CN116606279A - Fluoroquinolone compound and preparation method and application thereof - Google Patents
Fluoroquinolone compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN116606279A CN116606279A CN202310235371.7A CN202310235371A CN116606279A CN 116606279 A CN116606279 A CN 116606279A CN 202310235371 A CN202310235371 A CN 202310235371A CN 116606279 A CN116606279 A CN 116606279A
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- CN
- China
- Prior art keywords
- compound
- dihydro
- oxo
- hydroxypyrrolidinyl
- fluoro
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 229940124307 fluoroquinolone Drugs 0.000 title claims abstract description 33
- -1 2-fluorocyclopropyl Chemical group 0.000 claims description 103
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 241000894006 Bacteria Species 0.000 claims description 10
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 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
- 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
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-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
- 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 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
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 4
- 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 claims description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 claims description 4
- 125000006414 CCl Chemical group ClC* 0.000 claims description 4
- 229940126657 Compound 17 Drugs 0.000 claims description 4
- 241000233866 Fungi Species 0.000 claims description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 4
- 241000191967 Staphylococcus aureus Species 0.000 claims description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 4
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- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical class CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 claims description 3
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- 125000003118 aryl group Chemical group 0.000 claims description 3
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 claims description 3
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- 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
- 229950001320 clinafloxacin Drugs 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
- 238000013461 design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FYMHQCNFKNMJAV-HOTGVXAUSA-N finafloxacin Chemical compound C12=C(C#N)C(N3C[C@@H]4OCCN[C@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 FYMHQCNFKNMJAV-HOTGVXAUSA-N 0.000 description 1
- 229960002839 finafloxacin Drugs 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000006872 improvement Effects 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
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960003702 moxifloxacin Drugs 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
- 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
- 150000004885 piperazines Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005180 public health 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
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 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
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
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- 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
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Abstract
The invention relates to a fluoroquinolone compound, a preparation method and application thereof, belonging to the technical field of medicines.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a fluoroquinolone compound as well as a preparation method and application thereof.
Background
Bacterial resistance has currently posed a great threat to global public health and economic development due to the massive use of antibiotics and the slow development of new antibiotics. Fluoroquinolone antibacterial agents are a class of synthetic antibiotics with broad-spectrum bactericidal activity that inhibit gram-negative and gram-positive bacteria, including anaerobic bacteria. Over 50 years of development, it has become the most widely used first-line anti-infective chemotherapeutic drug clinically at present after cephalosporin. However, with the widespread use and even abuse of such drugs, bacterial resistance has increased year by year, becoming a worldwide troublesome problem, and even the problem of limited use (resistance) of antibiotics has arisen. Many new fluoroquinolones (e.g., delafloxacin, finafloxacin, nenofloxacin, etc.) have been approved or are undergoing later clinical development in recent years. Research and clinical results of the new generation of quinolones show that the combination of different substituents in the structure of the fluoroquinolones can bring about great improvement of antibacterial activity and drug resistance (J. Antiboot. 2016,70,3-24; med. Chem. Commun.2019,10, 1719-1739). Therefore, in order to cope with the rapid increase of bacterial drug resistance, the development process of novel fluoroquinolone antibacterial drugs is a feasible approach.
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 aims at providing a fluoroquinolone compound, a salt or hydrate thereof, or a pharmaceutically acceptable carrier, at providing a preparation method of the fluoroquinolone compound, at providing a pharmaceutical composition, and at providing an application of the fluoroquinolone compound in antibacterial aspect. 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:
a fluoroquinolone compound and a salt or hydrate thereof or a pharmaceutically acceptable carrier thereof, the fluoroquinolone compound having the following structural formula:wherein R is selected from C2-C6 linear alkyl, 2-fluoroethyl, 2-fluorocyclopropyl, substituted aryl and substituted pyridyl; a is selected from CH, C-halogen atom, C-alkoxy, C-cyano, C-nitro, C-amino and N; wherein when A is N, R is not ethyl, 4-hydroxyphenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 2,4, 6-trifluorophenyl, 3, 5-difluoro-2-pyridinyl, 2, 4-difluoro-5-aminophenyl; when A is CH, R is not ethyl, 4-fluorophenyl or 2, 4-difluorophenyl; when A is C-F, R is not ethyl, 2-fluoroethyl, 2, 4-difluoro-5-amino-phenyl; when A is C-Cl, R is not 4-nitro-2-pyridyl; a is C-OCH 3 When R is not 2-fluoroethyl.
