CN106008373A - Disubstituted bicyclic derivative and application thereof as efflux pump inhibitor to anti-microbial - Google Patents

Disubstituted bicyclic derivative and application thereof as efflux pump inhibitor to anti-microbial Download PDF

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CN106008373A
CN106008373A CN201610408309.3A CN201610408309A CN106008373A CN 106008373 A CN106008373 A CN 106008373A CN 201610408309 A CN201610408309 A CN 201610408309A CN 106008373 A CN106008373 A CN 106008373A
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CN106008373B (en
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马淑涛
汉丽埃塔·文特尔
王印虎
郭丽威
鲁玛纳·莫拉
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University of South Australia
Shandong University
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Shandong University
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Abstract

The invention discloses a disubstituted bicyclic derivative and application thereof as an efflux pump inhibitor to anti-microbial. It is proved by experiments that the disubstituted bicyclic derivative has a good inhibition function on multidrug-resistant bacteria carrying an AcrB efflux pump and can effectively recover or enhance antibacterial efficiency of existing antibiotics. The chemical structural formula of the disubstituted bicyclic derivative is as shown in a formula (I) (the formula can be seen in specification), and R1, R2, X, Y, Z and W are as defined in the specification.

Description

Disubstituted bicyclic derivant and as efflux pump inhibitor application in antibacterial
Technical field
The present invention relates to class disubstituted bicyclic derivant and preparation method thereof, and as Trimethoprim in antibacterial Application.
Background technology
Owing to being widely used of antibiotic is even abused, bacterial resistance sex chromosome mosaicism is on the rise, it has also become serious threat people One of key factor that class is healthy.The multi-drug resistant of antibacterials was increased by gram-negative bacteria day by day in the last few years, multiple resistance to The Gram-negative bacteria infections of medicine has become and has caused clinical patient main causes of death.Clinical most common multidrug resistant Grain-negative Bacterium includes escherichia coli, P. aeruginosa, clostridium perfringen, Acinetobacter bauamnnii etc., and wherein escherichia coli is in ICU ward Separation rate be up to 34%, multidrug resistant rate is up to 44%, often causes partes corporis humani position such as respiratory tract, digestive tract, urogenital The severe infections of road, blood, skin etc..
Efflux pump is the protein that a class is widely present on bacterial cell membrane, and under normal physiological conditions, it is permissible Harmful substance in own cells is pumped out extracellular, reaches the effect of a kind of self-protection.The overexpression of efflux pump causes Antibacterials in bacterial cell are discharged outside born of the same parents, make endobacillary drug level reduce, so that being not enough to play antibacterials Antibacterial action, thus cause the generation of multidrug resistance.Some efflux pumps optionally pump out some specific antibiotic, Such as tetracycline；But some efflux pumps can transport a series of uncorrelated compound of configurations, such as antibiotic (fluorine quinoline promise Ketone, Macrolide, tetracycline, chloromycetin etc.), metal ion, dyestuff etc., thus produce multidrug resistance phenotype.Research shows, AcrAB-TolC is most important efflux pump in gram-negative bacteria, and it can mediate the high-level drug resistance of gram-negative bacteria.Wherein AcrAB-TolC is the closest to the Correlation With Multidrug Resistance of mediation gram-negative bacteria.In AcrAB-TolC, AcrB efflux protein Being responsible for identification and the transduction of energy of substrate, this makes it play decisive role in discharging system, therefore arranges outside suppression AcrB The process LAN of pump seemingly recovers or strengthens the effective ways of existing antibiotic usefulness.
Efflux pump inhibitor can reduce the intrinsic resistance levels of antibacterial, reverses acquired drug-resistance, expands antimicrobial spectrum, reduces resistance to The incidence rate of medicine mutant strain.Send pump inhibitor to some other department to be possible not only to suppress drug-resistant bacteria and tumor cell that the outer row of medicine is made With, recover or improve antibiotic usefulness, improve drug-resistant bacteria and infect and the clinical therapeutic efficacy of tumor, and improving some medicine Pharmaco-kinetic properties (as improved the absorption of oral drugs, improve liver, the renal clearance) aspect of thing also has been widely used.Meanwhile, The infectivity and virulence of improving antibacterial are also had certain effect by efflux pump inhibitor.At present, directed toward bacteria AcrB efflux pump and The research of the efflux pump inhibitor carried out is focus, focus and the difficult point of research the most both at home and abroad, in the last few years outside new A crB The discovery of row's pump inhibitor rarely has report.Therefore, new effective AcrB efflux pump inhibitor is found to overcoming multidrug resistance to remove from office Blue negative microbial infections is significant.
Summary of the invention
For solving the problems referred to above, the invention provides two replacements pair that can effectively suppress antibacterial efflux pump that a class is novel Ring (heterocycle) derivant, the gram-negative bacteria of process LAN AcrB has been done antibacterial activity in vitro research by it and the suppression of outer row's substrate is ground Study carefully, find that target compound arranges inhibitory activity outside demonstrating preferably.
The present invention is achieved by the following technical solutions:
First purpose of the present invention be to provide a kind of disubstituted bicyclic (heterocycle) compound with general formula I or its Pharmaceutically acceptable salt.
