CN106866642B - Quinazoline compound containing aryl acylhydrazone structure and application thereof - Google Patents
Quinazoline compound containing aryl acylhydrazone structure and application thereof Download PDFInfo
- Publication number
- CN106866642B CN106866642B CN201710033645.9A CN201710033645A CN106866642B CN 106866642 B CN106866642 B CN 106866642B CN 201710033645 A CN201710033645 A CN 201710033645A CN 106866642 B CN106866642 B CN 106866642B
- Authority
- CN
- China
- Prior art keywords
- amino
- chloro
- fluorophenyl
- hydrazinecarboxamide
- tetrahydrofuran
- 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.)
- Active
Links
Classifications
-
- 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
- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a quinazoline compound containing an aryl acylhydrazone structure, which is shown as a general formula I:
Description
Technical Field
The invention relates to a quinazoline compound, in particular to a quinazoline compound containing an aryl acylhydrazone structure and application thereof.
Background
Cancer, also known as malignant tumor, is usually caused by aberrations in the cellular proliferation mechanisms. The number of new cancer cases worldwide will be 1930 ten thousand every year, and the visible cancer is always a big 'killer' threatening the health of human beings.
The Epidermal Growth Factor Receptor (EGFR) is one of ErbB family members, has tyrosine kinase activity, and is an important transmembrane receptor. EGFR is activated by ligand to start intracellular signal conduction, and through the cascade reaction of adaptor protein and enzyme in cytoplasm, regulates the transcription of transcription factor activating gene, guides cell migration, adhesion, proliferation, differentiation and apoptosis, and is closely related to the formation and deterioration of tumor. The development of EGFR inhibitors has been a focus in the direction of molecularly targeted treatment of human cancers. Numerous small molecule inhibitors of EGFR (shown by the following structural formula) have been reported, and among them, afatinib is reported to have a high effect on the biological cell activity and the antitumor enzyme activity in the literature (suda. k, murakami. i, katayama. T, et al. clin. cancer. res.16(2010)5489-5498.), and in addition, many small molecule inhibitors of EGFR have excellent antitumor activity, such as gefitinib (fukuoka. m, yano. s, Giaccone G, et al. j. clin. oncol.21(2003)2237-2246.), dacomitinib (gonzales. a. j, hook. e, althaus. i.i.w, Mol, et al. cancer. 7 (the) the study 0), lanoline.p.7 (the study of h. p. 9, lanqi, T. 7 (the study of the group h, T. p. h, T. No. 5, the study of the. A series of novel thieno [3,2-d ] pyrimidine derivatives containing acylhydrazone structures, in which the compounds (Z) -36 showed very excellent antitumor activity, were reported in the literature (Zijian Liu, Shashasha Wu, Yu Wang, et al Eur.J.Med.Chem.87(2014) 782-793).
According to the invention, a series of quinazoline compounds containing aryl acylhydrazone structures are designed and synthesized on the basis of reference documents, the series of compounds retain the main body structure of afatinib, and simultaneously acylhydrazone active groups are introduced, so that a plurality of quinazoline compounds containing acylhydrazone structures are designed and synthesized. The invention mainly researches the antitumor activity of the quinazoline compounds containing aryl acylhydrazone structures, so as to screen antitumor drugs with better activity and selectivity.
Disclosure of Invention
The invention aims to provide a quinazoline compound containing an aryl acylhydrazone structure and application thereof.
The invention provides a quinazoline compound containing an aryl acylhydrazone structure shown as a general formula I, a geometric isomer thereof, and a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the general formula I is as follows:
wherein:
R1is selected from (C)1～C4) Alkyl, (C)3～C6) A cycloalkyl group, a,S-tetrahydrofuran-3-yl, N-methylpiperidin-4-methyl or
Ar is selected from 1-3 same or different R3Substituted aryl or heteroaryl;
R2、R3each independently selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, trifluoromethoxy, (C)1～C4) Alkyl, (C)3～C6) Cycloalkyl group, (C)2～C4) Alkenyl, (C)2～C4) Alkynyl, (C)1～C4) Alkoxy, azido, (C)1～C4) Alkoxymethyl group, (C)1～C4) Alkyl acyl group, (C)1～C4) Alkylthio, allyl, (2-methyl) allyl or
R4、R5Are the same or different and are each independently (C)1～C6) Alkyl or (C)3～C6) Cycloalkyl radical, and R4And R5Containing 1-2 substitutions of hydrogen, hydroxyl, amino, halogen, sulfydryl or carboxyl; or R4And R5Together with the nitrogen atom to which they are attached form a 5-to 10-membered saturated heterocyclic group except for R4And R5Optionally containing 1 to 3 heteroatoms selected from O, N and S in addition to the attached nitrogen atom;
n is 0 to 3.
The present invention preferably relates to compounds of the general formula I as described above, geometric isomers thereof, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein:
R1selected from methyl, ethyl, N-propyl, isopropyl, N-butyl, tert-butyl, cyclopropyl, S-tetrahydrofuran-3-yl, N-methylpiperidin-4-methyl or
Ar is selected from 1-3 same or different R3Substituted aryl or heteroaryl;
R2、R3each independently selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, carboxy, trifluoromethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, propenyl, ethynyl, methoxy, ethoxy, cyclopropoxy, tert-butoxy, methoxymethyl, ethoxymethyl, isopropoxymethyl, formyl, acetyl, propionyl, cyclopropoxy, methylthio, ethylthio, allyl, (2-methyl) allyl, or
in the present invention, the quinazoline compound containing arylacylhydrazone structure of the general formula I is one selected from the following compounds, but these compounds are not meant to limit the present invention:
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-fluorobenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3-bromobenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-cyanobenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-nitrobenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2-chloro-4-fluorobenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2, 3-dichlorobenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-methoxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2,3, 4-trimethoxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3,4, 5-trimethoxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3-bromo-4-hydroxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3, 5-dibromo-4-hydroxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2, 4-dihydroxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3, 5-di-tert-butyl-4-hydroxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4- (diethylamino) -2-hydroxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-hydroxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-fluorobenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3-bromobenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-cyanobenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-nitrobenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2-chloro-4-fluorobenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2, 3-dichlorobenzylidene) hydrazinecarboxamide
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-methoxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2,3, 4-trimethoxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3,4, 5-trimethoxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3-bromo-4-hydroxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2- (3, 5-dibromo-4-hydroxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2, 4-dihydroxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3, 5-di-tert-butyl-4-hydroxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4- (diethylamino) -2-hydroxybenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-hydroxybenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- ((5-methylfuran-2-yl) methylene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- ((1- (morpholino) -1H-pyrrol-2-yl) methylene) hydrazinecarboxamide,
(S, E) -N- (4- ((4-fluoro-3- (trifluoromethyl) phenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide,
(E) -N- (4- ((4-cyanophenyl) amino) -7- (3- (piperidin-1-yl) propyl) quinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide,
(E) -N- (4- (4-allylphenyl) amino) -7-ethoxyquinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide,
(E) -N-4- ((3-methylthio) phenyl) amino) - (7- ((1-methylpiperidin-4-yl) methoxy) quinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide,
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yloxy) quinazolin-6-yl) -2- ((5-bromopyridin-2-yl) methylene) hydrazine carboxamide,
(E) -N- (7- (cyclopropylmethoxy) -4- ((4-morpholinophenyl) amino) quinolin-6-yl) -2- ((5-methylfuran-2-yl) methylene) hydrazine carboxamide,
(S, E) -2- ((1- (3-morpholinopropyl) -1H-pyrrol-2-yl) methyl) -N- (4- ((4-propionylphenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) hydrazinecarboxamide,
(E) -2- ((1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrrol-2-yl) methylene) -N- (7- (3- (piperidin-1-yl) propoxy) -4- ((4- (trifluoromethoxy) phenyl) amino) quinazolin-6-yl) hydrazine carboxamide,
(E) -2- ((1- ((1-methylpiperidin-4-yl) methyl) -1H-imidazol-2-yl) methylene) -N- (4- ((4- (2-oxopropyl) phenyl) amino) -7- (3- (piperidin-1-yl) propoxy) quinazolin-6-yl) hydrazine carboxamide,
(E) -2- ((5-methylthiophen-2-yl) methylene) -N- (7-methoxy-4- ((4-morpholinophenyl) amino) quinazolin-6-yl) hydrazine carboxamide.