Further preferably, R is selected from the group consisting of C2-C4 linear alkyl, 2-fluoroethyl, (2S) -2-fluorocyclopropyl, fluoroaryl, substituted 2-pyridyl; a is selected from CH, C-halogen, C-alkoxy, C-cyano, N.
As still further preferred R is selected from ethyl, 2-fluoroethyl, (2S) -2-fluorocyclopropyl, 2, 4-difluorophenyl, 2-pyridyl, 3, 5-difluoro-6-amino-2-pyridyl; a is selected from CH, C-halogen atom and C-OCH 3 C-cyano, N.
As still further preferred R is selected from ethyl, 2-fluoroethyl, (2S) -2-fluorocyclopropyl, 2, 4-difluorophenyl, 2-pyridyl, 3, 5-difluoro-6-amino-2-pyridyl; a is selected from CH, CCl, CF, C-OCH 3 Or N.
Still further, the fluoroquinolone compound is selected from the group consisting of:
compound 1:1- (2-fluoroethyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 2:1- ((2S) -2-fluorocyclopropyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 3:1- (2-pyridyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 4:1- (3, 5-difluoro-6-amino-2-pyridinyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 5: 1-ethyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 6: 1-ethyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 7:1- (2-fluoroethyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 8:1- ((2S) -2-fluorocyclopropyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 9:1- ((2S) -2-fluorocyclopropyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 10:1- (2, 4-difluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 11:1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 12:1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 13:1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3 (3R) -hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 14:1- ((2S) -2-fluorocyclopropyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 15:1- (2, 4-difluorophenyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 16:1- (2-pyridyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 17:1- (3, 5-difluoro-6-amino-2-pyridinyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 18: 1-ethyl-8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 19:1- ((2S) -2-fluorocyclopropyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 20:1- (2, 4-difluorophenyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 21:1- (2-pyridyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 22:1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 23:1- (2-fluoroethyl) -6-fluoro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid having the structural formula:
compound 24:1- (2-fluoroethyl) -6-fluoro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid having the structural formula:
compound 25:1- ((2S) -2-fluorocyclopropyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid having the structural formula:
compound 26:1- (2-pyridyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalic acid amide-3-carboxylic acid, having the structural formula:
compound 27:1- (3, 5-difluoro-6-amino-2-pyridinyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalic acid dimethylamide-3-carboxylic acid having the structural formula:
in a second aspect, the fluoroquinolone compound of the present invention is synthesized according to the following reaction scheme:
the reaction route is that after the addition coupling reaction of substituted benzoyl chloride and N, N-dimethylamino ethyl acrylate, the substituted benzoyl chloride and various primary amines are subjected to substitution reaction, then the cyclic closure is carried out through intramolecular nucleophilic substitution, then the compound V is obtained through hydrolysis, and finally the target product fluoroquinolone compound is obtained through aromatic nucleophilic substitution reaction with 3-hydroxy pyrrolidine.
In a third aspect, a pharmaceutical composition comprises the fluoroquinolone compound and a salt or hydrate thereof or a pharmaceutically acceptable carrier.
In a fourth aspect, the fluoroquinolone compound and its salt or hydrate or pharmaceutically acceptable carrier, or the application of the pharmaceutical composition in preparing antibacterial drugs.
Further, the bacteria are bacteria or fungi. Still further, the bacteria is any one or more of staphylococcus aureus, methicillin-resistant staphylococcus aureus, klebsiella pneumoniae (high resistance), salmonella (high resistance), micrococcus luteus, enterococcus faecalis (high resistance), bacillus subtilis, escherichia coli, pseudomonas aeruginosa (high resistance), 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 technical scheme of the invention will be clearly and completely described in the following in connection with the embodiments of the invention. Preparation of the 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 2,4, 5-trifluorobenzoyl chloride (4.2 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 6.3g of Compound II in 96% yield.
b) Compound II (6.3 g,20.8 mmol), ethanol (70 mL), glacial acetic acid (3 mL) are mixed, 2-fluoroethylamine hydrochloride (2.3 g,22.8 mmol) is added at room temperature, the mixture is heated to 40 ℃ after the dripping is finished, after the TLC monitoring reaction is finished, the mixture is cooled, a proper amount of water is slowly added into the reaction liquid, stirring and filtering are carried out, and the mixture is dried to obtain 6.3g of compound III with the yield of 95%. LC/MS [ M+H ]] + ＝320.08、[M+Na] + ＝342.06、[M+K] + ＝358.08。
c) Compound III (6.3 g,19.7 mmol), anhydrous potassium carbonate (4.1 g,29.6 mmol) and N, N-dimethylformamide (50 mL) were mixed, heated to 90℃and stirred for 1 hour, 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 5.6g in 96% yield. LC/MS [ M+H ]] + ＝300.07、[M+Na] + ＝322.06、[M+K] + ＝338.04。
d) Compound IV (5.6 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 compound V4.8 g is obtained after drying, and the yield is 94%. LC/MS [ M+H ]] + ＝272.04、[M+Na] + ＝294.03、[M+K] + ＝310.04。
e) Compound V (1.3 g,5.0 mmol) was added to a suspension of 3-hydroxypyrrolidine hydrochloride (0.9 g,7.5 mmol), triethylamine (1.5 g,15.0 mmol) and acetonitrile (20 mL), and the mixture was 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 afforded the desired product 1- (2-fluoroethyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidine) -4-oxo-3-quinolinecarboxylic acid 1.2g in 71% yield. LC/MS [ M+H ]] + ＝339.11、[M+Na] + ＝361.08、[M+K] + ＝375.10。
Example 2: preparation of 1- ((2S) -2-fluorocyclopropyl) -6-fluoro-1, 4-dihydro-7- (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, and the yield was 64%. LC/MS [ M+H ]] + ＝351.11、[M+Na] + ＝373.08、[M+K] + ＝390.09。
Example 3: preparation of 1- (2-pyridinyl) -6-fluoro-1, 4-dihydro-7- (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, and the yield was 58%. LC/MS [ M+H ]] + ＝370.11、[M+Na] + ＝392.10、[M+K] + ＝408.11。
Example 4: preparation of 1- (3, 5-difluoro-6-amino-2-pyridinyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 4):
compound 4 was produced in the same manner as in example 1 except that the corresponding starting materials were used, and the yield was 55%. LC/MS [ M+H ]] + ＝421.14、[M+Na] + ＝443.13、[M+K] + ＝459.11。
Example 5: preparation of 1-ethyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -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 usedThe rate was 63%. LC/MS [ M+H ]] + ＝355.08、[M+Na] + ＝377.10、[M+K] + ＝393.11。
Example 6: preparation of 1-ethyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -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 61%. LC/MS [ M+H ]] + ＝355.09、[M+Na] + ＝377.10、[M+K] + ＝393.08。
Example 7: preparation of 1- (2-fluoroethyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -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 ]] + ＝373.07、[M+Na] + ＝395.08、[M+K] + ＝411.09。
Example 8: preparation of 1- ((2S) -2-fluorocyclopropyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 8):
compound 8 was produced in the same manner as in example 1 except that the corresponding starting materials were used, and the yield was 66%. LC/MS [ M+H ]] + ＝385.07、[M+Na] + ＝407.10、[M+K] + ＝423.08。
Example 9: preparation of 1- ((2S) -2-fluorocyclopropyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -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 63%. LC/MS [ M+H ]] + ＝385.10、[M+Na] + ＝407.12、[M+K] + ＝423.08。
Example 10: preparation of 1- (2, 4-difluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -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, in a yield of 60%. LC/MS [ M+H ]] + ＝439.06、[M+Na] + ＝461.12、[M+K] + ＝477.10。
Example 11: preparation of 1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -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, and the yield was 59%. LC/MS [ M+H ]] + ＝404.07、[M+Na] + ＝426.05、[M+K] + ＝442.11。
Example 12: preparation of 1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -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, and the yield was 51%. LC/MS [ M+H ]] + ＝455.07、[M+Na] + ＝477.09、[M+K] + ＝493.08。
Example 13: preparation of 1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 13):
compound 13 was prepared in 54% yield by the same method as in example 1, except that the corresponding starting materials were used. LC/MS [ M+H ]] + ＝455.05、[M+Na] + ＝477.09、[M+K] + ＝493.10。
Example 14: preparation of 1- ((2S) -fluorocyclopropyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -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, yield 63%. LC/MS [ M+H ]] + ＝369.10、[M+Na] + ＝391.08、[M+K] + ＝407.13。
Example 15: preparation of 1- (2, 4-difluorophenyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -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, and the yield was 55%. LC/MS [ M+H ]] + ＝423.10、[M+Na] + ＝445.09、[M+K] + ＝461.10。
Example 16: preparation of 1- (2-pyridinyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -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, in 58% yield. LC/MS [ M+H ]] + ＝370.11、[M+Na] + ＝392.08、[M+K] + ＝408.10。
Example 17: preparation of 1- (3, 5-difluoro-6-amino-2-pyridinyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -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, yield 44%. LC/MS [ M+H ]] + ＝439.10、[M+Na] + ＝461.09、[M+K] + ＝477.11。
Example 18: preparation of 1-ethyl-8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 18):
compound 18 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 ]] + ＝351.13、[M+Na] + ＝373.09、[M+K] + ＝389.15。
Example 19: preparation of 1- ((2S) -2-fluorocyclopropyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 19):
compound 19 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield 46%. LC/MS [ M+H ]] + ＝381.12、[M+Na] + ＝403.09、[M+K] + ＝419.13。
Example 20: preparation of 1- (2, 4-difluorophenyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 20):
compound 20 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield 43%. LC/MS [ M+H ]] + ＝435.11、[M+Na] + ＝457.15、[M+K] + ＝473.10。
Example 21: preparation of 1- (2-pyridinyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 21):
compound 21 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield was 48%. LC/MS [ M+H ]] + ＝400.13、[M+Na] + ＝422.08、[M+K] + ＝438.07。
Example 22: preparation of 1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid (compound 22):
compound 22 was produced in the same manner as in example 1 except that the corresponding starting materials were used, with a yield of 45%. LC/MS [ M+H ]] + ＝451.12、[M+Na] + ＝473.08、[M+K] + ＝499.10。
Example 23: preparation of 1- (2-fluoroethyl) -6-fluoro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid (compound 23):
compound 23 was produced in the same manner as in example 1 except that the corresponding starting materials were used, and the yield was 59%. LC/MS [ M+H ]] + ＝340.11、[M+Na] + ＝362.08、[M+K] + ＝378.12。
Example 24: preparation of 1- (2-fluoroethyl) -6-fluoro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid (compound 24):
compound 24 was produced in the same manner as in example 1 except that the corresponding starting materials were used, yield 57%. LC/MS [ M+H ]] + ＝340.10、[M+Na] + ＝362.11、[M+K] + ＝378.09。
Example 25: preparation of 1- ((2S) -2-fluorocyclopropyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid (compound 25):
compound 25 was produced in the same manner as in example 1 except that the corresponding starting materials were used, and the yield was 64%. LC/MS [ M+H ]] + ＝352.10、[M+Na] + ＝374.07、[M+K] + ＝390.12。
Example 26: preparation of 1- (2-pyridinyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid (compound 26):
compound 26 was produced in the same manner as in example 1 except that the corresponding starting materials were used, in 53% yield. LC/MS [ M+H ]] + ＝371.11、[M+Na] + ＝393.06、[M+K] + ＝409.05。
Example 27: preparation of 1- (3, 5-difluoro-6-amino-2-pyridinyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid (compound 27):
compound 27 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 ]] + ＝422.09、[M+Na] + ＝444.08、[M+K] + ＝460.11。
Example 28: antibacterial Activity test of the Compounds of the invention
To clarify the utility of the synthesized compounds, the minimum inhibitory concentration (MIcs) of a portion of the target compounds was determined by agar dilution according to the CLSI standard. The experimental culture medium is Mueller.Hinton agar, and the culture plate is cultured for 18-24 hours at 35 ℃. 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 (10)
1. A fluoroquinolone compound and its salt or hydrate or pharmaceutically acceptable carrier, characterized in that: the fluoroquinolone compound has the following formulaThe following structural general formula:wherein R is selected from C2-C6 linear alkyl, 2-fluoroethyl, 2-fluorocyclopropyl, substituted aryl and substituted pyridyl; a is selected from CH, C-halogen atom, C-alkoxy, C-cyano, C-nitro, C-amino and N; wherein when A is N, R is not ethyl, 4-hydroxyphenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 2,4, 6-trifluorophenyl, 3, 5-difluoro-2-pyridinyl, 2, 4-difluoro-5-aminophenyl; when A is CH, R is not ethyl, 4-fluorophenyl or 2, 4-difluorophenyl; when A is C-F, R is not ethyl, 2-fluoroethyl, 2, 4-difluoro-5-amino-phenyl; when A is C-Cl, R is not 4-nitro-2-pyridyl; a is C-OCH 3 When R is not 2-fluoroethyl.
2. The fluoroquinolone compound and its salt or hydrate or pharmaceutically acceptable carrier according to claim 1, wherein: r is selected from C2-C4 linear alkyl, 2-fluoroethyl, (2S) -2-fluorocyclopropyl, fluoroaryl and substituted 2-pyridyl; a is selected from CH, C-halogen, C-alkoxy, C-cyano, N.