X preferred C, N；Y preferred CH, N；Z is selected from CH, N；W preferred O, NH；N=0,1,2；
R1Selected from amide groups ,-CONHR3, cyano group；
R3Selected from C1-C8Alkyl, alkynyl, cycloalkyl, aryl, substituted aryl；
Wherein:
Described C1-C8The preferred ethyl of alkyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, isopentyl, just oneself Base；
The preferred propinyl of alkynyl；
The preferred cyclopenta of cycloalkyl, cyclohexyl；
The preferred phenyl of aryl, benzyl；
Substituted aryl preferably comprises 1-2 substituent group phenyl, and substituent group is methyl, methoxyl group, amino, nitro, fluoroform Base, halogen；
R2Selected from hydrogen, C1-C8Alkyl, C3-C8Cycloalkyl, C3-C8Cycloheteroalkyl, ester group, OR4、NHR4、SR4, aryl, replacement Aryl；
Wherein:
Described C1-C8The preferred methyl of alkyl, ethyl, n-pro-pyl, isopropyl, isobutyl group, the tert-butyl group, isopentyl, 3-methyl Propyl group, 4-ethyl pentyl group；
C3-C8The preferred cyclopenta of cycloalkyl, cyclohexyl；
C3-C8Heterocyclylalkyl preferred nafoxidine-1-base, morpholine-1 base, piperidin-1-yl, piperazine-1-base, 4-acetyl group piperazine Piperazine-1-base, 4-phenylpiperazine-1-base；
Ester group preferred methyl formate base, methyl acetate base, ethyl acetate base, ethyl propionate base；
The preferred phenyl of aryl, benzyl；
Substituted aryl preferably comprises the phenyl of 1-2 substituent group, substituent group be methyl, amino, hydroxyl, nitro, methoxyl group, Trifluoromethyl, carbamoyl, halogen, and do not limit it in the nuclear substituted position of benzene；
R4Selected from hydrogen, straight or branched alkyl, alkynyl, cycloalkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl Base；
Wherein:
The described preferred methyl of straight or branched alkyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, Isopentyl, n-hexyl, isohesyl；
The preferred propinyl of alkynyl；
The preferred cyclopenta of cycloalkyl, cyclohexyl；
The preferred phenyl of aryl, benzyl；
The preferred furyl of heteroaryl, pyrrole radicals, pyridine radicals, imidazole radicals, thiazolyl, 1,2,3-triazol radical, 1,2,3,4- Tetrazole base, indyl, benzimidazolyl, benzothiazolyl；
Substituted aryl or substituted heteroaryl preferably comprise phenyl or the heteroaryl of 1-2 substituent group, and substituent group is methyl, first Epoxide, hydroxyl, amino, carboxyl, nitro, carbamoyl, halogen or trifluoromethyl, and it is nuclear substituted at virtue not limit it Position.
It is further preferred that described compound I is one of following:
Second object of the present invention is to provide the preparation side of disubstituted bicyclic (heterocycle) compound of a kind of general formula I Method is as follows:
When in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, R1For amide groups, R2Selected from hydrogen, C1-C8Alkyl, C3-C8 Cycloalkyl, C3-C8When cycloheteroalkyl, ester group, aryl, substituted aryl, its preparation method is:
As shown in synthetic route, specifically, benzaldehyde and dimethyl succinate occur Stobbe to be condensed in the basic conditions Reaction obtains formula 2 compound；Formula 2 compound cyclization in acid condition obtains formula 3 compound；The hydroxyl of formula 3 compound is through second Acylated protection obtains formula 4 compound；Formula 4 compound obtains formula 6 compound through chloride, ammonification；Then formula 6 compound and 1,2- Bromofume occurs substitution reaction to obtain formula 7 compound in the basic conditions；Last formula 6 compound reacts with brominated reagent and obtains A series compound (when in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, n=0 or 1, R1For amide groups, R2Selected from hydrogen, C1-C8Alkyl, C3-C8Cycloalkyl, C3-C8Cycloheteroalkyl, ester group, aryl, substituted aryl)；Formula 7 and corresponding HOR4、NH2R4、 HSR4React in the basic conditions obtain B series compound (when in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, n =2, R1For amide groups, R2Selected from OR4、NHR4、SR4)。
When in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, n=0, R1For-CONHR3,R2For isopentyl or benzyl Time, its preparation method is:
As shown in synthetic route, specifically, formula 3 compound reacts the formula of respectively obtaining 10 in the basic conditions with halides, 13 compounds；Formula 10,13 compounds hydrolyze the formula 11 that respectively obtains, 14 compounds under highly basic effect；Last formula 11,14 compound With NH2R3Condensation respectively obtains C series compound and D series compound.
When in Formulas I structural formula, X be C, Y be CH, Z be N, W be O, n=0,1 or 2, R1For amide groups, R2Selected from substituted C1-C8Alkyl, C3-C8Cycloalkyl, C3-C8When cycloheteroalkyl, substituted aryl, its preparation method is:
As shown in synthetic route, specifically, the hydroxyl of formula 16 compound obtains formula through acetyl group protection, chloride, ammonification 18 compounds, last formula 18 compound reacts with brominated reagent in the basic conditions and obtains E series compound.
When in Formulas I structural formula, X be C, Y be N, Z be N, W be NH, n=0,1 or 2, R1For amide groups or cyano group, R2Selected from taking The C in generation1-C8Alkyl, C3-C8Cycloalkyl, C3-C8When cycloheteroalkyl, substituted aryl or heteroaryl, its preparation method is:
As shown in synthetic route, specifically, formula 20 compound and ethyl oxalate obtain formula 21 compound through condensation reaction； Formula 21 compound obtains formula 22 compound through amidatioon；Formula 22 compound selectivity in the xylene solution of phosphorus pentoxide takes off Water obtains formula 25 compound；Then formula 22,25 compounds are at SOCl2Formula 23,26 compounds are respectively obtained under counterflow condition；Formula 23,26 compounds in the basic conditions with NH2(CH2)nR2Reaction respectively obtains F series compound and G series compound.
More specifically, described synthetic method comprises the following steps:
(1) metal Na is dissolved in the alcohols materials such as dehydrated alcohol and (can also directly use Feldalat NM, Sodium ethylate, the tert-butyl alcohol Potassio replaces), at reflux, it is slowly added dropwise dimethyl succinate and benzaldehyde successively, reacts 2～8h at 80～120 DEG C, steam Going out ethanol, add 15%NaOH aqueous solution back flow reaction 2～3h, be cooled to 20～30 DEG C, ethyl acetate extracts, and leaves and takes aqueous phase, adjusts PH=1-2, separates out solid, i.e. formula 2 compound；
(2) being dissolved in concentrated sulphuric acid or phosphoric acid by formula 2 compound, nitrogen is protected, normal-temperature reaction 8～72h, pours in frozen water and analyses Go out, filter, collect filter cake, be dried to obtain formula 3 compound；
(3) being dissolved in pyridine by formula 3 compound, add appropriate acetic anhydride, normal-temperature reaction 1～6h, steam pyridine, add water tune PH=3-4, through extraction, is dried, steams solvent and obtain formula 4 compound；
(4) by formula 4 compound dissolution obtained above in oxolane, add appropriate thionyl chloride, back flow reaction 3～ 6h, steams solvent, under the conditions of-10～0 DEG C, is slowly dropped in saturated strong aqua ammonia, drips and finishes, and room temperature reaction 3～8h steams molten Agent, extraction, it is dried, obtains formula 6 compound through silica gel column chromatography；
(5) formula 6 compound is dissolved in organic solvent, is sequentially added into potassium carbonate, glycol dibromide, in 50～150 DEG C Reaction 4～15h, production 7 compound；
(6) formula 6 compound is dissolved in DMF, is sequentially added into potassium carbonate, halogenating agent, in 50～100 DEG C reaction 3～ 24h, post processing obtains compound A through column chromatography；
(7) by formula 7 compound and corresponding HOR4、NH2R4Or HSR4The DMF solution of alkaline reagent potassium carbonate mixes, Reacting 6～24h in 60～100 DEG C, post processing obtains compound B through column chromatography；
(8) formula 3 compound and benzyl chlorine or bromine for Pentamethylene. in the DMF solution of alkaline reagent potassium carbonate, in 50～120 DEG C Reaction 5～8h, steams solvent, respectively obtains formula 11,14 compounds through 50% potassium hydroxide aqueous solution hydrolysis；
(9) by above-mentioned formula 11 or 14 compound dissolution in oxolane, appropriate N, N-dicyclohexylcarbodiimide are added (DCC) and I-hydroxybenzotriazole (HOBt), 1～6h is reacted in-5～5 DEG C, then by NH2R1It is mixed with, under room temperature, reacts 2 ～8h, obtain compound C and D through column chromatography.
