CN102060875A - 新型喹唑啉衍生物、制备方法和用途 - Google Patents
新型喹唑啉衍生物、制备方法和用途 Download PDFInfo
- Publication number
- CN102060875A CN102060875A CN 200910228308 CN200910228308A CN102060875A CN 102060875 A CN102060875 A CN 102060875A CN 200910228308 CN200910228308 CN 200910228308 CN 200910228308 A CN200910228308 A CN 200910228308A CN 102060875 A CN102060875 A CN 102060875A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- hydroxyl
- compound according
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- -1 nitro, methyl Chemical group 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 241001597008 Nomeidae Species 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical group [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 claims 1
- 125000005936 piperidyl group Chemical group 0.000 claims 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- 230000019491 signal transduction Effects 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 2
- 150000007524 organic acids Chemical class 0.000 abstract description 2
- 235000005985 organic acids Nutrition 0.000 abstract description 2
- 239000002585 base Substances 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 210000004027 cell Anatomy 0.000 description 26
- 239000007787 solid Substances 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 150000003246 quinazolines Chemical class 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000001871 ion mobility spectroscopy Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229960000241 vandetanib Drugs 0.000 description 3
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- LBGIYCBNJBHZSZ-UHFFFAOYSA-N 4-chloro-6-methoxy-7-phenylmethoxyquinazoline Chemical compound COC1=CC2=C(Cl)N=CN=C2C=C1OCC1=CC=CC=C1 LBGIYCBNJBHZSZ-UHFFFAOYSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 210000003606 umbilical vein Anatomy 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- WEEMDRWIKYCTQM-UHFFFAOYSA-N 2,6-dimethoxybenzenecarbothioamide Chemical compound COC1=CC=CC(OC)=C1C(N)=S WEEMDRWIKYCTQM-UHFFFAOYSA-N 0.000 description 1
- YLMFXCIATJJKQL-UHFFFAOYSA-N 2-bromo-4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1Br YLMFXCIATJJKQL-UHFFFAOYSA-N 0.000 description 1
- ZCUFFSHMOAEEIL-UHFFFAOYSA-N 6-methoxy-7-phenylmethoxy-1h-quinazolin-4-one Chemical compound COC1=CC2=C(O)N=CN=C2C=C1OCC1=CC=CC=C1 ZCUFFSHMOAEEIL-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000011960 computer-aided design Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001925 cycloalkenes Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 229940125436 dual inhibitor Drugs 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- FKOZQALYXWKSAF-UHFFFAOYSA-N methyl dipropan-2-yl phosphate Chemical compound CC(C)OP(=O)(OC)OC(C)C FKOZQALYXWKSAF-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- UPEHYJHYPMGWJC-UHFFFAOYSA-N n-(4-bromo-2-fluorophenyl)-6-methoxy-7-phenylmethoxyquinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC=3C=CC=CC=3)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F UPEHYJHYPMGWJC-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient 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
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属药物化学技术领域，涉及通式(I)喹唑啉衍生物，其中R1，R2，R3，A，X，m和n分别具有在说明书中限定的含义。本发明还涉及这些衍生物的制备方法，其与无机或有机的酸或碱所形成的生理上可接受的盐，含有它们的药物组合物。所述化合物具有有价值的药理性质，特别是对因酪氨酸激酶所引起的信号转导有抑制效果，本发明还关于其在治疗疾病，特别是肿瘤疾病上的用途及其制备方法。
Description
技术领域
本发明涉及新型喹唑啉衍生物或其药学上可接受的盐，这些化合物具有抗肿瘤活性。本发明还涉及制备所述喹唑啉衍生物的方法、含有这些衍生物的药物组合物和它们在抗肿瘤药物中的应用。
背景技术
肿瘤是一系列以异常细胞失控增生和扩散为特征的疾病，是严重威胁人类生命健康的重大疾病，据统计，每年全球肿瘤死亡总数约790多万人，我国每年死于肿瘤者160多万人，并逐渐增加，已成为城市人口的第一位死因。近年来，随着分子生物技术的不断发展，医学上已经证实，细胞功能活动受到复杂的信号转导通路(signaling pathway)的调控，精细调节的信号转导是正常生命活动的前提，而信号转导异常可以导致病理过程。例如，大量证据显示，许多疾病的发生与控制细胞生长、增生和死亡的信号转导通路障碍有关。随着分子靶点药物的研究日渐深入，细胞信号转导和凋亡的某些突破性研究成果，使得特异性抗癌新药的开发成为可能，此类药物的许多品种已进入临床研究并取得了可喜的疗效，细胞信号转导(signal transduction)已成为生物医学领域研究的重要热点之一。
目前许多合成的化合物具有抑制表皮生长因子受体酪氨酸激酶(EGFR-PTK)的活性，尤其以喹唑啉类化合物研究的最深入，其中ZD1839于2003年被FDA批准上市用于治疗非小细胞肺癌(Ranson，M.Epideraml growth factor receptor tyrosine kinase inhibitors.British J.Caneer 2004，90，2250-2255.)。ZD6474既具有抑制EGFR的活性，同时具有抑制VEGFR的活性，于2009年申报上市(Alessandro，M.Vandetanib(ZD6474)，a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor(VEGFR)and Epidermal Growth Factor Receptor(EGFR )Tyrosine Kinase：Current Status and Future DirectionsThe Oneologist2009，14，378-390.)。
通过对ZD6474的临床前、以及临床的数据、专利情况等的分析和对比，我们确立以其为先导化合物，然后根据已报道化合物及生物活性测试数据，利用计算机辅助设计的手段，有目的的对ZD6474的结构进行设计、合成与筛选，以期找到结构新颖、高特异、活性更好的新型靶向抗肿瘤化合物。
发明内容
本发明的目的是提供一类新型喹唑啉衍生物，以及该类化合物在抗肿瘤药物中作为活性成分的用途。
本发明即喹唑啉衍生物如通式(I)所示：
其中：
