[go: up one dir, main page]

WO2008046242A1 - Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations - Google Patents

Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations Download PDF

Info

Publication number
WO2008046242A1
WO2008046242A1 PCT/CN2006/002708 CN2006002708W WO2008046242A1 WO 2008046242 A1 WO2008046242 A1 WO 2008046242A1 CN 2006002708 W CN2006002708 W CN 2006002708W WO 2008046242 A1 WO2008046242 A1 WO 2008046242A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
propyl
group
bromophenyl
tert
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
Application number
PCT/CN2006/002708
Other languages
English (en)
Chinese (zh)
Inventor
Zhiqiang Feng
Xiaoguang Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS and PUMC
Original Assignee
Institute of Materia Medica of CAMS and PUMC
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Institute of Materia Medica of CAMS and PUMC filed Critical Institute of Materia Medica of CAMS and PUMC
Priority to PCT/CN2006/002708 priority Critical patent/WO2008046242A1/fr
Publication of WO2008046242A1 publication Critical patent/WO2008046242A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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

Definitions

  • Novel quinazoline derivatives their preparation and pharmaceutical compositions and uses
  • the present invention relates to a quinazoline derivative of the formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof, a polycrystal and a eutectic thereof, a precursor or derivative of the same biological function, and a preparation thereof
  • Chemotherapy is an important means to inhibit tumor growth and cancer cell proliferation, and to make tumors disappear.
  • Most of the traditional chemotherapy drugs are cytotoxic drugs that directly attack DNA or inhibit their synthesis and function. They also kill cancer cells and kill normal cells, and are effective only for tumors with rapid proliferation and strong side effects.
  • cytotoxic drugs that directly attack DNA or inhibit their synthesis and function. They also kill cancer cells and kill normal cells, and are effective only for tumors with rapid proliferation and strong side effects.
  • Another way of studying anticancer agents that do not inhibit the mechanism of DNA synthesis has been studied.
  • Epidermal growth factor receptor is a membrane surface transduction system with tyrosine kinase activity, which is ubiquitously expressed in human epidermal cells and stromal cells, and is highly expressed in various human malignant tumors, promoting tumor cell proliferation. , angiogenesis, adhesion, invasion and metastasis, inhibiting apoptosis of tumor cells (Pharmacol Ther, 82, 241 (1999)).
  • EGFR consists of three parts: the extracellular coordination region, the transmembrane region, and the intracellular tyrosine kinase domain.
  • the ligand When the ligand coordinates with the foreign domain of the receptor EGFR, it leads to dimerization between the receptor EGFR or dimerization with another ErbB receptor, and the formation of the dimer leads to activation of the receptor tyrosine kinase and binding to ATP. Autophosphorylation and transphosphorylation occur in the dimer, which promotes the phosphorylation of six specific tyrosine residues in the receptor. Finally, the six substrate enzymes of the SH2 protein are sequentially recognized, and the signal is introduced into the cell.
  • EGFR is highly expressed in a variety of human malignancies, including breast cancer, ovarian cancer, non-small cell lung cancer, and squamous cell carcinoma. Therefore, EGFR and its ligands play an important role in the development of various tumors.
  • EP0566226, W09961428, W00051587, W00375947, W00132651, W09633980, W09630347, etc. almost all have the structural characteristics of 4-anilinoquinazoline (II) -
  • W092 I 20642 discloses monocyclic or bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors.
  • An object of the present invention is to provide a novel 4-amido-substituted quinazoline derivative, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, polymorph or eutectic.
  • Another object of the present invention is to provide a process for the preparation of a 4-amido-substituted quinazoline derivative.
  • a further object of the present invention is to provide a pharmaceutical composition comprising one or more such compounds.
  • 3-morpholinopropyl 3-piperidinopropyl, 3-(piperazin-1-yl)propyl, 2-(4-methylpiperazine-bu)ethyl, 3- (4 -methylpiperazine-1-yl)propyl, 2-(2-methanesulfonylethoxy)ethyl, 2-(2-methanesulfonylethylamino)ethyl, 2-(2-methanesulfonyl) Ethyl)ethyl;
  • R n is particularly preferably independently selected from the group consisting of: methyl, 2-methoxyethyl, (N-methylpiperidin-4-yl)methyl, 3-morpholinopropyl;
