CN112778217B - Quinazoline compound and application thereof - Google Patents
Quinazoline compound and application thereof Download PDFInfo
- Publication number
- CN112778217B CN112778217B CN201911084758.7A CN201911084758A CN112778217B CN 112778217 B CN112778217 B CN 112778217B CN 201911084758 A CN201911084758 A CN 201911084758A CN 112778217 B CN112778217 B CN 112778217B
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- Prior art keywords
- cancer
- hydrogen
- compound
- general formula
- pharmaceutically acceptable
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- -1 Quinazoline compound Chemical class 0.000 title claims description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 8
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 7
- 201000010881 cervical cancer Diseases 0.000 claims abstract description 7
- 201000005202 lung cancer Diseases 0.000 claims abstract description 7
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 7
- 206010005003 Bladder cancer Diseases 0.000 claims abstract description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 6
- 208000032839 leukemia Diseases 0.000 claims abstract description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims abstract description 6
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims abstract description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims abstract description 5
- 206010025323 Lymphomas Diseases 0.000 claims abstract description 5
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims abstract description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims abstract description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 5
- 208000015634 Rectal Neoplasms Diseases 0.000 claims abstract description 5
- 206010038389 Renal cancer Diseases 0.000 claims abstract description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 5
- 201000007455 central nervous system cancer Diseases 0.000 claims abstract description 5
- 208000025997 central nervous system neoplasm Diseases 0.000 claims abstract description 5
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- 201000010982 kidney cancer Diseases 0.000 claims abstract description 5
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- 208000000453 Skin Neoplasms Diseases 0.000 claims abstract description 3
- 201000000849 skin cancer Diseases 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 5
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
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- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
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- 239000000651 prodrug Substances 0.000 abstract description 11
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- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 abstract description 3
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 abstract description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 14
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
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- 125000001188 haloalkyl group Chemical group 0.000 description 1
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
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- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 201000010106 skin squamous cell carcinoma Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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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
- C07D239/88—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
The invention relates to quinazoline-containing compounds shown in a general formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein substituent R 1 、R 2 、R 3 、R 4 、R 5 、R 6 P, m, n have the meanings given in the description. The invention also relates to application of the compound shown in the general formula (I) in preparing an anti-tumor medicament, and also relates to application of the compound and pharmaceutically acceptable salts, solvates and prodrugs thereof in preparing and/or preventing and relieving cancers caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a quinazoline compound and application thereof in preventing and/or treating cancers.
Background
The patent documents European Journal of Medicinal Chemistry (2016) 12-25 relate to research on the inhibition mechanism of quinazoline compounds on HepG2, MGC-803 and A549 tumor cells, but do not relate to research on inhibition of other cancers such as lung cancer, bladder cancer, colon cancer, leukemia and the like.
The patent CN 102977014B relates to in vitro anti-tumor inhibition activity research of a general formula compound A, but the structure of the compound is obviously different from that of the compound.
Patent CN106632287A relates to quinazoline compounds which have certain anticancer activity on human skin squamous cell carcinoma cell line A431 and human lung cancer cell line A549.
Despite the related disclosures of several patents, there is a continuing need to develop new anticancer compounds to control the risk of cancer to humans. All of the compounds disclosed in the above patents differ significantly in structure from the compounds of the present invention.
Disclosure of Invention
The invention aims to provide a quinazoline compound with a novel structure and application of the quinazoline compound in preventing and/or treating cancers.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a quinazoline compound is shown in a general formula (I),
in the method, in the process of the invention,
R 1 selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C unsubstituted or substituted by at least one of 1 -C 12 Alkyl, C 1 -C 12 Alkoxy, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 12 Alkylthio, C 1 -C 12 Alkylsulfonyl, C 1 -C 12 Alkylcarbonyl or C 1 -C 12 Alkoxycarbonyl, wherein the following groups are halogen, hydroxy, amino, cyano or nitro;
R 2 selected from hydrogen, C 1 -C 12 Alkyl, C 1 -C 12 Alkoxy, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 3 selected from hydrogen, C 1 -C 12 Alkyl, C 1 -C 12 Alkoxy, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 4 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one of 1 -C 12 Alkyl, C 1 -C 12 Alkoxy, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following groups are halogen, hydroxy, amino, cyano or nitro;
m is selected from 1-4;
R 5 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, unsubstituted orC substituted by at least one of the following groups 1 -C 12 Alkyl, C 1 -C 12 Alkoxy, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following is halogen, hydroxy, amino, cyano or nitro;
p is selected from 1-4;
R 6 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one of 1 -C 12 Alkyl, C 1 -C 12 Alkoxy, C 3 -C 12 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 12 Alkylthio, C 1 -C 12 Alkylsulfonyl, C 1 -C 12 Alkylcarbonyl or C 1 -C 12 Alkoxycarbonyl, wherein the following groups are halogen, hydroxy, amino, cyano and nitro;
n is selected from 1-5;
or an isomer of a compound represented by the general formula (I), and a pharmaceutically acceptable salt, solvate or prodrug thereof.
In the general formula (I) which is preferable,
R 1 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one of 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 4 Alkylthio, C 1 -C 4 Alkylsulfonyl, C 1 -C 4 Alkylcarbonyl or C 1 -C 4 Alkoxycarbonyl, wherein the following groups are halogen, hydroxy, cyano, nitro or amino;
R 2 selected from hydrogen, C 1 -C 4 Alkyl or C 3 -C 12 Cycloalkyl;
R 3 selected from hydrogen, C 1 -C 4 Alkyl or C 3 -C 12 Cycloalkyl;
R 4 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 Alkyl group、C 1 -C 4 Alkoxy or C 3 -C 6 Cycloalkyl;
m is selected from 1-4;
R 5 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or C 3 -C 6 Cycloalkyl;
p is selected from 1-4;
R 6 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 6 Cycloalkyl, heterocyclyl, aryl or heteroaryl;
n is selected from 1-5;
or an isomer of a compound represented by the general formula (I), and a pharmaceutically acceptable salt, solvate or prodrug thereof.
In the further preferable general formula (I),
R 1 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C substituted by one or more halogens 1 -C 4 Alkyl, C 1 -C 4 An alkoxy group;
R 2 selected from hydrogen, methyl, ethyl or cyclopropyl;
R 3 selected from hydrogen, methyl, ethyl or cyclopropyl;
R 4、 selected from hydrogen, fluorine, chlorine, methyl, ethyl or cyclopropyl;
m is selected from 1-4;
R 5、 selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, methoxy, ethoxy and propoxy;
p is selected from 1-4;
R 6 selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen 1 -C 4 Alkyl, C 1 -C 4 An alkoxy group;
n is selected from 1-5;
or an isomer of a compound represented by the general formula (I), and a pharmaceutically acceptable salt, solvate or prodrug thereof.
In the still further preferred general formula (I),
R 1 selected from hydrogen, trifluoromethyl or methyl;
R 2 selected from hydrogen or methyl;
R 3 selected from hydrogen or methyl;
R 4 selected from hydrogen;
R 5 selected from hydrogen or methoxy;
R 6 selected from hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, isopropyl;
n is selected from 1-5;
or an isomer of a compound represented by the general formula (I), and a pharmaceutically acceptable salt, solvate or prodrug thereof.
The corresponding salt of the compound shown in the general formula I or the isomer thereof is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methylsulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
Prodrugs of compounds of formula (I) according to the invention are derivatives of compounds of formula (I) which may themselves have a relatively weak activity or even no activity, but which are converted to the corresponding biologically active form under physiological conditions (e.g. by metabolism, solvolysis or otherwise) after administration.
The compound solvate of the general formula (I) is prepared from the compound of the general formula (I) or an isomer thereof, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dichloromethane, petroleum ether and acetonitrile.
The application of a compound shown in the general formula (I), an isomer thereof and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparing medicaments for treating cell proliferation diseases.
The cell proliferative disorder is selected from cancer, infection, inflammation or autoimmune disorder.
The cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or an isomer thereof, a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.
The application of the pharmaceutical composition in preparing medicines for treating cell proliferation diseases.
In the definition of compounds of the general formula (I) given above, the terms used in the collection generally represent the following substituents:
halogen: refers to fluorine, chlorine, bromine or iodine. Alkyl: linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl or tert-butyl. Haloalkyl: straight-chain or branched alkyl groups, hydrogen atoms on these alkyl groups may be partially or entirely substituted with halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and the like. An alkoxy group: a linear or branched alkyl group linked to the structure via an oxygen atom bond. Cycloalkyl: a substituted or unsubstituted heteroatom-containing cyclic alkyl group such as cyclopropyl, cyclopentyl or cyclohexyl. Substituents such as methyl, halogen, and the like. Is bonded to the structure via an oxygen atom bond. An alkoxy group: a linear or branched alkyl group linked to the structure via an oxygen atom bond. Alkylthio: a linear or branched alkyl group linked to the structure via a sulfur atom linkage. Alkylcarbonyl: the straight or branched alkyl group is attached to the structure via a carbonyl group (-CO-), such as an acetyl group. Alkoxycarbonyl: alkoxy groups are attached to the structure via carbonyl groups. Such as-COOCH 3 ,-COOCH 2 CH 3 . Alkylsulfonyl: straight or branched alkyl through sulfone (-SO) 2 (-) is attached to a structure such as methylsulfonyl. Aryl includes phenyl or naphthyl and the like. Heteroaryl groups containing 1 or moreFive-membered or six-membered rings of N, O, S heteroatoms. Such as furyl, pyrrolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, and the like.
In the partial compounds of the general formula I according to the invention (R 6 ) n The substituents are listed in Table 1, but the present invention is not limited thereto.
TABLE 1
Further to say that some of the compounds represented by formula (I) can be represented by Table 2,
TABLE 2
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The compounds of general formula (I) according to the present invention can be prepared as follows. The reaction formula is as follows, wherein each group is as defined above unless otherwise indicated:
the synthetic route of the general formula (I):
the preparation process comprises the following steps:
step one: cpd.1 and cpd.2 were added to formic acid, heated to 135℃and stirred for 5 hours. Pouring the reaction solution into a water bath to separate out a product, and filtering to obtain cpd.3.
Step two: cpd.3 was dissolved in a solvent, and a chlorinating agent was added thereto and heated under reflux for 3 hours. Desolventizing after the reaction is finished to obtain a product cpd.4.
Step three: dissolving cpd.4 and cpd.5 in a solvent, adding alkali, water and TBAB to react for 4 hours at 100 ℃, and purifying by column chromatography after the reaction is finished to obtain the product cpd.6.
Step four: cpd.6 and cpd.7 were dissolved in solvent, base and HBTU were added and stirred at room temperature for 6 hours, and column chromatography gave cpd.8.
The chlorinating agent may be selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, vilesmeier-Haack reagent, sulfonyl chloride, etc.
The base may be selected from sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, for example.
The solvent used in each step can be selected from ethanol, acetonitrile, tetrahydrofuran, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone or butanone.
The reaction temperature in each of the above steps may be between room temperature and the boiling point temperature of the solvent, preferably in the range of 20 to 150 ℃.
Intermediates cpd.1, cpd.2, cpd.5 and cpd.7 in the above reactions are commercially available.
Salts of the compounds of formula (I) may be prepared from the compounds of formula (I) and the corresponding acids in conventional manner. Suitable acids are selected from hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, ascorbic acid or oxalic acid and the like; further preferred are hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The invention comprises a preparation prepared by taking the compound contained in the general formula (I) as an active ingredient and the preparation of the preparation composition. The preparation method comprises the following steps: dissolving the compound covered by the invention into a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipoid, various cyclodextrins, fatty acids, fatty acid esters, phospholipids or a combination solvent thereof to prepare a preparation solution; adding physiological saline to obtain 1-20% carbohydrate. The organic solvent includes polyethylene glycol (PEG), ethanol, propylene glycol or a combination of these solvents.
The compounds, salts and prodrugs thereof contained in the general formula (I) are used for preparing anti-tumor drugs or pharmaceutical preparations for treating, preventing or relieving, and the active ingredients of the drugs are one or more than two quinazoline compounds shown in the general formula (I). Is especially suitable for treating or relieving cancers caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
The compound synthesized by the invention can be used as an active ingredient of an anti-tumor drug, can be used independently, and can also be combined with other anti-tumor and anti-virus drugs. The combination therapy contemplated by the present invention includes the use of at least one compound of the present invention, and active derivatives thereof, in combination with one or more other antineoplastic antiviral agents to increase the overall therapeutic effect. The dosage and the administration time of the combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.
The contemplated pharmaceutical formulations include an effective dose of the compounds of formula (I). An "effective dose" as used herein refers to the amount of the compound required to produce a therapeutic effect in a subject being treated. The effective dose or dosages may be varied by the practitioner as suggested by the individual circumstances. For example, the types of tumors treated are different, and the use of drugs is different; whether to be used together with other treatment methods such as other antitumor drugs or antiviral drugs, etc., the dosage can be changed. Can be made into any preparation formulation. If certain compounds are basic or acidic and can form non-toxic acids or salts, the salt forms of the compounds can be used. Organic acid salts which may be used in pharmacy include physiologically usable negative ion salts such as p-methylbenzenesulfonate, methylsulfonate, acetate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate, glycerophosphate and the like; inorganic salts that may be used include chlorides, bromides, fluorides, iodides, sulfates, nitrates, bicarbonates, carbonates, or phosphates, and the like; such as basic compounds like amines with suitable acids can be prepared in the form of said salts; the carboxylic acid-based compounds may form usable salts with alkali metals or alkaline earth metals.
The compounds encompassed in the general formula (I) in the present invention are generally readily soluble in organic solvents, water-soluble solvents and mixtures of organic solvents and water-soluble solvents with water. The water-soluble solvent is preferably an alcohol, polyethylene glycol, N-methyl-2-pyrrolidone, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, acetonitrile, or a combination thereof. The alcohol is preferably methanol, ethanol, isopropanol, glycerol or ethylene glycol. The compounds of the present invention may be formulated in combination with conventional formulation carriers. Dissolving the compound in water-soluble organic solvent, aprotic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or their mixture to obtain medicinal solution; adding physiological saline to obtain 1-20% carbohydrate such as glucose aqueous solution. The thus prepared formulation is stable and useful in animals and in clinic.
The product medicine prepared by taking the compound in the general formula (I) as an active ingredient can be administered by oral or parenteral routes, and also can be administered by an in vivo transplanted medicine pump and other methods, wherein the parenteral route refers to perfusion, subcutaneous intradermal, intramuscular, intravenous, intraarterial, intraatrial, intrasynovial, intrasternal, intrathecal, trauma site, intracranial injection or instillation technology and the like. The mixture is mixed by a conventional method by technicians to finally obtain the required pharmaceutical dosage form. Can be in the form of tablet, pill, capsule, granule, syrup, injection, lyophilized powder for injection, emulsion, powder, lyophilized powder, dripping pill, emulsion suspension, aqueous solution, colloid, colloidal solution, sustained release preparation, nanometer preparation or other dosage forms for animal or clinic.
The compounds of formula (I) of the present invention are useful in the preparation of medicaments for treating or alleviating cancer in a tissue or organ. The cancers include, but are not limited to, colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, kidney cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
Detailed Description
The following specific examples are provided to further illustrate the invention, but the invention is not limited to these examples. (the raw materials used are commercially available unless otherwise noted)
Synthetic examples
Example 1: preparation of Compound 1
Step one: intermediate a (20 g,101 mmol), amine formate (80 mL) and formic acid (8 mL) were added to a 250mL single-port flask, heated to 135℃and stirred for 5 hours. The reaction solution was poured into a water bath to precipitate a product, and the product was obtained by filtration.
Step two: intermediate b (5 g,24.3 mmol) was added to SOCl 2 (50 mL) was heated to reflux for 3h. Desolventizing after the reaction was completed to obtain 5.3g of a product.
Step three: intermediate c (5.3 g,23.7 mmol) and intermediate d (2.8 g,25.69 mmol) were dissolved in butanone (100 mL) and NaOH (3 g,75 mmol), H were added 2 O (20 mL,1.1 mol), and TBAB (4 g,12 mmol), heated to 100deg.C, reacted for 4 hours, and purified by column chromatography to give 2.6g of the product.
Step four: intermediate e (100 mg,0.337 mmol) and intermediate f (50 mg,0.325 mmol) were dissolved in THF (10 mL), DIPEA (200 mg,1.55 mmol) and HBTU (130 mg,0.343 mmol) were added and stirred at room temperature for 6 hours and column chromatography afforded compound 1 as 100mg.
1H NMR(600MHz,DMSO-d6)δ10.34(s,1H),8.54(s,1H),7.73–7.67(m,2H),7.56(s,1H),7.43(td,J=7.6,1.7Hz,1H),7.39(s,1H),7.33(ddd,J=7.4,5.6,1.9Hz,1H),7.28–7.24(m,2H),7.23–7.17(m,2H),3.99(d,J=8.9Hz,6H),3.77(s,2H).MS:433.44.
Example 2: preparation of Compound 2
Intermediate e was prepared in the same manner as in example 1. The preparation method of the compound 2 comprises the following steps:
step one: intermediate e (100 mg,0.337 mmol) and intermediate f (54 mg,0.325 mmol) were dissolved in THF (10 mL), DIPEA (200 mg,1.55 mmol) and HBTU (130 mg,0.343 mmol) were added and stirred at room temperature for 6 hours and column chromatography afforded compound 2 as 100mg.
1H NMR(600MHz,DMSO-d6)δ10.23(s,1H),8.53(s,1H),7.71–7.66(m,2H),7.55(s,1H),7.37(s,1H),7.30–7.26(m,2H),7.25–7.22(m,2H),6.92–6.88(m,2H),3.99(s,3H),3.97(s,3H),3.74(s,3H),3.59(s,2H).MS:445.16.
Example 3: preparation of Compound 3
Intermediate e was prepared in the same manner as in example 1. The preparation method of the compound 3 comprises the following steps:
step one: intermediate e (100 mg,0.337 mmol) and intermediate f (54 mg,0.325 mmol) were dissolved in THF (10 mL), DIPEA (200 mg,1.55 mmol) and HBTU (130 mg,0.343 mmol) were added and stirred at room temperature for 6 hours and column chromatography afforded compound 3 as 100mg.
1H NMR(600MHz,DMSO-d6)δ10.17(s,1H),8.53(s,1H),7.74–7.66(m,2H),7.55(s,1H),7.38(s,1H),7.28–7.22(m,4H),6.99(dd,J=8.1,1.1Hz,1H),6.92(td,J=7.4,1.1Hz,1H),3.99(s,3H),3.97(s,3H),3.79(s,3H),3.66(s,2H).MS:445.16.
Example 4: preparation of Compound 4
Intermediate e was prepared in the same manner as in example 1. The preparation method of the compound 4 comprises the following steps:
step one: intermediate e (100 mg,0.337 mmol) and intermediate f (55 mg,0.325 mmol) were dissolved in THF (10 mL), DIPEA (200 mg,1.55 mmol) and HBTU (130 mg,0.343 mmol) were added and stirred at room temperature for 6 hours and column chromatography afforded compound 4 as 100mg.
1H NMR(600MHz,DMSO-d6)δ10.30(s,1H),8.53(s,1H),7.72–7.66(m,2H),7.55(s,1H),7.43–7.35(m,5H),7.28–7.22(m,2H),3.99(s,3H),3.97(s,3H),3.68(s,2H).MS:499.84.
Example 5: preparation of Compound 5
Intermediate e was prepared in the same manner as in example 1. The preparation method of the compound 5 comprises the following steps:
step one: intermediate e (100 mg,0.337 mmol) and intermediate f (67 mg,0.325 mmol) were dissolved in THF (10 mL), DIPEA (200 mg,1.55 mmol) and HBTU (130 mg,0.343 mmol) were added and stirred at room temperature for 6 hours and column chromatography afforded compound 5 as 100mg.
1H NMR(600MHz,DMSO-d6)δ10.54(d,J=7.2Hz,1H),8.80(d,J=4.9Hz,1H),7.76–7.71(m,2H),7.65(dd,J=4.8,2.0Hz,2H),7.61(d,J=8.3Hz,1H),7.47(d,J=1.6Hz,1H),7.37(dd,J=8.3,2.0Hz,1H),7.31–7.26(m,2H),4.04–3.99(m,6H),3.75(s,2H).MS:484.33.
Other example compounds data are as follows:
compound 6:1H NMR (600 mhz, dmso-d 6) δ10.29 (s, 1H), 8.63 (s, 1H), 7.71 (d, j=8.6 hz, 2H), 7.59 (s, 1H), 7.40 (s, 1H), 7.26 (dd, j=8.3, 5.9hz, 3H), 6.97-6.93 (m, 2H), 6.83 (d, j=2.7 hz, 1H), 4.00 (d, j=10.9 hz, 6H), 3.76 (s, 3H), 3.64 (s, 2H) MS:445.16.
Compound 7:1H NMR (600 mhz, dmso-d 6) delta 10.37 (s, 1H), 8.54 (s, 1H), 7.74-7.67 (m, 2H), 7.54 (s, 1H), 7.46 (dt, j=7.1, 2.3hz, 2H), 7.37 (s, 1H), 7.35-7.30 (m, 2H), 7.27-7.24 (m, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 3.88 (s, 2H) MS 449.11.
Compound 8:1H NMR (600 mhz, dmso-d 6) delta 10.34 (s, 1H), 8.65 (s, 1H), 7.72-7.68 (m, 2H), 7.59 (s, 1H), 7.44 (t, j=1.9 hz, 1H), 7.39 (s, 1H), 7.35-7.32 (m, 3H), 7.28-7.25 (m, 2H), 4.01 (s, 3H), 3.99 (s, 3H), 3.71 (s, 2H) MS 449.11.
Compound 9:1H NMR (600 mhz, dmso-d 6) δ10.32 (s, 1H), 8.57 (s, 1H), 7.69 (d, j=8.5 hz, 2H), 7.57 (s, 1H), 7.39 (d, j=5.0 hz, 2H), 7.25 (d, j=8.6 hz, 2H), 7.20 (d, j=8.0 hz, 2H), 7.10 (d, j=2.4 hz, 1H), 3.99 (d, j=10.2 hz, 6H), 3.71 (s, 2H) MS:433.14.
Compound 10:1H NMR (600 mhz, dmso-d 6) delta 8.65 (s, 1H), 7.72-7.68 (m, 2H), 7.59 (s, 1H), 7.54 (d, j=8.1 hz, 2H), 7.52-7.48 (m, 2H), 7.33 (d, j=8.0 hz, 2H), 7.28-7.25 (m, 2H), 4.00 (d, j=11.5 hz, 6H), 3.67 (s, 2H) MS 493.06.
Compound 11:1H NMR (600 mhz, dmso-d 6) delta 10.35 (s, 1H), 8.54 (s, 1H), 7.88 (dd, j=7.8, 1.1hz, 1H), 7.72-7.69 (m, 2H), 7.56 (s, 1H), 7.42-7.38 (m, 3H), 7.28-7.24 (m, 2H), 7.04 (ddd, j=7.8, 6.7,2.3hz, 1H), 3.99 (d, j=8.2 hz, 6H), 3.88 (s, 2H) MS 541.05.
Compound 12:1H NMR (600 mhz, dmso-d 6) δ10.31 (s, 1H), 8.54 (s, 1H), 7.76 (t, j=1.7 hz, 1H), 7.72-7.67 (m, 2H), 7.64 (dt, j=7.9, 1.4hz, 1H), 7.55 (s, 1H), 7.39 (d, j=9.7 hz, 2H), 7.28-7.24 (m, 2H), 7.16 (t, j=7.8 hz, 1H), 3.98 (d, j=9.5 hz, 6H), 3.67 (s, 2H) MS 541.05.
1H NMR of the compound (600 MHz, DMSO-d 6) delta 10.30 (s, 1H), 8.54 (s, 1H), 7.73-7.66 (m, 4H), 7.55 (s, 1H), 7.38 (s, 1H), 7.27-7.23 (m, 2H), 7.20-7.15 (m, 2H), 3.98 (d, J=9.9 Hz, 6H), 3.65 (s, 2H) MS:541.05.
Compound 14:1H NMR (600 mhz, dmso-d 6) delta 10.28 (s, 1H), 8.54 (s, 1H), 7.73-7.67 (m, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 7.30-7.23 (m, 3H), 7.21-7.14 (m, 3H), 3.99 (d, j=9.1 hz, 6H), 3.72 (s, 2H), 2.33 (s, 3H) MS:429.17.
Compound 15:1H NMR (600 mhz, dmso-d 6) delta 10.26 (s, 1H), 8.54 (s, 1H), 7.71-7.67 (m, 2H), 7.56 (s, 1H), 7.38 (s, 1H), 7.27-7.22 (m, 4H), 7.15 (d, j=7.8 hz, 2H), 3.99 (d, j=9.8 hz, 6H), 3.62 (s, 2H), 2.29 (s, 3H) MS 429.17.
Compound 16:1H NMR (600 mhz, dmso-d 6) δ10.36 (s, 1H), 8.53 (s, 1H), 7.81 (d, j=1.8 hz, 1H), 7.75 (dt, j=7.7, 1.4hz, 1H), 7.70 (td, j=7.4, 6.8,1.7hz, 3H), 7.57 (t, j=7.8 hz, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.28-7.23 (m, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 3.79 (s, 2H) MS:440.15.
1H NMR of the compound (600 MHz, DMSO-d 6) delta 10.36 (s, 1H), 8.53 (s, 1H), 7.86-7.78 (m, 2H), 7.72-7.64 (m, 2H), 7.60-7.50 (m, 3H), 7.38 (s, 1H), 7.29-7.21 (m, 2H), 3.98 (d, J=9.8 Hz, 6H), 3.81 (s, 2H) MS:440.15.
Compound 18:1H NMR (600 mhz, dmso-d 6) delta 10.36 (s, 1H), 8.54 (s, 1H), 7.72-7.67 (m, 2H), 7.56 (s, 1H), 7.53 (dd, j=6.5, 2.8hz, 1H), 7.40 (ddd, j=9.0, 4.6,2.9hz, 1H), 7.38 (s, 1H), 7.29-7.26 (m, 2H), 7.26 (d, j=2.9 hz, 1H), 3.99 (d, j=8.9 hz, 6H), 3.80 (s, 2H) MS 467.10.
Compound 19:1H NMR (600 MHz, DMSO-d 6) delta 10.33 (s, 1H), 8.54 (s, 1H), 7.73-7.66 (m, 2H), 7.58-7.53 (m, 2H), 7.41 (dd, J=10.4, 1.9Hz, 1H), 7.38 (s, 1H), 7.28-7.24 (m, 2H), 7.23 (dd, J=8.4, 1.9Hz, 1H), 3.98 (d, J=9.7 Hz, 6H), 3.74 (s, 2H) MS:467.10
Compound 20:1H NMR (600 mhz, dmso-d 6) δ10.31 (s, 1H), 8.53 (s, 1H), 7.75 (t, j=1.8 hz, 1H), 7.70-7.66 (m, 2H), 7.60 (d, j=1.8 hz, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 7.27-7.24 (m, 2H), 3.98 (d, j=9.4 hz, 6H), 3.73 (s, 2H) MS 570.97.
Compound 21:1H NMR (600 mhz, dmso-d 6) delta 10.36 (s, 1H), 8.54 (s, 1H), 7.70-7.68 (m, 2H), 7.66 (dd, j=8.8, 5.4hz, 1H), 7.55 (s, 1H), 7.38-7.35 (m, 1H), 7.28-7.24 (m, 2H), 7.13 (td, j=8.5, 3.1hz, 1H), 3.98 (d, j=8.5 hz, 6H), 3.90 (s, 2H) MS 511.05.
According to the description of the above examples and the preparation process of the compound shown in the general formula (I) in the summary of the invention, other compounds shown in the general formula (I) can be further prepared;
the compound shown in the general formula (I) is obtained according to the preparation method, and the obtained compound reacts with corresponding salt to obtain pharmaceutically acceptable salt of the compound shown in the general formula (I).
Determination of antitumor Activity
Example 1: the in vitro test for tumor cell inhibition (MTT method) was as follows:
human cancer tumor cell lines: human colon cancer HT-29, human cervical cancer cell Hela.
The inhibition rate of 5 concentration test samples to the growth of each human cancer cell is measured by using the in vitro cell culture technology and the conventional MTT method by using human colon cancer HT-29 and human cervical cancer cell Hela.
MTT method: taking out cells from incubator, washing twice with PBS, digesting with 0.25% trypsin solution, and adding RPMI1640 for complete cultureDigestion was stopped in medium (containing 10% fbs), centrifuged, the supernatant was removed, and the whole medium was added to blow it to form a cell suspension and counted under an inverted microscope. Cells were formulated to a concentration of 5x10 4 Cell suspensions of each mL were added to 100 μl of cells per well of 96-well plates, placed in 5% carbon dioxide, incubated overnight in humidified air at 37 ℃ to remove supernatant, diluted to five different concentration gradients of 40 μg/mL, 8 μg/mL, 1.6 μg/mL, 0.32 μg/mL and 0.064 μg/mL with complete medium to obtain compounds of the above examples, allowed to react for 48h to remove supernatant, added with 0.5mg/mL MTT 100 μl, reacted for 4h, viable cells reduced MTT tetrazolium (tetrazolium) components to produce formazan (formazan) removed supernatant, then added with 100 μl DMSO to dissolve formazan, and finally absorbance at 460 nm measured on a 96-well plate reader.
Cell inhibition = (1-absorbance of experimental group/absorbance of control group) ×100%
Based on the inhibition rate of 5 concentration test samples, using GraphPad Prism6 software to calculate IC by nonlinear regression method 50 Values. The partial test results (see table 3) are as follows:
TABLE 3 cytotoxic Activity of Compounds against human tumor cells
As can be seen from the data in the table, the quinazoline compounds 1, 15 and 21 have very obvious inhibition effects on the high-expression cell strains of the Tubulin and C-Met targets, have certain anti-tumor activity, and can effectively inhibit the growth of tumor cells; the quinazoline and phenylacetamide derivative structures exist in the structure of the compound shown in the general formula (I); the compound has obvious difference from the reported compounds, and further the compounds in the general formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof are used for preparing and/or preventing and relieving cancers caused by tumor cells of human tissues or organs.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any of various other corresponding changes and modifications made according to the technical idea of the present invention should be included in the scope of the claims of the present invention.
Claims (9)
1. A quinazoline compound, characterized in that: the compound is shown in the general formula (I),
in the method, in the process of the invention,
R 1 selected from hydrogen;
R 2 selected from hydrogen;
R 3 selected from hydrogen;
R 4 selected from hydrogen;
m is selected from 1-4;
R 5 selected from hydrogen, C 1 -C 12 An alkoxy group;
p is selected from 1-4;
R 6 selected from halogen, unsubstituted C 1 -C 12 An alkyl group;
n is selected from 1-5;
or a pharmaceutically acceptable salt of the compound shown in the general formula (I).
2. A quinazoline compound according to claim 1, wherein: in the general formula (I),
R 1 selected from hydrogen;
R 2 selected from hydrogen;
R 3 selected from hydrogen;
R 4 selected from hydrogen;
m is selected from 1-4;
R 5 selected from hydrogen, C 1 -C 4 An alkoxy group;
p is selected from 1-4;
R 6 selected from halogen, unsubstituted C 1 -C 4 An alkyl group;
n is selected from 1-5;
or a pharmaceutically acceptable salt of the compound shown in the general formula (I).
3. A quinazoline compound according to claim 2, wherein: in the general formula (I),
R 1 selected from hydrogen;
R 2 selected from hydrogen;
R 3 selected from hydrogen;
R 4 selected from hydrogen;
R 5 selected from hydrogen or methoxy;
R 6 selected from halogen, methyl, ethyl, isopropyl;
n is selected from 1-5;
or a pharmaceutically acceptable salt of the compound shown in the general formula (I).
4. A compound according to any one of claims 1 to 3, wherein: the corresponding salt of the compound shown in the general formula I is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methylsulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
5. Use of a compound according to claim 1, characterized in that: the application of the compound shown in the general formula (I) in preparing a medicament for treating cell proliferation diseases.
6. The use of a compound according to claim 5, wherein: the cell proliferative disorder is selected from cancer, infection, inflammation or autoimmune disorder.
7. The use of a compound according to claim 6, wherein: the cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
8. A pharmaceutical composition characterized by: a compound as defined in any one of claims 1 to 4 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or excipients.
9. The use of a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of a cell proliferative disorder.
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