(10) formula 16 compound is dissolved in acetic anhydride, normal-temperature reaction 1～6h, in reactant liquor, is slowly added dropwise frozen water, directly To there being a large amount of yellow solid to separate out, use buchner funnel sucking filtration, be dried to obtain formula 17 compound；
(11) by formula 17 compound dissolution obtained above in oxolane, appropriate thionyl chloride, back flow reaction 2 are added ～8h, steam solvent, under the conditions of-10～0 DEG C, be slowly dropped in saturated strong aqua ammonia, drip and finish, room temperature reaction 4～10h, steams Go out solvent, extraction, it is dried, obtains formula 18 compound through silica gel column chromatography；
(12) formula 18 compound is dissolved in DMF, is sequentially added into potassium carbonate, halogenating agent, in 25～100 DEG C reaction 4～ 24h, obtains compound E through column chromatography；
(13) formula 20 compound mixing back flow reaction 3～10h with dimethyl oxalate., decompression steams solvent, through ethanol weight Crystallization obtains formula 21 compound；
(14) formula 21 compound is dissolved in proper ammonia, in 50～120 DEG C react 1～8h, then stirred overnight at room temperature, Produce a large amount of precipitation with acetic acid regulation pH=7, filter, filter cake water and washing with alcohol, be dried, obtain formula 22 compound；
(15) by formula 22 compound and the P of excess2O5It is dissolved in q. s. toluene, reacts 2～10h in 50～150 DEG C, decompression Steam solvent, add suitable quantity of water, Na2CO3Aqueous solution regulation pH is to neutral, and chloroform extracts, and saturated aqueous common salt washs, and is dried, decompression It is spin-dried for solvent, obtains formula 25 compound through ethyl acetate/normal hexane recrystallization；
(16) by formula 22,25 compounds are dissolved in SOCl2In, adding two DMF, back flow reaction 2～10h, decompression steams molten Agent, adds q. s. methylene chloride and uses NaHCO successively3Aqueous solution and saturated aqueous common salt washing, it is dried, solvent evaporated obtains formula respectively 23,26 compounds；
(17) by formula 23,26 compounds are dissolved in oxolane, are sequentially added into triethylamine, NH2R4, in 25～100 DEG C of reactions 0.5～12h, respectively obtain compound F and G through column chromatography.
In above-mentioned steps (1), alkaline reagent is Feldalat NM, Sodium ethylate, potassium tert-butoxide, preferred alcohol sodium；Solvent be methanol, Ethanol, the tert-butyl alcohol, preferred alcohol；The mol ratio of benzaldehyde, dimethyl succinate and Sodium ethylate is 1:(1.0～2): (1.5～ 5), preferably 1:1.5:2.0；
In above-mentioned steps (2), acid flux material is concentrated sulphuric acid, phosphoric acid, preferably concentrated sulphuric acid；48h is reacted at preferably 25 DEG C；
In above-mentioned steps (3), solvent is dichloromethane, DMF, pyridine, oxolane, preferably pyridine； Formula 3 compound is 1:2.0～10.0, preferably 1:4.0 with the mol ratio of acetic anhydride；3h is reacted at preferably 25 DEG C；
In above-mentioned steps (4), solvent is dichloromethane, DMF, ethyl acetate, oxolane, preferably Oxolane；Formula 4 compound is 1:1.2～10.0, preferably 1:2.0 with the mol ratio of thionyl chloride；5h is reacted at preferably 25 DEG C；
In above-mentioned steps (5), solvent is dichloromethane, DMF, 5%NaOH aqueous solution, acetonitrile, tetrahydrochysene Furan, preferably acetonitrile；Alkaline reagent is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, preferably potassium carbonate；Formula 6 Compound is 1:1.5～10, preferably 1:2.0 with the mol ratio of glycol dibromide；Preferably 80 DEG C reaction 8h；
In above-mentioned steps (6), solvent is dimethyl sulfoxide, DMF, dichloromethane, acetonitrile, acetic acid second Ester, oxolane, preferably DMF；Alkaline reagent be sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, three Ethamine, preferably potassium carbonate；Formula 6 compound is 1:1.0～10.0, preferably 1:1.2 with the mol ratio of halogenating agent；Preferably 70 DEG C anti- Answer 8h；
In above-mentioned steps (7), solvent be dimethyl sulfoxide, DMF, dichloromethane, ethyl acetate, four Hydrogen furan, preferably DMF；Alkaline reagent is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, Preferably potassium carbonate；Formula 7 compound is 1:1.0～10.0, preferably 1:2.0 with the mol ratio of replacement reagent；Preferably 70 DEG C reactions 10h；
In above-mentioned steps (8), alkaline reagent is sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydride, potassium carbonate, carbonic acid Sodium, triethylamine, preferably sodium carbonate；Formula 3 compound is 1:2.0～10.0, preferably 1:2.0 with the mol ratio of halogenating agent；Preferably 70 DEG C of reaction 6h；
In above-mentioned steps (9), solvent is dichloromethane, DMF, ethyl acetate, oxolane, preferably Oxolane；Corresponding replacement naphthoic acid and NH2R1Mol ratio be 1:1.0～4.0, preferably 1:1.2；Substituted benzoic acid and DCC Mol ratio be 1:1.0～3.0, preferably 1:1.4；Substituted benzoic acid is 1:1.0～3.0 with the mol ratio of HOBt, preferably 1: 1.4；Preferably 0 DEG C reaction 4h；
In above-mentioned steps (10), formula 3 compound is 1:2.0～20.0, preferably 1:10.0 with the mol ratio of acetic anhydride；Preferably 4h is reacted at 25 DEG C；
In above-mentioned steps (11), solvent is dichloromethane, DMF, ethyl acetate, oxolane, preferably Oxolane；Formula 16 compound is 1:1.2～10.0, preferably 1:2.5 with the mol ratio of thionyl chloride；
In above-mentioned steps (12), solvent is DMF, dichloromethane, acetonitrile, oxolane, preferably N, N- Dimethylformamide；Alkaline reagent is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, preferably potassium carbonate；Formula 18 Compound is 1:1.0～10.0, preferably 1:1.2 with the mol ratio of halogenating agent；Preferably 65 DEG C reaction 6h；
In above-mentioned steps (13), formula 20 compound is 1:1.0～20.0, preferably 1:5 with the mol ratio of ethyl oxalate；Excellent Select 185 DEG C of reaction 4.5h；
In above-mentioned steps (14), preferably 70 DEG C reaction 2h；
In above-mentioned steps (15), solvent is toluene, DMF, dichloromethane, ethyl acetate, tetrahydrochysene furan Mutter, preferably toluene；Formula 22 compound and P2O5Mol ratio be 1:1.0～5.0, preferably 1:3；Preferably 110 DEG C reaction 3h；
In above-mentioned steps (16), preferably 85 DEG C reaction 3h；
In above-mentioned steps (17), solvent is DMF, dichloromethane, acetonitrile, ethyl acetate, tetrahydrochysene furan Mutter, preferably oxolane；Alkaline reagent is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, preferably triethylamine； Formula 23,26 compounds and NH2R4It is 1:1.0～10.0:1.0～10, preferably 1:1.1:1.5 with the mol ratio of triethylamine；Preferably 30 DEG C reaction 0.5h.
The third object of the present invention be to provide disubstituted bicyclic (heterocycle) compound of a kind of general formula I or its pharmaceutically Acceptable salt or containing they any one of pharmaceutical composition preparation treatment antibacterial infect medicine in application.
Further, disubstituted bicyclic (heterocycle) compound of general formula I or its pharmaceutically acceptable salt and solvation Thing or containing they any one of pharmaceutical composition preparation suppression carry AcrB efflux pump antibacterial infect medicine in Application.
Further, described compound or its pharmaceutically acceptable salt or its solvate or containing in them any one Cooperating makes for the pharmaceutical composition planted and other antimicrobial products (such as antibacterials, erythromycin, chloromycetin, triphen gold) With.
Fourth object of the present invention is to provide a kind of efflux pump inhibitor, and its active component is above-mentioned general formula I Disubstituted bicyclic (heterocycle) compound or its pharmaceutically acceptable salt.
5th purpose of the present invention is to provide described efflux pump inhibitor in the medicine that preparation treatment antibacterial infects Application.
The invention has the beneficial effects as follows: disubstituted bicyclic (heterocycle) derivant of the present invention, there is antibacterial potentiation, with The potentiation antibacterial to Grain-negative fastbacteria of existing antibacterials use in conjunction is obvious, may be used for preparation treatment antibacterial and infects Medicine, when specifically preparing, this medicine contains disubstituted bicyclic (heterocycle) derivant of therapeutic dose or it is pharmaceutically acceptable Salt, and the pharmaceutic adjuvant of other routines or carrier.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1.
Benzylidene succinic acid preparation (formula 2 compound)
Benzaldehyde (15.0g, 141mmol) and dimethyl succinate (25.8g, 17.6mmol) are dissolved into ethanol (100mL) in, above-mentioned mixed liquor is slowly dropped in ethanol (150mL) solution of Sodium ethylate (19.2g, 282.0mmol), returns Stream 4h.After completion of the reaction, evaporated under reduced pressure, gained solid is dissolved in the NaOH aqueous solution (100mL) of 15%, is heated to reflux 3h, Reactant liquor is cooled to room temperature, extracts once by ethyl acetate (60mL), leave and take aqueous phase.Regulate pH < 2 with dense HCl, separate out white Solid, sucking filtration, filter cake washes twice with water.Filter cake dries to obtain white solid 21.75g, yield 75%.
Embodiment 2.
The preparation (formula 3 compound) of 4-hydroxy-2-naphthoic acid
Benzylidene succinic acid (20.6g, 100mmol) is slowly added at low temperatures stirring concentrated sulphuric acid (147g, In 1500mmol), nitrogen is protected, and is then transferred into room temperature reaction 48h.Reactant liquor is slowly dropped to the frozen water of stirring (300mL), in, yellow solid is separated out.Using buchner funnel sucking filtration, frozen water washs three times, obtains yellow-brown solid crude product.Finally use Ethanol/water recrystallization, obtains yellow solid 12.2g, yield 65%.
Embodiment 3.
The preparation (formula 4 compound) of 4-acetoxyl-2-naphthoic acid
4-hydroxy-2-naphthoic acid (12.2g, 65mmol) is dissolved in pyridine (80mL), under room temperature, is slowly added dropwise acetic acid Acid anhydride (26.5g, 260mmol), reacts 3h under room temperature.Evaporated under reduced pressure after completion of the reaction, adds water (120mL) in gained residue, Regulating pH=3 with 1N HCl, extract three times by ethyl acetate (3 × 80mL), merge organic facies, organic facies saturated common salt is washed Wash, anhydrous Na2SO4Being dried, filter, evaporated under reduced pressure obtains yellow-brown solid 13.3g, yield 89%.
Embodiment 4.
