consisting of hydrogen, -CN, hydroxy, halogen, -OR 8 and -NR 6 R 7 , or a radical selected from the group consisting of optionally mono- or polysubstituted C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-5 alkyloxy, C 2-5 alkenyloxy, C 2-5 alkynyloxy, C 1-6 alkylthio, C 1-6 alkylsulfoxo and C 1-6 alkylsulfonyl, wherein the the substituent (s) may be the same or different and are selected from the group consisting of halogen, -NO 2 ,
- Q 1 is a radical selected from the group consisting of optionally mono- or polysubstituted piperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, tropenyl, azacycloheptyl and -N (R 8 ) - (
- Q 2 either absent or a radical selected from the group consisting of singly or multiply optionally substituted C 1-16 alkylene, C 2-16 alkenylene, C 2-16 alkynylene, cycloalkyl, aryl, heterocyclyl and heteroaryl wherein the substituent (s ) may be the same or different and are selected from the group consisting of halogen, -NO 2 , R 8 , -OR 8 , -C (O) R 8 , -C (O) OR 8 , -C (O) NR 8 R 9 , -NR 8 R 9 , -NR 8 C (O) R 9 , -NR 8 C (O) OR 9 , -NR 8 C (O) NR 9 R 10 ,
- R 5 is hydrogen or a radical selected from the group consisting of optionally mono- or polysubstituted C 1-16 alkyl, C 2-16 alkenyl, C 2-16 alkynyl,
- R 6 , R 7 are each independently hydrogen or a radical selected from the group consisting of optionally mono- or polysubstituted C 1-16 alkyl, C 2-16 alkenyl, C 2-16 alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl wherein the / the substituent (s) may be the same or different and are selected from the group consisting of halogen, -NO 2 , -OR 8 , -C (O) R 8 , -C (O) OR 8 , -C (O) NR 8 R 9 , -NR 8 R 9 , -NR 8 C (O) R 9 , -NR 8 C (O) OR 9 , -NR 8 C (O) NR 9 R 10 , -NR 8 C (O) ONR 9 R 10 , -NR 8 SO 2 R 9 , -NOR 8 R 9 , -SR 8 , -SOR 8 , -SO 2 R 8 , -SO
- R 8 , R 9 and R 10 are each independently hydrogen or a radical selected from the group consisting of optionally substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent (s) may be the same or different and are selected from the group consisting of halogen, methyl, ethyl, amino, methylamino,
- n 0, 1, 2 or 3 optionally, in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures, and optionally their pharmacologically acceptable acid addition salts.
- One aspect of the invention are compounds of the general formula (1) wherein W is CR 4 .
- R b is a radical selected from the group consisting of hydrogen, -F, -Cl, methyl and ethyl.
- R a and R c are each independently hydrogen or fluorine; or an optionally monosubstituted or polysubstituted radical selected from the group consisting of C 1-2 AlCl y, C 2 alkenyl, C 2 alkylalkyl, C 3-6 cycloalkyl, aryl,
- substituent (s) may be the same or different and are selected from the group consisting of hydrogen, halogen,
- An additional aspect of the invention are compounds of the general formula (1) wherein R a and R c are each independently hydrogen or fluorine.
- R 1 and R 2 are each independently hydrogen or optionally substituted C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, or R 1 and R 2 together form a saturated or partially unsaturated 2-5-membered alkyl bridge in which a -CH 2 - group by O, S, -NR 8 or a -CH group may be replaced by N mean
- R 5 is hydrogen, methyl, ethyl, hydroxy, methoxy, ethoxy, amino, methylamino, dimethylamino, F, Cl, Br, O-propargyl, CN, methylthio, CONH 2 , ethynyl, propynyl, butynyl or allyl.
- One aspect of the invention is the use of compounds of general formula (1) as pharmaceuticals.
- Another aspect of the invention is the use of compounds of general formula (1) as medicaments with antiproliferative activity.
- Another aspect of the invention is the use of compounds of general formula (1) for the manufacture of a medicament for the treatment and / or prevention of diseases selected from the group consisting of cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapeutic induced alopecia and Mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases.
- diseases selected from the group consisting of cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapeutic induced alopecia and Mucositis, cardiovascular diseases, nephrological diseases, as well as chronic and acute neurodegenerative diseases.
