WO2013135176A1 - Dérivé d'aminoquinazoline et son utilisation dans la préparation d'un médicament anti-tumeur maligne - Google Patents

Dérivé d'aminoquinazoline et son utilisation dans la préparation d'un médicament anti-tumeur maligne Download PDF

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Publication number
WO2013135176A1
WO2013135176A1 PCT/CN2013/072528 CN2013072528W WO2013135176A1 WO 2013135176 A1 WO2013135176 A1 WO 2013135176A1 CN 2013072528 W CN2013072528 W CN 2013072528W WO 2013135176 A1 WO2013135176 A1 WO 2013135176A1
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formula
compound
cancer
pharmaceutically acceptable
prodrug
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PCT/CN2013/072528
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English (en)
Chinese (zh)
Inventor
殷建明
陶军华
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苏州迈泰生物技术有限公司
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Priority claimed from CN201210069348.7A external-priority patent/CN102838590B/zh
Application filed by 苏州迈泰生物技术有限公司 filed Critical 苏州迈泰生物技术有限公司
Priority to US14/385,734 priority Critical patent/US20150065709A1/en
Publication of WO2013135176A1 publication Critical patent/WO2013135176A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to aminoquinazoline derivatives and their use in the manufacture of a medicament for the prevention and/or treatment of malignant tumors. Background technique
  • the epidermal growth factor receptor (EGFR, HE l/erbB l ) family is one of the most representative receptors for transmembrane receptor tyrosine kinases and has a wide range of biological functions.
  • Various ligands such as epidermal growth factor and transforming growth factor- ⁇ bind to the extracellular portion of EGFR, and transmit mitotic signals to the cells, thereby regulating the cell cycle, regulating the normal differentiation of cells, and promoting damage repair.
  • EGFR also activates the downstream vascular epidermal growth factor receptor (VEGF), which promotes the formation of microvascular networks in solid tumors. Therefore, EGFR plays an important role in the occurrence, development, differentiation, repair and metastasis of tumor cells.
  • VEGF vascular epidermal growth factor receptor
  • EGFR epithelial-derived tumors
  • epithelial-derived tumors such as breast cancer, colorectal cancer, lung cancer, head and neck squamous cell carcinoma, and pancreatic adenocarcinoma.
  • TKI tyrosine kinase inhibitor
  • Human epidermal growth factor receptor-2 (HE2/neu, erbB-2) is a transmembrane receptor in many epithelial tumors such as breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, Overexpression in nasopharyngeal carcinoma, etc., about 25% to 30% of primary breast cancers have overexpression of the HER2/neu gene. Summary of the invention
  • the technical problem to be solved by the present invention is to provide a novel aminoquinazoline derivative which is an ideal EGFR and HER2 kinase inhibitor and can be effectively used for preventing or treating breast cancer, ovarian cancer, gastrointestinal cancer, esophageal cancer, A variety of malignant tumor diseases such as lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, epidermal squamous cell carcinoma, prostate cancer, glioma and nasopharyngeal cancer.
  • the present invention adopts the following technical solutions:
  • ⁇ 1 ⁇ is [12 ⁇ hydrocarbon group, -CH 2 F, -CHF 2, C 2 ⁇ C 12 fluorinated hydrocarbon group, C 2 ⁇ C 12 hydrocarbon chloro; or, as -CkHnO, wherein k is between 3 ⁇ 6 Integer
  • R 2 is fluorine, chlorine, ⁇ ⁇ 12 saturated alkyl or C 2 ⁇ C 12 unsaturated alkenyl or alkynyl or alkynyl;
  • R 3 is fluorine, chlorine, -OCiH 2i C 6 H 4 X, -OCiH 2i C 5 H 4 N, -OCiH 2i C 4 H 3 N 2 or -OCiH 2i C 3 H 2 N 3 , where i is 1 ⁇ An integer between 4;
  • n 0, 1, 2 or 3;
  • A is a five- or six-membered saturated or unsaturated and substituted and unsubstituted heterocyclic structure, a substituted or unsubstituted benzene ring, or A is -NR 5 R 6 , wherein R 5 and R 6 are independently Non-exchangeable hydrogen is unsubstituted in hydrogen, a hydrocarbyl group of 12 , a compound of the formula (I), a pharmaceutically acceptable salt, a hydrate thereof, a prodrug or a metabolite formed by any form of metabolism , or partially or completely replaced by ⁇ ;
  • R 2 is chlorine and R 3 is fluorine; and Ri, n and A have the same meanings as defined above.
