CN113402531A - 氟喹诺酮衍生物及作为抗菌性药物的应用 - Google Patents
氟喹诺酮衍生物及作为抗菌性药物的应用 Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- fluoroquinolone
- formula
- fluoroquinolone derivative
- carbon atoms
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 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
- 150000001335 aliphatic alkanes Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 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
- 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
- 230000000694 effects Effects 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- 238000013461 design Methods 0.000 abstract description 2
- -1 quinolone compound Chemical class 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
- 150000001875 compounds Chemical class 0.000 description 38
- 230000002401 inhibitory effect Effects 0.000 description 18
- 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
- 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
- 241001537924 Tetracoccus <angiosperm> Species 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
- 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
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
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。
Description
技术领域
本发明属于有机合成技术领域，具体是涉及一种氟喹诺酮衍生物及作为抗菌性药物的应用。
背景技术
细菌抗药性的增强已成为在抗微生物化学疗法的临床实践中的严重问题。由于耐甲氧西林金黄色葡萄球菌(MRSA)，万古霉素耐性链球菌(VRE)，和耐青霉素的链球菌(PRSP)等耐药菌的发病率呈上升趋势，所以迫切需要研制用于感染的有效药物。
喹诺酮类抗菌主要是通过抑制细菌中的DNA回旋酶和拓扑异构酶Ⅳ，进而导致DNA双链断裂，并阻止其再连接来实现的。第1代喹诺酮类药物1962年上市，其仅具有对革兰阴性菌的适度活性且口服吸收率低。通过结构修饰，第2、3和4代喹诺酮类药物相继被开发问世，其代表性的吡哌酸、环丙沙星和莫西沙星等.与第1代相比，具有更广谱的活性，并且改善了对革兰阴性菌的活性，使抗菌谱扩大，在治疗多种感染方面具有很高的临床疗效。
氟喹诺酮类药物是以4-氧代-1,4-二氢喹啉-3-羧酸为母核结构的化学合成药物，氟喹诺酮药物具有显著的药性特点，例如广谱杀菌性、较小的用后毒副作用、药物分子结构相对简单较易合成、适中的药物价格，并且具有广谱的活性，成为国内外合成、开发和应用较快的抗菌类药物(Chang,X.；Meyer,M.T.；Liu,X.；et al.Envrion.Pollut.2010,53,1444；Andreu,V.；Blasco,C.；Pic,Y.TrAC Trends in Analytical Chemistry.2007,26,534)。
发明内容
本发明提供了一种氟喹诺酮衍生物，具有良好的抑菌效果。
本发明还提供了一种抗菌性药物，其包括所述氟喹诺酮衍生物中的一种或多种，对于试细菌都有良好的抑菌效果。
一种氟喹诺酮衍生物，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；
通式(I)中，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，此时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。
作为优选，通式(I)中，苯环上O原子与R2相连时，R2选自取代或者未取代的C2～C3亚烷基；与R3相连时，R2选自C3～C4的环烷基，R3选自C1～C3的烷基。
作为进一步优选，所述R3选自甲基、乙基。
作为优选，具有通式(I-a)或(I-2)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：
