CN106800547A - A kind of disubstituted aryl class compound and its application - Google Patents

A kind of disubstituted aryl class compound and its application Download PDF

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CN106800547A
CN106800547A CN201710001729.4A CN201710001729A CN106800547A CN 106800547 A CN106800547 A CN 106800547A CN 201710001729 A CN201710001729 A CN 201710001729A CN 106800547 A CN106800547 A CN 106800547A
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double
acid
phenyl
piperidin
phenyls
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CN106800547B (en
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金永生
董怀怀
王元花
彭雪米
姚淞允
赵菲
张大志
姜远英
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Second Military Medical University SMMU
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The present invention relates to a kind of disubstituted aryl class compound and its application, described disubstituted aryl class compound structure is as shown in Formulas I, II or III, find that such disubstituted aryl class compound can be used in conjunction with triazole antifungal agent thing by experimental verification, sensitiveness of the drug-fast bacteria to azole drug can be improved, realize reversing drug resistance, therefore the present invention for the treatment of clinical drug-resistant fungi provides a kind of new way.

Description

A kind of disubstituted aryl class compound and its application
Technical field
The present invention relates to medical compounds technical field, specifically, be related to a kind of disubstituted aryl class compound and its Application in antimycotic and collaboration antifungal drug is prepared.
Background technology
Nosomycosis, i.e., by fungus-caused disease.The eucaryote in nature is widely present in as a class, fungi can Infect the different parts of human body.From clinical pathogenic situation, nosomycosis can be divided into superficial mycoses and deep mycosis two Major class.Many problems such as abuse of antibiotics cause normal flora symbiosis between bacterium and fungi to suffer certain destruction； Secondly, organ transfer operation is also more and more carried out in clinic, and it is normal that the use of postoperative immunosuppression agent have impact on body Immunologic function, makes resistance reduction of the human body to fungi.Problem above makes the fungal infection incidence of disease more and more higher of deep internal organs, Also it is serious all the more.Candida albicans is the Etiological of fungal infection.But a large amount of recently as antifungal drug use, Fungi gradually increases the drug resistance of medicine.The bacterial strain for having drug-resistant effect to Fluconazole would generally produce friendship to other azole drugs Fork drug-resistant effect so that the clinical medicine selection in terms of for treatment candida albicans infection is very difficult.Therefore, find anti-true Bacterium Drug-resistant reversal agent, produces the antifungic action for cooperateing with to improve sensitiveness of the fungi to medicine with existing medicine, is one Plant the important method for improving the therapeutic effect of existing medicine at present.
The content of the invention
The purpose of the present invention is directed to deficiency of the prior art, there is provided a kind of with the double of synergy overriding resistance fungi Substituted aryl class compound.
Another purpose of the invention be to provide described disubstituted aryl class compound hydrate or its pharmacologically The salt of permission.
Another purpose of the invention is to provide a kind of pharmaceutical composition.
Fourth object of the present invention is to provide described disubstituted aryl class compound, or described hydrate or its The purposes of the salt for pharmacologically allowing.
To realize above-mentioned first purpose, the present invention is adopted the technical scheme that：
A kind of disubstituted aryl class compound with synergy overriding resistance fungi, described disubstituted aryl class chemical combination The structure of thing is as shown in Formulas I, II or III：
The substitution situation of each group is selected from one of the following in Formulas I：
(1) n=0, m=0, X=oxygen, Y do not exist, and Ar is selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls, 4- hydroxy phenyls With 2- thienyls；
(2) n=1, m=0, Z do not exist, and X=oxygen, Y does not exist, Ar be selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxy phenyls；
(3) n=1, m=0, Z=CH2, X=oxygen, Y do not exist, and Ar is selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- Hydroxy phenyl；
(4) n=1, m=0, Z=NH, X=oxygen, Y do not exist, and Ar is selected from 3,4- methylenedioxyphenyls, to dimethylamino Phenyl, 3,4- Dimethoxyphenyls, p-fluorophenyl, rubigan, p-bromophenyl, to iodophenyl and p-trifluoromethyl phenyl；
(5) n=1, m=0, Z=N- methyl, X=oxygen, Y do not exist, and Ar is selected from 3,4- methylenedioxyphenyls, to diformazan Aminophenyl, 2- thienyls, p-methoxyphenyl, 2- furyls, p-fluorophenyl, rubigan, p-bromophenyl, to iodophenyl and P-trifluoromethyl phenyl；
(6) n=1, m=0, Z=N- ethyl, N- propyl group or N- butyl, X=oxygen, Y do not exist, and Ar is selected to dimethylamino Phenyl, to lignocaine phenyl and to dipropyl aminophenyl；
(7) n=1, m=0, Z=N- acetyl group, N- propionos or N- bytyries, X=oxygen, Y do not exist, and Ar is selected from 2- thiophenes Fen base, 2- furyls and p-trifluoromethyl phenyl；
(8) n=1, m=0, Z do not exist, and X=N-OH, Y does not exist, and Ar is selected from 2- furyls；
(9) n=0, m=1, X=nitrogen, Y=oxygen, Ar are selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxy phenyls；
(10) n=0, m=1, X=N, Y=NH, Ar are selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxy phenyls；
(12) n=0, m=1, X=N, Y=N- phenyl, Ar are selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls, 4- hydroxy benzenes Base and 3,4- Dimethoxyphenyls；
(13) n=0, m=1, X=N, Y=N- phenyl, N- methyl, Ar be selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls, 4- hydroxy phenyls and 3,4- Dimethoxyphenyls；
The substitution situation of each group is as follows in Formula II：
(14) Z=oxygen, W=oxygen, Ar be selected from 3- methoxyl group -4- hydroxy phenyls, 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxy phenyls；
The substitution situation of each group is as follows in formula III：
(15) Z=oxygen, W=oxygen, Ar be selected from 3- methoxyl group -4- hydroxy phenyls, 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxy phenyls.
As a preference of the invention, the structure of described disubstituted aryl class compound shown in formula I, wherein, n =0, m=1, X=N, Y=N- phenyl, N- methyl, Ar are selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls, 4- hydroxy phenyls and 3, 4- Dimethoxyphenyls.
It is highly preferred that described disubstituted aryl class compound is selected from：
(1) double (thiophene -2- bases) amyl- Isosorbide-5-Nitrae-diene -3- ketone of (1E, 4E) -1,5-,
(2) double (3, the 4- dihydroxy phenyl) amyl- Isosorbide-5-Nitrae-diene -3- ketone of (1E, 4E) -1,5-,
Double ((E) -3,4- dihydroxies benzal) pentamethylene -1- ketone of (3) 2,5-,
Double ((E) -3,4- dihydroxies benzal) hexamethylene -1- ketone of (4) 2,5-,
(5) double (benzo [d] [1,3] dioxole -5- methylenes)-piperidin-4-ones of (3E, 5E) -3,5-,
Double ((E) -4- (dimethylamino) benzal) piperidin-4-ones of (6) 3,5-,
Double ((E) -3,4- dimethoxies benzal)-piperidin-4-ones of (7) 3,5-,
Double ((the E) -4- fluorine benzal) piperidin-4-ones of (8) 3,5-,
Double ((the E) -4- trifluoromethyls) benzals of (9) 3,5-) piperidin-4-one,
(10) double (benzo [d] [1,3] dioxole -5- methylenes) -1- methyl piperidines -4- of (3E, 5E) -3,5- Ketone,
Double ((E) -4- (dimethylamino) benzene fork) -1- methyl piperidine -4- ketone of (11) 3,5-,
(12) (3E, 5E) -1- methyl -3, double (thiophene -2- the methylenes)-piperidin-4-ones of 5-,
Double ((E) -4- methoxyl groups benzal) -1- methyl piperidine -4- ketone of (13) 3,5-,
(14) double (furans -2- methylenes) -1- methyl piperidine -4- ketone of (3E, 5E) -3,5-,
Double ((E) -4- fluorine benzal) -1- methyl piperidine -4- ketone of (15) 3,5-,
(16) 1- methyl -3, double ((E) -4- (trifluoromethyl) benzals base) piperidin-4-ones of 5-,
Double ((E) -4- (dimethylamino) benzals base) -1- ethyl piperidine -4- ketone of (17) 3,5-,
Double ((E) -4- (dimethylamino) the benzal)-piperidin-4-one acetate of (18) 3,5-,
(19) 1- acetyl group -3, double ((E) -4- (trifluoromethyl) benzal) piperidin-4-ones of 5-,
(20) (3E, 5E) -1- acetyl group -3, double (furans -2- methylenes) piperidin-4-ones of 5-,
(21) (3E, 5E) -1- propionyl -3, double (thiophene -2- methylenes) piperidin-4-ones of 5-,
(22) double (furans -2- methylenes) -1- propiono piperidin-4-ones of (3E, 5E) -3,5-,
(23) double (furans -2- methylenes) pentamethylene -1- ketoximes of (2E, 5E) -2,5-,
(24) 3,5- pair ((E) -3,4- dihydroxystyryl) isoxazoles,
Double ((E) -3,4- dihydroxystyryls) -1H- pyrazoles of (25) 3,5-,
Double ((E) -3,4- dihydroxystyryls) -1- phenyl -1H- pyrazoles of (26) 3,5-,
Double (3,4- dihydroxyphenyl) heptane -3 of (27) 1,7-, 5- diketone,
(28) double (3,4- the Dimethoxyphenyl) -4- methyl hept- 1 of (1E, 6E) -1,7-, 6- diene -3,5- diketone,
(29) double (3,4- dihydroxymethyl phenyl) heptane -1 of (1E, 6E) -1,7-, 6- diene -3,5- diketone,
(30) double ((E) -3,4 dimethoxy styrene base) -1- methyl isophthalic acids-phenyl -1H pyrazoles of iodate 3,5-.
To realize above-mentioned second purpose, the present invention is adopted the technical scheme that：
The hydrate or its salt for pharmacologically allowing of described disubstituted aryl class compound, described pharmacologically permits Perhaps salt is inorganic acid salt or acylate.
Described inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid, hydroiodic acid or nitric acid；Described organic acid It is acetic acid, maleic acid, fumaric acid, tartaric acid, butanedioic acid, lactic acid, Loprazolam, p-methyl benzenesulfonic acid, salicylic acid or oxalic acid.
To realize above-mentioned 3rd purpose, the present invention is adopted the technical scheme that：
A kind of pharmaceutical composition, it contains described disubstituted aryl class compound, or described hydrate or its pharmacology The salt allowed on, and contain conventional pharmaceutical carrier.
Described pharmaceutical composition also contains azole antifungal compound.
Described azole antifungal compound is Fluconazole.
To realize above-mentioned 4th purpose, the present invention is adopted the technical scheme that：
Described disubstituted aryl class compound, or described hydrate or its salt for pharmacologically allowing are preparing azole Application in antifungal drug reversal agent of drug resistance.
Described fungi is Candida albicans.
Described triazole antifungal agent thing is Fluconazole.
The invention has the advantages that：The invention provides a kind of disubstituted aryl class compound, especially find that such pair takes Can be used in conjunction with triazole antifungal agent thing for aryl class compound, sensitiveness of the drug-fast bacteria to azole drug can be improved, it is real Existing reversing drug resistance.Therefore it is of the invention for the treatment of clinical drug-resistant fungi provides a kind of new way.
Specific embodiment
Present inventor is found that a class has collaboration triazole antifungal agent thing overriding resistance first by substantial amounts of experiment The compound of fungi.The concrete structure of partial target compound is as follows：
The structure of the target compound of table 1
The specific embodiment that the present invention is provided is elaborated below.
The total preparation method of compound of Formula I is：Acetone or cyclopentanone or cyclohexanone or piperidones or N- methylpiperidones (10mmol) is contracted under the catalysis of 10%~50%NaOH aqueous solution with the ethanol solution of substituted benzaldehyde (20mmol) by aldol Close reaction and obtain corresponding compound or intermediate, intermediate then again respectively with hydrazine hydrate or oxyammonia or phenylhydrazine or acetic anhydride or Chloroacetic chloride or propionic acid anhydride reactant obtain corresponding compound or intermediate, and intermediate is then in BBr3Demethylation obtains phase under low temperature Answer compound.
Embodiment 1：The preparation of double (thiophene -2- bases) the amyl- 1,4- diene -3- ketone of (1E, 4E) -1,5-
Acetone (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH aqueous solution is slowly added to after mixing at room temperature (40mmol) and 2 thiophene carboxaldehyde (20mmol), at room temperature stirring terminates until reacting, and reaction solution then is poured into 200ml frozen water In, yellow solid is separated out, filtering, drying, crude product ethyl alcohol recrystallization obtain yellow solid, 116~118 DEG C of fusing point, yield 63%.ESIMS m/z:247.0[M+H]+.
Embodiment 2：The preparation of double (3,4- dihydroxy phenyls) the amyl- 1,4- diene -3- ketone of (1E, 4E) -1,5-
Acetone (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH aqueous solution is slowly added to after mixing at room temperature (40mmol) and veratraldehyde (20mmol), at room temperature stirring terminates until reacting, and then pours into 200ml frozen water reaction solution, Yellow solid filtering, drying are separated out, crude product ethyl alcohol recrystallization obtains yellow solid.After drying, the yellow solid is then taken (1mmol), adds dry methylene chloride 20ml, and -15 DEG C are slowly added dropwise BBr3(12mmol), moves to room temperature and stirs after completion of dropping Mix, until reaction terminates, add water treatment, separate out solid, filtering, drying, crude product ethyl alcohol recrystallization obtains red solid. ESIMS m/z:299.1[M+H]+.
Embodiment 3：The preparation of double ((the E) -3,4- dihydroxies benzal) pentamethylene -1- ketone of 2,5-
Cyclopentanone (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and veratraldehyde (20mmol), at room temperature stirring terminate until reacting, and reaction solution then is poured into 200ml frozen water In, yellow solid filtering, drying are separated out, crude product ethyl alcohol recrystallization obtains yellow solid, and then the yellow solid is taken after drying (1mmol), adds dry methylene chloride 20ml, and -15 DEG C are slowly added dropwise BBr3(12mmol), moves to room temperature and stirs after completion of dropping Mix, until reaction terminates, add water treatment, separate out solid, filtering, drying, crude product ethyl alcohol recrystallization.ESIMS m/z:325.9 [M+H]+Embodiment 4：The preparation of 2,5- double ((E) -3,4- dihydroxies benzal) hexamethylene -1- ketone
Cyclohexanone (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and veratraldehyde (20mmol), at room temperature stirring terminate until reacting, and reaction solution then is poured into 200ml frozen water In, yellow solid filtering, drying are separated out, crude product ethyl alcohol recrystallization obtains yellow solid, and then the yellow solid is taken after drying (1mmol), adds dry methylene chloride 20ml, and -15 DEG C are slowly added dropwise BBr3(12mmol), moves to room temperature and stirs after completion of dropping Mix, until reaction terminates, add water treatment, separate out solid, filtering, drying, crude product ethyl alcohol recrystallization obtains red solid.ESIMS m/z:339.1[M+H]+.
Embodiment 5：Double (benzo [d] [1,3] dioxole -5- methylenes)-piperidin-4-ones of (3E, 5E) -3,5- Preparation
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and piperonal (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, and then pour into reaction solution In 200ml frozen water, yellow solid filtering, drying are separated out, crude product ethyl alcohol recrystallization obtains yellow solid.ESIMS m/z:364.0 [M+H]+.
Embodiment 6：The preparation of double ((E) -4- (dimethylamino) benzal) piperidin-4-ones of 3,5-
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and dimethylaminobenzaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then will be anti- Answer liquid to pour into 200ml frozen water, separate out red solid filtering, drying, crude product ethyl alcohol recrystallization obtains red solid.ESIMS m/z:362.2[M+H]+.
Embodiment 7：The preparation of double ((E) -3,4- dimethoxies benzal)-piperidin-4-ones of 3,5-
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and veratraldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, and then pour into reaction solution In 200ml frozen water, yellow solid filtering, drying are separated out, crude product ethyl alcohol recrystallization obtains yellow solid.ESIMS m/z:397.0 [M+H]+.
Embodiment 8：The preparation of 3,5- double ((E) -4- fluorine benzal)-piperidin-4-ones
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and 4-Fluorobenzaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then by reaction solution Pour into 200ml frozen water, separate out yellow solid filtering, drying, crude product ethyl alcohol recrystallization obtains yellow solid.ESIMS m/z: 312.1[M+H]+.
Embodiment 9：The preparation of double ((E) -4- (trifluoromethyl) benzal) piperidin-4-ones of 3,5-
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and p-trifluoromethyl benzaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, and then will Reaction solution is poured into 200ml frozen water, separates out yellow solid filtering, drying, and crude product ethyl alcohol recrystallization obtains yellow solid.ESIMS m/z:413.0[M+H]+.
Embodiment 10：Double (benzo [d] [1,3] dioxole -5- methylenes) -1- methyl piperazines of (3E, 5E) -3,5- The preparation of pyridine -4- ketone
N- methylpiperidones (10mmol) are taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and piperonal (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then will be anti- Answer liquid to pour into 200ml frozen water, separate out yellow solid filtering, drying, crude product ethyl alcohol recrystallization obtains yellow solid.Yield 68%.1H NMR(CDCl3):2.49(3H,s,-CH3),3.75(4H,s,-CH2-),6.03(4H,s,O-CH2-O),6.87- 6.96 (6H, m, Ar-H), 7.72 (2H ,-CH=).ESIMS m/z:378.1[M+H]+.
Embodiment 11：The preparation of double ((E) -4- (dimethylamino) benzene fork) -1- methyl piperidine -4- ketone of 3,5-
N- methylpiperidones (10mmol) are taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and dimethylaminobenzaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, Then reaction solution is poured into 200ml frozen water, separates out red solid filtering, drying, crude product ethyl alcohol recrystallization obtains red solid Body.Yield 65%.1H NMR(CDCl3):δ2.53(s,3H,N-CH3),3.07(s,12H),3.84(4H,s,-CH2-),6.76 (4H, d, J=8.40Hz, Ar-H), 7.39 (4H, d, J=8.40Hz, Ar-H), 7.80 (2H, s ,-CH=)
Embodiment 12：The preparation of double (thiophene -2- methylenes) piperidin-4-ones of (3E, 5E) -1- methyl -3,5-
N- methylpiperidones (10mmol) are taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and 2- thiophene aldehydes (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, and then will Reaction solution is poured into 200ml frozen water, separates out yellow solid filtering, drying, and crude product ethyl alcohol recrystallization obtains yellow solid.ESIMS m/z:302.8[M+H]+.
Embodiment 13：The preparation of 3,5- double ((E) -4- methoxyl groups benzal) -1- methyl piperidine -4- ketone
N- methylpiperidones (10mmol) are taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and P-methoxybenzal-dehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, Then reaction solution is poured into 200ml frozen water, separates out yellow solid filtering, drying, crude product ethyl alcohol recrystallization obtains yellow and consolidates Body.ESIMS m/z:350.9[M+H]+.
Embodiment 14：The preparation of double (furans -2- the methylenes) -1- methyl piperidine -4- ketone of (3E, 5E) -3,5-
N- methylpiperidones (10mmol) are taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and 2 furan carboxyaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then Reaction solution is poured into 200ml frozen water, yellow solid filtering, drying is separated out, crude product ethyl alcohol recrystallization obtains yellow solid. ESIMS m/z:270.7[M+H]+.
Embodiment 15：The preparation of double ((E) -4- fluorine benzal) -1- methyl piperidine -4- ketone of 3,5-
N- methylpiperidones (10mmol) are taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and 4- fluorobenzaldehydes (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then Reaction solution is poured into 200ml frozen water, yellow solid filtering, drying is separated out, crude product ethyl alcohol recrystallization obtains yellow solid. ESIMS m/z:326.9[M+H]+.
Embodiment 16：The preparation of double ((E) -4- (trifluoromethyl) benzals base) piperidin-4-ones of 1- methyl -3,5-
N- methylpiperidones (10mmol) are taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and p-trifluoromethyl benzaldehyde (20mmol), pyrrolidines 1ml, stirring is until reaction is tied at room temperature Beam, then pours into 200ml frozen water reaction solution, separates out yellow solid filtering, drying, and crude product ethyl alcohol recrystallization obtains yellow Solid.ESIMS m/z:427.0[M+H]+.
Embodiment 17：The preparation of 3,5- double ((E) -4- (dimethylamino) benzals base) -1- ethyl piperidine -4- ketone
N-ethylpiperidine ketone (10mmol) is taken, ethanol 20ml is added, 10%~50% is slowly added to after mixing at room temperature The NaOH aqueous solution (40mmol) and paradime thylaminobenzaldehyde (20mmol), pyrrolidines 1ml, stirring is until reaction is tied at room temperature Beam, then pours into 200ml frozen water reaction solution, separates out yellow solid filtering, drying, and crude product ethyl alcohol recrystallization obtains red Solid.ESIMS m/z:391.2[M+H]+.
Embodiment 18：The preparation of double ((E) -4- (dimethylamino) the benzal)-piperidin-4-one acetate of 3,5-
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and dimethylaminobenzaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then will be anti- Answer liquid to pour into 200ml frozen water, separate out the filtering of yellowish red color solid, drying, crude product ethyl alcohol recrystallization obtains red solid, takes this Compound (1mmol), adds 95% ethanol 20ml, and acetic acid (3mmol), 75 DEG C of backflows after 30 minutes, are taken out after natural cooling crystallization Filter, normal pressure drying, with ethyl alcohol recrystallization, obtains target compound.1HNMR(CD3OD):2.02(6H,s,CH3COOH),3.10 (12H, s, N-CH3), 4.53, (4H, s, CH2), 6.86 (4H, d, J=8.1, Ar-H), 7.42 (4H, d, J=8.1, Ar-H), 7.94(2H,Ar-H).
Embodiment 19：1- acetyl group -3, the preparation of double ((E) -4- (trifluoromethyl) benzal) piperidin-4-ones of 5-
Compound 9 (embodiment 9) 100mg is taken, is added in 10ml dry methylene chloride solution, then add 1ml tri- Ethamine, is uniformly mixed.Then chloroacetic chloride 30mg is taken, is dissolved in 5ml dichloromethane solutions.Then by chloroacetic chloride under ice bath Dichloromethane solution be slowly dropped in solution above, completion of dropping, return to room temperature continue react 3 hours, then will Reaction solution is poured into water, stirring, then separates dichloromethane layer with separatory funnel, and rotary evaporation removes dichloromethane, obtains Yellow solid.ESIMS m/z:454.5[M+H]+.
Embodiment 20：The preparation of double (furans -2- methylenes) piperidin-4-ones of (3E, 5E) -1- acetyl group -3,5-
Piperidones (30mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (70mmol) and 2 furan carboxyaldehyde (60mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then by reaction solution Pour into 200ml frozen water, separate out yellow solid filtering, drying, crude product ethyl alcohol recrystallization obtains yellow solid.Take this compound Solid 100mg, is added in 10ml dry methylene chloride solution.Then chloroacetic chloride 30mg is taken, 5ml dichloromethane solutions are dissolved in In.Then the dichloromethane solution of chloroacetic chloride is slowly dropped in solution above under ice bath, completion of dropping returns to room temperature Continue to react 3 hours, then reaction solution is poured into water, stir, then separate dichloromethane layer with separatory funnel, rotation is steamed Hair removes dichloromethane, obtains solid, with ethyl alcohol recrystallization, obtains yellow solid.ESIMS m/z:298.8[M+H]+.
Embodiment 21：The preparation of double (thiophene -2- methylenes) piperidin-4-ones of (3E, 5E) -1- propionyl -3,5-
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and 2 thiophene carboxaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then by reaction solution Pour into 200ml frozen water, separate out yellow solid filtering, drying, crude product ethyl alcohol recrystallization obtains yellow solid.Take this solid 50mg, is added in 10ml dry methylene chloride solution, then adds 0.2ml triethylamines, is uniformly mixed.Then third is taken Acyl chlorides 15mg, is dissolved in 5ml dichloromethane solutions.Then the dichloromethane solution of chloroacetic chloride is slowly dropped under ice bath In the solution in face, completion of dropping returns to room temperature and continues to react 3 hours, and then reaction solution is poured into water, stirs, then Dichloromethane layer is separated with separatory funnel, rotary evaporation removes dichloromethane, obtains solid, with ethyl alcohol recrystallization, obtains brown Solid.Yield 60%.1H NMR(CDCl3):1.17(3H,t,-CH3),2.47(2H,q,-CH2-),4.84(2H,s),5.00 (2H, s), 7.22 (2H, m, Ar-H), 7.44 (2H, d, J=3.60Hz, Ar-H), 7.65 (2H, s), 8.03 (2H, d, J= 5.40Hz).ESIMS m/z:344.8[M+H]+.
Embodiment 22：The preparation of double (furans -2- the methylenes) -1- propiono piperidin-4-ones of (3E, 5E) -3,5-
Piperidones (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and 2 furan carboxyaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then by reaction solution Pour into 200ml frozen water, separate out yellow solid filtering, drying, crude product ethyl alcohol recrystallization obtains yellow solid.Take this solid 50mg, is added in 10ml dry methylene chloride solution, then adds 0.2ml triethylamines, is uniformly mixed.Then third is taken Acyl chlorides 15mg, is dissolved in 5ml dichloromethane solutions.Then the dichloromethane solution of chloroacetic chloride is slowly dropped under ice bath In the solution in face, completion of dropping returns to room temperature and continues to react 3 hours, and then reaction solution is poured into water, stirs, then Dichloromethane layer is separated with separatory funnel, rotary evaporation removes dichloromethane, obtains solid, with ethyl alcohol recrystallization, obtains red Solid.1H NMR(CDCl3):1.09-1.17 (3H, t, J=7.5Hz ,-CH3)；3.37-3.45 (2H, q, J=7.5Hz ,- COCH2-)；4.77(2H,s,-CH2-)；4.92(2H,s,-CH2-)；7.12-7.18 (2H, q, J=4.5Hz, 4-H)；7.36- 7.37 (2H, s ,-CH=)；7.58-7.60 (2H, d, J=4.2Hz, 3-H)；7.96(2H,s,5-H).13C NMR(CDCl3): 9.14(-CH3)；26.34(-CH2-)；43.04,45.92(-CH2-)；128.02-131.22(Ar-C)；133.66-138.20(- CH=)；172.41(-CO-N-)；185.27(-CO-).ESIMS m/z:312.1[M+H]+.
Embodiment 23：The preparation of double (furans -2- methylenes) pentamethylene -1- ketoximes of (2E, 5E) -2,5-
The ketone of ring five (10mmol) is taken, ethanol 20ml is added, 10%~50%NaOH is slowly added to after mixing at room temperature water-soluble Liquid (40mmol) and 2- furans benzaldehyde (20mmol), pyrrolidines 1ml, at room temperature stirring terminate until reacting, then will reaction Liquid is poured into 200ml frozen water, separates out yellow solid filtering, drying, and crude product ethyl alcohol recrystallization obtains yellow solid.Then should Solid is heated to reflux for 80 DEG C with oxammonium hydrochloride (18mmol), reacts 24h, and column chromatography obtains white solid.1H NMRCDCl3): 3.00(4H,s,-CH2-),6.49(4H,t,J1=1.8Hz, J2=17.7Hz, Ar-H) .6.99 (1H, s), 7.52 (2H, dd, J1=1.8Hz, J2=17.7Hz, Ar-H), 8.21 (1H, s) .ESIMS m/z:256.1[M+H]+.
Embodiment 24：Double (the preparations of (E) -3,4- dihydroxystyryl) isoxazoles of 3,5-
Curcumin 2mmol, oxammonium hydrochloride 3.6mmol, glacial acetic acid 30ml, 85 DEG C are heated to reflux, and react 6h, until reaction knot Beam, then pours into 200ml frozen water reaction solution, uses saturation NaHCO3PH to neutrality is adjusted, red brown solid is separated out, suction filtration dries Dry, ethyl alcohol recrystallization obtains red solid.By red solid 1mmol, dry methylene chloride 20ml is added, -15 DEG C slowly drip Plus BBr3(6mmol), moves to after completion of dropping and is stirred at room temperature, until reaction terminates, add water treatment, ethyl acetate extraction, post layer Analysis, obtains aubergine solid.ESIMS m/z:338.1[M+H]+.
Embodiment 25：The preparation of double ((E) -3,4- the dihydroxystyryls) -1H- pyrazoles of 3,5-
Curcumin 2mmol, hydrazine hydrate 3.6mmol, glacial acetic acid 30ml, 118 DEG C are heated to reflux, and react 8h, until reaction knot Beam, then pours into 200ml frozen water reaction solution, uses saturation NaHCO3PH to neutrality is adjusted, red brown solid is separated out, suction filtration dries Dry, ethyl alcohol recrystallization obtains red solid.By red solid 1mmol, dry methylene chloride 20ml is added, -15 DEG C slowly drip Plus BBr3(6mmol), moves to after completion of dropping and is stirred at room temperature, until reaction terminates, add water treatment, ethyl acetate extraction, post layer Analysis, obtains aubergine solid.ESIMS m/z:337.1[M+H]+.
Embodiment 26：The preparation of double ((E) -3,4- the dihydroxystyryls) -1- phenyl -1H- pyrazoles of 3,5-
Curcumin 2mmol, phenylhydrazine 3.6mmol, glacial acetic acid 30ml, 110 DEG C are heated to reflux, and react 12h, until reaction knot Beam, then pours into 200ml frozen water reaction solution, uses saturation NaHCO3PH to neutrality is adjusted, red solid is separated out, suction filtration is dried, Ethyl alcohol recrystallization, obtains red solid.By red solid 1mmol, dry methylene chloride 20ml is added, -15 DEG C are slowly added dropwise BBr3(6mmol), moves to after completion of dropping and is stirred at room temperature, until reaction terminates, add water treatment, ethyl acetate extraction, column chromatography, Obtain red solid.ESIMS m/z:413.1[M+H]+.
Embodiment 27：The preparation of double (3,4- dihydroxyphenyls) heptane -3,5- diketone of 1,7-
Bisdemethoxycurcumin mmol, 10% palladium carbon, 1kPa hydrogen is stirred at room temperature 24h, until reaction terminates, column chromatography obtains first It is individual, white solid is obtained, by white solid 1mmol, dry methylene chloride 20ml is added, -15 DEG C are slowly added dropwise BBr3 (6mmol), is moved to after completion of dropping and is stirred at room temperature, until reaction terminates, add water treatment, and ethyl acetate extraction, column chromatography is obtained Red solid.ESIMS m/z:345.1[M+H]+.
Embodiment 28：Double (3,4- the Dimethoxyphenyls) -4- methyl hept- 1,6- diene -3,5- diketone of (1E, 6E) -1,7- Preparation
Bisdemethoxycurcumin mmol, CH3I 6ml, argon gas device, are stirred at room temperature 24h, until reaction terminates, column chromatography obtains the One point, yellow solid.ESIMS m/z:411.2[M+H]+.
Embodiment 29：Double (the 3,4- dihydroxymethyls phenyl) heptane -1,6- diene -3,5- diketone of (1E, 6E) -1,7-
Curcumin 2mmol, adds dry methylene chloride 30ml, and -15 DEG C are slowly added dropwise BBr3(12mmol), after completion of dropping Move to and be stirred at room temperature, until reaction terminates, add water treatment, ethyl acetate extraction, column chromatography obtains red solid.ESIMS m/ z:341.1[M+H]+.
Embodiment 30：Double ((E) -3,4 dimethoxy styrene base) -1- methyl isophthalic acids-phenyl -1H- pyrazoles of iodate 3,5-
Curcumin 2mmol, phenylhydrazine 3.6mmol, glacial acetic acid 30ml, 110 DEG C are heated to reflux, and react 12h, until reaction knot Beam, then pours into 200ml frozen water reaction solution, uses saturation NaHCO3PH to neutrality is adjusted, red solid is separated out, suction filtration is dried, Ethyl alcohol recrystallization, obtains red solid.Take the solid 1mmol, CH3I 6ml, argon gas device, are stirred at room temperature 24h, until reaction Terminate, column chromatography obtains white solid.1H NMRCDCl3):3.77(3H,s,N-Me),3.88(6H,s,O-Me),3.94(6H, S, O-Me), 6.95-6.01 (1H, d, J=16.2, Ar-H), 6.71-6.81 (2H, m, Ar-H), 7.05-7.11 (2H, m, Ar- H),7.15-7.23(1H,m,Ar-H),7.36-7.41(2H,m,Ar-H),7.48-7.50(2H,m,Ar-H),7.87-7.96 (2H,m,Ar-H),8.04-8.07(1H,m,Ar-H).ESIMS m/z:484.2[M+H]+.
Embodiment 31：Using checkerboard type dilution method In vitro chemo-drug sensitive test test the compounds of this invention collaboration Fluconazole overriding resistance Fungi acts on
First, experiment material
Candida albicans strain in following experiments is to be clinically separated the bacterium of resistance Candida albicans 103 for obtaining.All realities Test and draw plate activation in husky fort glucose agar medium (SDA) with bacterium, after being cultivated 2 weeks in 30 DEG C, difference picking monoclonal is again Secondary stroke of plate activation, takes second gained monoclonal and puts SDA inclined-planes, is preserved at 4 DEG C after being cultivated 2 weeks in 30 DEG C.Nutrient solution is The liquid mediums of RPMI 1640, carry out culture pre-treatment according to standard method.Fluconazole as antifungal medicine parenteral solution is by Dalian Pharmaceutcal corporation, Ltd of Pfizer provides；Dimethyl sulfoxide (DMSO) is purchased in Solution on Chemical Reagents in Shanghai company of Chinese Medicine group.Used Instrument has Multiskan MK3 types enzyme mark detector (Finland Labsystems)；Water isolation type electro-heating standing-temperature cultivator (is leaped in Shanghai Medical apparatus and instruments factory)；MJX type intelligent bacterium enzymes incubator (Ningbo south of the River instrument plant)；(Shanghai jumps THZ-82A Desk type constant-temperatureoscillator oscillators Enter medical apparatus and instruments factory)；SW-CT-IF types superpurgative working table (SuZhou Antai Air Tech Co., Ltd.)；Inverted microscope (Amersham Pharmacia)；Micro sample adding appliance (Finland Finnpette)；(Denmark Nunclon is public for 96 porocyte culture plates Department).
2nd, experimental procedure
1st, the configuration of fungi suspension
Before experiment, with inoculation circle from the bacterium of picking resistance Candida albicans 103 on 4 DEG C of SDA culture mediums of preservation (C.albicans 103) is seeded to 1ml YEPD nutrient solutions, and in 30 DEG C, 200rpm shaken cultivations activate 16h, are in fungi Later stage exponential phase of growth.Take in the bacterium solution to 1ml YEPD nutrient solutions, activate again in aforementioned manners, after 16h, use hemocytometer Number plate is counted, and bacterial concentration to 1 × 10 is adjusted with RPMI RPMI-1640s3-5×103CFU/ml。
2nd, the preparation of drug sensitive reaction plate
Aseptic 96 orifice plate is taken, adds the μ l of 1640 fluid nutrient mediums of RPMI 100 to make blank in No. 1 hole of every row；3-12 holes Respectively plus Fresh the μ l of bacterium solution 100；No. 2 holes add the μ l of the bacterium solution 160 and μ l of test-compound solution 40；No. 12 holes not drug containing, The μ l of bacterium solution 100 are only added to make Growth positive control.2-11 holes carry out doubling dilution, are respectively the final drug concentration in each hole 64th, 32,16,8,4,2 and 1 μ g/ml, DMSO contents are below 1% in each hole.One piece is prepared while preparing drug sensitive plate every time Quality Control bacterium drug sensitive plate, Quality Control bacterium：According to the suggestion of NCCLS M27-A schemes, we use Candida parapsilosis ATCC18062 for Quality Control bacterium, its MIC reference value is as follows：Fluconazole (FCZ)：MIC80Value 0.25-1.0 μ g/ml；AmB：MIC value 0.5-2.0 μ g/ml. Test with this bacterial strain as reference strain every time, only as its MIC80Think that test operation accurately may be used when above range, just in value circle Lean on.As while test strain well-grown, then it is believed that testing successfully, be as a result subjected to.Each drug sensitive plate is trained in 30 DEG C of insulating boxs Support.
3rd, the selection of In vitro chemo-drug sensitive test method
We have selected when the compound to synthesizing carries out the collaboration Fluconazole overriding resistance fungi external activity rating of effect Checkerboard type micro-dilution method.Checkerboard type micro-dilution method is the extension of In vitro chemo-drug sensitive test, that is, the two kinds of medicines for sharing are in 96 holes Vertical (A to H) horizontal stroke (2 to 11) two direction on plate with two-dimentional chessboard carries out two times of doubling dilution respectively.Such as compound 1 and After kind fluconazole as antifungal medicine is shared so that the μ g/ml of final concentration of 64,32,16,8,4,2 and 1 of Fluconazole, test compounds Final concentration of 64,32,16,8,4,2,1 μ g/ml of thing.Experiment agents useful for same, medicine, laboratory operating procedures are with above-mentioned external medicine Quick experiment.
4th, evaluation criterion
Part Mlc index (fractional inhibitory concentration index, FICI) is to comment The major parameter of two medicine interaction modes of valency drug combination.Mlc fraction (FIC), respectively each is medication combined When antibacterial required minimum inhibitory concentration (MIC) with it is alone when MIC ratio, and FIC indexes (FICI) then be equal to two kinds of medicine FIC Sum.Prescribed a time limit higher than detection highest when MIC value and be used to calculate FICI with the twice value of highest limit concentration.Many document reports are worked as The interaction of two medicines is defined as synergy during FICI≤0.5, and FIC indexes are smaller, acts synergistically stronger；0.5<FICI≤ The interaction of two medicines is defined as summation action when 1；1<It is unrelated effect during FICI≤4；Work as FICI>Two medicines produce antagonism when 4 Effect.The newest standards that the present invention is used from current foreign periodical：When FICI≤0.5, the interaction of two medicines is defined as Synergy；0.5<It is unrelated effect during FICI≤4；Work as FICI>Two medicines produce antagonism when 4.
3rd, test result
The results are shown in Table 2.Result shows that compound of the invention has preferably collaboration Fluconazole antifungal activity, therefore Can be used in conjunction with triazole antifungal agent thing, to improve sensitiveness of the drug-fast bacteria to azole drug, realize that reversing drug resistance is acted on.
The collaboration antifungic action of the target compound of table 2
Note：MIC80Value [μ g/mL] is compound and the MIC of 8.0 μ g/mL fluconazole medications in table80。
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as Protection scope of the present invention.

Claims (10)

1. it is a kind of with synergy overriding resistance fungi disubstituted aryl class compound, it is characterised in that described is disubstituted The structure of aryl class compound is as shown in Formulas I, II or III：
The substitution situation of each group is selected from one of the following in Formulas I：
(1) n=0, m=0, X=oxygen, Y do not exist, and Ar is selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls, 4- hydroxy phenyls and 2- Thienyl；
(2) n=1, m=0, Z do not exist, and X=oxygen, Y does not exist, and Ar is selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxyls Base phenyl；
(3) n=1, m=0, Z=CH2, X=oxygen, Y do not exist, and Ar is selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxyls Phenyl；
(4) n=1, m=0, Z=NH, X=oxygen, Y do not exist, Ar be selected from 3,4- methylenedioxyphenyls, to dimethylamino phenyl, 3,4- Dimethoxyphenyls, p-fluorophenyl, rubigan, p-bromophenyl, to iodophenyl and p-trifluoromethyl phenyl；
(5) n=1, m=0, Z=N- methyl, X=oxygen, Y do not exist, and Ar is selected from 3,4- methylenedioxyphenyls, to dimethylamino Phenyl, 2- thienyls, p-methoxyphenyl, 2- furyls, p-fluorophenyl, rubigan, p-bromophenyl, to iodophenyl and to three Trifluoromethylphenyl；
(6) n=1, m=0, Z=N- ethyl, N- propyl group or N- butyl, X=oxygen, Y do not exist, Ar be selected to dimethylamino phenyl, To lignocaine phenyl and to dipropyl aminophenyl；
(7) n=1, m=0, Z=N- acetyl group, N- propionos or N- bytyries, X=oxygen, Y do not exist, Ar be selected from 2- thienyls, 2- furyls and p-trifluoromethyl phenyl；
(8) n=1, m=0, Z do not exist, and X=N-OH, Y does not exist, and Ar is selected from 2- furyls；
(9) n=0, m=1, X=nitrogen, Y=oxygen, Ar are selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxy phenyls；
(10) n=0, m=1, X=N, Y=NH, Ar are selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxy phenyls；
(12) n=0, m=1, X=N, Y=N- phenyl, Ar be selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls, 4- hydroxy phenyls and 3,4- Dimethoxyphenyls；
(13) n=0, m=1, X=N, Y=N- phenyl, N- methyl, Ar are selected from 3,4- dihydroxy phenyls, 3- hydroxy phenyls, 4- hydroxyls Base phenyl and 3,4- Dimethoxyphenyls；
The substitution situation of each group is as follows in Formula II：
(14) Z=oxygen, W=oxygen, Ar is selected from 3- methoxyl group -4- hydroxy phenyls, 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxyls Base phenyl；
The substitution situation of each group is as follows in formula III：
(15) Z=oxygen, W=oxygen, Ar is selected from 3- methoxyl group -4- hydroxy phenyls, 3,4- dihydroxy phenyls, 3- hydroxy phenyls and 4- hydroxyls Base phenyl.
2. disubstituted aryl class compound according to claim 1, it is characterised in that described disubstituted aryl class chemical combination Thing is selected from：
(1) double (thiophene -2- bases) amyl- Isosorbide-5-Nitrae-diene -3- ketone of (1E, 4E) -1,5-,
(2) double (3, the 4- dihydroxy phenyl) amyl- Isosorbide-5-Nitrae-diene -3- ketone of (1E, 4E) -1,5-,
Double ((E) -3,4- dihydroxies benzal) pentamethylene -1- ketone of (3) 2,5-,
Double ((E) -3,4- dihydroxies benzal) hexamethylene -1- ketone of (4) 2,5-,
(5) double (benzo [d] [1,3] dioxole -5- methylenes)-piperidin-4-ones of (3E, 5E) -3,5-,
Double ((E) -4- (dimethylamino) benzal) piperidin-4-ones of (6) 3,5-,
Double ((E) -3,4- dimethoxies benzal)-piperidin-4-ones of (7) 3,5-,
Double ((the E) -4- fluorine benzal) piperidin-4-ones of (8) 3,5-,
Double ((the E) -4- trifluoromethyls) benzals of (9) 3,5-) piperidin-4-one,
(10) double (benzo [d] [1,3] dioxole -5- methylenes) -1- methyl piperidine -4- ketone of (3E, 5E) -3,5-,
Double ((E) -4- (dimethylamino) benzene fork) -1- methyl piperidine -4- ketone of (11) 3,5-,
(12) (3E, 5E) -1- methyl -3, double (thiophene -2- the methylenes)-piperidin-4-ones of 5-,
Double ((E) -4- methoxyl groups benzal) -1- methyl piperidine -4- ketone of (13) 3,5-,
(14) double (furans -2- methylenes) -1- methyl piperidine -4- ketone of (3E, 5E) -3,5-,
Double ((E) -4- fluorine benzal) -1- methyl piperidine -4- ketone of (15) 3,5-,
(16) 1- methyl -3, double ((E) -4- (trifluoromethyl) benzals base) piperidin-4-ones of 5-,
Double ((E) -4- (dimethylamino) benzals base) -1- ethyl piperidine -4- ketone of (17) 3,5-,
Double ((E) -4- (dimethylamino) the benzal)-piperidin-4-one acetate of (18) 3,5-,
(19) 1- acetyl group -3, double ((E) -4- (trifluoromethyl) benzal) piperidin-4-ones of 5-,
(20) (3E, 5E) -1- acetyl group -3, double (furans -2- methylenes) piperidin-4-ones of 5-,
(21) (3E, 5E) -1- propionyl -3, double (thiophene -2- methylenes) piperidin-4-ones of 5-,
(22) double (furans -2- methylenes) -1- propiono piperidin-4-ones of (3E, 5E) -3,5-,
(23) double (furans -2- methylenes) pentamethylene -1- ketoximes of (2E, 5E) -2,5-,
(24) 3,5- pair ((E) -3,4- dihydroxystyryl) isoxazoles,
Double ((E) -3,4- dihydroxystyryls) -1H- pyrazoles of (25) 3,5-,
Double ((E) -3,4- dihydroxystyryls) -1- phenyl -1H- pyrazoles of (26) 3,5-,
Double (3,4- dihydroxyphenyl) heptane -3 of (27) 1,7-, 5- diketone,
(28) double (3,4- the Dimethoxyphenyl) -4- methyl hept- 1 of (1E, 6E) -1,7-, 6- diene -3,5- diketone,
(29) double (3,4- dihydroxymethyl phenyl) heptane -1 of (1E, 6E) -1,7-, 6- diene -3,5- diketone,
(30) double ((E) -3,4 dimethoxy styrene base) -1- methyl isophthalic acids-phenyl -1H pyrazoles of iodate 3,5-.
3. the hydrate or its salt for pharmacologically allowing of the disubstituted aryl class compound described in claim 1, described medicine The salt allowed in Neo-Confucianism is inorganic acid salt or acylate.
4. the salt for pharmacologically allowing according to claim 3, it is characterised in that described inorganic acid be hydrochloric acid, sulfuric acid, Phosphoric acid, diphosphonic acid, hydrobromic acid, hydroiodic acid or nitric acid；Described organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, amber Acid, lactic acid, Loprazolam, p-methyl benzenesulfonic acid, salicylic acid or oxalic acid.
5. a kind of pharmaceutical composition, it is characterised in that it contains the disubstituted aryl class compound described in claim 1 or 2, or Hydrate or its salt for pharmacologically allowing described in claim 3 or 4, and contain conventional pharmaceutical carrier.
6. pharmaceutical composition according to claim 5, it is characterised in that it also contains azole antifungal compound.
7. pharmaceutical composition according to claim 6, it is characterised in that described azole antifungal compound is fluorine health Azoles.
8. the disubstituted aryl class compound described in claim 1 or 2, or hydrate or its pharmacology described in claim 3 or 4 Application of the salt allowed in triazole antifungal agent thing reversal agent of drug resistance is prepared.
9. application according to claim 8, it is characterised in that described fungi is Candida albicans.
10. application according to claim 9, it is characterised in that described triazole antifungal agent thing is Fluconazole.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108947924A (en) * 2018-08-26 2018-12-07 石河子大学 The preparation method and its usage of dihydro-isoxazole methanone derivatives and dihydro-isoxazole methanone derivatives

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030092772A1 (en) * 1997-02-20 2003-05-15 Reksohadiprodjo Mochammad Samhoedi Derivatives of benzylidene cyclohexanone, benzylidene cyclopentanone, and benzylidene acetone, and therapeutic uses thereof
WO2003105751A2 (en) * 2002-06-17 2003-12-24 Ho-Jeong Kwon Novel curcumin derivatives
US20040176384A1 (en) * 1999-12-03 2004-09-09 Emory University Curcumin analogs with anti-tumor and anti-angiogenic properties
WO2005006945A2 (en) * 2003-07-03 2005-01-27 The Salk Institute For Biological Studies Methods for treating neural disorders and compounds useful therefor
CN1646473A (en) * 2002-04-17 2005-07-27 北卡罗来纳查佩尔山大学 Novel curcumin analogues and uses thereof
CN101434600A (en) * 2008-12-25 2009-05-20 福建医科大学 Curcumin piperidone analog and use thereof in anti-tumor medicament
CN103626692A (en) * 2013-11-12 2014-03-12 中国人民解放军第二军医大学 3,5-diaryl-ylidene piperidone derivatives and application thereof in preparing blood glucose-reducing and fat-reducing medicine
US20150051294A1 (en) * 2012-04-06 2015-02-19 Universtiy Of South Florida Myricanol Derivatives and Uses Thereof for Treatment of Neurodegenerative Diseases
US20160221907A1 (en) * 2014-03-06 2016-08-04 Hong Kong Baptist University MTOR-independent activator of TFEB for autophagy enhancement and uses thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030092772A1 (en) * 1997-02-20 2003-05-15 Reksohadiprodjo Mochammad Samhoedi Derivatives of benzylidene cyclohexanone, benzylidene cyclopentanone, and benzylidene acetone, and therapeutic uses thereof
US20040176384A1 (en) * 1999-12-03 2004-09-09 Emory University Curcumin analogs with anti-tumor and anti-angiogenic properties
CN1646473A (en) * 2002-04-17 2005-07-27 北卡罗来纳查佩尔山大学 Novel curcumin analogues and uses thereof
WO2003105751A2 (en) * 2002-06-17 2003-12-24 Ho-Jeong Kwon Novel curcumin derivatives
WO2005006945A2 (en) * 2003-07-03 2005-01-27 The Salk Institute For Biological Studies Methods for treating neural disorders and compounds useful therefor
CN101434600A (en) * 2008-12-25 2009-05-20 福建医科大学 Curcumin piperidone analog and use thereof in anti-tumor medicament
US20150051294A1 (en) * 2012-04-06 2015-02-19 Universtiy Of South Florida Myricanol Derivatives and Uses Thereof for Treatment of Neurodegenerative Diseases
CN103626692A (en) * 2013-11-12 2014-03-12 中国人民解放军第二军医大学 3,5-diaryl-ylidene piperidone derivatives and application thereof in preparing blood glucose-reducing and fat-reducing medicine
US20160221907A1 (en) * 2014-03-06 2016-08-04 Hong Kong Baptist University MTOR-independent activator of TFEB for autophagy enhancement and uses thereof

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BRAULIO INSUASTY等: "Microwave-assisted synthesis of pyrimido[4,5-b][1,6]naphthyridin-4(3H)-ones with potential antitumor activity", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
KARUPPAIYAH SELVENDIRAN等: "Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones: Differential cytotoxicity in healthy and cancer cells", 《FREE RADICAL BIOLOGY & MEDICINE》 *
LU FAN 等: "Novel role of Sarco/endoplasmic reticulum calcium ATPase 2 in development of colorectal cancer and its regulation by F36, a curcumin analog", 《BIOMEDICINE & PHARMACOTHERAPY》 *
MICHAEL V. MAKAROV，等: "Synthesis, characterization and structure–activity relationship of novel N-phosphorylated E,E-3,5-bis(thienylidene)piperid-4-ones", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
NATARAJAN ARUMUGAM等: "A 1,3-dipolar cycloaddition–annulation protocol for the expedient regio-, stereo- and product-selective construction of novel hybrid heterocycles comprising seven rings and seven contiguous stereocentres", 《TETRAHEDRON LETTERS》 *
SATHIYAMOORTHI SIVAKUMAR等: "An atom economic synthesis and AChE inhibitory activity of novel dispiro 7-aryltetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole and 4-aryloctahydroindolizine N-methylpiperidin-4-one hybrid heterocycles", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
YALDA KIA等: "A facile chemo-, regio- and stereoselective synthesis and cholinesterase inhibitory activity of spirooxindole–pyrrolizine– piperidine hybrids", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
ZHI-PENG HU等: "Quinine-catalyzed enantioselective tandem conjugate addition / intramolecular cyclization of malononitrile and 1,4-dien-3-ones", 《ARKIVOC》 *
谭善伦， 张大志，姜远英: "具有协同抗耐药真菌活性的天然小分子化合物研究进展", 《药学学报》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108947924A (en) * 2018-08-26 2018-12-07 石河子大学 The preparation method and its usage of dihydro-isoxazole methanone derivatives and dihydro-isoxazole methanone derivatives
CN108947924B (en) * 2018-08-26 2022-05-10 石河子大学 Preparation method and application of dihydroisoxazole benzophenone derivative and dihydroisoxazole benzophenone derivative

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