CN113402531A - Fluoroquinolone derivative and application thereof as antibacterial drug - Google Patents
Fluoroquinolone derivative and application thereof as antibacterial drug Download PDFInfo
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- CN113402531A CN113402531A CN202110646773.7A CN202110646773A CN113402531A CN 113402531 A CN113402531 A CN 113402531A CN 202110646773 A CN202110646773 A CN 202110646773A CN 113402531 A CN113402531 A CN 113402531A
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- 229940124307 fluoroquinolone Drugs 0.000 title claims abstract description 22
- 229940124350 antibacterial drug Drugs 0.000 title claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 18
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 11
- 241000588724 Escherichia coli Species 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 6
- 125000003003 spiro group Chemical group 0.000 claims abstract description 5
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims description 9
- 239000003242 anti bacterial agent Substances 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- 241000500334 Tetragenococcus Species 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 19
- 241001537924 Tetracoccus <angiosperm> Species 0.000 abstract description 4
- 238000013461 design Methods 0.000 abstract description 2
- -1 quinolone compound Chemical group 0.000 abstract description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
- 150000001875 compounds Chemical class 0.000 description 38
- 239000007787 solid Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 241000894006 Bacteria Species 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229960003376 levofloxacin Drugs 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 2
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000015572 biosynthetic process Effects 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
- 239000012043 crude product Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 1
- ILNJBIQQAIIMEY-UHFFFAOYSA-N 4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CN=C21 ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 1
- PRSVXRUERNSVCI-UHFFFAOYSA-N 8-fluoro-2-methyl-5-(2-pyridin-4-ylethyl)-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(F)=CC=C1N2CCC1=CC=NC=C1 PRSVXRUERNSVCI-UHFFFAOYSA-N 0.000 description 1
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- 108010041052 DNA Topoisomerase IV Proteins 0.000 description 1
- 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 1
- 241000192041 Micrococcus Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000005782 double-strand break Effects 0.000 description 1
- 238000001035 drying Methods 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960003085 meticillin Drugs 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
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960003165 vancomycin Drugs 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
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) 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)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- 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
-
- 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
-
- 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
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- 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
本发明公开了一种氟喹诺酮衍生物，其特征在于，具有通式(I)所示的结构或其异构体或其可药用的盐或上述结构的混合物。其中：R1选自C1～C4的烷基；或者R1选自与其所连吡咯烷基共用一个或两个碳原子的螺环或桥环烷烃链，R1中包含1～6个碳原子；苯环上O原子择一与R2或者R3相连：与R2相连时，R2选自取代或者未取代的C2～C4亚烷基，R3不存在；与R3相连时，R2选自C3～C6的环烷基，R3选自C1～C3的烷基。本发明提供的氟喹诺酮衍生物，对大肠杆菌，金黄色葡萄球菌和四联球菌都有良好的抑制效果，为喹诺酮类化合物结构的进一步设计提供了一定的参考。The invention discloses a fluoroquinolone derivative, which is characterized in that it has the structure represented by the general formula (I) or an isomer or a pharmaceutically acceptable salt thereof or a mixture of the above structures. Wherein: R 1 is selected from C1-C4 alkyl groups; or R 1 is selected from spiro or bridged cycloalkane chains that share one or two carbon atoms with the pyrrolidinyl group to which it is attached, and R 1 contains 1 to 6 carbon atoms ; O atom on the benzene ring is connected with R 2 or R 3 alternatively: when connecting with R 2 , R 2 is selected from substituted or unsubstituted C2-C4 alkylene, and R 3 does not exist; When connecting with R 3 , R 2 2 is selected from C3-C6 cycloalkyl, and R 3 is selected from C1-C3 alkyl. The fluoroquinolone derivatives provided by the invention have good inhibitory effects on Escherichia coli, Staphylococcus aureus and Tetracoccus, and provide a certain reference for the further design of the quinolone compound structure.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a fluoroquinolone derivative and application thereof as an antibacterial drug.