n1为1～3的自然数；作为进一步的优选，n1为1或2。
作为优选，所述盐为盐酸盐。
作为优选，R1为与其所连吡咯烷基共用两个碳原子时，该碳原子为通式(I)中NH2所连的C原子。
作为优选，R1选自C1～C3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2～6个碳原子。作为进一步优选，R1为桥环(共用两个C原子)结构时，R1中包含1～4个碳原子；R1为螺环(共用一个C原子)结构时，R1中包含1～6个碳原子。
作为优选，1和2所标注的C为S、R构型、S、S构型、R、S构型、R、R构型。
作为优选，具有如下结构式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：
作为优选，由式(3)所示的原料与式(1)所示的原料经过取代反应、脱保护得到：
所述式(3)所示的原料可由
(2)在钯碳催化剂作用下，常压氢解脱去苄氧羰基保护基得到。
式(3)所示化合物与式(1)所示化合物反应时，作为优选，式(3)所示化合物与式(1)所示化合物的摩尔比为1.5～2.5:1。作为进一步优选，所述式(3)所示化合物与式(1)所示化合物的摩尔比为2:1。反应温度为90～110℃。反应溶剂为DMSO或者DMF等。反应完成后，利用萃取剂(比如二氯甲烷，氯仿，甲苯等)萃取，然后去除溶剂得到粗品，可以利用醇类溶剂(乙醇)进行重结晶得到目标产物。
本发明利用以式(2)为起始原料，在钯碳催化剂作用下，常压氢解脱去苄氧羰基保护基，以定量的产率得到产品(3)无须纯化，分别与式(1)所示的化合物在有机溶剂(比如DMSO)中加热至90～110℃下进行取代反应得到带有Boc保护基的中间体，在该步骤中，由于保证式(1)所示原料能够反应完全，利于后面的纯化，使式(3)所示的化合物的用量过量1倍，这样得到的粗品在浓盐酸作用下脱保护形成的盐酸盐，用乙醇结晶可以得到高纯度的化合物氟喹诺酮衍生物，总收率达到55％～65％。
一种抗菌性药物，含有上述任一项所述的氟喹诺酮衍生物中的一种或多种。
作为优选，所述抗菌性药物为抑制大肠杆菌、金黄色葡萄球菌及四联球菌中的一种或多种的抗菌性药物。
本文以式(2)所示化合物为起始原料，通过氢解，偶联(或者取代)及去保护合成了多种所述氟喹诺酮衍生物，总收率50％～65％。抗菌活性测试结果显示，在6mg·mL-1浓度下，本文合成的目标化合物对大肠杆菌，金黄色葡萄球菌和四联球菌都有良好的抑制效果，其中化合物中A1和A2分别对金黄色葡萄球菌和大肠杆菌抑制效果最好，微弱于左氧氟沙星；化合物A5(实施例所示)对四联球菌的抑制直径优于左氧氟沙星.实验结果表明将3-氨基吡咯烷引入氟喹诺酮C7位形成的化合物对三种供试细菌均有良好的抑制作用，这为喹诺酮类化合物结构的进一步设计提供了一定的参考。
具体实施方式
2a和2e参照文献制备，(Bohdan,A.；Chalyk,M.V.；Butko,O.O.；Yanshyna,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 Heterocyclic Compounds,2019,55:676-678和Stephen,T.W.WO 2012125893,2014.)2c和2d参照文献(Hisashi,T.,Satoshi,K.,Takahiro,K.,et al..US2014142096A1,2014)制备，2b、2f、2g和2h购于上海孟善化工有限公司。
实施例：A1～A6、B1～B4的合成
将上述吡咯烷2a～2h(1.15mmol)溶于30mL甲醇中，加入钯碳催化剂(20mg，5％Pd/C)，氢气条件下，常压氢化反应1h，TCL追踪反应，反应完毕后，过滤除去钯碳催化剂固体，减压去溶剂，得到定量中间体3a～3h，无需纯化直接进行下一步反应。
将化合物1a或1b(0.47mmol)溶于3mL DMSO中，加入上述中间体3a～3h(0.94mmol)，升温至100℃，2h反应结束，加入H2O稀释体系，DCM(20mL×3)萃取。合并DCM干燥后旋蒸除去溶剂，得到黄色固体，将固体置于冰浴中，加入浓盐酸(5mL)后，逐渐升温至常温，反应1h点板追踪反应结束，旋蒸除去溶剂后，固体用乙醇结晶，得到化合物A1～A6和B1～B4。
反应对应关系表格：
化合物A1:130mg,淡黄色固体,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,found374.1480.
化合物A2～A6和B1～B4同样参照上述方法合成.
化合物A2:90mg,淡黄色固体,59.6％.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.
化合物A3:88mg,淡黄色固体,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.
化合物A4:70mg,淡黄色固体,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.
化合物A5:66mg,淡黄色固体,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,found374.1485.
化合物A6:110mg,淡黄色固体,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.
