CN1473827A - 3-substituted quinolone derivatives and their application in medicine - Google Patents
3-substituted quinolone derivatives and their application in medicine Download PDFInfo
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- CN1473827A CN1473827A CNA031322964A CN03132296A CN1473827A CN 1473827 A CN1473827 A CN 1473827A CN A031322964 A CNA031322964 A CN A031322964A CN 03132296 A CN03132296 A CN 03132296A CN 1473827 A CN1473827 A CN 1473827A
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- Prior art keywords
- alkyl
- replacement
- amino
- aryl
- representative
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- -1 3-substituted quinolone Chemical class 0.000 title claims abstract description 62
- 239000003814 drug Substances 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000003118 aryl group Chemical group 0.000 claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 239000000460 chlorine Substances 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001924 cycloalkanes Chemical class 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 abstract description 7
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical group C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 abstract description 4
- 150000007660 quinolones Chemical class 0.000 abstract description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 143
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 122
- 238000005160 1H NMR spectroscopy Methods 0.000 description 71
- 238000004440 column chromatography Methods 0.000 description 71
- 239000007787 solid Substances 0.000 description 64
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical compound C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 44
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 37
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 31
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 29
- 239000002994 raw material Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 229910017604 nitric acid Inorganic materials 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 10
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 9
- NLAGKOJYUWGWKE-UHFFFAOYSA-N 3-(1,3-benzoxazol-2-yl)-7-chloro-1-ethyl-6-fluoroquinolin-4-one Chemical class O=C1C2=CC(F)=C(Cl)C=C2N(CC)C=C1C1=NC2=CC=CC=C2O1 NLAGKOJYUWGWKE-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000010813 municipal solid waste Substances 0.000 description 9
- CVYCDOBENDAYBG-UHFFFAOYSA-N CC(C1)NC(C)CN1C(C=C1N(C=C2)F)=CC=C1C2=O Chemical class CC(C1)NC(C)CN1C(C=C1N(C=C2)F)=CC=C1C2=O CVYCDOBENDAYBG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- DVUAWRQUZKVCJP-UHFFFAOYSA-N 3-(1,3-benzoxazol-2-yl)-1-ethyl-6-fluoro-7-piperazin-1-ylquinolin-4-one Chemical class C1=C2N(CC)C=C(C=3OC4=CC=CC=C4N=3)C(=O)C2=CC(F)=C1N1CCNCC1 DVUAWRQUZKVCJP-UHFFFAOYSA-N 0.000 description 6
- JGDRIEHYGTXDQK-UHFFFAOYSA-N 3-(1,3-benzoxazol-2-yl)-7-chloro-1-cyclopropyl-6-fluoroquinolin-4-one Chemical class C1=C(Cl)C(F)=CC(C(C(C=2OC3=CC=CC=C3N=2)=C2)=O)=C1N2C1CC1 JGDRIEHYGTXDQK-UHFFFAOYSA-N 0.000 description 6
- LHIBVOVQICTUCW-UHFFFAOYSA-N 3-(1,3-benzoxazol-2-yl)-7-chloro-6-fluoro-1H-quinolin-4-one Chemical class C1=CC=C2C(=C1)N=C(O2)C3=CNC4=CC(=C(C=C4C3=O)F)Cl LHIBVOVQICTUCW-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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
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- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 5
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- FCAZVIUTGBZFQK-UHFFFAOYSA-N 3-(1,3-benzoxazol-2-yl)-1-cyclopropyl-6-fluoro-7-piperazin-1-ylquinolin-4-one Chemical class C1CC1N2C=C(C(=O)C3=CC(=C(C=C32)N4CCNCC4)F)C5=NC6=CC=CC=C6O5 FCAZVIUTGBZFQK-UHFFFAOYSA-N 0.000 description 4
- SRURMEYSMWYDMY-UHFFFAOYSA-N 3-(1,3-benzoxazol-2-yl)-1-ethyl-7-(4-ethylpiperazin-1-yl)-6-fluoroquinolin-4-one Chemical class CCN1CCN(CC1)C2=C(C=C3C(=C2)N(C=C(C3=O)C4=NC5=CC=CC=C5O4)CC)F SRURMEYSMWYDMY-UHFFFAOYSA-N 0.000 description 4
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- AKCOBIDAJNERRN-UHFFFAOYSA-N 1-ethyl-2-methylpiperazine Chemical compound CCN1CCNCC1C AKCOBIDAJNERRN-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- VDKMFRGWRQALMU-UHFFFAOYSA-N 3-ethoxycarbonyl-4-oxo-1h-quinoline-6-carboxylic acid Chemical compound C1=CC(C(O)=O)=CC2=C(O)C(C(=O)OCC)=CN=C21 VDKMFRGWRQALMU-UHFFFAOYSA-N 0.000 description 1
- WNNSMMJBBOPPOT-UHFFFAOYSA-N 7-chloro-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound FC1=C(Cl)C=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 WNNSMMJBBOPPOT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- RIIWUGSYXOBDMC-UHFFFAOYSA-N benzene-1,2-diamine;hydron;dichloride Chemical compound Cl.Cl.NC1=CC=CC=C1N RIIWUGSYXOBDMC-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention discloses new quinolone derivatives with 3-position substituted by imidazol radical, benzoxazole and benzothiazole and possessing antitumor activity. The preparation process of the compounds is also disclosed.
Description
Technical field
The present invention relates to new 3-position substituted quinolone compounds, with and application in the medicine of preparation treatment tumour.
Background technology
The common pharmacologically active of carbostyril compound is antibiotic.According to another bibliographical information, benzoglyoxaline, benzoxazole and benzothiazole compound may have topoisomerase I and suppress active.The Russia scholar has reported the preparation of 3-(2-benzoglyoxaline)-1-methyl-4-quinolone, and as the synthetic corresponding five rings of raw material condensed compound, but report does not have anti-tumor activity [Ukr.Khim.Zh. (Russ.), 1986,52 (7): 742-6].
Summary of the invention
The technical problem to be solved in the present invention provides the compound that benzoglyoxaline, benzoxazole and benzothiazole that the new quinolone 3-position with anti-tumor activity was substituted or do not have replacement replace, and its application in the medicine of preparation treatment tumour is provided simultaneously.
The present invention is a starting raw material with the quinolone-3-formic acid of various replacements, with the o-amino thiophenol prepared in reaction of the Ortho-Aminophenol of the O-Phenylene Diamine of O-Phenylene Diamine, Ortho-Aminophenol, o-amino thiophenol, replacement, replacement or replacement the compounds that replaced by benzoglyoxaline, benzoxazole and benzothiazole of a series of new quinolone 3-positions, these compounds have the intensive anti-tumor activity.
The invention provides following technical scheme for solving the problems of the technologies described above:
Following general formula (I) compound
Wherein, R
1Represent alkyl H, replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement, aryl replacement or that do not have replacement;
R
3And R
5Identical or different, represent H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement, aryl replacement or that do not have replacement independently of one another;
R
6And R
7Identical or different, represent H, halogen, hydroxyl, alkyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, the aromatic heterocyclic that replaces or do not have replacement, nitro, amino independently of one another;
R
8Alkyl, nitro, amino, itrile group, hydroxyl, alkoxyl group, aralkoxy, the heterocycle alkoxyl group of representing H, halogen, alkyl, halogen to replace;
X represents O, S, NH;
Its formula of (I) does not comprise R
1=Me, R
3=H, R
5=H, R
6=H, R
7=H, R
8=H, the compound of X=NH.
In described general formula (I) compound: R
1, R
3, R
5, R
6, R
7Or R
8Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is a phenyl, or F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro or amino mono-substituted phenyl; R
1, R
3, R
5, R
6, R
7Or R
8The alkyl of representative or the alkyl in the aryl refer to have the alkyl of the straight or branched of 1-10 carbon atom or the cycloalkyl of 3-10 carbon atom; R
3, R
5, R
6, R
7Or R
8The alkoxyl group of representative or the alkyl in aralkoxy or the heterocycle alkoxyl group refer to have the alkyl of the straight or branched of 1-10 carbon atom;
R
1, R
3, R
5, R
6, R
7Or R
8Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one or more heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom; R
1, R
3, R
5Middle alkyl, the aryl of replacement, the heterocyclic radical of replacement or the aryl of replacement that replaces, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group or amido; R
6, R
7Aromatic heterocyclic replacement or that do not have replacement of representative is F, Cl, Br, I, C
1～10Alkyl, C
1～10Acyl group, C
1～10Alkoxyl group, C
1～10Alkylamino, nitro, the amino ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle that replace or that do not have replacement.
Described general formula (I) compound is characterized in that: R
1, R
3, R
5, R
6, R
7The aryl of representative is the phenyl ring base, perhaps is F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro, the amino phenyl that replaces; Aromatic heterocyclic is to contain 1～3 heteroatomic fragrant heterocyclic radical, perhaps is F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro, amino replace contain 1～3 heteroatomic aromaticity heterocyclic radical.
Described general formula (I) compound is characterized in that: amino is NH
2, R
9NH, R
10R
11N; R wherein
9, R
10Or R
11Be the described alkyl of claim 2, perhaps R
10R
11Connect into ring-type.
In described general formula (I) compound, it is characterized in that: R
1, R
3, R
5, R
6, R
7Or R
8Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is C
1～6Alkyl, C
1～6The phenyl that alkoxyl group replaces; R
1, R
3, R
5, R
6, R
7Or R
8The alkyl of representative or the alkyl in the aryl refer to have the alkyl of the straight or branched of 1-6 carbon atom or the cycloalkyl of 3-6 carbon atom; R
3, R
5, R
6, R
7Or R
8The alkoxyl group of representative or the alkyl in aralkoxy or the heterocycle alkoxyl group refer to have the alkyl of the straight or branched of 1-6 carbon atom; R
1, R
3, R
5, R
6, R
7Or R
8Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one, two or three heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom; R
6, R
7Aromatic heterocyclic replacement or that do not have replacement of representative is C
1～6Alkyl, C
1～6Acyl group, C
1～6Alkoxyl group, C
1～6Alkylamino, nitro, the amino ternary～hexa-member heterocycle that contains 1～3 nitrogen-atoms that replace or that do not have replacement.
Aforementioned formula (I) compound is characterized in that: wherein alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl; Wherein cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl; Wherein halogen is F, Cl, Br or I.
In described general formula (I) compound: wherein alkyl is the alkyl with straight or branched of 1-4 carbon atom; Cycloalkyl is the cycloalkyl with 3～6 carbon atoms; Heterocyclic radical is saturated heterocyclic or the aromatic heterocycle that contains 3～6 atoms; Halogen is F and Cl atom; R
6, R
7The ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle of the replacement of representative is not replacement and the mono-substituted five yuan～hexa-member heterocycle that contains 1～2 nitrogen-atoms.Its preferably compound be: R
1Expression H, C
1-C
4Side chain or the C that replaces of the alkyl of straight chain or cyclic alkane, halogen
1-C
4Branched-chain or straight-chain alkyl; R
8Expression H, halogen, C
1-C
4The alkyl of side chain or straight chain; Perhaps R
1With R
8Between warp-CH (CH
3) nCH
2O-is coupled to ring, and n is 1～3 in the formula; R
3Representative is replaced by halogen, nitro, amino or H respectively or simultaneously on 5 and/or 6 of aromatic ring; R
5And R
6Identical or different, H, amino or halogen are shown in representative independently of one another; R
7Expression H, halogen, hydroxyl, C
1-C
4Branched-chain or straight-chain alkyl, amino or C
1-C
4The amino that replaces of branched-chain or straight-chain alkyl, C
1-C
4Branched-chain or straight-chain alkyl replace or do not have a replacement contain five yuan of 1-2 nitrogen-atoms or hexa-member heterocycle, C
1-C
4Acyl substituted or do not have five yuan or the hexa-member heterocycle containing 1-2 nitrogen-atoms of replacement; X represents O, S, NH.
In described general formula (I) compound, even more ideal compound is: R
1Expression H, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, fluoro ethyl; R
8Expression H, Cl, F, methyl, second third, propyl group, sec.-propyl; Perhaps R
1With R
8Between warp-CH (CH
3) nCH
2O-is coupled to ring, and n is 1～2 in the formula; R
3Representative is replaced by chlorine, nitro, amino or H on 5 and/or 6 of aromatic rings at the same time or separately; R
5And R
6Identical or different, H, amino or fluorine are shown in representative independently of one another; R
7Represent H, Cl, hydroxyl, methyl, second third; propyl group, sec.-propyl, amino, dimethylamino; diethylamino, piperazinyl is gone up the piperazinyl that is replaced by methyl, ethyl or ethanoyl for 3,4 or 5, perhaps 3,5 piperazinyls that replaced by methyl, ethyl and/or ethanoyl.
Aforementioned any one application of compound in the medicine of preparation treatment tumour.
The preparation method of the carbostyril compound that the general formula that the present invention relates to (I) 3-position replaces can be represented by synthetic synoptic diagram:
A. get the quinolone-3-formic acid (A) of various replacements, with the O-Phenylene Diamine that replaces or do not have replacement, replace or do not have the adjacent ammonia of replacement
Base phenol or replacement or do not have the o-amino thiophenol (B) of replacement, condensation in polyphosphoric acid (being called for short PPA), condensation is anti-
Answering product is general formula (I) target compound.
B. (the column chromatography condition is: Haiyang Chemical Plant, Qingdao produces column chromatography silica gel, 100 orders through column chromatography with the condensation reaction products therefrom; Developping agent: add 1% triethylamine in the mixed solution of vinyl acetic monomer and methyl alcohol) purifying gets general formula (I) target compound.
Synthetic synoptic diagram
General formula (I)
In the above-mentioned synthetic synoptic diagram, R
1Expression H, alkyl, aryl, heterocyclic radical, aryl; And above-mentioned alkyl, aryl, heterocyclic radical, the aryl that has replaced.R
3Expression H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl, aryl, heterocyclic radical, aryl; And above-mentioned alkyl, aryl, heterocyclic radical, the aryl that has replaced.R
5Expression H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl, aryl, heterocyclic radical, aryl; And above-mentioned alkyl, aryl, heterocyclic radical, the aryl that has replaced.R
6Expression H, halogen, hydroxyl, alkyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, fragrant heterocycle, NO
2, amino, the ternary that contains 1-4 nitrogen-atoms----eight yuan of heterocycles of the ternary that contains 1 ~ 4 nitrogen-atoms----of eight yuan of heterocycles, replacement; R
7Expression H, halogen, hydroxyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, alkyl, aryl, fragrant heterocycle, NO
2, amino, the ternary that contains 1-4 nitrogen-atoms----eight yuan of heterocycles of the ternary that contains 1 ~ 4 nitrogen-atoms----of eight yuan of heterocycles, replacement; R
8The alkyl that expression H, halogen, alkyl, halogen replace, nitro, amino, itrile group, hydroxyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group; X represents O, S, NH.
Above-mentioned R
1, R
3, R
5, R
6, R
7Or R
8The alkyl of representative refers to have the alkyl of straight or branched of 1-10 carbon atom or the cycloalkyl of 3-10 carbon atom.Wherein alkyl can be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl.The alkyl that preferably has the straight or branched of 1-4 carbon atom.Wherein cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl.The cycloalkyl that preferably has 3-6 carbon atom.Above-mentioned R
1, R
3, R
5, R
6, R
7Or R
8The heterocyclic radical of representative refers to contain one or more heteroatomic saturated heterocyclic or aromatic heterocycle optional from oxygen, nitrogen, sulphur atom.The saturated heterocyclic or the aromatic heterocycle that preferably contain 3-6 atom.Above-mentioned R
1, R
3, R
5, R
6, R
7Or R
8The aryl of representative or the definition of alkyl in the aralkyl or alkyl are same as described above.Wherein said aryl can be benzene, also can be alkyl, the alkoxyl group of C1-10, nitro, the amino benzene that replaces of F, Cl, Br, I, C1-10.Above-mentioned R
1, R
3, R
5, R
6, R
7Or R
8The halogen of representative is F, Cl, Br or I.Preferred F and Cl atom.----eight yuan of heterocycles can be alkyl, the acyl group of C1-10, the alkoxyl group of C1-10, the alkylamino of C1 ~ 10, nitro, amino eight yuan of heterocycles of the ternary that contains 1-4 nitrogen-atoms----that replace of F, Cl, Br, I, C1-10 to the ternary that contains 1-4 nitrogen-atoms of the replacement of above-mentioned R6, R7 representative; Five yuan of----hexa-member heterocycles that do not replace and replace that preferably contain 1-2 nitrogen-atoms.Above-mentioned R
1, R
3, R
5Middle alkyl, aryl, heterocyclic radical, the aryl that replaces, its substituting group can be halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group and amido.Above-mentioned R
1, R
3, R
5, R
6, R
7The aryl of representative can be that phenyl ring can be alkyl, the alkoxyl group of C1-10, nitro, the amino benzene that replaces of F, Cl, Br, I, C1-10; The virtue heterocycle can be to contain the heteroatomic aromaticity heterocycle more than that contains that heteroatomic aromaticity heterocycle can replace for alkyl, the alkoxyl group of C1-10, nitro, the amino of F, Cl, Br, I, C1 ~ 10 more than.Above the amino of indication is NH
2, R
9NH, R
10R
11N.R wherein
9, R
10Or R
11Be alkyl referred to above, R
10R
11Can connect into ring-type.