Background
The increase in bacterial resistance has become a serious problem in the clinical practice of antimicrobial chemotherapy. Since the incidence of drug-resistant bacteria such as methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant streptococcus (VRE), and penicillin-resistant streptococcus (PRSP) is on the rise, there is an urgent need to develop effective drugs for infection.
Quinolone antibacterial agents are mainly achieved by inhibiting DNA gyrase and topoisomerase iv in bacteria, thereby causing DNA double strand breaks and preventing their reconnection. The 1 st generation quinolone drugs were marketed in 1962 with only moderate activity against gram-negative bacteria and low oral absorption. Through structural modification, 2 nd, 3 rd and 4 th generation quinolone medicaments are developed and produced, and representative thereof are pipemidic acid, ciprofloxacin, moxifloxacin and the like.
The fluoroquinolone medicaments are chemically synthesized medicaments taking 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as a parent nucleus structure, have remarkable medicinal properties, such as broad-spectrum bactericidal property, small toxic and side effects after use, relatively simple and easy synthesis of a medicament molecular structure, moderate medicament price and broad-spectrum activity, and become antibacterial medicaments which are synthesized, developed and applied quickly at home and abroad (Chang, X.; Meyer, M.T.; Liu, X.; et al. Envrion. Polluti.2010, 53,1444; Andreu, V.; Blasco C.; Pic, Y.TrAC Trends in antibacterial chemistry.2007,26,534).
Disclosure of Invention
The invention provides a fluoroquinolone derivative with a good antibacterial effect.
The invention also provides an antibacterial drug which comprises one or more of the fluoroquinolone derivatives and has a good antibacterial effect on test bacteria.
A fluoroquinolone derivative having a structure represented by general formula (I) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the foregoing structures:
wherein: r1Alkyl selected from C1-C4; or R1Selected from spiro or bridged alkane chains sharing one or two carbon atoms with the pyrrolidinyl group to which they are attached, R1Contains 1 to 6 carbon atoms;
in the general formula (I), one O atom on the benzene ring is selected from R2Or R3Connecting: and R2When they are linked, R2Selected from substituted or unsubstituted C2-C4 alkylene, when R is3Is absent; and R3When they are linked, R2Selected from the group consisting of C3-C6 cycloalkyl, R3Is selected from alkyl of C1-C3.
Preferably, in the general formula (I), the O atom and R on the benzene ring2When they are linked, R2Selected from substituted or unsubstituted C2 to C3 alkylene; and R3When they are linked, R2Selected from the group consisting of C3-C4 cycloalkyl, R3Is selected from alkyl of C1-C3.
As a further preference, the R group3Selected from methyl and ethyl.
Preferably, the compound has a structure represented by the general formula (I-a) or (I-2) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the above structures:
n1 is a natural number of 1-3; more preferably, n1 is 1 or 2.
Preferably, the salt is the hydrochloride salt.
Preferably, R1When they share two carbon atoms with the pyrrolidinyl group to which they are attached, the carbon atom is NH in formula (I)2The C atom to which it is attached.
Preferably, R1Alkyl selected from C1-C3; or R1Selected from spiro or bridged alkane chains sharing one or two carbon atoms with the pyrrolidinyl group to which they are attached, R1Contains 2 to 6 carbon atoms. As further preferred, R1In the structure of a bridged ring (sharing two C atoms), R1Contains 1 to 4 carbon atoms; r1Is a spiro ring(sharing a C atom) structure, R1Contains 1 to 6 carbon atoms.
Preferably, C designated by 1 and 2 is S, R configuration, S, S configuration, R, S configuration, R, R configuration.
Preferably, the compound has a structure represented by the following structural formula or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the above structures:
preferably, the compound is obtained by subjecting a raw material represented by formula (3) and a raw material represented by formula (1) to substitution reaction and deprotection:
the raw material shown in the formula (3) can be prepared from
(2) Under the action of palladium-carbon catalyst, removing protecting group of carbobenzoxy by normal pressure hydrogenolysis.
When the compound represented by the formula (3) and the compound represented by the formula (1) are reacted, the molar ratio of the compound represented by the formula (3) to the compound represented by the formula (1) is preferably 1.5 to 2.5: 1. More preferably, the molar ratio of the compound represented by the formula (3) to the compound represented by the formula (1) is 2: 1. The reaction temperature is 90-110 ℃. The reaction solvent is DMSO or DMF. After the reaction is finished, extracting with an extracting agent (such as dichloromethane, chloroform, toluene and the like), removing the solvent to obtain a crude product, and recrystallizing with an alcohol solvent (ethanol) to obtain the target product.
The method comprises the steps of removing a carbobenzoxy protecting group by normal pressure hydrogenolysis with a formula (2) as an initial raw material under the action of a palladium-carbon catalyst, obtaining a product (3) with a quantitative yield without purification, and heating the product and a compound shown in the formula (1) in an organic solvent (such as DMSO) to 90-110 ℃ for substitution reaction to obtain an intermediate with a Boc protecting group respectively, wherein in the step, the raw material shown in the formula (1) can be completely reacted, so that the subsequent purification is facilitated, the dosage of the compound shown in the formula (3) is 1 time excessive, the obtained crude product is deprotected under the action of concentrated hydrochloric acid to form a hydrochloride, the compound fluoroquinolone derivative with high purity can be obtained by ethanol crystallization, and the total yield reaches 55-65%.
An antibacterial drug comprising one or more of the fluoroquinolone derivatives described above.
Preferably, the antibacterial drug is an antibacterial drug inhibiting one or more of escherichia coli, staphylococcus aureus and tetracoccus.
The compound shown in the formula (2) is used as a starting material, and a plurality of fluoroquinolone derivatives are synthesized through hydrogenolysis, coupling (or substitution) and deprotection, wherein the total yield is 50-65%. The result of the antibacterial activity test shows that the content of the antibacterial agent is 6 mg.mL-1Under the concentration, the target compound synthesized by the method has good inhibition effect on escherichia coli, staphylococcus aureus and tetralococcus, wherein A1 and A2 in the compound respectively have the best inhibition effect on staphylococcus aureus and escherichia coli, and are weaker than levofloxacin; the compound A5 (shown in the example) has better inhibiting diameter on tetragenococcus than levofloxacin, and the experimental result shows that the compound formed by introducing 3-aminopyrrolidine into C7 position of fluoroquinolone has good inhibiting effect on three test bacteria, which provides a certain reference for further design of the structure of the quinolone compound.
Detailed Description
2a and 2e reference (Bohdan, A.; Chalyk, M.V.; Butko, O.O.; Yanhyna, K.S.; Gavrilenko, T.D.; Pavel, K.M.Chem.Eur.J.2017,23,16782; Elvira, R.Z., Alexander, Y.S., Nadezhda, S.B., et al.chemistry of heterocylic Compounds,2019,55:676 678 and Stephen, T.W.WO 2012125893,2014.)2c and 2d reference (Hisashi, T., Satoshi, K., Takahihi, K., et al. US2014142096A1,2014) and 2b, 2f, 2g and 2h are available from Shanghai chemical Co., Ltd.
Example (b): synthesis of A1-A6 and B1-B4
Dissolving the pyrrolidine 2 a-2 h (1.15mmol) in 30mL of methanol, adding a palladium-carbon catalyst (20mg, 5% Pd/C), carrying out hydrogenation reaction for 1h under normal pressure under the condition of hydrogen, carrying out TCL (thermal transfer chromatography) tracing reaction, filtering to remove palladium-carbon catalyst solids after the reaction is finished, and removing the solvent under reduced pressure to obtain quantitative intermediates 3 a-3 h, wherein the next reaction is directly carried out without purification.
Dissolving the compound 1a or 1b (0.47mmol) in 3mL DMSO, adding the intermediate 3 a-3H (0.94mmol), heating to 100 ℃, reacting for 2H, and adding H2The system was diluted with O and extracted with DCM (20 mL. times.3). And (3) drying the combined DCM, performing rotary evaporation to remove the solvent to obtain a yellow solid, putting the solid in an ice bath, adding concentrated hydrochloric acid (5mL), gradually heating to the normal temperature, reacting for 1h, performing plate tracking reaction, and crystallizing the solid by using ethanol after the solvent is removed by rotary evaporation to obtain compounds A1-A6 and compounds B1-B4.
Reaction correspondence table:
130mg of compound A1, light yellow solid, 67.6% m.p.229-230 ℃;1H NMR(600MHz,DMSO)δ15.34(s,1H),8.93(s,1H),8.31(s,2H),7.58(dd,J＝13.9,1.7Hz,1H),4.94～4.85(m,1H),4.57～4.52(m,1H),4.29(t,J＝9.7Hz,2H),4.26～4.16(m,1H),3.87(dd,J＝24.9,11.9Hz,1H),3.39(s,1H),1.45(dd,J＝6.6,2.1Hz,3H),1.12(dd,J＝9.0,4.7Hz,1H),0.90～0.83(m,1H),0.80～0.69(m,2H)；13C NMR(151MHz,DMSO)δ176.1,166.3,153.0,146.0,137.4,130.4,124.9,117.3,106.6,103.6,68.2,67.9,57.2,54.8,50.7,31.7,31.7,24.8,18.0；HRMS(ESI)calcd for[(C19H21ClFN3O4－HCl)+H]+＝C19H20FN3O4(M+H)+374.1511,found 374.1480.
compounds A2 to A6 and B1 to B4 were synthesized in the same manner as described above.
90mg of compound A2, namely a light yellow solid, 59.6 percent, m.p.231-232 ℃;1H NMR(600MHz,DMSO)δ15.37(s,1H),8.93(s,1H),8.43(s,2H),7.56(d,J＝13.2Hz,1H),4.93～4.86(m,1H),4.55(d,J＝10.8Hz,1H),4.34～4.22(m,1H),4.16～3.99(m,2H),3.81～3.69(m,3H),2.40～2.32(m,1H),2.17～2.07(m,1H),2.02～1.85(m,4H),1.46(t,J＝6.3Hz,3H)；13C NMR(151MHz,DMSO)δ176.2,166.3,146.3,130.3,125.2,125.0,116.5,106.3,104.0,103.8,68.2,67.9,55.6,55.0,45.9,31.5,24.1,18.3,17.9,15.3；HRMS(ESI)calcd for[(C20H23ClFN3O4－HCl)+H]+＝C20H22FN3O4(M+H)+388.1667,found 388.1640.
88mg of compound A3, light yellow solid, 60.2% m.p.232-233 ℃;1H NMR(600MHz,DMSO)δ15.37(s,1H),8.92(s,1H),8.43(s,2H),7.56(d,J＝13.9Hz,1H),4.89(s,1H),4.55(d,J＝11.4Hz,1H),4.30(t,J＝12.4Hz,1H),4.18(ddd,J＝16.1,11.2,4.5Hz,1H),3.92(ddd,J＝12.7,10.2,2.9Hz,1H),3.79(t,J＝12.9Hz,1H),3.60～3.49(m,2H),1.85(d,J＝9.7Hz,1H),1.65(dd,J＝21.2,10.9Hz,6H),1.54(dd,J＝11.6,5.9Hz,1H),1.46(dd,J＝6.3,3.5Hz,3H)；13C NMR(151MHz,DMSO)δ176.4,166.7,146.5,130.7,125.5,125.3,116.8,106.6,104.2,104.1,68.5,68.2,56.4,55.4,51.6,36.5,30.4,24.8,24.4,18.6,18.2；HRMS(ESI)calcd for[(C21H25ClFN3O4－HCl)+H]+＝C21H24FN3O4(M+H)+402.1824,found 402.1792.
