CN102101859A - Quinolone carboxylic acid derivatives and application thereof - Google Patents
Quinolone carboxylic acid derivatives and application thereof Download PDFInfo
- Publication number
- CN102101859A CN102101859A CN2009102139056A CN200910213905A CN102101859A CN 102101859 A CN102101859 A CN 102101859A CN 2009102139056 A CN2009102139056 A CN 2009102139056A CN 200910213905 A CN200910213905 A CN 200910213905A CN 102101859 A CN102101859 A CN 102101859A
- Authority
- CN
- China
- Prior art keywords
- carboxylic acid
- naphthyridines
- cyclopropyl
- dihydro
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 150000003053 piperidines Chemical group 0.000 claims abstract description 31
- 238000002360 preparation method Methods 0.000 claims description 40
- -1 substituted-phenyl Chemical group 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 16
- 230000000844 anti-bacterial effect Effects 0.000 claims description 12
- 150000007660 quinolones Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 150000003233 pyrroles Chemical class 0.000 claims description 6
- 229940088710 antibiotic agent Drugs 0.000 claims description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001409 amidines Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 150000001345 alkine derivatives Chemical class 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000004475 Arginine Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical class NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical class OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical class CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Chemical class OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 150000002357 guanidines Chemical class 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Chemical class OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229930182817 methionine Chemical class 0.000 claims description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 2
- 239000011707 mineral Substances 0.000 claims 2
- 150000007530 organic bases Chemical group 0.000 claims 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 24
- 241000894006 Bacteria Species 0.000 abstract description 6
- 208000035473 Communicable disease Diseases 0.000 abstract description 2
- 241000192125 Firmicutes Species 0.000 abstract 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 87
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 53
- 238000006243 chemical reaction Methods 0.000 description 36
- 239000007787 solid Substances 0.000 description 34
- 229940125898 compound 5 Drugs 0.000 description 31
- 239000000725 suspension Substances 0.000 description 31
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 239000005457 ice water Substances 0.000 description 24
- 229960003405 ciprofloxacin Drugs 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 241000191967 Staphylococcus aureus Species 0.000 description 9
- 230000000845 anti-microbial effect Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
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- 230000036457 multidrug resistance Effects 0.000 description 7
- 230000001580 bacterial effect Effects 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 5
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
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- 229940125961 compound 24 Drugs 0.000 description 3
- 229940125846 compound 25 Drugs 0.000 description 3
- 229940127204 compound 29 Drugs 0.000 description 3
- 229940125877 compound 31 Drugs 0.000 description 3
- 229940032049 enterococcus faecalis Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
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- 229940125851 compound 27 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 2
- 229960000210 nalidixic acid Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- 0 *c(nc(c1c2)N(C3CC3)C=C(C(O)=O)C1=O)c2F Chemical compound *c(nc(c1c2)N(C3CC3)C=C(C(O)=O)C1=O)c2F 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000009631 Broth culture Methods 0.000 description 1
- FRRFBIPLCUKOIQ-UHFFFAOYSA-N C=C(c1c2)C(C(O)=O)=CN(C3CC3)c1nc(N(CC1C3)C3CS1=O)c2F Chemical compound C=C(c1c2)C(C(O)=O)=CN(C3CC3)c1nc(N(CC1C3)C3CS1=O)c2F FRRFBIPLCUKOIQ-UHFFFAOYSA-N 0.000 description 1
- ZMJGMRJRXZHVNZ-UHFFFAOYSA-N C=CC[O-][NH+]=Cc1c[n](C(CC2)CCN2c(nc(c2c3)N(C4CC4)C=C(C(O)=O)C2=O)c3F)nn1 Chemical compound C=CC[O-][NH+]=Cc1c[n](C(CC2)CCN2c(nc(c2c3)N(C4CC4)C=C(C(O)=O)C2=O)c3F)nn1 ZMJGMRJRXZHVNZ-UHFFFAOYSA-N 0.000 description 1
- NEFQCHZPFXOUIM-KKSFZXQISA-N COC([C@H](C[C@@H](C1)[n]2nnc(-c3ccccc3)c2)N1c(nc(c1c2)N(C3CC3)C=C(C(O)=O)C1=O)c2F)=O Chemical compound COC([C@H](C[C@@H](C1)[n]2nnc(-c3ccccc3)c2)N1c(nc(c1c2)N(C3CC3)C=C(C(O)=O)C1=O)c2F)=O NEFQCHZPFXOUIM-KKSFZXQISA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 241000943303 Enterococcus faecalis ATCC 29212 Species 0.000 description 1
- AIJTTZAVMXIJGM-UHFFFAOYSA-N Grepafloxacin Chemical compound C1CNC(C)CN1C(C(=C1C)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 AIJTTZAVMXIJGM-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241000751182 Staphylococcus epidermidis ATCC 12228 Species 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- DIOIOSKKIYDRIQ-UHFFFAOYSA-N ciprofloxacin hydrochloride Chemical compound Cl.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 DIOIOSKKIYDRIQ-UHFFFAOYSA-N 0.000 description 1
- 229960001229 ciprofloxacin hydrochloride Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960000642 grepafloxacin Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FQJRZOYTUCCBQR-UHFFFAOYSA-N tert-butyl 2-methylheptanoate Chemical compound CCCCCC(C)C(=O)OC(C)(C)C FQJRZOYTUCCBQR-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229960001572 vancomycin hydrochloride Drugs 0.000 description 1
- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 description 1
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses quinolone carboxylic acid compounds of which the C7 positions are substituted by pyrrolidine derivatives and piperidine derivatives. The activity of the compounds on various strains is tested, and the compounds are proved to have activity on the various strains, and can be used for treating infectious diseases caused by Gram-negative bacteria and Gram-positive bacteria.
Description
Technical field
The present invention relates to pharmaceutical chemistry and chemotherapy field, be specifically related to the synthetic of quinlone compounds and the application in preparation treatment infectious disease medicament thereof.
Background technology
Quinlone is the important complete synthesis microbiotic of a class, because its good pharmacodynamics, pharmacokinetics character, and excellent anti-microbial property and less side effect and make its widespread use in clinical.But along with the antibiotic widespread use of quinlone class, the a large amount of medicine of anti-quinlone bacterial strains appears, comprise multidrug resistance bacterial strain such as methicillin resistant staphylococcus aureus (MRSA), methicillin resistant staphylococcus epidermidis (MRSE), penicillin-fast streptococcus pneumoniae (PRSP), the faecalis of vancomycin resistance (Mitscher such as (VRE), L.A. etc., Chem.Rev.2005,105,559) etc.
Although few side effects in the antibiotic clinical application of quinlone class, but the phenomenon of having withdrawn from market because serious adverse drug reaction has taken place is arranged.For example, Sparfloxacin and grepafloxacin are exactly the untoward reaction that is called " prolongation of QT gap " clinically, cause patient heart rate uneven, and have withdrawn from market (Patmore, L. etc., Eur.J.Pharmacol.2000,406,449).Recently, Murphy, people's such as S.T. result of study finds that " prolongation of QT gap " side effect of quinlone class medicine mainly is subjected to the influence of two factors, the one, quinlone parent nucleus fat-soluble is substituent alkalescence on the nitrogen heterocyclic of C7 position in addition.They find that the parent nucleus of quinlone is fat-soluble strong more, and substituent alkalescence is strong more on the nitrogen heterocyclic of C7 position, cause this side effect (Murphy, S.T. etc., Bioorg.Med.Chem.Lett.2007,17,2150) easily more.
Do not produce the novel quinlone medicine of this class side effect in order to seek good effect, we have adopted fat-soluble relatively poor parent nucleus Nalidixic Acid, designed pyrrole derivative that two groups of non-alkalescence replace and piperidine derivative substituting group, safer to develop, as to have broad spectrum antibiotic activity and good pharmacokinetic property new quinlone microbiotic as the C7 position.Thereby this bad side reaction appears in the quinlone of having avoided some antibacterial effect excellences.
Summary of the invention
One of purpose of the present invention provides novel quinlone compounds and its esters with anti-microbial activity.
Another object of the present invention provides described quinlone compounds and the application of its esters in the preparation antibacterials.
The The compounds of this invention molecular structure is shown in following general formula (I):
Wherein, R is the substituted nitrogen-containing heterocyclic structural unit, comprises group shown in following general formula (Ia) or general formula (Ib) or the general formula (Ic):
General formula (Ia) group is as shown below:
Wherein: R
1Be selected from one of following: hydrogen, C
1-8Direct-connected or the branched-chain alkyl that replaces, C
1-81,2 of carbalkoxy or replacement, the 3-triazol radical.R
2Be selected from one of following: hydrogen or hydroxyl.R
3Be selected from one of following: hydrogen, C
1-8Direct-connected or the branched-chain alkyl that replaces, C
1-81,2 of carbalkoxy or replacement, the 3-triazol radical.
General formula (Ib) group is as shown below:
Wherein X is S, SO, SO
2Or NCOOC (CH
3)
3
General formula (Ic) group is as shown below:
Wherein, R
1Be selected from one of following: substituted-phenyl, methylol, amine methyl, carbalkoxy, amide group, formyl radical, C
1-8The methylol that alkyl replaces, oximido, C
1-8The oximido that alkyl replaces.
Formula of of the present invention (Ia) (Ib) He (Ic) can have one or more unsymmetrical carbons, and its possible optical isomer can be optically active body or racemic modification form.By standard technique of organic chemistry well known in the art, as synthetic from chiral raw material or split by racemic modification and to obtain corresponding optically active substance.
The quinolone derivative of prior art known portions general formula (I) structure can exist with solvate or non-solvent compound form, for example hydrate forms exists, and the present invention also comprises the solvate of the quinolone derivative of general formula (I) structure with anti-microbial activity.
The present invention also comprises the above-claimed cpd pharmacy acceptable salt, and the pharmaceutical salts of suitable quinolone derivative of the present invention reaches and guanidine C for ammonia salt
1-8Alkyl substituted guanidines, amidine, C
1-8The alkyl substituted amidine, Methionin, arginine, the salt that Histidine etc. form.
Shown in the synthetic following reaction formula of The compounds of this invention:
Specifically, The compounds of this invention is the raw material 1 that can get from commercialization, in the presence of diacetyl oxide, obtain condensation product 2 with the triethyl orthoformate reaction, 2 obtain substitution product 3 with cyclopropylamine reaction, 3 exist ShiShimonoseki to encircle at NaH obtains product 4,4 in concentrated hydrochloric acid hydrolysis obtain Nalidixic Acid 5,5 and obtain target quinlone 6 with synthetic heterocyclic amine generation nucleophilic substitution reaction.
The compounds of this invention and salt thereof also can in an embodiment, also have been enumerated some representative methods by becoming known for preparing the method preparation of related compound, wherein, except that other explanation, n, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, X has any implication that above defines for formula (I) quinolone derivative, has also described the preparation of raw material in an embodiment, and perhaps the similar approach by prior art obtains necessary raw material.
Embodiment
Below in conjunction with embodiment the present invention is described further, but does not limit the present invention.
Embodiment one: 1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-(methoxycarbonyl) pyrroles-1-)-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 7);
Compound 7
The first step: 7-chloro-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 5);
Compound 5
In an exsiccant round-bottomed flask, add compound 1 (4.000g, 14.28mmol), add triethyl orthoformate (4.232g successively in room temperature, 23.56mmol) and diacetyl oxide (4.374g, 42.84mmol), mixture heating up to 130 ℃, reaction 20h, reaction is finished, and the mixture concentrating under reduced pressure gets oily matter.Gained oily matter is dissolved in (30ml) in the ethanol, at room temperature add cyclopropylamine (1.06g, 18.56mmol), stirring at room 2h, concentrating under reduced pressure, faint yellow solid.This solid is dissolved in the exsiccant tetrahydrofuran (THF) (40ml), under ice-water bath, slowly join NaH (0.589g, 14.72mmol) tetrahydrofuran (THF) (20ml) suspension in, stirring at room 2h afterwards, the solvent concentrating under reduced pressure adds chloroform (80ml) in the residue, saturated sodium bicarbonate solution (80ml), separatory, water merges the anhydrous MgSO of organic phase with chloroform (80ml) extraction
4Drying is filtered, and concentrates to obtain compound 4 (4.000g, three step productive rates 90%).Compound 4 (1.000g 3.22mmol) is dissolved in tetrahydrofuran (THF) (9ml), at room temperature add concentrated hydrochloric acid (3.1ml, 37.00mmol), the 4h that refluxes afterwards, reaction is finished.The solvent concentrating under reduced pressure adds H in the residue
2O (20ml), solid filtering is used ethanol (10ml) washing successively, ether (10ml) washing, vacuum-drying, the crude product that obtains recrystallization in chloroform, obtain pure product compound 5 (0.727g, 2.57mmol).Productive rate 80%.
1H?NMR(400MHz，CDCl
3)δ13.98(s，1H)，8.93(s，1H)8.48(d，J＝7.2Hz，1H)，3.85-3.79(m，1H)，1.43-1.38(m，2H)，1.17-1.14(m，2H).
13C?NMR(100MHz，CDCl
3)δ177.8，165.4，154.4，151.7，148.8，146.0，144.8，144.6，122.3，122.1，110.0，35.4，7.8；LC-ESIMS?for?C
12H
8ClFN
2O
3[M+H
+]calcd?282.0?found?283.0(M+H)。
Second step: 1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-(methoxycarbonyl) pyrroles-1-)-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 7)
(0.100g 0.354mmol) is added in the dry round-bottomed flask that contains the 3ml acetonitrile and becomes suspension, adds compound (2S again with compound 5,4R)-2-carboxylate methyl ester-4-hydroxyl pyrroles hydrochloride (0.097g, 0.531mmol) and triethylamine (0.144g, 1.416mmol), 80 ℃ of stirring reaction 4h, in ice-water bath, cool off 1h, add the 10ml ether, leave standstill filtration, the gained solid is successively used ethanol (3ml), ether (3ml) washing, vacuum-drying.Recrystallization gets compound 7 (0.100g, 0.256mmol, 72%) in the crude product chloroform.
1H?NMR(400MHz，CDCl
3)δ15.24(s，1H)，8.50(s，1H)，7.90(d，J＝11.6Hz，1H)，5.01(s，1H)，4.68(s，1H)，4.16(s，2H)，3.71(s，3H)，3.52(s，2H)，2.56(s，1H)，2.18(s，1H)，1.32-1.21(m，2H)，1.02(s，2H)；
13C?NMR(100MHz，CDCl
3)δ176.7，172.5，167.3，149.3，149.2，146.9，145.8，112.4，108.1，60.4，57.8，57.7，52.4，34.9，21.1，14.2，7.5，7.2；LC-ESIMS?forC
18H
18FN
3O
6[M+H
+]calcd?391.1?found?392.0(M+H).
Embodiment two: 1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-(methylol) pyrroles-1-)-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 8);
Compound 8
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), acetonitrile 3ml gets suspension, add again compound (3R, 5S)-3-hydroxyl-5-methylol pyrroles hydrochloride (0.137g, 0.890mmol) and triethylamine (0.144g, 1.416mmol), 80 ℃ of reaction 6h cool off 1h in the ice-water bath, leave standstill filtration, solid washs with ethanol (3ml), ether (3ml) washing, vacuum-drying, recrystallization obtains compound 8 (0.078g, 0.215mmol, 61%) in chloroform.
1H?NMR(400MHz，DMSO-d
6)δ15.40(s，1H)，8.57(s，1H)，7.99(d，J＝12.8Hz，1H)，5.08(s，1H)，4.79(s，1H)，4.57(s，1H)，4.47(s，1H)，3.88(s，1H)，3.69(s，3H)，3.07(d，J＝6.8Hz，1H)，2.19(d，J＝4.4Hz，1H)，1.97(s，1H)，1.18(d，J＝6.8Hz，4H)；
13C?NMR(100MHz，DMSO-d
6)δ176.2，165.7，147.3，147.1，146.5，144.7，117.6，117.4，110.8，107.3，60.2，57.7，45.5，34.9，8.5，7.1，6.5；LC-ESIMS?forC
17H
18FN
3O
5[M+H
+]calcd?363.1?found?364.0(M+H).
Embodiment three: 1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-((S)-1-hydroxyethyl) pyrroles-1-)-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 9);
Compound 9
In the exsiccant round-bottomed flask, add compound 5 (0.100g, 0.354mmol), the 3ml acetonitrile gets suspension, add again compound (3R, 5S)-5-((S)-1-hydroxyethyl)-3-hydroxyl pyrroles trifluoroacetate (0.055g, 0.419mmol) and triethylamine (0.088g, 0.873mmol), 80 ℃ of reaction 22h are cooled to room temperature, add entry (10ml).Slowly add dilute hydrochloric acid (2mol/L) and regulate pH to 2～3, solid filtering is successively used ethanol (5ml), ether (5ml) washing, and vacuum-drying, recrystallization obtains compound 9 (0.074g, 0.198mmol, 56%) in the chloroform.
1H?NMR(400MHz，DMSO-d
6)δ15.43(s，1H)，8.55(s，1H)，7.96(d，J＝11.6Hz，1H)，5.04(s，1H)，4.43(s，2H)，3.79(s，2H)，3.66(s，1H)，3.15(s，2H)，2.20(s，1H)，1.81(s，1H)，1.14(s，4H)，1.05(s，3H)；
13C?NMR(100MHz，DMSO-d
6)δ176.2，166.0，147.2，146.6，144.9，117.5，110.6，107.3，79.1，69.0，63.9，58.3，48.6，35.0，30.7，19.8，7.2，6.4；LC-ESIMS?for?C
18H
20FN
3O
5[M+H
+]calcd?377.1?found?378.0(M+H).
Embodiment four: 1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-((R)-1-hydroxyethyl) pyrroles-1-)-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 10);
Compound 10
In the exsiccant round-bottomed flask, add compound 5 (0.092g, 0.325mmol), the 3ml acetonitrile becomes suspension, adds compound (3R again, 5S)-5-((R)-1-hydroxyethyl)-3-hydroxyl pyrroles trifluoroacetate (0.064g, 0.488mmol) and triethylamine (0.166g, 1.626mmol), at 90 ℃ of reaction 20h, be cooled to room temperature, concentrate, add entry (15ml) in the system, filter, slowly add dilute hydrochloric acid (2mol/L) in the filtrate and regulate pH to 4～5, sedimentation and filtration, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying, recrystallization obtains compound 10 (0.051g, 0.135mmol, 42%) in chloroform.
1H?NMR(400MHz，DMSO-d
6)δ15.43(s，1H)，8.60(s，1H)，8.00(d，J＝12.8Hz，1H)，5.11(d，J＝2.8Hz，1H)，4.86(s，1H)，4.77(s，1H)，4.46(s，2H)，3.90(dd，J＝3.2，11.6Hz，1H)，3.81-3.73(m，2H)，2.19-2.11(m，1H)，1.96(s，1H)，1.27(t，J＝4.0Hz，2H)，1.20-1.17(m，1H)，1.10(s，1H)，1.00(d，J＝6.4Hz，3H)；
13C?NMR(100MHz，DMSO-d
6)δ176.2，165.9，165.8，149.6，149.5，147.1，146.6，146.5，117.7，117.5，111.1，111.0，107.3，62.5，58.1，58.3，35.0，7.0，6.5；LC-ESIMS?for?C
18H
20FN
3O
5[M+H
+]calcd?377.1?found?378.0(M+H).
Embodiment five: 1-cyclopropyl-7-((3R, 4R)-3, the 4-dihydroxy-pyrrolidine-1-)-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 11);
Compound 11
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add again compound (3R, 4R)-3,4-dihydroxy-pyrrolidine formate (0.143g, 0.956mmol) and triethylamine (0.215g, 2.124mmol), 90 ℃ of reaction 13h, be cooled to room temperature, sedimentation and filtration, filtrate decompression concentrates, add entry (5ml), filter out solid, filtrate is through the Zeo-karb purifying, obtain compound 11 (0.098g, 0.255mmol, 72%).
1H?NMR(400MHz，CD
3OD)δ7.35(d，J＝16.0Hz，1H)，7.21(s，1H)，4.47(d，J＝6.0Hz，1H)，4.03(s，1H)，3.13(d，J＝5.6Hz，2H)，1.86(s，4H)，1.59(d，J＝6.4Hz，2H)，1.24(s，4H)；
13C?NMR(100MHz，CD
3OD)δ177.2，162.4，139.9，130.3，130.1，129.7，128.7，127.3，79.7，79.6，79.4，79.0，38.4，17.8，9.5；LC-ESIMSfor?C
16H
16FN
3O
5[M+H
+]calcd?349.1?found?350.0(M+H).
Embodiment six: and 7-(5-(tertbutyloxycarbonyl)-2,5-diazabicyclo [2.2.1] heptane-2-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 12);
Compound 12
Adding compound 5 in the exsiccant round-bottomed flask (0.060g, 0.210mmol), the 2ml acetonitrile becomes suspension, add compound 2 again, and 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (0.050g, 0.252mmol) and triethylamine (0.053g, 0.525mmol), 80 ℃ of reaction 22h cool off in the ice-water bath, filter, solid is successively used ethanol (3ml), ether (3ml) washing, vacuum-drying, obtain compound 12 (0.040g, 0.090mmol, 43%).
1H?NMR(400MHz，CDCl
3)δ15.06(s，1H)，8.67(s，1H)，7.99(d，J＝12.0Hz，1H)，5.17(d，J＝6.0Hz，1H)，4.67(d，1H)，3.87-3.78(m，2H)，3.61-3.51(m，3H)，2.05(s，2H)，1.47(d，9H)，1.25(d，J＝6.8Hz，2H)，1.07(s，2H)；
13C?NMR(100MHz，CDCl
3)δ176.0，165.9，153.2，153.1，146.4，145.2，117.7，111.3，107.8，79.4，79.2，57.8，56.6，56.5，56.4，33.7，27.5，6.4；LC-ESIMS?for?C
22H
25FN
4O
5[M+H
+]calcd?444.2found?443.2(M+H).
Embodiment seven: and 7-(2-sulphur-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 13);
Compound 13
(0.100g 0.354mmol), becomes suspension in the 3ml acetonitrile to add compound 5 in the exsiccant round-bottomed flask, add again compound 2-sulphur-5-azabicyclo [2.2.1] heptane (0.061g, 0.531mmol) and triethylamine (0.090g, 0.885mmol), at 80 ℃ of reaction 4h, cool off in ice-water bath, filter, solid ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 13 (0.054g, 0.149mmol, 42%).
1H?NMR(400MHz，CDCl
3)：δ15.10(s，1H)，8.68(s，1H)，8.00(d，J＝12.4Hz，1H)，5.29(s，1H)，4.12(s，1H)，4.06(s，1H)，3.77(s，1H)，3.61(m，1H)，3.36(s，1H)，3.21(s，1H)，2.39(d，J＝8.4Hz，1H)，2.10(d，J＝10.0Hz，1H)，1.25(d，J＝6.4Hz，2H)，1.09(s，1H)，1.07(d，J＝3.2Hz，1H).
13C?NMR(100MHz，CDCl
3)δ177.0，166.9，147.5，146.2，118.6，118.4，112.1，108.8，61.7，61.6，59.9，45.8，34.7，7.4；LC-ESIMS?for?C
17H
16FN
3O
3S[M+H
+]calculated?361.1?found?362.0(M+H).
Embodiment eight: and 7-(2-(S)-sulfoxide-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 14);
Compound 14
Adding compound 5 in the exsiccant round-bottomed flask (0.056g, 0.198mmol), the 2ml acetonitrile becomes suspension, add again compound 2-(S)-sulfoxide-5-azabicyclo [2.2.1] heptane (0.052g, 0.396mmol) and triethylamine (0.060g, 0.594mmol), at 80 ℃ of reaction 12h, cool off in ice-water bath, filter, solid ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 14 (0.037g, 0.098mmol, 50%).
1H?NMR(400MHz，CDCl
3)：δ14.83(s，1H)，8.74(s，1H)，8.10(d，J＝12.4Hz，1H)，5.35(s，1H)，4.08(d，J＝10.8Hz，1H)，3.97(d，J＝4.0Hz，1H)，3.70(d，J＝12.8Hz，1H)，3.60(m，1H)，3.40(d，J＝11.6Hz，1H)，2.88(d，J＝12.0Hz，1H)，2.62(d，J＝12.4Hz，1H)，2.50(d，J＝11.6Hz，1H)，1.28(d，J＝7.6Hz，2H)，1.26(s，2H).LC-ESIMS?forC
17H
16FN
3O
4S[M+H
+]calculated?377.1?found?378.0(M+H).
Embodiment nine: and 7-(2-(R)-sulfoxide-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 15);
Compound 15
Adding compound 5 in the exsiccant round-bottomed flask (0.060g, 0.212mmol), the 2ml acetonitrile becomes suspension, add again compound 2-(R)-sulfoxide-5-azabicyclo [2.2.1] heptane (0.074g, 0.566mmol) and triethylamine (0.086g, 0.849mmol), at 80 ℃ of reaction 7h, cool off in ice-water bath, filter, solid is successively used ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 15 (0.076g, 0.201mmol, 95%).
1H?NMR(400MHz，CDCl
3)：δ14.89(s，1H)，8.66(s，1H)，8.03(d，J＝12.4Hz，1H)，5.28(s，1H)，4.66(d，J＝8.8Hz，1H)，4.02(t，J＝12.8Hz，1H)，3.64(d，J＝12.8Hz，1H)，3.53(s，1H)，3.21(d，J＝12.4Hz，1H)，2.55(d，J＝13.2Hz，1H)，2.45(t，J＝12.8Hz，1H)，1.91(d，J＝11.6Hz，1H)，1.19(s，4H).LC-ESIMS?for?C
17H
16FN
3O
4S[M+H
+]calculated?377.1?found?378.0(M+H).
Embodiment ten: and 7-(2-sulfone-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 16);
Compound 16
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add again compound 2-sulfone-5-azabicyclo [2.2.1] heptane (0.139g, 0.531mmol) and triethylamine (0.179g, 1.770mmol), 60 ℃ of reaction 12h cool off in ice-water bath, filter, solid is successively used ethanol (5ml) washing, ether (5ml) washing, vacuum-drying obtains compound 16 (0.127g, 0.322mmol, 91%).
1H?NMR(400MHz，DMSO-d
6)：δ15.23(s，1H)，8.63(s，1H)，8.14(d，J＝12.0Hz，1H)，5.29(s，1H)，4.17(s，1H)，4.11(d，J＝8.8Hz，1H)，3.71(s，1H)，3.47(s，1H)，3.09(q，J＝6.4Hz，1H)，2.59(d，J＝7.6Hz，1H)，2.34(s，1H)，1.25(d，J＝14.4Hz，1H)，1.18(t，J＝7.2Hz，2H)，1.11(d，J＝7.2Hz，2H).LC-ESIMS?for?C
17H
16FN
3O
5S[M+H
+]calculated?393.1?found?394.1(M+H).
Embodiment 11: (S)-1-cyclopropyl-6-fluoro-7-(2-(methylol) pyrroles-1-)-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 17);
Compound 17
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add again compound (S)-2-methylol pyrroles (0.054g, 0.531mmol) and triethylamine (0.179g, 1.770mmol), 80 ℃ of reaction 10h cool off in ice-water bath, filter, solid is successively used ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 17 (0.083g, 0.237mmol, 67%).
1H?NMR(400MHz，DMSO-d
6)：δ15.35(s，1H)，8.52(s，1H)，7.88(d，J＝13.2Hz，1H)，4.85(s，1H)，4.47(s，1H)，3.88(s，1H)，3.76-3.66(m，3H)，3.49(s，1H)，2.08(d，J＝5.6Hz，2H)，1.96(s，2H)，1.20(d，J＝6.8Hz，2H)，1.11(t，J＝5.2Hz，1H)，1.03(d，J＝9.2Hz，1H)；
13C?NMR(100MHz，DMSO-d
6)δ176.1，165.8，148.5，148.4，147.2，147.1，146.3，144.6，117.5，117.2，110.5，110.4，107.3，61.3，49.2，49.1，34.9，26.6，23.6，6.9，6.5；LC-ESIMS?forC
17H
18FN
3O
4[M+H
+]calculated?347.1?found?348.0(M+H).
Embodiment 12: (S)-1-cyclopropyl-6-fluoro-4-carbonyl-7-(2-((4-phenyl-1H-1,2, the methyl of 3-triazole-1-)) pyrroles-1-)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 18);
Compound 18
(0.100g 0.354mmol), becomes suspension in the 3ml acetonitrile to add compound 5 in the exsiccant round-bottomed flask, add compound 2-((4-phenyl-1H-1,2, the methyl of 3-triazole-1-)) pyrroles's trifluoroacetate (0.287g again, 0.885mmol) and triethylamine (0.215g, 2.124mmol), 70 ℃ of reaction 10h, cool off in the ice-water bath, filter, solid ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 18 (0.114g, 0.240mmol, 68%).
1H?NMR(400MHz，CDCl
3)：δ14.96(s，1H)，8.74(s，1H)，8.14-8.11(d，1H)，7.81(d，J＝7.6Hz，2H)，7.73(s，1H)，7.44(t，J＝7.2Hz，2H)，7.37(d，J＝7.2Hz，1H)，5.05(s，1H)，4.94(s，1H)，4.55(s，1H)，4.00(s，1H)，3.84(s，1H)，3.78(s，1H)，2.07(s，2H)，2.02(d，J＝10.8Hz，1H)，1.86(s，1H)，1.38(d，J＝14.4Hz，2H)，1.10(s，2H)；
13C?NMR(100MHz，DMSO-d
6)δ176.3，166.2，161.9，146.3，130.6，128.8，127.8，125.1，122.6，118.8，118.2，99.5，90.7，84.5，64.9，62.8，59.5，49.2，28.1，26.4，24.5，6.8；LC-ESIMS?forC
25H
23FN
6O
3[M+H
+]calculated?474.2?found?475.1(M+H).
Embodiment 13: (S)-1-cyclopropyl-6-fluoro-7-(2-((4-(methylol)-1H-1,2, the methyl of 3-triazole-1-)) pyrroles-1-)-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 19);
Compound 19
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 2-((4-methylol-1H-1,2, the methyl of 3-triazole-1-)) pyrroles's trifluoroacetate (0.247g again, 0.885mmol) and triethylamine (0.215g, 2.124mmol), 70 ℃ of reaction 72h, cool off in ice-water bath, filter, solid is successively used ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 19 (0.065g, 0.152mmol, 43%).
1H?NMR(400MHz，CDCl
3)：δ14.97(s，1H)，8.73(s，1H)，8.11(d，J＝12.4Hz，1H)，7.53(s，1H)，4.99(s，1H)，4.88(d，J＝14.0Hz，1H)，4.81(s，2H)，4.51-4.46(m，1H)，4.01-3.96(m，1H)，3.86-3.82(m，1H)，3.79-3.74(m，1H)，2.08-1.99(m，3H)，1.87-1.80(m，1H)，1.40-1.30(m，2H)，1.25(s，1H)，1.09(d，J＝4.0Hz，2H)；
13C?NMR(100MHz，DMSO-d
6)δ176.3，165.8，148.0，146.7，144.8，123.8，118.2，111.3，107.5，79.1，59.3，54.9，49.1，49.0，35.1，6.9，6.8；LC-ESIMS?for?C
20H
21FN
6O
4[M+H
+]calculated428.2?found?429.1(M+H).
Embodiment 14: 1-cyclopropyl-6-fluoro-7-((2S, 4S)-2-(methoxycarbonyl)-4-(4-phenyl-1H-1,2, the pyrroles of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 20);
In the exsiccant round-bottomed flask, add compound 5 (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add again compound (2S, 4S)-2-(methoxycarbonyl)-4-(4-phenyl-1H-1,2, pyrroles's trifluoroacetate (the 0.205g of 3-triazole-1-), 0.531mmol) and triethylamine (0.143g, 1.416mmol), 70 ℃ of reaction 12h, cool off in ice-water bath, filter, solid is successively used ethanol (5ml), ether (5ml) washing, vacuum-drying, obtain compound 20 (0.115g, 0.222mmol, 63%).
1H?NMR(400MHz，DMSO-d
6)：δ15.17(s，1H)，8.84(s，1H)，8.60(s，1H)，8.14(d，J＝9.6Hz，1H)，7.85(d，J＝4.4Hz，1H)，7.46(s，2H)，7.34(s，1H)，5.48(s，1H)，5.17(s，1H)，4.64(s，1H)，4.57(s，1H)，3.55(s，3H)，3.10(s，2H)，2.94(s，1H)，1.18(s，2H)，1.05(s，2H)；
13C?NMR(100MHz，DMSO-d
6)δ176.3，171.0，165.6，148.1，147.1，146.6，144.5，130.5，128.8，127.8，125.0，120.8，118.5，111.8，107.6，59.8，58.0，53.5，52.2，45.6，34.9，8.5，6.7；LC-ESIMS?for?C
26H
23FN
6O
5[M+H
+]calculated?518.2?found519.1(M+H).
Embodiment 15: 1-cyclopropyl-6-fluoro-7-((2S, 4S)-4-(4-(methylol)-1H-1,2, the 3-triazole-1-)-2-(methoxycarbonyl) pyrroles-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 21);
Compound 21
In the exsiccant round-bottomed flask, add compound 5 (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound (2S again, 4S)-4-(4-(methylol)-1H-1,2, and 3-triazole-1-)-2-(methoxycarbonyl) pyrroles trifluoroacetate (0.181g, 0.531mmol) and triethylamine (0.143g, 1.416mmol), at 80 ℃ of reaction 7h, cool off in room temperature, add chloroform (30ml), slowly drip dilute hydrochloric acid (0.1M) and regulate pH to 2～3, separatory, organic phase is washed with saturated nacl aqueous solution, MgSO
4Drying concentrates, gained solid recrystallization in methylene dichloride/normal hexane, and solid filtering, vacuum-drying obtains compound 21 (0.139g, 0.294mmol, 83%).
1H?NMR(400MHz，CDCl
3)：δ14.90(s，1H)，8.58(s，1H)，7.99(d，J＝12.0Hz，1H)，7.76(s，1H)，5.42-5.36(m，1H)，5.14(t，J＝7.2Hz，1H)，4.81(s，2H)，4.71-4.66(m，1H)，4.50(dd，J＝4.8，11.6Hz，1H)，3.68(s，3H)，3.54(s，1H)，3.18-3.10(m，1H)，2.99-2.93(m，1H)，1.91(s，1H)，1.26(s，2H)，1.08-1.03(m，2H)；
13C?NMR(100MHz，CDCl
3)δ175.7，170.3，165.7，147.5，147.4，146.7，145.7，145.4，120.3，118.0，111.8，107.4，59.1，55.3，53.1，51.8，33.9，28.7，13.1，6.3；LC-ESIMS?for?C
21H
21FN
6O
6[M+H
+]calculated?472.2?found?473.1(M+H).
Embodiment 16: and 1-cyclopropyl-6-fluoro-4-carbonyl-7-(4-(4-phenyl-1H-1,2, the piperidines of 3-triazole-1-)-1-)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 22);
Compound 22
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-phenyl-1H-1,2, the piperidines trifluoroacetate (0.182g of 3-triazole-1-) again, 0.531mmol) and triethylamine (0.143g, 1.416mmol), at 60 ℃ of reaction 17h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 22 (0.137g, 0.289mmol, 82%).
1H?NMR(400MHz，CDCl
3)：δ14.89(s，1H)，8.70(s，1H)，8.10(d，J＝11.6Hz，1H)，7.89(s，1H)，7.82(d，J＝6.4Hz，2H)，7.42(t，J＝6.0Hz，2H)，7.34(t，J＝7.2Hz，1H)，4.90(s，1H)，4.82(d，J＝10.8Hz，2H)，3.66(s，1H)，3.45(s，2H)，2.44(s，2H)，2.35(s，2H)，1.29(s，2H)，1.12(s，2H)；
13C?NMR(100MHz，CDCl
3)：δ177.1，166.6，148.8，147.9，146.8，146.7，130.5，128.9，128.3，125.7，120.5，117.7，113.8，108.9，57.8，46.1，46.1，34.8，32.4，29.7，7.5；LC-ESIMS?for?C
25H
23FN
6O
3[M+H
+]calcd?474.2?found?475.1(M+H).
Embodiment 17: and 1-cyclopropyl-6-fluoro-7-(4-(4-(methylol)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 23);
Compound 23
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-(methylol)-1H-1,2, the piperidines trifluoroacetate (0.157g of 3-triazole-1-) again, 0.531mmol) and triethylamine (0.143g, 1.416mmol), at 80 ℃ of reaction 11h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 23 (0.107g, 0.250mmol, 71%).
1H?NMR(400MHz，DMSO-d
6)：δ15.11(s，1H)，8.63(s，1H)，8.09(s，2H)，5.17(s，1H)，4.95(s，1H)，4.67(s，2H)，4.51(s，2H)，3.74(s，1H)，3.44(s，2H)，2.24(s，2H)，2.15(s，2H)，1.20(s，2H)，1.12(s，2H)；
13CNMR(100MHz，DMSO-d
6)：δ176.2，165.6，149.5，147.8，146.9，146.5，145.7，120.9，119.2，112.3，107.5，56.6，55.0，45.7，34.9，31.8，6.8；LC-ESIMS?for?C
20H
21FN
6O
4[M+H
+]calcd?428.2?found429.1(M+H).
Embodiment 18: and 7-(4-(4-(amine methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid; The preparation of (compound 24);
Compound 24
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-(amine methyl)-1H-1,2, the piperidines trifluoroacetate (0.266g of 3-triazole-1-) again, 0.708mmol) and triethylamine (0.215g, 2.124mmol), 80 ℃ of reaction 23h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 24 (0.115g, 0.269mmol, 76%).
1H?NMR(400MHz，DMSO-d
6)：δ8.65(s，1H)，8.23-8.18(d，1H)，8.10(d，J＝16.8Hz，1H)，5.02(s，1H)，4.67(d，J＝10.8Hz，1H)，4.09(s，1H)，4.75(d，J＝18.0Hz，2H)，3.47-3.42(m，6H)，2.95(dd，J＝13.6，6.4Hz，2H)，2.23-2.06(m，2H)，1.13(t，J＝7.2Hz，2H)；
13C?NMR(100MHz，DMSO-d
6)：δ176.0，166.4，158.5，149.3，147.3，146.4，140.4，122.7，121.5，118.5，115.6，54.7，45.5，42.2，34.0，31.8，29.0，8.7；LC-ESIMSfor?C
20H
22FN
7O
3[M+H
+]calcd?427.2?found?428.1(M+H).
Embodiment 19: and 1-cyclopropyl-6-fluoro-7-(4-(4-(methoxycarbonyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 25);
Compound 25
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-(methoxycarbonyl)-1H-1,2, the piperidines trifluoroacetate (0.174g of 3-triazole-1-) again, 0.566mmol) and triethylamine (0.215g, 2.124mmol), 50 ℃ of reaction 10h, be cooled to room temperature, add chloroform (200ml), slowly drip dilute hydrochloric acid (0.1M) and regulate pH to 2～3, separatory, organic phase is washed with saturated nacl aqueous solution, MgSO
4Drying concentrates, gained solid recrystallization in chloroform, and solid filtering, vacuum-drying obtains compound 25 (0.085g, 0.186mmol, 59%).
1H?NMR(400MHz，DMSO-d
6)：δ15.19(s，1H)，8.91(s，1H)，8.64(s，1H)，8.12(d，J＝13.5Hz，1H)，5.13-4.97(m，1H)，4.66(d，J＝13.2Hz，2H)，3.83(s，3H)，3.74(s，1H)，3.46(t，J＝12.5Hz，2H)，2.29(d，J＝10.4Hz，2H)，2.22-2.14(m，2H)，1.20(dd，J＝13.9，7.7Hz，2H)，1.13(s，2H)；
13CNMR(100MHz，DMSO-d
6)：δ176.4，165.5，160.7，149.7，147.3，146.6，145.8，138.6，127.5，119.3，107.5，79.1，57.4，51.7，45.7，45.6，34.9，31.5，6.8；LC-ESIMS?for?C
21H
21FN
6O
5[M+H
+]calcd456.2found?457.1(M+H).
Embodiment 20: and 7-(4-(4-amine formyl-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 26);
Compound 26
Adding compound 5 in the exsiccant round-bottomed flask (0.090g, 0.318mmol), the 3ml acetonitrile becomes suspension; add compound 4-(4-amine formyl-1H-1,2, the piperidines trifluoroacetate (0.165g of 3-triazole-1-) again; 0.566mmol) and triethylamine (0.215g, 2.124mmol), 50 ℃ of reaction 9h; be cooled to room temperature; add chloroform (200ml), slowly drip dilute hydrochloric acid (0.1M) and regulate pH to 2～3, separatory; organic phase is washed with saturated nacl aqueous solution, MgSO
4Drying concentrates, gained solid recrystallization in chloroform, and vacuum-drying obtains compound 26 (0.060g, 0.136mmol, 43%).
1H?NMR(400MHz，DMSO-d
6)：δ15.20(s，1H)，8.64(s，2H)，8.12(s，1H)，7.81(s，1H)，7.44(s，1H)，5.02(s，1H)，4.67(s，2H)，3.74(s，1H)，3.42(s，2H)，2.30(s，2H)，2.19(s，2H)，1.20(s，2H)，1.13(s，2H)；
13CNMR(100MHz，DMSO-d
6)：δ177.4，165.6，156.6，149.7，147.3，146.7，139.9，125.0，119.5，112.6，99.5，79.1，57.2，45.7，34.9，31.6，6.8；LC-ESIMS?for?C
20H
20FN
7O
4[M+H
+]calcd?441.2found442.1(M+H).
Embodiment 21: and 1-cyclopropyl-6-fluoro-7-(4-(4-formyl radical-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 27)
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension; add compound 4-(4-formyl radical-1H-1,2, the piperidines trifluoroacetate (0.147g of 3-triazole-1-) again; 0.531mmol) and triethylamine (0.179g, 1.77mmol), at 50 ℃ of reaction 16h; cool off in ice-water bath, filter, solid washs with ethanol (5ml); ether (5ml) washing, vacuum-drying obtains compound 27 (0.070g; 0.164mmol, 47%).
1H?NMR(400MHz，DMSO-d
6)δ15.19(s，1H)，10.02(s，1H)，9.01(s，1H)，8.64(s，1H)，8.13(d，J＝13.0Hz，1H)，5.14-5.02(m，1H)，4.68(d，J＝14.0Hz，2H)，3.75(s，1H)，3.46(t，J＝12.4Hz，2H)，2.31(d，J＝11.6Hz，2H)，2.26-2.11(m，2H)，1.20(d，J＝6.9Hz，2H)，1.12(d，J＝3.4Hz，2H)；
13C?NMR(400MHz，DMSO-d
6)：δ183.9，175.3，164.6，148.6，147.3，146.1，145.8，145.5，144.7，125.4，118.4，111.4，106.5，56.3，44.5，44.5，33.8，30.4，5.74；LC-ESIMS?for?C
20H
19FN
6O
4[M+H
+]calcd?426.1found?427.1(M+H).
Embodiment 22: and 1-cyclopropyl-6-fluoro-7-(4-(4-(1-hydroxyethyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 28)
Compound 28
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-(1-hydroxyethyl)-1H-1,2, the piperidines trifluoroacetate (0.166g of 3-triazole-1-) again, 0.566mmol) and triethylamine (0.179g, 1.77mmol), 90 ℃ of reaction 4h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 28 (0.109g, 0.246mmol, 70%).
1H?NMR(400MHz，DMSO-d
6)：δ14.90(s，1H)，8.59(s，1H)，8.08-7.97(m，2H)，4.93(t，J＝10.9Hz，1H)，4.81(dd，J＝12.4，6.1Hz，1H)，4.66(d，J＝13.1Hz，2H)，3.71(s，1H)，3.45(d，J＝12.6Hz，2H)，3.40(s，1H)，2.25(d，J＝9.9Hz，2H)，2.18-2.08(m，2H)，1.40(d，J＝6.4Hz，3H)，1.21(d，J＝6.2Hz，2H)，1.11(s，2H)；
13C?NMR(100MHz，DMSO-d
6)：δ176.2，165.5，152.4，149.5，148.3，147.1，146.6，145.7，119.5，112.4，61.5，56.7，45.8，45.7，34.8，31.9，31.8，26.2，23.6，6.8；LC-ESIMS?for?C
21H
23FN
6O
4[M+H
+]calcd?442.2?found?443.1(M+H).
Embodiment 23: and 1-cyclopropyl-6-fluoro-7-(4-(4-(1-hydroxypropyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 29)
Compound 29
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-(1-hydroxypropyl)-1H-1,2, the piperidines trifluoroacetate (0.173g of 3-triazole-1-) again, 0.566mmol) and triethylamine (0.179g, 1.77mmol), 90 ℃ of reaction 5h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 29 (0.113g, 0.248mmol, 70%).
1H?NMR(400MHz，DMSO-d
6)：δ15.14(s，1H)，8.59(s，1H)，8.04(s，1H)，8.01(s，1H)，4.93(s，1H)，4.66(d，J＝12.1Hz，2H)，4.56(s，1H)，3.72(s，1H)，3.50-3.40(m，3H)，2.24(s，2H)，2.14(d，J＝10.0Hz，2H)，1.84-1.59(m，2H)，1.21(d，J＝4.8Hz，2H)，1.11(s，2H)，0.86(t，J＝6.4Hz，3H)；
13C?NMR(100MHz，DMSO-d
6)：δ176.3，165.6，151.5，149.6，147.0，146.6，119.9，119.3，119.1，112.4，107.4，66.8，56.7，45.8，45.7，34.9，31.9，31.8，30.0，9.8，6.8；LC-ESIMS?for?C
22H
25FN
6O
4[M+H
+]calcd?456.2found457.1(M+H).
Embodiment 24: and 1-cyclopropyl-6-fluoro-7-(4-(4-((hydroxyl imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 30)
Compound 30
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-((hydroxyl imines) methyl)-1H-1,2, the piperidines trifluoroacetate (0.176g of 3-triazole-1-) again, 0.602mmol) and triethylamine (0.143g, 1.416mmol), at 80 ℃ of reaction 12h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 30 (0.099g, 0.224mmol, 64%).
1H?NMR(400MHz，DMSO-d
6)：δ15.21(s，1H)，11.87(s，1H)，8.73(s，1H)，8.62(s，1H)，8.10(d，J＝13.6Hz，1H)，7.68(s，1H)，5.05(s，1H)，4.69(d，J＝12.8Hz，2H)，3.74(s，1H)，3.44(t，J＝11.2Hz，2H)，2.33-2.20(m，4H)，1.20(d，J＝5.6Hz，2H)，1.12(s，2H)；
13C?NMR(100MHz，DMSO-d
6)：δ176.3，165.7，149.6，149.5，148.3，147.1，146.6，145.7，141.1，140.4，137.7，137.5，126.2，120.8，119.4，119.1，112.3，107.5，57.1，45.8，45.7，34.9，31.6，6.8；LC-ESIMS?for?C
20H
20FN
7O
4[M+H
+]calcd?441.2found442.1(M+H).
Embodiment 25: and 1-cyclopropyl-6-fluoro-7-(4-(4-((methoxy imino) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 31)
Compound 31
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-((methoxy imino) methyl)-1H-1,2, the piperidines trifluoroacetate (0.163g of 3-triazole-1-) again, 0.531mmol) and triethylamine (0.179g, 1.77mmol), 50 ℃ of reaction 16h, cool off in ice-water bath, filter, solid ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 31 (0.113g, 0.248mmol, 70%).
1H?NMR(400MHz，DMSO-d
6)：δ15.20(s，1H)，8.71(s，1/2H)，8.64(s，1/2H)，8.63(s，1/2H)，8.58(s，1/2H)，8.25(s，1/2H)，8.11(dd，J＝13.6，1.6Hz，1H)，7.74(s，1/2H)，5.03(ddd，J＝15.8，11.2，6.8Hz，1H)，4.68(t，J＝13.6Hz，2H)，3.96(s，3/2H)，3.86(s，3/2H)，3.74(s，1H)，3.48-3.41(m，2H)，2.26(s，2H)，2.22-2.15(m，2H)，1.20(dd，J＝14.0，7.6Hz，2H)，1.12(s，2H)；
13C?NMR(100MHz，DMSO-d
6)：δ176.3，165.6，149.6，149.6，148.3，148.3，147.1，146.6，145.7，145.7，141.1，140.0，138.2，137.0，126.7，121.6，119.4，119.2，112.5，107.5，62.1，61.6，57.2，45.7，45.7，45.6，34.9，31.7，31.6，8.6，6.8；LC-ESIMS?for?C
21H
22FN
7O
4[M+H
+]calcd?455.2found?456.1(M+H).
Embodiment 26: and 1-cyclopropyl-7-(4-(4-((ethoxy imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 32)
Compound 32
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-((ethoxy imines) methyl)-1H-1,2, the piperidines trifluoroacetate (0.170g of 3-triazole-1-) again, 0.531mmol) and triethylamine (0.179g, 1.77mmol), 50 ℃ of reaction 15h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 32 (0.108g, 0.230mmol, 65%).
1H?NMR(400MHz，CDCl
3)：δ14.87(s，1H)，8.74(s，1H)，8.25(s，1H)，8.13(d，J＝13.1Hz，1H)，7.75(s，1H)，4.93-4.72(m，3H)，4.33-4.16(m，2H)，3.65(s，1H)，3.41(t，J＝12.3Hz，2H)，2.42(d，J＝11.0Hz，2H)，2.38-2.20(m，2H)，1.37-1.26(m，5H)，1.11(s，2H)；
13C?NMR(100MHz，CDCl
3)：δ177.1，166.7，150.1，148.8，146.8，146.2，141.9，140.6，138.3，138.0，125.4，120.6，120.4，119.3，113.9，109.0，70.6，70.1，58.0，46.0，45.9，34.8，32.3，14.8，14.5，7.5；LC-ESIMS?for?C
22H
24FN
7O
4[M+H
+]calcd?469.2found?470.1(M+H).
Embodiment 27: and 7-(4-(4-((allyl oxygen imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 33)
Compound 33
Adding compound 5 in the exsiccant round-bottomed flask (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-((allyl oxygen imines) methyl)-1H-1,2, the piperidines trifluoroacetate (0.177g of 3-triazole-1-) again, 0.531mmol) and triethylamine (0.179g, 1.77mmol), 50 ℃ of reaction 7h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 33 (0.089g, 0.185mmol, 53%).
1H?NMR(400MHz，)δ15.18(s，1H)，8.68-8.57(m，2H)，8.09(d，J＝13.4Hz，1H)，7.78(s，1H)，6.16-5.87(m，1H)，5.30(d，J＝17.4Hz，1H)，5.22(d，J＝10.1Hz，1H)，5.06(s，1H)，4.71-4.60(m，4H)，3.73(s，1H)，3.43(t，J＝13.0Hz，2H)，2.28(s，2H)，2.21(d，J＝11.0Hz，2H)，1.20(d，J＝5.1Hz，2H)，1.12(s，2H)；
13C?NMR(400MHz，DMSO-d
6)：δ176.3，165.6，149.5，149.5，148.3，147.0，146.6，145.7，141.4，140.0，138.4，137.0，134.4，134.2，126.7，121.6，119.3，119.1，117.7，117.5，112.4，112.3，107.5，74.9，74.4，57.2，45.7，45.6，34.9，31.6，6.8；LC-ESIMS?for?C
23H
24FN
7O
4[M+H
+]calcd481.2found?482.1(M+H).
Embodiment 28: and 1-cyclopropyl-6-fluoro-4-carbonyl-7-(4-(4-((the alkynes third oxygen imines-2-) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 34)
Compound 34
In the exsiccant round-bottomed flask, add compound 5 (0.100g, 0.354mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-((the alkynes third oxygen imines-2-) methyl)-1H-1 again, 2, and the piperidines trifluoroacetate of 3-triazole-1-) (0.175g, 0.531mmol) and triethylamine (0.179g, 1.77mmol), at 60 ℃ of reaction 12h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 34 (0.080g, 0.167mmol, 48%).
1H?NMR(400MHz，DMSO-d
6)：δ15.12(s，1H)，8.72(s，1H)，8.62(s，1H)，8.09(d，J＝13.5Hz，1H)，7.86(s，1H)，5.17-4.97(m，1H)，4.81(d，J＝2.3Hz，2H)，4.69(t，J＝13.9Hz，2H)，3.73(tt，J＝7.1，3.7Hz，1H)，3.50(t，J＝2.3Hz，1H)，3.44(t，J＝11.7Hz，2H)，2.36-2.24(m，2H)，2.24-2.11(m，2H)，1.26-1.15(m，2H)，1.15-1.08(m，2H)；
13C?NMR(400MHz，DMSO-d
6)：δ176.2，165.6，149.5，149.4，148.2，146.9，146.5，145.7，142.4，139.6，139.3，136.8，126.9，122.0，119.3，119.0，112.3，107.5，80.2，77.5，61.7，61.3，57.2，45.7，45.6，34.9，31.7，6.8；LC-ESIMS?for?C
23H
22FN
7O
4[M+H
+]calcd?479.2found?480.1(M+H).
Embodiment 29: and 7-(4-(4-((benzyloxy imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1, the preparation of 8-naphthyridines-3-carboxylic acid (compound 35)
Compound 35
Adding compound 5 in the exsiccant round-bottomed flask (0.080g, 0.281mmol), the 3ml acetonitrile becomes suspension, add compound 4-(4-((benzyloxy imines) methyl)-1H-1,2, the piperidines trifluoroacetate (0.151g of 3-triazole-1-) again, 0.394mmol) and triethylamine (0.142g, 1.405mmol), 50 ℃ of reaction 12h, cool off in ice-water bath, filter, solid washs with ethanol (5ml), ether (5ml) washing, vacuum-drying obtains compound 35 (0.060g, 0.113mmol, 40%).
1HNMR(400MHz，DMSO-d
6)：δ15.19(s，1H)，8.74(s，1H)，8.63(s，1H)，8.10(d，J＝11.9Hz，1H)，7.79(s，1H)，7.49-7.12(m，5H)，5.25(s，2H)，5.02(dt，J＝10.8，8.3Hz，1H)，4.67(t，J＝13.2Hz，2H)，3.72(s，1H)，3.43(t，J＝12.4Hz，2H)，2.28(t，J＝13.9Hz，2H)，2.23-2.05(m，2H)，1.26-1.16(m，2H)，1.10(s，2H)；
13C?NMR(400MHz，DMSO-d
6)：δ176.3，165.7，149.5，148.3，147.1，146.5，145.7，141.7，139.9，138.7，138.0，137.5，137.0，129.7，129.2，128.3，128.2，128.0，127.8，127.7，127.6，126.8，121.7，119.4，119.2，114.9，112.5，107.5，75.8，75.4，59.7，57.2，45.7，45.6，45.6，34.8，31.7，31.6，28.9，20.7，14.0，6.8；LC-ESIMS?for?C
27H
26FN
7O
4[M+H
+]calcd?531.2found?532.1(M+H).
Embodiment 30: the antibacterial activity in vitro determination experiment
1. experiment material and instrument
Experimental bacteria: reference culture is all collected center bacterial strain (ATCC) from the US mode bacterial classification, be respectively streptococcus aureus ATCC25923, streptococcus pneumoniae ATCC49619, staphylococcus epidermidis ATCC12228, enterococcus faecalis ATCC29212, intestinal bacteria ATCC25922, Pseudomonas aeruginosa ATCC27853.Clinical multidrug resistance bacterial strain is respectively the multidrug resistance streptococcus aureus all from hospital general, the military region, Guangzhou, multidrug resistance hemolytic streptococcus pneumoniae, multidrug resistance Pseudomonas aeruginosa.
MUELLER-HINTON substratum (production of Britain OXOID company).
Testing compound: according to the compound of embodiment one to embodiment 29 preparation: 7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35.
Positive control: reference substance 1: ciprofloxacin hydrochloride; Reference substance 2: vancomycin hydrochloride.
2. test method
Antibacterial activity in vitro measure to adopt world health organisation recommendations to the optimum MUELLER-HINTON substratum of general bacterium, experimental bacteria is spent the night in the M-H broth culture and is diluted and makes inoculum size control about 1 * 10
6CFU.Drug level is taked micro-broth dilution method, and the drug test concentration gradient is followed successively by 32 μ g/mL, 16 μ g/mL, 8 μ g/mL, 4 μ g/mL, 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25 μ g/mL, 0.125 μ g/mL, 0.063 μ g/mL, 0.031 μ g/mL, 0.016 μ g/mL, 0.008 μ g/mL, 0.004 μ g/mL.The experimental bacteria suspension is inoculated in above-mentioned 96 orifice plates that contain all cpds and different concns with bull inoculation instrument, and 96 orifice plates are cultivated 18-24h, visual inspection experimental result at 35-37 ℃.The minimum concentration of inhibition test bacterial growth is minimum inhibitory concentration (MIC).The present invention is to provide the antibacterial activity in vitro (MIC, μ g/mL) of quinolonecarboxylic acid derivatives, measurement result sees Table 1 and table 2.
3. experimental result
The antibacterial activity in vitro of table 1 The compounds of this invention and positive control (MIC, μ g/mL)
The antibacterial activity in vitro of table 2 The compounds of this invention and positive control (MIC, μ g/mL)
From table 1 and table 2 as can be seen:
In the antibacterial activity in vitro test of selected nine bacterial strains, the testing compound overwhelming majority has showed stronger activity, in indivedual bacterial strains, particularly in the Resistant strain, has showed the activity stronger than reference substance.
At first compare 15 quinlones of tetramethyleneimine deutero-(table 1), be not difficult to find out four bridged ring quinlones 13,14,15,16 have demonstrated superior anti-microbial activity, particularly streptococcus pneumoniae and multidrug resistance hemolytic streptococcus pneumoniae have been shown outstanding anti-microbial activity, in these four quinlones, compound 13 and 16 activity are the strongest, they are 8 times of Ciprofloxacin to the activity of streptococcus aureus, 13 pairs of staphylococcic anti-microbial activities of epidermis of compound are 4 times of Ciprofloxacin, are 8 times of Ciprofloxacin to the activity of enterococcus faecalis.16 pairs of staphylococcic anti-microbial activities of epidermis of compound are suitable with Ciprofloxacin, are 16 times of Ciprofloxacin to the activity of enterococcus faecalis.Simultaneously, compound 13 and 16 pairs of colibacillary activity equate that with Ciprofloxacin particularly 13 pairs of Pseudomonas aeruginosas of compound have also shown good active.
Secondly relatively 14 quinlones (table 2) of piperidine derivatives are not difficult to find out, compound 22,23, and 27,31 have shown superior anti-microbial activity, 22 pairs of resistance streptococcus aureuses of compound have shown best activity, and the activity of enterococcus faecalis is equated with Ciprofloxacin.The activity of 23 pairs of streptococcus aureuses of compound equates with Ciprofloxacin.27 pairs of staphylococcic activity of epidermis of compound are 16 times of Ciprofloxacin, and the activity of streptococcus aureus is equated with Ciprofloxacin, and are suitable to colibacillary activity and Ciprofloxacin, simultaneously Pseudomonas aeruginosa also had certain activity.31 pairs of staphylococcic activity of epidermis of compound equate with Ciprofloxacin, and are suitable to activity and the Ciprofloxacin of streptococcus aureus.In this group compound, the streptococcus aureus of 35 pairs of multidrug resistances of compound has also shown good active in addition.
Claims (9)
1. following quinlone compound and the pharmacologically acceptable salts thereof of a class general formula:
Wherein R is nitrogenous heterocyclic radical, comprises group shown in following general formula (Ia) or general formula (Ib) or the general formula (Ic):
General formula (Ia) group is as shown below:
Wherein, R
1Be selected from one of following: hydrogen, C
1-8Direct-connected or the branched-chain alkyl that replaces, C
1-81,2 of carbalkoxy or replacement, the 3-triazol radical; R
2Be selected from one of following: hydrogen or hydroxyl; R
3Be selected from one of following: hydrogen, C
1-8Direct-connected or the branched-chain alkyl that replaces, C
1-81,2 of carbalkoxy or replacement, the 3-triazol radical;
General formula (Ib) group is as shown below:
Wherein X is S, SO, SO
2Or NCOOC (CH
3)
3
General formula (Ic) group is as shown below:
Wherein, R
1Be selected from one of following: substituted-phenyl, methylol, amine methyl, ester group, amide group, formyl radical, C
1-8The methylol that alkyl replaces, oximido, C
1-8The oximido that alkyl replaces.
2. the described quinlone compound of claim 1 is characterized in that being selected from one of following compounds:
1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-(methoxycarbonyl) pyrroles-1-)-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-(methylol) pyrroles-1-)-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-((S)-1-hydroxyethyl) pyrroles-1-)-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-((2S, 4R)-4-hydroxyl-2-((R)-1-hydroxyethyl) pyrroles-1-)-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-7-((3R, 4R)-3, the 4-dihydroxy-pyrrolidine-1-)-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(5-(tertbutyloxycarbonyl)-2,5-diazabicyclo [2.2.1] heptane-2-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(2-sulphur-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(2-(S)-sulfoxide-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(2-(R)-sulfoxide-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(2-sulfone-5-azabicyclo [2.2.1] heptane-5-)-1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
(S)-and 1-cyclopropyl-6-fluoro-7-(2-(methylol) pyrroles-1-)-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
(S)-and 1-cyclopropyl-6-fluoro-4-carbonyl-7-(2-((4-phenyl-1H-1,2, the methyl of 3-triazole-1-)) pyrroles-1-)-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
(S)-and 1-cyclopropyl-6-fluoro-7-(2-((4-(methylol)-1H-1,2, the methyl of 3-triazole-1-)) pyrroles-1-)-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-((2S, 4S)-2-(methoxycarbonyl)-4-(4-phenyl-1H-1,2, the pyrroles of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-((2S, 4S)-4-(4-(methylol)-1H-1,2, the 3-triazole-1-)-2-(methoxycarbonyl) pyrroles-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-4-carbonyl-7-(4-(4-phenyl-1H-1,2, the piperidines of 3-triazole-1-)-1-)-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(4-(4-(methylol)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(4-(4-(amine methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(4-(4-(methoxycarbonyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(4-(4-amine formyl-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(4-(4-formyl radical-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(4-(4-(1-hydroxyethyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(4-(4-(1-hydroxypropyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(4-(4-((hydroxyl imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(4-(4-((methoxy imino) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-7-(4-(4-((ethoxy imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(4-(4-((allyl oxygen imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
1-cyclopropyl-6-fluoro-4-carbonyl-7-(4-(4-((the alkynes third oxygen imines-2-) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid;
7-(4-(4-((benzyloxy imines) methyl)-1H-1,2, the piperidines of 3-triazole-1-)-1-)-and 1-cyclopropyl-6-fluoro-4-carbonyl-1,4-dihydro-1,8-naphthyridines-3-carboxylic acid.
3. claim 1 or 2 described quinolone derivative pharmacy acceptable salts.
4. the described quinolone derivative pharmacy acceptable salt of claim 3 is characterized by the salt that described quinolone derivative and mineral alkali or organic bases form.
5. the described quinolone derivative pharmacy acceptable salt of claim 4, it is one of following to it is characterized in that described organic bases or mineral alkali are selected from: ammoniacal liquor, guanidine, C
1-8Alkyl substituted guanidines, amidine, C
1-8The alkyl substituted amidine, Methionin, arginine, Histidine etc.
6. the application of the described quinolone derivative of claim 1 to 2 in the preparation antibacterials.
7. the application of the pharmacy acceptable salt of the described quinolone derivative of claim 3 in the preparation antibacterials.
8. the application of the pharmacy acceptable salt of the described quinolone derivative of claim 4 in the preparation antibacterials.
9. the application of the pharmacy acceptable salt of the described quinolone derivative of claim 5 in the preparation antibacterials.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017214A (en) * | 2015-06-15 | 2015-11-04 | 河南师范大学 | Piperidine link 1,2,3-triazole compound with antibacterial activity and preparation method therefor and application thereof |
| CN116157392A (en) * | 2020-03-03 | 2023-05-23 | 雷多纳治疗公司 | Compounds targeting RNA binding proteins or RNA modification proteins |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017214A (en) * | 2015-06-15 | 2015-11-04 | 河南师范大学 | Piperidine link 1,2,3-triazole compound with antibacterial activity and preparation method therefor and application thereof |
| CN116157392A (en) * | 2020-03-03 | 2023-05-23 | 雷多纳治疗公司 | Compounds targeting RNA binding proteins or RNA modification proteins |
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