化合物B1:80mg,棕红色固体,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.
化合物B2:60mg,淡黄色固体,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,found430.2096.
化合物B3:55mg,淡黄色固体,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.
化合物B4:102mg,淡黄色固体,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.
抗菌活性测试
为了评估氟喹诺酮衍生物的抗菌活性，本发明采用滤纸片法，以左氧氟沙星和DMSO作为阳性对照和阴性对照，测定了合成的10种目标化合物对大肠杆菌(Escherichiacoli)、金黄色葡萄球菌(Staphylococcus aureus)及四联球菌(Micrococcus tetragenus)的抑制活性，测试结果如表1所示：
表1目标化合物的抗菌活性
结果显示，在6mg·mL-1浓度下，本发明合成的10种目标化合物对3种供试细菌均有良好的抑制活性。目标化合物对大肠杆菌的抑制直径在16.1mm～25.9mm，其中A2对大肠杆菌抑制活性最高，抑菌半径达到左氧氟沙星的82.5％；目标化合物对金黄色葡萄球菌的抑制直径在13.9mm～24.0mm，其中A1对金黄色葡萄球菌的抑制活性最高，抑菌半径达到左氧氟沙星的81.6％；目标化合物对四联球菌的抑制直径在14.2mm～24.8mm，其中A5抑菌半径超过左氧氟沙星，抑菌半径为左氧氟沙星的119.3％。化合物A2与B1的C7位取代基相同，并且对三种供试细菌的抑制作用基本相同；化合物A4与B2的C7位的取代基相同，但是A4对金黄色葡萄球菌和四联球菌的抑制活性明显高于B2，对大肠杆菌的抑制活性无明显差异。总体而言，本发明所合成的10种化合物对三种供试细菌均有抑制活性，并且以原料1a为前体合成的六种化合物的抗菌活性略高于以原料1b为前体合成的四种化合物。
Claims (8)
1.一种氟喹诺酮衍生物，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。
2.根据权利要求1所述的氟喹诺酮衍生物，其特征在于，具有通式(I-a)或(I-2)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：
n1为1～3的自然数。
3.根据权利要求1或2所述的氟喹诺酮衍生物，其特征在于，所述盐为盐酸盐。
4.根据权利要求1或2所述的氟喹诺酮衍生物，其特征在于，R1为与其所连吡咯烷基共用两个碳原子时，该碳原子为通式(I)中NH2所连的C原子。
5.根据权利要求1或2所述的氟喹诺酮衍生物，其特征在于，具有如下结构式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：
6.根据权利要求1或2所述的氟喹诺酮衍生物，其特征在于，由式(3)所示的原料与式(1)所示的原料经过取代反应、脱保护得到：
7.一种抗菌性药物，其特征在于，含有权利要求1～6任一项所述的氟喹诺酮衍生物中的一种或多种。
8.根据权利要求7所述的抗菌性药物，其特征在于，为抑制大肠杆菌、金黄色葡萄球菌及四联球菌中的一种或多种的抗菌性药物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110646773.7A CN113402531A (zh) | 2021-06-10 | 2021-06-10 | 氟喹诺酮衍生物及作为抗菌性药物的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110646773.7A CN113402531A (zh) | 2021-06-10 | 2021-06-10 | 氟喹诺酮衍生物及作为抗菌性药物的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113402531A true CN113402531A (zh) | 2021-09-17 |
Family
ID=77683405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110646773.7A Pending CN113402531A (zh) | 2021-06-10 | 2021-06-10 | 氟喹诺酮衍生物及作为抗菌性药物的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113402531A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989165A (zh) * | 2022-05-30 | 2022-09-02 | 青岛大学附属医院 | 一种抗持留菌和生物膜菌的化合物或组合物及其用途 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040790A (zh) * | 1988-08-31 | 1990-03-28 | 第一制药株式会社 | 螺环化合物的制备 |
| CN1175251A (zh) * | 1995-02-02 | 1998-03-04 | 大日本制药株式会社 | 有双环氨基取代的吡啶酮羧酸衍生物，其酯及盐,以及可用作其中间体的双环类胺 |