Wherein, amino general formula (I) compound that replaces obtains corresponding nitro-compound reduction; And general formula (I) compound that hydroxyl replaces to be piperazinyl hydrolysis by corresponding replacement obtain.
At present, the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely.Experimental data shows: The compounds of this invention is that (A2780) and human liver cancer cell 7402 are that (Bel7402) has stronger cytotoxicity to human oral epidermoid carcinoma cell (KB), Proliferation of Human Ovarian Cell 2780.
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment
Agents useful for same is commercially available among the following embodiment.The quinolone of replacement involved in the present invention-3-formic acid market is on sale.The quinolone of the replacement that the present invention relates to-3-formic acid (A) and O-Phenylene Diamine, Ortho-Aminophenol or the o-amino thiophenol (B) that replace or do not have replacement, condensation reaction in polyphosphoric acid (being called for short PPA), also be conventional condensation reaction, referring to J Org Chem 1997,62:3552.
Embodiment 1
1-ethyl-3-(2-benzimidazolyl-)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (1)
Norfloxicin (Norxin) (3.19 grams, 0.1mol), mix porphyrize in O-Phenylene Diamine (the 1.08 gram 0.1mol) mortar, be added in the reaction flask, add 40 milliliters of polyphosphoric acid, decompression extracts that air produces to there being bubble in the reaction flask, feeds nitrogen, stirs slowly to be warming up to 140 ℃ and to be incubated reaction solution and to be homogeneous phase, be warmed up to 180 ℃ of reactions again after 4 hours, cool to about 100 ℃, reaction solution is stirred in the 250 gram trash ices of impouring down, leave standstill cooling, adjust pH is 9, suction filtration, dry crude product, the DMF recrystallization, be the developping agent column chromatography with methyl alcohol-triethylamine again, get off-white color crystallization 0.90 gram, mp 260-2 ℃, yield 23.4%.IR(cm
-1)：3923，2947，1630，1563，1542，1527，1492，1255，879；
1HNMR(δ，ppm，DMSO-d
6)：1.44(t，3H，-CH
3)，2.91(d，4H，-CH
2-*2)，3.17(d，4H，-CH
2-*2)，4.57(q，2H，-CH
2-)，7.13(m，3H，8-H?and?5’-Hand?6’-H)，7.61(m，2H，4’-H?and?7’-H)，7.95(d，1H，5-H)，9.17(s，1H，2-H)，12.69(s，1H，1’-H)；Formula：C
22H
22N
5OF?MW：391.44，Anal(C％，H％，N％，)Calc：67.50，5.66，17.89；Found：67.01，17.79，5.77；HRMS：M
+Meas?391.180167?Calcmass?391.180824?Error?0.657，MS(EI，m/s)：391(M
+)，349(base?peak)，306
Embodiment 2
1-ethyl-3-(2-benzimidazolyl-)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (2)
With the piperazine Flucloxacillin is raw material, and the preparation method uses the DMF recrystallization with embodiment 1.Column chromatography gets the off-white color solid, mp239-42 ℃ (decomposition), yield 26.4%.IR(cm-1)：3329，2925，1620，1550，1473，1284，789；1HNMR(δ，ppm，DMSO-d6)：1.44(t，3H，-CH
3)，2.25(s，3H，-CH
3)，2.50(m，4H，-CH
2-*2)，3.27(m，4H，-CH
2-*2)，4.56(q，2H，-CH
2-)，7.12(m，3H，8-H?and?5’-Hand?6’-H)，7.61(m，2H，4’-H?and?7’-H)，7.95(d，1H，5-H)，9.17(s，1H，1-H)，12.67(s，1H，1’-H)；Formula：C
23H
24N
5OF.2H
2O?MW：441.50，Anal(C％，H％，N％，)Calc：62.57，6.34，15.86?Found：62.02，6.13，16.26；HRMS：M
+Meas?405.197192?Calc?mass?405196474?Error-0.718，MS(EI，m/s)：(M
+)：405(base?peak)，306
Embodiment 3
(±) 6-(2-benzimidazolyl-)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen-7H-pyrido [1,2,3-de] [1,4] benzoxazine (3)
With the Ofloxacine USP 23 is raw material, and the preparation method uses the DMF recrystallization with embodiment 1.Column chromatography gets the off-white color solid, and mp230-2 ℃, yield 21.3%.
IR(cm-1)：3332，2930，1620，1575，1550，1473，1285，1259，789；1HNMR(δ，ppm，DMSO-d6)：1.48(d，3H，-CH
3)，2.32(s，3H，-CH
3)，2.51(s，4H，-CH
2-*2)，3.33(s，4H，-CH
2-*2)，4.39-4.59(m，2H，-CH
2-)，4.92(m，1H，-CH-)，7.14(m，2H，5’-Hand?6’-H)，7.60(d，3H，4’-H，7’-H?and8-H)，9.15(sH，5-H)，12.67(s，1H，1’-H)；Formula：C
24H
24N
5O
2F.1.5H
2O?MW：460.51，Anal(C％，H％，N％，)Calc：62.60?5.90，15.21?Found：62.94，5.46，15.00；HRMS：M+Meas433.191533?Calc?mass?433.191388?Error-0.145mu，MS(EI，m/s)：433(M+base?peak)。
Embodiment 4
(s)-and 6-(2-benzimidazolyl-)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (4)
With the Levofloxacin is raw material, and the preparation method uses the DMF recrystallization with embodiment 1.Column chromatography gets the off-white color solid, yield 24.3%, mp278 ℃.IR(cm-1)：3327，2931，1619，1576，1550，1473，1449，1285，1049，790；1HNMR(δ，ppm，DMSO-d6)：1.48(d，3H，-CH
3)，2.24(s，3H，-CH
3)，2.48(s，4H，-CH
2-*2)，3.28(s，4H，-CH
2-*2)，4.37-4.59(m，2H，-CH
2-)，4.92(m，1H，-CH-)，7.14(m，2H，5’-H?and?6’-H)，7.60(m，3H，4’-H，7’-H?and?8-H)，9.16(s，1H，5-H)，12.66(s，1H，1’-H)；Formula：C
24H
24N
5OF.1.5H
2O?MW：460.51，Anal(C％，H％，N％，)Calc：62.60?5.90，15.21?Found：62.70，5.80，15.71；MS(EI，m/s)：433(M+base?peak)。
Embodiment 5
1-(2-fluoro ethyl)-3-(2-benzimidazolyl-)-6,8-two fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (5)
With the fleroxacin is raw material, and the preparation method uses the DMF recrystallization with embodiment 1.Column chromatography gets yellow solid, mp255 ℃ of yield 15.4%.IR(cm-1)：3444，3066，1627，1476，1283，1028，789；1HNMR(δ，ppm，DMSO-d6)：2.26(s，3H，-CH
3)，2.48(s，4H，-CH
2-*2)，3.32(s，4H，-CH
2-*2)，4.86(d，2H，-CH
2-F)，4.99(d，2H，-CH
2-)，7.16(dd，2H，5’-H?and?6’-H)7.63(d，2H，4’-H，7’-H)，7.90(d，1H，5-H)，9.06(s，1H，2-H)，12.61(s，1H，1’-H)；Formula：C
23H
22N
5OF
3.H
2O?MW：459.44，Anal(C％，H％，N％，)Calc：60.13，5.27，15.24?Found：60.24，5.38，15.22；MS(EI，m/s)：441(M+base?peak)，324。
Embodiment 6
1-ethyl-3-(2-benzimidazolyl-)-6-fluoro-7-chloro-4 (1H)-quinolones (6)
With 1-ethyl-6-fluoro-7-chloro-1,2-dihydro-4-oxygen-quinoline-3-carboxylic acid is a raw material, and the preparation method uses recrystallizing methanol with embodiment 1.Column chromatography gets faint yellow solid, and mp285-9 ℃, yield 25.7%.IR(cm-1)：3411，3059，1637，1616，1493，1466，1263，745；1HNMR(δ，ppm，DMSO-d6)：1.42(t，3H，-CH
3)，4.60(q，2H，-CH
2-)，7.61(s，2H，5’-H?and?6’-H)，7.62(s，2H，4’-H?and?7’-H)，8.21(d，1H，5-H)，8.30(s，1H，8-H)，9.26(s，1H，2-H)，12.65(s，1H，1’-H)；Formula：C
18H
13N
3OClF.1.5H
2O?MW：368.81，Anal(C％，H％，N％，)Calc：58.62，4.37，11.39?Found：58.68，4.00，11.45；MS(EI，m/s)：341(M+)，313(base?peak)。
Embodiment 7
1-cyclopropyl-3-(2-benzimidazolyl-)-6-fluoro-7-chloro-4 (1H)-quinolones (7)
(2.81 grams, 0.01mol), (2.09 grams 0.01mol) and toluene (75ml), under the drying conditions, are heated to 75-80 ℃ to phosphorus pentachloride, till not having hydrogen chloride gas and emitting to add 1-cyclopropyl-6-fluoro-7-chloro-4-oxygen quinoline-3-carboxylic acid in the reaction flask.Cold slightly, reclaim toluene, residue is an acyl chlorides, it is dissolved in the anhydrous tetrahydro furan, and (1.08 grams are in tetrahydrofuran solution 0.01mol) slowly to drop to O-Phenylene Diamine under 5 ℃, drip triethylamine simultaneously and keep reaction mixture to be alkalescence, finish stirring at room 12 hours.Filter, washing, the tetrahydrofuran (THF) recrystallization gets the red solid amide intermediate.2.6g, yield 70%.
(2.6g, 0.007mol) and PPA (20ml), the N2 protection is down in 160 ℃ of reactions 3.5 hours for amide intermediate.Be cooled to 100 ℃ then, slowly impouring fills in the beaker of a large amount of trash ices, and vigorous stirring, separates out brown solid, filter, and washing, drying, column chromatography gets white solid 0.4g, and mp290-2 ℃, yield 15.7%.IR(cm-1)：3318，3248，1635，1614，1552，1476，1464，1317，1256，1037，748；1HNMR(δ，ppm，DMSO-d6)：1.23(m，2H，-CH
2-)，1.38(m，2H，-CH
2-)，3.83(m，1H，-CH-)，7.163(q，2H，5’-H?and?6’-H)，7.64(q，2H，4’-H?and?7’-H)，8.22(d，1H，5-H)，8.42(d，1H，8-H)，9.07(s，1H，2-H)，12.60(b，1H，1’-H)；Formula：C
19H
13N
3OFCl.1/2H
2O
MW：362.90，Anal(C％，H％，N％，)Calc：62.89，3.88，11.57?Found：63.34，3.91，11.52；MS(EI，m/s)：353(M+)，327(base?peak)。
Embodiment 8
1,4-dihydro-4-oxygen-6-(2-benzimidazolyl-)-3-quinoline carboxylic acid (8)
Para-amino benzoic acid 13.7 grams (0.1mol), ethoxymethylidene diethyl malonate 21.6 grams (0.1mol) are added in the reaction flask, stir and are warmed up to 120 ℃ of insulation reaction 1 hour, promptly get condensed products, add paraffin oil 150ml, be warmed up to 270 ℃, after half an hour, cooling is filtered, ethyl alcohol recrystallization gets, and 1,4-dihydro-4 oxo-3,6-quinoline dicarboxylic acid mono ethyl ester, the khaki color powder, 19.7 grams, yield 72.5%.
