CN105218531B - Cumarin quinolone heterozygote or its officinal salt and its preparation method and application - Google Patents

Cumarin quinolone heterozygote or its officinal salt and its preparation method and application Download PDF

Info

Publication number
CN105218531B
CN105218531B CN201510667385.1A CN201510667385A CN105218531B CN 105218531 B CN105218531 B CN 105218531B CN 201510667385 A CN201510667385 A CN 201510667385A CN 105218531 B CN105218531 B CN 105218531B
Authority
CN
China
Prior art keywords
quinolone
coumarin
compound
och
cumarin
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.)
Active
Application number
CN201510667385.1A
Other languages
Chinese (zh)
Other versions
CN105218531A (en
Inventor
周成合
彭莘媚
阿乌拉·斯里尼瓦萨·拉奥
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Southwest University
Original Assignee
Southwest University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Southwest University filed Critical Southwest University
Priority to CN201510667385.1A priority Critical patent/CN105218531B/en
Publication of CN105218531A publication Critical patent/CN105218531A/en
Application granted granted Critical
Publication of CN105218531B publication Critical patent/CN105218531B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention discloses formula I, II, cumarin quinolone heterozygote or its officinal salt shown in III, also disclose the preparation method of such compound, amino or the coumarin ring of hydroxyl substitution are obtained through multistep reaction using fortified phenol as raw material, then reacts with chloracetyl chloride or dibromide to obtain intermediate in the basic conditions, intermediate can be prepared by formula I in the alkaline solution of ethanol with quinolones reaction, compound shown in II, III.The cumarin quinolone heterozygote of the present invention has certain inhibitory activity to gram positive bacteria, gram-negative bacteria, fungi, available for preparation antibacterium and/or antimycotic medicine.R in formula1、R2、R3、R4、R5、R6、R7, X and n such as claims are defined.

