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WO2008002039A1 - Dérivés de quinazoline destinés à inhiber le développement de cellules cancéreuses - Google Patents

Dérivés de quinazoline destinés à inhiber le développement de cellules cancéreuses Download PDF

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Publication number
WO2008002039A1
WO2008002039A1 PCT/KR2007/003061 KR2007003061W WO2008002039A1 WO 2008002039 A1 WO2008002039 A1 WO 2008002039A1 KR 2007003061 W KR2007003061 W KR 2007003061W WO 2008002039 A1 WO2008002039 A1 WO 2008002039A1
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WO
WIPO (PCT)
Prior art keywords
chloro
pyrrolidine
quinazolin
acryloyl
carboxyamide
Prior art date
Application number
PCT/KR2007/003061
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English (en)
Inventor
Kwang-Ok Lee
Ji Hyeon Gong
Mi Young Cha
Chang Gon Lee
Young Hoon Kim
Kyuhang Lee
Tae Hun Song
Ji Yeon Song
Young-Jin Park
Eun Young Kim
Eunyoung Lee
Kyungik Lee
Maeng Sup Kim
Gwan Sun Lee
Original Assignee
Hanmi Pharm. Co., Ltd.
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
Priority claimed from KR1020070047460A external-priority patent/KR100929146B1/ko
Application filed by Hanmi Pharm. Co., Ltd. filed Critical Hanmi Pharm. Co., Ltd.
Publication of WO2008002039A1 publication Critical patent/WO2008002039A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel quinazoline derivative and a pharmaceutically acceptable salt thereof for inhibiting the growth of cancer cells induced by epithelial growth factor and its mutants, and a pharmaceutical composition comprising same as an active ingredient.
  • Protein tyrosine kinases play important roles in such cellular regulation, and their abnormal expression or mutation has been observed in cancer cells.
  • Protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to tyrosines located on protein substrates.
  • Many growth factor receptor proteins function as tyrosine kinases to transport cellular signals. The interaction between growth factors and their receptors normally controls the cellular growth, but abnormal signal transduction caused by the mutation or overexpression of any of the receptors often induces tumor cells or cancers.
  • Protein tyrosine kinases have been classified into many families in terms of growth factors, and epithelial cell growth factor (EGF)-related EGF receptor (EGFR) tyrosine kinases have been intensely studied.
  • An EGFR tyrosine kinase is composed of a receptor and tyrosine kinase, and delivers extracellular signals to cell nucleus through the cellular membrane.
  • Various EGFR tyrosine kinases are classified based on their structural differences into EGFR (Erb-Bl), Erb-B2, Erb-B3 and Erb-B4, and each of the above members can form a homodimer- or heterodimer-signal delivery complex. Also, overexpression of more than one of the above mentioned homodimers is often observed in malignant cells. In addition, it is known that both EGFR and Erb- B2 significantly contribute to the formation of heterodimer-signal delivery complexes.
  • Gefitinib drugs for the inhibition of EGFR tyrosine kinases
  • Erlotinib drugs for the inhibition of EGFR tyrosine kinases
  • Lapatinib drugs for the inhibition of EGFR tyrosine kinases
  • drugs for the inhibition of EGFR tyrosine kinases have been developed, e.g., Gefitinib, Erlotinib, Lapatinib and the like.
  • Gefitinib or Erlotinib selectively inhibits EGFR
  • Lapatinib simultaneously inhibits EGFR and Erb-B2, thereby arresting the growth of tumors.
  • T790M a mutant of an EGFR tyrosine kinase, wherein threonine present at a position 790 in exon 20 region of EGFR tyrosine kinase is replaced with methionine (see [Plos Medicine 2005, 2(3), 225-235]), and also that it provides no substantial clinical effect on T790M variation patients.
  • Ri is 2- methoxyethoxy, (tetrahydrofuran-2-yl)methoxy, 2-morpholinoethoxy, (4- methylthiazol-5-yl)ethoxy or 2-(l/7-l,2,4-triazol-l-yl)ethoxy; and R 2 is 3- chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-bromo-3-chloro-2- fluorophenyl, 2,3,4-trifluorophenyl, 3,4-dichlorophenyl, 3,4-dichloro-2- fluorophenyl or 3-chloro-2,4-fluorophenyl, in the quinazoline derivative of formula (I).
  • 'halo' refers to fluoro, chloro, bromo or iodo, unless otherwise indicated.