Last step reactor product (3.8 grams, 0.02mol) (2.16 grams 0.02mol) mix with O-Phenylene Diamine, behind the porphyrize, be added in the reaction flask in the mortar, add 50ml PPA again, charge into nitrogen, 170 ℃ were reacted 3 hours, cooling, in the impouring frozen water, suction filtration, drying, ethyl alcohol recrystallization, with the ethyl acetate is the moving phase column chromatography, gets off-white powder 0.6 gram.Mp273-4 ℃, yield 9.8%.IR(cm-1)：3410，3224，3059，2960，1697，1621，1589，1467，745；1HNMR(δ，ppm，DMSO-d6)：7.24(m，2H，5’-H?and?6’-H)，7.57(m，1H，7’-H)，7.69(m，1H，4’-H)，7.97(d，1H，5-H)，8.69(d，1H，6-H)，8.95(s，1H，8-H)，9.10(s，1H，2-H)，13.32(s，1H，1’-H)，15.35(s，1H，1-H)；
Formula：C
17H
11N
3O
3；MW：305.31，Anal(C％，H％，N％，)Calc：66.87，3.63，13.77；Found：66.78，3.60，13.82；MS(EI，m/s)：305(M+)，261(base?peak，M+-CO2)。
Embodiment 9
1-ethyl-3-(5-chloro-2-benzimidazolyl-)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (9)
(3.19 grams 0.01mol), mix porphyrize in 5-chlorine o-phenylendiamine dihydrochloride (the 2.14 gram 0.01mol) mortar to norfloxicin (Norxin), add 40 milliliters of polyphosphoric acid, decompression extracts the interior air of reaction flask and produces to there being bubble, feeds nitrogen, stir slowly and heat up, there are a large amount of HCl gases to produce, are incubated reaction solution in 140 ℃ and are homogeneous phase, be warmed up to 170 ℃ of reactions after 2 hours, cool to about 100 ℃, reaction solution is stirred in the 250 gram trash ices of impouring down, leave standstill cooling, adjust pH is 9, suction filtration, dry crude product, recrystallizing methanol is the developping agent column chromatography with methyl alcohol-triethylamine again, get yellow crystal 1.1 grams, mp 260-2 ℃, mp241-5 ℃, yield 25.8%.IR(cm-1)：3422，1629，1492，1255，791；1HNMR(δ，ppm，DMSO-d6)：1.44(t，3H，-CH
3)，2.92(d，4H，-CH
2-*2)，3.20(d，4H，-CH
2-*2)，4.57(q，2H，-CH
2-)，7.13(m，2H，8-H?and?7’-H)，7.56(d，1H，4’-H)，7.69(m，1H，6’-H)，7.94(d，1H，5-H)，9.14(s，1H，2-H)，12.84(b，1H，1’-H)；Formula：C
22H
21N
5OClF.2H
2O?MW：425.89，Anal(C％，H％，N％，)Calc：57.20，4.58，15.16?Found：56.87，5.27，15.57；HRMS：M+Meas?425.142062?Calc?mass?425.141853?Error-0.209；MS(EI，m/s)：425(M+)，383(base?peak)
Embodiment 10
1-ethyl-3-(5-chloro-2-benzimidazolyl-)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (10)
With the piperazine Flucloxacillin is raw material, and the preparation method uses recrystallizing methanol with embodiment 9.Column chromatography gets faint yellow solid, and mp:237-40 ℃, yield 35.6%.IR(cm-1)：3428，2936，1629，1492，1258，1140，791；1HNMR(δ，ppm，DMSO-d6)：1.44(t，3H，-CH
3)，2.27(s，3H，-CH
3)，2.52(s，2H，-CH
2-*2)，3.29(m，4H，-CH
2-*2)，4.57(q，2H，-CH
2-)，7.12(m，2H，8-H?and?7’-H)，7.56(s，1H，4’-H)，7.70(d，1H，6’-H)，7.96(d，1H，5-H)，9.15(s，1H，2-H)，12.82(d，1H，1’-H)
Formula：C
23H
23N
5OClF.1.5H
2O?MW：466.94，Anal(C％，H％，N％，)Calc：59.16，5.39，14.99Found：59.20，5.16，14.75；HRMS：M+Meas?439.157485?Calc?mass?439.157502?Error?0.007；MS(EI，m/s)：439(M+base?peak)，306。
Embodiment 11
(±) 6-(5-chloro-2-benzimidazolyl-)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (11)
With the Ofloxacine USP 23 is raw material, and the preparation method uses recrystallizing methanol with embodiment 9.Column chromatography gets yellow solid, and mp272-3 ℃, yield 32.9%.IR(cm-1)：3222，3088，1638，1612，1579，1480，1466，1311，1257，792；1HNMR(δ，ppm，DMSO-d6)：1.48(d，3H，-CH
3)，2.24(s，3H，-CH
3)，2.45(m，4H，-CH
2-*2)，3.26(m，4H，-CH
2-*2)，4.39-4.59(dd，2H，-CH
2-)，4.90(m，1H，-CH-)，7.18(m，1H，5-H)，7.54-7.71(m，3H，6’-H，4’-Hand，7’-H)，9.12(s，1H，2-H)，12.79(d，1H，1’-H，exchangedwith?D20)；
Formula：C
24H
23N
5O
2ClF.1.5H
2O?MW：494.92?Anal(C％，H％，N％，)Calc：58.19，5.25，14.14Found：57.94，5.55，14.24；HRMS：M+Meas?467.151736?Calc?mass?467.152416?Error0.68mu；MS(EI，m/s)：467(M+base?peak)。
Embodiment 12
1-(1-fluoro ethyl)-3-(5-chloro-2-benzimidazolyl-)-6,8-two fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (12)
With the fleroxacin is raw material, and the preparation method uses recrystallizing methanol with embodiment 9.Column chromatography gets the khaki color solid, and mp212-4 ℃, yield 34.8%.IR(cm-1)：3314，2933，1622，1551，1475，1448，1295，1006，789；1HNMR(δ，ppm，DMSO-d6)：2.24(s，3H，-CH
3)，2.50(s，4H，-CH
2-*2)，3.38(s，4H，-CH
2-*2)，4.85(d，2H，-CH
2-F)，4.98(d，2H，-CH
2-)，7.17(d，1H，7’-H)，7.59(d，1H，4’-H，)，7.67(m，1H，6’-H)，7.87(d，1H，5-H)，9.04(s，1H，2-H)，12.77(d，1H，1’-H)；Formula：C
23H
21N
5OClF
3.H
2O?MW：493.92，Anal(C％，H％，N％，)Calc：55.93，4.27，14.17??Found：55.99，4.90，14.41；MS(EI，m/s)：475(M+base?peak)。
Embodiment 13
1-ethyl-3-(5-chloro-2-benzimidazolyl-)-6-fluoro-7-chloro-4 (1H)-quinolones (13)
With the 1-ethyl--6-fluoro-7-chloro-1,2-dihydro-4-oxygen-quinoline-3-carboxylic acid be method for preparing raw material with embodiment 9, use recrystallizing methanol.Column chromatography gets the khaki color solid, and mp298-301 ℃, yield 35.7%.IR(cm-1)：3252，1614，1578，1493，1257，1033，922；
1HNMR(δ，ppm，DMSO-d6)：1.42(t，3H，-CH
3)，4.60(q，2H，-CH
2-)，7.16(m，1H，7’-H)，7.56(m，1H，4’-H)，7.67(m，1H，6’-H)，8.18(d，1H，5-H)，8.28(d，1H，8-H)，9.23(s，1H，2-H)，12.77(d，1H，1’-H)；Formula：C
18H
12N
3OC
12F.1/2H
2O?MW：385.24，Anal(C％，H％，N％，)Calc：56.12，3.40，10.90?Found：56.39，3.58，10.89；HRMS：M+Meas?375.034036?Calc?mass?375.034137Error?0.101mu；MS(EI，m/s)：375(M+base?peak)，347。
Embodiment 14
1-cyclopropyl-3-(5-chloro-2-benzimidazolyl-)-6-fluoro-7-chloro-4 (1H)-quinolones (14)
With 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxygen quinoline-3-carboxylic acid is a raw material, and the preparation method uses recrystallizing methanol with embodiment 9.Column chromatography gets white solid, and mp293-5 ℃, yield 33.5%.IR(cm-1)：3322，3088，1638，1612，1480，1466，1311，1257，792；1HNMR(δ，ppm，DMSO-d6)：1.23(m，2H，-CH
2-)，1.37(m，2H，-CH
2-)，3.82(m，1H，-CH-)，7.16(q，1H，7’-H)，7.63(m，2H，4’-H?and?6’-H)，8.15(d，1H，5-H)，8.36(d，1H，8-H)，9.00(s，1H，2-H)，12.70(b，1H，1’-H)。Formula：C
19H
12N
3OFC
12.1/2H
2O?MW：397.23；Anal(C％，H％，N％，)Calc：57.45，3.34，10.71?Found：57.51，3.47，10.95；HRMS：M+Meas?387.034149?Calc?mass?387.034137?Error-0.012mu；MS(EI，m/s)：387(M+base?peak)。
Embodiment 15
1-ethyl-3-(5-nitro-2-benzimidazolyl-)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (15)
1-ethyl-3-(2-benzimidazolyl-)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (2) (0.39 gram, 0.001mol) add among the vitriol oil 15ml, stir, drip concentrated nitric acid (0.1ml in 5 ℃, 0.0013mol), stirring at room 2 hours is in the reaction solution impouring frozen water, suction filtration, filter cake Na
2CO
3Adjust pH to 9, suction filtration, drying, the DMF recrystallization gets yellow solid 0.31 gram, and mp230-2 ℃, yield 68%.
IR(cm-1)：3249，2937，1629，1492，1310，1256，1139，1006，790；
1HNMR(δ，ppm，DMSO-d6)：1.45(t，3H，-CH
3)，3.06(s，3H，-CH
3)，2.58(s，4H，-CH
2-*2)，3.29(s，4H，-CH
2-*2)，4.59(q，2H，-CH
2-)，7.10(d，1H，6’-H)，7.8(dd，1H，7’-H)，7.93(m，1H，5-H)，8.05(m，1H，8-H)，8.78(d，1H，4’-H)，9.18(d，1H，2-H)，13.23(s，1H，1’-H)；Formula：C
23H
23N
6O
3F?MW450.47；HRMS：M+Meas?450.181602?Calc?mass?450.181551?Error?0.101mu；MS(EI，m/s)：450(M+base?peak)，405。
Embodiment 16
1-ethyl-3-(5-amino-2-benzimidazolyl-)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (16)
1-ethyl-3-(5-nitro-2-benzimidazolyl-)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (15) (0.45 gram, 0.001mol) be dissolved in the 1N hydrochloric acid (25ml), add palladium carbon, feed H2, reaction is to not inhaling till the hydrogen, filtering palladium carbon, adjust pH to 9, suction filtration, drying, get yellow-green colour solid 0.32 gram, mp:350 ℃ of yield 73.3%.
IR(cm-1)：3410，3334，1629，1495，1258，1139，790；
1HNMR(δ，ppm，DMSO-d6)：1.43(t，3H，-CH
3)，2.29(s，3H，-CH
3)，2.50(s，2H，-NH
2)，2.57(m，4H，-CH
2-*2)，3.28(m，4H，-CH
2-*2)，4.55(q，2H，-CH
2-)，6.50(s，1H，6’-H)6.77(s，1H，4’-H)，712(d，1H，7’-H)，7.26(d，1H，8-H)，7.94(d，1H?5-H)，9.05(s，1H，2-H)；Formula：C
23H
25N
6OFMW：420.49，HRMS：M+Meas?420.207218?Calc?mass?420.207372?Error?0.154；MS(EI，m/s)：420(M+base?peak)。
Embodiment 17
1-ethyl-3-(2-benzimidazolyl-)-6,8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (17)
With 1-ethyl-6,8-two fluoro-4-oxos-1,4-dihydro-7-(3-methyl isophthalic acid-piperazinyl)-3-quinoline carboxylic acid (lomefloxacin) (9g, 0.0212mol), O-Phenylene Diamine (2.3g, 0.0212mol) and PPA (90ml) add in the 250ml three-necked bottle, being warming up to 130--140 ℃ under the nitrogen protection is incubated reaction solution and is homogeneous phase, be warmed up to 180 ℃ of reactions again after 4 hours, be cooled to about 100 ℃, in the about 350 gram trash ices of reaction solution slow impouring under vigorous stirring, be neutralized to neutrality with sodium hydroxide, separate out a large amount of off-white color solids, suction filtration, drying, column chromatography, get off-white powder 1.2g, yield 13.4%, mp 272-5 ℃; IR (cm-1): 3313,3057,2980,2936,2736,1626,1574,1544,1527,1477,1385,1282,1250,1143,1051,924,790; HR-ESIMS (M+1): Found 424.1938 C23H24N5OF2 Requires 424.1943; 1HNMR (δ, ppm, DMSO-d6): 1.19 (d, 3H ,-CH
3), 1.46 (t, 3H ,-CH
3), 3.13 (m, 4H ,-CH
2-* 2), 3.39 (m, 3H ,-CH
2-, CH), 4.57 (q, 2H ,-CH
2-), 7.14 (m, 2H, 5 ', 6 '-H), 7.61 (m, 2H, 4 ', 7 '-H), 7.88 (d, 1H, 5-H), 9.08 (s, 1H, 2-H), 12.59 (br, NH).
Embodiment 18
1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (18)
Norfloxicin (Norxin) (3.19 grams, 0.1mol), Ortho-Aminophenol (1.08 grams, 0.1mol) mix porphyrize in the mortar, be added in the reaction flask, add polyphosphoric acid (40 milliliters), decompression extracts the interior air of reaction flask and produces to there being bubble, feed nitrogen, stir and slowly to be warming up to 140 ℃ and to be incubated reaction solution and to be homogeneous phase, be warmed up to 170 ℃ of reactions again after 4 hours, cool to about 120 ℃, reaction solution is stirred in the 250 gram trash ices of impouring down, leave standstill cooling, adjust pH is 9, suction filtration, dry crude product, the DMF recrystallization is the developping agent column chromatography with methyl alcohol-triethylamine (100: 1) again, gets off-white color crystallization 0.80 gram, mp285-90 ℃, yield 20.0%.IR(cm-1)：3413，2935，16281479，1453，1257，744；1HNMR(δ，ppm，DMSO-d6)：1.43(t，3H，-CH
3)，2.98(d，4H，-CH
2-*2)，3.25(d，4H，-CH
2-*2)，4.54(q，2H，-CH
2-)，7.13(d，1H，8-H)，7.38(m，2H，5’-H?and?6’-H)，7.72(m，2H，4’-H?and7’-H)，7.93(d，1H，5-H)，8.95(s，1H，2-H)；Formula：C
22H
21N
4O
2F?MW：392.44，HRMS：M+Meas392.165073?Calc?mass?392.164840?Error-0.233mu；MS(EI，m/s)：392(M+)，350(basepeak)
Embodiment 19
1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (19)
Its preparation method is with embodiment 18,1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-3-quinoline carboxylic acid (Pefloxacin) (0.0212mol), ortho-aminophenol (0.0212mol) and PPA (90ml), reaction back column chromatography gets the off-white color solid, mp263 ℃, yield 28.4%.IR(cm-1)：2930，1626，1487，1450，1376，1255，1145，1012，742；1HNMR(δ，ppm，DMSO-d6)：1.43(t，3H，-CH
3)，2.25(s，3H，-CH
3)，2.50(m，4H，-CH
2-*2)，3.27(m，4H，-CH
2-*2)，4.51(q，2H，-CH
2-)，7.10(d，1H，5-H)，7.37(m，2H，5’-Hand?6’-H)，7.72(m，2H，4’-H?and?7’-H)，7.87(d，1H，8-H)，8.94(s，1H，1-H)。Formula：C
23H
23N
4O
2F.1/2H
2O?MW：415.47，Anal(C％，H％，N％，)Calc：66.49，5.82，13.48Found：66.11，5.72，13.80；HRMS：M+Meas?406.181284?Calc?mass?406.180489?Error：-0.795mu；MS(EI，m/s)：406(M+base?peak)307，70。
Embodiment 20
(±) 6-(2-benzoxazolyl)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (20)
With the Ofloxacine USP 23 is raw material, and the preparation method uses the DMF recrystallization with embodiment 18.Column chromatography gets the off-white color solid, and mp284-7 ℃, yield 30.5%.IR (cm-1): 3458,2933,1630,1589,1476,1453,1298,1241,1093,787; 1HNMR (δ, ppm, DMSO-d6): 1.47 (d, 3H ,-CH
3), 2.25 (s, 3H ,-CH
3), 2.46 (s, 4H ,-CH
2-* 2), 3.17 (s, 4H ,-CH
2-* 2), 4.37-4.55 (dd, 2H ,-CH
2-), 4.82 (m, 1H ,-CH-), 7.38 (m, 2H, 5 '-H and 6 '-H), 7.50 (d, 1H, 5-H), 7.73 (m, 2H, 4 '-H, 7 '-H), 8.93 (s, 1H, 2-H);
Formula：C
24H
23N
4O
3F?MW：434.43，Anal(C％，H％，N％，)Calc：66.35?5.57?13.48?Found：65.63，4.91，12.82；HRMS：M+Meas?434.175014?Calc?mass?434.175403?Error?0.389；MS(EI，m/s)：434(M+，base?peak)。
Embodiment 21
1-cyclopropyl-3-(2-benzoxazolyl)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (21)
With the Ciprofloxacin is raw material, and the preparation method uses recrystallizing methanol with embodiment 18.Column chromatography gets yellow solid, and mp316-7 ℃, yield 33.6%.IR(cm-1)：3437，2934，1626，1553，1492，1478，1247，743
1HNMR(δ，ppm，DMSO-d6)：1.18(m，2H，-CH
2-)，1.31(m，2H，-CH
2-)，3.08(d，4H，-CH
2-*2)，3.32(m，4H，-CH
2-*2)，3.80(m，1H，-CH-)，7.37(m，2H，5’-H?and?6’-H)，7.50(d，1H，8-H)，7.73(m，2H，4’-H?and?7’-H)，7.86(m，1H，5-H)，8.71(s，1H，2-H)；
Formula：C
23H
21N
4O
2F?MW：404.45；HRMS：M+Meas?404.164916?Calc?mass?404.164840Error-0.076；MS(EI，m/s)：404(M+)，362(base?peak)，322。
Embodiment 22
1-ethyl-3-(2-benzoxazolyl)-6,8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (22)
With the lomefloxacin is raw material, and the preparation method is with embodiment 18.1-ethyl-6,8-two fluoro-4-oxos-1,4-dihydro-7-(3-methyl isophthalic acid-piperazinyl)-3-quinoline carboxylic acid (lomefloxacin) (0.0212mol), o-amino phenol (0.0212mol) and PPA (90ml), reaction back column chromatography gets brown solid, recrystallizing methanol.Column chromatography gets brown solid, and mp257 ℃, yield 32.0%.IR(cm-1)：3468，2929，1646，1623，1477，1238，1053，1014，833，788；1HNMR(δ，ppm，DMSO-d6)：0.99(d，3H，-CH
3)，1.44(t，3H，-CH
3)，2.79-2.94(m，4H，-CH
2-*2)，3.13(m，1H，-CH-)，3.30(m，2H，-CH
2-)，4.52(q，2H，-CH
2-)，7.38(q，2H，5’-H?and?6’-H)，7.74(m，2H，4’-H?and7’-H)，7.80(d，1H，5-H)，8.91(s，1H，2-H)；Formula：C
23H
22N
4O
2F
2?MW：424.45，Anal(C％，H％，N％，)Calc：65.08，5.22，13.20?Found：65.20，5.74，12.95；HRMS：M+Meas424.170881?Calc?mass?424.171065?Error?0.184mu；MS(EI，m/s)：424(M+)，368(base?peak)。
Embodiment 23
5-amino-1-cyclopropyl-3-(2-benzoxazolyl)-6,8-two fluoro-7-(3,5-dimethyl 1-piperazinyl)-4 (1H)-quinolones (23)
With the Sparfloxacin is raw material, and the preparation method uses the DMF recrystallization with embodiment 18.Column chromatography gets the khaki color solid, and mp225-7 ℃, yield 27.8%.