The preparation (formula 6 compound) of 4-hydroxyl-2-naphthalenecarboxamide
Being dissolved in anhydrous tetrahydro furan (60mL) by 4-acetoxyl-2-naphthoic acid (5.0g, 22.0mmol), room temperature is stirred Mix down and be slowly added to thionyl chloride (5.2g, 44.1mmol), be heated to reflux (about 90 DEG C) 5h.Reactant liquor is cooled to room temperature and subtracts Pressure is spin-dried for.Residue is dissolved in anhydrous tetrahydro furan (about 15mL), is cooled to-8 DEG C, by slow under solution stirring under low temperature bath Dropwise drop in saturated strong aqua ammonia (about 60mL).It is transferred to 5h is stirred at room temperature, after having reacted, reactant liquor is concentrated in vacuo, to Adding water in gained residue in (60mL), extract three times by ethyl acetate (3 × 30mL), merge organic facies, organic facies is with saturated Brine It, anhydrous Na2SO4Being dried, filter, steam solvent, (eluant is dichloromethane/first to residue silica gel column chromatography Alcohol, 30:1) obtain 4-hydroxyl-2-naphthalenecarboxamide (3.1g, 16.0mmol), yield 75%.
Embodiment 5.
The preparation (formula 7 compound) of 4-(2-bromine oxethyl)-2-naphthalenecarboxamide
4-hydroxyl-2-naphthalenecarboxamide (2.0g, 10.7mmol) is dissolved in acetonitrile (60mL), under room temperature, is sequentially added into carbon Acid potassium (2.96g, 21.4mmol), glycol dibromide (8.0g, 42.7mmol), be heated to 80 DEG C of reaction 8h, and reactant liquor is cold But to room temperature, being filtered to remove insoluble matter, add water in solution (40mL), extracts three times by ethyl acetate (3 × 30mL), is associated with Machine phase, organic facies saturated aqueous common salt washs, anhydrous Na SO4Being dried, filter, evaporated under reduced pressure obtains faint yellow solid 2.2g.Yield 67%.
Embodiment 6.
The preparation (compound A1) of 4-(isoamoxy)-2-naphthalenecarboxamide
4-hydroxyl-2-naphthalenecarboxamide (0.13g, 0.70mmol) is dissolved in DMF (10mL), adds anhydrous K2CO3 (0.30g, 2.10mmol), is stirred at room temperature 5min by above-mentioned mixed liquor, adds chloro-iso-butane (0.12g, 0.84mmol).Will Reactant liquor stirs 8h in 70 DEG C under nitrogen protection.Stopping heating, reactant liquor is cooled to room temperature, add water (30mL), uses acetic acid Ethyl ester (3 × 20mL) extracts three times, merges organic layer.Then wash twice, with anhydrous with saturated nacl aqueous solution (2 × 10mL) Na2SO4It is dried.Filter, evaporated under reduced pressure, obtain crude product.Silica gel column chromatography (eluant is methylene chloride/methanol, 30:1), obtains white Solid 0.09g, yield 66%.
The preparation method of compound A2～A14 is with embodiment 6, and the mol ratio of raw material dosage is same as in Example 6, each product Yield spectra be 52%～88%.
Embodiment 7.
The preparation (compound B-11) of 4-(2-(propylcarbamic) ethyoxyl)-2-naphthalenecarboxamide
By 4-(2-bromine oxethyl)-2-naphthalenecarboxamide, (0.20g, 0.68mmol are dissolved in DMF (10mL), are sequentially added into Anhydrous K2CO3(0.28g, 2.04mmol) n-propylamine (0.08g, 1.36mmol), stirs in 70 DEG C under nitrogen protection by reactant liquor Mix 10h.Add water in solution (40mL) after completion of the reaction, extracts three times by ethyl acetate (3 × 20mL), merges organic layer.So Wash twice with saturated nacl aqueous solution (2 × 10mL) afterwards, use anhydrous Na2SO4It is dried.Filter, evaporated under reduced pressure, obtain crude product.Silicagel column Chromatography (eluant is methylene chloride/methanol, 15:1), obtains white solid 0.14g, yield 78%.
The preparation method of compound B2～B28 is with embodiment 7, and the mol ratio of raw material dosage is similar to Example 7, each product Yield spectra be 37%～85%.
Embodiment 8.
The preparation (formula 11 compound) of 4-(benzyloxy)-2-naphthoic acid
4-hydroxy-2-naphthoic acid (1.22g, 6.5mmol) is dissolved in DMF (10mL), is slowly added to add anhydrous K2CO3(2.7g, 19.5mmol).By above-mentioned mixed liquor stirring at normal temperature 20min, it is slowly added to benzyl chlorine (1.65g, 13.0mmol), nitrogen 6h is stirred in 70 DEG C under gas shielded.Reactant liquor is cooled to room temperature, and add water (40mL), extracts three by ethyl acetate (3 × 20mL) Secondary, merge organic layer.Solvent evaporated, adds 50% potassium hydroxide aqueous solution (25mL) 90 DEG C reaction 5h to residue, uses dense HCl Regulation pH < 2, slowly separates out brown solid, uses buchner funnel sucking filtration, wash twice, filter cake ethyl acetate: petroleum ether=1:5 Recrystallization, obtains faint yellow solid 1.28g, productivity 71%.
Embodiment 9.
4-(benzyloxy)-N-propyl group-2-naphthalenecarboxamide (compound C1)
4-(benzyloxy)-2-naphthoic acid (0.15g, 0.54mmol) and HOBt (0.1g, 0.76mmol) are added THF (10mL) in, 0 DEG C of stirring, add DCC (0.16g, 0.76mmol) continue stirring 6h, add afterwards n-propylamine (0.04g, 0.65mmol), move to room temperature reaction 4h, after completion of the reaction evaporated under reduced pressure solvent, add appropriate ethyl acetate, filter, leave and take filter Liquid, filtrate is successively with saturated sodium bicarbonate solution, saturated aqueous common salt washing.Anhydrous Na2SO4Being dried, filter, evaporated under reduced pressure obtains slightly Product.Silica gel column chromatography (eluant is petrol ether/ethyl acetate, 10:1), obtains white solid 0.14g, productivity 81%.
The preparation method of compound C2～C12 is with embodiment 9, and the mol ratio of raw material dosage is the same as in Example 9, each product Yield spectra be 63%～86%.
Embodiment 10.
The preparation (formula 14 compound) of 4-(isoamoxy)-2-naphthoic acid
4-hydroxy-2-naphthoic acid (1.5g, 8.0mmol) is dissolved in DMF (10mL), is slowly added to add anhydrous K2CO3 (3.3g, 24mmol).By above-mentioned mixed liquor stirring at normal temperature 20min, it is slowly added to bromo isopentane (2.4g, 16.0mmol), in 70 DEG C of reaction 6h.Add water in solution (40mL) after completion of the reaction, extracts three times by ethyl acetate (3 × 20mL), merges organic Layer.Solvent evaporated, adds 50% potassium hydroxide aqueous solution (20mL) 90 DEG C reaction 5h to residue, regulates pH < 2 with dense HCl, slow Slowly separating out faint yellow solid, sucking filtration, filter cake is washed twice, and filter cake ethyl acetate: petroleum ether=1:4 recrystallization obtains faint yellow Solid 1.61g, productivity 78%.
