CN102532107A - 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof - Google Patents
4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof Download PDFInfo
- Publication number
- CN102532107A CN102532107A CN2010105963055A CN201010596305A CN102532107A CN 102532107 A CN102532107 A CN 102532107A CN 2010105963055 A CN2010105963055 A CN 2010105963055A CN 201010596305 A CN201010596305 A CN 201010596305A CN 102532107 A CN102532107 A CN 102532107A
- Authority
- CN
- China
- Prior art keywords
- compound
- general formula
- quinazoline
- derivatives
- methoxyl group
- 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 abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 150000007524 organic acids Chemical class 0.000 claims abstract description 3
- -1 methoxyl group Chemical group 0.000 claims description 17
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 9
- 241001597008 Nomeidae Species 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical group [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 102000001301 EGF receptor Human genes 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 8
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 235000005985 organic acids Nutrition 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 230000019491 signal transduction Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 108060006698 EGF receptor Proteins 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 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 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000010410 layer Substances 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-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
- 108091000080 Phosphotransferase Proteins 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
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 3
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 150000003246 quinazolines Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000008109 sodium starch glycolate Substances 0.000 description 3
- 229940079832 sodium starch glycolate Drugs 0.000 description 3
- 229920003109 sodium starch glycolate Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- 229960000241 vandetanib Drugs 0.000 description 3
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- NRQJIAVOKMKUOR-UHFFFAOYSA-N 2-piperazin-1-ylquinazoline Chemical compound C1CNCCN1C1=NC=C(C=CC=C2)C2=N1 NRQJIAVOKMKUOR-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Chemical class 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 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
- 206010020718 hyperplasia Diseases 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 231100000682 maximum tolerated dose Toxicity 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Chemical class 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-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
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 238000003043 HTRF KinEASE-TK Methods 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 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
- 238000012449 Kunming mouse Methods 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 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
- 208000008589 Obesity Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910000062 azane Inorganic materials 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium 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
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000009028 cell transition Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution 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
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 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
- 208000001848 dysentery Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000004108 freeze drying Methods 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
- 239000008103 glucose Substances 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 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
- 235000020824 obesity Nutrition 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Chemical class 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000000926 separation method Methods 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
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives (shown as a general formula I), and a preparation method and application thereof. In the general formula, R1, R2 and n are respectively defined in the specifications. The invention also relates to a preparation method for the derivatives, physiologically acceptable salts formed by the derivatives and inorganic or organic acids, and medicinal compositions containing the derivatives and the salts. The compounds have valuable pharmacological properties, have an effect of inhibiting signal transduction caused by protein tyrosine kinase (PTK), particularly have high activity of inhibiting mutant epidermal growth factor receptor EGFR (L858R/T790M), and have low toxicity. The invention also relates to application of the derivatives in treatment of diseases, particularly tumor diseases, and a preparation method for the derivatives. The general formula I is shown in the specifications.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to the preparation method of 4-substituted anilinic-high piperazinyl-quinazoline derivant of 7-substituted alcoxyl.
Background technology
Tumour is a series of with abnormal cells hyperplasia out of control and the disease that is diffused as characteristic; It is the healthy major disease of serious threat human life; According to statistics, about more than 790 ten thousand people of annual global tumor mortality sum, China dies from tumour person more than 160 ten thousand people every year; And increase gradually, become first cause of the death of urban population.
Protein tyrosine kinase (PTK) is one type of enzyme that in normal cell growth, plays an important role, and it can be transferred on the residue of protein substrate from ATP by the catalysis phosphate group.Many EGF-R ELISAs (EGFR) albumen all has the effect of protein tyrosine kinase, and the interaction of these acceptors and growth factor also is that the growth of normal regulating cell is necessary.Yet the over-expresses of EGFR through the effect of himself Tyrosylprotein kinase, can cause the cell transition increment, finally causes the generation of tumour.