  • R3 is selected from the group consisting of methyl, ethyl, n-propyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-acetoxypropyl, 4-acetoxybutyl, methoxy, ethoxy, n-propyl Oxyl, isopropoxy, tert-butoxy, acetomethoxymethoxy, tert-butyryloxymethoxy, benzyloxy, 3-fluorobenzyloxy,
  • R3 is selected from the group consisting of methyl, n-propyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-acetoxypropyl, 4-acetoxybutyl, methoxy, ethoxy, isopropoxy, Tert-butoxy, tert-butyryloxymethoxy, acetoxymethoxy, benzyloxy, 3-fluorobenzyloxy, 2-morpholinoethoxy
  • 3-morpholinopropoxy 2-piperidinoethoxy, 3-piperidinopropoxy, 2-(piperazine-1-yl)ethoxy, 3-(piperazine-1 -yl)propoxy, 2-(4-methylpiperazine-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-pyrrolidino Oxylate, 3-pyrrolidinopropoxy, 2-(2-oxopyrrolidino)ethoxy, 3-(2-oxopyrrolidino)propoxy, 2-(imidazole- 1-yl)-ethoxy, 3-(imidazol-1-yl)-propoxy, benzoyloxymethoxy.
  • R3 is more preferably n-propyl, 3-acetoxypropyl, methoxy, isopropoxy, tert-butoxy, benzyloxy, 2-morpholinoethoxy, 3-morpholinopropoxy , 3-piperidinopropoxy, tert-butyryloxymethoxy, 3-(piperazin-1-yl)propoxy, 3-(4-methylpiperazine-1-yl)propoxy , 3-pyrrolidinopropoxy, 3-(2-oxopyrrolidino)propoxy, 3-(oxazol-1-yl)-propoxy.
  • R3 is particularly preferably 3-acetoxypropyl, methoxy, isopropoxy, tert-butoxy, benzyloxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 3-piperidyl Pyridylpropoxy, tert-butyryloxymethoxy, acetoxymethoxy, benzoyloxymethoxy; Most preferably R3 is tert-butoxy, ethoxy, methoxy, ethyl, t-butyryloxymethoxy.
  • R4 is selected from the group consisting of: mono- or poly-substituted phenyl, mono- or poly-substituted benzyl, mono- or poly-substituted benzoyl, mono- or poly-substituted benzenesulfonyl; substituent selected from halogen, methyl , trifluoromethyl, hydroxymethyl, hydroxy, nitro, cyano, amino, substituted amino, acylamino, carboxy, ester, aminoacyl, alkoxy, alkanoyloxy, alkenyl, halobenzyl Oxyl, halobenzylamino, halophenoxy, halophenylamino;
  • R4 is preferably 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 3-cyanophenyl, 3,5-dibromo-4-hydroxy Phenyl, 3-chlorophenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-methylphenyl, 2-fluoro-4-bromophenyl, 1-phenylethyl, 4 -carbamoylphenyl, 3-alkenylphenyl, 3-alkynylphenyl, 2-methylbenzenesulfonyl, 3-chloro-4-(3-fluorobenzyloxy)phenyl, N-benzyl Isoxazolyl, 4-cyano-2-fluorophenyl, 3-hydroxy-4-methoxyphenyl, 2,4-difluorophenyl, 2-fluoro-4-methoxyphenyl;
  • R4 is 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3, 5-dibromo-4-hydroxyphenyl, 3-chlorophenyl, 3-fluorophenyl , 3-chloro-4-fluorophenyl, 3-methylphenyl, 2-fluoro-4-bromophenyl, phenylethyl, 2-methylbenzenesulfonyl, 3-chloro-4- (3 - fluoroquinone;
  • R4 is particularly preferably 3-bromophenyl, 3-bromo-4-hydroxyphenyl, 3-hydroxyphenyl, 3,5-dibromo-4-hydroxyphenyl, 3-chlorophenyl, 3-chloro-4 -fluorophenyl, 2-fluoro-4-bromophenyl; R4 is most preferably 3-bromophenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-bromophenyl. The most preferred compound is
  • a particularly preferred compound of the present invention is a quinazoline derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof, more preferably a methanesulfonate, and most preferably N-(6-morpholinyloxy) - 7 -Methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)-tert-butoxycarboxamide methanesulfonate to prepare the compound of formula I of the present invention
  • the preparation method of the present invention is to use a substituted aniline to react with an acid chloride or an ester or an anhydride to give an N-substituted amide, and then react with a quinazoline derivative having an easily leaving group at the 4-position in the presence of a base.
  • a 4-aminoamidoquinazoline derivative (X is an easy leaving group).
  • the easy leaving group includes a halogen substituent, an acyloxy group, a sulfonyl
  • the quinazoline derivatives of the formula I may exist in the form of solvates or unsolvates, and crystallization with different solvents may result in different solvates.
  • Salts of pharmaceutically acceptable basic quinazoline derivatives of the formula I include different acid addition salts, such as the following acid or organic acid addition salts: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, Methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid.
  • Salts of the pharmaceutically acceptable acidic quinazoline derivatives of the formula I include different alkali metal salts (lithium, sodium, potassium salts), alkaline earth metal salts (calcium, magnesium salts) and ammonium salts, and which provide physiological Salts of acceptable organic bases of cations such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris(2-hydroxyethyl)amine. All of these salts within the scope of the invention can be prepared by conventional methods. In the preparation of the quinazoline derivatives and their solvates and salts thereof, polycrystalline or eutectic may occur under different crystallization conditions.
