CN116606280A - Fluoroquinolone compound and application thereof in preparation of antibacterial drugs - Google Patents
Fluoroquinolone compound and application thereof in preparation of antibacterial drugs Download PDFInfo
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- CN116606280A CN116606280A CN202310235376.XA CN202310235376A CN116606280A CN 116606280 A CN116606280 A CN 116606280A CN 202310235376 A CN202310235376 A CN 202310235376A CN 116606280 A CN116606280 A CN 116606280A
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- compound
- chloro
- cyclopropyl
- dihydro
- oxo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 61
- 229940124307 fluoroquinolone Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 229940124350 antibacterial drug Drugs 0.000 title abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 19
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 18
- -1 amino-substituted pyrrolidines Chemical class 0.000 claims description 50
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 241000894006 Bacteria Species 0.000 claims description 6
- 241000191967 Staphylococcus aureus Species 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
- 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 claims description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 4
- 229940126657 Compound 17 Drugs 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940125797 compound 12 Drugs 0.000 claims description 4
- 229940126543 compound 14 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 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 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- LFKYEIUYPDDBKX-SECBINFHSA-N 8-chloro-1-cyclopropyl-6-fluoro-7-[(3r)-3-hydroxypyrrolidin-1-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound C1[C@H](O)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl LFKYEIUYPDDBKX-SECBINFHSA-N 0.000 claims description 3
- LFKYEIUYPDDBKX-VIFPVBQESA-N 8-chloro-1-cyclopropyl-6-fluoro-7-[(3s)-3-hydroxypyrrolidin-1-yl]-4-oxoquinoline-3-carboxylic acid Chemical compound C1[C@@H](O)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl LFKYEIUYPDDBKX-VIFPVBQESA-N 0.000 claims description 3
- 241000588724 Escherichia coli Species 0.000 claims description 3
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 244000063299 Bacillus subtilis Species 0.000 claims description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 claims description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 2
- 241000222122 Candida albicans Species 0.000 claims description 2
- 241000588697 Enterobacter cloacae Species 0.000 claims description 2
- 241000194032 Enterococcus faecalis Species 0.000 claims description 2
- 241000233866 Fungi Species 0.000 claims 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 claims description 2
- 241000191938 Micrococcus luteus Species 0.000 claims description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 150000003976 azacycloalkanes Chemical class 0.000 claims description 2
- 229940095731 candida albicans Drugs 0.000 claims description 2
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 2
- 230000002538 fungal effect Effects 0.000 claims description 2
- 229960003085 meticillin Drugs 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 17
- 238000012360 testing method Methods 0.000 abstract description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 21
- 239000007858 starting material Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 9
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 244000052769 pathogen Species 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000007660 quinolones Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical compound CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 description 2
- IEDMMCZBIKXEJP-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(F)C(Cl)=C1F IEDMMCZBIKXEJP-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 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 2
- 238000001035 drying Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- 150000003930 2-aminopyridines Chemical class 0.000 description 1
- 241000588626 Acinetobacter baumannii Species 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N alpha-aminopyridine Natural products NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- UQUPQEUNHVVNKW-UHFFFAOYSA-N azetidin-1-ium-3-ol;chloride Chemical compound Cl.OC1CNC1 UQUPQEUNHVVNKW-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229950001320 clinafloxacin Drugs 0.000 description 1
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 description 1
- 229950006412 delafloxacin Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000854 inhibitional effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a fluoroquinolone compound and application thereof in preparation of antibacterial drugs, belongs to the technical field of medicines, and relates to a fluoroquinolone compound with good antibacterial activity, and the prepared fluoroquinolone compound has good results in antibacterial activity test and good application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a fluoroquinolone compound and application thereof.
Background
ESKAPE (escherichia coli, staphylococcus aureus, klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, and enterobacter) pathogens can cause serious and fatal infections, such as blood infections and pneumonia. The ESKAPE pathogen has the potential to "escape" antibiotics and become increasingly resistant to all available antibiotics (clin.microbiol.rev., 2020,33, e 00181-19.). Currently, over 700 tens of thousands of people die annually from drug resistant ESKAPE pathogens, and if there is no new and better therapeutic strategy, 10 tens of thousands of people are expected to die in 2050. The increasing threat of the global pandemic and drug-resistant forms of drug-sensitive ESKAPE pathogens has created an urgent need to develop more potent antibacterial chemotherapeutic agents. Quinolones, one of the most commonly used antibiotics in the clinic, are effective weapons for treating ESKAPE infection (eur.j. Med. Chem.,2021,224,113741.). Unfortunately, ESKAPE pathogens have developed severe resistance to quinolones, which are mainly associated with mutations in the quinolone drug resistance determining region (QRDR) of type ii topoisomerase (Antibiotics, 2021,10,1455.). Therefore, there is a need to develop new quinolones to increase the efficacy of drug sensitive and resistant ESKAPE pathogens.
Structural analysis of quinolones is expected to provide some new sense of design and synthesis. Analyzing the structure of quinolone medicines, the new generation of anti-drug-resistant quinolone medicines are to introduce new structural modules at a plurality of positions of the quinolone parent nucleus structure or recombine different structural modules to enhance the antibacterial activity and drug resistance. For example, in the second-generation quinolone medicines, the N-1-position ethyl is replaced by cyclopropyl on the basis of norfloxacin to obtain ciprofloxacin, so that the antibacterial activity is enhanced; the third generation quinolone medicine is mainly characterized in that piperazine at the C-7 position is replaced by methyl substituted piperazine and pyrrolidinyl, and the N-1 position is expanded to an aromatic group with large molecular surface area; the fourth generation and the newly marketed quinolone drugs enrich the variety of C-7 substituent groups, an azabicyclo group and a huge side chain are added on pyrrolidinyl, more groups are introduced at C-5 and C-8 positions, and the substituted pyridine structure appears at N-1 position for the first time. For quinolone antibiotics, the most modified sites are N-1, C-7 and C-8, so that a solid compound library with various structures and sufficient quantity is constructed by recombining different structural modules (such as gatifloxacin and clinafloxacin) or introducing brand-new structural modules (such as moxifloxacin and delafloxacin), and then active molecules or anti-drug resistant molecules are searched by active screening, and the method provides a great opportunity for the discovery of new generation anti-drug resistant quinolone drugs.
Under the guidance of the thought, a huge number of quinolone compound libraries are synthesized and screened, so that a part of novel compounds with better activity are discovered. We consider this a new strategy for discovering the structure of novel anti-drug-resistant compounds.
Disclosure of Invention
In view of the above problems, the present invention provides a fluoroquinolone compound, a salt or hydrate thereof, or a pharmaceutically acceptable carrier, a pharmaceutical composition comprising the same, and an application of the same in preparing antibacterial drugs. The fluoroquinolone compound with good antibacterial activity is designed and synthesized, and the prepared compound shows good results in antibacterial activity test.
In order to achieve the above purpose, the invention adopts the following specific scheme:
in a first aspect, a fluoroquinolone compound and a salt or hydrate thereof or a pharmaceutically acceptable carrier thereof, wherein the fluoroquinolone compound is a compound shown in the following structural general formula (I):
in formula (I), R is selected from the group consisting of substituted azacycloalkanes and amino-substituted pyrrolidines attached to the fluoroquinolone core structure via an N-C bond.
Further, the fluoroquinolone compound has a structure represented by general formula (I-1) or (I-2):
wherein n is a natural number of 1-5, R 1 Nitrogen atom substituted nitrogen-containing and nitrogen-containing heterocycloalkanes.
Still further, the fluoroquinolone compound is selected from the group consisting of:
compound 1: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxycyclobutyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 2: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 3: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 4: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypiperidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 5: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypiperidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 6: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxycycloheptane) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 7: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3- (diethylamino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 8: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3- (diethylamino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 9: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3- (pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 10: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3- (pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 11: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-piperidinoalkyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 12: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-piperidinoalkyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 13: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (morpholinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 14: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (thiomorpholinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 15: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (thiomorpholine-1, 1-dioxido) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 16: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (piperazinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 17: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (N-methylpiperazino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
in a second aspect, a pharmaceutical composition comprises the fluoroquinolone compound and salts or hydrates thereof or a pharmaceutically acceptable carrier.
In a third aspect, the fluoroquinolone compound and its salt, hydrate or pharmaceutically acceptable carrier, or the application of the pharmaceutical composition in preparing antibacterial medicines.
Further, the antibacterial is antibacterial or/and fungal.
Still further, the bacteria is any one or more of staphylococcus aureus, methicillin-resistant staphylococcus aureus, klebsiella pneumoniae (high tolerance), salmonella (high tolerance), micrococcus luteus, enterococcus faecalis (high tolerance), bacillus subtilis, escherichia coli, pseudomonas aeruginosa (high tolerance), enterobacter cloacae and proteus; the fungus is candida albicans and/or candida.
The beneficial effects are that: the quinolone compound has wide bactericidal spectrum and very good inhibition or bactericidal activity on bacteria such as gram-negative bacteria, gram-positive bacteria and the like or high-resistance bacteria; the compounds can obtain good control effect at very low dosage. In addition, the preparation method of the compound disclosed by the invention is simple in preparation steps and higher in yield, so that the compound has a better application prospect.
Detailed Description
The fluoroquinolone compound can be synthesized according to the following reaction route:
the route is that 3-chloro-2, 4, 5-trifluoro benzoyl chloride and N, N-dimethylamino ethyl acrylate undergo addition coupling reaction, then undergo substitution reaction with various substituted 2-aminopyridine, then undergo cyclization through intramolecular nucleophilic substitution, then hydrolyze to obtain compound V, and finally undergo aromatic nucleophilic substitution reaction with various secondary amines to obtain the target product fluoroquinolone compound.
The technical scheme of the invention will be clearly and completely described in the following in connection with the embodiments of the invention.
Example 1: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxycyclobutyl) -4-oxo-3-quinolinecarboxylic acid (compound 1):
a) N, N-dimethylaminoethyl acrylate (3.1 g,24.0 mmol), triethylamine (2.6 g,26.2 mmol) and toluene (40 mL) were mixed, a mixed solution of 3-chloro-2, 4, 5-trifluorobenzoyl chloride (5 g,21.8 mmol) and toluene (20 mL) was added dropwise, the mixture was heated to 50℃and TLC was monitored for about 1 hour, after completion of the reaction, the mixture was concentrated to give 7.3g of Compound II in 99% yield. LC/MS [ M+H ]] + ＝336.05、[M+Na] + ＝358.08、[M+K] + ＝374.04。
b) Compound II (7 g,20.8 mmol), ethanol (70 mL), glacial acetic acid (3 mL) are mixed, cyclopropylamine (1.3 g,22.8 mmol) ethanol solution is added dropwise at room temperature, the mixture is heated to 40 ℃ after the dripping, TLC monitoring reaction is finished, cooling is carried out, a proper amount of water is slowly added into the reaction solution, stirring and filtering are carried out, and the compound III is obtained after drying, wherein the yield is 94%. LC/MS [ M+H ]] + ＝348.05、[M+Na] + ＝370.06、[M+K] + ＝386.05。
c) Compound III (6.8 g,19.6 mmol), anhydrous potassium carbonate (4.1 g,29.6 mmol) and N, N-dimethylformamide (50 mL) were mixed, heated to 90℃and stirred for 2 hours, after the TLC monitoring reaction was completed, cooled, and a proper amount of water was slowly added to the reaction solution, stirred and filtered, and dried to give compound IV 6.2g in 96% yield. LC/MS [ M+H ]] + ＝328.04、[M+Na] + ＝350.06、[M+K] + ＝366.04。
d) Compound IV (6.2 g,18.9 mmol), acetic acid (20 mL), 6M HCl (4 mL) are mixed, heated to 90-95 ℃ for reflux reaction for 4 hours, after TLC monitoring reaction is finished, cooled, a proper amount of water is slowly added into the reaction solution, stirred and filtered, a filter cake is washed to be neutral, and then compound V5.3 g is obtained after drying, and the yield is 94%. LC/MS [ M+H ]] + ＝300.01、[M+Na] + ＝322.03、[M+K] + ＝338.04。
e) Compound V (1.7 g,5.0 mmol) was added to a suspension of 3-hydroxyazetidine hydrochloride (0.8 g,7.5 mmol), triethylamine (1.5 g,15.0 mmol) and the mixture was then refluxed until no starting material was present as detected by TLC (typically 5-8 hours). The solution was cooled to room temperature and filtered, and the filter cake was washed with water and diethyl ether to give the crude product. Purification by recrystallisation (DMF/EtOH) then gave the desired product 1.0g in 58% yield. LC/MS [ M+H ]] + ＝353.06、[M+Na] + ＝375.05、[M+K] + ＝391.06。
Example 2: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 2):
compound 2 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield was 63%. LC/MS [ M+H ]] + ＝367.08、[M+Na] + ＝389.08、[M+K] + ＝405.09。
Example 3: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 3):
compound 3 was produced in the same manner as in example 1 except that the corresponding raw materials were used, yield 61%. LC/MS [ M+H ]] + ＝367.10、[M+Na] + ＝389.08、[M+K] + ＝405.12。
Example 4: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypiperidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 4):
compound 4 was produced in 58% yield by the same method as in example 1, except that the corresponding starting materials were used. LC/MS [ M+H ]] + ＝381.11、[M+Na] + ＝403.10、[M+K] + ＝409.11。
Example 5: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypiperidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 5):
compound 5 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield 61%. LC/MS [ M+H ]] + ＝381.10、[M+Na] + ＝403.08、[M+K] + ＝409.11。
Example 6: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxycycloheptane) -4-oxo-3-quinolinecarboxylic acid (compound 6):
compound 6 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield was 49%. LC/MS [ M+H ]] + ＝395.11、[M+Na] + ＝417.13、[M+K] + ＝433.11。
Example 7: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3- (diethylamino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 7):
compound 7 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield 56%. LC/MS [ M+H ]] + ＝422.09、[M+Na] + ＝444.15、[M+K] + ＝460.09。
Example 8: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3- (diethylamino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 8):
compound 8 was produced in 58% yield by the same method as in example 1, except that the corresponding starting materials were used. LC/MS [ M+H ]] + ＝422.09、[M+Na] + ＝444.10、[M+K] + ＝460.12。
Example 9: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3- (pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 9):
compound 9 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield was 49%. LC/MS [ M+H ]] + ＝420.14、[M+Na] + ＝442.10、[M+K] + ＝458.15。
Example 10: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3- (pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 10):
compound 10 was produced in the same manner as in example 1 except that the corresponding starting materials were used, with a yield of 50%. LC/MS [ M+H ]] + ＝420.10、[M+Na] + ＝442.15、[M+K] + ＝458.09。
Example 11: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-piperidinoalkyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 11):
compound 11 was produced in the same manner as in example 1 except that the corresponding starting materials were used, in a yield of 60%. LC/MS [ M+H ]] + ＝434.15、[M+Na] + ＝456.12、[M+K] + ＝472.10。
Example 12: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-piperidinoalkyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 12):
compound 12 was produced in the same manner as in example 1 except that the corresponding starting materials were used, in a yield of 60%. LC/MS [ M+H ]] + ＝434.14、[M+Na] + ＝456.12、[M+K] + ＝472.11。
Example 13: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (morpholino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (Compound 13):
compound 13 was prepared in 57% yield by the same method as in example 1, except that the corresponding starting materials were used. LC/MS [ M+H ]] + ＝436.14、[M+Na] + ＝458.13、[M+K] + ＝474.11。
Example 14: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (thiomorpholinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (Compound 14):
compound 14 was produced in the same manner as in example 1 except that the corresponding starting materials were used, with a yield of 53%. LC/MS [ M+H ]] + ＝452.11、[M+Na] + ＝474.09、[M+K] + ＝490.08。
Example 15: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (thiomorpholine-1, 1-dioxido) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (Compound 15):
compound 15 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield 61%. LC/MS [ M+H ]] + ＝484.10、[M+Na] + ＝506.08、[M+K] + ＝523.13。
Example 16: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (piperazinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 16):
compound 16 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield 46%. LC/MS [ M+H ]] + ＝435.15、[M+Na] + ＝457.09、[M+K] + ＝473.10。
Example 17: preparation of 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (N-methylpiperazino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 17):
compound 17 was produced in the same manner as in example 1 except that the corresponding raw materials were used, and the yield was 52%. LC/MS [ M+H ]] + ＝449.11、[M+Na] + ＝471.15、[M+K] + ＝487.17。
Example 18: antibacterial Activity test of the Compounds of the invention
To confirm the practicality of the synthesized compounds, the Minimum Inhibitory Concentration (MIC) of the target compound was determined by a micro broth dilution method, and the plates were incubated at 35℃for 18 to 24 hours. Specific antibacterial activity test specific results are shown in table 1.
Table 1 in vitro antibacterial activity of the compounds of the present invention.
Experimental results show that the compound contained in the invention generally has stronger drug-resistant bacteria activity.
It should be noted that the above-mentioned embodiments are to be understood as illustrative, and not limiting, the scope of the invention, which is defined by the appended claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made to the present invention without departing from its spirit or scope.
Claims (7)
1. A fluoroquinolone compound and a salt or hydrate thereof or a pharmaceutically acceptable carrier thereof, wherein the fluoroquinolone compound is a compound shown as the following structural general formula (I):
in formula (I), R is selected from the group consisting of substituted azacycloalkanes and amino-substituted pyrrolidines attached to the fluoroquinolone core structure via an N-C bond.
2. The fluoroquinolone compound and its salt or hydrate or pharmaceutically acceptable carrier according to claim 1, wherein the fluoroquinolone compound has a structure represented by general formula (I-1) or (I-2):
wherein n is a natural number of 1-5, R 1 Nitrogen atom substituted nitrogen-containing and nitrogen-containing heterocycloalkanes.
3. The fluoroquinolone compound and salts or hydrates thereof, or pharmaceutically acceptable carriers thereof, as claimed in claim 2, wherein the fluoroquinolone compound is selected from the group consisting of:
compound 1: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxycyclobutyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 2: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 3: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 4: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypiperidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 5: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypiperidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 6: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxycycloheptane) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 7: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3- (diethylamino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 8: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3- (diethylamino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 9: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3- (pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 10: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3- (pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 11: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-piperidinoalkyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 12: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-piperidinoalkyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 13: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (morpholinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 14: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (thiomorpholinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 15: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (thiomorpholine-1, 1-dioxido) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 16: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (piperazinyl) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 17: 1-cyclopropyl-8-chloro-6-fluoro-1, 4-dihydro-7- (3- (N-methylpiperazino) pyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
4. a pharmaceutical composition comprising the fluoroquinolone compound of any one of claims 1-3 and salts or hydrates thereof, or a pharmaceutically acceptable carrier.
5. Use of a fluoroquinolone compound and salts or hydrates thereof or a pharmaceutically acceptable carrier according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 4, in the preparation of an antibacterial medicament.
6. The use according to claim 5, wherein the antibacterial is antibacterial or/and fungal.
7. The use according to claim 6, wherein the bacteria are any one or more of staphylococcus aureus, methicillin-resistant staphylococcus aureus, klebsiella pneumoniae, salmonella, micrococcus luteus, enterococcus faecalis, bacillus subtilis, escherichia coli, pseudomonas aeruginosa, enterobacter cloacae and proteus; the fungus is candida albicans and/or candida.
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