3. A fluoroquinolone compound and its salts or hydrates or pharmaceutically acceptable carriers as claimed in claim 2, wherein: r is selected from ethyl, 2-fluoroethyl, (2S) -2-fluorocyclopropyl, 2, 4-difluorophenyl, 2-pyridyl, 3, 5-difluoro-6-amino-2-pyridyl; a is selected from CH, C-halogen atom and C-OCH 3 C-cyano, N.
4. A fluoroquinolone compound and its salts or hydrates or a pharmaceutically acceptable carrier as claimed in claim 3, wherein: r is selected from ethyl, 2-fluoroethyl, (2S) -2-fluorocyclopropyl, 2, 4-difluorophenyl, 2-pyridyl, 3, 5-difluoro-6-amino-2-pyridyl; a is selected from CH, CCl, CF, C-OCH 3 Or N.
5. The fluoroquinolone compound and its salt or hydrate or pharmaceutically acceptable carrier according to claim 4, wherein the fluoroquinolone compound is a pharmaceutically acceptable salt or hydrate of fluoroquinolone compound: the fluoroquinolone compound is selected from the following compounds:
compound 1:1- (2-fluoroethyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 2:1- ((2S) -2-fluorocyclopropyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 3:1- (2-pyridyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 4:1- (3, 5-difluoro-6-amino-2-pyridinyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 5: 1-ethyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 6: 1-ethyl-8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 7:1- (2-fluoroethyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 8:1- ((2S) -2-fluorocyclopropyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 9:1- ((2S) -2-fluorocyclopropyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 10:1- (2, 4-difluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 11:1- (2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 12:1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 13:1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-chloro-6-fluoro-1, 4-dihydro-7- (3 (3R) -hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 14:1- ((2S) -2-fluorocyclopropyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 15:1- (2, 4-difluorophenyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 16:1- (2-pyridyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 17:1- (3, 5-difluoro-6-amino-2-pyridinyl) -6, 8-difluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 18: 1-ethyl-8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 19:1- ((2S) -2-fluorocyclopropyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 20:1- (2, 4-difluorophenyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 21:1- (2-pyridyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the structural formula:
compound 22:1- (3, 5-difluoro-6-amino-2-pyridinyl) -8-methoxy-6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidinyl) -4-oxo-3-quinolinecarboxylic acid having the formula:
compound 23:1- (2-fluoroethyl) -6-fluoro-7- ((3S) -3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid having the structural formula:
compound 24:1- (2-fluoroethyl) -6-fluoro-7- ((3R) -3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid having the structural formula:
compound 25:1- ((2S) -2-fluorocyclopropyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalimide-3-carboxylic acid having the structural formula:
compound 26:1- (2-pyridyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalic acid amide-3-carboxylic acid, having the structural formula:
compound 27:1- (3, 5-difluoro-6-amino-2-pyridinyl) -6-fluoro-7- (3-hydroxypyrrolidinyl) -4-oxo-1, 4-dihydro-1, 8-phthalic acid dimethylamide-3-carboxylic acid having the structural formula:
6. a preparation method of fluoroquinolone compounds is characterized by comprising the following steps: the fluoroquinolone compound is synthesized according to the following reaction route:
the reaction route is that after the addition coupling reaction of substituted benzoyl chloride and N, N-dimethylamino ethyl acrylate, the substituted benzoyl chloride and various primary amines are subjected to substitution reaction, then the cyclic closure is carried out through intramolecular nucleophilic substitution, then the compound V is obtained through hydrolysis, and finally the target product fluoroquinolone compound is obtained through aromatic nucleophilic substitution reaction with 3-hydroxy pyrrolidine.
7. A pharmaceutical composition comprising the fluoroquinolone compound according to any one of claims 1 to 5, and a salt or hydrate thereof or a pharmaceutically acceptable carrier.
8. Use of a fluoroquinolone compound according to any one of claims 1 to 5, a salt or hydrate thereof, or a pharmaceutically acceptable carrier, or a pharmaceutical composition according to claim 7 for the preparation of an antibacterial drug.
9. The use according to claim 8, characterized in that: the bacteria are bacteria or/and fungi.
10. The use according to claim 9, characterized in that: the bacteria are any one or more of staphylococcus aureus, methicillin-resistant staphylococcus aureus, klebsiella pneumoniae, salmonella high-resistance, micrococcus luteus, enterococcus faecalis, enterococcus high-resistance, bacillus subtilis, escherichia coli, pseudomonas aeruginosa high-resistance and bacillus proteus; the fungus is candida albicans and/or candida.
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