- An additional aspect of the invention is the use of compounds of general formula (1) for the preparation of a medicament for inhibiting polo-like kinases.
- An essential aspect of the invention is the use of compounds of general formula (1) for the preparation of a medicament for the inhibition of polo-like kinases PLK1.
- An important aspect of the invention is the use of a compound of formula (1) for the manufacture of a medicament for the treatment and / or prevention of tumors based on overexpression of polo-like kinases.
- One aspect of the invention is a method of treating and / or preventing diseases selected from the group consisting of cancer, bacterial and viral infections, inflammatory and autoimmune diseases, chemotherapeutic induced alopecia and mucositis, cardiovascular diseases, nephrological diseases, and chronic and acute neurodegenerative diseases Diseases, characterized in that an effective amount of a compound of the general formula (1) is administered to a patient.
- compositions containing as active ingredient one or more compounds of general formula (1), optionally in combination with customary auxiliaries and / or carriers.
- alkyl substituents are meant in each case saturated, straight-chain or branched aliphatic hydrocarbon radicals (alkyl radical).
- alkenyl substituents are each straight-chain or branched, unsaturated alkyl radicals which have at least one double bond.
- Alkynyl substituents are to be understood as meaning in each case straight-chain or branched, unsaturated alkyl radicals which have at least one triple bond.
- Haloalkyl refers to alkyl radicals in which one or more hydrogen atoms are replaced by halogen atoms.
- Halogen refers to fluorine, chlorine, bromine and / or iodine atoms.
- Cycloalkyl is a monocyclic or bicyclic ring, it being possible for the ring system to be a saturated ring but also an unsaturated, nonaromatic ring which may optionally also contain double bonds, for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, Cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, spiro [5.5] undecane, spiro [5.4] decane and spiro [4.4] nonane.
- Heterocyclyl refers to saturated or unsaturated, non-aromatic, mono-, bicyclic, bridged or spirocyclic bicyclic rings containing 5 to 12 carbon atoms, which bear one or more identical or different heteroatoms, such as nitrogen, oxygen or sulfur, instead of one or more carbon atoms.
- the measurement is carried out in deuterated dimethyl sulfoxide-d6. If other solvents are used, these are explicitly stated in the examples or in the methods.
- the measured values are given on a delta scale in the unit ppm. As a standard, tetramethylsilane is used.
- the measurement is carried out on an Avance 400 (400 MHz NMR spectrometer) from Bruker Biospin GmbH.
- End point consists of 5% water and 95% acetonitrile.
- Such diseases include, for example: viral infections (eg HIV and Kaposi sarcoma); Inflammation and autoimmune diseases (eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin disorders (eg psoriasis); Bone diseases; cardiovascular diseases (eg restenosis and hypertrophy). Further, they are useful as protection of proliferating cells (eg, hair, intestinal, blood and progenitor cells) against DNA damage by radiation, UV treatment and / or cytostatic treatment (Davis et al., 2001).
- viral infections eg HIV and Kaposi sarcoma
- Inflammation and autoimmune diseases eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing
- bacterial, fungal and / or parasitic infections eg, colitis, arthritis, Alzheimer's disease, glomerulonephritis
- novel compounds can be used for the prevention, short-term or long-term treatment of the abovementioned diseases, also in combination with other active substances which are used for the same indications, for example cytostatics, hormones or antibodies.
- the effect of the compounds according to the invention was determined in the PLK1 inhibition assay, in the cytotoxicity test on cultured human tumor cells and / or in a FACS analysis, for example on HeLa S3 cells.
- the compounds showed a good to very good activity in both test methods, ie, for example, an EC 50 value in the HeLa S3 cytotoxicity test of less than 5 ⁇ mol / L, generally less than 1 ⁇ mol / L and an IC 50 value in the PLK1 inhibition assay smaller 1 ⁇ mol / L.
- Recombinant human and at its N-terminal end linked to GST PLK1 enzyme is isolated from baculovirus-infected insect cells (Sf21). The purification is carried out by affinity chromatography on glutathione Sepharose columns.
- the number of cells is determined, the cells are centrifuged off (5 minutes, 4 ° C., 800 rpm) and 1 ⁇ with PBS (8 g NaCM, 0.2 g KCl / l, 1.44 g Na 2 HPO 4 / l, 0.24 g KH 2 PO4 / 1). After centrifuging again, the pellet is frozen in liquid nitrogen shock.
- the pellet is thawed rapidly and poured into ice-cold lysis buffer (50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 5 ⁇ g / ml leupeptin, 5 ⁇ g / ml aprotinin, 100 ⁇ M NaF, 100 ⁇ M PMSF, 10 mM ⁇ -glycerol phosphate, 0.1 mM Na 3 VO 4 , 30 mM 4-nitrophenylphosphate) to IxIO 8 cells / 17.5 ml. The cells are lysed for 30 minutes on ice.
- ice-cold lysis buffer 50 mM HEPES pH 7.5, 10 mM MgCl 2 , 1 mM DTT, 5 ⁇ g / ml leupeptin, 5 ⁇ g / ml aprotinin, 100 ⁇ M NaF, 100 ⁇ M PMSF, 10 mM ⁇ -glyce
- the protein concentration is determined by Bradford assay.
- cells of the cervical carcinoma tumor cell line HeLa S3 obtained from American Type Culture Collection (ATCC) were cultured in Ham's F12 medium (Life Technologies) and 10% fetal bovine serum (Life Technologies) and tested in the log growth phase harvested.
- the HeLa S3 cells were then introduced into 96-well plates (Costar) with a density of 1000 cells per well and incubated overnight in an incubator (at 37 ° C. and 5% CO 2 ), with 6 wells on each plate only with Medium were filled (3 wells for medium control, 3 wells for incubation with reduced AlamarBlue reagent).
- the active substances were added to the cells in different concentrations (dissolved in DMSO; final DMSO concentration: 0.1%) (in triplicate in each case). After 72 hours of incubation, 20 ⁇ l of AlamarBlue reagent (AccuMed International) were added to each well and the cells were incubated for a further 7 hours.
- AlamarBlue reagent 20 ⁇ l of reduced AlamarBlue reagent were added to 3 wells (AlamarBlue reagent, which was autoclaved for 30 min). After 7 h of incubation, the color conversion of the AlamarBlue reagent in the individual wells was determined in a Perkin Elmer fluorescence spectrophotometer (Exitation 530 nm, emission 590 nm, Slits 15, Integrate time 0.1). The amount of reacted AlamarBlue reagent represents the metabolic activity of the cells. The relative cell activity was calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the drug concentration, which inhibits the cell activity to 50% (IC 50 ) derived. The values were calculated from the average of three individual determinations - with correction of the blank value (medium control).
- PI Propidium iodide
- PI Propidium iodide
- stoichiometrically binds to double-stranded DNA, and is thus capable of determining the proportion of cells in the Gl, S, and G2 / M phase of the cell cycle based on the cellular DNA content.
- Cells in the GO and Gl phases have a diploid DNA content (2N), while cells in G2 or mitosis have a 4N DNA content.
- 2N diploid DNA content
- G2 or mitosis have a 4N DNA content.
- PI staining for example, 0.4 ml HeLa S3 cells were seeded onto a 75 cm 2 cell culture flask, after 24 h either 0.1% DMSO was added as a control or the substance was added in various concentrations (in 0.1% DMSO).
- the cells were incubated with the substance or with DMSO for 24 h before the cells were washed twice with PBS and then with trypsin / EDTA.
- the cells were centrifuged (1000 rpm, 5 min, 4 ° C) and the cell pellet washed twice with PBS before the cells were resuspended in 0.1 ml PBS. Subsequently, the cells were fixed for 16 hours at 4 ° C or alternatively for 2 hours at -20 ° C with 80% ethanol.
- the fixed cells (10 6 cells) were centrifuged (1000 rpm, 5 min, 4 ° C), washed with PBS and then centrifuged again.
- the cell pellet was resuspended in 2 ml of Triton X-100 in 0.25% PBS and incubated on ice for 5 min before 5 ml of PBS was added and centrifuged again.
- the cell pellet was resuspended in 350 ⁇ l PI staining solution (0.1 mg / ml RNase A, 10 ⁇ g / ml prodidium iodide in 1 ⁇ PBS).
- the cells were incubated with the staining buffer for 20 min in the dark before being transferred to sample vials for the FACS scan.
- the DNA measurement was carried out in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest program (BD).
- the logarithmic PI fluorescence was determined with a band-pass filter (BP 585/42).
- the quantification of the cell populations in the individual cell cycle phases was carried out with the ModFit LT program of Becton Dickinson.
- compounds of the invention were tested on additional tumor cells.
- these compounds are based on carcinomas of various tissues (eg, breast (MCF7), colon (HCT16), head and neck (FaDu), lung (NCI-H460), pancreas (BxPC-3), prostate (DU145)).
- Sarcomas eg, SK-UT-IB
- leukemias and lymphomas eg, HL-60, Jurkat, THP-I
- other tumors eg, melanoma (BRO), gliomas (U-87MG )
- This demonstrates the broad applicability of the compounds according to the invention for the treatment of a wide variety of tumor types.
- the compounds of the general formula (I) can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances.
- Suitable application forms are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (s.c., i.V., i.m.) and infusion, juices, emulsions or dispersible powders.
- the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, i. in amounts sufficient to reach the dosage range given below.
- the said doses may, if necessary, be given several times a day.
- Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants, such as
- Magnesium stearate or talc, and / or agents for obtaining the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate are obtained.
- the tablets can also consist of several layers.
- Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
- the core can also consist of several layers.
- the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
- Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract.
- a sweetener such as saccharin, cyclamate, glycerol or sugar
- a taste-improving agent for example flavorings, such as vanillin or orange extract.
- Injection and infusion solutions are prepared in a conventional manner, e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, if appropriate using emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection vials or ampoules or infusion bottles.
- isotonic agents e.g. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, if appropriate using emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as solubilizer
- the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
- inert carriers such as lactose or sorbitol
- Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats or polyethylene glycol or its derivatives.
- suitable carriers such as neutral fats
- ground natural minerals eg kaolins, clays, talc, chalk
- ground synthetic minerals eg fumed silica and silicates
- sugars eg pipe, milk and dextrose
- emulsifiers eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone
- lubricants eg Magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
- the application is carried out in a customary manner, preferably orally or transdermally, particularly preferably orally.
- the tablets may, of course, besides the abovementioned excipients also additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
- the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
- solutions of the active ingredients may be employed using suitable liquid carrier materials.
- the dosage for intravenous use is 1 - 1000 mg per hour, preferably between 5 - 500 mg per hour.
- the finely ground active substance, lactose and part of the corn starch are mixed together.
- the mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
- the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
- the mixture is compressed into tablets of suitable shape and size.
- the active ingredient is dissolved in water at its own pH or optionally at pH 5.5-6.5 and treated with sodium chloride as isotonan.
- the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.
- the vials contain 5 mg, 25 mg and 50 mg active ingredient.
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05779168A EP1784406A1 (de) | 2004-08-27 | 2005-08-19 | Dihydropteridinone, verfahren zu deren herstellung und deren verwendung als arzneimittel |
JP2007528834A JP2008510771A (ja) | 2004-08-27 | 2005-08-19 | ジヒドロプテリジノン、その製造方法および医薬薬剤としてのその使用 |
CA002578560A CA2578560A1 (en) | 2004-08-27 | 2005-08-19 | Dihydropteridinones, method for the production thereof, and use thereof as a medicament |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04020339 | 2004-08-27 | ||
EP04020339.0 | 2004-08-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006021548A1 true WO2006021548A1 (de) | 2006-03-02 |
Family
ID=34926318
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2005/054099 WO2006021548A1 (de) | 2004-08-27 | 2005-08-19 | Dihydropteridinone, verfahren zu deren herstellung und deren verwendung als arzneimittel |
Country Status (5)
Country | Link |
---|---|
US (1) | US7371753B2 (de) |
EP (1) | EP1784406A1 (de) |
JP (1) | JP2008510771A (de) |
CA (1) | CA2578560A1 (de) |
WO (1) | WO2006021548A1 (de) |
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-
2005
- 2005-08-19 EP EP05779168A patent/EP1784406A1/de not_active Withdrawn
- 2005-08-19 CA CA002578560A patent/CA2578560A1/en not_active Abandoned
- 2005-08-19 JP JP2007528834A patent/JP2008510771A/ja active Pending
- 2005-08-19 WO PCT/EP2005/054099 patent/WO2006021548A1/de active Application Filing
- 2005-08-25 US US11/211,783 patent/US7371753B2/en active Active
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WO2001019825A1 (en) * | 1999-09-15 | 2001-03-22 | Warner-Lambert Company | Pteridinones as kinase inhibitors |
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WO2007071952A1 (en) * | 2005-12-21 | 2007-06-28 | Astrazeneca Ab | Piperazine compounds useful as antagonists of c-c chemokines (ccr2b and ccr5) for the treatment of inflammatory diseases |
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US8278450B2 (en) | 2007-04-18 | 2012-10-02 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
JP2010527364A (ja) * | 2007-05-16 | 2010-08-12 | イーライ リリー アンド カンパニー | トリアゾリルアミノピリミジン化合物 |
WO2009071480A3 (en) * | 2007-12-04 | 2009-11-05 | Nerviano Medical Sciences S.R.L. | Substituted dihydropteridin-6-one derivatives, process for their preparation and their use as kinase inhibitors |
JP2011505403A (ja) * | 2007-12-04 | 2011-02-24 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | 置換ジヒドロプテリジン−6−オン誘導体、その製造方法及びキナーゼ阻害剤としてのその使用 |
WO2009071480A2 (en) * | 2007-12-04 | 2009-06-11 | Nerviano Medical Sciences S.R.L. | Substituted dihydropteridin-6-one derivatives, process for their preparation and their use as kinase inhibitors |
US8598172B2 (en) | 2007-12-04 | 2013-12-03 | Nerviano Medical Sciences S.R.L. | Substituted dihydropteridin-6-one derivatives, process for their preparation and their use as kinase inhibitors |
EP2100894A1 (de) | 2008-03-12 | 2009-09-16 | 4Sc Ag | Pyridopyrimidinone verwendbar als Plk1 (polo-like kinase) Hemmen |
WO2009130016A1 (en) * | 2008-04-22 | 2009-10-29 | Gpc Biotech Ag | Dihydropteridinones as plk inhibitors |
EP2112152A1 (de) | 2008-04-22 | 2009-10-28 | GPC Biotech AG | Dihydropteridinones als Plk-Inhibitoren |
EP2325185A1 (de) | 2009-10-28 | 2011-05-25 | GPC Biotech AG | Plk-Inhibitor |
WO2012085126A1 (en) | 2010-12-21 | 2012-06-28 | Boehringer Ingelheim International Gmbh | Oxindolopyrimidine as igf1r receptor inhibitors |
US9006226B2 (en) | 2012-02-23 | 2015-04-14 | Boehringer Ingelheim International Gmbh | Dihydropteridinones I |
US8865716B2 (en) | 2012-02-23 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Dihydropteridinones II |
WO2014127816A1 (en) * | 2013-02-21 | 2014-08-28 | Boehringer Ingelheim International Gmbh | Dihydropteridinones ii |
WO2014127815A1 (en) * | 2013-02-21 | 2014-08-28 | Boehringer Ingelheim International Gmbh | Dihydropteridinones i |
WO2015011084A1 (de) * | 2013-07-23 | 2015-01-29 | Bayer Pharma Aktiengesellschaft | Substituierte dihydropyrido[3,4-b]pyrazinone als duale inhibitoren von bet-proteinen und polo-like kinasen |
CN105555786A (zh) * | 2013-07-23 | 2016-05-04 | 拜耳制药股份公司 | 作为BET蛋白和极体样激酶的双重抑制剂的取代的二氢吡啶并[3,4-b]吡嗪酮 |
WO2015193228A1 (de) * | 2014-06-19 | 2015-12-23 | Bayer Pharma Aktiengesellschaft | Bet-proteininhibitorische 1,4-dihydropyrido[3,4-b]pyrazinone mit para-substituierter aromatischer amino- oder ethergruppe |
DE102017005089A1 (de) | 2016-05-30 | 2017-11-30 | Bayer Pharma Aktiengesellschaft | Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one |
DE102017005091A1 (de) | 2016-05-30 | 2017-11-30 | Bayer Pharma Aktiengesellschaft | Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one |
Also Published As
Publication number | Publication date |
---|---|
US20060046990A1 (en) | 2006-03-02 |
JP2008510771A (ja) | 2008-04-10 |
CA2578560A1 (en) | 2006-03-02 |
EP1784406A1 (de) | 2007-05-16 |
US7371753B2 (en) | 2008-05-13 |
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