  • the invention further relates to a pharmaceutical composition comprising a compound of the invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung, and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w, w/o and double emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops Agent, nasal drops, lotion and expectorant, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • Tablets may also be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidant varieties used to prepare the tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizer, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizer or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, and most preferably from 2 to 30 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the compound of the present invention is a tyrosine kinase inhibitor or a precursor thereof, and has remarkable antitumor activity.
  • the compound of the invention has high bioavailability and can be used for the treatment of various human malignant tumors, including head and neck cancer, non-small cell lung cancer, pancreatic cancer, colorectal cancer, bladder cancer and breast cancer, ovarian cancer, flat cells. Cancer, etc. detailed description
  • Measuring instruments Yanaco micro melting point apparatus for melting point and Vaariaan Mercury 300 type nuclear magnetic resonance meter for nuclear magnetic resonance spectrum. Mass spectrometry was performed on a ZAD-2F and VG300 mass spectrometer.
  • Example 1 Preparation of N-(6,7-dimethoxyquinazolin-4-yl)-N-(3-bromophenyl)tert-butoxycarbonylamide.
  • the melting point is: 144 to 146 ° C. 3 ⁇ 4 MR (400M, CDC13), 8 (ppm) 8.61 (S, 1H, ArH), 8.04 (S, 1H, Aril), 7.77 (S, 1H, ArH), 7.12 (m, 2H, ArH), 6.92 ( m,lH, ArH) , 4.22 ( m, 2H, -0CH 2 ) , 3.96 (S, 3H, -0CH 3 ) , 3.72 (m, 4H, - C 0CH 2 - ), 2.51 (m, 6H, N_C ) , 2.06 (m, 2H, - CH 2 -), 1.64 (S, 9H, -CH 3 ) .
  • the cells were cultured in RPMI1640 medium containing 10% calf serum, containing penicillin 100 U/ml, streptomycin 10 ( ⁇ g/ml, subcultured in a 37 ° C, 5% CO 2 incubator.
  • the adherent tumor cells were digested with 0.3% trypsin, and the cell suspension was prepared in RPMI1640 medium containing 10% calf serum at a concentration of 6 ⁇ 10 3 cells/ml.
  • 200 ⁇ l (containing 1000 tumor cells) per well was seeded in a 96-well culture plate, and cultured at 37 ° C for 24 hours.
  • the drug-administered group was added with different concentrations of drugs, and each drug was set to 4 to 5 dose groups, and each group was provided with three parallel holes.
  • the control group was added with an equal volume of solvent. After being placed at 37 ° (4 days in 5% CO 2 incubator, discard the culture solution, add 200 ⁇ l of 0.2% MTT solution (RPMI1640) per well.
  • the dose response curve can be obtained by plotting the different concentrations of the drug and the inhibition rate of the cells, and the half-inhibition degree of the drug is determined therefrom (IC 5 ).
  • the tumor-bearing nude mice with strong tumor growth and no ulceration were selected, and the tumor tissue was cut into 1. 5 mm 3 under sterile conditions, and inoculated into the axilla of one side of the nude mouse.
  • the experiment was divided into three groups: the negative control group, the test drug 2mg/kg, and the positive drug 2mg/kg three different doses of the treatment group, four mice in each group.
  • the transplanted tumor volume grew to about 120 dishes 3 , the cells were grouped and started to be administered. All were administered by intraperitoneal injection.
  • the test drug and the positive drug were injected once a day, and the drug was administered 18 times a week.
  • the administration volume was 2 mg/kg body weight.
  • Example 1 21. 75 23. 17 101. 0415 97. 14% 0. 10 96. 67%
  • SU5271 is a positive control drug. Growth inhibitory effect of the compound of the present invention on human lung cancer A549 xenograft tumor in nude mice
  • Iressa 75 mg/kg*10 167.5 ⁇ 141.6 75.9% 0.16 ⁇ 0.12 71.2%
  • Example 6 37.5 mg kg*10 137.9+ 148.7* 80.1% 0.16 ⁇ 0.11 * 71.3%
  • Example 6 75 mg/kg*10 103.5 ⁇ 71.8* 85.1% 0.13 + 0.14* 76.2%
  • Iressa was a positive control drug, *P ⁇ 0.05 compared with the control group.
  • Example 6 Small 25mg/kg 17days 934. 5 ⁇ 482.9 53.39% 0.78+0.53 56.6%
  • Example 6 50mg/kgX 17days 901.9 ⁇ 353.9 55.02% 0.92 ⁇ 0.37 48.3%
  • Example 6 Large 100mg/kgX 17days 757.7 ⁇ 485.7 62.21% 0.62+0.46 65.1%

Landscapes

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

Abstract

La présente invention concerne de nouveaux dérivés quinazolines de formule générale (I), leurs sels, hydrates, solvates, polycristaux ou cristaux eutectiques pharmaceutiquement acceptables, leurs précurseurs ou dérivés qui présentent des fonctions biologiques analogues, leurs procédés de préparation et les compositions comprenant un ou des composés selon l'invention. La présente invention concerne également les utilisations des composés selon l'invention qui ont des activités antiproliférantes, pour la fabrication de médicaments pharmaceutiques pour le traitement de maladies associées, telle qu'un traitement anti-cancéreux.
PCT/CN2006/002708 2006-10-16 2006-10-16 Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations Ceased WO2008046242A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2006/002708 WO2008046242A1 (fr) 2006-10-16 2006-10-16 Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2006/002708 WO2008046242A1 (fr) 2006-10-16 2006-10-16 Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations

Publications (1)

Publication Number Publication Date
WO2008046242A1 true WO2008046242A1 (fr) 2008-04-24

Family

ID=39313585

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2006/002708 Ceased WO2008046242A1 (fr) 2006-10-16 2006-10-16 Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2008046242A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019067543A1 (fr) * 2017-09-26 2019-04-04 The Regents Of The University Of California Compositions et méthodes de traitement du cancer
US11377451B2 (en) 2019-03-15 2022-07-05 The Regents Of The University Of California Compositions and methods for treating cancer
US12545686B2 (en) 2021-09-23 2026-02-10 Katmai Pharmaceuticals, Inc. Polymorphic forms of (s)-n-(3-bromo-2-fluorophenyl)-7-((4-methylpiperazin-1-yl)methyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine as EGFR inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033980A1 (fr) * 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1999061428A1 (fr) * 1998-05-28 1999-12-02 Parker Hughes Institute Utilisation des quinazolines pour le traitement de tumeurs cerebrales
WO2001032651A1 (fr) * 1999-11-05 2001-05-10 Astrazeneca Ab Derives de quinazoline utilises en tant qu'inhibiteurs du facteur de croissance endotheliale vasculaire (vegf)
DE10040527A1 (de) * 2000-08-18 2002-02-28 Boehringer Ingelheim Pharma Chinazoline und Verfahren zu ihrer Herstellung