  • Examples of more preferred compounds of formula (I) according to the present invention are: l) (2 1 S)-l-acryloyl-N-[4-[3-chloro-2-fluoro ⁇ henylamino]-7-(2-methoxy- ethoxy)quinazolin-6-yl]pyrrolidine-2-carboxyamide;
  • Ri and R 2 have the same meanings as defined above.
  • a compound of formula (III) is subjected to a condensation reaction with N-(t ⁇ rt-Boc)-proline in an organic solvent to obtain a compound of formula (II).
  • the condensation agent which may be used in this reaction is l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) or its acid- addition salt.
  • the organic solvent used in this reaction may be pyridine, tetrahydrofuran, methylene chloride or chloroform.
  • an organic or inorganic acid e.g., trifluoroacetic acid or heavy hydrochloric acid
  • an organic solvent e.g., CHCl 3
  • a compound of formula (III) is subjected to a reaction with a compound of formula (V) in an organic solvent (e.g., ethanol) in the presence of acetic acid and sodium cyanoborohydride to obtain a compound of formula (IV).
  • an organic solvent e.g., ethanol
  • a compound of formula (Ib) which corresponds to the inventive compound of formula (I) wherein A is -CH 2 -, is prepared by reacting the compound of formula (IV) with an organic or inorganic acid (e.g., trifluoroacetic acid or concentrated hydrochloric acid) in an organic solvent (e.g., CHCI 3 ) to induce the removal of the protective f-butoxycarbonyl group from the compound of formula (IV), followed by treatment with acryloyl chloride in an organic solvent (e.g., a mixture of tetrahydrofuran and water) in the presence of a base (e.g., sodium bicarbonate).
  • an organic or inorganic acid e.g., trifluoroacetic acid or concentrated hydrochloric acid
  • an organic solvent e.g., CHCI 3
  • acryloyl chloride e.g., a mixture of tetrahydrofuran and water
  • a base e.g., sodium bicarbonate
  • the compound of formula (I) of the present invention can also be used in the form of a pharmaceutically acceptable salt formed with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic
  • inventive compound or a pharmaceutically acceptable salt thereof selectively and efficiently inhibits the growth of cancer cells induced by epithelial growth factor and its mutants, and provides enhanced anticancer effects when combined with another anticancer agent.
  • inventive compound or a pharmaceutically acceptable salt thereof is useful for enhancing the effects of an anticancer agent selected from the group consisting of cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological reaction modifiers, antihormonal agents and antiandrogen.
  • the present invention provides a pharmaceutical composition for inhibiting cancer cell growth comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the inventive compound or a pharmaceutically acceptable salt thereof may be administered orally or parenterally as an active ingredient in an effective amount ranging from about 0.01 to 100 mg/kg, preferably 0.2 to 50 mg/kg body weight per day in case of mammals including human in a single dose or in divided doses.
  • the dosage of the active ingredient may be adjusted in light of various relevant factors such as the condition of the subject to be treated, type and seriousness of illness, administration rate, and opinion of doctor. In certain cases, an amount less than the above dosage may be suitable. An amount greater than the above dosage may be used unless it causes deleterious side effects, and such amount can be administered in divided doses per day.
  • inventive pharmaceutical composition may be formulated in accordance with any of the conventional methods in the form of tablet, granule, powder, capsule, syrup, emulsion or microemulsion for oral administration, or for parenteral administration including intramuscular, intravenous and subcutaneous routes.
  • the inventive pharmaceutical composition for oral administration may be prepared by mixing the active ingredient with a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspension agent, emulsifier and diluent.
  • a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspension agent, emulsifier and diluent.
  • a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspension agent, emulsifier and diluent.
  • step (1-3) 300 mg of the compound prepared in step (1-3) was dissolved in 7 ml of pyridine. 356 mg of (25)-l-(ter?-butoxycarbonyl)pyrrolidine-2-carboxylic acid and 477 mg of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the resulting solution and stirred for 14 hrs. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent and the residue was washed with saturated sodium bicarbonate solution.
  • step (1-4) 476 mg of the compound prepared in step (1-4) was dissolved in 10 ml of methylene chloride. 10 ml of trifluoroacetic acid was added to the resulting solution and stirred for 5 hrs. After completion of the reaction, the reaction mixture was distilled under a reduced pressure to remove the solvent. Saturated sodium bicarbonate solution was added to the resulting residue to make it basic, followed by extraction with chloroform. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain 320 mg of the title compound (82%).
  • step (1-5) 300 mg of the compound prepared in step (1-5) was dissolved in 7 ml of tetrahydrofuran, cooled to 0 ° C, and 70 ⁇ i of acrylic acid was added slowly thereto. 0.12 ml of pyridine and 249 mg of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride were added to the resulting solution, and stirred for 4 hrs while heating slowly to room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added to the reaction mixture, which was extracted with chloroform.
  • Example 1 The procedure of Example 1 was repeated using 3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 600 mg of the title compound (28%).
  • Example 1 The procedure of Example 1 was repeated using 4-bromo-3-chloro-2- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 800 mg of the title compound (31%).
  • Example 1 The procedure of Example 1 was repeated using 2,3,4-trifluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 130 mg of the title compound (15%).
  • Example 1 The procedure of Example 1 was repeated using 3,4-dichlororoaniline in place of 3-chloro-2-fluoroaniline in step (1-I) 5 to obtain 140 mg of the title compound (12%).
  • Example 1 The procedure of Example 1 was repeated using 3-chloro-2,4- difluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 135 mg of the title compound (14%).
  • Example 1 The procedure of Example 1 was repeated using 3,4-dichloro-2- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1), to obtain 120 mg of the title compound (10%).
  • Example 1 The procedure of Example 1 was repeated using 3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and tetrahydrofuran-2-ylmethylalcohol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 50 mg of the title compound (11%).
  • Example 1 The procedure of Example 1 was repeated using 4-bromo-3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and tetrahydrofuran-2-ylmethylalcohol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 65 mg of the title compound (10%).
  • Example 10 Preparation of (25 r )-l-acryloyl-A/-r4-r4-bromo-3-chloro-2- fluorophenylamino1-7-(2-morpholinoethoxy)quinazolin-6-vnpyrrolidine-2- carboxyamide
  • Example 1 The procedure of Example 1 was repeated using 4-bromo-3-chloro-4- fluoroaniline in place of 3-chloro-2-fluoroaniline in step (1-1) and 2- morpholinoethanol in place of 2-methoxyethanol in step (1-2), respectively, to obtain 70 mg of the title compound (11%).
  • Example 1 The procedure of Example 1 was repeated using 2-(4-methylthiazol-5- yl)ethanol in place of 2-methoxyethanol in step (1-2), to obtain 65 mg of the title compound (34%).
  • Example 12 Preparation of (26 r )-l-acryloyl-N-(4-r3-chloro-2- fluorophenylaminol-7-r2- ⁇ /- r -1.2,4-triazol-l-yl ' )ethoxy "
  • Example 1 The procedure of Example 1 was repeated using 2-(l// ' -l,2,4-triazol-l- yl)ethanol in place of 2-methoxyethanol in step (1-2), to obtain 50 mg of the title compound (12%).
  • inventive compounds prepared in the Examples were formulated as follows:
  • Tablets for oral administration comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 1.
  • Injection formulations comprising each of the compounds of formula (I) obtained in Examples 1 to 13 as an active ingredient were prepared based on the recipes of Table 3, wherein when a salt of the compound of formula (I) was used, the pH value was not manupulated.
  • Test Example 1 Inhibition of EGFR enzyme
  • 10 ⁇ i of EGFR (EGFR type 1 kinase) was added to each well of a 96- well microplate.
  • EGFR inhibitor 10 ⁇ l of a serially diluted solution of each of the compounds obtained in Examples 1 to 13, Iressa (Astrazeneca) or Lapatinib (Glaxo SmithKline) was added to each well, and the plate was incubated at room temperature for 10 mins.
  • 10 ⁇ l of Poly (GIu, Tyr) 4 : 1 (Sigma) and 10 ⁇ i of ATP were successively added thereto to initiate a kinase reaction, and the resulting mixture was incubated at room temperature for 1 hour.
  • 10 ⁇ i of 100 mM EDTA was added to each well and stirred for 5 mins to terminate the kinase reaction.
  • 30 ⁇ l of FP (fluorescence polarization) diluted buffer were added to the reacted mixture, followed by incubating in dark at room temperature for 30 mins.
  • the FP value of each well was determined with VICTORIII fluorescence meter (Perkin Elmer) at 488 nm, and IC 5O , the concentration at which 50% inhibition was observed, was determined, wherein the maximum (0% inhibition) value was set at the polarized light value measured for the well untreated with EGFR inhibitor and the minimum value corresponded to 100% inhibition.
  • the calculation and analysis of IC 50 were carried out by using Microsoft Excel. The results are shown in Table 5.
  • Test Example 2 Inhibition of EGFR mutant enzyme (T790M)
  • EGF mutant receptor (EGFR T790M kinase, Upstate) was added to each well of a 96- well microplate.
  • EGF mutant receptor EGFR T790M kinase, Upstate
  • Iressa Astrazeneca
  • Lapatinib GaxoSmithKline
  • Test Example 3 Test of cancer cell growth inhibition
  • a skin cancer cell line, A431 (ATCC: CRL- 1555), a breast cancer cell line, SK-Br3 (ATCC: HTB-30), and a colon/rectal cancer cell line, SW-620 (ATCC: CCL-227) were used to test the degrees of the inventive compounds in inhibiting the cancer cell growth using a culture medium, DMEM (Dulbecco's Modified Eagle's Medium) having 4.5 g/1 of glucose and 1.5 g/1 of sodium bicarbonate added and supplemented with 10% FBS (fetal bovine serum).
  • DMEM Dulbecco's Modified Eagle's Medium
  • the cancer cell lines stored in a liquid nitrogen tank were each quickly thawed at 37 ° C, and centrifuged to remove the medium.
  • the resulting cell pellet was mixed with a culture medium, incubated in a culture flask at 37 ° C under 5% CO 2 for 2 to 3 days, and the medium was removed.
  • the remaining cells were washed with DPBS (Dulbecco's Phosphate Buffered Saline) and separated from the flask by using Tripsin-EDTA.
  • the separated cells were diluted with a culture medium to a concentration of 100,000 A431 cells/ml, except that in case of SK-Br3, the dilution was carried out to 200,000 cells/ml. 100 ⁇ i of the diluted cell solution was added to each well of a 96-well plate, and incubated at 37 ° C under 5% CO 2 for 1 day.
  • the compounds obtained in Examples 1 to 13 as well as the conventional EGFR inhibitors, Iressa and Lapatinib were each dissolved in 99.5% DMSO to a concentration of 25 mM.
  • DMSO a small amount of 1% HCl was added thereto and treated in a 40 °C water bath for 30 mins until complete dissolution was attained.
  • the test compound solution was diluted with a culture medium to a final concentration of 100 ⁇ M, and then diluted 10 time serially to 10 "6 ⁇ M (final concentration of DMSO was less than 1%). The medium was removed from each well of the 96-well microplate.
  • a test compound solution 100 id of a test compound solution was added to each well holding the cultured cells, and the microplate was incubated at 37 ° C under 5% CO 2 for 72 hours. After removing the medium from the plate, 50 ⁇ i of 10% trichloroacetic acid was added to each well, and the plate was kept at 37°C for 1 hour to fix the cells to the bottom of the plate. The added trichloroacetic acid was removed from each well, the plate was dried, 100 ⁇ i of an SRB (Sulforhodamine-B) dye solution was added thereto, and the resulting mixture was reacted for 10 mins.
  • the SRB dye solution was prepared by dissolving SRB in 1% acetic acid to a concentration of 0.4%.
  • IC 50 the concentration at which 50% inhibition occurs, was evaluated based on the difference between the final concentration of the test cells and the initial concentration of the cells incubated in a well not-treated with the test compound which was regarded as 100%. The calculation of IC 50 was carried out by using Microsoft Excel, and the results are shown in Table 5.
  • each of the inventive compounds showed, at a low concentration thereof, an excellent anticancer activity by effectively inhibiting EGFR kinase and EGFR mutant kinase (T790M), arresting the growth of A431 and SK-Br3 haivng overexpressed EGFR and Erb-B2, respectively, while none of the inventive compounds inhibited the growth of SW-620 containing no overexpressed EGFR or Erb-B2.
  • the compounds of formula (I) of the present invention can selectively inhibit the growth of specific cancer cells induced by epithelial growth factor and its mutants without any side effect.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau dérivé de quinazoline et un sel de qualité pharmaceutique de ce dérivé, destinés à inhiber le développement de cellules cancéreuses induit par le facteur de croissance épithéliale et ses mutants, ainsi qu'une composition pharmaceutique dans laquelle ce dérivé ou son sel de qualité pharmaceutique est utilisé comme principe actif.
PCT/KR2007/003061 2006-06-28 2007-06-25 Dérivés de quinazoline destinés à inhiber le développement de cellules cancéreuses WO2008002039A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2006-0058490 2006-06-28
KR20060058490 2006-06-28
KR1020070047460A KR100929146B1 (ko) 2006-06-28 2007-05-16 암세포 성장 억제 효과를 갖는 퀴나졸린 유도체
KR10-2007-0047460 2007-05-16

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100929146B1 (ko) 2006-06-28 2009-12-01 한미약품 주식회사 암세포 성장 억제 효과를 갖는 퀴나졸린 유도체
US8466283B2 (en) 2006-12-05 2013-06-18 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
CN105555782A (zh) * 2013-09-28 2016-05-04 正大天晴药业集团股份有限公司 喹唑啉衍生物及其制备方法
US10231973B2 (en) 2015-03-20 2019-03-19 Chai Tai Tianqing Pharmaceutical Group Co., Ltd. Salts of quinazoline derivative and method for preparing the same
CN113278012A (zh) * 2020-02-19 2021-08-20 郑州泰基鸿诺医药股份有限公司 用作激酶抑制剂的化合物及其应用
CN114437161A (zh) * 2022-01-27 2022-05-06 遵义医药高等专科学校 一种齐多夫定拼接4-苯胺喹唑啉类化合物及其制备方法与应用
CN114437046A (zh) * 2022-01-28 2022-05-06 遵义医药高等专科学校 5-氟尿嘧啶拼接4-苯胺喹唑啉类化合物及其制备方法与应用

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100929146B1 (ko) 2006-06-28 2009-12-01 한미약품 주식회사 암세포 성장 억제 효과를 갖는 퀴나졸린 유도체
US8466283B2 (en) 2006-12-05 2013-06-18 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
USRE46856E1 (en) 2006-12-05 2018-05-22 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
EP3050880A4 (fr) * 2013-09-28 2017-04-26 Chia Tai Tianqing Pharmaceutical Group Co.,Ltd Dérivé de quinazoline et son procédé de préparation
JP2016531937A (ja) * 2013-09-28 2016-10-13 正大天晴薬業集団股▲分▼有限公司Ｃｈｉａ Ｔａｉ Ｔｉａｎｑｉｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｇｒｏｕｐ Ｃｏ．， Ｌｔｄ． キナゾリン誘導体及びその製造方法
US9725439B2 (en) 2013-09-28 2017-08-08 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Quinazoline derivative and preparation method therefor
CN105555782B (zh) * 2013-09-28 2017-11-10 正大天晴药业集团股份有限公司 喹唑啉衍生物及其制备方法
CN107556295A (zh) * 2013-09-28 2018-01-09 正大天晴药业集团股份有限公司 喹唑啉衍生物及其制备方法
CN105555782A (zh) * 2013-09-28 2016-05-04 正大天晴药业集团股份有限公司 喹唑啉衍生物及其制备方法
US10231973B2 (en) 2015-03-20 2019-03-19 Chai Tai Tianqing Pharmaceutical Group Co., Ltd. Salts of quinazoline derivative and method for preparing the same
CN113278012A (zh) * 2020-02-19 2021-08-20 郑州泰基鸿诺医药股份有限公司 用作激酶抑制剂的化合物及其应用
WO2021164793A1 (fr) * 2020-02-19 2021-08-26 郑州同源康医药有限公司 Composé utilisé comme inhibiteur de kinase et son utilisation
CN113278012B (zh) * 2020-02-19 2022-07-12 郑州同源康医药有限公司 用作激酶抑制剂的化合物及其应用
CN114437161A (zh) * 2022-01-27 2022-05-06 遵义医药高等专科学校 一种齐多夫定拼接4-苯胺喹唑啉类化合物及其制备方法与应用
CN114437161B (zh) * 2022-01-27 2023-09-12 遵义医药高等专科学校 一种齐多夫定拼接4-苯胺喹唑啉类化合物及其制备方法与应用
CN114437046A (zh) * 2022-01-28 2022-05-06 遵义医药高等专科学校 5-氟尿嘧啶拼接4-苯胺喹唑啉类化合物及其制备方法与应用
CN114437046B (zh) * 2022-01-28 2023-09-12 遵义医药高等专科学校 5-氟尿嘧啶拼接4-苯胺喹唑啉类化合物及其制备方法与应用

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