Description

Cumarin quinolone heterozygote or its officinal salt and its preparation method and application
Technical field
The invention belongs to chemical field, and in particular to a kind of new organic compound cumarin quinolone heterozygote or its can Pharmaceutical salts, further relate to the preparation method and its medical usage of the compound.
Background technology
QNS is because with has a broad antifungal spectrum, antibacterial activity is high, mechanism of action is unique, oral result is notable, medicine generation The advantages that dynamics is good, synthesis technique is ripe, cheap is most widely used in the whole world after cephalosporins Synthesis class anti-infection drug.However, a large amount of uses with such medicine clinically, occur as gastrointestinal reaction, Numerous toxicity such as anaphylactic shock, dysfunction of liver, renal failure.Also, QNS in the last few years Widely use or even abuse, make the substantial amounts of bacterial strain of resistance to quinolone clinically occurred, greatly reduce its clinical therapeutic efficacy. Therefore, the QNS for researching and developing new structure is significant.
It is available for the site of modification more in quinolone mother nucleus structure, such as 1-, 3-, 6-, 7- and 8- position.Wherein, to quinoline promise The 7- positions of ketone carry out structural modification in anti-infectives research and development in occupation of very important status.It is well known that Coumarins Compound has good antimicrobial acivity and wide antimicrobial spectrum, although because the toxic side effects such as its hepatotoxicity wind agitation fail Clinically it is used widely, but Recent study person has found that coumarin kind compound has significantly to antibody-resistant bacterium such as MRSA etc. Inhibitory activity.In addition, coumarin ring is easy to carry out structural modification and can be readily incorporated into various functions group, in pharmaceutical field Play more and more important effect.Therefore, by the cumarin quinolone heterozygote obtained by cumarin and quinolones heterozygosis It is expected to turn into new efficient anti-infectives.
The content of the invention
In view of this, it is an object of the invention to provide the cumarin quinolone heterozygote of a kind of new structure or its can medicine With salt, and the preparation method of these compounds and its application in pharmaceutical field.
Through research, the present invention provides following technical scheme：
1. formula I, II, cumarin quinolone heterozygote or its officinal salt shown in III：
In formula：
R1For hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxyl group；
R2For ethyl, cyclopropyl；
R3For hydrogen, chlorine；
R4For hydrogen, fluorine, chlorine, methyl, methoxyl group；
R5For hydrogen, fluorine, chlorine, methyl, methoxyl group；
R6For hydrogen, fluorine, chlorine, methyl, methoxyl group；
R7For hydrogen, fluorine, chlorine, methyl, methoxyl group；
X is piperazinyl, amino-pyrroles alkyl；
N is 1-17 integer.
As currently preferred technical scheme：
R1For hydrogen, chlorine；
R2For ethyl, cyclopropyl；
R3For hydrogen, chlorine；
R4For hydrogen, methyl；
R5For hydrogen；
R6For hydrogen；
R7For hydrogen；
X is piperazinyl, amino-pyrroles alkyl；
N is 1,3,5.
The technical scheme further preferred as the present invention, it is any of following compounds or its officinal salt：
The further preferred technical scheme of the present invention, the officinal salt is hydrochloride, nitrate or acetate.
The preparation method of cumarin quinolone heterozygote or its officinal salt described in 2.,
A. amino or the coumarin ring of hydroxyl substitution are obtained through multistep reaction using fortified phenol as raw material, then in alkalescence condition Lower and chloracetyl chloride or dibromide react to obtain intermediate compound IV, V, VI, and formula is as follows：
R1For hydrogen, fluorine, chlorine, bromine, iodine, methyl or methoxy；R4、R5、R6、R7For hydrogen, fluorine, chlorine, methyl or methoxy；N is 1-17 integer；
B. intermediate compound IV, V, VI be can be prepared by into formula I, II, III in the alkaline solution of ethanol with quinolones reaction Shown compound.
As currently preferred technical scheme, in step b, the base reagent is sodium acid carbonate；The intermediate compound IV, V, The mol ratio of VI and base reagent is 1: 1.2~2.
As the preferred technical scheme of the present invention, formula I, II, the heterozygote of cumarin quinolone shown in III it is pharmaceutically acceptable The preparation of salt：By formula I, II, the heterozygote of cumarin quinolone shown in III is dissolved in ethanol, ether, tetrahydrofuran and chloroform Any of or a variety of in the mixed solvents, add aqueous hydrochloric acid solution, aqueous solution of nitric acid or aqueous acetic acid under agitation, Stirring reaction generates to without precipitation, that is, formula I, II, hydrochloride, the nitrate of the heterozygote of cumarin quinolone shown in III is made Or acetate.
Cumarin quinolone heterozygote or its officinal salt described in 3. is in antibacterium and/or antifungal drug is prepared Using.
The technical scheme further preferred as the present invention, the bacterium are staphylococcus aureus, methicillin-resistant gold Staphylococcus aureus, micrococcus luteus, hay bacillus, Escherichia coli, pseudomonas aeruginosa, proteus, Shigella dysenteriae and Any of Salmonella typhi is a variety of；The fungi is candida utili bacterium, Aspergillus flavus, saccharomyces cerevisiae, white Any of candida albicans and candidiasis are a variety of.
The beneficial effects of the present invention are：The present invention utilizes drug design principle of hybridization, by quinolones 7- positions and amino Or Hydroxycoumarin heterozygosis, and by changing the position on bridge chain group and coumarin ring, design has synthesized a series of new knot The cumarin quinolone heterozygote of structure, these compounds are detected through in vitro anti-microbial activity, found (golden yellow to gram positive bacteria Color staphylococcus, MASR, micrococcus luteus, hay bacillus), (Escherichia coli (DH52/JM109), verdigris are false single for gram-negative bacteria Born of the same parents bacterium, proteus, Shigella dysenteriae, Salmonella typhi) and fungi (candida utili bacterium, Aspergillus flavus, brewer's yeast Bacterium, Candida albicans, candidiasis) there is a certain degree of inhibitory activity, it can be used for preparing antibacterium and/or antimycotic Medicine, so as to provide more drug candidates efficiently, safe for clinical antimicrobial treatment, solution is contributed to be on the rise resistance to The clinical treatment problems such as the property of medicine, obstinate invasive organism and emerging harmful microorganism.In addition, these compounds Synthetic yield is high, preparation method is simple, and raw material is easy to get, and cost is relatively low.
Embodiment
The preferred embodiments of the present invention will be described in detail below.The experiment of unreceipted actual conditions in embodiment Method, generally according to normal condition or according to the condition proposed by manufacturer.
The preparation of embodiment 1, compound I-1
In 50mL round-bottomed flasks, by Norfloxacin (2.52mmol, 0.897g) and sodium acid carbonate (4.20mmol, Solvent 0.353g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate compound IV (2.10mmol, 0.500g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.853g, yield 78%.
Wherein, R1, R4, R5And R6It is hydrogen.
Compound I-1：White solid；Fusing point：>250℃；1H NMR(300MHz,DMSO-d6)δ:15.38(s,1H, COOH),9.85(s,1H,NHCO),8.98(s,1H,quinolone 2-H),8.65(s,1H,coumarin 4-H),7.95 (d, J=7.4Hz, 1H, quinolone 5-H), 7.78 (d, J=7.6Hz, 1H, coumarin 5-H), 7.56-7.51 (t, 1H, coumarin 7-H), 7.44 (d, J=8.0Hz, 1H, coumarin 8-H), 7.39-7.35 (t, 1H, coumarin 6- ), H 7.27-7.24 (d, J=6.8Hz, 1H, quinolone 8-H), 4.67-4.60 (m, 2H, CH2CH3),3.41(s,2H, NHCOCH2),2.89–2.73(m,4H,quinolone-piperazine-CH2),2.19–1.98(m,4H,piperazine- CH2), 1.43 (t, J=7.0Hz, 3H, CH2CH3)ppm。
The preparation of embodiment 2, compound I-2
In 50mL round-bottomed flasks, by Ciprofloxacin (1.32mmol, 0.485g) and sodium acid carbonate (2.20mmol, Solvent 0.185g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate compound IV (1.10mmol, 0.261g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.427g, yield 73%.
Wherein, R1, R4, R5And R6It is hydrogen.
Compound I-2：Yellow solid；Fusing point：>250℃；1H NMR(300MHz,DMSO-d6)δ:15.24(s,1H, COOH),9.86(s,1H,NHCO),8.68(s,1H,quinolone 2-H),8.64(s,1H,coumarin 4-H),7.96 (d, J=7.4Hz, 1H, quinolone 5-H), 7.78 (d, J=7.0Hz, 1H, coumarin 5-H), 7.64-7.61 (d, J =7.4Hz, 1H, coumarin 7-H), 7.53 (d, J=8.8Hz, 1H, quinolone 8-H), 7.44 (d, J=8.0Hz, 1H, coumarin 8-H), 7.37 (d, J=7.8Hz, 1H, coumarin 6-H), 3.89-3.84 (m, 1H, cyclopropyl- CH),3.42(s,2H,NHCOCH2),2.89–2.73(m,4H,quinolone-piperazine-CH2),2.17–1.99(m, 4H,piperazine-CH2), 1.32 (d, J=6.6Hz, 2H, cyclopropyl-CH2), 1.23 (d, J=6.6Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 3, compound I-3
In 50mL round-bottomed flasks, by Clinafloxacin (2.02mmol, 0.812g) and sodium acid carbonate (3.37mmol, Solvent 0.283g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate compound IV (1.68mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.895g, yield 94%.
Wherein, R1, R4, R5And R6It is hydrogen.
Compound I-3：Yellow solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:14.18(s,1H, COOH),10.64(s,1H,CONH),8.89(s,1H,quinolone 2-H),8.68(s,1H,coumarin 4-H),8.03 (d, J=11.6Hz, 1H, quinolone 2-H), 7.77 (d, J=7.7Hz, 1H, coumarin 5-H), 7.58-7.56 (t, J =7.2Hz, 1H, coumarin 7-H), 7.44 (d, J=8.3Hz, 1H, coumarin 8-H), 7.41-7.38 (t, J= 7.5Hz,1H,coumarin 6-H),4.49(s,2H,NHCH2),4.46–4.42(m,1H,cyclopropyl-CH),3.73– 3.69(m,3H,pyrrolyl 2,3-H),3.63–3.62(m,2H,pyrrolyl 5-H),3.54–3.43(m,2H, Pyrrolyl 4-H), 1.24-1.21 (q, J=6.3Hz, 2H, cyclopropyl-CH2), 1.03-1.02 (q, J=9.0Hz, 2H,cyclopropyl-CH2)ppm。
The preparation of embodiment 4, compound I-4
In 50mL round-bottomed flasks, by Norfloxacin (1.76mmol, 0.628g) and sodium acid carbonate (2.94mmol, Solvent 0.247g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate compound IV (1.47mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.546g, yield 67%.
Wherein, R1For Cl, R4, R5And R6It is hydrogen.
Compound I-4：White solid；Fusing point：229-230℃；1H NMR(600MHz,DMSO-d6)δ:15.35(s,1H, COOH),9.87(s,1H,NHCO),8.96(s,1H,quinolone 2-H),8.61(s,1H,coumarin 4-H),7.93 (d, J=7.4Hz, 1H, quinolone 5-H), 7.54 (d, J=8.5Hz, 1H, coumarin 5-H), 7.47 (d, J= 6.8Hz, 1H, coumarin 7-H), 7.23 (d, J=6.7Hz, 1H, quinolone 8-H), 7.18 (d, J=6.8Hz, 1H, coumarin 8-H),4.62–4.58(m,2H,CH2CH3),3.41-3.39(m,4H,quinolone-piperazine-CH2), 3.25(s,2H,NHCOCH2),2.73–2.71(m,4H,piperazine-CH2),1.43-1.41(t,3H,CH2CH3)ppm。
The preparation of embodiment 5, compound I-5
In 50mL round-bottomed flasks, by Ciprofloxacin (1.76mmol, 0.647g) and sodium acid carbonate (2.94mmol, Solvent 0.247g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate compound IV (1.47mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.574g, yield 69%.
Wherein, R1For Cl, R4, R5And R6It is hydrogen.
Compound I-5：Yellow solid；Fusing point：245-247℃；1H NMR(600MHz,DMSO-d6)δ:15.19(s,1H, COOH),9.88(s,1H,NHCO),8.67(s,1H,quinolone 2-H),8.60(s,1H,coumarin 4-H),7.93 (d, J=7.4Hz, 1H, quinolone 5-H), 7.73 (s, 1H, coumarin 5-H), 7.61 (d, J=7.3Hz, 1H, Coumarin 7-H), 7.53 (d, J=8.8Hz, 1H, quinolone 8-H), 7.44 (d, J=6.7Hz, 1H, coumarin8- H),3.42-3.39(m,1H,cyclopropyl-CH),3.25-3.23(m,4H,quinolone-piperazine-CH2), 2.82(s,2H,NHCOCH2),2.74–2.71(s,4H,piperazine-CH2),1.29-1.26(m,2H,cyclopropyl- CH2),1.22-1.20(m,2H,cyclopropyl-CH2)ppm。
The preparation of embodiment 6, compound I-6
In 50mL round-bottomed flasks, by Clinafloxacin (1.76mmol, 0.710g) and sodium acid carbonate (2.94mmol, Solvent 0.247g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate compound IV (1.47mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.619g, yield 70%.
Wherein, R1For Cl, R4, R5And R6It is hydrogen.
Compound I-6：Yellow solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:14.72(s,1H, COOH),10.70(s,1H,CONH),8.89(s,1H,quinolone 2-H),8.66(s,1H,coumarin 4-H),8.03 (d, J=11.6Hz, 1H, quinolone 2-H), 7.94 (s, 1H, coumarin 5-H), 7.58 (d, J=8.8Hz, 1H, Coumarin 6-H), 7.48 (d, J=8.8Hz, 1H, coumarin 8-H), 4.49 (s, 2H, NHCH2),4.45–4.42(m, 1H,cyclopropyl-CH),3.76–3.68(m,3H,pyrrolyl 2,3-H),3.65–3.59(m,2H,pyrrolyl 5- ), H 3.54-3.42 (m, 2H, pyrrolyl 4-H), 1.25-1.23 (q, J=6.9Hz, 2H, cyclopropyl-CH2), 1.05-1.02 (q, J=2.3Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 7, compound II-1
In 50mL round-bottomed flasks, by Norfloxacin (1.78mmol, 0.635g) and sodium acid carbonate (2.98mmol, Solvent 0.250g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.49mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.393g, yield 52%.
Wherein, R4, R5, R6And R7It is hydrogen, n=1.
Compound II-1：White solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:9.00(s,1H, Quinolone 2-H), 8.01 (d, J=9.3Hz, 2H, quinolone 5-H), 7.82 (d, J=9.2Hz, 1H, coumarin 5-H), 7.70 (t, 1H, coumarin 7-H), 7.42 (m, 2H, coumarin 6,8-H), 7.30 (d, J=7.2Hz, 1H, quinolone 8-H),6.07(s,1H,coumarin 3-H),4.70(m,2H,CH2CH3),4.64(t,2H,OCH2CH2), 3.86(t,2H,OCH2CH2),3.47(m,4H,quinolone-piperazine-CH2),3.19(m,4H,piperazine- CH2),1.44(t,3H,CH2CH3)ppm。
The preparation of embodiment 8, compound II-2
In 50mL round-bottomed flasks, by Ciprofloxacin (1.78mmol, 0.655g) and sodium acid carbonate (2.98mmol, Solvent 0.250g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.49mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.449g, yield 58%.
Wherein, R4, R5, R6And R7It is hydrogen, n=1.
Compound II-2：Yellow solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:15.24(s,1H, ), COOH 8.74 (s, 1H, quinolone 2-H), 8.04 (d, J=13.1Hz, 1H, quinolone 5-H), 8.00 (d, J= 12.9Hz, 1H, coumarin 5-H), 7.69-7.67 (t, 1H, coumarin 7-H), 7.66 (d, J=7.3Hz, 1H, quinolone 8-H),7.43(t,1H,coumarin 6-H),7.41–7.39(t,1H,coumarin 6-H),6.07(s, 1H,coumarin 3-H),4.73–4.72(t,2H,OCH2CH2),3.91–3.90(m,1H,cyclopropyl-CH),3.89– 3.81(m,4H,quinolone-piperazine-CH2),3.62–3.56(t,2H,OCH2CH2),2.61–2.58(m,4H, piperazine-CH2), 1.36 (d, J=6.4Hz, 2H, cyclopropyl-CH2), 1.22 (d, J=2.1Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 9, compound II-3
In 50mL round-bottomed flasks, by Clinafloxacin (1.78mmol, 0.718g) and sodium acid carbonate (2.98mmol, Solvent 0.250g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.49mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.792g, yield 96%.
Wherein, R4, R5, R6And R7It is hydrogen, n=1.
Compound II-3：Yellow solid；Fusing point：249-250℃；1H NMR(600MHz,DMSO-d6)δ:8.88(s,1H, Quinolone 2-H), 8.03 (d, J=5.0Hz, 1H, quinolone 5-H), 8.02 (d, J=9.3Hz, 1H, coumarin 5-H), 7.69 (t, 1H, coumarin 7-H), 7.44 (d, J=8.4Hz, 1H, coumarin 8-H), 7.40 (t, coumarin 6-H),6.06(s,1H,coumarin 3-H),4.72–4.70(t,2H,OCH2CH2), 4.43 (dd, J=8.8,5.1Hz, 1H, cyclopropyl-CH),3.90–3.88(t,2H,OCH2CH2),3.79(m,2H,pyrrolyl 2-H),3.65(m,3H, pyrrolyl 3,5-H),3.47(m,2H,pyrrolyl 4-H),1.22(m,2H,cyclopropyl-CH2),1.03(m,2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 10, compound II-4
In 50mL round-bottomed flasks, by Norfloxacin (1.62mmol, 0.575g) and sodium acid carbonate (2.70mmol, Solvent 0.227g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.35mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.470g, yield 65%.
Wherein, R4, R5, R6And R7It is hydrogen, n=3.
Compound II-4：Yellow solid；Fusing point：242-243℃；1H NMR(600MHz,DMSO-d6)δ:9.02(s,1H, Quinolone 2-H), 8.11 (d, J=9.3Hz, 2H, quinolone 5-H), 7.83 (d, J=9.2Hz, 1H, coumarin 5-H), 7.72 (t, 1H, coumarin 7-H), 7.45 (m, 2H, coumarin 6,8-H), 7.33 (d, J=7.2Hz, 1H, quinolone 8-H),6.07(s,1H,coumarin 3-H),4.71(m,2H,CH2CH3),4.65(t,2H,OCH2CH2), 3.86(t,2H,OCH2CH2),3.48(m,4H,quinolone-piperazine-CH2),3.20(m,4H,piperazine- CH2),1.91–1.89(m,2H,OCH2CH2CH2CH2),1.81–1.77(m,2H,OCH2CH2CH2CH2),1.44(t,3H, CH2CH3)ppm。
The preparation of embodiment 11, compound II-5
In 50mL round-bottomed flasks, by Ciprofloxacin (1.62mmol, 0.594g) and sodium acid carbonate (2.70mmol, Solvent 0.227g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.35mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.451g, yield 61%.
Wherein, R4, R5, R6And R7It is hydrogen, n=3.
Compound II-5：Yellow solid；Fusing point：217-219℃；1H NMR(600MHz,DMSO-d6)δ:15.26(s,1H, ), COOH 8.73 (s, 1H, quinolone 2-H), 8.06 (d, J=13.1Hz, 1H, quinolone 5-H), 8.01 (d, J= 12.9Hz, 1H, coumarin 5-H), 7.69-7.64 (t, 1H, coumarin 7-H), 7.67 (d, J=7.3Hz, 1H, quinolone 8-H),7.41(t,1H,coumarin 6-H),7.41–7.34(t,1H,coumarin 6-H),6.03(s, 1H,coumarin 3-H),4.74–4.72(t,2H,OCH2CH2),3.92–3.90(m,1H,cyclopropyl-CH),3.89– 3.80(m,4H,quinolone-piperazine-CH2),3.62–3.55(t,2H,OCH2CH2),2.63–2.58(m,4H, piperazine-CH2),1.92–1.88(m,2H,OCH2CH2CH2CH2),1.80–1.75(m,2H,OCH2CH2CH2CH2),1.38 (d, J=6.4Hz, 2H, cyclopropyl-CH2), 1.21 (d, J=2.1Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 12, compound II-6
In 50mL round-bottomed flasks, by Clinafloxacin (1.62mmol, 0.650g) and sodium acid carbonate (2.70mmol, Solvent 0.227g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.35mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.495g, yield 63%.
Wherein, R4, R5, R6And R7It is hydrogen, n=3.
Compound II-6：Yellow solid；Fusing point：221-223℃；1H NMR(600MHz,DMSO-d6)δ:8.87(s,1H, Quinolone 2-H), 8.04 (d, J=5.0Hz, 1H, quinolone 5-H), 8.01 (d, J=9.3Hz, 1H, coumarin 5-H), 7.70 (t, 1H, coumarin 7-H), 7.45 (d, J=8.4Hz, 1H, coumarin 8-H), 7.41 (t, coumarin 6-H),6.05(s,1H,coumarin 3-H),4.75–4.70(t,2H,OCH2CH2), 4.41 (dd, J=8.8,5.1Hz, 1H, cyclopropyl-CH),3.92–3.88(t,2H,OCH2CH2),3.75(m,2H,pyrrolyl 2-H),3.67(m,3H, pyrrolyl 3,5-H),3.49(m,2H,pyrrolyl 4-H),1.59–1.49(m,4H,OCH2CH2CH2CH2),1.21(m, 2H,cyclopropyl-CH2),1.03(m,2H,cyclopropyl-CH2)ppm。
The preparation of embodiment 13, compound II-7
In 50mL round-bottomed flasks, by Norfloxacin (1.48mmol, 0.525g) and sodium acid carbonate (2.46mmol, Solvent 0.207g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.23mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.499g, yield 72%.
Wherein, R4, R5, R6And R7It is hydrogen, n=5.
Compound II-7：Yellow solid；Fusing point：224-225℃；1H NMR(600MHz,DMSO-d6)δ:15.41(s,1H, ), COOH 8.99 (s, 1H, quinolone 2-H), 7.99 (d, J=13.0Hz, 1H, quinolone 5-H), 7.84 (d, J= 9.2Hz, 1H, coumarin 5-H), 7.66 (t, 1H, coumarin 7-H), 7.40 (d, J=8.2Hz, 1H, coumarin 8- ), H 7.37 (t, 1H, coumarin 6-H), 7.29 (d, J=7.2Hz, 1H, quinolone 8-H), 5.90 (s, 1H, coumarin 3-H),4.64(m,2H,CH2CH3),4.26(t,2H,OCH2CH2CH2CH2CH2CH2),3.94–3.68(m,4H, quinolone-piperazine-CH2), 3.34 (dd, J=22.9,10.4Hz, 4H, piperazine-CH2),3.25(s,2H, OCH2CH2CH2CH2CH2CH2),1.92–1.89(m,2H,OCH2CH2CH2CH2CH2CH2),1.80–1.77(m,2H, OCH2CH2CH2CH2CH2CH2),1.59–1.56(m,2H,OCH2CH2CH2CH2CH2CH2),1.46(m,5H, OCH2CH2CH2CH2CH2CH2,CH2CH3)ppm。
The preparation of embodiment 14, compound II-8
In 50mL round-bottomed flasks, by Ciprofloxacin (1.48mmol, 0.543g) and sodium acid carbonate (2.46mmol, Solvent 0.207g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.23mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.410g, yield 58%.
Wherein, R4, R5, R6And R7It is hydrogen, n=5.
Compound II-8：Yellow solid；Fusing point：246-247℃；1H NMR(600MHz,DMSO-d6)δ:8.70(s,1H, Quinolone 2-H), 7.97 (d, J=13.0Hz, 1H, quinolone 5-H), 7.83 (d, J=7.9Hz, 1H, coumarin 5-H), 7.66 (t, 1H, coumarin 7-H), 7.63 (d, J=7.4Hz, 1H, quinolone 8-H), 7.40 (d, J= 8.3Hz,1H,coumarin 8-H),7.37(t,1H,coumarin 6-H),5.90(s,1H,coumarin 3-H),4.26 (t, J=6.3Hz, 2H, OCH2CH2CH2CH2CH2CH2),3.93–3.91,3.70–3.69(m,4H,quinolone- piperazine-CH2), 3.85 (dd, J=7.2,3.4Hz, 1H, cyclopropyl-CH), 3.33 (d, J=9.5Hz, 4H, piperazine-CH2),3.26–3.22(t,2H,OCH2CH2CH2CH2CH2CH2),1.91–1.88(m,2H, OCH2CH2CH2CH2CH2CH2),1.80–1.76(m,2H,OCH2CH2CH2CH2CH2CH2),1.58–1.55(m,2H, OCH2CH2CH2CH2CH2CH2),1.48–1.44(m,2H,OCH2CH2CH2CH2CH2CH2),1.35(m,2H,cyclopropyl- CH2),1.21(m,2H,cyclopropyl-CH2)ppm。
The preparation of embodiment 15, compound II-9
In 50mL round-bottomed flasks, by Clinafloxacin (1.48mmol, 0.594g) and sodium acid carbonate (2.46mmol, Solvent 0.207g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate V (1.23mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.668g, yield 89%.
Wherein, R4, R5, R6And R7It is hydrogen, n=5.
Compound II-9：Yellow solid；Fusing point：193-195℃；1H NMR(600MHz,DMSO-d6)δ:14.55(s,1H, ), COOH 8.84 (s, 1H, quinolone 2-H), 7.93 (d, J=11.8Hz, 1H, quinolone 5-H), 7.82 (d, J= 8.6Hz, 1H, coumarin 5-H), 7.66 (t, 1H, coumarin 7-H), 7.40 (d, J=8.6Hz, 1H, coumarin 8- H),7.37(t,1H,coumarin 6-H),5.90(s,1H,coumarin 3-H),4.40–4.38(m,1H, cyclopropyl-CH),4.25–4.23(t,2H,OCH2CH2CH2CH2CH2CH2),2.65–2.62(m,4H,pyrrolyl 2- H,OCH2CH2CH2CH2CH2CH2),1.88–1.83(m,3H,pyrrolyl 3,5-H),1.54–1.49(m,6H,pyrrolyl 4-H,OCH2CH2CH2CH2CH2CH2),1.44–1.39(m,4H,OCH2CH2CH2CH2CH2CH2),1.21–1.18(m,2H, cyclopropyl-CH2),1.00–0.97(m,2H,cyclopropyl-CH2)ppm。
The preparation of embodiment 16, compound III-1
In 50mL round-bottomed flasks, by Norfloxacin (1.70mmol, 0.605g) and sodium acid carbonate (2.82mmol, Solvent 0.237g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.41mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.368g, yield 50%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=1.
Compound III-1：White solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:15.36(s,1H, ), COOH 8.96 (s, 1H, quinolone 2-H), 7.92 (d, J=13.3Hz, quinolone 5-H), 7.70 (d, J= 8.7Hz, 1H, coumarin 5-H), 7.19 (d, J=6.8Hz, 1H, quinolone 8-H), 7.04 (s, 1H, coumarin 8-H), 7.00 (d, J=8.2Hz, 1H, coumarin 6-H), 6.22 (s, 1H, coumarin 3-H), 4.59-4.56 (m, 2H, CH2CH3),4.26–4.21(t,2H,OCH2CH2),3.51–3.48(m,4H,quinolone-piperazine-CH2),2.84– 2.82(t,2H,OCH2CH2),2.73–2.70(m,4H,piperazine-CH2),2.41(s,3H,coumarin 4-CH3), 1.42–1.41(t,3H,CH2CH3)ppm。
The preparation of embodiment 17, compound III-2
In 50mL round-bottomed flasks, by Ciprofloxacin (1.70mmol, 0.625g) and sodium acid carbonate (2.82mmol, Solvent 0.237g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.41mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.361g, yield 48%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=1.
Compound III-2：Yellow solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:15.21(s,1H, ), COOH 8.66 (s, 1H, quinolone 2-H), 7.91 (d, J=13.3Hz, 1H, quinolone 5-H), 7.69 (d, J= 8.8Hz, 1H, coumarin 5-H), 7.57 (d, J=7.4Hz, 1H, quinolone 8-H), 7.03 (s, 1H, coumarin 8-H), 7.01 (d, J=2.2Hz, 1H, coumarin 6-H), 6.22 (s, 1H, coumarin 3-H), 4.27-4.24 (t, 2H, OCH2CH2),3.82–3.78(m,1H,cyclopropyl-CH),3.35–3.32(m,4H,quinolone-piperazine- CH2),2.84–2.81(t,2H,OCH2CH2),2.75–2.73(m,4H,piperazine-CH2),2.40(s,3H,coumarin 4-CH3), 1.31 (d, J=6.1Hz, 2H, cyclopropyl-CH2), 1.19 (d, J=6.1Hz, 2H, cyclopropyl-CH2) ppm。
The preparation of embodiment 18, compound III-3
In 50mL round-bottomed flasks, by Clinafloxacin (1.70mmol, 0.682g) and sodium acid carbonate (2.82mmol, Solvent 0.237g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.41mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.729g, yield 91%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=1.
Compound III-3：Yellow solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:14.93(s,1H, ), COOH 8.86 (s, 1H, quinolone 2-H), 7.99 (d, J=11.6Hz, 1H, quinolone 5-H), 7.72 (d, J= 8.8Hz, 1H, coumarin 5-H), 7.10 (s, 1H, coumarin 8-H), 7.05 (d, J=8.8Hz, 1H, coumarin 6- H),6.22(s,1H,coumarin 3-H),4.56–4.54(t,2H,OCH2CH2),4.42–4.38(m,1H,cyclopropyl- CH),3.76–3.74(m,3H,pyrrolyl 2,3-H),3.70–3.66(t,2H,OCH2CH2),3.59–3.57(t,2H, pyrrolyl 5-H),3.40–3.38(t,2H,pyrrolyl 4-H),2.40(s,3H,coumarin 4-CH3),1.20(q,J =6.8Hz, 2H, cyclopropyl-CH2), 1.00 (q, J=6.9Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 19, compound III-4
In 50mL round-bottomed flasks, by Norfloxacin (1.54mmol, 0.548g) and sodium acid carbonate (2.58mmol, Solvent 0.217g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.29mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.404g, yield 57%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=3.
Compound III-4：White solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:8.94(s,1H, Quinolone 2-H), 7.97 (d, J=13.0Hz, 1H, quinolone 5-H), 7.66 (d, J=8.6Hz, 1H, coumarin 5-H), 7.28 (d, J=7.1Hz, 1H, quinolone 8-H), 6.98 (s, 1H, coumarin 8-H), 6.96 (d, J= 2.3Hz, 1H, coumarin 6-H), 6.17 (s, 1H, coumarin 3-H), 4.61 (q, J=7.0Hz, 2H, CH2CH3),4.18 (t, J=5.9Hz, 2H, OCH2CH2CH2CH2),3.94-3.73(m,4H,quinolone-piperazine-CH2),3.42– 3.37(m,2H,OCH2CH2CH2CH2),3.37–3.32(m,4H,piperazine-CH2),2.40(s,3H,coumarin 4- CH3), 1.97 (dd, J=15.4,7.8Hz, 2H, OCH2CH2CH2CH2), 1.91 (dd, J=12.8,6.3Hz, 2H, OCH2CH2CH2CH2), 1.48 (t, J=7.1Hz, 3H, CH2CH3)ppm。
The preparation of embodiment 20, compound III-5
In 50mL round-bottomed flasks, by Ciprofloxacin (1.54mmol, 0.566g) and sodium acid carbonate (2.58mmol, Solvent 0.217g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.29mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.522g, yield 72%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=3.
Compound III-5：Yellow solid；Fusing point：241-243℃；1H NMR(600MHz,DMSO-d6)δ:15.19(s, 1H, COOH), 8.67 (s, 1H, quinolone 2-H), 7.92 (d, J=13.2Hz, 1H, quinolone 5-H), 7.68 (d, J =8.7Hz, 1H, coumarin 5-H), 7.57 (d, J=7.5Hz, 1H, quinolone 8-H), 7.00 (s, 1H, coumarin 8-H), 6.97 (d, J=8.2Hz, 1H, coumarin 6-H), 6.21 (s, 1H, coumarin 3-H), 4.23-4.20 (m, 1H, cyclopropyl-CH),4.15–4.13(t,2H,OCH2CH2CH2CH2),3.84–3.80(m,4H,quinolone- piperazine-CH2),2.76–2.71(m,2H,OCH2CH2CH2CH2),2.69–2.58(m,4H,piperazine-CH2), 2.40(s,3H,coumarin 4-CH3),1.82–1.80(m,2H,OCH2CH2CH2CH2), 1.31 (d, J=5.9Hz, 2H, cyclopropyl-CH2),1.24–1.23(m,2H,OCH2CH2CH2CH2), 1.19 (d, J=2.8Hz, 2H, cyclopropyl- CH2)ppm。
The preparation of embodiment 21, compound III-6
In 50mL round-bottomed flasks, by Clinafloxacin (1.54mmol, 0.620g) and sodium acid carbonate (2.58mmol, Solvent 0.217g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.29mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.592g, yield 77%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=3.
Compound III-6：Yellow solid；Fusing point：211-212℃；1H NMR(600MHz,CDCl3)δ:14.40(s,1H, ), COOH 8.90 (s, 1H, quinolone 2-H), 8.02 (d, J=11.6Hz, 1H, quinolone 2-H), 7.50 (d, J= 8.8Hz, 1H, coumarin 5-H), 6.86 (s, 1H, coumarin 8-H), 6.82 (d, J=2.3Hz, 1H, coumarin6- ), H 6.13 (s, 1H, coumarin 3-H), 4.36-4.32 (m, 1H, cyclopropyl-CH), 4.10-4.08 (t, J= 6.2Hz,2H,OCH2CH2CH2CH2),3.48(m,4H,OCH2CH2CH2CH2,pyrrolyl 2-H),2.75(m,3H, pyrrolyl3,5-H),2.61(m,2H,pyrrolyl 4-H),2.40(s,3H,coumarin 4-CH3),1.93–1.89(m, 2H,OCH2CH2CH2CH2),1.81(m,2H,OCH2CH2CH2CH2), 1.32-1.28 (q, J=7.0Hz, 2H, cyclopropyl- CH2), 0.97-0.95 (q, J=6.6Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 22, compound III-7
In 50mL round-bottomed flasks, by Norfloxacin (1.42mmol, 0.505g) and sodium acid carbonate (2.36mmol, Solvent 0.198g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.18mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.511g, yield 75%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=5.
Compound III-7：Yellow solid；Fusing point：>250℃；1H NMR(600MHz,DMSO-d6)δ:8.98(s,1H, Quinolone 2-H), 7.99 (d, J=13.0Hz, 1H, quinolone 5-H), 7.68 (d, J=8.5Hz, 1H, Coumarin 5-H), 7.30 (d, J=7.2Hz, 1H, quinolone 8-H), 6.98 (s, 1H, coumarin 8-H), 6.96 (d, J=2.4Hz, 1H, coumarin 6-H), 6.20 (s, 1H, coumarin 3-H), 4.64 (q, J=7.0Hz, 2H, CH2CH3), 4.13 (t, J=6.4Hz, 2H, OCH2CH2CH2CH2CH2CH2),3.95–3.72(m,4H,quinolone- piperazine-CH2),3.41–3.32(m,4H,piperazine-CH2),3.29–3.24(m,2H, OCH2CH2CH2CH2CH2CH2),2.42(s,3H,coumarin 3-H),1.86–1.79(m,4H,OCH2CH2CH2CH2CH2CH2), 1.58–1.54(m,2H,OCH2CH2CH2CH2CH2CH2),1.50–1.46(m,5H,OCH2CH2CH2CH2CH2CH2,CH2CH3)ppm。
The preparation of embodiment 23, compound III-8
In 50mL round-bottomed flasks, by Ciprofloxacin (1.42mmol, 0.522g) and sodium acid carbonate (2.36mmol, Solvent 0.198g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.18mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.515g, yield 74%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=5.
Compound III-8：Yellow solid；Fusing point：227-229℃；1H NMR(600MHz,DMSO-d6)δ:15.21(s, 1H, COOH), 8.66 (s, 1H, quinolone 2-H), 7.90 (d, J=13.1Hz, 1H, quinolone 5-H), 7.75 (d, J =13.4Hz, 1H, coumarin 5-H), 7.67 (d, J=8.5Hz, 1H, quinolone 8-H), 6.97 (s, 1H, Coumarin 8-H), 6.95 (d, J=2.5Hz, 1H, coumarin 6-H), 6.19 (s, 1H, coumarin 3-H), 4.23- 4.19(m,1H,cyclopropyl-CH),4.10-4.08(m,2H,OCH2CH2CH2CH2CH2CH2),3.41-3.32(m,4H, quinolone-piperazine-CH2),2.62-2.59(m,2H,OCH2CH2CH2CH2CH2CH2),2.59–2.51(m,4H, piperazine-CH2),2.39(s,3H,coumarin 4-CH3), 1.78-1.75 (d, J=7.4Hz, 2H, OCH2CH2CH2CH2CH2CH2),1.49-1.47(m,2H,OCH2CH2CH2CH2CH2CH2),1.39-1.32(m,2H, OCH2CH2CH2CH2CH2CH2), 1.31 (d, J=1.9Hz, 2H, cyclopropyl-CH2),1.26-1.20(m,2H, OCH2CH2CH2CH2CH2CH2), 1.18 (d, J=1.9Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 24, compound III-9
In 50mL round-bottomed flasks, by Clinafloxacin (1.42mmol, 0.569g) and sodium acid carbonate (2.36mmol, Solvent 0.198g) is made with ethanol (8mL), stirring reaction 2h at 60 DEG C, is cooled to room temperature, add intermediate VI (1.18mmol, 0.400g), be warming up to return stirring reaction, thin-layer chromatography, which tracks to reaction, to be terminated, then concentrated, extraction, column chromatography for separation, do It is dry to obtain 0.504g, yield 70%.
Wherein, R4For methyl, R5, R6And R7It is hydrogen, n=5.
Compound III-9：Yellow solid；Fusing point：228-229℃；1H NMR(600MHz,CDCl3)δ:14.40(s,1H, ), COOH 8.90 (s, 1H, quinolone 2-H), 8.02 (d, J=11.5Hz, 1H, quinolone 5-H), 7.49 (d, J= 8.8Hz, 1H, coumarin 5-H), 6.85 (s, 1H, coumarin 8-H), 6.80 (d, J=8.8Hz, 1H, coumarin6- ), H 6.13 (s, 1H, coumarin 3-H), 4.36-4.32 (m, 1H, cyclopropyl-CH), 4.05-4.02 (t, J= 6.4Hz,2H,OCH2CH2CH2CH2CH2CH2),3.52(m,4H,OCH2CH2CH2CH2CH2CH2,pyrrolyl 2-H),2.77(s, 3H,pyrrolyl 3,5-H),2.57(s,2H,pyrrolyl 4-H),2.40(s,3H,coumarin 4-CH3),1.86– 1.83(m,2H,OCH2CH2CH2CH2CH2CH2),1.68(m,2H,OCH2CH2CH2CH2CH2CH2),1.56–1.52(m,2H, OCH2CH2CH2CH2CH2CH2),1.47–1.43(m,2H,OCH2CH2CH2CH2CH2CH2), 1.32-1.28 (q, J=7.1Hz, 2H, cyclopropyl-CH2), 0.98-0.95 (q, J=5.1Hz, 2H, cyclopropyl-CH2)ppm。
The preparation of embodiment 25, cumarin quinolone heterozygote officinal salt
By compound made from embodiment 1~24 be dissolved in any of ethanol, ether, tetrahydrofuran and chloroform or A variety of in the mixed solvents, aqueous hydrochloric acid solution, aqueous solution of nitric acid or aqueous acetic acid, stirring reaction to nothing are added under agitation Precipitation generation, that is, hydrochloride, nitrate or the acetate of compound is made.
Embodiment 26, in vitro anti-microbial activity experiment
Clinical trial standard (the National Committee for formulated using United States National Committee in 1993 is met Clinical Laboratory Standards, NCCLS) 96 hole micro-dilution methods, made from detection embodiment I, II, III Cumarin quinolone heterozygote is to MRSA, staphylococcus aureus, micrococcus luteus, hay bacillus, proteus, Escherichia coli (DH52/JM109), Bacillus typhosus, pseudomonas aeruginosa, Shigella dysenteriae, candida utili bacterium, Aspergillus flavus, beer Brewer yeast bacterium, Candida albicans, the minimum inhibitory concentration (MIC) of candidiasis, by testing compound with a small amount of dimethyl sulfoxide Dissolving, add water dilution and the solution that concentration is 1.28mg/mL is made, then 1024 μ g/mL, 37 DEG C of cultures 24 are diluted to nutrient solution ~72 hours, culture plate is put after fully being stirred evenly on oscillator, MIC (μ g/mL) is determined at wavelength 490nm, the results are shown in Table 1 He Table 2.
The antibacterial activity (MIC, μ g/mL) of the cumarin quinolone heterozygote of table 1
As can be seen from Table 1, all testing compounds show certain inhibitory activity to tested bacterium, wherein changing Compound I-4, II-3 and III-3 show preferable antibacterial activity to all test bacteriums, or even to some test bacteriums Inhibitory activity is suitable with reference drug or is better than reference drug, and especially compound III-3 is minimum to Escherichia coli (DH52) Inhibition concentration as little as 0.5 μ g/mL, be reference drug chloramphenicol (MIC=32 μ g/mL) activity 64 times, Norfloxacin (MIC=1 μ g/mL), Ciprofloxacin (MIC=1 μ g/mL) and Clinafloxacin (MIC=1 μ g/mL) activity 2 times.
The antifungal activity (MIC, μ g/mL) of the cumarin quinolone heterozygote of table 2
As can be seen from Table 2, nearly all testing compound shows certain inhibitory activity to tested fungi, and In addition to compound II-1, all compounds are suitable with reference drug Fluconazole to the inhibitory activity of Aspergillus flavus or better than fluorine health Azoles.Wherein, compound I-3, II-2, II-3, II-8, II-9, III-3 reaches 0.5 μ g/ to the inhibitory activity of Candida albicans ML, it is better than Fluconazole (MIC=1 μ g/mL).
Embodiment 27, drug combination drug sensitive experiment
It is husky according to measured cumarin quinolone heterozygote I-4, II-2, III-3 and reference drug chloramphenicol, promise fluorine Star, Ciprofloxacin, Clinafloxacin and Fluconazole are to the MIC value of test bacterium, fungi, antimicrobial work as defined in foundation NCCLS Property testing standard, use chessboard method (when cumarin quinolone heterozygote and reference drug concentration is independent medications MIC 1/32, 1/16th, 1/8,1/4,1/2,1,2 and 4 times) determine cumarin quinolone heterozygote I-4, II-2, III-3 and reference drug chlorine Bacterium, fungi growth inhibition ability when mycin, Norfloxacin, Ciprofloxacin, Clinafloxacin and Fluconazole are combined.Combination Effect is examined with FIC indexes.Test result is shown in Table 3-7.
Cumarin quinolone heterozygote I-4, II-2, the III-3 of table 3 and chloramphenicol drug combination effect
Cumarin quinolone heterozygote I-4, II-2, the III-3 of table 4 and Norfloxacin drug combination effect
Cumarin quinolone heterozygote I-4, II-2, the III-3 of table 5 and Ciprofloxacin drug combination effect
Cumarin quinolone heterozygote I-4, II-2, the III-3 of table 6 and Clinafloxacin drug combination effect
Cumarin quinolone heterozygote I-4, II-2, the III-3 of table 7 and Fluconazole drug combination effect
Result shown in table 3-7 shows cumarin quinolone heterozygote I-4, II-2, III-3 and reference drug chloramphenicol, promise Effect is partly combined as synergy after Flucloxacillin, Ciprofloxacin and Clinafloxacin combination.Wherein compound I-4, II-2, III- 3 with chloramphenicol, I-4, II-2 and Norfloxacin, III-3 and Ciprofloxacin and III-3 with after Clinafloxacin combination to MRSA's Antibacterial activity significantly improves, and is expected to overcome the drug resistance of QNS and slows down its toxic side effect.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical Cross above preferred embodiment the present invention is described in detail, it is to be understood by those skilled in the art that can be Various changes are made to it in form and in details, without departing from claims of the present invention limited range.

Claims (4)

1. cumarin quinolone heterozygote or its officinal salt, it is characterised in that for any of following compounds or its can Pharmaceutical salts：
2. cumarin quinolone heterozygote according to claim 1 or its officinal salt, it is characterised in that described pharmaceutically acceptable Salt is hydrochloride, nitrate or acetate.
3. cumarin quinolone heterozygote or its officinal salt described in any one of claim 1 to 2 prepare antibacterium and/or Application in antifungal drug.
4. application according to claim 3, it is characterised in that the bacterium is staphylococcus aureus, methicillin-resistant Staphylococcus aureus, micrococcus luteus, hay bacillus, Escherichia coli, pseudomonas aeruginosa, proteus, Shigella dysenteriae With any of Salmonella typhi or a variety of；The fungi is candida utili bacterium, Aspergillus flavus, saccharomyces cerevisiae, white Any of color candida albicans and candidiasis are a variety of.
CN201510667385.1A 2015-10-14 2015-10-14 Cumarin quinolone heterozygote or its officinal salt and its preparation method and application Active CN105218531B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510667385.1A CN105218531B (en) 2015-10-14 2015-10-14 Cumarin quinolone heterozygote or its officinal salt and its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510667385.1A CN105218531B (en) 2015-10-14 2015-10-14 Cumarin quinolone heterozygote or its officinal salt and its preparation method and application

Publications (2)

Publication Number Publication Date
CN105218531A CN105218531A (en) 2016-01-06
CN105218531B true CN105218531B (en) 2018-03-16

Family

ID=54987864

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510667385.1A Active CN105218531B (en) 2015-10-14 2015-10-14 Cumarin quinolone heterozygote or its officinal salt and its preparation method and application

Country Status (1)

Country Link
CN (1) CN105218531B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105837545B (en) * 2016-04-01 2018-08-21 西北农林科技大学 Coumarin derivatives and its preparation method and application containing halogen or benzimidazole functional group
CN112358445B (en) * 2020-10-10 2022-06-14 广东省微生物研究所（广东省微生物分析检测中心） N-acylhydrazone-ciprofloxacin heterozygote and preparation method and application thereof
CN112358466B (en) * 2020-10-10 2021-10-26 广东省微生物研究所（广东省微生物分析检测中心） 1,2, 4-triazole-norfloxacin heterozygote and preparation method and application thereof
CN115636785B (en) * 2022-09-23 2024-05-28 西南大学 Quinolone cyanoacetate compound and pharmaceutically acceptable salt thereof, and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1176252A (en) * 1996-07-26 1998-03-18 普利瓦药物，化学，食品，化妆品工业公司 Novel coumarin quinolone carboxylic acids and processes for preparation thereof
CN1679540A (en) * 2003-05-15 2005-10-12 中国科学院上海有机化学研究所 Medicine against fungus

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1176252A (en) * 1996-07-26 1998-03-18 普利瓦药物，化学，食品，化妆品工业公司 Novel coumarin quinolone carboxylic acids and processes for preparation thereof
CN1679540A (en) * 2003-05-15 2005-10-12 中国科学院上海有机化学研究所 Medicine against fungus

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Synthesis and Antibacterial Activity of Quinolone-Based Compounds Containing a Coumarin Moiety;Saeed Emami，等;《Arch.Pharm.Chem.Life Sci.》;20080131;第341卷(第1期);第45页表2，第44页方案1，第46页倒数第2段 *
Synthesis and Biological Evaluation of Coumarin Linked Fluoroquinolones,Phthalimides and Naphthalimides as Potential DNA Gyrase Inhibitors;A.Kamal，等;《Letters in Drug Design & Discovery》;20060731;第3卷(第7期);494-502 *
Synthesis and In-Vitro Antimycobacterial Activity of Fluoroquinolone Derivatives Containing a Coumarin Moiety;Qiang Guo，等;《Arch.Pharm.Chem.Life Sci.》;20111012;第344卷(第12期);802-809 *
Synthesis of ciprofloxacin dimers for evaluation of bacterial permeability in atypical chemical space;Audrey G. Ross，等;《Bioorganic & Medicinal Chemistry Letters》;20150709;第25卷(第17期);第3471-3473页表1和2 *

Also Published As

Publication number Publication date
CN105218531A (en) 2016-01-06

Similar Documents

Publication Publication Date Title
CN105218531B (en) Cumarin quinolone heterozygote or its officinal salt and its preparation method and application
CN101486703B (en) Flavone compound with antineoplastic activity, preparation thereof and uses thereof
CN104024228B (en) Imidazolidinedione compounds and their uses
CN104557973B (en) 3,3 '-methylene of a kind of chirality piperazine quinoline ring-bis-fluoro quinolone derivatives and its preparation method and application
CN100497337C (en) Folacin dimethylbiguanide and process for production thereof
CN108658962A (en) 3- substituted cumarins Furazan Derivatives and its purposes in preparing anti-multidrug resistance of tumor drug
WO2019196955A1 (en) Hydrophilic berberine derivative with r10 and r11 connected and application thereof in preparation of drugs
CN106831824A (en) Pyrrolopyridines and its application containing naphthyridones structure
CN102471273B (en) 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof
CN109651353A (en) Aminothiazole quinolone oxime compound and its preparation method and application
KR100953271B1 (en) 1-Cyclopropyl-6-fluoro-7-8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid aspartic acid salt, process for the preparation thereof and pharmaceutical composition comprising the same for antimicrobial
CN107383110B (en) Water-soluble IDO inhibitor platinum and preparation method thereof
CN105175360A (en) Ether aryl piperazine derivatives, and salts, preparation methods and application thereof
CN106749213B (en) A kind of indole derivatives and preparation method with 1,2,4- oxadiazoles structure and the application in preparation antibacterials
CN105017195B (en) The purposes of 4 Hydroxycoumarin, 3 schiff bases analog derivative and its treatment Alzheimer's disease
CN102531949A (en) Substituted benzamide compounds and preparation method and application thereof
CN103804388B (en) 4 β-nitrogen substituted furan tertiary amines podophyllotoxin derivative and preparation method thereof and application
CN104072426A (en) Preparing method of anticancer medicine
CN104098457B (en) Tetrahydrocurcumin analogue, preparation and application thereof
CN107375279A (en) Application of the novel thiazole analog derivative in inflammatory bowel disease is treated
CN104211682B (en) Pyridine compounds and their and application thereof
TW200536856A (en) Process for producing flavone C glycoside derivatives
CN103265559B (en) Replace three ring benzoquinone compounds and preparation method thereof and application
CN105130981B (en) The application of berberine benzimidazoles compound
CN106866642A (en) The quinazoline compounds of the structure of acylhydrazone containing aryl and its application

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant