CN101792437B - Tolyltriazole derivatives, preparation method thereof and use thereof - Google Patents

Abstract

The invention belongs to the technical field of antifungal medicaments and provides tolyltriazole derivatives having a structure shown as a general formula (1) and pharmaceutically acceptable salts thereof. In the general formula (1), R1, R2 and R3 are defined in the description. The invention also relates to a method for preparing the compounds and also discloses medicinal compositions using the compounds or the pharmaceutically acceptable salts thereof as active ingredients and the use of the medicinal compositions as antifungal medicaments.

Description

The verivate of tolyltriazole, Preparation Method And The Use

Technical field

The invention belongs to medical technical field, or rather, relate to one type of compound, its preparation method, compsn and application with anti-mycotic activity.

Background technology

Fungi infestation is invaded position difference according to it can be divided into two types in superficial part and deep.Mycotic infection of superficial part is a kind of common disease, frequently-occurring disease, is more common in skin and first portion; What deep fungal was more common is Candida albicans and Cryptococcus neoformans, though the low harm of sickness rate is bigger, but infects threat to life when serious.Particularly in recent decades; Along with being widely used of broad-spectrum antibiotics, cortin, antitumor drug and immunosuppressor; Extensively carrying out of radiotherapy and organ transplantation, generally the carrying out of conduit and intubate, and especially AIDS patient's increase rapidly of immunodeficient patient; Destroyed the symbiotic relationship of normal flora; Human body is reduced the resistibility of fungi, thus cause fungi infestation particularly deep fungal infection rise significantly, and become one of major disease main causes of death such as AIDS and tumour.

In the existing antifungal drug, azole drug is to have a type of better prospect, has obtained clinically using widely.The nitrogen azole drug is especially comparatively desirable to the curative effect of deep fungal infection, so be the focus of studying in the antifungal drug always.They can suppress fungal cell's cytochrome p 450 3A and rely on C14-α-demethylase (ERG11), and this enzyme is the key enzyme that changes into lanosterol ergosterol.Its mechanism of action is a blocking-up substrate hydroxylation reaction, and the interior methylated sterol of lanosterol 14-of fungus body is accumulated in a large number, and ergosterol is synthetic to be lacked, and causes many enzyme activity changes on membrane permeability and the film, thereby suppresses fungi growth.

With fluconazole (Fluconazole, FCZ) and itraconazole (Itraconazole is the choice drug of treating at present deep fungal infection clinically for the Research of Triazole Antifungal Agents of representative ICZ).(Voriconazole VOR) is a kind of novel antifungal drug in triazole class to Vorionazole, is the fluconazole verivate.Add 1 methyl in its structure on the propyl group skeleton and replaced 1 triazole ring in the fluconazole with 1 fluorinated pyrimidine ring.Vorionazole through the fluconazole structure of modification is obtained is not only wider than former medicine anti-fungus spectra, and anti-mycotic activity is also stronger.

But still there are some problems in the Research of Triazole Antifungal Agents of present clinical first-selection: the antimicrobial spectrum relative narrower of fluconazole, and very low to the activity of fungies such as aspergillus tubigensis, and be prone to produce resistance; Itraconazole exists oral administration biaavailability unstable, problems such as GI irritation.Though Vorionazole toxicity is less, also be prone to produce resistance.Report from clinical isolating 851 strain Candida albicanss 37.2% pair of fluconazole resistance is arranged, 47.6% pair of itraconazole resistance.

Limitation to existing medicine exists except the preparation of optimizing the existing medicine of improvement, makes the research of novel anti fungi-medicine become one of hot fields of global new drug development.In addition, the interaction between medicine makes the deep fungal infection treatment become complicated more, therefore, and the clinical novel deep antifungal drug that presses for high-efficiency low-toxicity, has a broad antifungal spectrum, highly selective.

Linezolid is a kind of novel oxazolidine ketone antimicrobial drug, has broad spectrum antibacterial function, and antimicrobial spectrum comprises gram positive organism and anerobes, especially the multidrug resistant gram-positive bacteria is had very strong restraining effect.It mainly brings into play anti-microbial activity through suppressing bacterioprotein synthetic earliest stages, and does not have cross resistance with other antibacterials.Document EP 311090, EP609905, WO93/23384, WO93/09103 has report among the WO90/02744.Qi oxazole ring has been proved to be the crucial pharmacophoric group into anti-microbial activity.

