CN103145732A - Antifungal derivatives of piperazine, as well as preparation method and application thereof - Google Patents
Antifungal derivatives of piperazine, as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of antifungal medicines, and provides piperazine derivatives with structures as shown in a formula I, and pharmaceutically acceptable salts of the piperazine derivatives. The definition of the R1 is in line with the description of the specifications. The invention also relates to a preparation method of the compounds, and also discloses pharmaceutical compositions which adopt the compounds or the pharmaceutically acceptable salts as the effective and active components, and application of the compounds or the pharmaceutically acceptable salts in service of antifungal medicines.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to compound, its preparation method, composition and application that a class has anti-mycotic activity.
Background technology
Fungi infestation is invaded the position difference according to it can be divided into superficial part and deep two classes.Mycotic infection of superficial part is a kind of common disease, frequently-occurring disease, is more common in skin and first section; What deep fungal was more common is Candida albicans and Cryptococcus neoformans, though the low harm of sickness rate is larger, but threat to life when infection is 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 carrying out of conduit and intubate, and especially AIDS patient's increase rapidly of immune deficiency patient, destroyed the symbiotic relationship of normal flora, human body is reduced the resistibility of fungi, thereby cause fungi infestation particularly deep fungal infection significantly rise, and become one of major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.
In existing antifungal drug, the nitrogen azole drug has obtained using widely clinically.The nitrogen azole drug is especially comparatively desirable to the curative effect of deep fungal infection, so be the focus in antifungal drug research always.Treat clinically at present the choice drug of deep fungal infection, mainly contain the glyoxaline compound take KETOKONAZOL (Ketoconazole), miconazole (Miconazole), tioconazole (Tioconazole) as representative, and the Research of Triazole Antifungal Agents take fluconazole (Fluconazole), itraconazole (Itraconazole) and voriconazole (Voriconazole) as representative.But along with long-term widespread use, engender the Resistant strain to existing nitrogen azole drug, and the trend of showed increased is arranged.Have been reported title Candida albicans B41628 to existing multi-medicament resistance, the resistance problem makes the mycosis control face more stern challenge.Find simultaneously existing medicine in clinical large-scale experiment for many years, mostly have to a certain degree toxic side effect such as hepatic disorder, gi tract infringement, fash etc., cause its clinical application to be restricted.
The limitation that exists for existing medicine is as narrow antimicrobial spectrum, resistance is serious, bioavailability is low, the stronger problems such as toxic side effect are arranged.Except the preparation of optimizing the existing medicine of improvement, make novel antifungal drugs research become one of hot fields of global new drug development.In addition, the interaction between medicine makes Therapy of Invasive Fungal Infections become more complicated, therefore, and clinical novel deep antifungal drug in the urgent need to high-efficiency low-toxicity, has a broad antifungal spectrum, highly selective.
piperazine derivative is widely used in sedative hypnotic drug as the important medicine intermediate of a class, antihistamine drug, antitussive medicine, antimicrobial agents, antiplatelet drug (Husbands S M, Izenwasser S, Kopajtic T, el a1.Structure-Activity Relationships at the Monoamine Transporters and σ Receptors for a Novel Series of9-[3-(cis-3, 5-Dimethyl-1-piperaziny1)-propy1] carbaz-ole (Rimcazole) Analogues[J] .Journal of Medicinal Chemistry, 1999, 42 (21): 4446-4455. plum of old winter, Chen Kai, Wang Hai. the anti thrombotic action of morpholine ring and piperazine ring analog derivative and molecular mechanism [J] thereof. Acta Pharmaceutica Sinica, 2003, 38(9): 641-645.).Its toxicity is little, easily forms a plurality of hydrogen bonds or ionic linkage, often the lipid of regulating drug and acid base equilibrium constant effectively.Be introduced into molecule, can effectively increase the alkalescence of molecule and water-soluble, thereby strengthen the activity (Cai Jiali of molecule, Lu Yihui, the sweet pouring tinkling of pieces of jade, etc. contain piperazines antimicrobial agents progress [J]. Chinese microbiotic magazine, 2009,34(8): 454-462,484.).The KETOKONAZOL of above introduction, itraconazole, Triaconazole, posaconazole etc. are all clinical antifungal drugs with piperazine structure commonly used.
The KETOKONAZOL itraconazole
The contriver finds that the compound in the present invention has certain anti-mycotic activity in the process of research Thienopyridines bridged piperazine derivatives, 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 nitrogen azole compounds, the development of new antifungal drug discloses derivative and the pharmaceutical salts thereof of a class piperazine.
Another object of the present invention is, discloses the preparation method of formula I compound and pharmaceutical salts thereof.
A further object of the present invention is, disclosing formula I compound and pharmaceutical salts thereof is the pharmaceutical composition of main active ingredient.