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996033980A1 (fr) * 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1999061428A1 (fr) * 1998-05-28 1999-12-02 Parker Hughes Institute Utilisation des quinazolines pour le traitement de tumeurs cerebrales
WO2001032651A1 (fr) * 1999-11-05 2001-05-10 Astrazeneca Ab Derives de quinazoline utilises en tant qu'inhibiteurs du facteur de croissance endotheliale vasculaire (vegf)
DE10040527A1 (de) * 2000-08-18 2002-02-28 Boehringer Ingelheim Pharma Chinazoline und Verfahren zu ihrer Herstellung

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019067543A1 (fr) * 2017-09-26 2019-04-04 The Regents Of The University Of California Compositions et méthodes de traitement du cancer
CN111868039A (zh) * 2017-09-26 2020-10-30 加利福尼亚大学董事会 用于治疗癌症的组合物和方法
US11377451B2 (en) 2019-03-15 2022-07-05 The Regents Of The University Of California Compositions and methods for treating cancer
US12545686B2 (en) 2021-09-23 2026-02-10 Katmai Pharmaceuticals, Inc. Polymorphic forms of (s)-n-(3-bromo-2-fluorophenyl)-7-((4-methylpiperazin-1-yl)methyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine as EGFR inhibitors

Similar Documents

Publication Publication Date Title
CN108349981B (zh) 新型的吡唑并[3，4－d]嘧啶化合物或其盐
EP0824525B1 (fr) Derives de quinazoline
EP0823901B1 (fr) Derive de quinazoline
EP0824527B1 (fr) Derives de quinazoline
US6015814A (en) Quinazoline derivative
KR100296656B1 (ko) 퀴나졸린유도체
JPH10508616A (ja) アニリン誘導体
JP2000505441A (ja) キナゾリン化合物
JP2014521613A (ja) キナゾリン誘導体、その製造方法、中間体、組成物及びその適用
KR101579148B1 (ko) 4-페닐아미노 퀴나졸린 유도체의 다형체, 그 제조 방법 및 용도
JP4564713B2 (ja) 窒素性複素環式化合物、ならびに窒素性複素環式化合物およびその中間体を作製するための方法
CN103304544B (zh) 4-(取代苯胺基)喹唑啉衍生物二甲苯磺酸盐的多晶型物及其制备方法和用途
JP5165680B2 (ja) 不可逆性タンパク質チロシンキナーゼ阻害剤およびその調整方法と使用
CN1854130B (zh) 喹唑啉衍生物、及其制法和药物组合物与用途
CN102531949A (zh) 一种取代苯甲酰胺类化合物及其制备方法和用途
CN110467616B (zh) 含杂芳基取代哒嗪酮结构的三唑并吡嗪类化合物的制备及应用
WO2008046242A1 (fr) Nouveaux dérivés quinazolines, leurs procédés de préparation et leurs utilisations
CN101932326A (zh) 4-苯胺喹唑啉衍生物的制药用途
CN101423513B (zh) 胺基嘧啶衍生物、及其制法和药物组合物与用途
WO2010083649A1 (fr) Dérivés de bisarylurée et leur utilisation
CN120157657A (zh) 含有哌嗪酮的酞嗪酮类化合物、其制备方法、药物组合物和用途
CN119912506A (zh) 1,2-二氮杂䓬-5-甲酰胺类化合物及其制备方法和应用
HK1257146B (en) Novel pyrazolo[3, 4-d] pyrimidine compound or salt thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06804932

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06804932

Country of ref document: EP

Kind code of ref document: A1