The contriver finds that the compound among the present invention has good anti-mycotic activity in grinding the process of studying carefully oxazolidine ketone antimicrobial compounds, their chemical structure is different from any existing antifungal drug, is expected to become novel antifungal drug.

Summary of the invention

One object of the present invention is, in order to overcome the deficiency of existing triazole compound, development novel anti fungi-medicine discloses one and had three azo-cycles with the compound of oxazole ring and pharmaceutical salts thereof roughly the same the time.

Another object of the present invention is, discloses the preparation method of compound of Formula I and pharmaceutical salts thereof.

A further object of the present invention is, discloses the pharmaceutical composition that compound of Formula I and pharmaceutical salts thereof are main active ingredient.

A further object of the invention is, discloses compound of Formula I and pharmaceutical salts thereof, as the purposes of antifungal drug aspect.

Combine goal of the invention that content of the present invention is specifically described at present.

The compound and the pharmacy acceptable salt thereof of general formula I structure involved in the present invention are following:

Wherein:

R ¹Be hydrogen or fluorine;

R ²For

Wherein B is a nitrogen when A is carbon, and B is a carbon when A is nitrogen;

R ³For: (a)

R wherein ⁴, R ⁵Be fluorine or chlorine;

(b)

R wherein ⁴, R ⁵Be fluorine or chlorine;

(c)

R wherein ⁶Be hydrogen or itrile group.

The compound with formula I structure or its pharmacy acceptable salt among the present invention, wherein part of compounds is:

I-A-1) 3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-{ [1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazole-1-yl) oxyethyl group] methyl } oxazolidine-2-ketone;

I-A-2) 3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-{ [1-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazole-1-yl) oxyethyl group] methyl } oxazolidine-2-ketone;

I-B-1) 3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-{{{2-(2,4 difluorobenzene base)-2-[(1H-1,2,4-triazole-1-yl) methyl]-1,3-dioxolanyl-4-yl } methoxyl group } methyl } oxazolidine-2-ketone;

I-B-2) 3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-{{{2-(2,4 dichloro benzene base)-2-[(1H-1,2,4-triazole-1-yl) methyl]-1,3-dioxolanyl-4-yl } methoxyl group } methyl } oxazolidine-2-ketone;

I-C-1) 3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-[(1H-1,2,4-triazole-1-yl) methyl] oxazolidine-2-ketone;

I-C-2) 3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-[(3-itrile group-1H-1,2,4-triazole-1-yl) methyl] oxazolidine-2-ketone.

Compound or its pharmacy acceptable salt with formula I structure of the present invention means: the salt that The compounds of this invention is become with mineral acid, organic acid.Wherein preferred especially salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; Tosilate, PHENRAMINE MALEATE, benzoate, SUMATRIPTAN SUCCINATE, tartrate, Citrate trianion, fumarate, taurate or the like.

Persons skilled in the art referenced patent CN 200710060531.X; US 4404216; EP 0096569; US 4335125, article Journal of Medicinal Chemistry, 1996,39 (3): 673～378; Blancafort, P., Sweetman, A.J., Drugs Fut., 1979,4 (7): 496, can synthesize midbody ( 1)～( 15).The synthetic route chart Succinct representation is following:

Wherein X is a chlorine or bromine, A, B, R ¹, R ⁴, R ⁵Define ditto said.

With midbody ( 4) be dissolved among the DMF, add the DMF solution of sodium hydride, stir, the adding midbody ( 10), reaction can make I-A series target compound; Midbody under the same reaction conditions ( 4) and midbody ( 15) reaction can make I-B series target compound; Wherein a kind of with methylene dichloride, trichloromethane, toluene, acetone, methyl alcohol or ethanol is reaction solvent, and midbody under the situation that one or both acid binding agents exist in triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium hydrogencarbonate, saleratus, Pottasium Hydroxide or sodium hydroxide ( 5) and R ⁶Substituted triazole compound reaction can make I-C series target compound.The reaction scheme Succinct representation is following:

Wherein A, B, R ¹, R ⁴, R ⁵, R ⁶Define ditto said.

Reaction is made various midbodys or products therefrom be dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, dropping inorganic acid or organic acid solution are processed pharmacy acceptable salt.

Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, the dripping hydrochloric acid diethyl ether solution is processed hydrochloride to pH=2 under ice-water bath; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, and adding and wait a mole toxilic acid, heated and stirred gets its PHENRAMINE MALEATE; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ETHYLE ACETATE or the DMSO, drips concentrated sulfuric acid solution down to pH=3, process vitriol in ice-water bath, or the like.

This compounds is effective for the human fungal infectious disease of treatment.Although compound of the present invention can be without the direct administration of any preparation, described all cpds preferably uses with the form of pharmaceutical prepn, and route of administration can be non-enteron aisle approach (like vein, muscle administration) and oral administration.

The preparation of pharmaceutical compositions method of The compounds of this invention is following: use standard and conventional technology; Acceptable solid or liquid vehicle are combined, and make it at random with technology of pharmaceutics on acceptable auxiliary and vehicle combine to be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, Ucar 35, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension-s for example injection, pulvis or the like.

The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of used compound or concentration are regulated in the scope of a broad.Usually, the scope of active compound amount is 0.05%～90% (weight) of compsn, and another preferred range is 0.05%-70%.

Compound or its pharmacy acceptable salt with formula I structure of the present invention has the obvious suppression effect to fungi.Adopt standard micro-dilution method (NCCLSM-27A) to measure its minimum inhibitory concentration below, further specify the external bacteriostatic activity of The compounds of this invention clinical several frequently seen fungi.Concentration (the MIC that suppresses selected fungi 90% growth with target compound ₉₀) as judging terminal point.

Test strain: 5 kinds of deep fungals: Candida albicans (Candida albicans; C.alb.) ATCC76615, Cryptococcus neoformans (Cryptococcus neoformans; C.neo.) ATCC 32609, Oidium tropicale (Candida tropicalis; C.tro.) ATCC 12034, Candida parapsilosis (Candidaparopsilosis, C.par.) ATCC 22019, smoke aspergillus fumigatus (Aspergillus fumigatus, A.fum.).3 kinds of superficial fungis: trichophyton (Trichophyton rubrum, T.rub.), sporotrichum schenckii (Sporothrix schenckii, S.sch.) and fonsecaea pedrosoi (Fonsecaeapedrosoi, F.ped.).Above bacterial strain provides by our unit pharmacological experiment chamber.

Test drug: The compounds of this invention (I-A-1～I-C-2), select for use itraconazole (ICZ), DMSO 99.8MIN. (DMSO), AR level (the triumphant letter chemical industry in Tianjin ltd) as positive control drug (mesophytization ltd is closed in Wuhan).ELIASA, BIO-RAD680.

TP: with RPMI-1640 (Sigma) is nutrient solution, and it is 1 * 10 that experimental strain is made into concentration ⁴～1 * 10 ⁵The suspension of/ml.Compound with sterile purified water and DMSO dissolving, is processed medicine storage liquid (6400 μ g/ml), and-20 ℃ of preservations are for use.Be diluted to 640 μ g/ml with RPMI-1640 during use, establish solvent control and blank simultaneously.Get the flat microtest plate in aseptic 96 holes; No. 1 hole adds RPMI-1640100 μ L and makes blank, and No. 2 the hole adds bacteria suspension 180 μ L and soup 20 μ L, and the 3-12 hole respectively adds bacteria suspension 100 μ L; The 10 grades of doubling dilutions in 2-11 hole, 100 μ L of sucking-off abandon from No. 11 holes at last.Each hole drug level is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ gmL ^-1No. 12 the hole does not add soup, makes the medicine negative control.Candida is observed the growing state of 3d in 35 ℃ of constant temperature culture 24h.Cryptococcus neoformans is measured the result after cultivating 72h, and 26 ℃ of constant temperature culture of superficial mycosis are observed the growing state in 1 week.Analyze with ELIASA, compare with the medicine negative control hole, suppressing pairing lowest drug concentration with 90% is its minimal inhibitory concentration value (MIC ₉₀).

In?vitro?antifungal?activities?of?compounds(MIC ₉₀，μg·mL ^-1)

Visible through external antibacterial test experiments result; All target compounds all have anti-mycotic activity to a certain degree to 8 kinds of pathomycetes; Basically it is quite active to reach clinical treatment deep fungal medicine itraconazole, and active even be superior to contrasting medicine to the inhibition of indivedual bacterial strains.Especially to clinically the most common with produce drug-fast monilial infection on a large scale and have stronger external activity.This type of total appraisal new compound has wide spectrum, highly active advantage, has further further investigation and is worth.

Below further through the restraining effect of minimal inhibitory concentration (MIC) determination test explanation The compounds of this invention to bacterium.

Substratum: microorganism identification medium pH 7.9 ± 0.1, Beijing three medicine scientific and technological development Company products; Bacterial classification: standard gold staphylococcus aureus CMCC26003, color standard white staphylococcus CMCC26101, standard faecalis CMCC32220, standard staphylococcus epidermidis CMCC26069, above bacterial classification all purchase in Chinese pharmaceutical biological product and identify institute.

TP:, adopt doubling dilution with the positive contrast medicine of Linezolid.Add bacterium liquid and broth culture contrast in first 1 hole, 12 holes respectively at already sterilised 96 orifice plates; Then in the 2-11 hole, from the lower concentration to the high density, add above-mentioned sample solution 0.25～128 μ gmL successively with the substratum doubling dilution with micro-adjustable pipette ^-1, every hole 100 μ L make that sample concentration is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ gmL in each hole ^-1Place and shake 1min on the vibrator; Make in the hole behind the abundant mixing of solution; Microwell plate is added a cover blended rubber paper sealing and is hatched the evaporation in the process with minimizing, in 37 ℃ of incubators, hatches 18h, and naked-eye observation does not have the contained lowest drug concentration in bacterial growth hole and is minimal inhibitory concentration.

Invitro?antibacterial?activities?of?compounds(MIC，μg·mL ^-1)

Visible through external antibacterial test experiments result, target compound has certain restraining effect to streptococcus aureus, Staphylococcus albus, faecalis and staphylococcus epidermidis.

Embodiment

Below in conjunction with embodiment the present invention is done further explanation, it is indicative that embodiment is merely, and means that never it limits scope of the present invention by any way.Described compound is through performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as ir spectra (IR), nuclear magnetic resonance spectrum ( ¹HNMR, ¹³C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.

Reference implementation example 1:

Midbody ( 1-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 1-fluoro-4-oil of mirbane 14.1g (0.1mol) and 45mL exsiccant ETHYLE ACETATE, stir.Drip the 16mL triethylamine, add 1,2 then, 3-triazole 6.9g (0.1mol) is heated to the about 6h of back flow reaction (the flaggy demonstration reacts completely).Stopped reaction, the reaction solution cooling, the suitable quantity of water washing, layering, the organic layer drying, solvent is to the greatest extent steamed in filtration, decompression, gets bullion, with acetone-crystal's system, gets yellow solid product (HPLC:98.4%).

With reference to the method for reference implementation example 1, persons skilled in the art can conveniently make midbody ( 1-2).

Reference implementation example 2:

Midbody ( 2-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 19.0g (0.1mol) midbody ( 1-1), is dissolved in 150mL acetone, stirs adding ammonium formate 18.8g down.After dissolving fully under 45～50 ℃ of stirrings, add an amount of palladium carbon (10%), the about 4h of insulation reaction (the flaggy demonstration reacts completely).Stopped reaction filters, and gets filtrating.

With reference to the method for reference implementation example 2, persons skilled in the art can conveniently make midbody ( 2-2).

Reference implementation example 3:

Midbody ( 3-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add midbody ( 2-1) solution stirs adding 224mL sodium hydrogen carbonate solution (5%) down, slowly drips the 16.6g chloroformic acid benzyl ester, has flocks to generate (the flaggy demonstration reacts completely).Stopped reaction filters, and filter cake is used petroleum ether, and proper amount of acetone-crystal's system gets light yellow solid product (HPLC:97.6%).

With reference to the method for reference implementation example 3, persons skilled in the art can conveniently make midbody ( 3-2).

Reference implementation example 4:

Midbody ( 4-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 2.9g (0.01mol) midbody ( 3-1) and the 55mL THF, then is cooled to-40 ℃, stirs and slowly drip 6mL n-Butyl Lithium/hexane solution down, stir 1h.Continue to drip 2mL Glycidyl butyrate (with the dilution of 10mL THF), the about 1.5h of stirring reaction.Stop cooling, continue to stir 2h, until rising to room temperature (the flaggy demonstration reacts completely).Add 1.1mL saturated ammonium chloride solution, 27mL zero(ppm) water, stir layering, (3 * 15mL) extractions merge organic layer, with an amount of saturated common salt water washing, drying to water layer with ETHYLE ACETATE.Filter, remove solvent under reduced pressure, get the faint yellow solid product, sherwood oil-re-crystallizing in ethyl acetate gets light yellow solid product (HPLC:98.0%).

With reference to the method for reference implementation example 4, persons skilled in the art can conveniently make midbody ( 4-2).

Reference implementation example 5:

Midbody ( 5-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 2.6g (0.01mol) midbody ( 4-1), be added dropwise to excessive thionyl chloride under the ice-water bath cooling, drip off, the refluxing and stirring reaction waits not produce acid tail gas stopped reaction.Remove excessive thionyl chloride under reduced pressure, the residue cut be midbody ( 5-1).

With reference to the method for reference implementation example 5, persons skilled in the art can conveniently make midbody ( 5-2).

Reference implementation example 6:

Midbody ( 6-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 2-chloro-1-(2,4 difluorobenzene base) ethyl ketone 19.1g (0.1mol), add the 80mL absolute ethyl alcohol again, stir and dissolve clearly.12g (0.3mol) Peng Qinghuana is dissolved in the 50mL zero(ppm) water, slowly goes into reaction system under the ice-water bath, finish the about 1.5h of reaction under room temperature (the flaggy demonstration reacts completely).Stopped reaction adds dilute hydrochloric acid solution, removes ethanol under reduced pressure, with chloroform extraction 3 times, and saturated aqueous sodium carbonate washing, organic layer drying.Remove solvent under reduced pressure, get white solid product.

With reference to the method for reference implementation example 6, persons skilled in the art can conveniently make midbody ( 6-2).

Reference implementation example 7:

Midbody ( 7-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 19.3g (0.1mol) midbody ( 6-1), adds 60mL toluene again, stir and dissolve clearly.The ice bath cooling adds the 11g triethylamine down, then the 14.1g Benzoyl chloride 99min. is slowly splashed into, and dropwises continued insulation reaction 2h (the flaggy demonstration reacts completely).Reaction solution is cooled to room temperature, use (toluene layer is dry for 3 * 60mL) distilled water washs, separatory, filtration, and filtrate decompression is steamed and is removed toluene, gets light yellow oily product.

With reference to the method for reference implementation example 7, persons skilled in the art can conveniently make midbody ( 7-2).

Reference implementation example 8:

Midbody ( 8-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 29.7g (0.1mol) midbody ( 7-1) and the 150mL chloroform.Stir adding 6.9g (0.1mol) 1,2 down, the 4-triazole is slowly gone into the 20.2g triethylamine subsequently, finishes the about 4h of back flow reaction (the flaggy demonstration reacts completely).Stopped reaction, water washing reaction liquid 3 times, drying.Remove solvent under reduced pressure, get yellow solid product (HPLC:98.6%).

With reference to the method for reference implementation example 8, persons skilled in the art can conveniently make midbody ( 8-2).

Reference implementation example 9:

Midbody ( 9-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 32.9g (0.1mol) midbody ( 8-1) and 80mL ethanol, stir dissolve clear.Add 38% sodium hydroxide solution again and react about 0.5h (the flaggy demonstration reacts completely) down in reflux state.Stopped reaction removes ethanol under reduced pressure, adds the 80mL methylene dichloride, layering, and extraction, the water washing dichloromethane layer, drying is filtered.Remove solvent under reduced pressure, get white solid product (HPLC:98.9%).

With reference to the method for reference implementation example 9, persons skilled in the art can conveniently make midbody ( 9-2).

Reference implementation example 10:

Midbody ( 10-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 2.3g (0.01mol) midbody ( 9-1), add 20mL toluene again, the anhydrous piperidines of 1mL stirs and dissolves clearly.Slowly the toluene solution (the 2.2g Tosyl chloride is dissolved in the 10mL toluene) of Tosyl chloride is added in the reaction system down in the ice bath cooling.Finish the about 5h of reaction under room temperature (the flaggy demonstration reacts completely).Stopped reaction filters, and filtrate decompression is steamed and removed toluene, gets yellow solid product, petroleum ether-ethyl acetate recrystallization (HPLC:98.0%).

With reference to the method for reference implementation example 10, persons skilled in the art can conveniently make midbody ( 10-2).

Reference implementation example 11:

Midbody ( 11-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 2-chloro-1-(2,4 difluorobenzene base) ethyl ketone 19.1g (0.1mol), add 100mL toluene again, stir and dissolve clearly.Then add 11g (0.12mol) glycerine successively, 20mL propyl carbinol and 0.6g tosic acid reflux and also to divide the water reaction, treat the branch water back stopped reaction that finishes.Reaction solution is cooled to room temperature, use (toluene layer is dry for 3 * 150mL) distilled water washs, separatory, filtration, and filtrate decompression is steamed and is removed toluene, gets white solid product, re-crystallizing in ethyl acetate (HPLC:98.5%).

With reference to the method for reference implementation example 11, persons skilled in the art can conveniently make midbody ( 11-2).

Reference implementation example 12:

Midbody ( 12-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 26.5g (0.1mol) midbody (11-1), add 100mL toluene again, stir and dissolve clearly.The ice bath cooling adds the 11g triethylamine down, then the 14.1g Benzoyl chloride 99min. is slowly splashed into, and dropwises continued insulation reaction 3h (the flaggy demonstration reacts completely).Reaction solution is cooled to room temperature, use (toluene layer is dry for 3 * 150mL) distilled water washs, separatory, filtration, and filtrate decompression is steamed and is removed toluene, gets light yellow oily product.

With reference to the method for reference implementation example 12, persons skilled in the art can conveniently make midbody ( 12-2).

Reference implementation example 13:

Midbody ( 13-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 36.9g (0.1mol) midbody ( 12-1) and the 150mL chloroform.Stir adding 6.9g (0.1mol) 1,2 down, the 4-triazole adds the 20.2g triethylamine subsequently, finishes the about 6h of back flow reaction (the flaggy demonstration reacts completely).Stopped reaction, water washing reaction liquid 3 times, drying is filtered.Remove solvent under reduced pressure, get yellow solid product (HPLC:97.2%).

With reference to the method for reference implementation example 13, persons skilled in the art can conveniently make midbody ( 13-2).

Reference implementation example 14:

Midbody ( 14-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 40.0g (0.1mol) midbody ( 13-1) and 100mL ethanol, stir dissolve clear.Add 38% sodium hydroxide solution again and react about 0.5h (the flaggy demonstration reacts completely) down in reflux state.Stopped reaction removes ethanol under reduced pressure, adds the 100mL methylene dichloride, layering, and extraction, the water washing dichloromethane layer, drying is filtered.Remove solvent under reduced pressure, get white yellow solid product (HPLC:98.9%).

With reference to the method for reference implementation example 14, persons skilled in the art can conveniently make midbody ( 14-2).

Reference implementation example 15:

Midbody ( 15-1) preparation

In the reaction flask that stirring, condensing surface, TM are housed, add 3.0g (0.01mol) midbody ( 13-1), add 20mL toluene again, the anhydrous piperidines of 1mL stirs and dissolves clearly.Slowly the toluene solution (the 2.2g Tosyl chloride is dissolved in the 10mL toluene) of Tosyl chloride is added reaction system down in the ice bath cooling.Finish the about 6h of reaction under room temperature (the flaggy demonstration reacts completely).Stopped reaction filters, and filtrate decompression is steamed and removed toluene, gets the light yellow solid product, sherwood oil-re-crystallizing in ethyl acetate (HPLC:98.4%).

With reference to the method for reference implementation example 15, persons skilled in the art can conveniently make midbody ( 15-2).

Embodiment 1:

3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-{ [1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazole-1-yl) oxyethyl group] methyl } oxazolidine-2-ketone (compound I-A-1)

In the reaction flask that stirring, condensing surface, TM are housed, add 2.6g (0.01mol) midbody ( 4-1) and 20mL DMF, stir make dissolve clear.The DMF solution that adds 0.6g (0.012mol) sodium hydride again continues to stir.Adding 3.8g (0.01mol) midbody ( 10-1), continues reaction 4h (the flaggy demonstration reacts completely) down in 80 ℃.Reaction solution is cooled to room temperature, adds suitable quantity of water, with dichloromethane extraction for several times, merge organic layer, wash to pH be 7, anhydrous sodium sulfate drying.Filter, solvent is to the greatest extent steamed in decompression, and cooling is placed, and separates out crystallization, and the absolute ethyl alcohol recrystallization promptly gets pale brown look solid product (HPLC:98.3%). ¹H?NMR(DMSO-d ₆，400MHz)δ：3.08～3.16(m，2H)，3.34～3.49(m，2H)，4.21～4.29(m，1H)，4.38～4.46(m，2H)，4.71(m，1H)，6.68～6.73(m，2H)，6.81～6.87(m，1H)，7.06～7.20(m，2H)，7.49～7.56(d，2H)，7.70～7.75(m，2H)，7.88～7.91(d，2H)。MS，m/Z：468.16[M+H] ⁺。

Embodiment 2:

3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-{ [1-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazole-1-yl) oxyethyl group] methyl } oxazolidine-2-ketone (compound I-A-2)

With reference to the method for embodiment 1, with midbody ( 4-2) and midbody ( 10-2) react, can make The compounds of this invention I-A-2, (HPLC:98.8%).MS，m/Z：518.09[M+H] ⁺。

Embodiment 3:

3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-{{{2-(2,4 difluorobenzene base)-2-[(1H-1,2,4-triazole-1-yl) methyl]-1,3-dioxolanyl-4-yl } methoxyl group } methyl } oxazolidine-2-ketone (compound I-B-1)

With reference to the method for embodiment 1, with midbody ( 4-1) and midbody ( 15-1) reacts, can make The compounds of this invention I-B-1, (HPLC:99.2%).MS，m/Z：540.17[M+H] ⁺。

Embodiment 4:

3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-{{{2-(2,4 dichloro benzene base)-2-[(1H-1,2,4-triazole-1-yl) methyl]-1,3-dioxolanyl-4-yl } methoxyl group } methyl } oxazolidine-2-ketone (compound I-B-2)

With reference to the method for embodiment 1, with midbody ( 4-2) and midbody ( 15-2) react, can make The compounds of this invention I-B-2, (HPLC:98.5%).MS，m/Z：590.10[M+H] ⁺。

Embodiment 5:

3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-[(1H-1,2,4-triazole-1-yl) methyl] oxazolidine-2-ketone (compound I-C-1)

Adding 2.8g midbody in the reaction flask that stirring, condensing surface, TM are housed ( 5-1) and the 10mL methylene dichloride, stirs and add Anhydrous potassium carbonate 2.76g down.With 1,2,4-triazole 0.7g adds reaction system in batches.Add, continue reaction 6h (the flaggy demonstration reacts completely) down in reflux temperature.Filter, with 3 * 15mL water washing filtrating, obtain dichloromethane layer, use the SODIUM SULPHATE ANHYDROUS 99PCT thorough drying, filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets orange/yellow solid product (HPLC:98.8%). ¹H?NMR(DMSO-d ₆，400MHz)δ：3.14～3.21(m，2H)，4.36～4.44(m，1H)，4.53～4.58(m，2H)，6.70～6.75(d，2H)，6.83～6.90(d，2H)，7.70～7.75(m，2H)，7.98～8.01(m，1H)，8.33～8.36(m，1H)。MS，m/Z：312.11[M+H] ⁺。

Embodiment 6:

3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-[(3-itrile group-1H-1,2,4-triazole-1-yl) methyl] oxazolidine-2-ketone (compound I-C-2)

With reference to the method for embodiment 5, with midbody ( 5-1) and 3-itrile group-1,2, the 4-triazole reacts, and can make The compounds of this invention I-C-2, (HPLC:99.1%).MS，m/Z：355.11[M+H] ⁺。

Embodiment 7:

Compound I-A-1 becomes hydrochloride: get I-A-1 solid product 1.5g, be dissolved in the 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 ℃, and dripping 11.1% hydrochloric acid diethyl ether solution pH is 2, continues at stir about 1h under the ice-water bath.Filter, get light yellow solid.

Embodiment 8:

Compound I-B-2 becomes PHENRAMINE MALEATE: get I-B-2 solid product 2.0g, be dissolved in the 15mL absolute ethyl alcohol.Be heated to the back adding that refluxes and wait a mole toxilic acid, continue at the about 3h of stirring reaction down that refluxes.Reaction finishes, and under room temperature, leaves standstill 24h.Filter, get light yellow solid.

Embodiment 9:

Compound I-C-1 becomes vitriol: get I-C-1 solid product 1.7g, be dissolved in the 20mL anhydrous methanol.Ice-water bath is cooled to 5 ℃, and dripping concentrated sulfuric acid solution pH is 3, continues at stir about 2h under the ice-water bath.Filter, get yellow solid.

For the pharmaceutical composition of triazole class verivate of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, said embodiment only is used for explanation, rather than is used to limit scope of the present invention.Said preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment 1-9.

Embodiment 10:

Prepare hard gelatin capsule with following compositions:

Consumption/capsule

Compound I-A-2 40mg

Pregelatinized Starch 100mg

Prist 4mg

Sodium starch glycolate 10mg

Magnesium Stearate 20mg

10% polyvidone ethanolic soln is an amount of

Preparation technology: supplementary material is dry in advance, and it is subsequent use to cross 100 sieves.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieves three times, add an amount of 10% polyvidone ethanol (95%) solution system softwood, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the whole grain of 16 mesh sieves, are packed in the hard gelatin capsule.

Embodiment 11:

Prepare tablet with following compositions:

Consumption/sheet

Compound I-B-1 60mg

Starch 45mg

Microcrystalline Cellulose 40mg

CMS sodium salt 4.5mg

Magnesium Stearate 1mg

Talcum powder 1mg

Prist 3mg

Preparation technology: supplementary material is dry in advance, and it is subsequent use to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material; Cross 20 sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the arrangement of 16 mesh sieves; Measure midbody content, mix compressing tablet on tabletting machine.

Embodiment 12:

The preparation of injection liquid:

The PHENRAMINE MALEATE 50mg of compound I-B-2

Ucar 35 100mg

Polysorbate 80 is an amount of

Zero(ppm) water 300mL

Preparing method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and Ucar 35, add medicinal basic adjusting pH value 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.

Embodiment 13:

The preparation of injection lyophilized powder:

The hydrochloride 45mg of compound I-A-1

Medicinal basic 0.1-7.0%

N.F,USP MANNITOL 55-80%

Preparing method: get activeconstituents and add water for injection, regulate pH value 4～8 with medicinal basic and make its dissolving.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrating is carried out packing, adopts freeze-drying, makes loose block, seals, and promptly gets.

Claims (6)

1. the compound or its pharmacy acceptable salt that have formula I structure:

Wherein:

R ¹Be hydrogen or fluorine;

R ²For

Wherein B is a nitrogen when A is carbon, and B is a carbon when A is nitrogen;

R ³For:

R wherein ⁴, R ⁵Be fluorine or chlorine;

R wherein ⁴, R ⁵Be fluorine or chlorine;

R wherein ⁶Be hydrogen or itrile group.

2. the compound with formula I structure or its pharmacy acceptable salt described in claim 1, representation compound is following:

I-A-1) 3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-{ [1-(2,4 difluorobenzene base)-2-(1H-1,2,4-triazole-1-yl) oxyethyl group] methyl } oxazolidine-2-ketone;

I-A-2) 3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-{ [1-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazole-1-yl) oxyethyl group] methyl } oxazolidine-2-ketone;

I-B-1) 3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-{{{2-(2,4 difluorobenzene base)-2-[(1H-1,2,4-triazole-1-yl) methyl]-1,3-dioxolanyl-4-yl } methoxyl group } methyl } oxazolidine-2-ketone;

I-B-2) 3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-{{{2-(2,4 dichloro benzene base)-2-[(1H-1,2,4-triazole-1-yl) methyl]-1,3-dioxolanyl-4-yl } methoxyl group } methyl } oxazolidine-2-ketone;

I-C-1) 3-[4-(1H-1,2,3-triazole-1-yl) phenyl]-5-[(1H-1,2,4-triazole-1-yl) methyl] oxazolidine-2-ketone;

I-C-2) 3-[3-fluoro-4-(1H-1,2,4-triazole-1-yl) phenyl]-5-[(3-itrile group-1H-1,2,4-triazole-1-yl) methyl] oxazolidine-2-ketone.

3. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1, its pharmacy acceptable salt refers to the salt that formula I compound is become with mineral acid, organic acid.

4. the compound with formula I structure or its pharmacy acceptable salt described in claim 3, wherein preferred especially salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, PHENRAMINE MALEATE, benzoate, SUMATRIPTAN SUCCINATE, tartrate, Citrate trianion, fumarate, taurate.

5. one kind has the anti-fungal activity medicaments compsn, it comprise the treatment significant quantity like each described compound or its pharmacy acceptable salt and one or more pharmaceutical excipient of claim 1～4 with formula I structure.

Like each formula I compound in the claim 1～4 in the application of preparation aspect the antifungal drug.