| US20080045520A1 (en) * | 2004-05-13 | 2008-02-21 | Daiichi Pharmaceutical Co., Ltd. | Substituted Pyrrolidine Derivative |
| CN101189222A (zh) * | 2005-05-19 | 2008-05-28 | 第一三共株式会社 | 三-、四-取代-3-氨基吡咯烷衍生物 |
-
2021
- 2021-06-10 CN CN202110646773.7A patent/CN113402531A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1040790A (zh) * | 1988-08-31 | 1990-03-28 | 第一制药株式会社 | 螺环化合物的制备 |
| CN1175251A (zh) * | 1995-02-02 | 1998-03-04 | 大日本制药株式会社 | 有双环氨基取代的吡啶酮羧酸衍生物，其酯及盐,以及可用作其中间体的双环类胺 |
| US20080045520A1 (en) * | 2004-05-13 | 2008-02-21 | Daiichi Pharmaceutical Co., Ltd. | Substituted Pyrrolidine Derivative |
| CN101189222A (zh) * | 2005-05-19 | 2008-05-28 | 第一三共株式会社 | 三-、四-取代-3-氨基吡咯烷衍生物 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989165A (zh) * | 2022-05-30 | 2022-09-02 | 青岛大学附属医院 | 一种抗持留菌和生物膜菌的化合物或组合物及其用途 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100423778B1 (ko) | 항미생물성 퀴놀론, 그의 조성물 및 용도 | |
| JP2844079B2 (ja) | ピリドンカルボン酸系抗菌剤 | |
| WO2016094730A1 (en) | Heterocyclic compounds as antibiotic potentiators | |
| CA2890748A1 (en) | Indole compounds and their use as antimicrobials | |
| US6586604B2 (en) | Tricyclic amine derivatives | |
| CN113402531A (zh) | 氟喹诺酮衍生物及作为抗菌性药物的应用 | |
| JP2788043B2 (ja) | キノロン−又はナフチリドンカルボン酸類 | |
| JPH04502317A (ja) | 抗菌性キノロン化合物 | |
| JPH02292289A (ja) | 置換アゼチジニルイソチアゾロピリドン誘導体、その製造法及びその医薬用途 | |
| JPH07138256A (ja) | キノリン誘導体 | |
| JPH02290870A (ja) | 対掌体的に純粋な７‐（３‐アミノ‐１‐ピロリジニル）‐キノロン‐および‐ナフチリドンカルボン酸 | |
| EP0549857A1 (en) | Antibacterial quinolone carboxylic acid derivatives | |
| AU726378B2 (en) | Cycloalkylaminomethylpyrrolidine derivatives | |
| KR20160003244A (ko) | 퀴놀론 유도체 | |
| Zhang et al. | Synthesis and structure–activity relationship of 7-(substituted)-aminomethyl-4-quinolone-3-carboxylic acid derivatives | |
| EP0726269A1 (en) | Quinolinecarboxylic acid derivative and salt thereof | |
| KR930003611B1 (ko) | 퀴놀론 카복실산 유도체의 제조방법 | |
| CN114315685A (zh) | 氰基胍衍生物及其制备方法、抗结核菌药物 | |
| CN107987131B (zh) | 一组具有抗耐药性细菌活性的化合物、其制备方法和应用 | |
| EP1437354B1 (en) | 4-oxoquinolizine antimicrobials having 2-pyridone skeleton as partial structure | |
| JP2989871B2 (ja) | 三環式化合物 | |
| WO2006119694A1 (fr) | Derives de l'acide quinolinone carboxylique, leur preparation et leur utilisation | |
| CN112239457B (zh) | 一种乙酰基连接的加替沙星-1,2,3-三氮唑-靛红杂合体及其制备方法和应用 | |
| JPH07300472A (ja) | 新規キノロンカルボン酸誘導体およびその製造方法 | |
| KR0166179B1 (ko) | 새로운 퀴놀론 카르복실산 유도체 및 그 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210917 |