The following synthetic scheme illustrates the preparation of the quinazolines containing arylacylhydrazone structures of the general formula I of the present invention, all starting materials are prepared by the means described in the synthetic scheme, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final quinazoline compounds of the present invention are prepared by the methods described in the synthetic schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in the synthetic route are as defined below or in the claims.
Taking (S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- ((5-methylfuran-2-yl) methylene) hydrazine carboxamide as an example, the synthetic procedure is shown below, and all starting materials are commercially available and analytically pure.
Scheme 1 synthetic route to the subject compounds
The invention firstly synthesizes an intermediate IX, and then the intermediate IX reacts with aryl aldehydes with different substituents to obtain a target compound I.
The quinazoline compound containing arylacylhydrazone structure of the general formula I in the present invention may form a pharmaceutically acceptable salt with an acid according to some conventional methods in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are those of formula I above which may themselves be less active or even inactive, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched chain alkylene; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "saturated or partially saturated heterocyclyl" refers to monocyclic or polycyclic ring systems containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
The quinazoline compound containing the aryl acylhydrazone structure and the pharmaceutically acceptable salt, hydrate or solvate thereof which are shown in the general formula I can be used as active ingredients, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition and prepared into a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The clinical dosage of the quinazoline compound containing the aryl acylhydrazone structure, provided by the invention, applied to a patient can be determined according to the following formula: the therapeutic efficacy and bioavailability of the active ingredients in vivo, their metabolic and excretory rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10 to 500mg, preferably 50 to 300 mg. Therefore, when the pharmaceutical composition of the present invention is prepared into a unit dosage form, each unit dosage form should contain 10 to 500mg, preferably 50 to 300mg, of the quinazoline compound containing an arylacylhydrazone structure of the general formula I. These formulations may be administered in several doses (preferably one to six times) at regular intervals, according to the guidance of a doctor or pharmacist.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The invention also discloses application of the quinazoline compound containing the aryl acylhydrazone structure in preparation of medicines for treating and/or preventing proliferative diseases. The active compounds of the present invention or their pharmaceutically acceptable salts and solvates thereof may be used alone as the sole anti-proliferative agent or in combination with anti-proliferative agents now on the market for the treatment and/or prevention of proliferative diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis.
The invention also discloses application of the quinazoline compound containing the aryl acylhydrazone structure in preparation of a medicament for treating and/or preventing cancers. The compound of the present invention has an activity of inhibiting the growth of tumor cells in vitro, and therefore, it can be used for the preparation of a medicament for the treatment and/or prevention of cancers, such as cancers of breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, esophagus, leukemia, neuroblastoma, and the like.
The invention also discloses application of the quinazoline compound containing the aryl acylhydrazone structure in preparation of medicines for treating and/or preventing prostate cancer, lung cancer, cervical cancer and breast cancer.
Through in vitro inhibition lung cancer cell A549, human prostate cancer cell PC-3, human breast cancer cell MCF-7 and cervical cancer cell Hela activity tests, the compound has a remarkable inhibition effect on lung cancer cells, prostate cancer cells, breast cancer cells and cervical cancer cells, and is particularly used for preparing medicines for treating and/or preventing prostate cancer, lung cancer and cervical cancer.
The test on the activity of EGFR and VEGFR2/KDR kinase shows that the compound has the obvious activity of inhibiting EGFR and VEGFR2/KDR kinase, has stronger inhibiting effect on lung cancer cells with high expression of EGFR, human prostate cancer cells, breast cancer cells, cervical cancer cells and the like, and is particularly used for preparing medicaments for treating and/or preventing lung cancer.
The active compound or the medicinal salt and the solvate thereof can be used alone as a unique antitumor medicament or can be used together with the antitumor medicaments (such as platinum medicament cisplatin, camptothecin medicament irinotecan, vinca base medicament novinova, deoxycytidine medicament gemcitabine, etoposide, taxol and the like) on the market at present. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The results of screening the anti-tumor activity of various EGFR inhibitor high-expression cell strains in vitro show that the EGFR inhibitor high-expression cell strains have stronger anti-tumor activity and selectivity, and a plurality of compounds are also subjected to in vivo activity tests of EGFR and VEGFR2/KDR kinase. Experiments show that some compounds have high antitumor activity.
Detailed Description
In order to better explain the invention, the following detailed description of the invention is given in conjunction with specific examples, which are not intended to limit the invention.
The examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the derivatives was measured by Bruker ARX-400 and Mass Spectroscopy by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
Quinazoline compounds containing aryl acylhydrazone structures of the general formula I:
the structural formulas of the embodiments 1 to 42 of the invention are shown in the following table 1.
TABLE 1 structural formulas of examples 1 to 42
Step A Synthesis of 7-fluoroquinazolin-4-one (II)
50.0g of 4-fluoro-2-aminobenzoic acid and 67.0g of formamidine acetate were sequentially added to a three-necked flask containing 300mL of anhydrous ethanol, and the mixture was heated under reflux for 24 hours. After the reaction is finished, most of the solvent is evaporated by reduced pressure, the reaction solution is poured into 1000mL of sodium chloride aqueous solution and stirred for 30min, the solution is filtered, a filter cake is washed by 60% of ethanol aqueous solution and dried to obtain 51.0g of white solid, namely 7-fluoroquinazoline-4-ketone (II), and the yield is as follows: 96.4 percent.
mp 260.1-261.0，1H NMR(400MHz,CDCl3)δ12.35(s,1H),8.17(d,J＝6.8Hz,1H),8.14(d,J＝7.2Hz,1H),7.43(d,J＝9.8Hz,1H),7.37(t,J＝8.8Hz,1H).