IR(cm-1)：3420，3305，29621648，1626，1577，1524，1453，1287，1242，1082，742；1HNMR(δ，ppm，DMSO-d6)：0.98(s，3H，-CH
3)，1.00(s，3H，-CH
3)，1.09(m，4H，-CH
2-*2)，2.73(m，2H，-CH
2-)，2.89(m，2H，-CH
2-)，3.22(m，2H，-CH-*2)，3.97(m，1H，-CH-)，7.36(m，4H，4’-H?and5’-H?and?6’-H?and?7’-H)，7.71(m，2H，-NH
2)，8.55(s，1H，2-H)；Formula：C
25H
25N
5O
2F
2?MW：465.51，HRMS：M+Meas?465.197691?Calc?mass?465.197612?Error-0.079；MS(EI，m/s)：465(M+)，395(base?peak)。
Embodiment 24
1-(2-fluoro ethyl)-3-(2-benzoxazolyl)-6,8-two fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (24)
With the fleroxacin is raw material, and the preparation method uses the DMF recrystallization with embodiment 18.Column chromatography gets faint yellow needle-like crystal, and mp260-2 ℃, yield 27.4%.IR(cm-1)：2789，1639，1623，1476，1448，1375，1239，1043，743；1HNMR(δ，ppm，DMSO-d6)：2.26(s，3H，-CH
3)，2.50(s，4H，-CH
2-*2)，3.32(s，4H，-CH
2-*2)，4.82(s，2H，-CH
2-)，4.95(d，2H，-CH
2-F)，7.40(m，2H，5’-H?and?6’-H)，7.75(m，2H，4’-H，7’-H)，7.83(d，1H，5-H)，8.86(s，1H，2-H)；Formula：C
23H
21N
4O
2F
3?MW：442.45，Anal(C％，H％，N％，)Calc：62.44，4.78，12.66?Found：62.30，4.95，12.40；MS(EI，m/s)：442(M+base?peak)，71。
Embodiment 25
1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-chloro-4 (1H)-quinolones (25)
1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-chloro-3-quinoline carboxylic acid (0.0212mol), ortho-aminophenol (0.0212mol) and PPA (90ml), the preparation method uses the DMF recrystallization with embodiment 18.Column chromatography gets white solid, and mp292-5 ℃, yield 31.6%.IR(cm-1)：1651，1612，1487，1262，1018，749；1HNMR(δ，ppm，DMSO-d6)：1.41(t，3H，-CH
3)，4.54(q，2H，-CH
2-)，7.38(m，2H，5’-H?and6’-H)，7.73(m，2H，4’-H?and?7’-H)，8.13(d，1H，5-H)，8.27(d，1H，8-H)，9.05(s，1H，2-H)；Formula：C
18H
12N
2O
2ClF?MW：342.75，Anal(C％，H％，N％，)Calc：63.08，3.53，8.17?Found：63.27，3.61，8.06；HRMS：M+Meas?342.057420?Calc?mass?342.057124?Error-0.296；MS(EI，m/s)：342(M+base?peak)，314。
Embodiment 26
3-(2-benzoxazolyl)-6-fluoro-7-chloro-4 (1H)-quinolones (26)
With 6-fluoro-7-chloro-1,2-dihydro-4-oxygen-quinoline-3-carboxylic acid is a raw material, and the preparation method uses the DMF recrystallization with embodiment 18.Column chromatography gets white solid, and mp330 ℃, yield 26.9%.IR(cm-1)：3434，3066，1624，1586，1472，1382，1160，741；1HNMR(δ，ppm，DMSO-d6)：7.26(m，2H，5’-H?and?6’-H)，7.65(m，2H，4’-H?and?7’-H)，7.72(d，1H，8-H)，7.97(d，1H，5-H)，8.91(s，1H，2-H)；
Formula：C
16H
8N
2O
2ClF.1/2H
2O?MW：323.71，Anal(C％，H％，N％，)Calc：59.36，2.72，8.41Found：58.72，2.46，8.70；HRMS：M+Meas?314.025795?Calc?mass：314.025826?Error0.031；MS(EI，m/s)：314(M
+base?peak)。
Embodiment 27
1-cyclopropyl-3-(2-benzoxazolyl)-6-fluoro-7-chloro-4 (1H)-quinolones (27)
With 1-cyclopropyl-6-fluoro-7-chloro-1,2-dihydro-4-oxygen-quinoline-3-carboxylic acid is a raw material, and the preparation method uses the DMF recrystallization with embodiment 18.Column chromatography gets white solid, and mp200-4 ℃, yield 21.8%.IR(cm
-1)：3436，1649，1617，1600，1458，1474，1263，771；
1HNMR(δ，ppm，DMSO-d
6)：1.22(m，2H，-CH
2-)，1.31(m，2H，-CH
2-)，3.77(m，1H，-CH-)，7.38(q，2H，5’-H?and?6’-H)，7.75(q，2H，4’-Hand?7’-H)，8.13(d，1H，8-H)，8.37(d，1H，5-H)，9.79(s，1H，2-H)；Formula：C
19H
12N
2O
2F?MW：354.76，Anal(C％，H％，N％，)Calc：64.32，3.41，7.90?Found：63.94，3.45，7.83；HRMS：M
+Meas354.056947?Calc?mass?354.057124?Error?0.177；MS(EI，m/s)：354(M
+base?peak)，354(M
+)。
Embodiment 28
(s)-and 6-(2-benzoxazolyl)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (28)
(s)-(-)-9-fluoro-2; 3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1; 2; 3-de] [1; 4] benzoxazine-6-carboxylic acid (levofloxacin) (1g; 2.7mmol), o-aminophenol (0.3g, 2.7mmol) and PPA (10ml) add in the 100ml three-necked bottle; being warming up to 130--140 ℃ under the nitrogen protection is incubated reaction solution and is homogeneous phase; be warmed up to 190 ℃ of reactions again after 4 hours, be cooled to about 100 ℃, in the about 350 gram trash ices of reaction solution slow impouring under vigorous stirring; be neutralized to pH6-7 with sodium hydroxide; separate out a large amount of class yellow solids, suction filtration, drying; column chromatography; get yellow powder 0.32g, yield 26.8%, mp254-8 ℃.IR(cm
-1)：3091，3005，2933，2842，2791，2746，2685，1631，1590，1555，1540，1476，1454，1391，1349，1299，1241，1152，1086，1050，985，914，787，748；HR-ESIMS(M+1)：Found?435.1868?C
24H
24FN
4O
3?Requires?435.1827；
1HNMR(δ，ppm，DMSO-d6)：46(d，3H，CH
3)，2.29(s，3H，NCH
3)，2.51(m，4H，CH
2*2)，3.51(m，4H，CH
2*2)，4.39(d，1H，NCH)，4.56(d，1H，OCH)，4.82(m，1H，OCH)，7.38(m，2H，5’，6’-H)，7.49(d，1H，5-H)，7.71(m，2H，4’，7’-H)，8.92(s，1H，2-H)；
Embodiment 29
1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-(4-ethyl-1-piperazinyl)-4 (1H)-quinolones (29)
With 1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolone (18) (0.54g, 1.37mmol) be suspended among the DMSO (8ml), add salt of wormwood (1.1g) then, after being heated to 60 ℃, slowly drip EtI (0.12ml, 1.47mmol), be incubated 1.5 hours, react completely.Concentrate, add suitable quantity of water, filter, drying, column chromatography gets the 0.15g light yellow product, yield 25.9%.mp206-9℃。IR(cm
-1)：3050，2968，2933，2809，1628，1550，1491，1453，1381，1356，1251，1152，1127，1022，836，788，745；HR-ESIMS(M+1)：Found421.2015?C
24H
26N
4O
2F?Requires?421.2034；
1HNMR(δ，ppm，DMSO-d6)：1.03(t，3H，CH
3)，1.42(t，3H，CH
3)，2.42(q，2H，CH
2)，2.57(m，4H，CH
2*2)，3.62(m，4H，CH
2*2)，4.47(q，2H，CH
2)，7.07(d，1H，7′-H)，7.36(m，2H，5′、6′-H)，7.71(t，2H，8、4′-H)，7.87(d，1H，5-H)，8.89(s，1H，2-H).
Embodiment 30
1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (30)
Norfloxicin (Norxin) (3.19 grams, 0.1mol) be added in the reaction flask, (1.08 gram 0.1mol) is wetting with o-amino thiophenol, adds 40 milliliters of polyphosphoric acid, and decompression extracts the interior air of reaction flask and produces to there being bubble, feed nitrogen, stir and slowly to be warming up to 140 ℃ and to be incubated reaction solution and to be homogeneous phase, be warmed up to 170 ℃ of reactions again after 2 hours, cool to about 120 ℃, reaction solution is stirred in the 250 gram trash ices of impouring down, leave standstill cooling, adjust pH is 9, suction filtration, dry crude product, the DMF recrystallization is the developping agent column chromatography with methyl alcohol-triethylamine again, gets yellow crystal 0.90 gram, mp290-5 ℃, yield 22.0%.IR(cm
-1)：3429，2938，1615，1493，1254，1010，759；
1HNMR(δ，ppm，DMSO-d
6)：1.46(t，3H，-CH
3)，3.08(d，4H，-CH
2-*2)，3.35(d，4H，-CH
2-*2)，4.62(m，2H，-CH
2-)，7.15(d，1H，8-H)，7.38(t，1H，5’-H)，7.49(t，1H，6’-H)，7.95(m，2H，5-Hand?7’-H)，8.09(d，1H，4’-H)，9.23(s，1H，2-H)；Formula：C
22H
21N
4OSF?MW：408.44；HRMS：M
+Meas?408.141773?Calc?mass?408.141999?Error?0.226；MS(EI，m/s)：408(M
+)，366(basepeak)。
Embodiment 31
1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolone (31) 1-ethyl-6-fluoro-4-oxos-1,4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-3-quinoline carboxylic acid (Pefloxacin) (0.0212mol), o-amino thiophenol (0.0212mol) and PPA (90ml), the preparation method uses recrystallizing methanol with embodiment 30.Column chromatography gets yellow solid, and mp260-5 ℃, yield 25.7%.IR(cm
-1)：3417，2931，1617，1570，1497，1452，1259，1009，758。
1H?NMR(δ，ppm，DMSO-d
6)：1.47(t，3H，-CH
3)，2.28(s，3H，-CH
3)，2.54(s，4H，-CH
2-*2)，3.33(m，4H，-CH
2-*2)，4.61(q，2H，-CH
2-)，7.16(d，1H，8-H)，7.37(t，1H，5’-H)，7.50(t，1H，6’-H)，7.92-7.97(m，2H，5-H?and?7’-H)，8.10(d，1H，4’-H)，9.24(s，1H，1-H)；Formula：C
23H
23N
4OSF.1/2H
2O?MW：431.47，Anal(C％，H％，N％，)Calc：64.03，5.61，12.98?Found：63.63，13.25，5.43；HRMS：M
+Meas?422.157394?Calc?mass422.157648?Error?0.254；MS(EI，m/s)：422(M
+base?peak)，323。
Embodiment 32
(±) 6-(2-[4-morpholinodithio base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (32)
(±)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (Ofloxacine USP 23) (0.0212mol), o-amino thiophenol (0.0212mol) and PPA (90ml), the preparation method uses recrystallizing methanol with embodiment 30.Column chromatography gets orange/yellow solid, and mp239-42 ℃, yield 25.4%.IR(cm
-1)：3495，2932，1611，1544，1473，1296，1233，1046，757；
1HNMR(δ，ppm，DMSO-d
6)：1.49(d，3H，-CH
3)，2.25(s，3H，-CH
3)，2.50(m，4H，-CH
2-*2)，3.29(s，4H，-CH
2-*2)，4.35-4.62(dd，2H，-CH
2-)，4.98(m，1H，-CH-)，7.38(t，1H，5’-H)，7.50(t，1H，6’-H)，7.59(d，1H，5-H)，7.96(d，1H，7’-H)，8.11(d，1H，4’-H)，9.23(s，1H，2-H)；Formula：C
24H
23N
4O
2SF.H
2O?MW：468.45，Anal(C％，H％，N％，)Calc：61.53，5.37，11.96?Found：61.22，5.04，11.85；HRMS：M
+Meas?450.152205?Calc?mass?450.152562?Error?0.357；MS(EI，m/s)：450(M
+base?peak)。
Embodiment 33
1-cyclopropyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (33) are raw material with the Ciprofloxacin, and the preparation method uses recrystallizing methanol with embodiment 30.Column chromatography gets the glassy yellow solid, and mp302-3 ℃, yield 33.2%.IR(cm
-1)：3422，2944，1629，1492，1255，1146，791；
1HNMR(δ，ppm，DMSO-d
6)：1.22(m，2H，-CH
2-)，1.35(m，2H，-CH
2-)，2.92(m，4H，-CH
2-*2)，3.20(m，4H，-CH
2-*2)，3.80(m，1H，-CH-)，7.37(m，1H，5’-H)，7.50(m，2H，8-H?and?6’-H)，7.88(d，1H，5-H)，7.97(d，1H?7’-H)，8.09(d，1H，4’-H)，9.04(s，1H，2-H)；Formula：C
23H
21N
4OSF.H
2O?MW：438.47，Anal(C％，H％，N％，)Calc：63.00，5.29，12.79?Found：63.70，5.10，13.14；HRMS：M
+Meas?420.142591?Calc?mass?420.141999?Error-0.592；MS(EI，m/s)：420(M
+)，378(basepeak)。
Embodiment 34
1-ethyl-3-(2-[4-morpholinodithio base)-6,8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinoline promise (34) 1-ethyls-6,8-two fluoro-4-oxos-1,4-dihydro-7-(3-methyl isophthalic acid-piperazinyl)-3-quinoline carboxylic acid (lomefloxacin) (0.0212mol), o-amino thiophenol (0.0212mol) and PPA (90ml), the preparation method uses recrystallizing methanol with embodiment 30.Column chromatography gets the deep yellow solid, and mp223-9 ℃, yield 35.2%.IR(cm
-1)：3428，2956，1611，1491，1323，1054，755；
1H?NMR(δ，ppm，DMSO-d
6)：0.99(d，3H，-CH
3)，1.44(t，3H，-CH
3)，2.80-2.91(m，4H，-CH
2-*2)，3.24-3.33(m，3H，-CH-and-CH
2-)，4.59(q，2H，-CH
2-)，7.39(t，1H，5’-H)，7.50(t，1H，6’-H)，7.83(d，1H，5-H)，7.90(d，1H，7’-H)，8.11(d，1H，4’-H)，9.16(s，1H，2-H)；Formula：C
23H
22N
4OSF
2.H
2O?MW：458.54，Anal(C％，H％，N％，)Calc：60.24，4.83，15.27?Found：60.30，5.06，11.84；HRMS：M
+Meas440.148452?Calc?mass?440.148223?Error-0.229mu；MS(EI，m/s)：440(M
+)，384(base?peak)。
Embodiment 35
1-cyclopropyl-3-(2-[4-morpholinodithio base)-5-amino-6,8-two fluoro-7-(3,5-dimethyl 1-piperazinyl)-4 (1H)-quinolones (35)
With the Sparfloxacin is raw material, and the preparation method uses recrystallizing methanol with embodiment 30.Column chromatography gets the yellow-green colour solid, mp207 ℃ (decomposition), yield 27.6%.