Embodiment 11.
The preparation (compound D1) of 4-(isoamoxy)-N-isopropyl-2-naphthalenecarboxamide
4-(benzyloxy)-2-naphthoic acid (0.15g, 0.54mmol) and HOBt (0.1g, 0.76mmol) are added THF (10mL) in, 0 DEG C of stirring, add DCC (0.16g, 0.76mmol) continue stirring 6h, add afterwards 2-aminopropane. (0.038g, 0.65mmol), move to room temperature reaction 5h, after completion of the reaction evaporated under reduced pressure solvent, add appropriate ethyl acetate, filter, leave and take filter Liquid, filtrate is successively with saturated sodium bicarbonate solution, saturated aqueous common salt washing.Anhydrous Na2SO4Being dried, filter, evaporated under reduced pressure obtains slightly Product.Silica gel column chromatography (eluant is petrol ether/ethyl acetate, 15:1), obtains white solid 0.12g, productivity 75%.
The preparation method of compound D2～D13 is with embodiment 11, and the mol ratio of raw material dosage is identical with embodiment 11, respectively produces The yield spectra of thing is 58%～89%.
Embodiment 12.
The preparation (formula 17 compound) of 4-acetoxyl group quinaldic acid
4-hydroxy-2-naphthoic acid (1.89g, 10mmol) is dissolved in acetic anhydride (20mL), under room temperature, stirs 4h.Low temperature Downhill reaction liquid being slowly added dropwise frozen water, until there being a large amount of yellow solid to separate out, using buchner funnel sucking filtration, be dried to obtain yellow solid 1.79g, productivity 82%.
Embodiment 13.
The preparation (formula 18 compound) of 4-hydroxyquinoline-2-Methanamide
4-acetoxyl group quinaldic acid (1.5g, 6.9mmol) is dissolved in anhydrous tetrahydro furan (20mL), room temperature It is slowly added to thionyl chloride (5.2g, 13.7mmol) under stirring, is heated to reflux (about 90 DEG C) 4h.Reactant liquor is cooled to room temperature also Decompression is spin-dried for.Residue is dissolved in anhydrous tetrahydro furan (about 10mL), is cooled to-8 DEG C, by slow under solution stirring under low temperature bath Slowly dropwise drop in saturated strong aqua ammonia (about 20mL).It is transferred to 5h is stirred at room temperature, after having reacted, reactant liquor is concentrated in vacuo, Adding water in gained residue in (30mL), extract three times by ethyl acetate (3 × 20mL), merge organic facies, organic facies is with full And brine It, anhydrous Na2SO4Being dried, filter, steam solvent, (eluant is dichloromethane/first to residue silica gel column chromatography Alcohol, 25:1) obtain 4-hydroxyquinoline-2-Methanamide 0.96g, yield 74%.
Embodiment 14.
The preparation (compound E1) of 4-propoxyl group quinoline-2-formamide
4-hydroxyquinoline-2-Methanamide (0.18g, 1.0mmol) is dissolved in DMF (10mL), adds anhydrous K2CO3 (0.28g, 3.0mmol), is stirred at room temperature 10min by above-mentioned mixed liquor, adds n-propyl bromide (0.14g, 1.1mmol).Will Reactant liquor stirs 6h in 65 DEG C under nitrogen protection.Stopping heating, reactant liquor is cooled to room temperature, add water (30mL), uses acetic acid Ethyl ester (3 × 20mL) extracts three times, merges organic layer.Then wash twice with saturated nacl aqueous solution (2 × 10mL), anhydrous Na2SO4It is dried, filters, evaporated under reduced pressure, obtain crude product.Silica gel column chromatography (eluant is methylene chloride/methanol, 25:1), obtains white Solid 0.15g, yield 63%.
The preparation method of compound E2～E6 is with embodiment 14, and the mol ratio of raw material dosage is identical with embodiment 14, respectively produces The yield spectra of thing is 49%～82%.
Embodiment 15.
The preparation (formula 21 compound) of 4-oxo-3,4-dihydroquinazoline-2-Ethyl formate
Anthranilamide (5g, 36.7mmol) is dissolved in 15mL ethyl oxalate, reactant liquor is protected at nitrogen Under in 185 DEG C stir 4.5h, stopped reaction, decompression steam unnecessary solvent, residue obtains white solid through the pure crystallization of ethanol 6.3g, productivity 78%.
Embodiment 16.
The preparation (formula 22 compound) of 4-oxo-3,4-dihydroquinazoline-2-Methanamide
By compound 4-oxo-3,4-dihydroquinazoline-2-Ethyl formate (4g, 18.3mmol) is dissolved in strong aqua ammonia (20mL) In, it is heated to 70 DEG C of reaction 2h, stops heating, reactant liquor is cooled to stirred overnight at room temperature.PH=7 is regulated, analysis with glacial acetic acid Go out a large amount of precipitation, filter, filter cake water and cold washing with alcohol, be dried to obtain white solid 3.4g, productivity 98%.
Embodiment 17.
The preparation (formula 25 compound) of 2-cyano group-4-oxo-3,4-dihydroquinazoline
By compound 4-oxo-3,4-dihydroquinazoline-2-Methanamide (1.89g, 10mmol) is dissolved in toluene (10mL), Being subsequently adding the phosphorus pentoxide (4.23g, 30mmol) of excess, be heated to 110 DEG C of reaction 3h, stopped reaction, evaporated under reduced pressure is molten Agent, add water 20mL, and aqueous sodium carbonate regulation pH, to neutral, extract three times by ethyl acetate (3 × 20mL), merges organic layer. Then wash twice with saturated nacl aqueous solution (2 × 10mL), anhydrous Na2SO4It is dried, filters, activated carbon decolorizing, evaporated under reduced pressure, Crude product.Solid 1.60g, productivity 84% is obtained through ethyl acetate/normal hexane recrystallization.
Embodiment 18.
