CN112778217A - Quinazoline compound and application thereof - Google Patents
Quinazoline compound and application thereof Download PDFInfo
- Publication number
- CN112778217A CN112778217A CN201911084758.7A CN201911084758A CN112778217A CN 112778217 A CN112778217 A CN 112778217A CN 201911084758 A CN201911084758 A CN 201911084758A CN 112778217 A CN112778217 A CN 112778217A
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- China
- Prior art keywords
- cancer
- hydrogen
- halogen
- cyano
- compound
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- -1 Quinazoline compound Chemical class 0.000 title claims description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 239000000651 prodrug Substances 0.000 claims abstract description 17
- 229940002612 prodrug Drugs 0.000 claims abstract description 17
- 239000012453 solvate Substances 0.000 claims abstract description 16
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 8
- 206010058467 Lung neoplasm malignant 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
- 206010008342 Cervix carcinoma Diseases 0.000 claims abstract description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims abstract description 6
- 201000010881 cervical cancer 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
- 201000004101 esophageal cancer Diseases 0.000 claims abstract description 5
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 5
- 201000010982 kidney cancer Diseases 0.000 claims abstract description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 201000001441 melanoma Diseases 0.000 claims abstract description 5
- 201000008968 osteosarcoma Diseases 0.000 claims abstract description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 5
- 206010038038 rectal cancer Diseases 0.000 claims abstract description 5
- 201000001275 rectum cancer Diseases 0.000 claims abstract description 5
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 5
- 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 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 150000002431 hydrogen Chemical class 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 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 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
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- 201000010099 disease Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 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 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 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 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
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- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229940050390 benzoate Drugs 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229940001468 citrate Drugs 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 229940049920 malate Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 229940095064 tartrate Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 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
- 125000001153 fluoro group Chemical group F* 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
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- 210000000056 organ Anatomy 0.000 abstract description 4
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 abstract description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 abstract description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to quinazoline-containing compounds shown as a general formula (I), and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein a substituent R1、R2、R3、R4、R5、R6P, m, n have the meanings given in the description. The invention also relates to the application of the compound shown in the general formula (I) in preparing antitumor drugsAnd also relates to the application of the compounds and the 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, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic 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
Although studies on the mechanism of quinazoline compounds inhibiting the proliferation of HepG2, MGC-803 and A549 tumor cells have been described in European Journal of Medicinal Chemistry 107(2016)12-25, no studies have been made on the inhibition of other cancers such as lung cancer, bladder cancer, colon cancer and leukemia.
The patent CN 102977014B relates to the research on the in vitro anti-tumor inhibitory activity of the compound A with the general formula, but the structure of the compound is obviously different from that of the compound of the invention.
Patent CN106632287A relates to quinazoline compounds with certain anticancer activity on human skin squamous cell carcinoma cell line A431 and human lung cancer cell line A549.
Despite the numerous patents mentioned in connection with the introduction, there is a continuing need to develop new anti-cancer compounds to control the harm of cancer to humans. All of the compounds disclosed in the above patents are structurally distinct 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 compound in preventing and/or treating cancer.
In order to achieve the purpose, the invention adopts the following technical scheme:
a quinazoline compound, which is shown in a general formula (I),
in the formula (I), the compound is shown in the specification,
R1selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxy, amino, cyano or nitro;
R2selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R3selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxyl, amino, cyano, nitro;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
In the preferred general formula (i),
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl or C1-C4Alkoxycarbonyl wherein the following are halogen, hydroxy, cyano, nitro or amino;
R2selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R3selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl or heteroaryl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
In a further preferred general formula (i),
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy, C substituted by one or more halogens1-C4Alkyl radical, C1-C4An alkoxy group;
R2selected from hydrogen, methyl, ethyl or cyclopropyl;
R3selected from hydrogen, methyl, ethyl or cyclopropyl;
R4、selected from hydrogen, fluoro, chloro, methyl, ethyl or cyclopropyl;
m is selected from 1 to 4;
R5、selected from hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl, methoxy,Ethoxy and propoxy groups;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4An alkoxy group;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
Still further preferably, in the general formula (i),
R1selected from hydrogen, trifluoromethyl or methyl;
R2selected from hydrogen or methyl;
R3selected from hydrogen or methyl;
R4selected from hydrogen;
R5selected from hydrogen or methoxy;
R6selected from hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, isopropyl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
The salt corresponding to the compound of the general formula I or the isomer thereof is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
According to the invention, prodrugs of compounds of formula (I) are derivatives of compounds of formula (I) which may themselves have a weaker activity or even no activity, but which, after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) into the corresponding biologically active form.
The compound solvate of the general formula (I) is prepared by reacting the compound of the general formula (I) or an isomer thereof with methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dichloromethane, petroleum ether and acetonitrile.
The application of the compound shown in the general formula (I), the isomer thereof, and the pharmaceutically acceptable salt, solvate or prodrug thereof in preparing a medicament for treating cell proliferation diseases.
The cell proliferation diseases are selected from cancer, infection, inflammation or autoimmune diseases.
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 its isomer, and pharmaceutically acceptable salts, solvates or prodrugs 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 definitions of the 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 groups: straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl or tert-butyl. Halogenated alkyl groups: straight-chain or branched alkyl groups in which the hydrogen atoms may be partially or completely substituted by halogen atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and the like. Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages. Cycloalkyl groups: substituted or unsubstituted heteroatom-containing cyclic alkyl groups, such as cyclopropyl, cyclopentyl, or cyclohexyl. Substituents such as methyl, halogen, and the like. Attached to the structure via an oxygen atom bond. Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages. Alkylthio group: straight or branched chain alkyl groups attached to the structure via a sulfur atom. An alkylcarbonyl group: straight or branched chainThe alkanyl group is linked to the structure via a carbonyl (-CO-) group, such as acetyl. Alkoxycarbonyl group: the alkoxy group is attached to the structure via a carbonyl group. Such as-COOCH3,-COOCH2CH3. An alkylsulfonyl group: straight-chain or branched alkyl group via sulfone group (-SO)2-) is attached to a structure, such as a methylsulfonyl group. Aryl includes phenyl or naphthyl and the like. Heteroaryl is a five or six membered ring containing 1 or more heteroatoms N, O, S. Such as furyl, pyrrolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl and the like.
In the compounds of the invention of the partial general formula I (R)6)nThe substituents are listed in Table 1, but do not limit the present invention.
TABLE 1
Further, some of the compounds of formula (I) may be represented by Table 2,
TABLE 2
The compounds of the general formula (I) according to the invention can be prepared as follows. The reaction is as follows, wherein the groups are as defined above unless otherwise indicated:
synthetic routes of general formula (I):
the preparation process comprises the following steps:
the method comprises the following steps: cpd.1 and cpd.2 were added to formic acid and heated to 135 ℃ with stirring for 5 hours. The reaction solution was poured into a water bath to precipitate the product, which was then filtered to obtain cpd.3.
Step two: the cpd.3 is dissolved in a solvent, a chlorinating agent is added, and the reaction is heated under reflux for 3 hours. And after the reaction is finished, desolventizing to obtain the product cpd.4.
Step three: dissolving cpd.4 and cpd.5 in a solvent, adding alkali, water and TBAB at 100 ℃ for reacting for 4h, and after the reaction is finished, performing column chromatography purification to obtain a product cpd.6.
Step four: cpd.6 and cpd.7 were dissolved in solvent, added base and HBTU, stirred at rt for 6h, and column chromatographed to give cpd.8.
The chlorinating agent may be selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, Vilesmeier-Haack reagent, sulfuryl chloride, and the like.
The base is selected from sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, and potassium bicarbonate.
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, etc.
The reaction temperature in the above steps may be between room temperature and the boiling temperature of the solvent, preferably in the range of 20-150 ℃.
Intermediates cpd.1, cpd.2, cpd.5 and cpd.7 in the above reactions are commercially available.
The salts of the compounds of the formula (I) can be prepared from the compounds of the formula (I) and the corresponding acids in a conventional manner. Suitable acids are selected from hydrochloric, sulfuric, nitric, carbonic, phosphoric, formic, acetic, trifluoroacetic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, benzoic, citric, malic, tartaric, maleic, succinic, ascorbic or oxalic acids 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 a preparation consisting of the preparation. The preparation method comprises the following steps: dissolving the compound covered by the present invention in a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, various cyclodextrins, fatty acids, fatty acid esters, phospholipids or a combination 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 covered in the general formula (I) and the salts and prodrugs thereof are used for preparing anti-tumor medicaments or medicinal preparations for treating, preventing or relieving tumor, and the active ingredients of the medicaments are one or more quinazoline compounds shown in the general formula (I). Is especially suitable for treating or relieving cancer caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic 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 component of an anti-tumor medicament, can be used independently, and can also be used together with other anti-tumor and anti-virus medicaments. The combination therapy of the present invention includes the use of at least one compound of the present invention and its active derivatives in combination with one or more other anti-tumor and anti-viral agents to increase the overall therapeutic effect. The dosage and administration time of the combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.
The pharmaceutical formulation contemplated includes an effective dose of the compound of formula (I). An "effective amount" as used herein refers to the amount of the compound required to produce a therapeutic effect in the subject being treated. The effective dose or dosages may be varied by the experiential person according to the recommendations of the individual case. For example, the types of tumors to be treated are different, and the use of drugs is different; whether the composition is 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 available dosage form. If certain compounds have basic or acidic properties and can form non-toxic acids or salts, the salt forms of the compounds can be used. Pharmaceutically acceptable organic acid salts include physiologically acceptable negative ion salts such as p-toluenesulfonate, methanesulfonate, acetate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or glycerophosphate, and the like; inorganic salts that may be used include chlorides, bromides, fluorides, iodides, sulfates, nitrates, bicarbonates, carbonates, or phosphates, and the like; basic compounds such as amines with suitable acids can be prepared in the form of the salts; the carboxylic acid 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 easily soluble in organic solvents, water-soluble solvents, and mixed solvents of organic solvents and water-soluble solvents with water. The water-soluble solvent is preferably alcohol, polyethylene glycol, N-methyl-2-pyrrolinone, 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 can be formulated by mixing 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 water solution. The thus-prepared preparation is stable and useful for animals and clinics.
The product medicine prepared by using the compound in the general formula (I) as an active ingredient can be administrated by oral or parenteral routes, and also can be administrated by a medicine pump transplanted in vivo and other methods, wherein the parenteral route administration refers to perfusion, subcutaneous intracutaneous, intramuscular, intravenous, intra-arterial, intra-atrial, intra-synovial, intrasternal, intrathecal, intra-traumatic, intracranial injection or instillation technology and the like. The technical personnel mix the components by a conventional method to finally obtain the required medicament form. Can be made into tablet, pill, capsule, granule, syrup, injection, lyophilized powder for injection, emulsion, powder, lyophilized powder, dripping pill, emulsion suspension, aqueous suspension, water solution, colloid solution, sustained release preparation, nanometer preparation, or other dosage forms for animal or clinical use.
The compound in the general formula (I) is used for preparing a medicine for treating or relieving cancer of a certain tissue or organ. The cancer includes but is not limited to 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 cancer or gastric cancer.
Detailed Description
The following specific examples are provided to further illustrate the present invention, but the present invention is not limited to these examples. (all materials are commercially available unless otherwise noted)
Synthetic examples
Example 1: preparation of Compound 1
The method comprises the following steps: intermediate a (20g,101mmol), amine formate (80mL) and formic acid (8mL) were added to a 250mL single-neck flask and heated to 135 deg.C with stirring for 5 hours. The reaction solution was poured into a water bath to precipitate the product, which was then filtered to obtain 23g of the product.
Step two: intermediate b (5g,24.3mmol) was added to SOCl2(50mL), the reaction was heated under reflux for 3 h. After the reaction, the product 5.3g was obtained by desolventizing.
Step three: intermediate c (5.3g,23.7mmol) and intermediate d (2.8g,25.69mmol) were dissolved in butanone (100mL), NaOH (3g,75mmol), H were added2O (20mL,1.1mol), and TBAB (4g,12mmol), heating to 100 deg.C, reacting for 4h, and purifying by column chromatography to obtain 2.6 g.
Step four: intermediate e (100mg, 0.337mmol) and intermediate f (50mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of Compound 1.
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 as in example 1. The preparation method of the compound 2 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (54mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of Compound 2.
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 as in example 1. The preparation method of the compound 3 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (54mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of Compound 3.
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 as in example 1. The preparation method of the compound 4 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (55mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of compound 4.
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 as in example 1. The preparation method of the compound 5 comprises the following steps:
the method comprises the following steps: intermediate e (100mg, 0.337mmol) and intermediate f (67mg,0.325mmol) were dissolved in THF (10mL), DIPEA (200mg, 1.55mmol) and HBTU (130mg,0.343mmol) were added and stirred at room temperature for 6 hours, and column chromatography gave 100mg of compound 5.
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 compound data are as follows:
compound 6:1H NMR (600MHz, DMSO-d6) δ 10.29(s,1H),8.63(s,1H),7.71(d, J ═ 8.6Hz,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 ═ 2.7Hz,1H),4.00(d, J ═ 10.9Hz,6H),3.76(s,3H),3.64(s,2H). MS:445.16.
Compound 7:1H NMR (600MHz, DMSO-d6) δ 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 (600MHz, DMSO-d6) δ 10.34(s,1H),8.65(s,1H), 7.72-7.68 (m,2H),7.59(s,1H),7.44(t, J ═ 1.9Hz,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 (600MHz, DMSO-d6) δ 10.32(s,1H),8.57(s,1H),7.69(d, J ═ 8.5Hz,2H),7.57(s,1H),7.39(d, J ═ 5.0Hz,2H),7.25(d, J ═ 8.6Hz,2H),7.20(d, J ═ 8.0Hz,2H),7.10(d, J ═ 2.4Hz,1H),3.99(d, J ═ 10.2Hz,6H),3.71(s,2H). MS:433.14.
Compound 10:1H NMR (600MHz, DMSO-d6) δ 8.65(s,1H), 7.72-7.68 (m,2H),7.59(s,1H),7.54(d, J ═ 8.1Hz,2H), 7.52-7.48 (m,2H),7.33(d, J ═ 8.0Hz,2H), 7.28-7.25 (m,2H),4.00(d, J ═ 11.5Hz,6H),3.67(s,2H). MS:493.06.
Compound 11:1H NMR (600MHz, DMSO-d6) δ 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 ═ 8.2Hz,6H),3.88(s,2H). MS:541.05.
Compound 12:1H NMR (600MHz, DMSO-d6) δ 10.31(s,1H),8.54(s,1H),7.76(t, J ═ 1.7Hz,1H), 7.72-7.67 (m,2H),7.64(dt, J ═ 7.9,1.4Hz,1H),7.55(s,1H),7.39(d, J ═ 9.7Hz,2H), 7.28-7.24 (m,2H),7.16(t, J ═ 7.8Hz,1H),3.98(d, J ═ 9.5Hz,6H),3.67(s,2H). MS:541.05.
Compound 13:1H NMR (600MHz, DMSO-d6) δ 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 ═ 9.9Hz,6H),3.65(s,2H). MS:541.05.
Compound 14:1H NMR (600MHz, DMSO-d6) δ 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 ═ 9.1Hz,6H),3.72(s,2H),2.33(s,3H). MS:429.17.
Compound 15:1H NMR (600MHz, DMSO-d6) δ 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 ═ 7.8Hz,2H),3.99(d, J ═ 9.8Hz,6H),3.62(s,2H),2.29(s,3H). MS:429.17.
Compound 16:1H NMR (600MHz, DMSO-d6) δ 10.36(s,1H),8.53(s,1H),7.81(d, J ═ 1.8Hz,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 ═ 7.8Hz,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.
Compound 17:1H NMR (600MHz, DMSO-d6) δ 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 ═ 9.8Hz,6H),3.81(s,2H). MS:440.15.
Compound 18:1H NMR (600MHz, DMSO-d6) δ 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 ═ 2.9Hz,1H),3.99(d, J ═ 8.9Hz,6H),3.80(s,2H). MS:467.10.
Compound 19: 1H NMR (600MHz, DMSO-d6) δ 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 ═ 9.7Hz,6H),3.74(s,2H). MS:467.10
Compound 20:1H NMR (600MHz, DMSO-d6) δ 10.31(s,1H),8.53(s,1H),7.75(t, J ═ 1.8Hz,1H), 7.70-7.66 (m,2H),7.60(d, J ═ 1.8Hz,2H),7.55(s,1H),7.38(s,1H), 7.27-7.24 (m,2H),3.98(d, J ═ 9.4Hz,6H),3.73(s,2H). MS:570.97.
Compound 21:1H NMR (600MHz, DMSO-d6) δ 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 ═ 8.5Hz,6H),3.90(s,2H). MS:511.05.
According to the descriptions of the above examples and the preparation process of the compound of formula (i) in the summary of the invention, other compounds represented by formula (i) can be further prepared;
and (3) obtaining the compound shown in the general formula (I) according to the preparation method, and reacting the obtained compound with a corresponding salt to obtain a pharmaceutically acceptable salt of the compound shown in the general formula (I).
Determination of antitumor Activity
Example 1: the in vitro assay for tumor cell inhibition (MTT assay) was as follows:
the human cancer tumor cell line: human colon cancer HT-29 and human cervical carcinoma cell Hela.
The inhibition rate of 5 concentration samples to the growth of each human cancer cell is determined by adopting an in vitro cell culture technology and using a conventional MTT method to measure the inhibition rate of the human colon cancer HT-29 and the human cervical cancer Hela.
MTT method: the cells were removed from the incubator, washed twice with PBS solution, digested with 0.25% trypsin solution, digested by addition of RPMI1640 complete medium (containing 10% FBS), centrifuged, and the supernatant was spun off, and the cell suspension was formed by addition of complete medium, and counted under an inverted microscope. Cells were formulated at a concentration of 5x104The method comprises the steps of adding 100 mu L of cells into each well of a 96-well plate, placing the 96-well plate in a humidified air at 37 ℃ for overnight culture, removing supernatant by placing the 96-well plate in a humidified air at 5% carbon dioxide, adding complete culture medium for dilution into five different concentration gradients of 40 mu g/mL, 8 mu g/mL, 1.6 mu g/mL, 0.32 mu g/mL and 0.064 mu g/mL to obtain a compound to be tested, removing the supernatant after the complete culture medium acts for 48 hours, adding 100 mu L of 0.5mg/mL MTT, reacting for 4 hours, reducing MTT tetrazolium (tetrazole) components by living cells to generate formazan (formazan) to remove the supernatant, adding 100 mu L of DMSO to dissolve the formazan, and finally measuring the absorbance value of 490nm and 630nm on a 96-well plate reader.
The cell inhibition rate (1-absorbance of experiment/absorbance of control) x 100%
According to the inhibition rate of 5 concentration test samples, IC is calculated by GraphPad Prism6 software by a nonlinear regression method50The value is obtained. Part of the test results (see table 3) are as follows:
TABLE 3 cytotoxic Activity of Compounds on human tumor cells
The data in the table show that the quinazoline compounds 1, 15 and 21 have very obvious inhibition effects on high-expression cell strains of Tubulin and C-Met targets, have certain antitumor 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 with the reported compounds, and the compound with the general formula (I) and the pharmaceutically acceptable salts, solvates and prodrugs thereof can be 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 should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A quinazoline compound characterized in that: the compound is shown in a general formula (I),
in the formula (I), the compound is shown in the specification,
R1selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxy, amino, cyano or nitro;
R2selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R3selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxyl, amino, cyano, nitro;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
2. The quinazoline compound according to claim 1, wherein: in the general formula (I), the first step is,
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl or C1-C4Alkoxycarbonyl, wherein the following radicals are halogen, hydroxy,Cyano, nitro or amino;
R2selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R3selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl or heteroaryl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
3. The quinazoline compound according to claim 2, wherein: in the general formula (I), the first step is,
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy, C substituted by one or more halogens1-C4Alkyl radical, C1-C4An alkoxy group;
R2selected from hydrogen, methyl, ethyl or cyclopropyl;
R3selected from hydrogen, methyl, ethyl or cyclopropyl;
R4selected from hydrogen, fluorine, chlorine, methyl, ethyl or cyclopropylA group;
m is selected from 1 to 4;
R5selected from hydrogen, fluoro, chloro, methyl, ethyl, cyclopropyl, methoxy, ethoxy and propoxy;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4An alkoxy group;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
4. The quinazoline compound according to claim 3, wherein: in the general formula (I), the first step is,
R1selected from hydrogen, trifluoromethyl or methyl;
R2selected from hydrogen or methyl;
R3selected from hydrogen or methyl;
R4selected from hydrogen;
R5selected from hydrogen or methoxy;
R6selected from hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, methyl, ethyl, isopropyl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
5. The compound of any one of claims 1-4, wherein: the salt corresponding to the compound of the general formula I or the isomer thereof is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
6. Use of a compound according to claim 1, wherein: the compound shown in the general formula (I), isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or prodrugs thereof are applied to preparation of medicines for treating cell proliferation diseases.
7. Use of a compound according to claim 6, characterized in that: the cell proliferation diseases are selected from cancer, infection, inflammation or autoimmune diseases.
8. Use of a compound according to claim 7, characterized in that: 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.
9. A pharmaceutical composition characterized by: containing a therapeutically effective amount of a compound of any one of claims 1 to 6, or an isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with one or more pharmaceutically acceptable carriers or excipients.
10. Use of the pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of a cell proliferative disorder.
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