IR(cm
-1)：3467，3401，2958，1629，1570，1485，1453，1294，1081，1054，761；
1HNMR(δ，ppm，DMSO-D
6)：0.98(s，3H，-CH
3)，1.00(s，3H，-CH
3)，1.14(m，4H，-CH
2-*2)，2.73(m，2H，-CH
2-)，2.89(m，2H，-CH
2-)，3.22(m，2H，-CH-*2)，4.01(m，1H，-CH-)，7.33(m，2H，5’-H?and6’-H)，7.51(m，2H，4’-H?and7’-H)，7.95-8.08(dd，2H，-NH
2)8.92(s，1H，2-H)；Formula：C
25H
25N
5OSF
2?MW：481.58；HRMS：M
+Meas?481.174771?Calc?mass?481.176599?Error?0.183；MS(EI，m/s)：481(M
+)，411(base?peak)。
Embodiment 36
1-(1-fluoro-ethyl)-3-(2-[4-morpholinodithio base)-6,8-two fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (36) are raw material with the fleroxacin, the preparation method uses recrystallizing methanol with embodiment 30.Column chromatography gets yellow solid, and mp243-6 ℃, yield 30.8%.IR(cm
-1)：3428，2932，1614，1475，1374，1041，758；
1HNMR(δ，ppm，DMSO-d
6)：2.25(s，3H，-CH
3)，2.50(s，4H，-CH
2-*2)，3.33(s，4H，-CH
2-*2)，4.89(d，2H，-CH
2-F)，5.01(s，2H，-CH
2-)，7.40(t，1H，5’-H)，7.54(t，1H，6’-H)，7.90(d，1H，5-H)，7.94(d，1H，7’-H)，8.12(d，1H，4’-H)，9.14(s，1H，2-H)；Formula：C
23H
21N
4OSF
3.1/2H
2O?MW：467.53，Anal(C％，H％，N％，)Calc：59.09，4.74，11.98Found：58.63，4.84.11.50；MS(EI，m/s)：458(M
+base?peak)，341，71。
Embodiment 37
1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-chloro-4 (1H)-quinolones (37) are with the 1-ethyl--6-fluoro-7-chloro-1, and 2-dihydro-4-oxygen-quinoline-3-carboxylic acid is a raw material, the preparation method uses recrystallizing methanol with embodiment 30.Column chromatography gets yellow solid, and mp311-3 ℃, yield 30.2%.IR(cm
-1)：3500，2979，1628，1609，1497，1262，990，769；
1HNMR(δ，ppm，DMSO-d
6)：1.45(t，3H，-CH
3)，4.65(q，2H，-CH
2-)，7.40(t，1H，5’-H)，7.52(t，1H，6’-H)，7.98(d，1H，7’-H)，8.13(d，1H，4’-H)，8.23(d，1H，5-H)，8.34(d，1H，8-H)，9.35(s，1H，2-H)；Formula：C
18H
12N
2OSClF?MW：358.82，Anal(C％，H％，N％，)Calc：60.25，3.37，7.81?Found：60.77，3.40，7.82；HRMS：M
+Meas?358.033507?Calc?mass358.034283??Error?0.776MS(EI，m/s)：358(M
+)，330(base?peak)。
Embodiment 38
1-cyclopropyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-chloro-4 (1H)-quinolones (38) are with the 1-cyclopropyl--6-fluoro-7-chloro-1,2-dihydro-4-oxygen-quinoline-3-carboxylic acid be method for preparing raw material with embodiment 30, use recrystallizing methanol.Column chromatography gets yellow needle-like crystal, and mp328-31 ℃, yield 33.7%.IR(cm
-1)：3082，1610，1577，1492，1470，1458，1258，991，769；
1HNMR(δ，ppm，DMSO-d
6)：1.25(m，2H，-CH
2-)，1.39(m，2H，-CH
2-)，3.85(m，1H，-CH-)，7.40(t，1H，5’-H)，7.51(t，1H，6’-H)，8.02(d，1H，7’-H)，8.12(d，1H，4’-H)，8.18(d，1H，5-H)，8.43(d，1H，8-H)，9.14(s，1H，2-H)。Formula：C
19H
12N
2O
2F?MW：370.83，Anal(C％，H％，N％，)Calc：61.54，3.23，7.55?Found：61.54，3.24，7.75；HRMS：M
+Meas?370.034367?Calc?mass?370.034283?Error-0.084；MS(EI，m/s)：370(M
+)，369(M
+base?peak)。
Embodiment 39
(s)-and 6-(2-[4-morpholinodithio base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (39)
(s)-(-)-9-fluoro-2; 3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1; 2; 3-de] [1; 4] benzoxazine-6-carboxylic acid (levofloxacin) (8g; 0.0231mol), o-amino thiophenol (2.9g, 0.0231mol) and PPA (90ml) add in the 250ml three-necked bottle; being warming up to 130--140 ℃ under the nitrogen protection is incubated reactant and is homogeneous phase; be warmed up to 192 ℃ of reactions again after 4 hours, be cooled to about 100 ℃, in the about 350 gram trash ices of reaction solution slow impouring under vigorous stirring; be neutralized to pH5-6 with sodium hydroxide; separate out a large amount of class yellow solids, suction filtration, drying; column chromatography; get yellow powder 5.3g, yield 50.9%, mp259-62 ℃.Ultimate analysis: Found C 64.12% H 5.21% N 11.93%requires C 64.03% H 5.14%N 12.35%; IR (cm
-1): 3010,2976,2924,2797,1611,1585,1547,1479,1468,1452,1296,1236,1133,1046,1011,786,760; HR-ESIMS (M+1): Found 451.1580C
24H
24N
4O
2FS Requires 451.1599;
1HNMR (δ, ppm, DMSO-d6): 1.49 (d, 1H, CH
3), 2.25 (s, 3H, CH
3), 2.46 (m, 4H, CH
2* 2), 3.28 (m, 4H, CH
2* 2), 4.40 (m, 1H, NCH), 4.60 (m, 1H, OCH), 4.97 (m, 1H, OCH), 7.38 (m, 1H, 6 '-H), 7.50 (m, 1H, 5 '-H), 7.58 (d, 1H, 7 '-H), 7.95 (d, 1H, 4 '-H), 8.10 (d, 1H, 5-H), 9.22 (s, 1H, 2-H).
Embodiment 40
1-cyclopropyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(4-ethyl-1-piperazinyl)-4 (1H)-quinolones (40)
1-cyclopropyl-6-fluoro-4-oxo-1, (5g, 0.0139mol), (1.74g, 0.0139mol) and PPA (55ml), other operate with embodiment 30 o-amino thiophenol 4-dihydro-7-(4-ethyl-1-piperazinyl)-3-quinoline carboxylic acid (anthracene Flucloxacillin).Column chromatography gets the 0.65g faint yellow solid, yield 10%, mp256 ℃ (dec.).IR(cm
-1)：3100，2974，2945，2814，1613，1568，1494，1453，1255，1198，1127，1018，787，762，727；HR-ESIMS(M+1)：Found449.1782?C
25H
26N
4OFS?Requires?449.1806；
1HNMR(δ，ppm，DMSO-d6)：1.06(t，3H，CH
3)，1.23(m，2H，CH
2)，1.37(m，2H，CH
3)，2.41(q，2H，CH
2)，2.57(m，4H，CH
2*2)，3.19(m，1H，CH)，3.29(m，4H，CH
2*2)，7.09(d，1H，7′-H)，7.38(m，1H，6′-H)，7.51(m，2H，5′、8-H)，??7.95(d，1H，5-H)，8.10(d，1H，4′-H)，9.06(s，1H，2-H).
Embodiment 41
1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(4-ethyl-1-piperazinyl)-4 (1H)-quinolones (41)
(0.25g, 0.613mmol), other operate with embodiment 29 raw material 1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones.Column chromatography gets light yellow product 0.08g, yield 29.9%, mp210-3 ℃.IR(cm-1)：3059，2973，2936，2817，2764，1617，1570，1496，1473，1452，1254，1196，1125，1011，946，761，728；HR-ESIMS(M+1)：Found?437.1803?C
24H
26N
4OFS?Requires?437.1806；
1HNMR(δ，ppm，DMSO-d6)：1.05(t，3H，CH
3)，1.47(t，3H，CH
3)，2.41(q，2H，CH
2)，2.57(m，4H，CH
2*2)，3.34(m，4H，CH
2*2)，4.62(q，2H，CH
2)，7.14(d，1H，7′-H)，7.37(m，1H，6′-H)，7.50(m，1H，5′-H)，7.93(d，1H，4′-H)，7.97(s，1H，8-H)，8.10(d，1H，5-H)，9.25(s，1H，2-H).
Embodiment 42
1-ethyl-3-(2-[4-morpholinodithio base)-6,8-two fluoro-7-(4-ethyl-3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (42)
1-ethyl-3-(2-[4-morpholinodithio base)-6, (0.3g, 0.68mmol), other operate with embodiment 29 8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (34).Column chromatography gets light yellow product 0.06g, yield 14.1%, mp172-6 ℃.Ultimate analysis: Found C 64.35% H 5.84% N 12.37% requires C 64.10% H 5.62% N 12.08%; IR (cm-1): 3058,2967,2932,2875,2819,1613,1585,1541,1492,1474,1453,1380,1325,1241,1088,1054,1011,930,786,757,727; HR-ESIMS (M+1): Found 469.1843 C25H27N4OF2SRequires 469.1868; 1HNMR (δ, ppm, DMSO-d6): 0.98 (s, 3H, CH
3), 1.03 (t, 3H, CH
3), 1.48 (t, 3H, CH
3), 2.41 (m, 2H, CH
2), 2.50 (q, 2H, CH
2(CH
3)), 2.51 (m, 2H, CH
2), 2.83 (m, 2H, CH
2), 2.99 (m, 1H, CH), 4.61 (q, 2H, CH
2), 7.40 (m, 1H, 6 '-H), 7.49 (m, 1H, 5 '-H), 7.87 (d, 1H, 7 '-H), 7.96 (d, 1H, 4 '-H), 8.11 (d, 5-H), 9.17 (s, 1H, 2-H).
Embodiment 43
(S)-6-[2-(6-chloro-benzimidazolyl-)]-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (43)
The preparation method is with embodiment 17.(s)-(-)-and 9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (levofloxacin) (6g, 0.017mol), 4-chloro-1,2-phenylenediamine (2.46g, 0.017mol) and PPA (70ml) temperature of reaction be 188 ℃, column chromatography, tawny solid 1.3g, yield 16%, mp232-6 ℃ (dec.).IR(cm
-1)：3423，3100，2987，2858，1623，1567，1553，1476，1396，1300，1090，1055，982，920，787，501；HR-ESIMS(M+1)：Found?468.1580?C
24H
24N
5O
2FCl?Requires468.1597；
1HNMR(δ，ppm，DMSO-d6)：1.23(d，3H，CH
3)，2.40(s，3H，CH
3)，2.68(m，4H，CH
2*2)，3.35(m，4H，CH
2*2)，4.39(d，1H，NCH)，4.58(d，1H，OCH)，4.94(m，1H，OCH)，7.17(dd，1H，5′-H)，7.60(m，3H，4′、7′、5-H)，9.15(s，1H，2-H).
Embodiment 44
1-ethyl-3-[2-(6-chloro-benzimidazolyl-)-6,8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (44)
The preparation method is with embodiment 17.1-ethyl-6,8-two fluoro-4-oxos-1, and 4-dihydro-7-(3-methyl isophthalic acid-piperazinyl)-3-quinoline carboxylic acid (lomefloxacin) (7g, 0.0165mol), 4-chloro-1, the 2-phenylenediamine (2.35g, 0.0165mol) and PPA (75ml), temperature of reaction is 190 ℃, column chromatography, get tawny solid 1g, yield 13.2%, mp269 ℃ (dec.).IR(cm-1)：3421，3229，3112，3067，2980，2936，2856，2471，1626，1574，1545，1524，1480，1455，1253，1054，919，790；HR-ESIMS(M+1)：Found?458.1540?C
23H
23N
5OF
2Cl?Requires?458.1554；
1HNMR(δ，ppm，DMSO-d6)：1.21(d，3H，CH
3)，1.47(t，3H，CH
3)，3.16(m，4H，CH
2*2)，3.42(m，3H，CH
2、CH)，4.58(q，2H，CH
2)，7.17(dd，1H，5′-H)，7.61(m，2H，4′、7′-H)，7.88(d，1H，5-H)，9.08(s，1H，2-H).
Embodiment 45
1-ethyl-3-[2-(6-chloro benzimidazole base)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (45)
Its preparation method is with embodiment 17,1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-(1-piperazinyl)-3-quinoline carboxylic acid (norfloxicin) (0.025mol), 4-chloro-1,2-phenylenediamine (0.025mol) and PPA (90ml), get yellow solid, yield 21%, mp261-2 ℃ behind the column chromatography of reaction back; IR (cm
-1): 3422,1629,1492,1255,791;
1HNMR (δ, ppm, DMSO-d
6): 1.44 (t, 3H ,-CH
3), 2.92 (d, 4H ,-CH
2-* 2), 3.20 (d, 4H ,-CH
2-* 2), 4.57 (q, 2H ,-CH
2-), 7.13 (m, 2H, 8-H and 7 '-H), 7.56 (d, 1H, 4 '-H), 7.69 (m, 1H, 6 '-H), 7.94 (d, 1H, 5-H), 9.14 (s, 1H, 2-H), 12.84 (b, 1H, 1 '-H); Anal (C%, H%, N%) Calc:57.20,4.58,15.16 Found:56.87,5.27,15.57; HRMS (M): found 425.142062 C
22H
21N
5OClF requires425.141853; MS (EI, m/s): 425 (M
+), 383 (base peak).
Embodiment 46
1-ethyl-3-[2-(6-nitrobenzimidazole base)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (46)
With above gained 1-ethyl-3-(2-benzimidazolyl-)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolone (1) (0.8g, 0.0025mol) be dissolved into fully in an amount of vitriol oil, cryosel is bathed and is chilled to about 0 ℃, slowly drip concentrated nitric acid (0.26ml, 0.0037mol), interior temperature is no more than 5 ℃ of stirrings.Add the back and continue to stir, be warming up to after the room temperature restir naturally 1 hour, use 35-40 ℃ of heating in water bath 2 hours then.In a large amount of trash ices of impouring under the reaction solution stirring, be neutralized to pH8 with sodium hydroxide, separate out a large amount of yellow solids, suction filtration, washing, drying.Column chromatography gets golden yellow solid 0.3 gram, yield 33%, mp236-40 ℃.IR(cm
-1)：3414，2978，2841，1628，1568，1524，1493，1451，1385，1311，1269，1191，1140，1057，828；HR-ESIMS(M+1)：Found?437.1725?C
22H
22N
6O
3F?Requires?437.1732；
1HNMR(δ，ppm，DMSO-d6)：1.46(t，3H，CH
3)，3.07(m，4H，CH
2*2)，3.17(m，4H，CH
2*2)，4.59(q，2H，CH
2)，7.16(s，1H，8-H)，7.68、7.84(dd，1H，5′-H)，7.96(d，1H，4′-H)，8.07(d，1H，5-H)，8.38、8.59(d，1H，7′-H)，9.22(s，1H，2-H)，13.23(NH).
Embodiment 47
1-ethyl-3-[2-(6-nitrobenzimidazole base)-6,8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (47)
1-ethyl-3-(2-benzimidazolyl-)-6, (1g, 0.00236mol), (0.3ml, 0.0043mol), other operate with embodiment 46 concentrated nitric acid 8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (17).Get yellow solid 0.3g yellow solid, yield 27.1%, mp269 ℃ (dec.) behind the column chromatography.IR(cm
-1)：3420，3069，2982，2937，2853，2733，1622，1580，1526，1477，1389，1333，1249，1143，1089，1053，829，736；HR-ESIMS(M+1)：Found?469.1785?C
23H
23N
6O
3F
2?Requires?469.1794；
1HNMR(δ，ppm，DMSO-d6)：1.06(d，3H，CH
3)，1.48(t，3H，CH
3)，3.16、3.33(m，7H，CH
2*3、CH)，4.57(q，2H，CH
2)，7.65(d，0.5H)，7.80(d，0.5H)(4′-H)，7.84(dd，1H，5′-H)，8.03(d，1H，5-H)，8.31(d，0.5H)，8.54(d，0.5H)(7′-H)，9.10(s，1H，2-H)，13.11(br，NH).
Embodiment 48
(s)-and 6-[2-(6-nitrobenzimidazole base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (48)
(s)-and 6-(2-benzimidazolyl-)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (4) (2.2g, 0.005mol), (0.3ml, 0.006mol), other operate with embodiment 46 concentrated nitric acid.Get yellow solid 1.3g, yield 53.3%, mp243-245 ℃ behind the column chromatography.
IR:3409.11,2931.30,1620.43,1553.18,1477.71,1339.41,1304.89,1264.66,1051,790.66cm-1; Formula:C24H23FN6O44.5H2OMW:559.5, and ultimate analysis: Anal (C%, H%, N%) Calc:51.47,5.72,15.01 Found:51.42,5.72,14.851HNMR (δ, ppm, DMSO-d6): 1.49 (d, 3H ,-CH
3, J=6.63 HZ), 2.88 (m, 3H ,-CH
3), 3.38-3.52 (m, 8H ,-CH
2* 4), 4.40-4.61 (dd, 2H, O-CH
2-), 4.95 (d, 1H ,-CH-, J=6.69Hz), 7.62 (d, 1H, 5-H, J=12.15 HZ), 7.74 (s, 1H, 4 '-H), 8.07 (m, 1H, 5 '-H), 8.51 (s, 1H, 7 '-H), 9.21 (s, 1H, 2-H), 13.21 (s, 1H ,-NH-) MS[ESI (+) 70V, m/z]: 479.2
Embodiment 49
1-ethyl-3-[2-(6-Xiao base benzoxazolyl)]-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (49)
(2g, 4.93mmol), (0.48ml, 6.90mmol), other operate with embodiment 46 concentrated nitric acid 1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (19).Column chromatography gets deep yellow solid 0.12g, yield 5.4%, mp 245-8 ℃.IR(cm
-1)：3100，3050，2926，1628，1606，1551，1535，1489，1453，1341，1268，1168，1042，998，829，790，762；HR-ESIMS(M+1)：Found?452.1721?C
23H
23FN
5O
4?Requires452.1728；
1HNMR(δ，ppm，DMSO-d6)：1.44(t，3H，CH
3)，2.26(s，3H，NCH
3)，2.50(m，4H，CH
2*2)，3.56(m，4H，CH
2*2)，4.53(q，2H，CH
2)，7.08(d，1H，5-H)，7.83(s，1H，8-H)，7.87(dd，1H，5’-H)，8.27(d，1H，4’-H)，8.60(d，1H，7’-H)，9.02(s，1H，2-H).
Embodiment 50
(s)-and 6-[2-(6-Xiao base benzoxazolyl)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (50)
(s)-and 6-(2-benzoxazolyl)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (28) (4g, 0.0092mol), (0.82ml, 0.0118mol), other operate with embodiment 46 concentrated nitric acid.Get yellow solid 0.53g, yield 14.6%, 287 ℃ of mp behind the column chromatography.IR(cm
-1)：3430，3100，2935，2883，2840，2741，1631，1619，1553，1538，1476，1450，1342，1302，1249，1130，1050，825，788；HR-ESIMS(M+1)：Found?480.1678?C
24H
23N
5O
5F?Requires480.1678；
1HNMR(δ，ppm，DMSO-d6)1.47(d，3H，CH
3)，2.43(s，3H，NCH
3)，2.43～2.51(m，4H，CH
2*2)，3.26～3.30(m，4H，CH
2*2)，4.37～4.41(m，1H，NCH)，4.55～4.59(m，1H，OCH)，4.85～4.88(m，1H，OCH)，7.47(d，1H，5-H)，7.89(d，1H，4′-H，J＝8.6)，8.30(dd，1H，5′-H)，8.63(d，1H，7′-H，J＝2.1)
Embodiment 51
(s)-and 6-[2-(6-Xiao base benzoxazolyl)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-hydroxyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (51)
Separate a less polar nitro thing that obtains, mp271 ℃ (dec.) in embodiment 50 reactions.IR(cm
-1)：3429，3107，2999，2954，1636，1624，1598，1540，1478，1341，1304，1264，1081，1057，826，785，733；HR-ESIMS(M+1)：Found?398.0785?C
19H
13N
3O
6F?Requires?398.0783；
1HNMR(δ，ppm，DMSO-d6)：1.48(d，3H，CH
3)，4.37(m，1H，NCH)，4.54(m，1H，OCH)，4.87(m，1H，OCH)，7.56(d，1H，5-H)，7.92(d，1H，4′-H，J＝8.7)，8.31(dd，1H，5′-H)，9.03(d，1H，7′-H，J＝2.1).
Embodiment 52
1-ethyl-3-[2-(6-nitre base benzoxazolyl)]-6,8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (52)
1-ethyl-3-(2-benzoxazolyl)-6, (4.2g, 0.0093mol), (0.82ml, 0.0118mol), other operate with embodiment 46 concentrated nitric acid 8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (22).Get yellow solid 1.2g yellow solid, yield 25.8%, mp218 ℃ (dec.) behind the column chromatography.IR(cm
-1)：3423，3100，3062，2975，2931，2849，2727，1644，1623，1539，1521，1476，1340，1269，1057，827，788，734；HR-ESIMS(M+1)：Found470.1621?C
23H
22N
5O
4F
2?Requires?470.1634；
1HNMR(δ，ppm，DMSO-d6)：1.06(d，3H，CH
3)，1.45(t，3H，CH
3)，2.90(m，4H，CH
2*2)，3.46(m，3H，CH
2、CH)，4.53(q，2H，CH
2)，7.80(d，1H，4′-H)，7.91(d，1H，5-H)，8.27(d，1H，5′-H)，8.62(dd，1H，7′-H)，8.99(s，1H，2-H).
Embodiment 53
1-ethyl-3-[2-(6-Xiao base benzoxazolyl)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (53)
1-ethyl-3-[2-(benzoxazolyl)]-(1.08g, 0.0315mol), (0.26ml, 0.00375mol), other operate with embodiment 46 concentrated nitric acid 6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (18).Get yellow solid 0.8, yield 65.6%, mp 291-4 ℃ behind the column chromatography.IR(cm
-1)：3010，2930，1648，1609，1537，1482，1340，1328，1278，1265，1055，1013，827，790，760；HR-ESIMS(M+1)：Found?388.0509?C
18H
12N
3O
4FCL?Requires388.0495；
1HNMR(δ，ppm，DMSO-d6)：1.43(t，3H，CH
3)，4.51(q，2H，CH
2)，7.80(d，1H，4′-H)，8.00(d，1H，5-H)，8.16(dd，1H，5′-H)，8.20(d，1H，7′-H)，8.48(s，1H，8-H)，9.00(s，1H，2-H).
Embodiment 54
1-ethyl-3-[2-(6-nitrobenzene thiazole base)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolone (54) 1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolone (30) (1.75g, 0.0043mol), concentrated nitric acid (0.35ml, 0.0051mol), other are operated with embodiment 46.Get yellow solid 0.6g yellow solid, yield 31.4%, 244 ℃ of mp (dec.) behind the column chromatography.IR(cm
-1)：3416，3026，2944，2839，1616，1573，1496，1444，1328，1264，1126，894，752；HR-ESIMS(M+1)：Found?454.1344?C
22H
21N
5O
3FS?Requires?454.1344；
1HNMR(δ，ppm，DMSO-d6)：1.48(t，3H，CH
3)，3.08(m，4H，CH
2*2)，3.32(m，4H，CH
2*2)，4.61(q，2H，CH
2)，7.12(d，1H，8-H)，7.88(d，1H，4′-H)，7.98(d，1H，5-H)，8.24(dd，1H，5′-H)，9.08(d，1H，7′-H)，9.24(s，1H，2-H).
Embodiment 55
1-ethyl-3-[2-(6-nitrobenzene thiazole base)]-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (55)
(1g, 0.00237mol), (0.2ml, 0.0029mol), other operate with embodiment 46 concentrated nitric acid 1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (31).Get yellow solid 0.23g yellow solid, yield 20.8%, mp248 ℃ (dec.) behind the column chromatography.IR(cm
-1)：3050，2972，2934，2838，1617，1568，1511，1494，1334，1306，1294，1260，1195，1121，1009，896，756；HR-ESIMS(M+1)：Found468.1495?C
23H
23N
5O
3FS?Requires?468.1500；
1HNMR(δ，ppm，DMSO-d6)：9.28(s，1H，2-H)，9.11(s，1H，8-H)，8.28(dd，1H，5′-H)，8.04(d，1H，7′-H)，7.92(d，1H，5-H)，7.14(d，1H，4′-H)，4.63(q，2H，CH
2)，3.71(m，4H，CH
2*2)，2.63(m，4H，CH
2*2)，2.34(s，3H，CH
3)，1.40(t，3H，CH
3).
Embodiment 56
(±)-6-[2-(6-nitrobenzene thiazole base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (56)
(±)-6-(2-[4-morpholinodithio base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (32) (7.24g, 0.016mol), (1.3ml, 0.0194mol), other operate with embodiment 46 concentrated nitric acid.Get yellow solid 1.1g yellow solid, yield 14%, mp265 ℃ (dec.) behind the column chromatography.IR(cm
-1)：3100，3010，2791，1614，1571，1547，1513，1476，1331，1295，1235，1127，1047，1006，784，754；HR-ESIMS(M+1)：Found?496.1444?C
24H
23N
5O
4FS?Requires?496.1449；
1HNMR(δ，ppm，DMSO-d6)：1.56(d，3H，CH
3)，2.29(s，3H，NCH
3)，2.50(m，4H，CH
2*2)，3.30(m，4H，CH
2*2)，4.42(d，1H，NCH)，4.59(d，1H，OCH)，4.98(m，1H，OCH)，7.49(d，1H，4′-H)，7.92(d，1H，5-H)，8.22(dd，1H，5′-H)，9.02(d，1H，7′-H)，9.21(s，1H，2-H).
Embodiment 57
(±)-6-[2-(6-nitrobenzene thiazole base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-hydroxyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (57)
Separate in embodiment 56 reactions and obtain a less polar nitro thing 0.7g, yield 10%, mp254 ℃ (dec.).IR(cm
-1)：3449，3010，1619，1581，1509，1477，1332，1293，1250，1126，1089，1053，889，784；HR-ESIMS(M+1)：Found?414.0579?C
19H
13N
3O
5FS?Requires?414.0555；
1HNMR(δ，ppm，DMSO-d6)：1.51(d，3H，CH
3)，4.41(d，1H，NCH)，4.60(d，1H，OCH)，5.01(m，1H，OCH)，7.62(d，1H，4′-H)，8.05(d，1H，5-H)，8.32(dd，1H，5′-H)，9.13(d，1H，7′-H)，9.29(s，1H，2-H).
Embodiment 58
(s)-6-[2-(6-nitrobenzene thiazole base)]-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (58)
(s)-and 6-(2-[4-morpholinodithio base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (39) (2.56g, 5.69mmol), (0.56ml, 8.04mmol), other operate with embodiment 46 concentrated nitric acid.Get 0.47g yellow solid, yield 17%, mp266 ℃ behind the column chromatography.IR(cm
-1)：3100，3010，2973，2931，2840，1614，1573，1513，1476，1440，1332，1294，1235，1126，1047，1006，784，753；HR-ESIMS(M+1)：Found?496.1456?C
24H
23N
5O
4FS?Requires?496.1449；
1HNMR(δ，ppm，DMSO-d6)：1.51(d，3H，CH
3)，2.26(s，3H，CH
3)，2.48(m，4H，CH
2*2)，3.24(m，4H，CH
2*2)，4.42(m，1H，NCH)，4.60(m，1H，OCH)，4.99(m，1H，OCH)，7.54(d，1H，4′-H)，8.02(d，1H，5-H)，8.29(dd，1H，5′-H)，9.12(d，1H，7′-H)，9.26(s，1H，2-H).
Embodiment 59
(s)-6-[2-(6-nitrobenzene thiazole base)]-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-hydroxyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (59)
Separate in embodiment 58 reactions and obtain the less nitro thing 0.3g of a polarity, yield 13%, mp284 ℃; IR (cm
-1): 3378,3081,2903,1618,1571,1514,1481,1334,1320,1290,1254,1092,1057,890,786,753; HR-ESIMS (M+1): Found 414.0583 C
19H
13FN
3O
5S Requires 414.0554;
1HNMR (δ, ppm, DMSO-d6): 1.51 (d, 3H, CH
3), 4.42 (d, 1H, NCH), 4.62 (d, 1H, OCH), 5.01 (m, 1H, OCH), 7.61 (d, 1H, 5-H), 8.03 (d, 1H, 4 '-H), 8.29 (dd, 1H, 5 '-H), 9.13 (d, 1H, 7 '-H), 9.28 (s, 1H, 2-H), 10.88 (s, 1H, OH).
Embodiment 60
1-ethyl-3-[2-(6-chloro-5-nitrobenzimidazole base)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (60)
1-ethyl-3-[2-(6-chloro benzimidazole base)]-(4.11g, 0.00966mol), (0.81ml, 0.0116mol), other operate with embodiment 46 concentrated nitric acid 6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (45).Get tawny solid 0.68g, yield 14.9%, mp ℃ behind the column chromatography.IR(cm
-1)：3407，3037，2955，2843，2725，1628，1570，1528，1494，1455，1327，1309，1271，1193，1138，1088，999，913，829，792；HR-ESIMS(M+1)：Found471.1378?C
22H
21N
6O
3FCL?Requires?471.1342；
1HNMR(δ，ppm，DMSO-d6)：46(t，3H，CH
3)，3.32(m，4H，CH
2*2)，3.52(m，4H，CH
2*2)，4.61(q，2H，CH
2)，7.84(s，1H，8-H)，7.96(d，1H，5-H)，8.24(s，1H，2-H)，9.31(s，1H，7’-H)，9.61(s，1H，4’-H)
Embodiment 61
1-ethyl-3-[2-(6-nitrobenzene thiazole base)-6,8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (61)
1-ethyl-3-(2-[4-morpholinodithio base)-6, (1.74g, 0.0039mol), (0.33ml, 0.0048mol), other operate with embodiment 46 concentrated nitric acid 8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (34).Get deep yellow solid 0.28g, yield 14.6%, 217 ℃ of mp (dec.) behind the column chromatography.IR(cm
-1)：3418，3081，3055，2981，2841，1609，1546，1509，1482，1381，1333，1250，1124，1056，787，753；HR-ESIMS(M+1)：Found?486.1398?C
23H
22N
5O
3F
2SRequires?486.1406；
1HNMR(δ，ppm，DMSO-d6)：1.04(d，3H，CH
3)，1.48(t，3H，CH
3)，2.78(m，4H，CH
2*2)，3.03(m，3H，CH
2、CH)，4.65(q，2H，CH
2)，7.88(d，1H，4′-H)，8.08(d，1H，5′-H)，8.18(s，1H，5-H)，8.31(d，1H，7′-H)，9.25(s，1H，2-H).
Embodiment 62
1-ethyl-3-[2-(the amino benzimidazolyl-of 6-)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (62)
1-ethyl-3-[2-(6-nitrobenzimidazole base)]-(0.3g 0.00069mol) is suspended in the 1N hydrochloric acid (6ml) 6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (46), adds the Pd-C of catalytic amount, and normal pressure hydrogenation is to no longer inhaling hydrogen.Filter, filtrate is neutralized to pH9 with sodium hydroxide, separates out a large amount of yellow-green colour solids, filters washing, drying.Column chromatography gets yellow solid 0.15g, yield 65.1%, mp244-6 ℃.IR(cm
-1)：3408，3310，3211，2926，2815，2769，2719，2655，2488，1632，1571，1520，1496，1272，1186，1124，1035，828；HR-ESIMS(M+1)：Found?407.1991?C
22H
24N
6OFRequires?407.1990；
1HNMR(δ，ppm，DMSO-d6)：1.50(t，3H，CH
3)，2.51(m，4H，CH2*2)，3.55(m，4H，CH
2*2)，4.55(q，2H，CH
2)，6.82(dd，1H，5′-H)，6.99(s，1H，8-H)，7.26(d，1H，7′-H)，7.50(d，1H，4′-H)，8.00(d，1H，5-H)，9.37(br)，9.46(s，1H，2-H).
Embodiment 63
1-ethyl-3-[2-(the amino benzoxazolyl of 6-)]-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (63)
1-ethyl-3-[2-(6-Xiao base benzoxazolyl)]-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (48) (0.8g), normal pressure catalytic hydrogenation (with 62), column chromatography, moral 0.21g yellow solid, yield 28.1%, mp173 ℃ (dec.).IR(cm
-1)：3415，2928，2882，1628，1600，1492，1384，1355，1260，790；HR-ESIMS(M+1)：Found422.1963?C
23H
25N
5O
2F?Requires?422.1987；
1HNMR(δ，ppm，DMSO-d6)：1.41(t，3H，CH
3)，2.26(s，3H，CH
3)，2.51(m，4H，CH
2*2)，3.26(m，4H，CH
2*2)，4.47(q，2H，CH
2)，6.71(d，1H，7′-H)，6.79(s，1H，8-H)，7.07(dd，1H，5′-H)，7.42(d，1H，4′-H)，7.86(d，J＝13.7，1H，5-H)，8.27(s，1H，2-H)，8.79(NH
2).
Embodiment 64
(s)-and 6-[2-(the amino benzoxazolyl of 6-)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (64)
(s)-and 6-[2-(6-Xiao base benzoxazolyl)-9-fluoro-2, [(0.4g 0.00084mol), presses embodiment 62 process operations to 1,4] benzoxazine (49) to 3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de].Column chromatography gets the pale brown look solid of 0.17g, yield 45.4%, mp200-5 ℃; IR (cm-1): 3418,3352,3224,3056,2932,2886,2803,1630,1588,1476,1342,1297,1246,1088,1074,786; HR-ESIMS (M+1): Found 450.1929 C
24H
25N
5O
3F Requires 450.1936; 1HNMR (δ, ppm, DMSO-d6): 1.42 (d, 3H, CH
3), 2.36 (s, 3H, NCH
3), 2.61 (m, 4H, CH
2* 2), 3.30 (m, 4H, CH
2* 2), 4.36 (d, 1H, NCH), 4.54 (d, 1H, OCH), 4.79 (m, 1H, OCH), 6.62 (dd, 1H, 5 '-H), 6.79 (d, 1H, 7 '-H), 7.35 (d, 1H, 4 '-H), 7.48 (d, 1H, 5-H), 8.77 (s, 1H, 2-H);
Embodiment 65
1-ethyl-3-[2-(6-aminobenzothiazole base)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (65)
1-ethyl-3-[2-(6-nitrobenzene thiazole base)]-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolone (53) (0.4g, 0.00088mol) reduce with iron powder (0.8g), other post-processing operation also get the yellow product of 0.29g behind the column chromatography with embodiment 62, yield 77.6%, mp262 ℃ (dec.).IR(cm
-1)：3342，3266，2981，2843，2803，1628，1615，1566，1490，1454，1383，1269，1256，1189，1013，787；HR-ESIMS(M+1)：Found?424.1590?C
22H
23N
5OFSRequires?424.1602；
1HNMR(δ，ppm，DMSO-d6)：1.45(t，3H，CH
3)，2.71(m，4H，CH
2*2)，3.17(m，4H，CH
2*2)，4.59(q，2H，CH
2)，5.30(br)，6.78(dd，1H，5′-H)，7.09(s，1H，8-H)，7.17(d，1H，7′-H)，7.62(d，1H，4′-H)，8.10(d，1H，5-H)，9.09(s，1H，2-H).
Embodiment 66
1-ethyl-3-[2-(6-aminobenzothiazole base)]-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (66)
1-ethyl-3-[2-(6-nitrobenzene thiazole base)]-6-fluoro-7-(4-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolone (54) (0.4g, 0.88mmol) reduce with iron powder (0.8g), other post-processing operation are with embodiment 62, column chromatography, get the 0.19g yellow solid, yield 25.8%, mp244 ℃ (dec.).IR(cm
-1)：3421，3334，3214，3054，2971，2935，2805，1618，1566，1492，1454，1376，1296，1258，1196，1140，1010，833，810，785，761；HR-ESIMS(M+1)：Found?438.1728?C
23H
25N
5OFS?Requires?438.1758；
1HNMR(δ，ppm，DMSO-d6)：9.07(s，1H，2-H)，7.92(d，J＝13.5，1H)，7.62(1H，8-H)，7.13(d，J＝7.1，1H，4′-H)，7.09(d，J＝2.0，1H，7′-H)，6.778(dd，1H，5′-H)，4.57(q，2H，CH
2)，3.32(m，4H，CH
2*2)，2.63(m，4H，CH
2*2)，2.33(s，3H，NCH
3)，1.44(t，3H，CH
3).
Embodiment 67
(±)-6-[2-(6-aminobenzothiazole base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (67)
(±)-6-[2-(6-nitrobenzene thiazole base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (56) (0.95g, 0.00192mol) reduce with iron powder (0.4g), other post-processing operation are with embodiment 62.Get yellow solid 0.37g yellow solid, yield 41%, mp141 ℃ (dec.) behind the column chromatography.IR(cm
-1)：3413，3336，3219，3030，2974，2936，2884，2799，2676，2494，1609，1577，1547，1472，1398，1297，1272，1132，1049，784；HR-ESIMS(M+1)：Found?466.1710?C
24H
25N
5O
2FSRequires?466.1708；
1HNMR(δ，ppm，DMSO-d6)：1.47(d，3H，CH
3)，2.44(s，3H，CH
3)，2.73(m，4H，CH
2*2)，3.08(m，4H，CH
2*2)，4.39(m，1H，NCH)，4.58(m，1H，OCH)，4.94(m，1H，OCH)，7.09(d，1H，7′-H)，7.59(m，2H，4′、5′-H)，8.14(s，1H，5-H)，9.08(s，1H，2-H).
Embodiment 68
(s)-and 6-[2-(6-aminobenzothiazole base)-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (68)
(s)-6-[2-(6-nitrobenzene thiazole base)]-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (58) is (2.54g), reduce with iron powder (0.8g), other post-processing operation are with embodiment 62, and column chromatography gets the yellow product of 0.7g, yield 29.3%, mp266 ℃ (dec.).Ultimate analysis: Found C 61.98% H 5.25% N 15.22% requires C 61.91% H 5.20% N 15.12%; IR (cm
-1): 3402,3234,3010,2916,2810,2580,1623,1592,1513,1489,1478,1440,1354,1305,1247,1050,987,779,629; HR-ESIMS (M+1): Found 466.1710 C
24H
25N
5O
2FS Requires 466.1708;
1HNMR (δ, ppm, DMSO-d6): 1.48 (d, 3H, CH
3), 2.39 (s, 3H, NCH
3), 2.66 (m, 4H, CH
2* 2), 3.34 (m, 4H, CH
2* 2), 4.39 (m, 1H, NCH), 4.58 (m, 1H, OCH), 4.93 (m, 1H, OCH), 5.32 (br), 6.78 (dd, 1H, 5 '-H), 7.10 (d, 1H, 7 '-H), 7.55 (d, 1H, 4 '-H), 7.65 (d, 1H, 5-H), 9.08 (s, 1H, 2-H).
Embodiment 69
(s)-6-[2-(6-aminobenzothiazole base)]-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-hydroxyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (69)
The preparation method is with embodiment 67.(s)-6-[2-(6-nitrobenzene thiazole base)]-9-fluoro-2,3-dihydro-3-methyl isophthalic acid 0-hydroxyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine (59) (0.5g, 0.0012mol), iron powder reducing gets the 0.21g amino substance, 246 ℃ of yield 45.7%mp (dec.).IR(cm
-1)：3406，3142，3060，2980，2916，2848，2594，1622，1593，1489，1479，1354，1248，1050，779，689；HR-ESIMS(M+1)：Found?384.0838C
19H
15N
3O
3FS?Requires?384.0813；
1HNMR(δ，ppm)：1.50(d，3H，CH
3)，4.40(m，1H，NCH)，4.60(m，1H，OCH)，4.99(m，1H，OCH)，7.50(dd，1H，5′-H)，7.64(d，1H，5-H)，8.03(d，1H，4′-H)，8.13(d，1H，7′-H)，9.25(s，1H，2-H)，10.50(br).
Embodiment 70
1-ethyl-3-(2-benzimidazolyl-)-6-fluoro-7-(4-ethanoyl-1-piperazinyl)-4 (1H)-quinolones (70)
With 1-ethyl-3-(2-benzimidazolyl-)-(0.2g 0.51mmol) is suspended among the DMSO (8ml) 6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (1), adds aceticanhydride (0.067ml then, 0.71mmol), be heated to 120 ℃ of insulations 2 hours, concentrate, add suitable quantity of water, filter, drying, column chromatography gets 0.058g canescence product, yield 26.4%, mp224-6 ℃.IR(cm
-1)：3450，3087，3062，2983，2821，1650，1628，1566，1544，1525，1496，1478，1429，1248，1193，1141，1001，987，895，793，742；HR-ESIMS(M+1)：Found?434.1961?C
24H
25N
5O
2F?Requires434.1987；
1HNMR(δ，ppm，DMSO-d6)：1.47(t，3H，CH
3)，2.07(s，3H，COCH
3)，3.25(m，4H，CH
2*2)，3.67(m，4H，CH
2*2)，4.57(q，2H，CH
2)，7.15(1H，8-H)，7.15(m，2H，5′-H，6′-H)，7.62(m，2H，4′-H，7′-H)，7.98(d，1H，5-H)，9.17(s，1H，2-H)，12.73(br，NH).
Embodiment 71
1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-(4-ethanoyl-1-piperazinyl)-4 (1H)-quinolones (71)
(1.4g, 3.6mol), (0.48ml, 5.1mol), other operate with embodiment 70 aceticanhydride 1-ethyl-3-(2-benzoxazolyl)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (18).With ethyl acetate and sherwood oil recrystallization, get canescence product 0.82g, yield 54.4%, mp258-61 ℃.IR(cm
-1)：3100，3010，2950，1650，1627，1593，1550，1488，1453，1440，1387，1248，1187，1028，996，832，790，771；HR-ESIMS(M+1)：Found?435.1824C
24H
24N
4O
3F?Requires?435.1827；
1HNMR(δ，ppm，DMSO-d6)：1.43(t，3H，CH
3)，2.07(s，3H，CH
3)，3.23(m，4H，CH
2*2)，3.66(m，4H，CH
2*2)，4.51(q，2H，CH
3)，7.13(d，1H，7′-H)，7.38(m，2H，8、4′-H)，7.73(m，2H，5′、6′-H)，7.91(d，1H，5-H)，8.95(s，1H，2-H).
Embodiment 72
1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(4-ethanoyl-1-piperazinyl)-4 (1H)-quinolones (72)
(0.25g, 0.61mmol), (0.086ml, 0.98mmol), other operate with embodiment 70 aceticanhydride 1-ethyl-3-(2-[4-morpholinodithio base)-6-fluoro-7-(1-piperazinyl)-4 (1H)-quinolones (30).Column chromatography gets light yellow product 0.12g, yield 43.5%, mp268-71 ℃.IR(cm
-1)：3100，3050，2900，1647，1620，1571，1543，1500，1438，1246，1203，1152，1011，1001，979，789，764，728；HR-ESIMS(M+1)：Found?451.1606?C
24H
24N
4O
2FS?Requires451.1599；
1HNMR(δ，ppm，DMSO-d6)：1.47(t，3H，CH
3)，2.07(s，3H，COCH
3)，3.25(m，4H，CH
2*2)，3.66(m，4H，CH
2*2)，4.61(q，2H，CH
2)，7.17(d，1H，7′-H)，7.38(m，1H，6′-H)，7.51(m，1H，5′-H)，7.95(d，1H，4′-H)，8.00(s，1H，8-H)，8.10(d，1H，5-H)，9.25(s，1H，2-H).
Embodiment 73
1-ethyl-3-(2-[4-morpholinodithio base)-6,8-two fluoro-7-(4-ethanoyl-3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (73)
1-ethyl-3-(2-[4-morpholinodithio base)-6, (0.3g, 0.68mmol), (0.08ml, 0.91mmol), other operate with embodiment 70 aceticanhydride 8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (34).Column chromatography gets light yellow product 0.16g, yield 49.7%, mp 227-31 ℃.IR(cm
-1)：3058，2973，2931，2841，1630，1613，1586，1542，1474，1454，1386，1327，1225，1169，1087，1056，1011，787，759，729；HR-ESIMS(M+1)：Found?483.1642C
25H
25N
4O
2F
2S?Requires?483.1661；
1HNMR(δ，ppm，DMSO-d6)：1.48(t，3H，CH
3)，2.06(d，3H，CH
3)，3.11(m，4H，CH
2*2)，3.32(m，3H，CH
2、CH)，4.61(q，2H，CH
2)，7.40(m，1H，6′-H)，7.49(m，1H，5′-H)，7.89(d，1H，5-H)，7.96(d，1H，7′-H)，8.10(d，1H，4′-H)，9.17(s，1H，2-H).
Embodiment 74
1-ethyl-3-[2-(6-chloro benzimidazole base)]-6,8-two fluoro-7-(4-ethanoyl-3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (74)
1-ethyl-3-[2-(6-chloro-benzimidazolyl-)]-6, (0.2g, 0.437mmol), (0.06ml, 0.64mmol), other operate with embodiment 70 aceticanhydride 8-two fluoro-7-(3-methyl isophthalic acid-piperazinyl)-4 (1H)-quinolones (44).Column chromatography gets brown product 0.16g, yield 73.2%, mp169-71 ℃.IR(cm
-1)：3438，3068，2974，2930，2846，1650，1625，1574，1544，1476，1454，1389，1335，1291，1249，1148，1054，1010，916，790，597；HR-ESIMS(M+1)：Found?500.1638?C
25H
25N
5O
2F
2CL?Requires?500.1659；
1HNMR(δ，ppm，DMSO-d6)：1.24(d，3H，CH
3)，1.46(t，3H，CH
3)，2.05(s，3H，CH
3)，3.26(m，4H，CH
2*2)，3.73(m，2H，CH
2)，4.13(m，1H，CH)，4.57(q，2H，CH
2)，7.18(dd，1H，5′-H)，7.60(d，1H，4′-H)，7.64(d，1H，7′-H)，7.89(d，1H，5-H)，9.07(s，1H，2-H).
Embodiment 75
The cytotoxic activity data of target compound among the embodiment.
This mensuration adopts bromination tetrazole indigo plant (MTT) method routinely, promptly use the trysinization tumour cell, to contain the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 10000 cells/ml, and 100 μ l (containing 1000 cells/well) are inoculated in every hole in 96 well culture plates.If different pharmaceutical concentration is established three parallel holes for every group.Put to cultivate after 4 days in 37 ℃, 5%CO2 incubator and discard nutrient solution, every hole adds 100 μ l 0.5%MTT solution (RPMI 1640 preparations).37 ℃ are incubated 4 hours, abandon supernatant, and every hole adds DMSO 150 μ l dissolving Formazan particle, and vibration detects (reference wavelength 450nm, detection wavelength 570nm) with microplate reader, calculates the inhibiting rate of medicine cell growth.With the drug level logarithmic value inhibiting rate is done linear regression, get straight-line equation, therefrom obtain the half-inhibition concentration (IC of medicine cancer cells
50).
Reagent source: MTT: bromination tetrazole indigo plant (Thiazolyl Blue Tetrazolum Bromide), the import of Sigma company; RPMI 1640 substratum: GIBCO company product; Pancreatin (Trypsin): the product DMSO of GIBCO company: dimethyl sulfoxide (DMSO), the Beijing Chemical Plant produces; Calf serum: military region animal doctor's centre of prevention and cure
ND: undetermined
| Numbering | General formula (I) compound | ?????????????IC 50(μM) | ||||||||
| ????R 1 | ????R 8 | ????R 3 | ??R 5 | ??R 6 | ????????R 7 | ??X | ????KB | ???A2780 | ??Bel7402 | |
| ????1 | ????Et | ????H | ????H | ????H | ????F | Piperazinyl-1- | NH | ????4.1 | ????0.31 | ????10.7 |
| ????2 | ????Et | ????H | ????H | ????H | ????F | 4-methylpiperazine base-1- | NH | ????36.2 | ????0.29 | ????5.34 |
| ????3 | ????(±)-CH(CH 3)CH 2O- | ????H | ????H | ????F | 4-methylpiperazine base-1- | NH | ????3.56 | ????0.89 | ????8.30 | |
| ????4 | ????(S)-CH(CH 3)CH 2O- | ????H | ????H | ????F | 4-methylpiperazine base-1- | NH | ????3.47 | ????0.48 | ????9.92 | |
| ????5 | ????-CH 2CH 2F | ????F | ????H | ????H | ????F | 4-methylpiperazine base-1- | NH | ????3.70 | ????3.13 | ????11.08 |
| ????6 | ????Et | ????H | ????H | ????H | ????F | ????Cl | NH | ????11.93 | ????2.20 | ????4.37 |
| ????7 | Cyclopropyl | ????H | ????H | ????H | ????F | ????Cl | NH | ????28.11 | ????0.85 | ????55.38 |
| ????8 | ????H | ????H | ????H | ????H | ????H | ????H | NH | ????52.08 | ????9.24 | ????＞164 |
| ????9 | ????Et | ????H | ????5’-Cl | ????H | ????F | Piperazinyl-1- | NH | ????0.73 | ????2.07 | ????1.22 |
| ????10 | ????Et | ????H | ????5’-Cl | ????H | ????F | 4-methylpiperazine base-1- | NH | ????67.18 | ????85.92 | ????9.96 |
| ????11 | ????(±)-CH(CH 3)CH 2O- | ????5’-Cl | ????H | ????F | 4-methylpiperazine base-1- | NH | ????19.98 | ????1.15 | ????2.02 | |
| ????12 | ????-CH 2CH 2F | ????F | ????5’-Cl | ????H | ????F | 4-methylpiperazine base-1- | NH | ????8.54 | ????5.28 | ????5.49 |
| ????13 | ????Et | ????H | ????5’-Cl | ????H | ????F | ????Cl | NH | ????＞130 | ????146.7 | ????＞130 |
| ????14 | Cyclopropyl | ????H | ????5’-Cl | ????H | ????F | ????Cl | NH | ????36.4 | ????5.13 | ????12.29 |
| ??15 | ????Et | ????H | ????5’-NO 2 | ??H | ??F | 4-methylpiperazine base-1- | ??NH | ??＜1.11 | ??＜1.11 | ??1.18 |
| ??16 | ????Et | ????H | ????5’-NH 2 | ??H | ??F | 4-methylpiperazine base-1- | ??NH | ??35.5 | ??25.2 | ??3.64 |
| ??17 | ????Et | ????F | ????H | ??H | ??F | 3-methylpiperazine base-1- | ??NH | ??8.2 | ??4.9 | ??12.8 |
| ??18 | ????Et | ????H | ????H | ??H | ??F | Piperazinyl-1- | ??O | ??10.95 | ??7.56 | ??10.95 |
| ??19 | ????Et | ????H | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??34.7 | ??0.82 | ??13.47 |
| ??20 | ??(±)-CH(CH 3)CH 2O- | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??8.06 | ??0.64 | ??22.79 | |
| ??21 | Cyclopropyl | ????H | ????H | ??H | ??F | Piperazinyl-1- | ??O | ??10.68 | ??40.12 | ??4.50 |
| ??22 | ????Et | ????F | ????H | ??H | ??F | 3-methylpiperazine base-1- | ??O | ??8.0 | ??35.5 | ??2.4 |
| ??23 | Cyclopropyl | ????F | ????H | ??NH 2 | ??F | 3,5-lupetazin base-1- | ??O | ??7.95 | ??10.44 | ??7.56 |
| ??24 | ??-CH 2CH 2F | ????F | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??14.46 | ??10.17 | ??14.01 |
| ??25 | ????Et | ????H | ????H | ??H | ??F | ??Cl | ??O | ??3.5 | ??26.8 | ??9.9 |
| ??26 | ????H | ????H | ????H | ??H | ??F | ??Cl | ??O | ??56.22 | ??10.63 | ??51.28 |
| ??27 | Cyclopropyl | ????H | ????H | ??H | ??F | ??Cl | ??O | ??37.77 | ??10.46 | ??19.73 |
| ??28 | ??(S)-CH(CH 3)CH 2O- | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??1.6 | ??ND | ??2.4 | |
| ??29 | ????Et | ????H | ????H | ??H | ??F | 4-ethyl piperazidine base-1- | ??O | ??16.5 | ??59.5 | ??47.0 |
| ??30 | ????Et | ????H | ????H | ??H | ??F | Piperazinyl-1- | ??S | ??11.7 | ??4.6 | ??9.84 |
| ??31 | ????Et | ????H | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??8.0 | ??47.9 | ??11.4 |
| ??32 | ??(±)-CH(CH 3)CH 2O- | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??9.2 | ??24.4 | ??33.5 | |
| ??33 | Cyclopropyl | ????H | ????H | ??H | ??F | Piperazinyl-1- | ??S | ??42.76 | ??48.53 | ??30.90 |
| ??34 | ????Et | ????F | ????H | ??H | ??F | 3 methylpiperazine base-1- | ??S | ??10.3 | ??4.1 | ??6.3 |
| ??35 | Cyclopropyl | ????F | ????H | ??NH 2 | ??F | 3,5-lupetazin base-1- | ??S | ??35.69 | ??16.90 | ??10.13 |
| ??36 | ??-CH 2CH 2F | ????F | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??45.62 | ??27.36 | ??44.68 |
| ??37 | ????Et | ????H | ????H | ??H | ??F | ??Cl | ??S | ??8.01 | ??35.36 | ??2.40 |
| ??38 | Cyclopropyl | ????H | ????H | ??H | ??F | ??Cl | ??S | ??＞135 | ??＞135 | ??＞135 |
| ??39 | ??(S)-CH(CH 3)CH 2O- | ????H | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??27.1 | ??10.6 | ??41.6 | |
| ??40 | Cyclopropyl | ????H | ????H | ??H | ??F | 4-ethyl piperazidine base-1- | ??S | ??34.2 | ??65.2 | ??34.8 |
| ??41 | ????Et | ????H | ????H | ??H | ??F | 4-ethyl piperazidine base-1- | ??S | ??4.4 | ??56.5 | ??10.6 |
| ??42 | ????Et | ????F | ????H | ??H | ??F | 4-ethyl-3-methylpiperazine base-1- | ??S | ??6.6 | ??70.1 | ??20.1 |
| ??43 | ??(S)-CH(CH 3)CH 2O- | ????6’-Cl | ??H | ??F | 4-methylpiperazine base-1- | ??NH | ??3.1 | ??0.19 | ??4.8 | |
| ??44 | ????Et | ????F | ????6’-Cl | ??H | ??F | 3-methylpiperazine base-1- | ??NH | ??4.3 | ??1.5 | ??4.9 |
| ??45 | ????Et | ????H | ????6’-Cl | ??H | ??F | Piperazinyl-1- | ??NH | ??0.72 | ??2.1 | ??1.2 |
| ??46 | ????Et | ????H | ????6’-NO 2 | ??H | ??F | Piperazinyl-1- | ??NH | ??0.55 | ??0.66 | ??0.94 |
| ??47 | ????Et | ????F | ????6’-NO 2 | ??H | ??F | 3-methylpiperazine base-1- | ??NH | ??＜1.1 | ??＜1.1 | ??0.47 |
| ??48 | ??(S)-CH(CH 3)CH 2O- | ????6’-NO 2 | 4-methylpiperazine base-1- | ??NH | ??ND | ??ND | ??ND | |||
| ??49 | ????Et | ????H | ????6’-NO 2 | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??0.22 | ??ND | ??0.71 |
| ??50 | ??(S)-CH(CH 3)CH 2O- | ????6’-NO 2 | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??11.7 | ??34.6 | ??23.2 | |
| ??51 | ??(S)-CH(CH 3)CH 2O- | ????6’-NO 2 | ??H | ??F | ??OH | ??O | ??122.4 | ??125.9 | ??131.4 | |
| ??52 | ????Et | ????F | ????6’-NO 2 | ??H | ??F | 3-methylpiperazine base-1- | ??O | ??0.26 | ??0.15 | ??0.15 |
| ??53 | ????Et | ????H | ????6’-NO 2 | ??H | ??F | Piperazinyl-1- | ??O | ??18.2 | ??17.9 | ??22.7 |
| ??54 | ????Et | ????H | ??6’-NO 2 | ??H | ??F | Piperazinyl-1- | ??S | ??0.31 | ??0.26 | ??0.83 |
| ??55 | ????Et | ????H | ??6’-NO 2 | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??81.8 | ??91.3 | ??112.2 |
| ??56 | ??(±)-CH(CH 3)CH 2O- | ??6’-NO 2 | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??8.1 | ??8.3 | ??36.6 | |
| ??57 | ??(±)-CH(CH 3)CH 2O- | ??6’-NO 2 | ??H | ??F | ??OH | ??S | ??18.7 | ??11.9 | ??27.1 | |
| ??58 | ??(S)-CH(CH 3)CH 2O- | ??6’-NO 2 | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??2.7 | ??2.0 | ??3.6 | |
| ??59 | ??(S)-CH(CH 3)CH 2O- | ??6’-NO 2 | ??H | ??F | ??OH | ??S | ??7.4 | ??ND | ??＞24.2 | |
| ??60 | ????Et | ????H | ??5’-NO 2??6’-Cl | ??H | ??F | Piperazinyl-1- | ??NH | ??3.7 | ??4.5 | ??2.9 |
| ??61 | ????Et | ????F | ??6’-NO 2 | ??H | ??F | 3-methylpiperazine base-1- | ??S | ??0.33 | ??0.58 | ??1.0 |
| ??62 | ????Et | ????H | ??6’-NH 2 | ??H | ??F | Piperazinyl-1- | ??NH | ??35.3 | ??51.2 | ??91.5 |
| ??63 | ????Et | ????H | ??6’-NH 2 | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??39.0 | ??93.5 | ??35.8 |
| ??64 | ??(S)-CH(CH 3)CH 2O- | ??6’-NH 2 | ??H | ??F | 4-methylpiperazine base-1- | ??O | ??29.7 | ??5.6 | ??31.8 | |
| ??65 | ????Et | ????H | ??6’-NH 2 | ??H | ??F | Piperazinyl-1- | ??S | ??3.7 | ??3.6 | ??10.0 |
| ??66 | ????Et | ????H | ??6’-NH 2 | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??8.9 | ??37.4 | ??42.2 |
| ??67 | ??(±)-CH(CH 3)CH 2O- | ??6’-NH 2 | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??35.4 | ??4.6 | ??39.8 | |
| ??68 | ??(S)-CH(CH 3)CH 2O- | ??6’-NH 2 | ??H | ??F | 4-methylpiperazine base-1- | ??S | ??12.5 | ??7.5 | ??16.9 | |
| ??69 | ??(S)-CH(CH 3)CH 2O- | ??6’-NH 2 | ??H | ??F | ??OH | ??S | ??130.5 | ??130.5 | ??140.1 | |
| ??70 | ????Et | ????H | ????H | ??H | ??F | 4-ethanoyl piperazinyl-1- | ??NH | ??111.4 | ??11.7 | ??78.3 |
| ??71 | ????Et | ????H | ????H | ??H | ??F | 4-ethanoyl piperazinyl-1- | ??O | ??82.1 | ??57.2 | ??65.8 |
| ??72 | ????Et | ????H | ????H | ??H | ??F | 4-ethanoyl piperazinyl-1- | ??S | ??21.6 | ??11.2 | ??50.2 |
| ??73 | ????Et | ????F | ????H | ??H | ??F | 4-ethanoyl-3-methyl-piperazinyl-1- | ??S | ??14.3 | ??13.5 | ??41.8 |
| ??74 | ????Et | ????F | ????Cl | ??H | ??F | 4-ethanoyl-3-methyl-piperazinyl-1- | ??NH | ??100.2 | ??＞110.2 | ??＞100.2 |
| 10-hydroxycamptothecine | ??1.18 | ??ND | ??1.51 | |||||||
Above-mentioned experimental data shows: The compounds of this invention is that (A2780) and human liver cancer cell 7402 are that (Bel7402) has strong cytotoxicity to human oral epidermoid carcinoma cell (KB), Proliferation of Human Ovarian Cell 2780.Wherein, compound 4 and 14 cytotoxic activity are suitable with the positive control drug 10-hydroxycamptothecine.Because the screening of antineoplastic compound is that cytotoxic activity with compound embodies routinely,, can mix the preparation antitumor drug so The compounds of this invention has anti-tumor activity with pharmaceutical carrier.
Claims (10)
1, following general formula (I) compound
Wherein, R
1Represent alkyl H, replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement, aryl replacement or that do not have replacement;
R
3And R
5Identical or different, represent H, halogen, nitro, amino, itrile group, hydroxyl, alkoxyl group, alkyl replacement or that do not have replacement, aryl replacement or that do not have replacement, heterocyclic radical replacement or that do not have replacement, aryl replacement or that do not have replacement independently of one another;
R
6And R
7Identical or different, represent H, halogen, hydroxyl, alkyl, alkoxyl group, aralkoxy, heterocycle alkoxyl group, aryl, the aromatic heterocyclic that replaces or do not have replacement, nitro, amino independently of one another;
R
8Alkyl, nitro, amino, itrile group, hydroxyl, alkoxyl group, aralkoxy, the heterocycle alkoxyl group of representing H, halogen, alkyl, halogen to replace;
X represents O, S, NH;
Its formula of (I) does not comprise R
1=Me, R
3=H, R
5=H, R
6=H, R
7=H, R
8=H, the compound of X=NH.
2, according to the described general formula of claim 1 (I) compound, it is characterized in that: R
1, R
3, R
5, R
6, R
7Or R
8Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is a phenyl, or F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro or amino mono-substituted phenyl;
R
1, R
3, R
5, R
6, R
7Or R
8The alkyl of representative or the alkyl in the aryl refer to have the alkyl of the straight or branched of 1-10 carbon atom or the cycloalkyl of 3-10 carbon atom;
R
3, R
5, R
6, R
7Or R
8The alkoxyl group of representative or the alkyl in aralkoxy or the heterocycle alkoxyl group refer to have the alkyl of the straight or branched of 1-10 carbon atom;
R
1, R
3, R
5, R
6, R
7Or R
8Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one or more heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom;
R
1, R
3, R
5Middle alkyl, the aryl of replacement, the heterocyclic radical of replacement or the aryl of replacement that replaces, its substituting group is halogen, nitro, amino, hydroxyl, ether, carboxyl, ester group or amido; R
6, R
7Aromatic heterocyclic replacement or that do not have replacement of representative is F, Cl, Br, I, C
1～10Alkyl, C
1～10Acyl group, C
1～10Alkoxyl group, C
1～10Alkylamino, nitro, the amino ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle that replace or that do not have replacement.
3, according to the described general formula of claim 1 (I) compound, it is characterized in that: R
1, R
3, R
5, R
6, R
7The aryl of representative is the phenyl ring base, perhaps is F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro, the amino phenyl that replaces; Aromatic heterocyclic is to contain 1～3 heteroatomic fragrant heterocyclic radical, perhaps is F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group, nitro, amino replace contain 1～3 heteroatomic aromaticity heterocyclic radical.
4, according to the described general formula of claim 1 (I) compound, it is characterized in that: the amino NH of being
2, R
9NH, R
10R
11N; R wherein
9, R
10Or R
11Be the described alkyl of claim 2, perhaps R
10R
11Connect into ring-type.
5, according to the described general formula of claim 1 (I) compound, it is characterized in that: R
1, R
3, R
5, R
6, R
7Or R
8Aryl in aryl, aryl, aralkoxy or the aromatic heterocyclic of representative is C
1～6Alkyl, C
1～6The phenyl that alkoxyl group replaces;
R
1, R
3, R
5, R
6, R
7Or R
8The alkyl of representative or the alkyl in the aryl refer to have the alkyl of the straight or branched of 1-6 carbon atom or the cycloalkyl of 3-6 carbon atom;
R
3, R
5, R
6, R
7Or R
8The alkoxyl group of representative or the alkyl in aralkoxy or the heterocycle alkoxyl group refer to have the alkyl of the straight or branched of 1-6 carbon atom;
R
1, R
3, R
5, R
6, R
7Or R
8Heterocyclic radical in heterocyclic radical, heterocycle alkoxyl group or the aromatic heterocyclic of representative refers to contain one, two or three heteroatomic saturated heterocyclyl or fragrant heterocyclic radical optional from oxygen, nitrogen, sulphur atom;
R
6, R
7Aromatic heterocyclic replacement or that do not have replacement of representative is C
1～6Alkyl, C
1～6Acyl group, C
1～6Alkoxyl group, C
1～6Alkylamino, nitro, the amino ternary～hexa-member heterocycle that contains 1～3 nitrogen-atoms that replace or that do not have replacement.
6, according to the described general formula of one of claim 1-5 (I) compound, it is characterized in that: wherein alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl; Wherein cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl; Wherein halogen is F, Cl, Br or I.
7, according to the described general formula of claim 6 (I) compound, it is characterized in that: wherein alkyl is the alkyl with straight or branched of 1-4 carbon atom; Cycloalkyl is the cycloalkyl with 3～6 carbon atoms; Heterocyclic radical is saturated heterocyclic or the aromatic heterocycle that contains 3～6 atoms; Halogen is F and Cl atom; R
6, R
7The ternary that contains 1～4 nitrogen-atoms～eight yuan heterocycle of the replacement of representative is not replacement and the mono-substituted five yuan～hexa-member heterocycle that contains 1～2 nitrogen-atoms.
8, according to the described general formula of claim 7 (I) compound, it is characterized in that:
Wherein, R
1Expression H, C
1-C
4Side chain or the C that replaces of the alkyl of straight chain or cyclic alkane, halogen
1-C
4Branched-chain or straight-chain alkyl;
R
8Expression H, halogen, C
1-C
4The alkyl of side chain or straight chain;
Perhaps R
1With R
8Between warp-CH (CH
3) nCH
2O-is coupled to ring, and n is 1～3 in the formula;
R
3Representative is replaced by halogen, nitro, amino or H respectively or simultaneously on 5 and/or 6 of aromatic ring;
R
5And R
6Identical or different, H, amino or halogen are shown in representative independently of one another;
R
7Expression H, halogen, hydroxyl, C
1-C
4Branched-chain or straight-chain alkyl, amino or C
1-C
4The amino that replaces of branched-chain or straight-chain alkyl, C
1-C
4Branched-chain or straight-chain alkyl replace or do not have a replacement contain five yuan of 1-2 nitrogen-atoms or hexa-member heterocycle, C
1-C
4Acyl substituted or do not have five yuan or the hexa-member heterocycle containing 1-2 nitrogen-atoms of replacement;
X represents O, S, NH.
9, described according to Claim 8 general formula (I) compound is characterized in that:
Wherein, R
1Expression H, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, fluoro ethyl;
R
8Expression H, Cl, F, methyl, second third, propyl group, sec.-propyl;
Perhaps R
1With R
8Between warp-CH (CH
3) nCH
2O-is coupled to ring, and n is 1～2 in the formula;
R
3Representative is replaced by chlorine, nitro, amino or H on 5 and/or 6 of aromatic rings at the same time or separately;
R
5And R
6Identical or different, H, amino or fluorine are shown in representative independently of one another;
R
7Represent H, Cl, hydroxyl, methyl, second third; propyl group, sec.-propyl, amino, dimethylamino; diethylamino, piperazinyl is gone up the piperazinyl that is replaced by methyl, ethyl or ethanoyl for 3,4 or 5, perhaps 3,5 piperazinyls that replaced by methyl, ethyl and/or ethanoyl.
10, any one application of compound in the medicine of preparation treatment tumour in the claim 1～9.
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| CNB031322964A CN1191252C (en) | 2003-08-11 | 2003-08-11 | 3-position substituted quinolone derivativers and its use in pharmacy |
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