Based on the vital role that the receptor kinase of lacking of proper care is risen in cancer pathology, specific ptk inhibitor is the research focus of present carcinostatic agent as the exploitation of potential anticancer therapeutic agent.Therefore present many synthetic compounds all have the activity of inhibition epidermal growth factor recipient tyrosine kinase (EGFR-PTK); Especially the most deep with quinazoline compounds research; Wherein ZD1839 was used to treat nonsmall-cell lung cancer (Ranson in 2003 by FDA approval listing; M.Epideraml growth factor receptor tyrosine kinase inhibitors.British J.Cancer 2004,90,2250-2255.).ZD6474 had both had the activity that suppresses EGFR; Has the activity that suppresses VEGFR simultaneously; Declared listing (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 Oncologist 2009 in 2009; 14,378-390.).The verivate that WO 99/06378, WO 2000/31048 and WO2000/06555 (Chinese patent CN99808949) also relate to some substituted quinazoline has irreversible ptk inhibitor activity.
Traditional quinazoline derivant is in the disease that the treatment cell hyperplasia causes; Need a very big metering just can reach efficacious therapy; This tends to aggravate the spinoff such as dysentery and fash of its generation, need further study the medicine of seeking effective and low toxic side effect for this reason.
WO 97/30035 disclose quinazoline derivative ZD6474 with and as the application of ptk inhibitor.Experiment showed, that this compounds has good inhibitory effect to Human umbilical vein endothelial cells (HUVEC).
In China, high piperazine is mainly used in pharmaceutical industry, is that the pharmaceuticals of raw material have kind more than 20 with it.At present, the medicinal efficacy of the high bridged piperazine derivatives of external popular exploitation.Can be used as antiphlogistic with high some verivate of piperazine synthetic, the other verivate can lowering blood glucose, thereby to the treatment mellitus, obesity etc. have effect preferably.The seven membered heterocyclic of high piperazine is polygon ring, and their midbody majority has intensive biological activity and pharmaceutical use.The high piperazine of nitrogen-containing heterocycle compound is a medicine synthetic important intermediate.Contained dinitrogen atom can with many organic compound reactions, especially the structural modification of chemicals with transform in important role is arranged.Can effectively combine after the butt joint of high piperazine dinitrogen atom and quinazoline, the activity of tumour medicine is significantly improved with the tumour target.Simultaneously, compare with the ZD6474 analog derivative, comprise side chains such as piperidines and piperazine, high piperazine structure can improve the physical and chemical parameter of whole molecule preferably, improves its pharmacokinetic property, thereby the research of high piperazine series compound is more and more come into one's own.
Therefore; High piperazine and quinazoline parent nucleus are organically combined, the EGFR and the VEGFR2 of T790M and L858R sudden change shown high tolerance activity, and toxic side effect is lower; Obtained beyond thought action effect; Its external activity is ZD6474 more than ten times, to having broad application prospects as drug research, this shows it is synthesized and the research of verivate has practical value.
Summary of the invention
The purpose of this invention is to provide one type of novel 4-substituted anilinic-high piperazinyl-quinazoline derivant of 7-substituted alcoxyl, and this compounds in antitumor drug as the purposes of activeconstituents.
The present invention be quinazoline derivant shown in general formula (I):
General formula (I)
Wherein:
R1 representes: hydrogen, methoxyl group, preferably from methoxyl group;
R2 representes: hydrogen, methyl, ethyl, preferably from hydrogen and methyl;
N representes: 1 or 2 or 3 or 4, and preferably from 3.
Below be the preparation method of The compounds of this invention, wherein initial compounds (II) can be purchased.
Compound (II) prepares compound III with sulfur oxychloride through chlorination reaction, and compound III and 2-fluoro-4 bromo-aniline obtain compound IV through the azane glycosylation reaction; Compound IV debenzylation under three fluoro acetate conditions obtains V, and compound V obtains compound VI with the reaction of different halogenated alkane again, again with the high piperazine reaction of Boc-, take off Boc, the N-alkylation obtains general formula (I) target compound.
R wherein
1, R
2As above define with n.
The pharmacy acceptable salt of formula according to the invention (I) compound can contain carboxyl or amido according to different verivates, and carboxyl can react with alkaline matter (like oxyhydroxide, carbonate and the supercarbonate of basic metal or earth alkali metal); They include, but are not limited to: sodium hydroxide, Pottasium Hydroxide; Calcium hydroxide; Yellow soda ash etc. form pharmacy acceptable salt, like corresponding sodium salts, and sylvite or calcium salt or the like.Also can adopt nontoxic organic bases such as methylamine, triethylamine, meglumine etc. to generate salt; Amido can react with acidic substance (example hydrochloric acid, Hydrogen bromide, sulfuric acid etc.), and they include, but are not limited to: hydrochloric acid, and Hydrogen bromide, sulfuric acid, phosphoric acid etc. form pharmacy acceptable salt, also can adopt organic acid such as acetate, oxalic acid, Hydrocerol A etc. to generate salt.The compound of formula (I) and the form of salt thereof have anti-tumor activity,
Formula according to the invention (I) compound or its pharmacy acceptable salt can be processed pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be processed formulations such as solid orally ingestible, liquid oral medicine, injection.
Said solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, oral cavity disintegration tablet, capsule, syrup, granule, oral solution.Can adopt lactose or starch carrier as said solid orally ingestible; Use gelatin, methylcellulose gum, hypromellose, Vinylpyrrolidone polymer, starch slurry etc. are as tackiness agent; Use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, PVPP, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, little part of silica gel, stearin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.The preparation method of said solid orally ingestible may further comprise the steps: with activeconstituents and carrier and optionally with a disintegration additive composition mixture; Make the aqs soln of this mixture and tackiness agent then; Alcohol property or aqueous alcohol property solution carry out wet method or dry granulation in suitable device; Dried particles, the disintegrating agent, lubricant and the antisticking agent that add other are subsequently processed appropriate formulations.
Said injection comprises: little pin, freeze-dried powder and infusion solutions etc.The preparation method of said injection may further comprise the steps: get water for injection, the auxiliary material that takes by weighing recipe quantity stirs and makes dissolving, adds the sample stirring and dissolving; Adjust pH is to proper range; After adding the charcoal absorption certain hour of 0.1%-0.5%, decarburization, filtration, packing or freeze-drying again.
The present invention shows through vitro homogeneous time-resolved fluorescence method (HTRF) test: the quinazoline derivant with general formula I structure has very strong restraining effect to EGFR (L858R/T790M) and VEGFR-2; Test shows that this type of toxicity of compound is lower to mouse body inner model simultaneously.
Embodiment
Following embodiment can make those skilled in the art more comprehensively understand the present invention, but does not limit the present invention in any way.
The preparation of embodiment 17-(3-(1,4-Diazesuberane-1-yl) propoxy-)-N-(4-bromo-2-fluorophenyl)-6-methoxyl group quinazoline-4-amine (VIII)
The first step: (5.0g 0.018mol) is dissolved among the DMF (20mL), drips thionyl chloride, reflux 3h with 7-benzyloxy-6-methoxyl group quinazoline-4-one.Steaming desolventizes, and re-crystallizing in ethyl acetate obtains white solid 7-benzyloxy-4-chloro-6-methoxyl group quinazoline (4.8g, 90.2%), m.p.247 ℃;
1H NMR (400MHz, DMSO): δ 3.84 (s, 3H, CH
3O), 5.26 (s, 2H, CH
2O), 7.23 (s, 1H, ArH), 7.41-7.55 (m, 7H, ArH), 7.99 (s, 1H, Ar) .ESI-MS:m/z 301 [M+H]
+.
Second step: (4.8g, 0.016mol) (3.0g 0.016mol) is dissolved in the Virahol (100mL) reflux 2h with 2-fluoro-4-bromo-aniline with 7-benzyloxy-4-chloro-6-methoxyl group quinazoline.After the solution cooling, filter, Virahol and ether are washed, dry 7-benzyloxy-N-(2-bromo-4-fluorophenyl)-6-methoxyl group quinazoline-4-amine (6.9g, 95.8%), m.p.231-233 ℃ of getting;
1HNMR (400MHz, DMSO): δ 3.99 (s, 3H, CH
3O), 5.26 (s, 2H, CH
2O), 7.38-7.50 (m, 10H, ArH), 8.13 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z455 [M+H]
+.
The 3rd step: (6.9g 0.015mol) is dissolved in the three fluoro acetic acid of 50mL reflux 1h with 7-benzyloxy-N-(4-bromo-2-fluorophenyl)-6-methoxyl group quinazoline-4-amine.After the cooling, mixture is poured in the trash ice, filters, and solid is dissolved in the methyl alcohol; Using ammoniacal liquor to regulate pH is 11, concentrates after-filtration, and ether is washed, vacuum-drying; Obtain white solid 4-(4-bromo-2-fluoroaniline)-6-methoxyl group quinazoline-7-phenol (4.9g, 88.6%), m.p.145-147 ℃;
1H NMR (400MHz, DMSO): δ 3.94 (s, 3H, CH
3O), 7.33-7.55 (m, 4H, ArH), 7.56-7.88 (m, 2H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ESI-MS:m/z 364 [M+H]
+.
The 4th the step: with 4-(4-bromo-2-fluoroaniline)-6-methoxyl group quinazoline-7-phenol (4.9g, 0.013mol), 3-bromine n-propyl chloride (2.0g, 0.013mol), salt of wormwood (3.7g, 0.026mol) with 100mL DMF be heated to 60 ℃ the reaction 10h.Solvent evaporated, bullion column chromatography (ETHYLE ACETATE: sherwood oil=4: 1) obtain white solid N-(4-bromo-2-fluoroanilino)-7-(3-chloropropane base)-6-methoxyl group quinazoline-4 amine 5.0g, yield 71.0%, m.p.134-136 ℃;
1HNMR (400MHz, DMSO): δ 1.22-1.65 (m, 2H, CH
2), 1.98-1.2.01 (m, 2H, CH
2), 2.38-2.55 (m, 2H, CH
2), 3.94 (s, 3H, CH
3O), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 440 [M+H]
+
The 5th step: with 5.0g (11.36mmol) N-(4-bromo-2-fluoroanilino)-7-(3-chloropropane base)-6-methoxyl group quinazoline-4 amine and high piperazine of 2.8g (140mmol) N-BOC-, be dissolved among the 70mlDMA, add salt of wormwood 4.7g (34.08mmol); Be warming up to 70 ℃ of reaction 3h, the TLC detection reaction finishes, and is cooled to room temperature; Reaction solution is poured in the frozen water, had yellow solid to separate out, filter; The washing filter cake, drying, re-crystallizing in ethyl acetate get the yellow solid tertiary butyl-4-(3-((4-((4 bromo-2-fluorophenyl) amino)-6-methoxyl group quinazoline-7-yl) oxygen base) propyl group)-1; 4-Diazesuberane-1-carboxylicesters 5.49g, productive rate 80%, m.p.154-155 ℃;
1H NMR (400MHz, DMSO): δ 1.05 (s, 9H, 3 * CH
3), 1.22-1.65 (m, 2H, CH
2), 1.98-2.01 (m, 2H, CH
2), 2.38-2.55 (m, 2H, CH
2), 2.71-3.42 (m, 10H, 5 * CH
2), 3.94 (s, 3H, CH
3O), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 604 [M+H]
+
The 6th step: with 5.0g (8.28mmol) tertiary butyl-4-(3-((4-((4 bromo-2-fluorophenyl) amino)-6-methoxyl group quinazoline-7-yl) oxygen base) propyl group)-1,4-Diazesuberane-1-carboxylicesters drops in the reaction flask, adds the 60ml methylene dichloride, is partly dissolved; Stir adding 60ml trifluoroacetic acid down, reaction solution is clarified fully, and the reaction solution color becomes brown; Stirring at room reaction 1h, the TLC detection reaction is complete, and decompression steams trifluoroacetic acid; Wash 2 times with a small amount of ether, discard ether layer, water layer is transferred pH to 10 with 2M sodium hydroxide; Which floor dichloromethane extraction is associated with, anhydrous magnesium sulfate drying; Filter, the evaporated under reduced pressure methylene dichloride obtains yellow solid, and (3-(1 to obtain yellow solid 7-with re-crystallizing in ethyl acetate; 4-Diazesuberane-1-yl) propoxy-)-and N-(4-bromo-2-fluorophenyl)-6-methoxyl group quinazoline-4-amine (VIII) 3.75g, productive rate 90%, m.p.177-179 ℃;
1H NMR (400MHz, DMSO): δ 1.22-1.65 (m, 2H, CH
2), 1.98-2.01 (m, 2H, CH
2), 2.08-2.09 (m, 1H, NH), 2.38-2.55 (m, 2H, CH
2), 2.71-3.42 (m, 10H, 5 * CH
2), 3.94 (s, 3H, CH
3O), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 504 [M+H]
+
The preparation of embodiment 2N-(4-bromo-2-fluorophenyl)-6-methoxyl group-7-(3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) propoxy-) quinazoline-4-amine (I-1)
1.0g (3.96mmol) 7-(3-(1,4-Diazesuberane-1-yl) propoxy-)-N-(4-bromo-2-fluorophenyl)-6-methoxyl group quinazoline-4-amine solvent in 20ml formic acid, is added 10ml37% formaldehyde under the stirring at room, it is brown finishing reaction solution; Be warmed up to 95 ℃ of reaction 4h, the TLC detection reaction finishes, and decompression steams unreacted formic acid and formaldehyde, is dissolved in water; Water layer is transferred pH=11 with 2M sodium hydroxide, and water layer is used ethyl acetate extraction, merges organic layer; Anhydrous magnesium sulfate drying filters, and mother liquor is directly mixed appearance; Preparative column separation and purification (ethyl acetate/methanol=10: 1) fast obtains yellow solid N-(4-bromo-2-fluorophenyl)-6-methoxyl group-7-(3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) propoxy-) quinazoline-4-amine (I-1) 1.64g; Productive rate 80%,, m.p.166-167 ℃;
1H NMR (400MHz, DMSO): δ 1.22-1.65 (m, 2H, CH
2), 1.98-2.01 (m, 2H, CH
2), 2.23 (S, 3H, CH
3N), 2.38-2.55 (m, 2H, CH
2), 2.71-3.42 (m, 10H, 5 * CH
2), 3.94 (s, 3H, CH
3O), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 518 [M+H]
+
Embodiment 3
Method for preparing tablet thereof is following:
Prescription consumption/sheet
I-1 100mg
Microcrystalline Cellulose 50mg
Starch 40mg
Polyvidone 8mg
Sodium starch glycolate 10mg
Magnesium Stearate qs
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively, take by weighing the main ingredient and auxiliary material (half sodium starch glycolate) thorough mixing of recipe quantity, add the Vinylpyrrolidone polymer aqueous solution and make softwood in right amount; Cross 24 mesh sieves; Make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, will remain sodium starch glycolate and Magnesium Stearate and particle and mix, whole; Measure midbody content, with the shallow stamping of Φ 8mm.
Embodiment 4
The preparation of injection liquid
I-3 200mg
SODIUM PHOSPHATE, MONOBASIC 10mg
Hydrocerol A 30mg
Water for injection 50ml
Technology: get water for injection 50ml, the Hydrocerol A, the SODIUM PHOSPHATE, MONOBASIC that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, use the hydrochloric acid of 0.1mol/L or sodium hydroxide adjust pH to be 4.0-5.0, the charcoal absorption of adding 0.1% 20 minutes.Filter with 0.45 μ m filter membrane earlier, again with the smart filter of 0.22 μ m.Press 5 milliliters of cans of per ampoule, 105 ℃ of high-temperature sterilizations promptly got injection liquid in 30 minutes.
The anxious poison test of mouse in the extracorporeal anti-tumor enzymic activity test of compound VIII and I-1 and the body
One, extracorporeal anti-tumor enzymic activity test
(1) material and instrument:
1 experiment material: the test kit HTRF KinEASE-TK kit of Cisbio company (article No.: 62TKOPEB); Distilled water
2 detecting instruments: SpectraMax M5:Mplecular Devices product
(2) testing sequence:
1. the preparation of solution and reaction density
2. experimental procedure:
1) calculates all ingredients institute expense.
2) prepare the working fluid of ATP, TK Substrate-biotin.
3) ratio ATP by volume: TK Substrate-biotin: Kinase buffer=2: after getting the liquid mixing at 2: 1, get mixed solution to the BP pipe by 5 μ L/ holes.
4) add medicine, 2 μ L/ holes.No medicine hole is with 2 μ L kinase buffer polishings.Mixing.
5) prepare the working fluid of enzyme.
6) add enzyme, 3 μ L/ holes.No enzyme hole is with 3 μ L kinase buffer polishings.Mixing.
7) reaction solution is transferred in 384 orifice plates.
8) put 37 ℃ of incubation 30min.
9) working fluid of preparation Streptavidin-XL665 calculates consumption, by volume ratio Streptavidin-XL665: TK Antibody-Cryptate=1: 1 mixing.Incubation is got mixed solution by 10 μ L/ holes and is added in the reaction system after finishing, and mixing is with termination reaction.
10) room temperature is placed the 30min detection, excites in the single wavelength of ELIASA 314nm, measures 620nm and 665nm emission light, and test-results is seen table 1 and table 2.
Inhibiting rate (%)=[1-(experimental group
665nm/620nm-blank control group
665nm/620nm)/(control group
665nm/620nm-blank control group
665nm/620nm)] * 100%.The Bliss method is calculated test-compound IC
50Value.
3. result
The inhibiting rate (%) of table 1. couple EGFR (L858R/T790M) and VEGFR-2
The IC of table 2. couple EGFR (L858R/T790M) and VEGFR-2
50(nM)
Two, the anxious poison test of mouse in the body
Laboratory animal: Kunming mouse (male and female half and half)
Experimental technique:
1. test last late fasting 12 hours;
2. mouse random packet, male and female half and half are weighed in;
3. mouse is provided with 2-3 dose groups administration, and medicine is weighed, and adds tween-80 and grinds the 1%CMC-Na dissolved dilution;
4. every mouse 0.5mL oral administration (ig);
5. observe mouse administration afterreaction; Record toxicity symptom, time length and recovery situation; As death appears, then write down death time of animal and dead preceding symptom etc.;
6. dead mouse is dissected inspection, the record anatomical results;
7. observed weighing every day mouse body weight, record changes of weight situation continuously 7 days;
8. obtain medium lethal dose(LD&-{50}) (LD50) or maximum tolerated dose (MTD).
Claims (8)
1. general formula (I) quinazoline derivant or its pharmacy acceptable salt:
General formula (I)
Wherein:
R1 representes: hydrogen, methoxyl group;
R2 representes: hydrogen, methyl, ethyl;
N representes: 1, or 2, or 3, or 4.
2. compound according to claim 1 is characterized in that R1 is preferably from methoxyl group.
3. compound according to claim 1 is characterized in that R2 is preferably from hydrogen and methyl.
4. compound according to claim 1 is characterized in that n is preferably from 3.
5. pharmaceutically can connect according to the defined general formula of claim 1-4 (I) compound or its
The salt that receives, said compound or its pharmacy acceptable salt are selected from,
N-(4-bromo-2-fluorophenyl)-6-methoxyl group-7-(3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) propoxy-) quinazoline-4-amine
7-(3-(1,4-Diazesuberane-1-yl) propoxy-)-N-(4-bromo-2-fluorophenyl)-6-methoxyl group quinazoline-4-amine.
6. according to the described compound of claim 1-5, it is characterized in that its corresponding medicinal salt is: formula 1 compound H qX, X represents halogen, sulfate radical, nitrate radical, phosphate radical, organic acid, q are 1, or 2, or 3.
According to the described arbitrary compound of claim 1-6 as antitumor drug or as the purposes of the activeconstituents in the anti-tumor composition.
8. pharmaceutical composition contains the defined general formula of claim 1 (I) compound or its pharmacy acceptable salt and the appropriate carriers or the vehicle of pharmacy effective dose.
The described compound of claim 1-8 or its pharmacy acceptable salt, wherein, described compound or its pharmacy acceptable salt comprise various solid orally ingestibles, liquid oral medicine, injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010596305.5A CN102532107B (en) | 2010-12-20 | 2010-12-20 | 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010596305.5A CN102532107B (en) | 2010-12-20 | 2010-12-20 | 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102532107A true CN102532107A (en) | 2012-07-04 |
| CN102532107B CN102532107B (en) | 2014-03-12 |
Family
ID=46340280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010596305.5A Expired - Fee Related CN102532107B (en) | 2010-12-20 | 2010-12-20 | 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102532107B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016023330A1 (en) * | 2014-08-11 | 2016-02-18 | 石药集团中奇制药技术（石家庄）有限公司 | Quinazoline derivative |
| CN111909163A (en) * | 2020-04-21 | 2020-11-10 | 南开大学 | Quinolamine compound with IDO1 inhibition function and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995019774A1 (en) * | 1994-01-25 | 1995-07-27 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| CN1116286C (en) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4-anilinoquinazoline derivatives |
| WO2007068552A1 (en) * | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof |
-
2010
- 2010-12-20 CN CN201010596305.5A patent/CN102532107B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995019774A1 (en) * | 1994-01-25 | 1995-07-27 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| CN1116286C (en) * | 1996-03-05 | 2003-07-30 | 曾尼卡有限公司 | 4-anilinoquinazoline derivatives |
| WO2007068552A1 (en) * | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016023330A1 (en) * | 2014-08-11 | 2016-02-18 | 石药集团中奇制药技术（石家庄）有限公司 | Quinazoline derivative |
| CN106660970A (en) * | 2014-08-11 | 2017-05-10 | 石药集团中奇制药技术（石家庄）有限公司 | Quinazoline derivative |
| JP2017526668A (en) * | 2014-08-11 | 2017-09-14 | 石薬集団中奇制薬技術（石家庄）有限公司 | Quinazoline derivatives |
| US10421754B2 (en) | 2014-08-11 | 2019-09-24 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Quinazoline derivative |
| RU2704125C2 (en) * | 2014-08-11 | 2019-10-24 | СиЭсПиСи ЧЖУНЦИ ФАРМАСЬЮТИКАЛ ТЕКНОЛОДЖИ (ШИЦЗЯЧЖУАН) КО., ЛТД. | Quinazoline derivatives |
| CN106660970B (en) * | 2014-08-11 | 2020-07-10 | 石药集团中奇制药技术（石家庄）有限公司 | Quinazoline derivatives |
| US10774079B2 (en) | 2014-08-11 | 2020-09-15 | Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. | Quinazoline derivative |
| CN111909163A (en) * | 2020-04-21 | 2020-11-10 | 南开大学 | Quinolamine compound with IDO1 inhibition function and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102532107B (en) | 2014-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100658891B1 (en) | Quinazoline derivatives inhibiting the growth of cancer cell and preparation thereof | |
| CN102464658B (en) | Oxazolidinone derivative and preparation method and application thereof | |
| JP5268902B2 (en) | Salt of pyrrolopyrimidinone derivative and process for producing the same | |
| CN102295635B (en) | Antitumor medicament tetralin amide compounds and pharmaceutically acceptable salts thereof as well as preparation method and application of antitumor medicament tetralin amide compounds | |
| EP2985283B1 (en) | Anti-angiogenesis compound, intermediate and use thereof | |
| KR20080003599A (en) | Gentisate of pyrrolopyrimidinone derivative and process for preparing it | |
| EP0991627B1 (en) | Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same | |
| BRPI0609962B1 (en) | ORAL PHARMACEUTICAL COMPOSITION | |
| CN102485724B (en) | Substituted thiophene base pyrazolo-pyridines and medicinal use thereof | |
| CN101575333A (en) | Quinazoline derivatives and medical application thereof | |
| CN104250253B (en) | Substituted-tetrahydro naphthoyl aminated compounds and its pharmaceutically acceptable salt and preparation method and application | |
| CN113307791B (en) | Pyrimidylpiperazine urea TRPV1 antagonistic/MOR agonistic double-target compound and preparation method and application thereof | |
| CN102532107B (en) | 4-substituted aniline-7-substituted alcoxylhomopiperazine-quinazoline derivatives, and preparation method and application thereof | |
| KR20140036312A (en) | Novel compound having parp inhibitory activity | |
| CN102532103B (en) | Quinazolinyl aryl urea derivatives and preparation method and application thereof | |
| CN102268000A (en) | Novel spiroheterocyclic compound and application of same serving as therapeutic agent | |
| CN102101858B (en) | Preparation method of ramosetron derivatives and applications thereof | |
| CN107513040A (en) | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine | |
| WO2019001307A1 (en) | Amide compound, composition containing same, and use thereof | |
| CN101659659B (en) | Pyridine derivative and medical application thereof | |
| CN102060875B (en) | Quinazoline derivative, and preparation method and application thereof | |
| CN110204493A (en) | Tricyclic antidepressants XOR inhibitor and its preparation method and application | |
| CN102617465A (en) | Tacrine-caffeic acid hetero-blends, their preparation method and medicinal compositions | |
| CN103626722A (en) | Hypoglycemic compound of nitric oxide donor type, preparation method and purpose thereof | |
| CN108299397B (en) | A kind of active medicine and preparation method thereof for blood pressure lowering |
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 | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 300193 Anshan West Road, Nankai District, Nankai District, Tianjin Patentee after: Tianjin Institute of Pharmaceutical Research Co.,Ltd. Address before: 300193 Anshan West Road, Nankai District, Nankai District, Tianjin Patentee before: Tianjin Institute of Pharmaceutical Research |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20190220 Address after: 300301 No. 308 Huiren Road, Binhai Science Park, Tianjin Binhai High-tech Zone Patentee after: NEW DRUGS EVALUATE Co.,Ltd. TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH Address before: 300193 Anshan West Road, Nankai District, Nankai District, Tianjin Patentee before: Tianjin Institute of Pharmaceutical Research Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CP03 | Change of name, title or address |
Address after: 300301 No. 308, Huiren Road, Binhai Science Park, Binhai high tech Zone, Binhai New Area, Tianjin Patentee after: Tianjin Tiancheng new drug evaluation Co.,Ltd. Address before: 300301 No. 308 Huiren Road, Binhai Science Park, Tianjin Binhai High-tech Zone Patentee before: NEW DRUGS EVALUATE Co.,Ltd. TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH |
|
| CP03 | Change of name, title or address | ||
| 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 |