R1表示：氢，三氟甲基，硝基，甲基，氰基，C1-4烷基，C1-4烷氧基，N-(C1-4)烷基胺，卤素，羟基，N，N-二氮(C1-4)烷基胺，C1-4烷基硫，C1-4烷基磺酰基；R1优选自氢，三氟甲基，硝基，甲基，氰基，卤素，特别是氟原子和溴原子。
R2表示：氢，羟基，C1-4烷基，卤代(C1-4)烷基，羟基(C1-4)烷基，C1-4烷氧基、C1-4磷酰胺，C1-4磷酸酯基及其盐；R2优选自羟基(C1-4)烷基，C1-4烷氧基、C1-4磷酰胺，C1-4磷酸酯基及其盐。
R3表示：氢，羟基，氨基，硝基，(C1-6)酰胺基，(C1-6)烷氧基；X表示：SO、SO2、CON、SO2N、CH2OR2；R3优选自氢、甲氧基。X优选自CON、SO2N、CH2OR2。
A表示：(C3-7)环烷基、(C3-7)环烷基-(C1-6)烷基、(C3-7)环烯基、(C3-7)环烯基-(C1-6)烷基、杂环基或环基-(C1-6)烷基，其中任何烷基或烯基可以连接一个或多个卤基或(C1-6)烷基取代基或者连接一个选自一下的取代基：羟基、氰基、氨基、羧基、氨基甲酰基、(C1-6)烷基、(C1-6)烷氧基、卤代烷基；A优选自C6杂环基，特别优选自哌啶基。
m表示：1，或2，或3；
n表示：0，或1，或2。
以下是本发明化合物的制备方法，其中起始化合物(II)可以商购。
化合物(II)与氯化亚砜经氯化反应制备得到化合物2，化合物2与不同取代的芳香伯胺经氮烷基化反应得到化合物3；化合物3在催化氢化条件下脱苄基得到4，化合物4再与不同取代基团的卤代烃胺化得到式(I)目标化合物。
其中R1，R2，R3，A，X，m和n如上所定义。
本发明所述式(I)化合物的药学上可接受的盐，根据不同衍生物可以含有羧基或胺基，羧基可与碱性物质(如碱金属或碱土金属的氢氧化物、碳酸盐和碳酸氢盐)反应，它们包括，但不限于：氢氧化钠，氢氧化钾，氢氧化钙，碳酸钠等形成药学上可接受的盐，如相应的钠盐，钾盐或钙盐等等。也可采用无毒的有机碱如甲胺、三乙胺、葡甲胺等生成盐；胺基可与酸性物质(如盐酸、氢溴酸、硫酸等)反应，它们包括，但不限于：盐酸，氢溴酸，硫酸，磷酸等形成药学上可接受的盐，也可采用有机酸如乙酸、草酸、柠檬酸等生成盐。式(I)的化合物及其盐的形式具有抗肿瘤活性，
本发明所述式(I)化合物或其药学上可接受的盐，可以与一种或多种药学上可接受的载体、赋形剂或稀释剂共同制成药物组合物。该药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。
所述固体及液体口服制剂包括：片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖浆剂、颗粒剂、口服溶液剂。可采用乳糖或淀粉作为所述固体口服制剂的载体；使用明胶，甲基纤维素、羟丙甲纤维素、聚乙烯吡咯烷酮、淀粉浆等作为粘合剂；使用淀粉、羧甲基纤维素钠、羧甲淀粉钠、低取代羟丙甲纤维素、交联聚维酮、微晶纤维素作为崩解剂；使用滑石粉，微份硅胶，硬脂酸甘油酯，硬脂酸钙或镁等作为抗粘合剂和润滑剂。所述固体口服制剂的制备方法包括以下步骤：将活性成分与载体以及选择性地与一份崩解添加剂组成混合物，然后使该混合物与粘合剂的含水溶液，醇性或含水醇性溶液在合适的设备中进行湿法或干法制粒，干燥颗粒，随后加入其它的崩解剂、润滑剂和抗粘剂制成适当的制剂。
所述注射剂包括：小针、冻干粉针和大输液等。所述注射剂的制备方法包括以下步骤：取注射用水，称取处方量的辅料搅拌使溶解，加入样品搅拌溶解，调pH值至适当范围，加入0.1％-0.5％的活性炭吸附一定时间后，脱碳、滤过，再分装或冻干。
本发明通过体外四氮唑盐还原法(MTT法)试验表明：具有通式I结构的喹唑啉衍生物对人脐静脉内皮细胞(HUVEC)、人肺腺癌细胞(A-549)、人髓状甲状腺细胞(TT)、人结直肠腺癌细胞(Colo205)、人前列腺癌细胞(PC-3)、人卵巢癌细胞(SKOV-3)、人乳腺癌细胞(MCF-7)、人白血病细胞(HL-60)等具有很强的细胞增殖抑制作用。
具体实施方式
下面的实施例可以使本专业技术人员更全面的理解本发明，但不以任何方式限制本发明。
实施例1(4-((4-(4-溴-2-氟苯胺基)喹唑啉-7-基氧基)甲基)哌啶-1-基)甲基二异丙基磷酸酯的制备
第一步：将7-苄氧基-6-甲氧基喹唑啉-4-酮(5.0g，0.018mol)溶解在DMF(20mL)中，滴加二氯亚砜，加热回流3h。蒸除溶剂，乙酸乙酯重结晶，得到白色固体7-苄氧基-4-氯-6-甲氧基喹唑啉(4.8g，90.2％)，m.p.247℃；1H NMR(400MHz，DMSO)：δ3.84(s，3H，CH3O)，5.26(s，2H，CH2O)，7.23(s，1H，ArH)，7.41-7.55(m，6H，ArH)，7.99(s，1H，Ar).ESI-MS：m/z 301[M+H]+.
第二步：将7-苄氧基-4-氯-6-甲氧基喹唑啉(4.8g，0.016mol)和2-溴-4-氟苯胺(3.0g，0.016mol)溶解在异丙醇(100mL)中，加热回流2h。溶液冷却后，过滤，异丙醇和乙醚洗，干燥得7-苄氧基-N-(2-溴-4-氟苯基)-6-甲氧基喹唑啉-4-胺(6.9g，95.8％)，m.p.231-233℃；1H NMR(400MHz，DMSO)：δ3.99(s，3H，CH3O)，5.26(s，2H，CH2O)，7.38-7.50(m，9H，ArH)，8.13(s，1H，Ar)，8.77(s，1H，Ar).ESI-MS：m/z 455[M+H]+.
第三步：将7-苄氧基-N-(4-溴-2-氟苯基)-6-甲氧基喹唑啉-4-胺(6.9g，0.015mol)溶解在50mL的三氟代醋酸中，加热回流1h。
冷却后，混合物倒入碎冰中，过滤，固体溶解在甲醇中，用氨水调节pH为11，浓缩后过滤，乙醚洗，真空干燥，得到白色固体4-(4-溴-2-氟苯胺)-6-甲氧基喹唑啉-7-酚(4.9g，88.6％)，m.p.145-147℃；1H NMR(400MHz，DMSO)：δ3.94(s，3H，CH3O)，7.33-7.55(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ES I-MS：m/z364[M+H]+.
第四步：将4-(4-溴-2-氟苯胺)-6-甲氧基喹唑啉-7-酚(4.9g，0.013mol)、(4-(氯甲基)哌啶-1-基)甲基二异丙基磷酸酯(5.3g，0.013mol)、碳酸钾(3.7g，0.026mol)和100mL DMF加热到60℃反应10h。蒸干溶剂，粗品柱层析(乙酸乙酯∶石油醚＝4∶1)得到白色固体(4-((4-(4-溴-2-氟苯胺基)喹唑啉-7-基氧基)甲基)哌啶-1-基)甲基二异丙基磷酸酯(I-1)5.0g，收率71.0％，m.p.169-171℃；1H NMR(400MHz，DMSO)：δ1.22-1.65(m，4H，2×CH2)，1.98(m，1H，CH)，2.38-2.55(m，4H，2×CH2)，3.99(s，2H，CH2O)，4.71-4.79(m，2H，2×CH)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ESI-MS：m/z625[M+H]+。
实施例2-8
参照实施例1的操作，区别在于用不同结构的(4-(氯甲基)哌啶-1-基)甲基磷酸酯衍生物与4-(4-溴-2-氟苯胺)-喹唑啉衍生物反应，得到下述式I的化合物。
(4-((4-(4-溴-2-氟苯胺基)喹唑啉-7-基氧基)甲基)哌啶-1-基)甲基二氢磷酸酯，m.p.211-212℃；1H NMR(400MHz，DMSO)：δ1.21-1.37(m，12H，4×CH3)，1.32-1.61(m，4H，2×CH2)，2.34-2.45(m，4H，2×CH2)，2.81-2.89(m，2H，CH2)，4.71-4.79(m，2H，2×CH)，5.07-5.11(m，2H，CH2O)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar)，11.96(2×s，2H，2×OH).ESI-MS：m/z541[M+H]+。
(4-((4-(4-溴-2-氟苯胺基)喹唑啉-7-基氧基)甲基)哌啶-1-基)甲基二钠磷酸酯，m.p.211-212℃；1H NMR(400MHz，DMSO)：δ1.32-1.61(m，4H，2×CH2)，2.34-2.45(m，4H，2×CH2)，2.81-2.89(m，2H，CH2)，4.71-4.79(m，2H，2×CH)，5.07-5.11(m，2H，CH2O)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ESI-MS：m/z585[M+H]+。
(4-((4-(4-溴-2-氟苯胺基)-6-甲氧基喹唑啉-7-基氧基)甲基)哌啶-1-基)甲基二异丙基磷酸酯，m.p.198-199℃；1H NMR(400MHz，DMSO)：δ1.21-1.37(m，12H，4×CH3)，1.42-1.65(m，4H，2×CH2)，1.98(m，1H，CH)，2.38-2.55(m，4H，2×CH2)，2.81-2.89(m，2H，CH2)，3.94(s，3H，CH3O)，4.71-4.79(m，2H，2×CH)，5.10-5.21(m，2H，CH2O)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ESI-MS：m/z655[M+H]+。
(4-((4-(4-溴-2-氟苯胺基)-6-甲氧基喹唑啉-7-基氧基)甲基)哌啶-1-基)甲基二氢磷酸酯，m.p.211-212℃；1H NMR(400MHz，DMSO)：δ1.32-1.61(m，4H，2×CH2)，2.34-2.45(m，4H，2×CH2)，2.81-2.89(m，2H，CH2)，3.94(s，3H，CH3O)，4.71-4.79(m，2H，2×CH)，5.07-5.11(m，2H，CH2O)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar)，11.96(2×s，2H，2×OH).ES I-MS：m/z571[M+H]+。
(4-((4-(4-溴-2-氟苯胺基)-6-甲氧基喹唑啉-7-基氧基)甲基)哌啶-1-基)甲基二钠磷酸酯，m.p.211-212℃；1H NMR(400MHz，DMSO)：δ1.32-1.61(m，4H，2×CH2)，2.34-2.45(m，4H，2×CH2)，2.81-2.89(m，2H，CH2)，3.94(s，3H，CH3O)，4.71-4.79(m，2H，2×CH)，5.07-5.11(m，2H，CH2O)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ESI-MS：m/z 615[M+H]+。
4-((4-(4-溴-2-氟苯胺基)-6-甲氧基喹唑啉-7-基氧基)甲基)哌啶-1-甲酰胺，m.p.154-155℃；1H NMR(400MHz，DMSO)：δ1.22-1.65(m，4H，2×CH2)，1.98(m，1H，CH)，2.38-2.55(m，4H，2×CH2)，3.94(s，2H，CH2O)，3.99(s，3H，CH3O)，6.01(s，2H，NH2)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ES I-MS：m/z 504[M+H]+。
4-((4-(4-溴-2-氟苯胺基)-6-甲氧基喹唑啉-7-基氧基)甲基)哌啶-1甲磺酰胺，m.p.161-162℃；1H NMR(400MHz，DMSO)：δ1.22-1.65(m，4H，2×CH 2)，1.98(m，1H，CH)，2.38-2.55(m，4H，2×CH2)，2.91(s，3H，CH3)，3.94(s，2H，CH2O)，3.99(s，3H，CH3O)，6.31(s，2H，NH2)，7.31-7.51(m，4H，ArH)，8.11(s，1H，Ar)，8.67(s，1H，Ar).ESI-MS：m/z 540[M+H]+。
实施例9
片剂制备方法如下：
工艺：将活性成分辅料分别过100目筛，称取处方量的主药和辅料(一半羧甲基淀粉钠)充分混合，加入聚乙烯吡咯烷酮水溶液适量制软材，过24目筛，制得湿颗粒于50-60℃烘箱中干燥约2-3小时，将剩余羧甲基淀粉钠和硬脂酸镁与颗粒混合均匀，整粒，测定中间体含量，用Φ8mm浅冲压片。
实施例10
注射液的制备
工艺：取注射用水50ml，称取处方量的柠檬酸、磷酸二氢钠搅拌使溶解，加入样品搅拌溶解，用0.1mol/L的盐酸或氢氧化钠调pH值为4.0-5.0，加入0.1％的活性炭吸附20分钟。先用0.45μm滤膜滤过，再用0.22μm精滤。按每安瓿5毫升灌装，105℃高温灭菌30分钟即得注射液。
化合物I的体外抗肿瘤活性试验
(1)材料
细胞株：人脐静脉内皮细胞(HUVEC)、人肺腺癌细胞(A-549)、人髓状甲状腺细胞(TT)、人结直肠腺癌细胞(Colo205)、人前列腺癌细胞(PC-3)、人卵巢癌细胞(SKOV-3)、人乳腺癌细胞(MCF-7)、人白血病细胞(HL-60)。天津药物研究院药物创新研究中心冻存。
试剂：MTT，Amresco公司；DMEM、DMEM/F12培养基，Gibco公司；小牛血清，兰州民海生物；胰蛋白酶，Amresco公司。
仪器：超净工作台，苏州净化设备厂；CO2培养箱，Thermo公司，型号：HERA Cell150；倒置显微镜，Carl Zeiss公司，型号：Axiovert 200；酶联免疫检测仪，TECAN公司，型号：Sunrise；离心机，Kerdro公司，型号：Heraeus。
(2)方法
细胞培养：细胞接种在含10％小牛血清，100IU/ml青霉素G钠盐及100ug/ml硫酸链霉素的DMEM或DMEM/F12完全培养液中，置37℃、100％相对湿度、含5％C02的培养箱中，传代3次后备用。
MTT比色法检测：取对数生长期的细胞，经0.25％胰蛋白酶消化后(悬浮细胞无须消化)，悬浮于含10％小牛血清的培养液中，用玻璃滴管轻轻吹打成单细胞悬液，显微镜下用血细胞记数板记数活细胞。96孔培养板每孔接种细胞悬液90μl(细胞浓度为3-6×104个/mL)，置培养箱24h后，每孔加10μl药液。另外，每个浓度设阴性对照(等浓度DMSO)及空白本底(不加细胞)，各组均设6个复孔。再连续培养48h，然后每孔加入10μl 5mg/mL的MTT溶液，继续培养4h后，仔细吸去上清液。每孔加入100μl DMSO，置微量振荡器震荡5mi n以使结晶完全溶解，于酶标仪492nm单波长比色，测定OD值，试验结果见表1。
抑制率(％)＝[1-(实验组OD均值-空白组OD均值)/(对照组OD均值-空白组OD均值)]×100％。Bliss法计算受试化合物IC50值。
(3)结果
表1.对体外培养细胞生长的IC50(μg/ml)
Claims (8)
1.一种通式(I)喹唑啉衍生物或其药学上可接受的盐：
其中：
R1表示：氢，三氟甲基，硝基，甲基，氰基，C1-4烷基，C1-4烷氧基，N-(C1-4)烷基胺，卤素，羟基，N，N-二氮(C1-4)烷基胺，C1-4烷基硫，C1-4烷基磺酰基；
R2表示：氢，羟基，C1-4烷基，卤代(C1-4)烷基，羟基(C1-4)烷基，C1-4烷氧基、C1-4磷酰胺，C1-4磷酸酯基及其盐；
R3表示：氢，羟基，氨基，硝基，(C1-6)酰胺基，(C1-6)烷氧基；X表示：SO、SO2、CON、SO2N、CH2OR2；
A表示：(C3-7)环烷基、(C3-7)环烷基-(C1-6)烷基、(C3-7)环烯基、(C3-7)环烯基-(C1-6)烷基、杂环基或环基-(C1-6)烷基，其中任何烷基或烯基可以连接一个或多个卤基或(C1-6)烷基取代基或者连接一个选自一下的取代基：羟基、氰基、氨基、羧基、氨基甲酰基、(C1-6)烷基、(C1-6)烷氧基、卤代烷基；
m表示：1，或2，或3；
n表示：0，或1，或2。
2.根据权利要求1所述的化合物，其特征在于R1优选自氢，三氟甲基，硝基，甲基，氰基，卤素，特别是氟原子和溴原子。
3.根据权利要求1所述的化合物，其特征在于R2优选自羟基(C1-4)烷基，C1-4烷氧基、C1-4磷酰胺，C1-4磷酸酯基及其盐。
4.根据权利要求1所述的化合物，其特征在于R3优选自氢、甲氧基。
5.根据权利要求1所述的化合物，其特征在于X优选自CON、SO2N、CH2OR2。
6.根据权利要求1所述的化合物，其特征在于A优选自C6杂环基，特别优选自哌啶基。
7.根据权利要求1所述的化合物，其特征在于其相应的药用盐为：式1化合物·HqX，X代表卤素，硫酸根，硝酸根，磷酸根，q为1，或2，或3。
8.如权利要求1-5所述的任一化合物在制备抗肿瘤药物或抗肿瘤药物组合物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910228308.0A CN102060875B (zh) | 2009-11-18 | 2009-11-18 | 喹唑啉衍生物、制备方法和用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910228308.0A CN102060875B (zh) | 2009-11-18 | 2009-11-18 | 喹唑啉衍生物、制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102060875A true CN102060875A (zh) | 2011-05-18 |
| CN102060875B CN102060875B (zh) | 2014-03-12 |
Family
ID=43996395
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910228308.0A Expired - Fee Related CN102060875B (zh) | 2009-11-18 | 2009-11-18 | 喹唑啉衍生物、制备方法和用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102060875B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554091A (zh) * | 2013-11-05 | 2014-02-05 | 沈阳工业大学 | 喹唑啉衍生物及其制备方法和用途 |
| CN103804308A (zh) * | 2012-11-06 | 2014-05-21 | 天津药物研究院 | 7-取代环己基喹唑啉衍生物及其制备方法和用途 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1274692T3 (da) * | 2000-04-07 | 2006-10-30 | Astrazeneca Ab | Quinazolinforbindelser |
| GB0207323D0 (en) * | 2002-03-28 | 2002-05-08 | Astrazeneca Ab | Compounds |
| JP4036885B2 (ja) * | 2003-09-19 | 2008-01-23 | アストラゼネカ アクチボラグ | キナゾリン誘導体 |
-
2009
- 2009-11-18 CN CN200910228308.0A patent/CN102060875B/zh not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804308A (zh) * | 2012-11-06 | 2014-05-21 | 天津药物研究院 | 7-取代环己基喹唑啉衍生物及其制备方法和用途 |
| CN103554091A (zh) * | 2013-11-05 | 2014-02-05 | 沈阳工业大学 | 喹唑啉衍生物及其制备方法和用途 |
| CN103554091B (zh) * | 2013-11-05 | 2016-05-18 | 沈阳工业大学 | 喹唑啉衍生物及其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102060875B (zh) | 2014-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114901661B (zh) | 新型K-Ras G12C抑制剂 | |
| CN113767103B (zh) | 新型螺环类K-Ras G12C抑制剂 | |
| JP6141568B1 (ja) | 新規なピラゾロ［３，４−ｄ］ピリミジン化合物又はその塩 | |
| CA3004372C (en) | Pyrimidine derivative and use thereof | |
| EP2799437B1 (en) | Quinoline and cinnoline derivatives and use thereof | |
| JP6704422B2 (ja) | キナゾリン誘導体の塩およびその製造方法 | |
| EP3169687B1 (en) | FUSED QUINOLINE COMPUNDS AS PI3K, mTOR INHIBITORS | |
| EP1992622B1 (en) | 4-(3-benzoylaminophenyl)-6,7-dimethoxy-2- methylaminoquinazoline derivative | |
| AU2020424661A1 (en) | Disubstituted adamantyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for suppressing cancer growth comprising same as active ingredient | |
| WO2018159613A1 (ja) | ピラゾロ［３，４－ｄ］ピリミジン化合物を用いた抗腫瘍効果増強剤 | |
| CN119552166B (zh) | 一种parp1/cdk6双靶点抑制剂及其制备方法与应用 | |
| CN102060875A (zh) | 新型喹唑啉衍生物、制备方法和用途 | |
| CN109265449B (zh) | Egfr和her2双靶点酪氨酸激酶抑制剂及制备方法和用途 | |
| CN116120300B (zh) | 一种含异羟肟酸片段的嘧啶类化合物其制备方法和应用 | |
| CN111732597A (zh) | 含4-酰胺苯氧基的2-氨基嘧啶杂环类化合物的制备及应用 | |
| CN105646448B (zh) | 吡啶类化合物及其用途 | |
| BRPI0708098B1 (pt) | Derivados de 4-benzoilaminofenil)-6,7-dimetóxi-2-metilaminoquinazolina, composição farmacêutica e agente antiprurítico | |
| CN114634453B (zh) | 喹唑啉衍生物制备方法及其应用 | |
| WO2016127949A1 (zh) | 作为t790变异抑制剂的嘧啶衍生物 | |
| CN112961081B (zh) | 一种联苯甲酰胺脲类化合物及其制备方法和应用 | |
| CA3134826A1 (en) | Quinoline derivatives and their use for the treatment of cancer | |
| CN103554091B (zh) | 喹唑啉衍生物及其制备方法和用途 | |
| CN118772107A (zh) | Hdac抑制剂及其用途 | |
| HK40114306A (zh) | 多环类化合物及其用途 | |
| HK40116388A (zh) | 用作cdk7激酶抑制剂的化合物及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| DD01 | Delivery of document by public notice |
Addressee: Wu Jiang Document name: payment instructions |
|
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Wu Jiang Document name: Notice of Termination of Patent Rights |
|
| DD01 | Delivery of document by public notice | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140312 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |