CN109096278A - Fluoquinolone-nitrogen azoles hybrid derivatives, preparation method and its usage - Google Patents

Fluoquinolone-nitrogen azoles hybrid derivatives, preparation method and its usage Download PDF

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CN109096278A
CN109096278A CN201811122153.8A CN201811122153A CN109096278A CN 109096278 A CN109096278 A CN 109096278A CN 201811122153 A CN201811122153 A CN 201811122153A CN 109096278 A CN109096278 A CN 109096278A
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compound
halogen
raceme
stereoisomer
bacterium
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CN109096278B (en
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杨大成
陈菲菲
范莉
罗鹏
张书虹
潘建芳
徐兴然
聂福平
陈冉樾
张园
张泽朝
胡军华
王帆
周成合
刘耀
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Southwest University
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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 linked by a chain containing hetero atoms as chain links
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against 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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Abstract

The invention discloses fluoquinolone shown in formula I-nitrogen azole derivatives, the pharmacophore of fluoquinolone and nitrogen azole drug is connected with each other by the analog derivative by suitable connection structure, it is verified by biological activity test, such compound has the double activity for inhibiting bacterium and fungi simultaneously, has a good application prospect.

Description

Fluoquinolone-nitrogen azoles hybrid derivatives, preparation method and its usage
Technical field
The present invention relates to a kind of for treating the compound more particularly to ten serial fluorine of bacterium and/or fungal infection Quinolone-nitrogen azoles hybrid derivatives.
Background technique
With the extensive use of broad-spectrum antibiotic, hormone, immunosuppressor, the sprawling of AIDS, organ transplant and intervention skill The popularization and application of art, make the microorganism infections such as fungi, bacterium disease incidence present ascendant trend, the report in relation to antibody-resistant bacterium by Cumulative more, the treatment of fungi and bacterium infection is faced with formidable challenges.
Azole antifungals are current clinical main fungal infection therapeutic agents, such drug has metabolism steady It is fixed, not only orally available but also injectable, the advantages that superficial mycosis and all effective in cure deep fungal.Wherein the fragrant ethyl such as ketoconazole is cyclic annular Ketal compounds are the choice drugs for treating mycotic infection of superficial part, anti-true as the third generation of representative using Fluconazole and Itraconazole Bacterium drug is the first choice for treating deep infection.But azole antifungals can be with multiple cytochrome p450 proteins of human body Effect, therefore there is more serious adverse reaction.The antimicrobial spectrum relative narrower of Fluconazole, it is very low to fungi activities such as Aspergillus, And it is also easy to produce drug resistance, there is also the unstable equivalent topics of oral administration biaavailability for Itraconazole.
Fluoroquinolones lists successively in the 1980s, and there is has a broad antifungal spectrum, antibacterial activity height, tissue to wear The advantages that permeability is strong, bioavilability is high, long half time, blood concentration are high, Tissue distribution is wide and can single medicine use, to the blue sun of leather Property bacterium and gram-negative bacteria show good antibacterial activity, are widely used in urogenital system, respiratory system, digestive system The treatment of infectious diseases.But as the clinical irrational use of antibacterials increases, resistance problems also become increasingly conspicuous.
For the defect of above-mentioned antimycotic and bacterial drug, scientists constantly looking for always it is new have it is antimycotic and The compound of bacterial activity.Such as: CN108368053A discloses a kind of for Gram-negative bacteria UDP-3-O- (R-3- hydroxyl Myristoyl)-N- acetyl glucosamine deacetylase (LpxC) target benzo-aza pimelie kelone compounds, to evade Plasmid common at present.CN108368102A discloses a kind of diazine compound, less antimycotic for studying The true glucan synthase of target β (echinocandin) carries out drug design being capable of conduct when polyenoid and triazole antifungal agent object drug resistance Alternative medicine uses.Although antimycotic and bacterial drug research and development constantly have new achievement to occur, current R&D direction It is all based on the research of single target spot, there is not yet the report of the drug of fungi and bacterium target spot can be acted on simultaneously.With egg The development of the subjects such as white matter group and genomics, for drug mechanism of action in vivo understanding gradually from cellular level It is deep into molecular level, for certain diseases, even if target spot selects very accurate, the activity and selectivity of the compound of design Also very strong, but it is final because drug is influenced to cause drug effect not fully up to expectations in vivo by many factors.Therefore, for disease The research of the multiple target point drug of the origin cause of formation is increasingly becoming hot spot.The most common design method of multiple target point drug is known as skeleton joint side Method, this method use the molecule of the different target spots of two targetings as initial compounds, retain the main body knot including pharmacophore After structure, backbone integration is carried out to the two.However it is a large amount of practice have shown that, although backbone integration method theoretically have it is certain feasible Property, but due to the compound structure and physicochemical property after integration and integrate preceding possible widely different, if it remains to retain to original The affinity of target spot has not predictability.
Summary of the invention
The pharmacophore of azole antifungals and fluoroquinolones by linker heterozygosis, is obtained one by the present invention Class has both antimycotic and bacterial activity fluoquinolone-nitrogen azoles Hybrid compounds, and specific technical solution of the present invention is as follows:
Compound shown in formula I, raceme, stereoisomer, tautomer, nitrogen oxides or their pharmacy can Receive salt:
Wherein X is selected from: C1-C6 alkyl;C3-C6 naphthenic base;The aryl of substituted or unsubstituted C6-C10, on the aryl Substituent group be one or more, be independently selected from: halogen;Amino;Hydroxyl;C1-C6 alkyl;C3-C6 naphthenic base;
Z is selected from: N or C-R1;R1Selected from H;C1-C6 alkoxy or halogen;
Q is selected from CH or N;
R ' is selected from halogen;
Y is selected from:
Wherein n is selected from 1,2 or 3;R2Selected from H, halogen or C1-C6 alkyl;R " is selected from hydrogen or C1-C6 alkyl;Mark the one of * Side indicates the connecting pin with L;
L indicates connection structure.
In above-mentioned technical proposal, the preferably following group of L:
Wherein, R3、R4It is individually optional from H, halogen, hydroxyl, amino or C1-C6 alkyl;M is selected from 0,1,2 or 3;Mark * *'s Side is for indicating and the connecting pin of Y.
Preferably, Q is selected from N in above-mentioned any technical solution;R ' is selected from fluorine;
L is selected from:
Preferably, X is selected from above-mentioned any technical solution: methyl, ethyl, propyl, cyclopropyl, substituted or unsubstituted Phenyl, the substituent group on the phenyl is one or more, is independently selected from: halogen;Amino;Hydroxyl or C1-C3 alkyl;
Z is selected from: N or C-R1;R1Selected from H;Methoxyl group, ethyoxyl or halogen.
The present invention also provides TM1~TM10 in such as specific embodiment and moiety intermediate compound represented, racemizations Body, stereoisomer, tautomer, nitrogen oxides or their pharmaceutically acceptable salt.
A kind of pharmaceutical composition, including above-mentioned any compound, its raceme, alloisomerism is also claimed in the present invention Body, tautomer, nitrogen oxides or their pharmaceutically acceptable salt.
Preferably, any compound of the invention, its raceme, stereoisomer, tautomer, nitrogen oxides or Their pharmaceutically acceptable salt, can be made pharmaceutically acceptable any dosage form, i.e., pharmaceutical composition of the invention can also wrap Include pharmaceutically acceptable carrier and/or auxiliary agent.
Preferably, can according to need by one or more other active components and any compound of the invention, its Compound medicine is made in raceme, stereoisomer, tautomer, nitrogen oxides or their pharmaceutically acceptable salt.
Above-mentioned any compound, its raceme, stereoisomer, tautomer, nitrogen oxidation is also claimed in the present invention The purposes of object or their pharmaceutically acceptable salt in the drug of preparation treatment fungal infection and/or bacterium infection associated diseases.
Fungal infection of the present invention includes but is not limited to aspergillus fumigatus, Candida tropicalis, Candida albicans and close Candida glabrata infection;Particularly preferred aspergillus fumigatus infection.Bacterium infection of the present invention includes but is not limited to golden yellow grape Coccus, Escherichia coli, vibrio parahaemolytious, pseudomonas aeruginosa, salmonella, acinetobacter calcoaceticus, drug resistance citric acid bacillus, drug resistance gold Staphylococcus aureus and the infection of drug resistance Friedlander's bacillus.
Term definition and explanation:
Unless otherwise indicated, group and the term definition recorded in present specification and claims, including its work For recorded in the definition of example, illustrative definition, preferred definition, table definition, particular compound determines in embodiment Justice etc., can any combination and combination each other.Group definition and compound structure after such combination and combination, should Belong in the range of present specification record.
Unless otherwise indicated, it when " the compounds of this invention " used herein or " the compound of the present invention ", is at least intended to Cover Formulas I compound represented, its raceme, stereoisomer, tautomer, nitrogen oxides or theirs is pharmaceutically acceptable Salt.
Term " halogen " refers to F, Cl, Br and I.In other words, F, Cl, Br and I can be described as " halogen " in the present specification.
Term " C1-C6 " is interpreted as the preferred linear chain or branched chain saturation monovalent hydrocarbon for indicating to have 1-6 carbon atom, example Such as methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, isobutyl group, sec-butyl, tert-butyl, isopentyl, 2- methyl fourth Base, 1- methyl butyl, 1- ethyl propyl, 1,2- dimethyl propyl, neopentyl, 1,1- dimethyl propyl, 4- methyl amyl, 3- first Base amyl, 2- methyl amyl, 1- methyl amyl, 2- ethyl-butyl, 1- ethyl-butyl, 3,3- dimethylbutyl, 2,2- dimethyl Butyl, 1,1- dimethylbutyl, 2,3- dimethylbutyl, 1,3- dimethylbutyl or 1,2- dimethylbutyl etc. or theirs is different Structure body.
Term " C6-C10 aryl " is interpreted as the preferred armaticity or partial aromatic for indicating to have 6-10 carbon atom Monocyclic, bicyclic or tricyclic hydrocarbon, especially with the ring (" C6 aryl ") of 6 carbon atoms, such as phenyl;Or xenyl, or It is the ring (" C9 aryl ") with 9 carbon atoms, such as indanyl or indenyl, or the ring (" C10 with 10 carbon atoms Aryl "), such as tetrahydro naphthyl, ihydro naphthyl or naphthalene.
Compound pharmaceutically acceptable salt mentioned by the present invention can be ackd salt, be also possible to basic salt.Such as Inorganic acid salt, acylate, organic alkali salt or inorganic base salts.
The compounds of this invention preferably passes through normal in unmodified form or with conventional use of adjuvant in the preparation of this field Rule technological means obtains such as liquid preparation (such as stock solution, emulsion, suspension, solution, emulsifiable concentrate, solution Concentrate), semisolid preparation (such as creme, ointment, patch, gelling agent, Liposomal formulation) and solid pharmaceutical preparation (such as dissipate Agent, granule, tablet etc.).
Term pharmaceutically acceptable carrier and/or auxiliary agent include but is not limited to: carbohydrate, such as lactose, sucrose, mannitol And sorbierite;Starch, such as cornstarch, tapioca and potato starch;Cellulose and its derivates, such as carboxymethyl are fine Tie up plain sodium, ethyl cellulose and methylcellulose;Calcium phosphate, such as Dicalcium Phosphate and tricalcium phosphate;Sodium sulphate;Calcium sulfate; Polyvinylpyrrolidone;Polyvinyl alcohol;Stearic acid;Alkali earth metal stearate, such as magnesium stearate and calcium stearate;Vegetable oil Class, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil;Nonionic, cation and anionic surfactant;It is poly- Ethylene glycol;Fatty alcohols;With hydrolyzed cereal solids and other nontoxic compatible fillers, adhesive, disintegrating agent, slow Electuary, preservative, antioxidant, lubricant, colorant etc. commonly use auxiliary material in pharmaceutical preparation.
Specific embodiment
The synthesis of embodiment one, TM1 series compound
General routes outlined is as follows:
It is added 2' in 250mL round-bottomed flask, the fluoro- 2- of 4'- bis- [1- (1H-1,2,4- triazolyl)] acetophenone (1.115g, 5mmol) and 10mL methanol, it is stirred at room temperature, KBH is added portionwise under condition of ice bath4(0.405g, 7.5mmol), finishes, and removes Ice bath, 20-40 DEG C of stirring, TLC detect reaction process.After the reaction was completed, revolving removes solvent, adds water 15mL, concentrated hydrochloric acid tune pH =1~3,1h, 10%K is stirred at room temperature2CO3PH=8~9 are adjusted, are stood, are filtered, washes (10mL × 3), obtains white solid IM1.
IM1 (0.672g, 3mmol), succinic anhydride (0.603g, 6mmol), acetone are added in 100mL round-bottomed flask 6mL, Et3N 0.15mL, is warming up to reflux under stirring, TLC monitors reaction process.After the reaction was completed, water is added into reaction solution 10mL stirs lower crystallization, solid is collected by filtration, ethyl alcohol recrystallization obtains white solid IM1-2.
IM1-2 (1.0mmol), HBTU (1.2mmol), Sha Xing (1.1mmol) are sequentially added in 100mL round-bottomed flask and are done Dry DCM 10mL, is stirred at room temperature, and DIPEA or Et is added under condition of ice bath3It is anti-to remove ice bath continuation room temperature by N (2.0mmol) It answers, TLC monitors reaction process.After the reaction was completed, stop stirring.It filters, filter cake is washed with DCM (10mL × 3);Filtrate is collected, Successively to be saturated NaHCO3Solution (15mL × 2), 1.5N diluted hydrochloric acid aqueous solution (15mL × 2), saturation NaCl solution (15mL × 2) Washing, stratification, anhydrous Na2SO4It is dry, evaporated under reduced pressure, column chromatographic purifying (DCM/CH3OH=80/1), eluent is collected, Evaporated under reduced pressure;Vacuum drying, obtains TM1, related experiment the results are shown in Table 1.
The composite result and characterization of 1 TM1 series compound of table
The synthesis of embodiment two, TM2 series compound
General routes outlined is as follows:
NaH (0.813g, 20mmol), THF 15mL is added in 250mL there-necked flask, is stirred at room temperature;Use constant pressure funnel The solution that IM1 (2.245g, 10mmol) is dissolved in THF 10mL is slowly added dropwise, finishes 80 DEG C of oil bath reaction 30min of immigration;Slowly drop 2- methyl bromoacetate (1.735g, 15mmol) is added to be dissolved in the solution of THF 10mL.TLC monitors reaction process.Stop stirring, it will be anti- It answers mixture to be concentrated under reduced pressure, pours into cold water (30mL), methylene chloride extracts (2 × 20mL).Merge organic extract liquid, saturation food Salt water (2 × 20mL) washing, anhydrous sodium sulfate is dry, evaporated under reduced pressure, column chromatographic purifying (PE/EA=1/2), collects eluent, Evaporated under reduced pressure, vacuum drying, obtains sterling IM2-2.
It is molten in the mixing that 100mL round-bottomed flask sequentially adds IM2-2 (1.930g, 6.5mmol), methanol 9mL and water 5mL LiOHH is added in agent, electromagnetic agitation2O (0.819g, 19.5mmol), continues to stir, and TLC monitors reaction process.Reaction is completed Afterwards, methanol is removed under reduced pressure, cooling, pH value is transferred to 2~3, and faint yellow solid is precipitated, and filters, and filter cake washes (2 × 10mL), collects Filter cake obtains faint yellow solid IM2-3.
IM2-3 (1.0mmol), HBTU (1.2mmol), Sha Xing (1.0mmol) are sequentially added in 100mL round-bottomed flask and are done Dry DCM 15mL, stirring, ice bath is cooling, and DIPEA or Et is added3N (2.0mmol) removes ice bath and continues to react at room temperature.TLC Reaction process is monitored, when product point essentially unchangedization, stops stirring.It filters, filter cake is washed with DCM (10mL × 3);Collect filter Liquid, successively to be saturated NaHCO3Solution (15mL × 2), 1.5N diluted hydrochloric acid aqueous solution (15mL × 2), saturation NaCl solution (15mL × 2) it washs, anhydrous Na2SO4It is dry, evaporated under reduced pressure, column chromatographic purifying (DCM/CH3OH=120/1), eluent, decompression are collected It is evaporated, is dried in vacuo, obtains sterling TM2, related experiment the results are shown in Table 2.
2 TM2 series compound composite result of table and characterization
The synthesis of embodiment three, TM3 series compound
General routes outlined is as follows:
Husky star (2mmol), DCM 5mL and alkali (NaHCO are added in 100mL round-bottomed flask3Or Et3N, 3mmol), ice bath Stirring, is added dropwise the DCM solution 5mL of the solid phosgene (BTC) of 1mmol, is stirred at room temperature, and TLC monitors reaction process.Reaction terminates Afterwards, 15mL saturated salt solution is added, adjusts pH value 4~5, liquid separation, saturated common salt water washing (10mL × 3).Liquid separation, anhydrous sodium sulfate Dry, revolving removes solvent and obtains intermediate compound I M3-1~IM3-8.
IM1 (1.2mmol), DCM 10mL, Et are added in 100mL round-bottomed flask3N (1.5mmol) and DMAP (0.05mmol), ice bath stirring are added IM3-X (X=1~8) (1mmol), are warming up to room temperature, continue to stir, TLC monitoring reaction Process.After reaction, 15mL DCM is added, and washes (25mL × 3), anhydrous Na with acid saturated common salt aqueous2SO4It is dry, subtract Pressure is evaporated, column chromatographic purifying (DCM/CH3OH=150/1), eluent is collected, evaporated under reduced pressure obtains sterling TM3.Using above-mentioned Method, has synthesized serial 8 target compounds of TM3, and related experiment the results are shown in Table 3.
3 TM3 series compound composite result of table and characterization
The synthesis of example IV, TM4 series compound
General routes outlined is as follows:
IM1 (0.5mmol), alkali (1mmol) and 6mL DCM are sequentially added in 100mL round-bottomed flask, after stirring 20min, drop The solution of chlorination chloroacetic chloride (0.75mmol), -5 DEG C of sustained responses, TLC tracking and monitoring to reaction terminate.Vacuum rotary steam removes molten Agent adds water 15mL, EA to extract (15mL × 3), collects organic phase, and saturated common salt washes (15mL × 3), anhydrous Na2SO4It is dry, subtract Pressure is evaporated, column chromatographic purifying (PE/EA=1/1), collects eluent, and evaporated under reduced pressure, room temperature is spacious to put one day, is dried in vacuo, obtains Intermediate compound I M4-2, it is spare.
Sha Xing (1mmol), Et are sequentially added in 100mL round-bottomed flask3N (1.5mmol) and 5mL DMF, after stirring 20min It is added IM4-2 (1.2mmol), moves to 60 DEG C of oil baths and be stirred to react, TLC, which is monitored to reaction, to be terminated.30mL ice water and 15mL is added DCM adjusts pH=3 or so, liquid separation, and saturated common salt washes (20mL × 5), anhydrous Na2SO4Dry, evaporated under reduced pressure, column chromatographs pure Change (DCM/CH3OH=150/1), eluent, evaporated under reduced pressure are collected, vacuum drying obtains sterling TM4, related experiment result is shown in Table 4.
4 TM4 series compound composite result of table and characterization
The synthesis of embodiment five, TM5 series compound
General routes outlined is as follows:
In IM1 (0.5mmol), 5mL DCM, alkali 1.0mmol are added in 100mL round-bottomed flask, it is anti-that reaction flask moves to low temperature 0 DEG C of reaction in device is answered, is added dropwise 3- chlorpromazine chloride (1.0mmol), is added DMAP (0.1mmol), TLC monitoring.It revolves after reaction Solvent is evaporated off, water 10mL, EA is added to extract (5mL × 3), saturated common salt water washing (10mL × 3), anhydrous Na2SO4It is dry, decompression It is evaporated, obtains IM5-2, be directly used in the next step.
IM5-2 (0.6mmol), 4mL DMF are added in 100mL reaction flask, after stirring and dissolving, husky star is added (0.5mmol), alkali (1.5mmol) is stirred to react at 65-100 DEG C, and TLC monitors reaction process.After reaction, add water 20mL, DCM 30mL is added, adjusts its pH to 2-3, liquid separation, organic phase washs 4 times (15mL water+2mL 1.5N HCl), anhydrous Na2SO4It is dry It is dry, revolving, column chromatographic purifying (DCM/CH3OH=130/1), eluent, evaporated under reduced pressure are collected, vacuum drying obtains TM5, phase It closes experimental result and is shown in Table 5.
5 TM5 composite result of table and characterization
The synthesis of embodiment six, TM6 series compound
General routes outlined is as follows:
In IM1 (0.113g, 0.5mmol), DCM 4mL, alkali (1.0mmol) are added in 100mL round-bottomed flask, reaction flask is moved 0 DEG C of reaction into low-temp reaction device, is added dropwise 4- chlorobutanoylchloride (0.141g, 1.0mmol), stirring, TLC monitoring.After reaction Revolving removes solvent, and water 10mL is added, and EA extracts (5mL × 3), saturated common salt water washing (10mL × 3), anhydrous Na2SO4It is dry, Evaporated under reduced pressure obtains IM6-2.
IM6-2 (1.2mmol), Sha Xing (1mmol) and 4mL DMF, Et are sequentially added in 100mL round-bottomed flask3N (1.2mmol), 70-95 DEG C is stirred to react, and TLC, which is monitored to reaction, to be terminated.30mL ice water, 25mL DCM is added, it is left to adjust pH=3 The right side, liquid separation, saturated common salt wash (20mL × 5), anhydrous Na2SO4It is dry, evaporated under reduced pressure, column chromatographic purifying (DCM/CH3OH= 150/1) eluent, is collected, evaporated under reduced pressure obtains TM6, and related experiment the results are shown in Table 6.
6 TM6 composite result of table and characterization
The synthesis of embodiment seven, TM7 series compound
General routes outlined is as follows:
Ph is sequentially added in 100mL round-bottomed flask3P (1mmol), 3mL toluene and 2- methyl bromoacetate (1.2mmol), room Temperature stirring 10min, is moved into 60-80 DEG C of oil bath and heats reaction, temperature is raised to 120 DEG C of reflux after 6h, and flow back 3h, and room temperature is cold But, white solid is precipitated, filters, filter cake washes (2mL × 5) with ether, obtains white solid IM7-1.
DMF 1.5mL is sequentially added in 100mL there-necked flask, 0.5h is stirred at room temperature in NaH (0.03g, 0.75mmol), nitrogen guarantor The DMF solution (3mL) of IM7-1 (0.311g, 0.75mmol) is added dropwise under shield again, 2h is stirred at room temperature, 1mL 2' is added dropwise, 4'- bis- is fluoro- The DMF solution of 2- [1- (1H-1,2,4- triazolyls)] acetophenone (0.113g, 0.5mmol), is stirred at room temperature, TLC monitoring.Reaction After, it adds water and stirs, filters and remove a part of triphenylphosphinc oxide, filtrate is extracted until without product in water phase with EA, is associated with Machine phase is washed (20mL × 2), and saturated common salt washes (20mL × 3), anhydrous Na2SO4Dry, evaporated under reduced pressure, column chromatographic purifying obtains To sterling IM7-2.
The mixed solvent of IM7-2 (2.1g, 7.5mmol), 10mL methanol and 5mL water is sequentially added in 100mL round-bottomed flask, LiOHH is added2O (1.26g, 30mmol), ice bath stirring, TLC monitor reaction process.After having reacted, vacuum distillation removes first Alcohol, pH value are transferred to 2~3, EA (10mL × 3) extraction, merge organic phase, anhydrous Na2SO4Dry, evaporated under reduced pressure obtains IM7-3.
IM7-3 (0.294g, 1.1mmol), HBTU (0.455g, 1.2mmol), sand are sequentially added in 100mL round-bottomed flask Star (1.0mmol) and dry DCM 8mL, are stirred at room temperature, and DIPEA or Et is added3N (2.0mmol), continues to react at room temperature, TLC Reaction process is monitored, when product point essentially unchangedization, stops stirring.Filter, filter cake washs with DCM (5mL × 3), filtrate according to It is secondary to be saturated NaHCO3Solution (10mL × 2), 1.0N HCL aqueous solution (15mL × 2), saturation NaCl solution (15mL × 2) are washed It washs, anhydrous Na2SO4Drying, evaporated under reduced pressure, column chromatographic purifying, evaporated under reduced pressure obtain sterling TM7.Utilize the above method, synthesis TM7 8 target compounds of series, related experiment the results are shown in Table 7.
7 TM7 composite result of table and characterization
The synthesis of embodiment eight, TM8 series compound
General routes outlined is as follows:
Sequentially added in 100mL round-bottomed flask IM1 (10mmol), acetonitrile 15mL, 4,6- dichloro pyrimidine (12mmol), K2CO3(23mmol) is stirred to react in 90 DEG C of oil baths, TLC monitoring reaction.Reaction terminates, and revolving removes solvent, and 30mL is added DCM and 15mL water, electromagnetic agitation are stood, liquid separation, and water phase is stripped (10mL × 2) with DCM, merge organic phase, saturated common salt washing (30mL × 3), anhydrous Na2SO4It is dry, evaporated under reduced pressure, column chromatographic purifying (PE/EA=6/1), collection eluent, evaporated under reduced pressure, Obtain IM8-2.
IM8-2 (1.1mmol), Sha Xing (1mmol), DMF 3.0mL, K are sequentially added in 100mL round-bottomed flask2CO3 (1.5mmol), electromagnetic agitation in 90 DEG C of oil baths, TLC monitoring.Reaction terminates, and ice water 30mL and DCM15mL is added, and adjusts pH=4 Left and right, liquid separation, saturated common salt wash (20mL × 5), anhydrous Na2SO4It is dry, evaporated under reduced pressure, column chromatographic purifying (DCM/CH3OH= 120/1) eluent, evaporated under reduced pressure, are collected, vacuum drying obtains TM8, related experiment the results are shown in Table 8.
8 TM8 composite result of table and characterization
The synthesis of embodiment nine, TM9 and TM10 series compound
General routes outlined is as follows:
IM1 (2.25g, 10mmol), 20mL ethyl alcohol and 2.5mL water are sequentially added in 100mL round-bottomed flask, 9~11 DEG C are stirred 20min is mixed, NaOH (1.20g, 30mmol), TBAB (0.31g, 0.1mmol) are added, reaction flask is moved into 30 DEG C of water-baths and is added Heat is added dropwise (S)-epoxychloropropane or (R)-epoxychloropropane (9.21g, 100mmol), reaction temperature is risen to 50 DEG C of reactions, TLC monitors reaction process.After having reacted, vacuum distillation removes ethyl alcohol, and water 15mL, EA (25mL × 2) extraction, saturated common salt is added Water washing (20mL × 3), anhydrous Na2SO4Dry, evaporated under reduced pressure obtains yellow oil, and column chromatography obtains yellowish grease IM9-2 (being derived from S- epoxychloropropane) or IM10-2 (being derived from R- epoxychloropropane).
IM9-2 (or IM10-2) 1mmol, dehydrated alcohol 3mL, Sha Xing are sequentially added in 100mL round-bottomed flask (1.1mmol) and NaHCO3(1.5mmol), 85 DEG C of oil baths are stirred to react, and TLC, which is monitored to reaction, to be terminated.Revolving removes solvent, adds Water 15mL, DCM 25mL, stirring, pH are transferred to 5~6, stand, liquid separation, saturated common salt water washing (20mL × 3), anhydrous Na2SO4It is dry Dry, evaporated under reduced pressure obtains crude product, and column chromatographs to obtain sterling TM9 or TM10 list of target compound, and low temperature is protected after vacuum drying It deposits, related experiment the results are shown in Table 9.
Table 9 TM9 and TM10 synthesis and characterization result
Embodiment ten, fungi, bacterium and the test of drug-fast bacteria inhibitory activity
(1), universal sample, culture medium and reagent
1, fluoquinolone raw medicine, control and its derivative sample
(Shanghai reaches auspicious fine for gatifloxacin (GAT), enoxacin (ENX), Lomefloxacin (LOM), Balofloxacin (BAL) Chemical Co., Ltd., AR);Ciprofloxacin (CIP), Norfloxacin (NOR), sarafloxacin (SAR), (Zhengzhou Clinafloxacin (CLX) Ke Ertai biochemical technology Co., Ltd, > 95%);Fluconazole (Fuz) (Tianjin medicine company group);Fluoquinolone nitrogen azoles hybrid molecule Make by oneself.
2, culture medium and reagent
Beef-protein medium: beef extract 0.3%, peptone 1%, sodium chloride 0.5%, agar powder 1%, deionization Water.PH to 7.0~7.2 is adjusted, is sub-packed in 500mL conical flask, 121 DEG C, high pressure steam sterilization is spare within 20 minutes;
Common liq culture medium: beef extract 0.3%, peptone 1%, sodium chloride 0.5%, deionized water.Adjust pH to 7.0 ~7.2, it is sub-packed in 500mL conical flask, 121 DEG C, high pressure steam sterilization is spare within 20 minutes;
0.9% physiological saline, 1M Na2HPO4Solution, 1M NaH2PO4Solution prepares latter equal 121 DEG C, and high pressure is steamed within 30 minutes Vapour sterilizing is spare.
(2), external fungi inhibitory activity test
1, test strain
Aspergillus fumigatus;Candida tropicalis;Candida albicans;Candida albicans ATCC90023;Candida parapsilosis ATCC22019 (above-mentioned bacterial strains are provided by clinical labororatory of Sichuan Academy of Medical Sciences, People's Hospital, Sichuan Prov.).
2, minimal inhibitory concentration (MIC) measuring method
The preparation of 2.1 prepare liquids
According to the potency of determinand or content and required volume, amount needed for calculating determinand, and accurately claim Required various antibacterial determinands are taken, determinand is diluted to required concentration (sample quality with suitable solvent and diluent For 3.2mg, it is first made into mother liquor 3.2mg/mL=3200 μ g/mL, then draws 320 μ L stock solutions, with broth dilution to 1024 μ g/ ML is prepare liquid A).
The preparation of 2.2 bacteria suspensions
The bacterial strain saved is inoculated in common liq culture medium, is placed in 37 DEG C of constant-temperature table activation cultures 17 hours.Activation It is diluted to 10 respectively with brain heart infusion broth culture medium (BHI) afterwards5The bacteria suspension of CFU/mL is spare.
2.3 sample-addings and culture
Under aseptic condition, prepare liquid (concentration is 1024 μ g/mL) the 100 μ L prepared are added in the first hole of each row, then Doubling dilution is carried out to determinand, i.e. be added in the first hole after prepare liquid sufficiently blown and beaten (at least more than three times) with liquid-transfering gun make to It surveys object to mix well with meat soup, then draws 100 μ L and the second hole is added, then sufficiently piping and druming is allowed to mix well with meat soup, like this It is repeated up to the tenth hole, 100 μ L is drawn and discards;Every hole testing concentration is from left to right followed successively by 512,256,128,64 at this time, 32,16,8,4,2,1μg/mL.Last 2 hole is free of determinand, respectively as bacterial growth control and negative control.Again in 1-11 The 100 μ L of bacterium solution diluted is added in hole, every hole testing concentration, that is, final testing concentration is from left to right followed successively by this time 256,128,64,32,16,8,4,2,1,0.5μg/mL;Bacterium solution is not added in last hole, is negative control.By inoculated 96 hole Plate is put into 37 DEG C of constant incubator cultures for 24 hours.
2.4 result judgement
After the completion of culture, 96 orifice plates are taken out from insulating box, bacterial growth situation in peep hole.Determine result it Before, result is just significant when the bacterium normal growth that determine growth control hole, negative control hole are without bacterial growth.Naked eyes are seen Examine MIC of the drug concentration in the not hole of bacterial growth as the drug to the bacterium.If there is hole phenomenon is jumped, then weight is needed Retrial is verified.
3, MIC value result and discussion
Novel fluoquinolone nitrogen azoles hybrid molecule is to aspergillus fumigatus, Candida tropicalis, Candida albicans, Candida albicans The MIC value measurement result of bacterium ATCC90023 and Candida parapsilosis ATCC22019 is shown in Table 10.
MIC value measurement of 10 determinand of table to 5 fungal strains (unit is μ g/mL)
By table 10 it is found that the compound of TM1-TM10 of the present invention series has remarkable inhibiting activity to fungi, especially Positive control medicine is significantly better than to the bacteriostatic activity of aspergillus fumigatus.
(3), external bacteriostatic activity test
Part fluoquinolone-nitrogen azoles hybrid molecule is selected, the micro broth dilution method recommended using NCCLS measures them To staphylococcus aureus ATCC6538, Escherichia coli ATCC25922, vibrio parahaemolytious ATCC17802, pseudomonas aeruginosa The inhibition situation of ATCC27853, salmonella ATCC13076, acinetobacter calcoaceticus ATCC19606, obtain corresponding MIC value, and with Fluoquinolone (positive control) is compared.
1, test strain
Staphylococcus aureus ATCC6538, Escherichia coli ATCC25922, vibrio parahaemolytious ATCC17802, verdigris are false single (bacterial strain is imported and exported by Chongqing City and examines inspection by born of the same parents bacterium ATCC27853, salmonella ATCC13076, acinetobacter calcoaceticus ATCC19606 Epidemic disease office provides)
2, minimal inhibitory concentration (MIC) measures
(1) preparation of prepare liquid
According to the potency of determinand or content and required volume, amount needed for calculating determinand, and accurately claim Required various antibacterial determinands are taken, determinand is diluted to required concentration (sample quality with suitable solvent and diluent For 1mg, it is first made into mother liquor 1mg/0.195mL=5.12mg/mL=5120 μ g/mL, then draws 100 μ L stock solutions, it is dilute with meat soup It releases to 512 μ g/mL, is prepare liquid A).
(2) preparation of bacteria suspension
The bacterial strain saved is inoculated in common liq culture medium, is placed in 37 DEG C of constant-temperature table activation cultures 17 hours.Activation Base, which is supported, with brain heart infusion broth training (BHI) afterwards is diluted to 10 respectively5The bacteria suspension of CFU/mL is spare.
(3) sample-adding and culture
Under aseptic condition, 100 μ L of blank meat soup is added in each hole of 96 orifice plates.The first hole of each row add prepare to Liquid (concentration is 512 μ g/mL) 100 μ L are surveyed, doubling dilution then is carried out to determinand, is i.e. uses and moves after addition prepare liquid in the first hole Liquid rifle, which is sufficiently blown and beaten, (at least more than three times) mixes well determinand with meat soup, then draws 100 μ L and the second hole is added, then fill Divide piping and druming to be allowed to mix well with meat soup, be repeated up to the tenth hole like this, draws 100 μ L and discard;Every hole testing concentration at this time 256,128,64,32,16,8,4,2,1,0.5 μ g/mL are from left to right followed successively by, last 2 hole is free of determinand, and one as thin Bacterium growth control, one is used as negative control.The 100 μ L of bacterium solution diluted is added in the hole 1-11 again, at this time every hole determinand Concentration, that is, final testing concentration is from left to right followed successively by 128,64,32,16,8,4,2,1,0.5,0.25,0 μ g/mL;Last Bacterium solution is not added in hole, is negative control.Inoculated 96 orifice plate is put into 37 DEG C of constant incubator culture culture 16-20h.
(4) result judgement
After the completion of culture, 96 orifice plates are taken out from insulating box, bacterial growth situation in peep hole.Determine result it Before, result is just significant when the bacterium normal growth that determine growth control hole, negative control hole are without bacterial growth.Naked eyes are seen Examine MIC of the drug concentration in the not hole of bacterial growth as the drug to the bacterium.If there is hole phenomenon is jumped, then weight is needed Retrial is verified.
MIC value of 11 determinand of table to six kinds of bacteriums (unit is μ g/mL)
By table 11 it is found that the part of compounds of TM1-TM10 of the present invention to survey six plants of bacteriums with stronger inhibition make With.
(4), external drug-fast bacteria inhibitory activity test
It is false single to sensitive bacterial Escherichia coli, verdigris first to measure determinand for the micro broth dilution method recommended using NCCLS The MIC of born of the same parents bacterium PA01, staphylococcus aureus ATCC25129, staphylococcus aureus ATCC33591 obtain all targets point The antibacterial activity of son.The compound for picking out the μ of MIC≤4 g/mL carries out the MIC value measurement of drug-fast bacteria.
1 test strain
Sensitive bacteria: Escherichia coli;Pseudomonas aeruginosa PA01;Staphylococcus aureus ATCC25129;Staphylococcus aureus Bacterium ATCC33591 (this bacterial strain is provided by pharmaceutical college of Southwest University teacher Xu Xingran laboratory).
Drug-fast bacteria: resistant Staphylococcus aureus (strain number is 806S and 817S);Drug resistance Friedlander's bacillus (bacterium Strain number is 747K and 810K);Drug resistance citric acid fungus (strain number is 822N) (this bacterial strain is provided by Third Military Medical University).
2 minimal inhibitory concentrations (MIC) measurement
(1) preparation of prepare liquid: according to the potency of determinand or content and required volume, determinand institute is calculated The amount needed, and required various antibacterial determinands are accurately weighed, needed for determinand is diluted to suitable solvent and diluent Concentration (sample quality 3.2mg is first made into mother liquor 3.2mg/1mL=3.2mg/mL=3200 μ g/mL, then draw 50 μ L storage Standby liquid, it is prepare liquid A that being diluted to 500 μ L concentration with sterile water, which is 32 μ g/mL).
(2) preparation of bacteria suspension: being inoculated with the bacterial strain of preservation in common liq culture medium, is placed in 37 DEG C of constant-temperature table activation Culture 17 hours.It is diluted to 10 respectively with brain heart infusion broth culture medium (BHI) after activation5The bacteria suspension of CFU/mL is spare.
(3) it is loaded and cultivates: 80 μ L of blank meat soup is added in the first hole of each column of 96 orifice plates, blank meat is added in remaining hole 50 μ L of soup.Add prepare liquid (concentration is 32 μ g/mL) the 20 μ L prepared in the first hole of each column, two times then are carried out to determinand Dilution.That is, sufficiently being blown and beaten (at least more than three times) after prepare liquid is added in the first hole with liquid-transfering gun keeps determinand abundant with meat soup It mixes, then draws 50 μ L and the second hole is added, then sufficiently piping and druming is allowed to mix well with meat soup, is repeated up to octal like this, 50 μ L are drawn to discard;Every hole testing concentration is from left to right followed successively by 64,32,16,8,4,2,1,0.5 μ g/mL at this time, and each piece Last the two of plate are classified as control, and two column are all free of determinand, and bacterium solution is added as bacterial growth control in a column, and another column are made Bacterium solution is not added for negative control.The 50 μ L of bacterium solution that dilute is added in the hole 1-8 again, at this time every hole testing concentration be finally to It surveys object concentration and is from left to right followed successively by 32,16,8,4,2,1,0.5,0.25 μ g/mL.Inoculated 96 orifice plate is put into 37 DEG C of perseverances Then warm incubator culture culture 20-24h observes and records result.
(4) result judgement: after the completion of culture, 96 orifice plates are taken out from insulating box, bacterial growth situation in peep hole.? Before determining result, result is just intentional when the bacterium normal growth that determine growth control hole, negative control hole are without bacterial growth Justice.Using the drug concentration in the hole for being virtually free from bacterial growth as the drug to the MIC of the bacterium.Every kind of determinand pair Each bacterial strain does 2 parallel tests simultaneously, many places such as occurs and jumps hole, then should not report as a result, need to repeat to test.
3 results
The MIC value measurement of 3.1 pairs of certain sensitive strains
Target molecule is to Escherichia coli, pseudomonas aeruginosa PA01, staphylococcus aureus ATCC25129, golden yellow Portugal The MIC value of grape coccus ATCC33591 measures, and completes in pharmaceutical college of Southwest University teacher Xu Xingran laboratory, test result is as follows Table 12.
MIC value (μ g/mL) of 12 determinand of table to sensitive bacterial
By table 12 it is found that the compound of TM1-TM10 of the present invention series has inhibitory activity, partization to sensitive bacterial The bacteriostatic activity for closing object is significantly better than positive control medicine.
The MIC value measurement of 3.2 pairs of part antibody-resistant bacterium
The compound of the μ of MIC≤4 g/mL is selected from table 12, carries out drug resistance citric acid bacillus (822N), resistant S Portugal The measurement of the MIC value of grape coccus (806S and 817S) and drug resistance Friedlander's bacillus (747K and 810K), the results are shown in Table 13.
MIC value (μ g/ of 13 determinand of table to drug resistance citric acid bacillus, staphylococcus aureus and Friedlander's bacillus mL)
By table 13 it is found that the compound of TM1-TM10 of the present invention series is to drug resistance citric acid bacillus, resistant S Portugal Grape coccus and drug resistance Friedlander's bacillus have inhibitory activity, especially significantly excellent to the bacteriostatic activity of drug resistance citric acid bacillus In positive control medicine.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this In the scope of the claims of invention.

Claims (10)

1. compound shown in formula I, raceme, stereoisomer, tautomer, nitrogen oxides or their pharmacy can be connect By salt:
Wherein X is selected from: C1-C6 alkyl;C3-C6 naphthenic base;The aryl of substituted or unsubstituted C6-C10, taking on the aryl Dai Jiwei is one or more, is independently selected from: halogen;Amino;Hydroxyl;C1-C6 alkyl;C3-C6 naphthenic base;
Z is selected from: N or C-R1;R1Selected from H;C1-C6 alkoxy or halogen;
Q is selected from CH or N;
R ' is selected from halogen;
Y is selected from:
Wherein n is selected from 1,2 or 3;R2Selected from H, halogen or C1-C6 alkyl;R " is selected from hydrogen or C1-C6 alkyl;Mark the side table of * Show the connecting pin with L;
L indicates connection structure.
2. compound as described in claim 1, raceme, stereoisomer, tautomer, nitrogen oxides or their medicine Learn acceptable salt:
Wherein, L is selected from:
Wherein, R3、R4It is individually optional from H, halogen, hydroxyl, amino or C1-C6 alkyl;M is selected from 0,1,2 or 3;Mark the side of * * For indicating and the connecting pin of Y.
3. compound as claimed in claim 1 or 2, raceme, stereoisomer, tautomer, nitrogen oxides or they Pharmaceutically acceptable salt: where Q be selected from N;R ' is selected from fluorine;
L is selected from:
4. compound as claimed in claim 3, raceme, stereoisomer, tautomer, nitrogen oxides or their medicine Learn acceptable salt:
Wherein X is selected from: methyl, ethyl, propyl, cyclopropyl, substituted or unsubstituted phenyl, and the substituent group on the phenyl is one It is a or multiple, it is independently selected from: halogen;Amino;Hydroxyl or C1-C3 alkyl;
Z is selected from: N or C-R1;R1Selected from H;Methoxyl group, ethyoxyl or halogen.
5. compound as follows, raceme, stereoisomer, tautomer, nitrogen oxides or their pharmacy can Receive salt:
6. any compound, its raceme, stereoisomer, tautomerism in a kind of pharmaceutical composition, including claim 1-5 Body, nitrogen oxides or their pharmaceutically acceptable salt.
7. pharmaceutical composition as claimed in claim 6, which is characterized in that described pharmaceutical composition further include: a) pharmaceutically acceptable Carrier and/or auxiliary agent;And/or b) one or more suitable other active components.
8. compound, its raceme, stereoisomer, tautomer, nitrogen as described in claim any in claim 1-5 The use of oxide or their pharmaceutically acceptable salt in the drug of preparation treatment fungal infection and/or bacterium infection associated diseases On the way.
9. purposes as claimed in claim 8, which is characterized in that the fungal infection include aspergillus fumigatus, Candida tropicalis, Infection caused by Candida albicans or Candida parapsilosis.
10. purposes as claimed in claim 8, which is characterized in that the bacterium infection includes staphylococcus aureus, large intestine bar Bacterium, vibrio parahaemolytious, pseudomonas aeruginosa, salmonella, acinetobacter calcoaceticus, drug resistance citric acid bacillus, resistant S grape ball Infection caused by bacterium and drug resistance Friedlander's bacillus.
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