CN102503901B - Zole antifungal compounds, and preparation method and application thereof - Google Patents
Zole antifungal compounds, and preparation method and application thereof Download PDFInfo
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- CN102503901B CN102503901B CN201110330955.XA CN201110330955A CN102503901B CN 102503901 B CN102503901 B CN 102503901B CN 201110330955 A CN201110330955 A CN 201110330955A CN 102503901 B CN102503901 B CN 102503901B
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- XFYHXHGFFRCGTD-UHFFFAOYSA-N OC(Cc1c[n](Cc2ccccc2)nn1)(C[n]1ncnc1)c(ccc(F)c1)c1F Chemical compound OC(Cc1c[n](Cc2ccccc2)nn1)(C[n]1ncnc1)c(ccc(F)c1)c1F XFYHXHGFFRCGTD-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to the technical field of medicines, in particular to zole antifungal compounds, and a preparation method and application thereof. The compounds have a chemical structural general formula shown in the specifications, wherein R is one or more of hydrogen, C1-4 alkyl, halogen, cyan, nitro, amino and C1-4 alkoxy, and n is an integer ranging from 1 to 5. The compounds have high antifungal activity; and compared with the conventional antifungal medicines clinically applied, the compounds have the advantages of high efficiency, low toxicity, wide antifungal spectrum and the like, so the compounds can be used for preparing antifungal medicines.
Description
Technical field
The present invention relates to medical technical field, is novel azole antifungal compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-substituted benzyl-1H-1,2,3 triazole-4-yls]-2-alcohol compound, and their preparation method and purposes.
Background technology
In recent years, along with the widespread use of Broad spectrum antibiotics, antitumor drug, immunosuppressor, peritoneal dialysis, organ transplantation, radiocurablely generally carry out, and the especially rapid spread of acquired immune deficiency syndrome (AIDS) of immunodeficiency diseases, the sickness rate of the opportunistic deep fungal infections such as Candida albicans, cryptococcus neoformans and aspergillus fumigatus sharply rises.Deep fungal infection has risen to the third-largest communicable disease clinically, and the mankind's life and health in serious threat.The antifungal drug of at present clinical application, mostly exists that toxic side effect is large, narrow antimicrobial spectrum, easily produces the defects such as resistance, effectively antifungal drug particularly anti-deep fungal medicine extremely lack, far can not satisfy the demand.Existing antifungal drug is mainly the propylamine that acts on squalene epoxidase, acts on the nitrogen azole of lanosterol 14a-demethylase, and acts on cell walls and-1, the lipopeptid class of 3-beta glucan synthetic enzyme etc.But so far there are no nitrogen azole compounds 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-substituted benzyl-1H-1,2,3 triazole-4-yls] report of-2-alcohol and anti-mycotic activity thereof.
Summary of the invention
The object of this invention is to provide the nitrogen azole compounds 1-that a class is new (1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-substituted benzyl-1H-1,2,3 triazole-4-yls]-2-alcohol.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
The present invention also has an object to be to provide a purposes of stating compound.
Object of the present invention can reach by following measures:
Novel azole antifungal compound 1-of the present invention (1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-substituted benzyl-1H-1,2,3 triazole-4-yls] chemical structure of general formula of-2-alcohol is as follows:
Wherein,
R is selected from hydrogen, C
1～4alkyl, halogen, cyano group, nitro, amino or C
1～4one or more in alkoxyl group; R can be monosubstituted or polysubstituted, the integer that n is 1～5, and when n is 2 when above, each R can be identical or different.
In compound of the present invention, R is preferably selected from C
1～4alkyl, halogen or C
1～4one or more in alkoxyl group, one or more in further preferred halogen, are most preferably selected from one or more in F, I, Cl or Br.
In compound of the present invention, n is preferably 1,2 or 3, most preferably is 1 (monosubstituted), and now R group can be 2,3 or 4.
In a kind of preferred version, the present invention can be selected from following compound:
Salt of the present invention can be pharmaceutically conventional salt, and it can be further hydrochloride, nitrate, hydrobromate or methane sulfonates.
1-of the present invention (1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-substituted benzyl-1H-1,2,3 triazole-4-yls]-2-alcohol compound can be raceme, can be also R type or S type isomer.
The preparation method of the compounds of this invention, can comprise following reaction,
Wherein, the definition of R and n is described above.This reaction can comprise the steps:
1) there is Friedel-Crafts reaction generation chloro-2 ', the 4 ' difluoro acetophenone of 2-(2) in 2,4 difluorobenzene (1) under the condition of aluminum trichloride (anhydrous) existence with chloroacetyl chloride;
2) compound 2 and triazole, 3-ethyl benzyl ammonium chloride and salt of wormwood are at CH
2cl
2middle 0-5 DEG C reaction, generates 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone (3);
3) intermediate 3 reacts in DMF and tetrahydrofuran (THF) with propargyl bromide and zinc powder, generates 5-(1H-1,2,4-triazol-1-yl)-4-(2,4 difluorobenzene base)-pentyne-2-alcohol intermediate 4;
4) intermediate 4 reacts in methyl-sulphoxide, cupric sulfate pentahydrate and sodium ascorbate with sodium azide, replacement bromobenzyl, generate target compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(1-substituted benzyl-1H-1,2,3 triazole-4-yls)-2-alcohol (5).
In a kind of preferred version, the preparation method of the compounds of this invention is as follows:
1. prepare intermediate 3, reaction scheme is as follows:
2. prepare target compound, reaction scheme is as follows;
Concrete steps are:
1. chloro-2 ', the 4 '-difluoro acetophenone of preparation 2-, intermediate 2
Under the condition of aluminum trichloride (anhydrous) existence, there is Friedel-Crafts reaction with chloroacetyl chloride and generate chloro-2 ', the 4 ' difluoro acetophenone 2 of 2-in 2,4 difluorobenzene (1);
2. preparation 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone, intermediate 3
2 and triazole, 3-ethyl benzyl ammonium chloride (TEBA) and salt of wormwood are at CH
2cl
2middle 0-5 DEG C of reaction 5 hours, then, room temperature reaction 12 hours, generates 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone 3;
3. preparation 5-(1H-1,2,4-triazol-1-yl)-4-(2,4 difluorobenzene base)-pentyne-2-alcohol, intermediate 4
Intermediate (3) and propargyl bromide, zinc powder is at N, in dinethylformamide (DMF) and tetrahydrofuran (THF) (THF), 60 DEG C are reacted 4 hours, generate 5-(1H-1,2,4-triazol-1-yl)-4-(2,4 difluorobenzene base)-pentyne-2-alcohol intermediate 4.
4. prepare target compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-) 1-substituted benzyl-1H-1,2,3 triazole-4-yls)-2-alcohol 5
Intermediate 4 reacts in methyl-sulphoxide, cupric sulfate pentahydrate and sodium ascorbate with sodium azide, replacement bromobenzyl, generate target compound 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(1-substituted benzyl-1H-1,2,3 triazole-4-yls)-2-alcohol 5.
The compounds of this invention passes through pharmacological evaluation, show deep fungal anti-mycotic activity strong, particularly in table 1, listed compound has certain representativeness, compared with the antifungal drug of existing clinical application, there is the advantages such as efficient, low toxicity, anti-fungus spectra be wide, therefore can be used for preparing antifungal drug, particularly anti-candida albicans, cryptococcus neoformans, Candida parapsilosis, Oidium tropicale, trichophyton, Ke Lushi candidiasis, microsporum lanosum or smoke the fungi-medicines such as aspergillus fumigatus.
Preparation method's productive rate of the present invention is high, and compound anti-mycotic efficiency is good, and has the advantages such as efficient, low toxicity, anti-fungus spectra be wide, and the present invention provides new nitrogen azole compounds for preparing antifungal drug.
Embodiment
Below in conjunction with embodiment, the present invention is described in detail.
Embodiment 1: prepare intermediate 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone
1, chloro-2 ', the 4 '-difluoro acetophenone of preparation 2-
Aluminum trichloride (anhydrous) 200g (1.494mol) and m-difluorobenzene 150g (1.30mol) are placed in 1000mL three-necked bottle, under room temperature, stir, slowly drip chloroacetyl chloride 150g (1.30mol), after dropwising, continue under room temperature and stir 30 minutes, slowly be warming up to 45 DEG C, at this temperature, continue to stir 4.5 hours, routinely reaction solution is poured in frozen water, separate out solid, filter; Filtrate extracts at twice with methylene dichloride 800mL, combined dichloromethane extracting solution, be washed to neutrality, anhydrous sodium sulfate drying, filters, after reclaiming solvent, obtain solid, merge gained solid ethyl alcohol recrystallization twice, obtain 2-chlorine 2 ', 4 '-difluoro acetophenone 215g, yield 88.2%, fusing point: 46-48 DEG C.
2, preparation 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone
Triazole 54g (0.4mol), TEBA0.8g, Anhydrous potassium carbonate 82g (0.3mol) are added to 400mLCH
2cl
2in suspension; Chloro-2-2 ', 4 '-difluoro acetophenone 76g (0.4mol) is dissolved in to 60mLCH
2cI
2in, under condition of ice bath, be added dropwise in above-mentioned 400mL suspension, within approximately 2 hours, drip off, drip finish after 0～5 DEG C reaction 5 hours, normal-temperature reaction 24 hours.Then filter filter cake CH
2cl
2wash for several times, collect filtrate, filtrate water is washed 3 times, each 200mL, anhydrous Na
2sO
4dry, steam CH
2cl
2.Residue is dissolved in 200mL anhydrous ethyl acetate, stirs lower dropping concentrated nitric acid, till no longer separating out to yellow solid; Filter, filter cake is washed for several times by a small amount of ethyl acetate, dry, is dissolved in 200mL water, with 30% the NaOH aqueous solution (w/w) adjust pH be 9, separate out solid, filter, be dried to obtain crude product, with normal hexane: 1: 1 recrystallization of ethyl acetate (V/V), obtain compound 76g, yield 41.7%, fusing point: 104～105 DEG C.
Embodiment 2: preparation 5-(1H-1,2,4-triazol-1-yl)-3-(2,4 difluorobenzene base)-pentyne-2-alcohol
Propargyl bromide 5.33g (44.8mmol) is added to 20mL N, dinethylformamide-tetrahydrofuran (THF) mixing solutions (volume ratio DMF: THF=1: 1), add again 5g (22.4mmol) 2-(1H-1,2,4-triazol-1-yl)-2 ', 4 '-difluoro acetophenone, room temperature lower magnetic force stirs, and makes abundant dissolving.Add again 4.36g (66.7mmol) zinc powder (hydrochloric acid with 2%, washed several times with water, vacuum-drying) in batches.Room temperature lower magnetic force stirs, reaction solution boiling after 2-5min, rising temperature of reaction to 60 DEG C after question response liquid stops seething with excitement, magnetic agitation 7h.Reaction solution is poured in 4M hydrochloric acid, ethyl acetate extraction (40mL × 3), ethyl acetate layer washes with water again adjusts PH to 7 left and right, and ethyl acetate layer anhydrous sodium sulfate drying 4h, filters, and decompression is extracted solvent and is obtained product 4g, yield 67.9%.
Embodiment 3: preparation 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(2-fluorophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol (compound 5a in table 1)
In 25mL eggplant-shape bottle, add sodium azide 100mg (1.4mmol), adjacent fluorine bromobenzyl 200mg (1.2mmol), methyl-sulphoxide 15mL, room temperature lower magnetic force stirring reaction 6h.Then add 5-(1H-1,2,4-triazol-1-yl)-3-(2,4 difluorobenzene base)-pentyne-2-alcohol 200mg (0.76mmol), sodium ascorbate 20mg, CuSO
45H
2o 25mg, water 1mL, stirring at room temperature reaction 10min, pours reaction solution in weak ammonia into, ethyl acetate extraction (20mL × 2), dilute hydrochloric acid acidifying (20mL × 2), point water-yielding stratum, water layer Na for ethyl acetate layer
2cO
3adjust PH to 7 left and right, ethyl acetate extraction (20mL × 2), ethyl acetate layer anhydrous sodium sulfate drying 4h, filters, and decompression is extracted solvent and obtained product 1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(2-fluorophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol 206mg, yield 65.5%.(spectroscopic data is in table 1).
Compound 5b in table 1,5c, 5d, 5e, 5f, 5g, 5h, adopts the replacement bromobenzyl of corresponding R group as raw material time prepared by 5i, and method is with embodiment 3.
Enforcement of the present invention is not limited to above embodiment, time prepared by all the other target compounds, adopts the replacement bromobenzyl of corresponding R group as raw material, and method is the same.
In embodiment, agents useful for same is commercially available analytical pure.
The R productive rate of part target compound of the present invention and nucleus magnetic hydrogen spectrum data are in table 1.
R group, productive rate and the nucleus magnetic hydrogen spectrum data sheet of table 1. part of compounds of the present invention
The pharmacological evaluation of the compounds of this invention:
(1) experimental technique: adopt conventional In Vitro Bacteriostasis experimental technique (to refer to: Antimicrob Agents Chemother 1995,39 (5): 1169)
(1) experimental strain
This experiment has selected following 8 kinds of common human body cause illness's standard fungal bacterial strains as screening object:
Deep fungal: Candida albicans, cryptococcus neoformans, Oidium tropicale, Candida parapsilosis;
Superficial mycosis: trichophyton;
Subcutaneous fungi: ulotrichy sporule silk bacterium, Ke Lushi candidiasis, fumigation aspergillus tubigensis.
(2) test method
Bacteria suspension preparation: above-mentioned fungi is cultivated 16 hours through 35 DEG C of YEPD liquid nutrient mediums, twice activation, with blood cell counting plate counting, adjusts bacteria concentration to 1X10 with RPM1640 liquid nutrient medium
4～1X10
5individual/mL.
Liquid preparation: get testing compound of the present invention and be dissolved in methyl-sulphoxide, be made into the medicine storage liquid of 8.0mg/mL, be diluted to 640 μ g/mL with RPM1640 before experiment.
Inoculation: 96 No. 1, orifice plate holes add RPM1640 100 μ l and make blank, 3-12 hole respectively adds bacteria suspension 100 μ l, No. 2 hole adds bacteria suspension 180 μ l and liquid 20 μ l, 10 grades of doubling dilutions of drug level in 2-11 hole, each hole drug level is respectively 64,32,16,8,4,2,1,0.0.5,0.25,0.125 μ l/mL.No. 12 hole does not add liquid, makes positive control.Medicine contrast is fluconazole (FCZ.), itraconazole (ICZ.), KETOKONAZOL (KCZ.), voriconazole (VCZ.) and terbinafine (TRB.).
Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, taking optical density value than positive control hole lower than 80% lowest concentration of drug as minimal inhibitory concentration value (MIC
80).
(2) experimental result
In Vitro Bacteriostasis experimental result is in table 2.
Table 2 part target compound In Vitro Anti fungi minimal inhibitory concentration value (MIC
80, μ g/mL)
Note: C.alb. Candida albicans, C.neo. cryptococcus neoformans, C.par. Candida parapsilosis C.tro. Oidium tropicale, T.rub. trichophyton, C.kru. Ke Lushi candidiasis, M.gyp. microsporum lanosum, A.fum smokes aspergillus fumigatus, KCZ. KETOKONAZOL, FCZ. fluconazole, VCZ. voriconazole, ICZ. itraconazole, TRB. terbinafine.
Compound 5a:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(2-fluorophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5b:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(3-fluorophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5c:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(4-fluorophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5d:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(2-chloro-phenyl-)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5e:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(3-chloro-phenyl-)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5f:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(4-chloro-phenyl-)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5g:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(2-bromophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5h:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(3-bromophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol
Compound 5i:1-(1H-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-[1-(4-bromophenyl)-1H-1,2,3 triazole-4-yls]-2-alcohol
From table 2, the compounds of this invention has good anti-mycotic activity, and wherein multiple compounds are far better than amphotericin B and Terbinafine to the vitro inhibition activity of selected fungi, and therefore the compounds of this invention and its esters can be used for preparing antifungal drug.
Claims (3)
1. azole compounds and salt thereof, chemical structure of general formula is as follows:
Wherein,
2. compound according to claim 1 and salt thereof, is characterized in that described salt is hydrochloride, nitrate, hydrobromate or methane sulfonates.
3. compound claimed in claim 1 and salt thereof are in the application of preparing in antifungal drug; Described fungi is Candida albicans or cryptococcus neoformans.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104817508B (en) * | 2015-03-10 | 2017-12-05 | 中国人民解放军第二军医大学 | A kind of trinitrogenazole alcohol analog derivative and its preparation method and application |
| CN111349050B (en) * | 2020-02-26 | 2022-03-29 | 中国人民解放军海军军医大学 | Triazole CYP51-HDAC double-target antifungal compound and preparation method and application thereof |
| CN112194629B (en) * | 2020-09-18 | 2023-10-24 | 聊城大学 | Phenethyl azole derivative and preparation method and application thereof |
| CN117159570B (en) * | 2023-11-01 | 2024-01-23 | 云南中医药大学 | Application of 6-acyloxy mannose azido glycoside derivative and fluconazole in preparation of drug-resistant candida albicans drugs in combination |
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|---|---|---|---|---|
| CN1188765A (en) * | 1994-02-07 | 1998-07-29 | 卫材株式会社 | Antifungal agent and its preparation method and intermediate |
| CN101573344A (en) * | 2006-12-29 | 2009-11-04 | 大熊制药株式会社 | Antifungal triazole derivatives, method for the preparation thereof and pharmaceutical composition containing same |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1188765A (en) * | 1994-02-07 | 1998-07-29 | 卫材株式会社 | Antifungal agent and its preparation method and intermediate |
| CN101573344A (en) * | 2006-12-29 | 2009-11-04 | 大熊制药株式会社 | Antifungal triazole derivatives, method for the preparation thereof and pharmaceutical composition containing same |
Non-Patent Citations (2)
| Title |
|---|
| 《新型氮唑类化合物的设计、合成》;俞世冲;《中国博士学位论文全文数据库》;20110901;第1-17页 * |
| 俞世冲.《新型氮唑类化合物的设计、合成》.《中国博士学位论文全文数据库》.2011,第1-17页. |
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