Step B Synthesis of 7-fluoro-6-nitroquinazolin-4-one (III)
50.0g of 7-fluoroquinazoline-4-ketone is slowly added into mixed acid prepared from 103mL of concentrated sulfuric acid and 105mL of fuming nitric acid under ice bath, stirred for 1h at room temperature and heated to 110 ℃ for reaction for 3 h. After the reaction is finished, cooling to room temperature, pouring the reaction solution into 1000mL of ice-water mixture, stirring vigorously, filtering, washing the filter cake with 500mL of water, heating and refluxing the dried filter cake with 300mL of ethanol for 30min, filtering while hot, and drying to obtain 48.5g of light yellow solid, namely 7-fluoro-6-nitroquinazoline-4-ketone (III), wherein the yield is as follows: 76.1 percent.
mp 277.3-278.5，ESI-MS[M-H]m/z:208,1H NMR(400MHz,DMSO)δ12.77(s,1H),8.68(dd,J＝8.2,2.7Hz,1H),8.28(s,1H),7.73(dd,J＝12.2,2.8Hz,1H).
Step C7-fluoro-6-nitro-4-chloroquinazoline (IV) synthesis
Adding 48.0g of 7-fluoro-6-nitroquinazoline-4-one into a mixed solution of 407.0mL of thionyl chloride and 75.0mL of phosphorus oxychloride, dropwise adding 2.4mL of N, N-Dimethylformamide (DMF) into the mixed solution, heating and refluxing for 3h at 80 ℃, and heating and refluxing for 6h at 110 ℃ after the reaction solution turns yellow and is clear. After the reaction is finished, the redundant solvent is evaporated to dryness under reduced pressure, a small amount of solvent is taken away by toluene, solid powder is slowly poured into an ice sodium bicarbonate aqueous solution and stirred for 1 hour, and the mixture is subjected to suction filtration, water washing and drying to obtain 50.7g of yellow solid, namely 7-fluoro-6-nitro-4-chloroquinazoline, wherein the yield is as follows: 97.0 percent.
mp 118.2-119.3℃，1H NMR(400MHz,DMSO)δ8.66(dd,J＝8.2,1.2Hz,1H),8.41(s,1H),7.75(d,J＝12.2Hz,1H).
Step D Synthesis of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-fluoroquinazoline (V)
50.0g of 7-fluoro-6-nitro-4-chloroquinazoline and 32.3g of 4-fluoro-3-chloroaniline were added to 400mL of isopropanol in this order, 34.0mL of triethylamine was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. After the reaction is finished, performing suction filtration, washing a filter cake with isopropanol and water, drying, adding water into a filtrate, stirring to separate out a solid, performing suction filtration, washing with water, drying, and combining to obtain 65.0g of a dark yellow solid, namely 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-fluoroquinolizoline, wherein the yield is as follows: 87.8 percent.
mp 261.4-262.5，ESI-MS[M+H]m/z:337.1,1H NMR(400MHz,DMSO)δ10.43(s,1H),9.51(d,J＝7.8Hz,1H),8.68(s,1H),8.08(d,J＝6.4Hz,1H),7.79(d,J＝5.2Hz,1H),7.76(s,1H),7.45(t,J＝9.0Hz,1H).
Step E Synthesis of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7- [ (S) - (tetrahydrofuran-3-yl) -oxy ] -quinazoline (VIa)
4.7g of 60% sodium hydride was added to 400mL of Tetrahydrofuran (THF) and stirred, and 12.0mL of (S) -3-hydroxytetrahydrofuran was slowly added dropwise and stirred in ice bath for 45 min. 20.0g of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-fluoroquinazoline (dissolved in 200mL of THF) was slowly added dropwise thereto, and the reaction was carried out at room temperature for 5 hours. After the reaction is finished, the solvent is evaporated by reduced pressure, 500mL of sodium bicarbonate aqueous solution is added, the mixture is stirred for 30min, the filtration is carried out, a filter cake is washed by 40% of ethanol aqueous solution and dried, 23.9g of dark yellow solid, namely 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7- [ (S) - (tetrahydrofuran-3-yl) -oxy ] -quinazoline is obtained, and the yield is as follows: 99.5 percent.
mp 210.1-211.0，[M+H]m/z:405.1,1H NMR(400MHz,DMSO)δ10.10(d,J＝11.8Hz,1H),9.16(d,J＝13.2Hz,1H),8.62(d,J＝13.4Hz,1H),8.13(d,J＝6.8Hz,1H),7.75(s,1H),7.45–7.35(m,2H),5.40(s,1H),3.99–3.79(m,4H),2.34(dd,J＝13.8,6.2Hz,1H),2.04(d,J＝5.6Hz,1H).
Step F Synthesis of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-methoxy ] -quinazoline (VIb)
Adding 11.37g of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-fluoroquinazoline into 227mL of methanol and 15mL of 50% aqueous sodium hydroxide solution, heating and refluxing for 1.5h, cooling to room temperature after the reaction is finished, pouring into 200mL of ice water, vigorously stirring for 30min, carrying out suction filtration, washing with water, and drying to obtain 11.2g of a yellow solid, namely, 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7-methoxy ] -quinazoline, wherein the yield is as follows: 94.9 percent.
m.p.292.3-293.0℃.ESI-MS m/z:[M+H]349.1，1H NMR(400MHz,DMSO)δ10.13(s,1H),9.20(s,1H),8.66(s,1H),8.20–8.10(m,1H),7.84–7.73(m,1H),7.51–7.41(m,2H),4.05(s,3H).
Step G Synthesis of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-amino-7- [ (S) - (tetrahydrofuran-3-yl) -oxy ] -quinazoline (VIIa)
21.4g of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-nitro-7- [ (S) - (tetrahydrofuran-3-yl) -oxy ] -quinazoline were added to 700mL of ethanol, heated to 60 ℃ 15.0g of activated carbon, 4.2g of ferric chloride were added, 24.5mL of 80% hydrazine hydrate was slowly added dropwise as the temperature increased to 80 ℃, and heating and refluxing were continued for 1.5 h. After the reaction, the reaction mixture is filtered while hot, the filter residue is washed by ethyl acetate, the filtrate is evaporated under reduced pressure, 500mL of water is added when the solvent is rotated to 10%, the mixture is stirred intensively, filtered and dried, and 17.3g of off-white solid, namely 4- [ (3-chloro-4-fluorophenyl) amino ] -6-amino-7- [ (S) - (tetrahydrofuran-3-yl) -oxy ] -quinazoline is obtained, wherein the yield is as follows: 87.3 percent.
mp 139.3-140.1，[M+H]m/z:375.2,1H NMR(400MHz,DMSO)δ9.41(s,1H),8.38(s,1H),8.17(t,J＝12.6Hz,1H),7.88–7.73(m,1H),7.38(dd,J＝17.2,8.2Hz,2H),7.05(s,1H),5.41(s,2H),5.20(s,1H),4.00–3.87(m,3H),3.77(dd,J＝12.6,7.8Hz,1H),2.29(td,J＝14.2,7.2Hz,1H),2.19–2.06(m,1H).
VIIb can be synthesized from VIb according to step G.
Step H Synthesis of (S) -phenyl-N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) carbamic acid (VIIIa)
Adding 5.5mL of N, N-Diisopropylethylamine (DIPEA) into 102.0mL of 1, 4-dioxane, 4.2mL of phenyl chloroformate into the mixture, adding 5.07g of 4- [ (3-chloro-4-fluorophenyl) amino ] -6-amino-7- [ (S) - (tetrahydrofuran-3-yl) -oxy ] -quinazoline into 30.0mL of 1, 4-dioxane, slowly dropping the mixture into the mixture under ice bath, adding 200.0mL of water after the reaction is finished to quench the reaction, filtering, washing the filter cake with water, and drying to obtain 5.36g of a yellow solid, namely (S) -phenyl-N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) carbamic acid, yield: 80 percent. 494.2 is [ M + H ] M/z.
VIIIb can be synthesized from VIIb according to step H.
Step I Synthesis of (S) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) hydrazinecarboxamide (IXa)
2.0g of (S) -phenyl-N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) carbamic acid was added to a 10.0mL mixture of 1, 4-dioxane and 2.0mL of 80% hydrazine hydrate and heated at 80 ℃ for 30min, after the reaction was completed, suction filtered while hot, and dried to obtain 1.49g of a white solid, namely (S) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) hydrazine formamide, with the yield: 85 percent.
[M+H]m/z:433.2，1H NMR(400MHz,DMSO)δ9.78(s,1H),9.28(s,1H),8.92(s,1H),8.43(d,J＝12.7Hz,1H),8.07(d,J＝6.6Hz,1H),7.92(s,1H),7.76(d,J＝8.6Hz,1H),7.40(t,J＝9.1Hz,1H),7.24(s,1H),5.36(s,1H),4.68(s,2H),4.01(dd,J＝10.2,4.0Hz,1H),3.98-3.86(m,2H),3.82(dd,J＝12.4,7.9Hz,1H),2.37(td,J＝14.2,7.5Hz,1H),2.15–1.84(m,1H).
IXb can be synthesized from VIIIb according to step I.
Step J (S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-fluorobenzylidene) hydrazinecarboxamide
0.1g of (S) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) hydrazinecarboxamide and p-fluorobenzaldehyde were added to 8.0mL of ethanol, 2 drops of glacial acetic acid were added, and heating and refluxing were carried out for 3 hours, after the reaction was completed, suction filtration was carried out while hot, and drying was carried out to obtain 0.11g of a white solid, that is, (S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-fluorobenzylidene) hydrazinecarboxamide, yield: 85.2 percent.
Example 1
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-fluorobenzylidene) hydrazinecarboxamide
Firstly synthesizing 4- [ (3-chloro-4-fluorophenyl) amino group according to the steps A to D]-6-nitro-7-fluoroquinazoline (V), and then neutralizing
Synthesis of 4- [ (3-chloro-4-fluorophenyl) amino group from intermediate V by step E]-6-nitro-7- [ (S) - (tetrahydrofuran-3-yl) -oxy
Base of]Quinazoline (VIa), and synthesis of 4- [ (3-chloro-4-fluorophenyl) amino group by step G]-6-amino-7- [ (S) - (tetrahydrofuran)
Pyran-3-yl) -oxy]-quinazoline (VIIa);
synthesizing (S) -phenyl-N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) carbamic acid (VIIIa) by step H and (S) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) hydrazine carboxamide (IXa) by step I; finally, the (S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-fluorobenzylidene) hydrazinecarboxamide is obtained by step J.
mp 299.8-304.0，[M+H]m/z:540.2，1H NMR(400MHz,DMSO)δ11.21(s,1H),9.86(s,1H),9.13(s,1H),9.00(s,1H),8.51(s,1H),8.09(d,J＝6.3Hz,1H),8.03(s,1H),7.85–7.75(m,3H),7.42(s,1H),7.33(s,1H),7.28(t,J＝8.5Hz,2H),5.45(s,1H),4.04(s,2H),3.95(s,1H),3.87(d,J＝4.9Hz,1H),2.42(dd,J＝13.8,6.6Hz,1H),2.19–2.10(m,1H).
According to the method of the embodiment 1, firstly synthesizing an intermediate V according to the steps A to D, then synthesizing an intermediate VIa or VIb from the intermediate V through the step E or F, and then synthesizing VIIa or VIIb through the step G; synthesizing VIIIa or VIIIb respectively according to the step H, and then synthesizing IXa or IXb through the step I; finally, the compounds of examples 2-42 were prepared by step J with the corresponding substituted aldehydes, respectively.
Example 2
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3-bromobenzylidene) hydrazinecarboxamide
mp 297.3-300.2，ESI-MS m/z:[M+H]601.1，1H NMR(400MHz,DMSO)δ11.31(s,1H),9.86(s,1H),9.02(d,J＝14.6Hz,2H),8.51(s,1H),8.10(s,1H),8.01(s,1H),7.93(s,1H),7.83–7.71(m,2H),7.62(d,J＝7.2Hz,1H),7.40(d,J＝8.1Hz,2H),7.32(s,1H),5.44(s,1H),4.03(d,J＝9.5Hz,2H),3.96(d,J＝7.9Hz,1H),3.86(s,1H),2.20(s,1H),1.99(s,1H).
Example 3
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-cyanobenzylidene) hydrazinecarboxamide
mp 303.9-305.0，ESI-MS m/z:[M+H]547.1，1H NMR(400MHz,DMSO)δ11.47(s,1H),9.86(s,1H),9.12(s,1H),8.98(s,1H),8.49(d,J＝17.5Hz,1H),8.08(d,J＝10.4Hz,2H),7.91(d,J＝6.4Hz,4H),7.77(s,1H),7.41(t,J＝9.0Hz,1H),7.33(s,1H),5.45(s,1H),4.04(s,2H),3.95(t,J＝7.7Hz,1H),3.87(d,J＝4.3Hz,1H),2.41(dt,J＝14.2,7.2Hz,1H),2.19–2.10(m,1H).
Example 4
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino-7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-nitrobenzylidene) hydrazinecarboxamide
mp 304.3-305.6，ESI-MS m/z:[M+H]567.1，1H NMR(400MHz,DMSO)δ11.55(s,1H),9.87(s,1H),9.16(s,1H),8.99(s,1H),8.51(s,1H),8.27(d,J＝8.3Hz,2H),8.12(s,1H),8.09(d,J＝6.1Hz,1H),8.00(d,J＝8.4Hz,2H),7.77(s,1H),7.42(t,J＝9.1Hz,1H),7.36(s,1H),5.46(s,1H),4.07(d,J＝6.2,8.1Hz,2H),3.99–3.93(m,1H),3.88(d,J＝4.3Hz,1H),2.47–2.37(m,1H),2.18–2.10(m,1H).
Example 5
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2-chloro-4-fluorobenzylidene) hydrazinecarboxamide
mp 280.4-282.7，ESI-MS m/z:[M+H]574.1.1H NMR(400MHz,DMSO)δ11.41(s,1H),9.86(s,1H),9.10(s,1H),8.98(s,1H),8.51(s,1H),8.36(s,1H),8.09(s,2H),7.77(s,1H),7.57(d,J＝8.3Hz,1H),7.42(t,J＝8.9Hz,1H),7.36–7.25(m,2H),5.44(s,1H),4.02(s,2H),3.97–3.89(m,1H),3.86(s,1H),2.40(dd,J＝13.3,6.7Hz,1H),2.12(d,J＝13.6Hz,1H).
Example 6
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2, 3-dichlorobenzylidene) hydrazinecarboxamide
mp 305.4-306.2，ESI-MS m/z:[M+H]592.1，1H NMR(400MHz,DMSO)δ11.51(s,1H),9.85(d,J＝15.4Hz,1H),9.12(s,1H),8.99(s,1H),8.51(s,1H),8.42(s,1H),8.07(t,J＝10.1Hz,1H),8.05(s,1H),7.75(d,J＝11.0Hz,1H),7.74(s,1H),7.43(dd,J＝12.8,8.7Hz,2H),7.33(s,1H),5.44(s,1H),4.02(s,2H),3.99–3.88(m,1H),3.84(d,J＝4.5Hz,1H),2.46–2.34(m,1H),2.13(d,J＝6.9Hz,1H).
Example 7
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-methoxybenzylidene) hydrazinecarboxamide
mp 289.2-290.5，ESI-MS m/z:[M+H]552.1，1H NMR(400MHz,DMSO)δ11.06(s,1H),9.85(s,1H),9.13(s,1H),9.00(s,1H),8.50(s,1H),8.06(t,J＝11.6Hz,1H),7.93(d,J＝6.4Hz,1H),7.78(d,J＝8.0Hz,1H),7.68(d,J＝8.1Hz,2H),7.40(dd,J＝12.7,12.5Hz,1H),7.32(s,1H),7.01(s,2H),5.45(s,1H),4.04(s,2H),3.96(t,J＝7.6Hz,1H),3.86(dd,J＝12.9,4.9Hz,1H),3.81(s,3H),2.47–2.35(m,1H),2.19–2.08(m,1H).
Example 8
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2,3, 4-trimethoxybenzylidene) hydrazinecarboxamide
mp 285.4-286.9，ESI-MS m/z:[M+H]612.2，1H NMR(400MHz,DMSO)δ11.04(d,J＝12.4Hz,1H),9.86(s,1H),9.10(s,1H),9.01(s,1H),8.50(s,1H),8.22(s,1H),8.09(d,J＝6.6Hz,1H),7.78(d,J＝8.2Hz,1H),7.63(d,J＝8.8Hz,1H),7.42(t,J＝9.2Hz,1H),7.37–7.23(m,1H),6.88(d,J＝9.0Hz,1H),5.45(s,1H),4.02(d,J＝9.9Hz,2H),3.96(t,J＝6.9Hz,1H),3.91(d,J＝12.8Hz,1H),3.86(s,3H),3.84(s,3H),3.78(s,3H),2.42(dd,J＝13.8,6.1Hz,1H),2.19–2.09(m,1H).
Example 9
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3,4, 5-trimethoxybenzylidene) hydrazinecarboxamide
mp 287.2-289.9，ESI-MS m/z:[M+H]612.2，1H NMR(400MHz,DMSO)δ11.11(s,1H),9.84(s,1H),8.97(s,1H),8.77(s,1H),8.45(d,J＝8.3Hz,1H),8.11(d,J＝4.5Hz,1H),7.98(s,1H),7.73(d,J＝13.9Hz,1H),7.42(t,J＝9.0Hz,1H),7.31(s,1H),7.02(s,2H),5.35(d,J＝12.6Hz,1H),4.02(s,2H),3.96(d,J＝10.5Hz,2H),3.86(s,9H),2.40(d,J＝7.1Hz,1H),2.07(d,J＝8.2Hz,1H).
Example 10
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3-bromo-4-hydroxybenzylidene) hydrazinecarboxamide
mp 295.7-299.0，ESI-MS m/z:[M+H]617.0，1H NMR(400MHz,DMSO)δ11.08(s,1H),10.77(s,1H),9.85(s,1H),9.08–8.95(m,2H),8.50(s,1H),8.09(d,J＝6.4Hz,1H),7.90(d,J＝10.6Hz,1H),7.89(s,1H),7.76(s,1H),7.57(d,J＝8.2Hz,1H),7.40(dd,J＝10.0,11.0Hz,1H),7.36(s,1H),7.02(d,J＝8.4Hz,1H),5.44(s,1H),4.03(t,J＝9.5Hz,2H),3.94(dd,J＝12.6,11.4Hz,1H),3.86(d,J＝4.6Hz,1H),2.46–2.38(m,1H),2.24–2.12(m,1H).
Example 11
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3, 5-dibromo-4-hydroxybenzylidene) hydrazinecarboxamide
mp 290.7-293.8，ESI-MS m/z:[M+H]696.0，1H NMR(400MHz,DMSO)δ11.18(s,1H),9.86(s,1H),8.99(s,1H),8.92(s,1H),8.51(s,1H),8.10(s,1H),7.90(s,3H),7.78(s,1H),7.42(t,J＝9.1Hz,1H),7.29(s,1H),5.42(s,1H),4.12–3.96(m,2H),3.98–3.91(m,1H),3.87(s,1H),2.43(dd,J＝13.2,7.0Hz,1H),2.23(s,1H).
Example 12
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (2, 4-dihydroxybenzylidene) hydrazinecarboxamide
mp 215.3-216.7，ESI-MS m/z:[M+H]554.1，1H NMR(400MHz,DMSO)δ10.89(s,1H),9.89(s,1H),9.76(s,1H),9.00(s,1H),8.51(s,1H),8.22(s,1H),8.08(d,J＝6.2Hz,1H),7.76(s,1H),7.61(d,J＝8.0Hz,1H),7.42(t,J＝8.7Hz,1H),7.31(s,1H),6.34(s,2H),5.40(d,J＝12.5Hz,1H),4.03(s,2H),3.95(dd,J＝15.4,7.7Hz,1H),3.85(d,J＝4.8Hz,1H),2.42(dd,J＝13.7,7.0Hz,1H),2.20–2.08(m,1H).
Example 13
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (3, 5-di-tert-butyl-4-hydroxybenzylidene) hydrazinecarboxamide
mp 211.9-214.3，ESI-MS m/z:[M+H]650.3，1H NMR(400MHz,DMSO)δ10.88(s,1H),9.89(s,1H),8.98(s,1H),8.61(s,1H),8.52(s,1H),8.11(d,J＝6.2Hz,1H),7.99(s,1H),7.79(s,1H),7.41(d,J＝4.9Hz,4H),7.30(s,1H),5.37(s,1H),4.04(d,J＝5.7Hz,1H),3.88(dd,J＝12.3,9.1Hz,2H),3.76(d,J＝5.2Hz,1H),2.40(dd,J＝13.3,6.9Hz,1H),2.09(d,J＝6.6Hz,1H),1.33(d,J＝12.1Hz,18H)..
Example 14
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4- (diethylamino) -2-hydroxybenzylidene) hydrazinecarboxamide.
mp 285.2-287.2，ESI-MS m/z:[M+H]609.2.
Example 15
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-hydroxybenzylidene) hydrazinecarboxamide.
mp 316.8-318.2，ESI-MS m/z:[M+H]538.1.
Example 16
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-fluorobenzylidene) hydrazinecarboxamide
mp 298.6-299.2，ESI-MS m/z:[M+H]484.1，1H NMR(400MHz,DMSO)δ11.15(s,1H),9.83(s,1H),9.05(s,1H),8.90(s,1H),8.52(s,1H),8.11(d,J＝6.6Hz,1H),8.02(s,1H),7.84–7.71(m,3H),7.42(t,J＝9.0Hz,1H),7.33(t,J＝8.3Hz,3H),4.11(s,3H).
Example 17
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3-bromobenzylidene) hydrazinecarboxamide
mp 288.8-289.0，ESI-MS m/z:[M+H]542.0，1H NMR(400MHz,DMSO)δ11.26(s,1H),9.84(s,1H),9.13(s,1H),8.89(s,1H),8.53(s,1H),8.11(d,J＝6.6Hz,1H),8.00(d,J＝11.6Hz,2H),7.78(s,1H),7.70(d,J＝7.6Hz,1H),7.61(d,J＝7.9Hz,1H),7.49–7.38(m,2H),7.33(s,1H),4.12(s,3H).
Example 18
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-cyanobenzylidene) hydrazinecarboxamide
mp287.6-290.4，ESI-MS m/z:[M+H]491.1，1H NMR(400MHz,DMSO)δ11.38(s,1H),9.83(s,1H),9.07(s,1H),8.87(s,1H),8.53(s,1H),8.15–8.08(m,1H),8.07(d,J＝6.9Hz,1H),7.93(s,4H),7.79(d,J＝7.4Hz,1H),7.42(t,J＝9.0Hz,1H),7.33(s,1H),4.10(s,3H).
Example 19
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-nitrobenzylidene) hydrazinecarboxamide
mp 290.2-291.0，ESI-MS m/z:[M+H]511.1，1H NMR(400MHz,DMSO)δ11.46(s,1H),9.84(s,1H),9.10(s,1H),8.89(s,1H),8.53(s,1H),8.34(d,J＝8.3Hz,2H),8.12(s,2H),8.00(d,J＝8.1Hz,2H),7.78(s,1H),7.42(t,J＝9.0Hz,1H),7.33(s,1H),4.13(s,3H).
Example 20
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2-chloro-4-fluorobenzylidene) hydrazinecarboxamide
mp 291.8-293.5，ESI-MS m/z:[M+H]518.1，1H NMR(400MHz,DMSO)δ11.32(s,1H),9.83(s,1H),9.03(s,1H),8.88(s,1H),8.52(s,1H),8.34(s,1H),8.09(d,J＝13.8Hz,2H),7.75(d,J＝12.6Hz,1H),7.56(d,J＝8.7Hz,1H),7.41(t,J＝8.9Hz,2H),7.32(s,1H),4.09(s,3H).
Example 21
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2, 3-dichlorobenzylidene) hydrazinecarboxamide
mp 306.9-309.4，ESI-MS m/z:[M+H]534.0，1H NMR(400MHz,DMSO)δ11.42(s,1H),9.83(s,1H),9.04(s,1H),8.88(s,1H),8.52(s,1H),8.40(s,1H),8.09(t,J＝14.0Hz,1H),8.05(s,1H),7.76(d,J＝8.9Hz,1H),7.74(s,1H),7.50(dd,J＝11.6,10.0Hz,1H),7.46(s,1H),7.32(s,1H),4.09(s,3H).
Example 22
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-methoxybenzylidene) hydrazinecarboxamide
mp 275.3-278.0，ESI-MS m/z:[M+H]496.1，1H NMR(400MHz,DMSO)δ11.01(s,1H),9.84(s,1H),9.06(s,1H),8.92(s,1H),8.52(s,1H),8.10(d,J＝6.5Hz,1H),7.95(d,J＝11.7Hz,1H),7.77(s,1H),7.67(d,J＝8.0Hz,2H),7.42(t,J＝9.1Hz,1H),7.32(d,J＝7.5Hz,1H),7.06(d,J＝8.1Hz,2H),4.12(s,3H),3.82(s,3H).
Example 23
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2,3, 4-trimethoxybenzylidene) hydrazinecarboxamide
mp 300.3-302.9，ESI-MS m/z:[M+H]556.1，1H NMR(400MHz,DMSO)δ11.02(s,1H),9.84(s,1H),9.04(s,1H),8.93(s,1H),8.52(s,1H),8.20(s,1H),8.10(d,J＝6.2Hz,1H),7.78(s,1H),7.60(d,J＝8.8Hz,1H),7.42(t,J＝9.1Hz,1H),7.32(d,J＝8.1Hz,1H),6.99(t,J＝12.2Hz,1H),4.11(s,3H),3.85(d,J＝8.2Hz,6H),3.78(s,3H).
Example 24
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3,4, 5-trimethoxybenzylidene) hydrazinecarboxamide
mp 284.3-287.6，ESI-MS m/z:[M+H]556.1，1H NMR(400MHz,DMSO)δ11.17(s,1H),9.85(s,1H),9.04(s,1H),8.95(s,1H),8.52(s,1H),8.08(t,J＝12.2Hz,1H),7.95(s,1H),7.78(s,1H),7.42(t,J＝9.1Hz,1H),7.33(s,1H),7.06(s,2H),4.06(s,3H),3.88(s,6H),3.71(s,3H).
Example 25
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3-bromo-4-hydroxybenzylidene) hydrazinecarboxamide
mp 292.1-292.7，ESI-MS m/z:[M+H]558.1，1H NMR(400MHz,DMSO)δ11.04(s,1H),10.76(s,1H),9.84(s,1H),9.10(s,1H),8.90(s,1H),8.52(s,1H),8.10(d,J＝6.1Hz,1H),7.91(d,J＝12.7Hz,2H),7.79(s,1H),7.52(d,J＝8.2Hz,1H),7.42(t,J＝9.0Hz,1H),7.33(s,1H),7.03(d,J＝8.4Hz,1H),4.13(s,3H).
Example 26
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2- (3, 5-dibromo-4-hydroxybenzylidene) hydrazinecarboxamide
mp 301.2-302.4，ESI-MS m/z:[M+H]639.9，1H NMR(400MHz,DMSO)δ11.17(s,1H),9.85(s,1H),9.15(s,1H),8.87(s,1H),8.52(s,1H),8.10(d,J＝5.0Hz,1H),7.95(s,2H),7.87(s,1H),7.78(s,1H),7.41(t,J＝9.0Hz,1H),7.33(s,1H),4.12(s,3H).
Example 27
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (2, 4-dihydroxybenzylidene) hydrazinecarboxamide
mp 302.1-303.8，ESI-MS m/z:[M+H]498.1，1H NMR(400MHz,DMSO)δ10.83(s,1H),9.80(d,J＝13.2Hz,2H),8.92(s,2H),8.51(s,1H),8.18(d,J＝15.3Hz,1H),8.10(d,J＝6.5Hz,1H),7.77(s,1H),7.52(d,J＝5.1Hz,1H),7.41(t,J＝8.9Hz,1H),7.31(s,1H),6.35(s,2H),4.09(s,3H).
Example 28
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (3, 5-di-tert-butyl-4-hydroxybenzylidene) hydrazinecarboxamide
mp 296.4-298.2，ESI-MS m/z:[M+H]594.2，1H NMR(400MHz,DMSO)δ10.97(s,1H),9.84(s,1H),9.01(s,2H),8.51(s,1H),8.09(d,J＝6.6Hz,1H),7.94(s,1H),7.77(d,J＝8.5Hz,1H),7.49(s,2H),7.41(s,2H),7.33(s,1H),4.08(s,3H),1.44(s,18H).
Example 29
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4- (diethylamino) -2-hydroxybenzylidene) hydrazinecarboxamide
mp 273.3-275.2，ESI-MS m/z:[M+H]553.2
Example 30
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinolin-6-yl) -2- (4-hydroxybenzylidene) hydrazinecarboxamide
mp288.4-289.2，ESI-MS m/z:[M+H]482.1
Example 31
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- ((5-methylfuran-2-yl) methylene) hydrazine carboxamide.
ESI-MS m/z:[M+H]526.1
Example 32
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- ((1- (morpholino) -1H-pyrrol-2-yl) methylene) hydrazine carboxamide
ESI-MS m/z:[M+H]610.2
Example 33
(S, E) -N- (4- ((4-fluoro-3- (trifluoromethyl) phenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide
ESI-MS m/z:[M+H]640.2
Example 34
(E) -N- (4- ((4-cyanophenyl) amino) -7- (3- (piperidin-1-yl) propyl) quinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide
ESI-MS m/z:[M+H]634.3
Example 35
(E) -N- (4- (4-allylphenyl) amino) -7-ethoxyquinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide
ESI-MS m/z:[M+H]552.3
Example 36
(E) -N-4- ((3-methylthio) phenyl) amino) - (7- ((1-methylpiperidin-4-yl) methoxy) quinazolin-6-yl) -2- (4-morpholinobenzylidene) hydrazinecarboxamide
ESI-MS m/z:[M+H]641.3.
Example 37
(S, E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((tetrahydrofuran-3-yloxy) quinazolin-6-yl) -2- ((5-bromopyridin-2-yl) methylene) hydrazine carboxamide
ESI-MS m/z:[M+H]602.0.
Example 38
(E) -N- (7- (cyclopropylmethoxy) -4- ((4-morpholinophenyl) amino) quinolin-6-yl) -2- ((5-methylfuran-2-yl) methylene) hydrazine carboxamide
ESI-MS m/z:[M+H]542.2.
Example 39
(S, E) -2- ((1- (3-morpholinopropyl) -1H-pyrrol-2-yl) methyl) -N- (4- ((4-propionylphenyl) amino) -7- ((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) hydrazinecarboxamide
ESI-MS m/z:[M+H]641.3.
Example 40
(E) -2- ((1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrrol-2-yl) methylene) -N- (7- (3- (piperidin-1-yl) propoxy) -4- ((4- (trifluoromethoxy) phenyl) amino) quinazolin-6-yl) hydrazine carboxamide
ESI-MS m/z:[M+H]722.4.
EXAMPLE 41
(E) -2- ((1- ((1-methylpiperidin-4-yl) methyl) -1H-imidazol-2-yl) methylene) -N- (4- ((4- (2-oxopropyl) phenyl) amino) -7- (3- (piperidin-1-yl) propoxy) quinazolin-6-yl) hydrazine carboxamide
ESI-MS m/z:[M+H]696.4.
Example 42
(E) -2- ((5-methylthiophen-2-yl) methylene) -N- (7-methoxy-4- ((4-morpholinophenyl) amino) quinazolin-6-yl) hydrazine carboxamide
ESI-MS m/z:[M+H]532.2.
Pharmacological study of the products of the invention
In vitro cytotoxic Activity
The quinazoline compound containing the aryl acylhydrazone structure shown in the general formula I is subjected to in vitro activity screening for inhibiting lung cancer cells A549, prostate cancer PC-3, breast cancer cells MCF-7 and cervical cancer cells Hela, and a reference substance afatinib is prepared according to a method disclosed in a patent document (WO2007085638A 1).
1) Cells were revived and passagedAfter 2-3 times stabilization, the cells were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture medium was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
3) The drug-containing culture solution in the 96-well plate is discarded, the cells are washed twice by using Phosphate Buffer Solution (PBS), 100 mu L of MTT (tetrazole) (0.5mg/mL) is added into each well and put into an incubator for 4h, the MTT solution is discarded, and 100 mu L of dimethyl sulfoxide is added. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the activity of the compound on breast cancer cells MCF-7, lung cancer cells A549 and prostate cancer PC-3 are shown in Table 2.
EGFR, VEGFR enzyme Activity test
Using afatinib as positive control, testing the inhibition of EGFR or VEGFR kinase by new synthesized compound by HTRF technology, and testing IC of partial compound for EGFR or VEGFR kinase inhibition50The value is obtained.
The specific method comprises the following steps: preparing a working solution of ATP, TK Substrate-biotin (TK-Substrate biotin) and Kinase buffer with required concentration, and uniformly mixing the ATP, TK Substrate-biotin and Kinase buffer according to the volume ratio of 2: 2; diluting the medicine with a Kinase buffer to prepare the required concentration; and preparing EGFR and VEGFR enzyme working solution. In a white 384-well plate, 6. mu.L of the homogenate, 2. mu.L of the drug and 2. mu.L of the kinase were added to each well, mixed, and reacted at 37 ℃ for 30 min. Then 5. mu.L of streptokinase labeled XL-665 and 5. mu.L of cryptate antibody bound with Eu3+ were added and mixed well. Standing at room temperature for 30min, exciting at 314nm with a microplate reader, detecting the fluorescence at 665 nm and 620nm, and calculating the inhibition rate of the kinase.
Inhibition Ratio (%) (Ratio665/620 control wells-Ratio 665/620 dosing wells)/Ratio 665/620 control wells × 100%
The results of the experiment are shown in table 2. IC in Table 250<1 μ M, indicated as "+++", 10 μ M>IC50>1 μ M, indicated by "+", 50 μ M>IC50>10 μ M, indicated by "+", IC50>50 μ M, indicated as "-", and "ND" means not tested.
TABLE 2 target Compound enzymatic Activity and in vitro antitumor Activity
From the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity.
The compounds of general formula I of the present invention can be administered alone, but usually are administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments for external use and ointments, respectively, of such compounds.
Application example 1: tablet formulation
5g of the compound obtained in example 5 was mixed with 10g of an adjuvant by a usual tableting method in pharmacy, and the mixture was compressed into 50 tablets each weighing 150 mg.
Application example 2: capsule preparation
5g of the compound of example 5 is mixed with 10g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into hollow capsules, wherein each capsule weighs 150 mg.
Application example 3: injection preparation
5g of the compound obtained in example 8 was adsorbed by activated carbon in accordance with a conventional pharmaceutical procedure, filtered through a 0.65 μm microporous membrane, and then filled in a nitrogen tank to prepare a hydroinjection preparation, each containing 2mL, in 50 bottles.
Application example 4: aerosol formulation
5g of the compound in example 9 is dissolved in a proper amount of propylene glycol, and then distilled water and other additives are added to prepare 250mL of clear solution.
Application example 5: suppository
The compound 5g of the compound of the embodiment 10 is ground into powder and added with proper amount of glycerol, the mixture is evenly ground and added with the melted glycerol gelatin, the mixture is evenly ground and poured into a model coated with a lubricant, and 25 particles of the suppository are prepared
Application example 6: film agent
5g of the compound of example 12 was dissolved by heating after swelling with stirring polyvinyl alcohol, medicinal glycerin, water, etc., and filtered with a 80-mesh screen, and the compound of example 12 was dissolved by stirring in the filtrate, and 50 films were formed by a film coating machine.
Application example 7: drop pills
15g of the compound obtained in example 13 and 50g of a base such as gelatin are heated, melted and mixed uniformly, and then the mixture is dropped into low-temperature liquid paraffin to obtain 1000 pills.
Application example 8: external liniment
10g of the compound in example 15 is mixed with 2.5g of auxiliary materials such as emulsifier and the like according to a conventional pharmaceutical method, ground and added with distilled water to 200mL to prepare the compound.
Application example 9: ointment formulation
Prepared by grinding 5g of the compound in example 18, and then uniformly grinding the ground compound and 250g of oil-based substances such as vaseline and the like.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (2)
1. A quinazoline compound containing an aryl acylhydrazone structure is characterized in that the structure is shown as the following general formula I:
the compound of the general formula I is one selected from the following compounds:
2. the application of the quinazoline compound containing the aryl acylhydrazone structure as claimed in claim 1 in preparation of medicines for treating and/or preventing prostate cancer, lung cancer and cervical cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610645484 | 2016-08-09 | ||
| CN2016106454844 | 2016-08-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106866642A CN106866642A (en) | 2017-06-20 |
| CN106866642B true CN106866642B (en) | 2020-01-03 |
Family
ID=59157438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710033645.9A Active CN106866642B (en) | 2016-08-09 | 2017-01-17 | Quinazoline compound containing aryl acylhydrazone structure and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106866642B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108456165B (en) * | 2018-05-30 | 2021-05-25 | 江西科技师范大学 | Sulfonylurea compound and preparation method and application thereof |
| CN111518088B (en) * | 2020-06-10 | 2021-09-03 | 山东创新药物研发有限公司 | Preparation method and application of aniline quinazoline intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103717590A (en) * | 2011-05-17 | 2014-04-09 | 江苏康缘药业股份有限公司 | Quinazoline-7-ether compounds and methods of use |
| CN104230845A (en) * | 2014-08-22 | 2014-12-24 | 沈阳药科大学 | Semicarbazone derivatives and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6562319B2 (en) * | 2001-03-12 | 2003-05-13 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy |
-
2017
- 2017-01-17 CN CN201710033645.9A patent/CN106866642B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103717590A (en) * | 2011-05-17 | 2014-04-09 | 江苏康缘药业股份有限公司 | Quinazoline-7-ether compounds and methods of use |
| CN104230845A (en) * | 2014-08-22 | 2014-12-24 | 沈阳药科大学 | Semicarbazone derivatives and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors;Xin Zhai, et al.;《Bioorganic & Medicinal Chemistry》;20160204;第24卷(第6期);第1332页左栏第2段第6行，第1337页右栏第3段第6行 * |
| Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents;Rania S.M. Ismail, et al.;《Future Journal of Pharmaceutical Sciences》;20160303;第2卷(第1期);第13页左栏第2段，表3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106866642A (en) | 2017-06-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6047184B2 (en) | Triazines, pyrimidines, and pyridine analogs, and their use as therapeutics and diagnostic probes | |
| CN106883213B (en) | Dual inhibitor of EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) | |
| KR101013319B1 (en) | Novel amide derivatives for inhibiting the growth of cancer cells | |
| JP5719770B2 (en) | Icotinib hydrochloride, compound, crystallographic form, concomitant drug and its use | |
| CN103003278B (en) | Aryl amine purine derivative and preparation method thereof and in purposes pharmaceutically | |
| EP2799437B1 (en) | Quinoline and cinnoline derivatives and use thereof | |
| CN106831725B (en) | The quinazoline compounds and its application of quinoline containing indoline and similar structures | |
| CN106008511A (en) | Pteridinone derivatives and application of pteridinone derivatives as EGFR (epidermal growth factor receptor tyrosine kinase), BLK (B lymphocyte tyrosine kinase) and FLT3 (FMS-like tyrosine kinase 3) inhibitors | |
| WO2018145621A1 (en) | Quinoline compound, preparation method and medical use therefor | |
| JP5649652B2 (en) | Substituted hydrazide compounds and their applications | |
| Zhai et al. | Design, synthesis and biological evaluation of novel 4-phenoxy-6, 7-disubstituted quinolines possessing (thio) semicarbazones as c-Met kinase inhibitors | |
| JP2022533740A (en) | Disubstituted sulfamide-based selective BCL-2 inhibitors containing methyl and trifluoromethyl groups | |
| CN104230952B (en) | Compound containing pyrimidine skeleton, and preparation method and use of compound | |
| JP6916562B2 (en) | Compounds, pharmaceutically acceptable salts thereof, solvates, stereoisomers and tautomers, and drug compositions, hyperproliferative disorder therapeutic agents, hyperproliferative disorder prophylaxis agents, drugs, cancer therapeutic agents, cancer Prophylactic agents and kinase signaling regulators | |
| CN113880772B (en) | CDK kinase inhibitors and application thereof | |
| Yan et al. | Design, synthesis, and biological evaluation of novel diphenylamine derivatives as tubulin polymerization inhibitors targeting the colchicine binding site | |
| CN107151233B (en) | Hydrazone-containing pyrimidine derivative and application thereof | |
| CN106866642B (en) | Quinazoline compound containing aryl acylhydrazone structure and application thereof | |
| CN106892907B (en) | Quinazoline compound containing acylhydrazone structure and application thereof | |
| CN114249702A (en) | N-aryl- [2,4 '-bithiazole ] -2' -amine compound and preparation and application thereof | |
| CN108456214B (en) | Quinazoline compound containing oxazole or imidazole structure and application thereof | |
| CN110467616B (en) | Preparation and application of triazolopyrazine compound containing heteroaryl substituted pyridazinone structure | |
| CN111825719A (en) | Arylamine-substituted pyrrolopyrimidine compound, and preparation method and application thereof | |
| CN111732597B (en) | Preparation and application of 2-aminopyrimidine heterocyclic compound containing 4-amidophenoxy | |
| CN110407839B (en) | Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |