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WO2006119675A1 - Procede de preparation de derives de quinazoline et application pour la fabrication pour le traitement d'une maladie tumorale - Google Patents

Procede de preparation de derives de quinazoline et application pour la fabrication pour le traitement d'une maladie tumorale Download PDF

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WO2006119675A1
WO2006119675A1 PCT/CN2005/000662 CN2005000662W WO2006119675A1 WO 2006119675 A1 WO2006119675 A1 WO 2006119675A1 CN 2005000662 W CN2005000662 W CN 2005000662W WO 2006119675 A1 WO2006119675 A1 WO 2006119675A1
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group
compound
salt
methyl
alkyl
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Wenlin Huang
Xiaohong Zhou
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Priority to CNA200580049762XA priority Critical patent/CN101180279A/zh
Priority to DE112005003498T priority patent/DE112005003498T5/de
Priority to PCT/CN2005/000662 priority patent/WO2006119675A1/fr
Publication of WO2006119675A1 publication Critical patent/WO2006119675A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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 invention belongs to the field of chemical synthesis, and relates to a novel tyrosine kinase inhibitor with anti-tumor effect and a preparation method thereof. Specifically, the invention relates to a preparation method of a quinazoline derivative and a preparation thereof for treating tumor diseases Applications.
  • solid tumors account for the vast majority, and the occurrence, development, recurrence and metastasis of solid tumors depend on the formation of tumor neovascularization.
  • Tumor angiogenesis is a prerequisite for solid tumor growth and metastasis.
  • Tumors that inhibit tumor angiogenesis and block the blood supply of tumor tissues, "starvation therapy”, are considered to be one of the most promising new methods for treating solid tumors.
  • Cancer is an abnormal cellular behavior caused by a dysregulated signal transduction pathway, such as cell growth, survival, altered function, and the ability to form a tumor without loss of differentiation.
  • Tumor growth depends on the ability of the parasitic host to produce new blood vessels to utilize the nutrients and oxygen of the host.
  • the development of solid tumors depends on a tumor-producing growth factor that stimulates host endothelial cell signaling and extends the tumor vasculature (angiogenesis) from existing blood vessels.
  • angiogenesis tumor vasculature
  • VEGF Vascular Endothelial Growth Factor
  • angiogenesis a variety of diseases including malignant tumors Disease is associated with angiogenesis (Fan, et al, 1995, Trends Pharmacol. Sci. 16, 57-66; Folkman, 1995, Nature Medicinel, 27-31). Changes in vascular permeability are thought to play a role in both normal and diseased physiological processes (Cullinan-Bove, et al, 1993, Endocrinology 133, 829-837; Senger, et al, 1993, Cancer and Metastasis Reviews.
  • VEGF is an important stimulator of normal and diseased angiogenesis and vascular permeability changes (Jakeman, et al, 1993, Endocrinology 133, 848-859; Kolch, et al, 1995, Breast Cancer Research and Treatment, 36, 139 -155; Connolly, et al, 1989, J. Biol. Chem. 264, 20017-20024 VEGF antagonism by antibody sequestration with VEGF inhibits tumor growth (Kim, 1993, Nature 362, 841-844) ).
  • Increased expression of VEGF is the result of stimulation of multiple factors, including activation of proto-oncogenes and hypoxemia.
  • Hypoxemia of solid tumors can be caused by inappropriate perfusion of tumor patients, and VEGF promotes neovascularization.
  • VEGF promotes the permeability of the blood vessel wall, accelerates the nutrient and metabolic exchange of the tumor and adjacent tissues, and reduces the natural barrier of the blood vessel wall to cause distant metastasis of the tumor.
  • VEGF has tyrosine kinase activity.
  • the binding of VEGF to its receptor, tyrosine kinase activates the corresponding signal transduction pathway and promotes the formation and proliferation of tumor angiogenesis.
  • the binding of VEGF to its receptor-activated tyrosine kinases (RTs) plays an important role in the biochemical signal transduction pathway of the plasma membrane, which in turn affects tumor growth and metastasis.
  • RTs receptor-activated tyrosine kinases
  • Binding of the ligand to the receptor stimulates the tyrosine kinase activity associated with the receptor, resulting in phosphorylation of tyrosine residues on the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate signal chain-locking and produce a variety of cellular responses.
  • RTK subfamilies defined by amino acid sequence homology have been identified, one of which currently includes a fins-like tyrosine kinase receptor Fit or Fltl, a kinase-containing insertion domain receptor KDR (also known as Flk-1) and another fms-like tyrosine kinase receptor Flt4.
  • VEGF is a positive and direct key regulator of vascular endothelial cells in the process of angiogenesis in solid tumors.
  • VEGF and its receptor KDR/Flk-1 pathway have become resistant.
  • One of the main targets of tumor vascular therapy Inhibition of tyrosine kinase activity is an important way to block tumor angiogenesis.
  • the object of the present invention is to provide a tyrosine kinase inhibitor compound (I) as a tyrosine kinase inhibitor which is a VEGF-associated endothelial cell receptor which contains a kinase receptor insertion domain.
  • Another object of the present invention is to provide a process for the preparation of a tyrosine kinase inhibitor.
  • the present invention discloses a quinazoline derivative relating to the compound (I), a preparation method thereof and a pharmaceutical application as a tumor growth inhibitor.
  • X represents hydrogen, methyl, d-4 fluorenyl; preferably hydrogen, methyl, most preferably hydrogen.
  • Y represents a substituted phenyl group ""( R5 ) n , n is the number of substituents 1, 2, or 3, or 4, and the phenyl group may be simultaneously substituted by 1 to 4 substituents R 5 , respectively, and R 5 may be the same It can also be different.
  • R 5 represents hydrogen, methyl, trifluoromethane, nitro, cyano, C 2 -4 alkyl, C 2 - 4 alkoxy, N-(C 2 - 4 )alkylamine, enzyme, hydroxyl, NN-triazo(4-4)alkylamine, 4- alkylsulfide, Ci- 4 -mercaptosulfonyl;
  • R 5 is preferably C 2 -4 alkyl, nitro, cyano, C 2 - 4 decyloxy, N-(C 2 - 4 )decylamine, hydroxy, -4 alkylsulfide; more preferably C 2 - 4 fluorenyl, C 2 - 4 decyloxy, N-(C 2 - 4 )alkylamine.
  • Z represents a C, 0, S, NH; preferably a 0, S, most preferably a C ⁇ .
  • Z represents a C, 0, S, NH; preferably a 0, S, most preferably a C ⁇ .
  • Z represents methyl, d-4 alkyl; most preferred is methyl.
  • R 2 represents an alkyl group Q- 5 -R 6, C 2 - 6 alkenyl -, C 2 _ 6 alkynyl -, is 4-piperidinyl or 4-piperidinyl substituted in the alkyl group, alkenyl group
  • the alkynyl group and the 4-piperidinyl group may have one or more alkynyl groups, an enzyme group, and an amine group as a substituent.
  • 5 mercapto-, C 2 - 6 alkenyl- is 4-piperidinyl or substituted 4-piperidinyl, and may have 1 on alkyl, alkenyl, alkynyl and 4-piperidinyl or A plurality of alkynyl groups, enzymes, and amine groups are used as a substituent, and R 2 is more preferably d- 5 fluorenyl-R 6; R 6 is preferably a 4-piperidinyl group, and most preferably 4-ethylpiperidinyl group.
  • the compound (I) of the present invention and a salt thereof can be synthesized by reacting the compound (III) with the compound (IV).
  • R 2 , R 3 , , Z, L 1 and X and Y are respectively described as follows:
  • X represents hydrogen, methyl, -4 alkyl
  • ⁇ represents a substituted phenyl group ⁇ Q ⁇ (R 5 ) n , n is 1 to 4, and a phenyl group may be simultaneously substituted with 1 to 4 substituents R 5 , respectively, and R 5 may be the same or different.
  • R 5 represents hydrogen, methyl, trifluoromethyl hydrazine, nitro, cyano, C 2 - 4 alkyl, C 2 - 4 decyloxy, N-(C 2 -4)alkylamine, enzyme, hydroxy , NN- three nitrogen (- 4) alkyl with an amine - 4 alkyl with sulfur, sulfonyl embankment 4;
  • Z represents 0, NH, one or S
  • R 2 represents an alkyl group Q- 5 -R 6, C 2 - 6 alkenyl -, C 2 - 6 alkynyl group -R 6,
  • R 6 is 4-piperidinyl or 4-piperidinyl substituted in the embankment group,
  • the alkenyl group, the alkynyl group and the 4-piperidinyl group may have one or more alkynyl groups, an enzyme group, and an amine group as a substituent;
  • R 3 represents hydrogen, methyl, -4 embankment group, C 2 -6 alkenyl group, C 2 - 6 alkynyl group, a cycloalkyl group embankment, firing of heterocyclic group;
  • L 1 represents a group which can be easily substituted, such as a halogen group, a sulfonyloxy group.
  • the presence of a base facilitates the completion of this reaction.
  • the base can be an organic amino base (such as pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, morphine, N-methylmorphine or diazabicyclo[5,4,0 Eleven carbon-7-ene or alkali metal, alkaline earth metal carbonate or hydroxide (such as sodium carbonate s potassium carbonate, calcium carbonate, NaOH, KOH) o
  • the alkali may also be an alkali metal hydride ( For example, sodium hydride or an alkali metal, alkaline earth metal amino compound (such as sodium amide, sodium bis(trimethylsilyl)amide), preferably 2,6-dimethylpyridine.
  • reaction is better accomplished in the presence of an inert solvent or diluent, such as an alkyl alcohol or ester (such as methanol, 'ethanol, isopropanol or ethyl acetate), a halogenated hydrocarbon (such as dichloromethane, trichloromethane).
  • an inert solvent or diluent such as an alkyl alcohol or ester (such as methanol, 'ethanol, isopropanol or ethyl acetate), a halogenated hydrocarbon (such as dichloromethane, trichloromethane).
  • Bismuth carbon tetrachloride
  • ethers such as tetrahydrofuran, 1,4-dioxane
  • aromatic hydrocarbons such as toluene
  • nonpolar solvents with dipole moments such as hydrazine, hydrazine-dimethylformamide, hydrazine
  • ⁇ -dimethylacetamide ⁇ -methylpyrrol-2-one or dimethyl sulfoxide
  • This reaction can produce the free base of the compound of the invention or its salt (with an HL 1 acid, where L 1 is as described above).
  • its salt can be treated in a conventional manner using the base mentioned above.
  • the compound (I) of the present invention or a salt thereof can also be synthesized by known chemical synthesis methods and procedures.
  • the necessary starting materials can be synthesized according to standard organic chemistry procedures, and the synthesis of these starting materials will be described in the following examples (without limitation). Other necessary starting materials can be synthesized according to similar method steps as described in the Organic Chemistry Handbook.
  • R 5 represents hydrogen, methyl, trifluoromethane, nitrate
  • Z represents 0, NH, a C or S
  • Ri represents methyl, -4- alkyl
  • R 2 represents fluorenyl-R 6 , C 2 - 6 alkenyl-, C 2 - 6 alkynyl-Re; wherein is 4-piperidinyl or substituted 4-piperidinyl, in alkyl, alkenyl, The alkynyl group and the 4-piperidinyl group may have one or more alkynyl groups, an enzyme group, and an amine group as a substituent;
  • R 3 represents hydrogen, methyl, - 4 fluorenyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, cycloalkyl, Heterocyclic sulfhydryl;
  • P 1 represents a phenolic hydroxyl protecting group
  • an inert solvent or diluent e.g., a halogenated solvent of methylene chloride, chloroform or carbon tetrachloride, or an aromatic hydrocarbon solvent, benzene, toluene
  • a certain temperature range such as 10 to 150 ° C (especially 40 to 100 ° C) is conducive to the completion of the reaction.
  • the present invention (a tyrosine kinase inhibitor) is a chemical compound that specifically acts on a tyrosine kinase to inhibit its activity, thereby inhibiting the activity of two high-affinity receptors of VEGF factor, thereby regulating VEGF Secretion.
  • VEGF is a major angiogenic factor in tumor vascular tissue, and the expression of VEGF in tumors is closely related to the complications of some malignant solid tumors. Preclinical studies indicate that established animal models show significant anti-tumor effects after very good tolerated doses in animal experiments. By inhibiting the secretion of VEGF factor, tumor growth can be indirectly inhibited for therapeutic purposes. Compared with the traditional treatment of cancer, the treatment of the invention has the advantages of good targeting, small toxic side effects and the like.
  • Tyrosine kinase receptors have been shown to be important intracellular signal transduction regulators. These proteins are composed of an extracellular ligand binding site linked to an intracellular tyrosine kinase site by a transmembrane motif. Binding of the body forms receptors, aggregates, and activates RTK sites. These enzyme activities catalyze the specific inhibition of the V-phosphate cluster from ATP transfer to the receptor enzyme's own tyrosine associated with KDP to prevent VEGF-regulated signaling in endothelial cells. Promoting the growth of solid tumors is the result of the continuous formation of blood vessels. The formation of blood vessels is a necessary condition for the growth of all solid tumors and the formation of metastases.
  • VEGF plays a key role in action and is a protein inhibition of KDR tyrosine kinase.
  • Factor which is used to inhibit angiogenesis driven by VEGF, thereby inhibiting tumor growth and treating tumors, has broad clinical application prospects.
  • Figure 1 The present invention produced a dose-dependent rat rat glenoid growth plate.
  • Figure 3 shows the inhibitory effect of the compounds of the invention on the growth of colon cancer cells Lovo.
  • Figure 4 shows the inhibitory effect of the compounds of the present invention on tumors in a nude mouse transplantation model of colon cancer LoVo tumor. The invention is described in detail below with reference to the drawings and specific embodiments.
  • the compound of the present invention is a solid substance which is white and powdery.
  • the compound is soluble in water, acidic, and has a pH of about 6.4.
  • the compound (I) and its salt are prepared by a synthesis reaction of the compound (III) and the compound (IV).
  • X is H
  • Y is a tolyl group
  • Z is a C ⁇
  • 1 is a methyl group
  • R 3 is a methyl group and is 11 and L 1 is a 0- + P(CH 2 CH 2 CH 2 CH 3 ) 3 group.
  • the reaction is carried out in a 0.3 mol/L solution of 2,6-dimethylpyridine, and equimolar amounts of the compound (III) and the compound (IV) are added to the reaction liquid, and the reaction liquid contains 0.05% of the total reaction liquid volume.
  • moL/L ethyl acetate the mixture was stirred and heated in a 70 Torr water bath. After 30 minutes, the resulting precipitate was separated by filtration and dried to obtain a product.
  • the product was a white powder which was soluble in water and had a pH of 6.4.
  • the compound (I) and its salt are prepared by a synthesis reaction of the compound (III) and the compound (IV).
  • X is methyl
  • Y is ethylphenyl
  • Z is a C
  • R 2 is 4-vinylpiperidine
  • R 3 is H
  • L 1 is 0- + P( ⁇ >) 3 base.
  • reaction solution contained 0.05 mol/L of trichloromethane as a volume of 8% of the total reaction solution, and the mixture was stirred and heated in a 50-inch water bath, and after 30 minutes, the precipitate formed by filtration was separated and dried. , that is, the product.
  • the product was a white powder which was soluble in water and had a pH of 6.4.
  • the compound (I) and its salt are prepared by a synthesis reaction of the compound (III) and the compound (IV).
  • X is methyl
  • Y is tolyl
  • Z is NH
  • R 2 is 4-ethynylpiperidine.
  • R 3 is an ethyl group and is hydrogen, and L 1 is a 0-+P( ⁇ ) 3 group.
  • the reaction was carried out in a 0.1 mol/L potassium carbonate solution, and equimolar amounts of the compound (III) and the compound (IV) were added to the reaction liquid, and the reaction liquid contained 0.05 mol of IOL isopropanol in an amount of 15% by volume of the total reaction liquid.
  • the reaction was heated in a locrc water bath, and after 20 minutes, the resulting precipitate was separated by filtration and dried to obtain a product.
  • the product was a white powder which was soluble in water and had a pH of 6.4.
  • the compound (I) and its salt are prepared by a synthesis reaction of the compound (III) and the compound (IV).
  • R 2 is 4-vinylpiperidine
  • R 3 is pentynyl
  • X is propyl
  • Y is a nitro group
  • Z is NH
  • L 1 is a 0- + P(CH 2 CH 2 CH 2 CH 3 ) 3 group.
  • the reaction was carried out in a 0.15 moL/L solution of trimethylpyridine, and equimolar amounts of the compound (III) and the compound (IV) were added to the reaction liquid, and the reaction liquid contained 0.08 mol/L of toluene, which was 12% by volume of the total reaction liquid.
  • the reaction was heated in a water bath at 10 ° C, and after 60 minutes, the resulting precipitate was separated by filtration and dried to obtain a product.
  • the product was a white powder which was soluble in water and had a pH of 6.4.
  • the compound (I) and its salt are prepared by a synthesis reaction of the compound (III) and the compound (IV).
  • Ri is propyl
  • R 2 is 4-vinylpiperidine
  • R 3 is H
  • X is methyl
  • Y is ethylphenyl
  • Z is S
  • L 1 is 0- + P(_ ⁇ > ) 3 base.
  • the reaction is carried out in a solution of 0.08 moL/L of 2,6-dimethylpyridine, and an equimolar amount of the compound (III) and the compound (IV) are added to the reaction liquid, and the reaction liquid contains 0.05% by volume of the total reaction liquid.
  • moL/L tetrahydrofuran the mixture was stirred and heated in a water bath at 20 ° C. After 40 minutes, the resulting precipitate was separated by filtration and dried to obtain a product.
  • the product was a white powder which was soluble in water and had a pH of 6.4.
  • the compound (I) and its salt are prepared by a synthesis reaction of the compound (III) and the compound (IV).
  • 1 is ethyl
  • R 2 is 4-vinylpiperidine
  • R 3 is butenyl
  • methyl is methyl
  • X is methyl
  • Y is ethylphenyl
  • Z is one
  • L 1 is 0- + P(C3 ⁇ 4CH 2 CH 2 CH 3 ) 3 group.
  • the reaction was carried out in a 0.2 mol/L sodium amide solution, and equimolar amounts of the compound (III) and the compound (IV) were added to the reaction liquid, and the reaction liquid contained 0.15 mol/LN, N of 5% by volume of the total reaction liquid.
  • Dimethylacetamide the mixture was stirred and heated in a water bath at 60 ° C, and after 30 minutes, the resulting precipitate was separated by filtration and dried to obtain a product.
  • the product was a white powder which was soluble in water and had a pH of 6.4.
  • Examples 7-13 are partial pharmacodynamic experiments of the following compounds
  • Oral administration of the present invention inhibits human xenografts in nude mice.
  • NS is not significant
  • the compound of the present invention inhibits the proliferation of VEGFR tyrosine kinase inhibitor of human umbilical fetal vascular endothelial cells induced by VEGF, but has no effect on the growth of non-VEGF-induced basal cells.
  • VEGFR tyrosine kinase inhibitor of human umbilical fetal vascular endothelial cells induced by VEGF but has no effect on the growth of non-VEGF-induced basal cells.
  • DETAILED DESCRIPTION case containing the 3 H thymidine pyridine ( ⁇ / mL) to a cell concentration of 1 X 10 5 / mL HUVEC were co-cultured, 1H calibrated to be integrated in HUVEC thymidine piperidine, press 10-1 gradient ( The compound of the present invention was diluted at an initial concentration of 800 mg/L, and cultured in HUVEC after integration with 1H of thymosidine to observe the division of HUVEC in the presence or absence of VEGF, EGF or bFGF, and the half inhibitory amount of the compound against HUVEC was measured. .
  • the compound of the present invention strongly and selectively inhibited the proliferation of human umbilical fetal endothelium cells induced by VEGF, and had no effect on the growth of basal endothelial cells at a concentration of 50-fold.
  • This synthetic enzyme analysis (inhibition degree KDR> EGFR> FGFR1) and cell composition analysis (inhibition degree VEGF> EGF> bFGF), also proved that this inhibition of this compound is selective.
  • the compounds of the invention induce growth factor and inhibit basal endothelial cell division
  • EGF endothelial growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • the ability of the present invention to directly inhibit tumor cell growth in vitro is tested to ascertain whether it is directly anti-tumor cell division or indirect anti-tumor growth in the body as considered by most people (e.g., anti-angiogenesis or inhibition of tumor vascular permeability). ), cell division was assessed by thymidine containing 3 H. Specific embodiments as follows: By containing 3 H thymidine nucleoside ( ⁇ / mL) labeled tumor cells, i.e.
  • the compound of the present invention was diluted, and tumor cells in which 3 H-containing thymidine was integrated were added, and the amount of the compound to the tumor cells was measured.
  • the compound of the present invention inhibited tumor cell growth IC 5 () in the range of 0.8 to 1.4 mm (Table 3) at a concentration of 13 to 230 times that of inhibiting VEGF-induced HUVEC division (Table 3).
  • Table 3 The above data indicate that the anti-tumor effect of this compound is mainly to inhibit endothelial cell VEGF signaling factor, rather than directly Anti-tumor cell division.
  • Lovo cell proliferation inhibition assay was performed by MTT assay: Lovo cells in logarithmic growth phase were cultured in 96-well culture plates, and after 48 h, the experimental group was added with 0 to 10 ( ⁇ g/mL of the compound of the present invention, each concentration). Six replicate wells were set up, and the same volume of RPMI 1640 medium containing no compound of the present invention was added to the control well, and blank control wells (cell-free, containing only RPMI 1640 medium) were added.
  • the compound of the present invention has a significant growth inhibitory effect on Lovo cells in a dose-dependent manner: a growth inhibition rate of 50% at a drug concentration of 12.5 ug/mL and a growth inhibition rate at a drug concentration of 25 g/mL. Up to 90% or more.
  • nude mice were divided into two groups: 100mg/kg/day group and 50mg/kg/day group, intraperitoneal injection, continuous administration for 30 days; another blank control group, intraperitoneal injection 0.5% DMSO, 0.2 mL/only, the animals were sacrificed after 30 days of continuous administration, and the tumor volume T/C ratio was calculated, and the T/C ratio was used as an evaluation index; the tumor was weighed, and the tumor inhibition rate was calculated.
  • Fig. 4 The results are shown in Fig. 4.
  • the compound of the present invention can selectively inhibit the phosphorylation of KDR tyrosine kinase, block the tyrosine kinase signal transduction pathway, and thus has an anti-tumor angiogenesis effect, and has obvious tumor growth in the colon cancer LoVo nude mouse xenograft model. Inhibition.

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Abstract

L'invention concerne des dérivés de quinazoline du composé (I), et leur procédé de préparation et leur application en tant que médicament d'inhibition de la croissance tumorale. Les groupes X, Y, Z, R1, R2, R3, R4 du composé (I) sont définis dans la description. Des composés de l'invention peuvent inhiber sélectivement la phosphorylation de la tyrosine kinase, et bloquer la voie de transduction du signal de la tyrosine kinase, inhiber en particulier l'activité de la tyrosine kinase, et ainsi avoir pour effet d'inhiber la vascularisation tumorale et d'atteindre l'objectif de traiter une tumeur maligne.
PCT/CN2005/000662 2005-05-12 2005-05-12 Procede de preparation de derives de quinazoline et application pour la fabrication pour le traitement d'une maladie tumorale Ceased WO2006119675A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CNA200580049762XA CN101180279A (zh) 2005-05-12 2005-05-12 一种作为抗肿瘤药物应用的酪氨酸激酶抑制剂及其制备方法
DE112005003498T DE112005003498T5 (de) 2005-05-12 2005-05-12 Herstellungsverfahren für Chinazolinderivate und Anwendung zur Herstellung zur Behandlung von Tumorerkrankungen
PCT/CN2005/000662 WO2006119675A1 (fr) 2005-05-12 2005-05-12 Procede de preparation de derives de quinazoline et application pour la fabrication pour le traitement d'une maladie tumorale

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Application Number Priority Date Filing Date Title
PCT/CN2005/000662 WO2006119675A1 (fr) 2005-05-12 2005-05-12 Procede de preparation de derives de quinazoline et application pour la fabrication pour le traitement d'une maladie tumorale

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0635498A1 (fr) * 1993-07-19 1995-01-25 Zeneca Limited Dérivés de quinazoline et leur utilisation comme agents anti-cancereux
CN1211240A (zh) * 1996-02-14 1999-03-17 曾尼卡有限公司 作为抗肿瘤剂的喹唑啉衍生物
CN1211239A (zh) * 1996-02-13 1999-03-17 曾尼卡有限公司 作为vegf抑制剂的喹唑啉衍生物
CN1231662A (zh) * 1996-09-25 1999-10-13 曾尼卡有限公司 喹唑啉衍生物和含有喹唑啉衍生物的药用组合物
CN1542004A (zh) * 2003-04-30 2004-11-03 黄文林 一种酪氨酸激酶抑制剂及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0635498A1 (fr) * 1993-07-19 1995-01-25 Zeneca Limited Dérivés de quinazoline et leur utilisation comme agents anti-cancereux
CN1211239A (zh) * 1996-02-13 1999-03-17 曾尼卡有限公司 作为vegf抑制剂的喹唑啉衍生物
CN1211240A (zh) * 1996-02-14 1999-03-17 曾尼卡有限公司 作为抗肿瘤剂的喹唑啉衍生物
CN1231662A (zh) * 1996-09-25 1999-10-13 曾尼卡有限公司 喹唑啉衍生物和含有喹唑啉衍生物的药用组合物
CN1542004A (zh) * 2003-04-30 2004-11-03 黄文林 一种酪氨酸激酶抑制剂及其制备方法和用途

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DE112005003498T5 (de) 2008-03-27

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