  • n is 0 or 1; and j R 2 , R 3 and A have the same meanings as defined above.
  • A is selected from the group consisting of -N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 3 -N(CH 3 )CH 2 Ph, imidazole, Pyridine, and one of unsubstituted and alkyl-substituted butylactam and valerolactam, Ri, R 2 , R 3 and n are as defined above.
  • the compound includes not only a single form of a certain compound, but also a mixture of a plurality of structures satisfying the requirements of the general formula (I), and different isomer forms of the same compound, such as a racemate. , enantiomers, diastereomers, and the like.
  • the pharmaceutically acceptable salts include, but are not limited to, hydrochloride, phosphate, sulfate, acetate, maleate, methanesulfonate, besylate, benzoate, toluenesulfonate , succinate, fumarate, fumarate, tartrate, gallate, citrate, and the like.
  • the compound of formula (I) “Pharmaceutical” means a substance which, upon administration by an appropriate method, is converted into a compound of the formula (I) or a salt thereof by metabolic or chemical reaction in a subject.
  • alkyl refers to a straight-chain, branched or cyclic hydrocarbon group, such as an alkyl group, including but not limited to methyl, ethyl, n-propyl, isopropyl, Isobutyl, tert-butyl, cyclopentyl, cyclohexyl and the like.
  • hydrocarbyl group includes aliphatic hydrocarbon groups and aromatic hydrocarbon groups, wherein the aliphatic hydrocarbon group may be in the form of a linear chain, a branched chain or a ring.
  • the chemical group -CkH ⁇ O in the present invention encompasses all groups satisfying the requirements of the formula, and atoms connected by " - " are attached to other groups.
  • a representative group satisfying Ck ⁇ wO is tetrahydrofuranyl.
  • the preparation of the compounds of the invention can be carried out by synthetic routes to analogous methods well known in the chemical art, especially in accordance with the description contained herein.
  • the reagents are generally obtained from commercial sources or are readily prepared using methods well known to those skilled in the art.
  • the compound provided by the present invention is a novel aminoquinazoline derivative which is an ideal highly efficient dual irreversible tyrosine kinase inhibitor.
  • the compounds of the invention are useful in the preparation of a variety of indications for the treatment or prevention of EGFR and HER2 kinase function, including but not limited to breast cancer, ovarian cancer, gastrointestinal cancer, esophageal cancer, lung cancer, head and neck squamous cell carcinoma, pancreatic cancer , a variety of malignant tumor diseases such as epidermal squamous cell carcinoma, prostate cancer, glioma and nasopharyngeal cancer.
  • Figure 1 is a graphical representation showing the inhibition of the reversibility of EGFR kinase enzyme activity by a compound of formula Ie according to the present invention
  • Fig. 2 is a schematic view showing the inhibition of tumor growth of a nude mouse model H 1975 by the compound of the formula Ie according to the present invention.
  • Figure 3 is a comparative schematic diagram showing the inhibitory effect of the compound of the formula Ie according to the present invention on tumor growth in a nude mouse model H 1975;
  • Figure 4 is a comparative diagram showing the inhibitory effect of the compound of the formula Ie according to the present invention on tumor growth of a nude mouse model A549;
  • Figure 5 is a comparative schematic diagram showing the inhibitory effect of the compound of the formula Ie according to the present invention on tumor growth of a nude mouse model HCC827
  • Figure 6 is a comparative diagram showing the inhibitory effect of the compound of the formula le according to the present invention on tumor growth of a nude mouse model A43 1;
  • Figure 7 is a comparative diagram showing the inhibitory effect of the compound of the formula le according to the present invention on the growth of N87 tumor in a nude mouse model
  • Figure 8 is a comparative diagram showing the inhibitory effect of the compound of the formula le according to the present invention on tumor growth of the nude mouse model MDA-MB-468;
  • Fig. 9 is a comparative diagram showing the inhibitory effect of the compound of the formula le according to the present invention on tumor growth of a nude mouse model CAL27.
  • the compound of formula la can be obtained by the following synthetic route:
  • the obtained target product la was subjected to hydrogen nuclear magnetic resonance iH-NMR (400 MHz, MeOD) and mass spectrometry. The results are as follows:
  • the compound of formula lb has the following chemical formula: This compound can be obtained by subjecting the intermediate 3 and the intermediate 3 a described in Example 1 to a substitution reaction. For the specific preparation process, see Example 1.
  • the obtained target product lb was subjected to hydrogen nuclear magnetic resonance 1 H NMR (400 MHz, MeOD) and mass spectrometry, and the results were as follows:
  • the compound of formula Ic can be obtained by the following synthetic route
  • the preparation method of the compound of formula Ic specifically includes the following steps:
  • the Ie formula Ie compound can be obtained by the following synthetic route:
  • the obtained target product Ie was subjected to hydrogen nuclear magnetic resonance iH-NMR (400 MHz, MeOD) and mass spectrometry, and the results were as follows:
  • the semi-inhibitory concentration of the compound, IC 5Q (the concentration of the compound required to inhibit the enzymatic activity to 50%), is determined by mixing a specific substrate with a fixed enzyme and varying concentrations of the test compound.
  • the assay used was the Caliper Mobility Shift Assay, the kinases tested were EGFR and HER2, and the standard reference compound used was staurosporine.
  • IC 5Q concentration of the compound required to inhibit the enzymatic activity to 50%
  • Table 1 shows the results of inhibition experiments of compound enzyme activity.
  • the results showed that the target compounds (Ia, Ib, Ic, Id, and Ie) had a strong inhibitory effect on EGFR kinase, and the results showed that the target compounds (Ia, Ib, Ic, and Ie) also strongly inhibited HER2 kinase.
  • the inhibitory activity of the compound of formula Ie on EGFR kinase is more than 2 times higher than that of Afatinib, Neratinib and Gefitinib.
  • Table 2 summarizes the results of the EGFR kinase activity inhibition assay for mutants of the compound of formula Ie. The results show that the compound of formula Ie also has a very strong inhibitory effect on the three mutant EGFR kinases, including the single mutant EGFR L858R , EGFR T79OM and the double mutant EGFR L858R/T79() M kinase. Table 2 Results of inhibition of EGFR kinase activity by three compounds of formula Ie
  • test compound The test compound was first dissolved in 100% DMSO in an in vitro study and diluted to the desired concentration with a final concentration of 0.1% DMSO. 0.1% (v/v) DMSO was added to the medium as a solvent control with 9 concentration gradients and the test was repeated twice.
  • Tumor cell line The tumor cell line was cultured in RPMI10 medium containing 10% fetal bovine serum in a 5% C0 2 37 °C incubator.
  • the tumor cell lines tested were: BT474 MDA-MB-23 SK-Br-3 A431 H292 H1975 HCC827 A549 H1650 and H1734
  • MTS method Cells were seeded in 96-well plates at 3000 cells per well and incubated overnight in a 5% C0 2 37 °C humidified incubator. The test compound was added to the wells the next day and incubated for an additional 72 hours. Cell viability was measured using MTS. IC 5Q was calculated (the concentration of drug required to induce 50% inhibition of cell growth compared to the DMSO control group, calculated using nonlinear regression analysis of GraphPad Prism software).
  • WST method A more sensitive WST method was used for further cell viability validation experiments.
  • 9 dose concentrations were set for each test compound, 3 wells per well, ⁇ /well loading; cell control and negative control wells were replaced with dilutions.
  • each well to be tested was added to a ⁇ complete medium cell suspension containing the corresponding number of cells to ensure that the cells of the cell control group just covered the bottom surface of the well when the time required for the culture was reached. Incubate for 48 hours at 37 ° C [0 2 incubator. Aspirate the liquid in the hole to be tested.
  • test results of the compound of formula le listed in Table 3 below and the test results of the compound of formula le listed in Table 4 are obtained by the WST method.
  • Target compound (Ia, Ib, Ic, Id, and le) to BT474, MDA-MB-23 SK-Br-3 A431 BT474, H292, H1975, H cc 827 MDA-MB-231 SK-Br-3 A549, H1650 And H1734 tumor cell inhibitory activity is summarized in Table 3.
  • A549 is greater than 10
  • H1650 is greater than 10
  • MDA-MB-231 is greater than 10000
  • the compounds of the present invention exhibit inhibitory activity against various tumor cells. among them H 1975, A549, H 1650 and HI 734 are tumor cell lines resistant to gefitinib and erlotinib. Further experiments showed that the compound of formula Ie also had a strong inhibitory effect on other various tumor cells, and some of the results are shown in Table 4.
  • the drug was administered orally for 21 days and administered orally (in which Docetaxel was administered once a week).
  • Tumor size and body weight of nude mice were recorded twice a week from the first day of treatment.
  • the volume of the tumor is calculated using the formula (lxw 2 )/, where 1 and w represent the largest and smallest dimensions for each measurement. According to the calculated results, the relationship between the average tumor volume and the number of days after tumor transplantation was plotted.
  • non-small cell lung cancer HCC827 (non-small cell lung cancer), A43 1 (EGFR), N87 (stomach cancer),
  • MDA-MD-468 breast cancer
  • CAL27 head and neck cancer
  • Tumor models such as A549 show better than other similar targeted drugs (such as Erlotinib, Lapatinib, and
  • Afatinib or cytotoxic chemotherapy drug Docetaxel is more potent in inhibiting tumor cell growth.
  • mice CD-I mice, male, 6-7 weeks; body weight: 20 ⁇ 25g;
  • test compound is formulated into 0.2 mg/mL (for intravenous administration) and l .Omg/mL (for oral administration), ready for use.
  • Route of administration Oral / intravenous.
  • Dosing capacity and frequency 5 mL/kg, single administration.
  • Sample collection Blood was collected at the following time points, 3 animals per time point, and about 0.5 - 1.0 mL of whole blood. Blood was taken at 5 min, 15 min, 30 min, l h, 2 h, 4 h, 8 h, and 24 h after administration. All animals were euthanized after the trial was completed.
  • results of the tests in CD-I mice indicate that the compounds of the invention have good pharmacokinetic characteristics including low clearance, good oral absorption, long half-life and high tissue distribution.
  • the compounds of the present invention have excellent physicochemical properties and their drug properties are very good.
  • Experimental method Experimental animals: Rat, female, 6-8 weeks, Weight: 1 80 ⁇ 250g; Canine, female, ⁇ 24 months, Weight: 7 ⁇ 10kg.
  • test sample In the rat test, the mixed powder of the compound of formula Ie is formulated into 0.1, 0.3 and 1 mg/mL hooked suspension for use; route of administration: oral; dosage and frequency of administration: 10 mL/kg , administered once a day for 28 days. Tablets prepared from the compound of formula Ie were directly administered to dogs in a canine test. Afatinib is formulated as a 1 or 2 mg/kg hook suspension to be fed to rats or dogs, respectively.
  • Sample collection Blood was collected on days 1, 10, 20, and 28 at the following time points, with 3 animals at each time point and approximately 120-200 ⁇ whole blood. Blood was taken at 1 h, 4 h, 8 h and 24 h after administration.
  • Sample analysis The collected samples were tested using the LC-MS/MS method.
  • the instrument model used is SHIMADZU20A-API4000.
  • Pharmacokinetic data analysis The obtained plasma concentration data were fitted and calculated using WinNolin according to the non-compartmental model method.
  • the exposure dose (AUC) of the compound of formula Ie in rats was about 5 times higher than that of Afatinib at the same dose, and 1 mg/kg of compound Ie of formula Ie was equivalent to 5 mg/kg of Afatinib drug AUC.
  • AUC exposure dose
  • no toxicity was observed in the 1 mg/kg compound of the compound of the formula Ie, and the animals in the 5 mg/kg Afatinib group at the same AUC had a more toxic reaction; 3 mg/kg of the compound in the compound group Ie were not observed.
  • animals in the 10 mg/kg Afatinib group similar to AUC had very significant toxic effects.
  • the exposure of the compound of formula Ie was similar to Afatinib at the same dose, and no toxicity was observed in the 1 mg/kg compound of the compound of formula Ie, 5 mg/kg of the compound of formula Ie and the animal of 5 mg/kg of Afatinib Toxic reactions have occurred, and the animal toxicity of the Afatinib group is greater than that of the compound of the formula Ie.
  • the toxic side effects of the compound of formula Ie are reversible, and the animal can return to a normal state after the administration is stopped.
  • the compound of the formula Ie (lmg/kg, 3 mg/kg and 10 mg/kg) recovered very quickly, and all animals were very close to the control group after 5-6 days of withdrawal; while Afatinib recovered To be slower, especially in the 10 mg/kg Afatinib high-dose group, the body weight decreased somewhat during the recovery period.
  • the compound of formula Ie showed better safety at the same dose than other similar compounds (such as Afatinib). The effect is smaller.
  • the compounds of the present invention are ideal highly effective dual irreversible tyrosine kinase inhibitors, which are expected to be useful for treating or preventing breast cancer, ovarian cancer, gastrointestinal cancer, esophageal cancer, lung cancer, head and neck. Severe squamous cell carcinoma, pancreatic cancer, epidermal squamous cell carcinoma, prostate cancer, glioma and nasopharyngeal carcinoma have achieved very good results. They can also be combined with different types of medicinal salts to form oral preparations. (tablets or capsules, etc.). Tablets or capsules made with the compounds of the invention may be taken one or more times a day. The compound of the present invention can also be combined with other drugs to prepare a compound preparation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne un nouveau dérivé d'aminoquinazoline et son utilisation dans la préparation d'un médicament anti-tumeur maligne destiné à la prévention et/ou au traitement de celle-ci. Le composé d'aminoquinazoline de la présente invention est un inhibiteur de kinase double idéal, hautement efficace et irréversible pour l'EGFR et le HER2, utilisable dans le traitement ou la prévention de diverses maladies à tumeurs malignes telles que le cancer du sein, le cancer de l'ovaire, le cancer gastro-intestinal, le cancer de l'œsophage, le cancer du poumon, le carcinome à cellules squameuses de la tête et du cou, le cancer du pancréas, le cancer à cellules squameuses de la peau, le cancer de la prostate, le gliome et le cancer naso-pharyngien.
PCT/CN2013/072528 2011-06-21 2013-03-13 Dérivé d'aminoquinazoline et son utilisation dans la préparation d'un médicament anti-tumeur maligne WO2013135176A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/385,734 US20150065709A1 (en) 2011-06-21 2013-03-13 Aminoquinazoline Derivative And Use Thereof In Preparing Anti-Malignant Tumor Medicament

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201210069348.7 2012-03-16
CN201210069348.7A CN102838590B (zh) 2011-06-21 2012-03-16 氨基喹唑啉衍生物及其在制备抗恶性肿瘤药物中的用途
CN201210078590.0 2012-03-23
CN201210078590.0A CN102838550B (zh) 2011-06-21 2012-03-23 喹唑啉巴豆基化合物及其在制备抗恶性肿瘤药物中的用途

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018373A1 (fr) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives de quinazoline, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
CN1751033A (zh) * 2003-02-20 2006-03-22 贝林格尔·英格海姆国际有限公司 双环杂环类,含所述化合物的药物制剂，其用途及制备方法
WO2007054551A1 (fr) * 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Traitement combine du cancer comprenant des inhibiteurs de egfr/her2
WO2007054550A1 (fr) * 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Derives de quinazoline pour le traitement des affections cancereuses
CN102838590A (zh) * 2011-06-21 2012-12-26 苏州迈泰生物技术有限公司 氨基喹唑啉衍生物及其在制备抗恶性肿瘤药物中的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018373A1 (fr) * 2000-08-26 2002-03-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives de quinazoline, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
CN1751033A (zh) * 2003-02-20 2006-03-22 贝林格尔·英格海姆国际有限公司 双环杂环类,含所述化合物的药物制剂，其用途及制备方法
WO2007054551A1 (fr) * 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Traitement combine du cancer comprenant des inhibiteurs de egfr/her2
WO2007054550A1 (fr) * 2005-11-11 2007-05-18 Boehringer Ingelheim International Gmbh Derives de quinazoline pour le traitement des affections cancereuses
CN102838590A (zh) * 2011-06-21 2012-12-26 苏州迈泰生物技术有限公司 氨基喹唑啉衍生物及其在制备抗恶性肿瘤药物中的用途
CN102838550A (zh) * 2011-06-21 2012-12-26 苏州迈泰生物技术有限公司 喹唑啉巴豆基化合物及其在制备抗恶性肿瘤药物中的用途

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