The preparation (formula 23 compound) of 4-chloro-quinazoline-2-Methanamide
By compound 4-oxo-3,4-dihydroquinazoline-2-Methanamide (1.89g, 10mmol) is dissolved in thionyl chloride (20mL) in, back flow reaction 2h, solvent evaporated after reaction completely, add 20mL dichloromethane, use sodium bicarbonate aqueous solution successively (20mL), saturated nacl aqueous solution (20mL) washing, anhydrous Na2SO4Being dried, filter, evaporated under reduced pressure obtains white solid 1.82g, produces Rate 88%.
The preparation method of formula 26 compound is with embodiment 18, and the mol ratio of raw material dosage is identical with embodiment 18, and formula 26 is changed The yield of compound is 82%.
Embodiment 19.
The preparation (compound F1) of 4-(isobutylamino) quinazoline-2-Methanamide
Compound 4-chloro-quinazoline-2-Methanamide (0.21g, 1mmol) is dissolved in oxolane (20mL), adds successively Entering triethylamine (0.15g, 1.5mmol), isobutane bromide (0.14g, 1mmol), room temperature reaction 30min, decompression steams solvent, silicon Plastic column chromatography (eluant is methylene chloride/methanol, 15:1), obtains solid 1.95g, productivity 81%.
Compound F2～F6, G1～G5 preparation method with embodiment 19, the mol ratio of raw material dosage and embodiment 19 phase With, the yield spectra of each product is 52%～92%.
Structural identification:
Embodiment 20.
The antibacterial synergistic activity of disubstituted bicyclic (heterocycle) derivant measures
The compound measured is A, B, C, D series.
Continuous micropore doubling dilution is used to determine each disubstituted bicyclic (heterocycle) derivant and erythromycin (ERY), chlorine Mycin (CAM) and the MIC of triphen gold (TPP), according to the result of MIC, determine that erythromycin, chloromycetin, triphen gold and two takes Synergy drug level scope for dicyclo (heterocycle) derivant；Use chessboard micropore doubling dilution, double according to two replacements Ring (heterocycle) derivant and the result of antibacterials (erythromycin, chloromycetin and triphen gold) use in conjunction, filter out and have relatively Disubstituted bicyclic (heterocycle) derivant of strong antibacterial potentiation, result is as shown in table 1:
The antibacterial activity in vitro of table 1. target compound associating antibacterials
Embodiment 21.
Outer row's inhibitory activity of disubstituted bicyclic (heterocycle) derivant measures
The compound measured is A, B, C, D series compound.
Efflux pump inhibitor allows for reducing the outer row of horizontal of outer row's substrate, and Nile red is the large intestine angstrom of process LAN AcrB Outer row's substrate of uncommon bacterium, we evaluate disubstituted bicyclic (heterocycle) derivant with the outer row of suppression Nile red and press down as efflux pump Preparation reduces the ability of outer row of horizontal.Nile red shows the most weak fluorescence in water-soluble solution, but in non-polar solution such as In cell membrane, its fluorescence intensity strengthens rapidly, containing and do not contain the cell of disubstituted bicyclic (heterocycle) derivant pre-installed Buddhist nun Luo Hong, when cell is activated, evaluates to arrange outside disubstituted bicyclic (heterocycle) derivant by the change of observation fluorescence intensity and presses down The height of system activity.
Test result indicate that, when concentration is 200 μMs, A3, A5, A12, B9, B10, C3, C4, D3, D6 can completely inhibit The outer row of Nile red；When concentration is 500 μMs, A1, A7, A8, B3, B13, B14, B28, C5, C11, D2, D11 can completely inhibit The outer row of Nile red；When concentration is 500 μMs, A2, A9, A10, A11, B15, C12 can partly suppress the outer row of Nile red.
From experimental result, the antibacterial carrying AcrB is had well by disubstituted bicyclic (heterocycle) derivant of the present invention Antibacterial synergistic activity and outer row's inhibitory activity.This is to be found for the first time in this compounds.
A, B, C and the D measured except embodiment 20 and 21, through experimental verification and analysis, other in the present invention have logical The compound of Formulas I also has good antibacterial synergistic activity and outer row's inhibitory activity to the antibacterial carrying AcrB, the most superfluous at this State.
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention are not by above-described embodiment Limit, the change made under other any spirit without departing from the present invention and principle, modify, substitute, combine, simplify, All should be the substitute mode of equivalence, within being included in protection scope of the present invention.

Claims (9)

1. having compound or its pharmaceutically acceptable salt of general formula I, it is characterized in that, formula I is as follows:
Wherein, X is selected from C, N；Y is selected from CH, N；Z is selected from CH, N；W is selected from O, NH；N=0,1,2；
R1Selected from amide groups ,-CONHR3, cyano group；
R3Selected from C1-C8Alkyl, alkynyl, cycloalkyl, aryl, substituted aryl；
R2Selected from hydrogen, C1-C8Alkyl, C3-C8Cycloalkyl, C3-C8Cycloheteroalkyl, ester group, OR4、NHR4、SR4, aryl, substituted aryl；
R4Selected from hydrogen, C1-C10Straight or branched alkyl, alkynyl, cycloalkyl, heteroaryl, aryl, substituted aryl, substituted heteroaryl Base.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, is characterized in that: R2Representative C1-C8Alkyl For methyl, ethyl, n-pro-pyl, isopropyl, isobutyl group, the tert-butyl group, isopentyl, 3-methyl-propyl, 4-ethyl pentyl group；R2Representative C3-C8Cycloalkyl is cyclopenta, cyclohexyl；R2Representative C3-C8Heterocyclylalkyl be nafoxidine-1-base, morpholine-1-base, Piperidin-1-yl, piperazine-1-base, 4-Acetylpiperazine-1-base, 4-phenylpiperazine-1-base；R2Representative ester group is formic acid first Ester group, methyl acetate base, ethyl acetate base, ethyl propionate base；R2Representative substituted aryl is that phenyl contains 1-2 replacement Base, substituent group is methyl, amino, hydroxyl, nitro, methoxyl group, trifluoromethyl, carbamoyl, halogen, and does not limit it at benzene Nuclear substituted position；R3Representative C1-C8Alkyl is ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, different Amyl group, n-hexyl；R3Representative alkynyl is propinyl；R3Representative cycloalkyl is cyclopenta, cyclohexyl；R3Representative Aryl is phenyl, benzyl；R3Representative substituted aryl is that phenyl contains 1-2 substituent group, substituent group be methyl, methoxyl group, Amino, nitro, trifluoromethyl, halogen；R4Representative straight or branched alkyl is methyl, ethyl, n-pro-pyl, isopropyl, just Butyl, isobutyl group, the tert-butyl group, isopentyl, n-hexyl, isohesyl；R4Representative alkynyl is propinyl；R4Representative cycloalkanes Base is cyclopenta, cyclohexyl；R4Representative aryl is phenyl；R4Representative heteroaryl be furyl, pyrrole radicals, pyridine radicals, Imidazole radicals, thiazolyl, 1,2,3-triazol radical, 1,2,3,4-tetrazole base, indyl, benzimidazolyl, benzothiazolyl；R4 Representative substituted aryl or substituted heteroaryl are phenyl or heteroaryl contains 1-2 substituent group, and substituent group is methyl, methoxy Base, hydroxyl, amino, carboxyl, nitro, carbamoyl, halogen, trifluoromethyl, and do not limit it in fragrant nuclear substituted position.