70mg of compound A4, light yellow solid, 49.8% m.p.233-234 ℃;1H NMR(600MHz,DMSO)δ15.35(s,1H),8.94(s,1H),8.25(s,2H),7.58(d,J＝13.8Hz,1H),4.89(s,1H),4.55(d,J＝11.2Hz,1H),4.37～4.29(m,1H),4.20～4.10(m,1H),3.87～3.71(m,2H),3.63(dd,J＝20.5,9.9Hz,1H),3.52(s,1H),1.67～1.52(m,6H),1.46(d,J＝6.6Hz,3H),1.34～1.21(m,4H)；13C NMR(151MHz,DMSO)δ176.2,166.3,146.3,136.3,125.1,125.1,116.8,106.4,103.9,103.7,68.1,67.9,57.9,56.6,54.9,43.3,33.5,28.5,25.4,22.5,18.1,17.9；HRMS(ESI)calcd for[(C22H27ClFN3O4－HCl)+H]+＝C22H26FN3O4(M+H)+416.1980,found 416.1945.
66mg of compound A5, light yellow solid, 58.8% m.p.215-216 ℃;1H NMR(600MHz,DMSO)δ15.25(s,1H),8.99(s,1H),8.62(s,2H),7.63(d,J＝12.8Hz,1H),4.94(d,J＝6.7Hz,1H),4.61(d,J＝11.3Hz,1H),4.40(d,J＝11.3Hz,1H),3.91(dd,J＝53.9,10.3Hz,1H),3.67(d,J＝10.2Hz,1H),3.58(s,1H),3.55～3.46(m,1H),2.98(d,J＝3.3Hz,1H),2.36(dd,J＝23.2,15.4Hz,1H),2.16(dd,J＝13.7,8.0Hz,2H),1.68(dd,J＝21.1,12.0Hz,1H),1.47(d,J＝6.5Hz,3H),1.23(s,2H)；13C NMR(151MHz,DMSO)δ176.5,166.7,146.6,130.6,130.6,125.6,125.3,116.8,106.7,104.3,68.5,68.2,55.3,46.2,31.8,24.4,18.6,18.2,15.6；HRMS(ESI)calcd for[(C19H21ClFN3 O 4－HCl)+H]+＝C19H20FN3 O 4(M+H)+374.1511,found 374.1485.
110mg of compound A6, light yellow solid, 65.6% m.p.228-229 ℃;1H NMR(600MHz,DMSO)δ8.91(s,1H),7.53(d,J＝13.4Hz,1H),4.87(d,J＝6.5Hz,1H),4.54(d,J＝11.3Hz,1H),4.30(d,J＝11.3Hz,1H),3.82(dt,J＝17.5,8.2Hz,1H),3.67～3.44(m,3H),2.12(s,1H),1.96(td,J＝14.0,7.0Hz,1H),1.78～1.66(m,3H),1.64～1.58(m,1H),1.42(dd,J＝20.8,6.7Hz,4H)；13C NMR(151MHz,DMSO)δ176.6,166.7,146.4,139.3,129.8 125.2,119.1,106.9,103.9,103.7,68.5,59.5,56.5,56.3,55.6,55.4,41.1,28.5,19.1,18.2；HRMS(ESI)calcd for[(C20H23ClFN3O4－HCl)+H]+＝C20H22FN3O4(M+H)+388.1667,found 388.1635.
80mg of compound B1, a red-brown solid, 60.1%. m.p.215-216 ℃;1H NMR(600MHz,DMSO)δ15.12(s,1H),8.66(s,1H),8.51(s,2H),7.69(d,J＝11.8Hz,1H),4.14(s,1H),3.88(dd,J＝132.3,23.9Hz,5H),3.54(s,3H),2.16(s,1H),1.92(s,5H),1.17(s,1H),1.06(d,J＝32.1Hz,2H),0.91(s,1H)；13C NMR(151MHz,DMSO)δ176.0,166.0,163.6,152.0,150.4,141.0,136.3,134.4,117.6,106.3,61.6,59.5,55.5,53.4,45.9,40.8,30.7,24.0,15.2,9.5,8.6；HRMS(ESI)calcd for[(C21H25ClFN3O4－HCl)+H)+＝C21H24FN3O4(M+H)+402.1824,found 402.1789.
60mg of compound B2, light yellow solid, 55.5% m.p.235-236 ℃;1H NMR(600MHz,DMSO)δ15.12(s,1H),8.67(s,1H),7.70(d,J＝13.9Hz,1H),4.17～4.12(m,1H),4.02(dd,J＝12.3,7.0Hz,1H),3.84(dd,J＝10.6,4.2Hz,1H),3.68～3.59(m,3H),3.57(s,3H),1.65～1.45(m,8H),1.41～1.26(m,4H),1.13(dd,J＝12.6,5.7Hz,1H),1.08～1.00(m,2H),1.01～0.92(m,1H)；13C NMR(151MHz,DMSO)δ176.2,166.0,152.2,150.6,141.3,136.6,134.6,117.9,106.9,106.6,62.1,57.8,56.5,53.7,43.4,40.8,40.1,33.5,28.5,25.5,22.5,9.3,8.9；HRMS(ESI)calcd for[(C23H29ClFN3O4－HCl)+H]+＝C23H28FN3O4(M+H)+430.2064,found 430.2096.
55mg of compound B3, light yellow solid, 58.9%. m.p.212-213 ℃;1H NMR(600MHz,DMSO)δ15.14(s,1H),8.66(s,1H),8.39(s,2H),7.68(d,J＝13.9Hz,1H),4.18～4.11(m,1H),4.04(dd,J＝11.7,4.8Hz,1H),3.90(s,1H),3.75(dd,J＝9.0,4.3Hz,2H),3.66(d,J＝11.9Hz,1H),3.56(s,3H),2.43～2.32(m,1H),1.59(dt,J＝13.8,6.9Hz,1H),1.51～1.42(m,1H),1.26～1.08(m,3H),1.01(d,J＝7.3Hz,1H),0.98(t,J＝7.3Hz,3H),0.88(dd,J＝10.6,6.0Hz,1H)；13C NMR(151MHz,DMSO)δ176.4,166.3,152.3,150.8,141.3,137.0,135.0,117.9,107.1,106.7,62.4,55.9,53.9,51.9,42.6,41.1,19.8,12.9,10.1,8.8；HRMS(ESI)calcd for[(C20H25ClFN3O4－HCl)+H]+＝C20H24FN3O4(M+H)+390.1824,found 390.1785.
102mg of compound B4, light yellow solid, 55.6% m.p.223-224 ℃;1H NMR(600MHz,DMSO)δ8.73(s,2H),8.64(s,1H),7.62(d,J＝13.7Hz,1H),4.14(s,1H),3.89(t,J＝7.5Hz,1H),3.87～3.82(m,1H),3.75(dd,J＝10.3,6.0Hz,1H),3.59(s,3H),3.54(s,1H),3.49～3.45(m,1H),2.33(d,J＝4.8Hz,1H),1.79(dd,J＝12.6,6.1Hz,1H),1.42～1.33(m,1H),1.14(s,1H),1.08～1.00(m,2H),0.94(t,J＝7.3Hz,5H)；13C NMR(151MHz,DMSO)δ176.1,165.9,154.0,152.4,150.4,141.8,136.2,134.4,118.1,106.5,62.0,54.5,54.1,53.2,43.5,40.8,23.5,12.0,9.3,8.8；HRMS(ESI)calcd for[(C20H25ClFN3O4－HCl)+H]+＝C20H24FN3O4(M+H)+390.1824,found 390.1798.
antimicrobial Activity test
In order to evaluate the antibacterial activity of fluoroquinolone derivatives, the present invention uses a filter paper method, and uses levofloxacin and DMSO as a positive control and a negative control, and the inhibitory activity of synthesized 10 target compounds on Escherichia coli (Escherichia coli), Staphylococcus aureus (Staphylococcus aureus) and tetracoccus (Micrococcus tetragenus) is determined, and the test results are shown in table 1:
TABLE 1 antibacterial Activity of the target Compounds
The results showed that the concentration was 6 mg. multidot.mL-1At the concentration, the 10 target compounds synthesized by the invention have good inhibitory activity on 3 test bacteria. The inhibiting diameter of the target compound to the escherichia coli is 16.1-25.9 mm, wherein the inhibiting activity of A2 to the escherichia coli is the highest, and the inhibiting radius reaches levofloxacin82.5% of; the inhibiting diameter of the target compound to staphylococcus aureus is 13.9-24.0 mm, wherein the inhibiting activity of A1 to staphylococcus aureus is the highest, and the inhibiting radius reaches 81.6% of that of levofloxacin; the inhibiting diameter of the target compound to the tetracoccus is 14.2-24.8 mm, wherein the inhibiting radius of A5 exceeds that of levofloxacin, and the inhibiting radius is 119.3% of that of levofloxacin. The substituent at the C7 position of the compound A2 and the substituent at the C1 are the same, and the inhibition effect on the three test bacteria is basically the same; the substituent of the C7 position of the compound A4 is the same as that of the C2, but the inhibitory activity of the A4 to staphylococcus aureus and tetralococcus is obviously higher than that of the B2, and the inhibitory activity to escherichia coli is not obviously different. In general, 10 compounds synthesized by the present invention have inhibitory activity against three test bacteria, and the antibacterial activity of six compounds synthesized using the raw material 1a as a precursor is slightly higher than that of four compounds synthesized using the raw material 1b as a precursor.
Claims (8)
1. A fluoroquinolone derivative having a structure represented by general formula (I) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the foregoing structures:
wherein: r1Alkyl selected from C1-C4; or R1Selected from spiro or bridged alkane chains sharing one or two carbon atoms with the pyrrolidinyl group to which they are attached, R1Contains 1 to 6 carbon atoms;
selecting one O atom on benzene ring and R2Or R3Connecting: and R2When they are linked, R2Selected from substituted or unsubstituted C2-C4 alkylene, R3Is absent; and R3When they are linked, R2Selected from the group consisting of C3-C6 cycloalkyl, R3Is selected from alkyl of C1-C3.
2. The fluoroquinolone derivative according to claim 1, having a structure represented by general formula (I-a) or (I-2) or an isomer thereof or a pharmaceutically acceptable salt thereof or a mixture of the aforementioned structures:
n1 is a natural number of 1 to 3.
3. A fluoroquinolone derivative according to claim 1 or 2, wherein the salt is a hydrochloride salt.
4. A fluoroquinolone derivative according to claim 1 or 2, wherein R1When they share two carbon atoms with the pyrrolidinyl group to which they are attached, the carbon atom is NH in formula (I)2The C atom to which it is attached.
5. A fluoroquinolone derivative according to claim 1 or 2, having the structure shown in the following structural formula or isomers thereof or pharmaceutically acceptable salts thereof or mixtures of the above structures:
6. the fluoroquinolone derivative according to claim 1 or 2, wherein the fluoroquinolone derivative is obtained by subjecting a raw material represented by formula (3) and a raw material represented by formula (1) to substitution reaction and deprotection:
7. an antibacterial drug comprising one or more fluoroquinolone derivatives according to any one of claims 1 to 6.
8. The antibacterial agent according to claim 7, wherein the antibacterial agent is an antibacterial agent that inhibits one or more of Escherichia coli, Staphylococcus aureus, and Tetragenococcus.
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| CN114989165A (en) * | 2022-05-30 | 2022-09-02 | 青岛大学附属医院 | Compound or composition for resisting retention bacteria and biofilm bacteria and application thereof |
| CN117903163A (en) * | 2024-01-10 | 2024-04-19 | 广东工业大学 | Fluoroquinolone compound with spiro structure at C7 position and application thereof |
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| US20080045520A1 (en) * | 2004-05-13 | 2008-02-21 | Daiichi Pharmaceutical Co., Ltd. | Substituted Pyrrolidine Derivative |
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| CN1175251A (en) * | 1995-02-02 | 1998-03-04 | 大日本制药株式会社 | Pyridonecarboxylic acid derivative substituted by bicyclic amino group, ester thereof, salt thereof, and bicyclic amine as intermediate thereof |
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| CN114989165A (en) * | 2022-05-30 | 2022-09-02 | 青岛大学附属医院 | Compound or composition for resisting retention bacteria and biofilm bacteria and application thereof |
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