EP0885226A1 - 4-amino-pyrimidin-derivate, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung - Google Patents
4-amino-pyrimidin-derivate, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellungInfo
- Publication number
- EP0885226A1 EP0885226A1 EP97907066A EP97907066A EP0885226A1 EP 0885226 A1 EP0885226 A1 EP 0885226A1 EP 97907066 A EP97907066 A EP 97907066A EP 97907066 A EP97907066 A EP 97907066A EP 0885226 A1 EP0885226 A1 EP 0885226A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- amino
- alkyl
- piperidinyl
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
-
- 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
Definitions
- the present invention relates to 4-aminopyrimidine derivatives of the general formula
- R a is a hydrogen atom or a methyl group
- Rb is a phenyl group substituted by the radicals Rj to R3 or a phenylalkyl group in which the phenyl part is substituted by the radicals R * j to R3, where
- RI is a hydrogen, fluorine, chlorine, bromine or iodine atom, an alkyl, trifluoromethyl, ethenyl, ethynyl, alkyloxy, C3_6 cycloalkyl, trifluoromethoxy, cyano, amino, alkylamino , Dialkylamino or nitro group
- R2 is a hydrogen, fluorine, chlorine or bromine atom or an alkyl group and
- R3 represent a hydrogen, fluorine, chlorine or bromine atom
- R c is a morpholine group which is optionally substituted by one or two alkyl groups
- a 1-Piperaz ⁇ nyl distr in the 4-position by a C3_6-cycloalkyl group, by a 3-tetrahydrofuranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 3-pyrrolidin yl, 1-alkyl-3-pyrrolidinyl, 3rd -P ⁇ peridinyl-, 4-Piper ⁇ dinyl-, 1-alkyl-3-p ⁇ peridinyl or 1-alkyl-4-piper ⁇ d ⁇ nyl group is substituted,
- R4 is a hydroxy, alkyloxy, amino, alkylamino, dialkylamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, 2-oxo-1-pyrrolidinyl, 2-oxo-1-p ⁇ pe ⁇ dinyl, alkyl-oxycarbonylamino -, N-Alkyl-alkyloxycarbonylamino-, alkylsulfonylamino-, N-alkyl-alkylsulfonylamino-, C3_6-cycloalkyl-, tetrahydrofuranyl-, tetrahydropyranyl-, pyrrolidinyl-, 1-alkyl-pyrrolid ⁇ nyl-, piperidinyl-, 1-alkynyl-alkyl -, Morpholino-, 1-piperazyl, 4-alkyl-1-piperazinyl, aminoalkyl, alkylamino
- a 1 -azet ⁇ d ⁇ nyloli in the 2 hydrogen atoms in the 3-position are replaced by a straight-chain alkylene bridge with 4 or 5 carbon atoms, wherein in the above-mentioned alkylene bridges each a methylene group by an oxygen atom or by an imino or N- Alkyl imino group can be replaced
- R c represents a (R5NR6) group in which
- R5 represents a hydrogen atom or an alkyl group
- Rg is a C5_7-cycloalkyl group substituted by R4, where R4 is defined as mentioned above, a 3-tetrahydrofuranyl group,
- a 3-Pyrrol ⁇ d ⁇ nyl- or 3- or 4-Piper ⁇ d ⁇ nyixx wherein the ring nitrogen atom of the above-mentioned groups each by an alkyl, alkylcarbonyl, alkyl ⁇ sulfonyl, alkyloxycarbonyl, C3_6-cycloalkyl, 3-tetrahydrofuranyl, 3- or 4-tetra-hydropyranyl, 3-pyrrolidinyl, 1-alkyl-3-pyrrolidinyl, 3- or 4-pipe ⁇ dinyl, 1-alkyl-3-piprodinyl or 1-alkyl-4-piperidnyl group may be substituted ,
- alkyl parts mentioned above each contain 1 to 4 carbon atoms
- R a is a hydrogen atom or a methyl group
- Rb is a phenyl group substituted by the radicals R-j to R3, where
- R- a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, ethyl, trifluoromethyl, methoxy, cyclopropyl, trifluoromethoxy, cyano, nitro or amino group,
- R2 is a hydrogen, fluorine, chlorine or bromine atom
- R3 represent a hydrogen, fluorine, chlorine or bromine atom
- R c is a morpholine group optionally substituted by one or two methyl groups
- R4 is an amino, methylamino, dimethylamino, pyrrolidinyl, 1-methylpyrrolidinyl, piperidinyl, 1-methyip ⁇ pe ⁇ dinyl, morpholino, 1-piperazinyl, 4-methyl-1-piperazin ⁇ yl, hydroxy, methoxy -, carboxy, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, or morpholinocarbonyl group,
- R5 represents a hydrogen atom or a methyl or ethyl group
- RQ is a cyclopentyl or cyclohexyl group substituted by R4, where R4 is defined as mentioned above,
- R a is a hydrogen atom
- Rb is a phenyl group substituted by the radicals R-j to R3, where
- R-j is a hydrogen, fluorine, chlorine or bromine atom, a methyl or amino group
- R2 is a hydrogen, fluorine, chlorine or bromine atom
- R3 represent a hydrogen, fluorine, chlorine or bromine atom
- R c is a morpholino group
- R5 is a hydrogen atom or a methyl group
- Rß is a cyclohexyl group which is substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl or hydroxy group,
- R a and Rb are as defined in the introduction
- Zj is a leaving group such as a halogen atom, a substituted hydroxyl, mercapto, sulfinyl or sulfonyl group such as a fluorine, chlorine or bromine atom, a methoxy, ethoxy, phenoxy, methylsulfinyl, ethylsulfinyl, methylsulfonyl - Or ethyl sulfonyl group and the left end of these bridges is linked to position 5 and the right end of these bridges to position 6 of the py ⁇ midine ring, with a compound of the general formula
- Xt represents one of the radicals mentioned for R c
- the reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, N-methyl-pyrrolid ⁇ n-2-one, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, if appropriate in the presence of an inorganic base, eg sodium carbonate or potassium hydroxide.
- a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, N-methyl-pyrrolid ⁇ n-2-one, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, if appropriate in the presence of an inorganic base, eg sodium carbonate or potassium hydrox
- reaction can also be carried out without a solvent or in an excess of the compound of the general formula III used.
- a reaction accelerator such as a copper salt, a corresponding amino hydrohalide or alkali metal halide at temperatures between 0 and 180 ° C. but preferably carried out at temperatures between 20 and 150 ° C.
- the reaction can also be carried out without a solvent or in an excess of the compound of the general formula III used.
- the subsequent alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, ethyl bromide.
- a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, ethyl bromide.
- Dimethyl sulfate or benzyl chloride optionally in the presence of a tertiary organic base or in the presence of an inorganic base, is advantageously carried out at temperatures between 0 and 150X, preferably at temperatures between 0 and 100 ° C.
- the subsequent reductive alkylation is advantageously carried out with a corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde or acetone in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride at a pH of 6-7 and at room temperature or in the presence a hydrogenation catalyst, for example using hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
- a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride
- a hydrogenation catalyst for example using hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
- the methylation can also be carried out in the presence of formic acid as a reducing agent at elevated temperatures, for example at temperatures between 60 and 120 ° C.
- the subsequent amidation is carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding amine, if appropriate in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran or dioxane, it being possible for the amine used to serve simultaneously as a solvent , optionally in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, 2- (1 H-benzotriazole-1 -yl) -1, 1, 3,3-tetramethyl-uronium tetrafluoroborate, N, N ' -dicyctohexylcarbodiimide, N, N '
- any reactive groups present such as amino or imino groups or carboxy groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
- the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert comes as a protective residue for an amino or imino group.
- the protective radicals for a carboxy group are the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group.
- Any subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, methanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
- an aqueous solvent e.g. in water, methanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
- an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
- an alkali base such as sodium hydroxide or
- a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example using hydrogen in the presence of a Catalyst such as palladium / carbon in a suitable solvent such as methanol.
- Ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
- a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
- cleavage of a tert-butyl or tert. -Butyloxycarbonylres.es is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
- an acid such as trifluoroacetic acid or hydrochloric acid
- iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
- Trifluoracetylrestes are preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C or by treatment with sodium hydroxide solution optionally in the presence of a solvent such Tetrahy ⁇ drofuran at temperatures between 0 and 50 C C
- a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol. Toluene / water or dioxane at temperatures between 20 and 50 ° C.
- the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
- cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
- the cis / trans mixtures obtained can be chromatographed into their ice and trans isomers, the compounds of the general formula I which occur in racemates and obtained by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, in their Separate diastereomers which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above
- the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives such as esters or amides, in particular acids and their activated derivatives or alcohols, with the racemic compound and separation of the diastereomeric salt mixture or derivative obtained in this way, for example due to various solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
- optically active acids are, for example, the D and L forms of tartaric acid or dibenzoylwemic acid, di-o-tolylwine acid, apple acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or china acid.
- the optically active alcohol is, for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example Either (+) - or (-) - menthyloxycarbonyl into consideration
- the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
- acids used for this are hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, fumaric acid, Succinic acid, lactic acid, citric acid, tartaric acid or maleic acid
- the compounds of general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular a specific inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), these for example, by inhibiting ligand binding, receptor diminution or the tyrosine kinase itself. It is also possible for the signal transmission to be blocked on further downward-lying components
- EGF-R epidermal growth factor receptor
- the inhibition of the EGF-R mediated signal transmission can e.g. can be detected with cells which express human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha.
- An ⁇ -terleukin-3 (IL-3) -dependent cell line of murine origin was used here, which was genetically modified in such a way that it expresses functional human EGF-R.
- the proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 7, 2749-2756 (1988) and Pierce. JH et al. In Science 239: 628-631 (1988)).
- the FDC-Pi cell line the production of which by Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980).
- other growth factor-dependent cells can also be used (see, for example, Pierce, JH et al. In Science 239, 628-631 (1988), Shibuya, H. et al. In Cell 70, 57-67 (1992) and Alexander , WS et al. In EMBO J. 10, 3683-3691 (1991)).
- human EGF-R cDNA see Ullrich, A. et al.
- Retrovire ⁇ were used, as in von Rüden, T. et al., EMBO J. 7, 2749 -2756 (1988), with the difference that the retroviral vector LXSN (see Miller, AD et al. In BioTechniques 7, 980-990 (1989)) was used to express the EGF-R cDNA and the line GP as packaging cell + E86 (see Markowitz, D. et al. In J. Virol. 62, 1120-1124 (1988)).
- F / L-HERc cells were in RPMI / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (Bio Whittaker), standard antibiotics and 20 ng / ml human EGF (Promega), cultivated at 37 ° C and 5% CO2.
- FCS fetal bovine serum
- FCS Boehringer Mannheim
- FCS 2 mM glutamine
- standard antibiotics 20 ng / ml human EGF (Promega)
- 20 ng / ml human EGF Promega
- 1.5 ⁇ 10 4 cells per well were cultured in triplicates in 96-well plates in the above medium (200 ⁇ l), the proliferation of the cells using either EGF (20 ng / ml) or murine IL-3 was stimulated.
- the compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overfunction of tyrosine kinases.
- pathophysiological processes which are caused by overfunction of tyrosine kinases.
- tyrosine kinases are, for example, benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
- the compounds of general formula I and their physiologically tolerable salts can be used for the treatment of other diseases which are caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation hematopoietic Cells etc..
- diseases which are caused by aberrant function of tyrosine kinases, such as epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation hematopoietic Cells etc.
- the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitotic inhibitors (e.g. vinblastine), compounds interacting with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc. ), Cytokines (eg interferons), antibodies etc. These combinations can be administered either simultaneously or sequentially.
- topoisomerase inhibitors e.g. etoposide
- mitotic inhibitors e.g. vinblastine
- compounds interacting with nucleic acids e.g. cis-platinum, cyclophosphamide, adriamycin
- hormone antagonists e
- the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg.
- these are mixed with one or more conventional inert carriers and / or diluents, e.g.
- 1 coated tablet contains:
- the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.
- the dragee cores thus produced are coated with a film which essentially consists of hydroxypropylmethyl cellulose.
- the finished film coated tablets are polished with beeswax.
- 1 tablet contains:
- Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50X, sieving is carried out again (1.5 mm mesh size) and the lubricant is added. The finished mixture is processed into tablets.
- Diameter 10 mm, biplane with facet on both sides and partial notch on one side.
- 1 tablet contains:
- the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a 1.5 mm mesh size.
- 1 capsule contains: active ingredient 150.0 mg
- the active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.
- the final mix is filled into size 1 hard gelatin capsules.
- Capsule shell hard gelatin capsule size 1.
- 1 suppository contains:
- Polyethylene glycol 1500 550.0 mg
- Carboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
- the distilled water is heated to 70X.
- Methyl p-hydroxybenzoate and propyl ester and glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring.
- the mixture is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously.
- the sorbitol solution and the Aromas the suspension for evacuation is evacuated under stirring
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE1996108631 DE19608631A1 (de) | 1996-03-06 | 1996-03-06 | 4-Amino-pyrimidin-Derivate, diese Verbindungen enthaltende Arnzeimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE19608631 | 1996-03-06 | ||
DE19629652 | 1996-07-23 | ||
DE19629652A DE19629652A1 (de) | 1996-03-06 | 1996-07-23 | 4-Amino-pyrimidin-Derivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
PCT/EP1997/001057 WO1997032881A1 (de) | 1996-03-06 | 1997-03-03 | 4-amino-pyrimidin-derivate, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
Publications (1)
Publication Number | Publication Date |
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EP0885226A1 true EP0885226A1 (de) | 1998-12-23 |
Family
ID=26023531
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP97907066A Ceased EP0885226A1 (de) | 1996-03-06 | 1997-03-03 | 4-amino-pyrimidin-derivate, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP0885226A1 (pt) |
JP (1) | JP2000506847A (pt) |
KR (1) | KR19990087550A (pt) |
CN (1) | CN1212695A (pt) |
AU (1) | AU710274B2 (pt) |
BG (1) | BG102708A (pt) |
BR (1) | BR9708312A (pt) |
CA (1) | CA2243994A1 (pt) |
CZ (1) | CZ281798A3 (pt) |
DE (1) | DE19629652A1 (pt) |
EE (1) | EE9800277A (pt) |
HU (1) | HUP9901820A3 (pt) |
IL (1) | IL125404A0 (pt) |
NO (1) | NO984084L (pt) |
NZ (1) | NZ331546A (pt) |
PL (1) | PL328771A1 (pt) |
SK (1) | SK120598A3 (pt) |
TR (1) | TR199801749T2 (pt) |
WO (1) | WO1997032881A1 (pt) |
Families Citing this family (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SK285141B6 (sk) | 1996-02-13 | 2006-07-07 | Astrazeneca Uk Limited | Použitie chinazolínového derivátu, chinazolínový derivát, spôsob jeho prípravy a farmaceutická kompozícia, ktorá ho obsahuje |
KR100489174B1 (ko) | 1996-03-05 | 2005-09-30 | 제네카-파마 소시에떼아노님 | 4-아닐리노퀴나졸린유도체 |
EP1396489A1 (en) * | 1999-01-27 | 2004-03-10 | Pfizer Products Inc. | Heteroaromatic bicyclic derivatives useful as anticancer agents |
UA71945C2 (en) * | 1999-01-27 | 2005-01-17 | Pfizer Prod Inc | Substituted bicyclic derivatives being used as anticancer agents |
ATE398120T1 (de) | 1999-11-05 | 2008-07-15 | Astrazeneca Ab | Neue quinazolin-derivate |
EP1638965A1 (en) | 2003-06-24 | 2006-03-29 | NeuroSearch A/S | Novel 8-aza-bicyclo¬3.2.1|octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
WO2006088836A2 (en) * | 2005-02-16 | 2006-08-24 | Schering Corporation | Piperazine-piperidines with cxcr3 antagonist activity |
EP2349235A1 (en) | 2008-11-07 | 2011-08-03 | Triact Therapeutics, Inc. | Use of catecholic butane derivatives in cancer therapy |
WO2010063352A1 (en) * | 2008-12-01 | 2010-06-10 | Merck Patent Gmbh | 2, 5-diamino-substituted pyrido [4, 3-d] pyrimidines as autotaxin inhibitors against cancer |
WO2010099139A2 (en) | 2009-02-25 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Combination anti-cancer therapy |
US20110171124A1 (en) | 2009-02-26 | 2011-07-14 | Osi Pharmaceuticals, Inc. | In situ methods for monitoring the EMT status of tumor cells in vivo |
US8642834B2 (en) | 2009-02-27 | 2014-02-04 | OSI Pharmaceuticals, LLC | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
WO2010099138A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
WO2010099364A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
EP2408479A1 (en) | 2009-03-18 | 2012-01-25 | OSI Pharmaceuticals, LLC | Combination cancer therapy comprising administration of an egfr inhibitor and an igf-1r inhibitor |
CA2780875A1 (en) | 2009-11-13 | 2011-05-19 | Pangaea Biotech, S.L. | Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer |
EP2468883A1 (en) | 2010-12-22 | 2012-06-27 | Pangaea Biotech S.L. | Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer |
US9134297B2 (en) | 2011-01-11 | 2015-09-15 | Icahn School Of Medicine At Mount Sinai | Method and compositions for treating cancer and related methods |
EP2492688A1 (en) | 2011-02-23 | 2012-08-29 | Pangaea Biotech, S.A. | Molecular biomarkers for predicting response to antitumor treatment in lung cancer |
WO2012129145A1 (en) | 2011-03-18 | 2012-09-27 | OSI Pharmaceuticals, LLC | Nscle combination therapy |
JP2014519813A (ja) | 2011-04-25 | 2014-08-21 | オーエスアイ・ファーマシューティカルズ,エルエルシー | 癌薬剤発見、診断、および治療におけるemt遺伝子シグネチャーの使用 |
US20130084286A1 (en) | 2011-08-31 | 2013-04-04 | Thomas E. Januario | Diagnostic markers |
CN104066851A (zh) | 2011-09-30 | 2014-09-24 | 基因泰克公司 | 肿瘤或肿瘤细胞中上皮或间充质表型的诊断性甲基化标志物和对egfr激酶抑制剂的响应 |
WO2013152252A1 (en) | 2012-04-06 | 2013-10-10 | OSI Pharmaceuticals, LLC | Combination anti-cancer therapy |
WO2013190089A1 (en) | 2012-06-21 | 2013-12-27 | Pangaea Biotech, S.L. | Molecular biomarkers for predicting outcome in lung cancer |
EP2961412A4 (en) | 2013-02-26 | 2016-11-09 | Triact Therapeutics Inc | CANCER THERAPY |
WO2014147246A1 (en) | 2013-03-21 | 2014-09-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of chronic liver diseases associated with a low hepcidin expression |
WO2015035410A1 (en) | 2013-09-09 | 2015-03-12 | Triact Therapeutic, Inc. | Cancer therapy |
US20170027940A1 (en) | 2014-04-10 | 2017-02-02 | Stichting Het Nederlands Kanker Instituut | Method for treating cancer |
AU2015371312B2 (en) | 2014-12-24 | 2022-01-27 | Genentech, Inc. | Therapeutic, diagnostic and prognostic methods for cancer of the bladder |
EP4001269A1 (en) | 2016-12-22 | 2022-05-25 | Amgen Inc. | Benzoisothiazole, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine and pyrido[2,3-d]pyrimidine derivatives as kras g12c inhibitors for treating lung, pancreatic or colorectal cancer |
JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
SG11202001499WA (en) | 2017-09-08 | 2020-03-30 | Amgen Inc | Inhibitors of kras g12c and methods of using the same |
EP3788038B1 (en) | 2018-05-04 | 2023-10-11 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
WO2019213526A1 (en) | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
EP3790886B1 (en) | 2018-05-10 | 2024-06-26 | Amgen Inc. | Kras g12c inhibitors for the treatment of cancer |
WO2019232419A1 (en) | 2018-06-01 | 2019-12-05 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
US20190375749A1 (en) | 2018-06-11 | 2019-12-12 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
EP3807276A2 (en) | 2018-06-12 | 2021-04-21 | Amgen Inc. | Kras g12c inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer |
US20210393632A1 (en) | 2018-10-04 | 2021-12-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Egfr inhibitors for treating keratodermas |
JP2020090482A (ja) | 2018-11-16 | 2020-06-11 | アムジエン・インコーポレーテツド | Kras g12c阻害剤化合物の重要な中間体の改良合成法 |
EP3883565A1 (en) | 2018-11-19 | 2021-09-29 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
US20220073504A1 (en) | 2018-12-20 | 2022-03-10 | Amgen Inc. | Kif18a inhibitors |
PE20211475A1 (es) | 2018-12-20 | 2021-08-05 | Amgen Inc | Inhibidores de kif18a |
AU2019401495A1 (en) | 2018-12-20 | 2021-06-24 | Amgen Inc. | Heteroaryl amides useful as KIF18A inhibitors |
US20220056015A1 (en) | 2018-12-20 | 2022-02-24 | Amgen Inc. | Kif18a inhibitors |
SG11202109422WA (en) | 2019-03-01 | 2021-09-29 | Revolution Medicines Inc | Bicyclic heterocyclyl compounds and uses thereof |
MX2021010319A (es) | 2019-03-01 | 2021-12-10 | Revolution Medicines Inc | Compuestos biciclicos de heteroarilo y usos de estos. |
EP3738593A1 (en) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosing of kras inhibitor for treatment of cancers |
CN114144414A (zh) | 2019-05-21 | 2022-03-04 | 美国安进公司 | 固态形式 |
JP2022542392A (ja) | 2019-08-02 | 2022-10-03 | アムジエン・インコーポレーテツド | Kif18a阻害剤としてのピリジン誘導体 |
MX2022001295A (es) | 2019-08-02 | 2022-02-22 | Amgen Inc | Inhibidores de kif18a. |
WO2021026101A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
AU2020324406A1 (en) | 2019-08-02 | 2022-03-17 | Amgen Inc. | KIF18A inhibitors |
EP4048671A1 (en) | 2019-10-24 | 2022-08-31 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
MX2022005357A (es) | 2019-11-04 | 2022-06-02 | Revolution Medicines Inc | Inhibidores de ras. |
EP4055028A1 (en) | 2019-11-04 | 2022-09-14 | Revolution Medicines, Inc. | Ras inhibitors |
AU2020379734A1 (en) | 2019-11-04 | 2022-05-05 | Revolution Medicines, Inc. | Ras inhibitors |
MX2022005525A (es) | 2019-11-08 | 2022-06-08 | Revolution Medicines Inc | Compuestos de heteroarilo bicíclicos y usos de estos. |
US20230192681A1 (en) | 2019-11-14 | 2023-06-22 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
WO2021097207A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
CN114980976A (zh) | 2019-11-27 | 2022-08-30 | 锐新医药公司 | 共价ras抑制剂及其用途 |
TW202140011A (zh) | 2020-01-07 | 2021-11-01 | 美商銳新醫藥公司 | Shp2抑制劑給藥和治療癌症的方法 |
CN115916194A (zh) | 2020-06-18 | 2023-04-04 | 锐新医药公司 | 用于延迟、预防和治疗针对ras抑制剂的获得性抗性的方法 |
MX2023002248A (es) | 2020-09-03 | 2023-05-16 | Revolution Medicines Inc | Uso de inhibidores de sos1 para tratar neoplasias malignas con mutaciones de shp2. |
JP2023541916A (ja) | 2020-09-15 | 2023-10-04 | レボリューション メディシンズ インコーポレイテッド | がんの治療における、ras阻害剤としてのインドール誘導体 |
EP4267250A1 (en) | 2020-12-22 | 2023-11-01 | Qilu Regor Therapeutics Inc. | Sos1 inhibitors and uses thereof |
CN117500811A (zh) | 2021-05-05 | 2024-02-02 | 锐新医药公司 | 共价ras抑制剂及其用途 |
KR20240017811A (ko) | 2021-05-05 | 2024-02-08 | 레볼루션 메디슨즈, 인크. | 암의 치료를 위한 ras 억제제 |
CA3217393A1 (en) | 2021-05-05 | 2022-11-10 | Elena S. Koltun | Ras inhibitors |
AR127308A1 (es) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | Inhibidores ras |
WO2023114954A1 (en) | 2021-12-17 | 2023-06-22 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
WO2024081916A1 (en) | 2022-10-14 | 2024-04-18 | Black Diamond Therapeutics, Inc. | Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL112249A (en) * | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
DE4431867A1 (de) * | 1994-09-07 | 1996-03-14 | Thomae Gmbh Dr K | Pyrimido[5,4-d]pyrimidine, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
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1996
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- 1997-03-03 NZ NZ331546A patent/NZ331546A/xx unknown
- 1997-03-03 CA CA002243994A patent/CA2243994A1/en not_active Abandoned
- 1997-03-03 SK SK1205-98A patent/SK120598A3/sk unknown
- 1997-03-03 BR BR9708312A patent/BR9708312A/pt not_active IP Right Cessation
- 1997-03-03 CZ CZ982817A patent/CZ281798A3/cs unknown
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BR9708312A (pt) | 1999-08-03 |
KR19990087550A (ko) | 1999-12-27 |
CA2243994A1 (en) | 1997-09-12 |
IL125404A0 (en) | 1999-03-12 |
NZ331546A (en) | 2000-03-27 |
CZ281798A3 (cs) | 1999-02-17 |
HUP9901820A2 (hu) | 1999-09-28 |
DE19629652A1 (de) | 1998-01-29 |
TR199801749T2 (xx) | 1998-12-21 |
JP2000506847A (ja) | 2000-06-06 |
WO1997032881A1 (de) | 1997-09-12 |
HUP9901820A3 (en) | 2001-10-29 |
SK120598A3 (en) | 1999-06-11 |
PL328771A1 (en) | 1999-02-15 |
EE9800277A (et) | 1999-02-15 |
NO984084D0 (no) | 1998-09-04 |
NO984084L (no) | 1998-09-04 |
AU1925197A (en) | 1997-09-22 |
BG102708A (en) | 1999-09-30 |
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