3. compound as claimed in claim 1 or its pharmaceutically acceptable salt, is characterized in that, selected from having following shown knot The compound of structure:
4. the preparation method of compound described in claim 1 or 2, is characterized in that:
(1) when in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, n=0 or 1, R1For amide groups, R2Selected from hydrogen, C1-C8Alkane Base, C3-C8Cycloalkyl, C3-C8When cycloheteroalkyl, ester group, aryl, substituted aryl, the preparation method of this compound of formula I include with Lower step:
Benzaldehyde and dimethyl succinate occur Stobbe condensation reaction to obtain formula 2 compound in the basic conditions；Formula 2 compound Cyclization obtains formula 3 compound in acid condition；The hydroxyl of formula 3 compound obtains formula 4 compound through acetylation protection；Formula 4 is changed Compound obtains formula 6 compound through chloride, ammonification；Then formula 6 compound takes in the basic conditions with glycol dibromide Generation reaction obtains formula 7 compound；Last formula 6 compound reacts with brominated reagent and obtains this compound of formula I；
(2) when in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, n=2, R1For amide groups, R2Selected from OR4、NHR4、SR4 Time, the preparation method of this compound of formula I comprises the following steps:
Described formula 7 and HOR4、NH2R4Or HSR4React in the basic conditions and obtain this compound of formula I；
(3) when in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, n=0, R1For-CONHR3,R2For isopentyl or benzyl Time, the preparation method of this compound of formula I comprises the following steps:
Described formula 3 compound reacts the formula of respectively obtaining 10 compound in the basic conditions with halides；Formula 10 compound is at highly basic The lower hydrolysis of effect respectively obtains formula 11 compound；Last formula 11 compound and NH2R3It is condensed to yield this compound of formula I；
(4) when in Formulas I structural formula, X be C, Y be CH, Z be CH, W be O, n=0, R1For-CONHR3,R2During for benzyl, this Formulas I The preparation method of compound comprises the following steps:
Described formula 3 compound reacts the formula of respectively obtaining 13 compound in the basic conditions with halides；Formula 13 compound is at highly basic The lower hydrolysis of effect respectively obtains formula 14 compound；Last formula 14 compound and NH2R3It is condensed to yield this compound of formula I；
(5) when in Formulas I structural formula, X be C, Y be CH, Z be N, W be O, n=0,1 or 2, R1For amide groups, R2Selected from substituted C1- C8Alkyl, C3-C8Cycloalkyl, C3-C8When cycloheteroalkyl, substituted aryl, the preparation method of this compound of formula I comprises the following steps:
The hydroxyl of described formula 16 compound obtains formula 18 compound, last formula 18 compound through acetyl group protection, chloride, ammonification React with brominated reagent in the basic conditions and obtain this compound of formula I；
(6) when in Formulas I structural formula, X be C, Y be N, Z be N, W be NH, n=0,1 or 2, R1For amide groups, R2Selected from substituted C1- C8Alkyl, C3-C8Cycloalkyl, C3-C8When cycloheteroalkyl, substituted aryl or heteroaryl, the preparation method of this compound of formula I include with Lower step:
Described formula 20 compound and ethyl oxalate obtain formula 21 compound through condensation reaction；Formula 21 compound obtains through amidatioon Formula 22 compound；Then formula 22 compound is at SOCl2Formula 23 compound is obtained under counterflow condition；Formula 23 compound is in alkalescence condition Descend and NH2(CH2)nR2Reaction obtains this compound of formula I；
(7) when in Formulas I structural formula, X be C, Y be N, Z be N, W be NH, n=0,1 or 2, R1For amide groups or cyano group, R2Selected from taking The C in generation1-C8Alkyl, C3-C8Cycloalkyl, C3-C8When cycloheteroalkyl, substituted aryl or heteroaryl, the preparation side of this compound of formula I Method comprises the following steps:
Described formula 22 compound selectively dewatering in the xylene solution of phosphorus pentoxide obtains formula 25 compound；Then formula 25 Compound is at SOCl2Formula 26 compound is obtained under counterflow condition；Formula 26 compound in the basic conditions with NH2(CH2)nR2Reaction point Do not obtain this compound of formula I.
5. compound or its pharmaceutically acceptable salt or its solvate according to any one of claims 1 to 3 or contain They any one of pharmaceutical composition preparation treatment antibacterial infect medicine in application.
Apply the most as claimed in claim 5, it is characterized in that: described compound or its pharmaceutically acceptable salt or its solvent Compound or containing they any one of pharmaceutical composition preparation suppression carry AcrB efflux pump antibacterial infect medicine In application.
Apply the most as claimed in claim 5, it is characterized in that: described compound or its pharmaceutically acceptable salt or its solvent Compound or containing they any one of pharmaceutical composition be used in conjunction with each other with other antimicrobial products.
8. an efflux pump inhibitor, is characterized in that: its active component is the chemical combination according to any one of claims 1 to 3 Thing or its pharmaceutically acceptable salt.
9. the application in the medicine that preparation treatment antibacterial infects of the efflux pump inhibitor described in claim 8.
CN201610408309.3A 2016-06-12 2016-06-12 Disubstituted bicyclic derivative and its application as efflux pump inhibitor in antibacterial Expired - Fee Related CN106008373B (en)

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CN114524792B (en) * 2022-03-07 2023-11-14 聊城大学 Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial
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CN115385886B (en) * 2022-06-28 2024-04-19 山东大学 AcrB efflux pump inhibitor and preparation method and application thereof

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