A further object of the invention is, discloses formula I compound and pharmaceutical salts thereof as the purposes of antifungal drug aspect.
Now in conjunction with goal of the invention, content of the present invention is specifically described.
Compound and the pharmacy acceptable salt thereof of formula I structure involved in the present invention are as follows:
Wherein:
R
1Be selected from: (1)
R wherein
2, R
3, R
4, R
5Be hydrogen at the same time or separately, C
1～C
4Alkyl, halogen, nitro, cyano group, trifluoromethyl;
(2)
R wherein
6, R
7Be hydrogen at the same time or separately, halogen, trifluoromethyl;
(3)
R wherein
8Be hydrogen.
The compound with formula I structure in the present invention, preferred compound is as follows:
Compound with formula I structure of the present invention, its pharmacy acceptable salt means: the salt that the compounds of this invention becomes with mineral acid, organic acid.Wherein particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate etc.
The compou nd synthesis route of formula I structure is as follows:
Chloroacetyl chloride and substituted-piperazinyl are in methylene dichloride, trichloromethane, toluene, ethanol, acetone equal solvent, under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide existed ,-10 ℃～85 ℃ reactions made the intermediate II.
Intermediate II and 4,5,6,7-tetramethylene sulfide also [3,2-c] hydrochloride of pyridine is in methylene dichloride, trichloromethane, acetonitrile or toluene equal solvent, under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide existed ,-10 ℃～105 ℃ reactions made chemical compounds I.
The reaction products therefrom is dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drips mineral acid or organic acid solution, make pharmacy acceptable salt.
Specifically various compounds are dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip the hydrochloric acid diethyl ether solution to pH=2 under ice-water bath, make hydrochloride; Or various compounds are dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, and mole citric acid such as adding, heated and stirred gets its Citrate trianion; Or various compounds are dissolved in a kind of in ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or DMSO, drip the vitriol oil to pH=1 under ice-water bath, make vitriol, etc.
This compounds is effective for treatment mankind fungal infectious disease.Although compound of the present invention can be without the direct administration of any preparation, described various compounds preferably use with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The pharmaceutical composition preparation method of the compounds of this invention is as follows: Application standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.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, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis etc.
The amount of the active ingredient that contains in pharmaceutical composition and 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 compound used or concentration are regulated in a wider scope.Usually, the scope of active compound amount is 0.05%～90%(weight of composition), another preferred scope is 0.05%～70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention has obvious restraining effect to fungi.The below adopts the standard micro-dilution method, and (NCCLSM-27A) measure its minimum inhibitory concentration further illustrates the compounds of this invention to the In Vitro Bacteriostatic of clinical several frequently seen fungi.Concentration (the MIC that suppresses selected fungi 90% growth with target compound
90) as the judgement terminal point.
Test strain: 5 kinds of deep fungals: Candida albicans (Candida albicans, C.alb.) ATCC76615, Cryptococcus neoformans (Cryptococcus neoformans, C.neo.) ATCC32609, Oidium tropicale (Candida tropicalis, C.tro.) ATCC12034, Candida parapsilosis (Candida paropsilosis, C.par.) ATCC22019, 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 (Fonsecaea pedrosoi, F.ped.).Above bacterial strain provides by our unit's pharmacological experiment chamber.
Test drug: the vitriol of the hydrochloride of the compounds of this invention I-1～I-16, I-4, the Citrate trianion of I-6, I-9, select amphotericin B (AmB) (magnificent medicine group) and KETOKONAZOL (KCZ) (Wuhan close mesophytization Manufacturing Co., Ltd) as positive control drug, dimethyl sulfoxide (DMSO) (DMSO), AR level (Tianjin triumphant letter chemical industry company limited).Microplate reader, BIO-RAD680.
Test method: take RPMI-1640(Sigma) be nutrient solution, 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 made medicine storage liquid (6400 μ g/m1), and-20 ℃ of preservations are stand-by.Be diluted to 640 μ g/m1 with RPMI-1640 during use, establish simultaneously solvent control and blank.Get the aseptic 96 flat microtest plates in hole, No. 1 hole adds RPMI-1640100 μ L and makes blank, and No. 2 the hole adds bacteria suspension 180 μ L and liquid 20 μ L, and the 3-12 hole respectively adds bacteria suspension 100 μ L, 10 grades, 2-11 hole doubling dilution, 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 liquid, makes the medicine negative control.Candida is observed the growing state of 3d in 35 ℃ of constant temperature culture 24h.Measurement result after Cryptococcus neoformans cultivation 72h, 26 ℃ of constant temperature culture of superficial mycosis are observed the growing state in 1 week.Analyze with microplate reader, compare with the medicine negative control hole, suppress corresponding lowest drug concentration as its minimal inhibitory concentration value (MIC take 90%
90), the results are shown in Table 1.
Table 1In vitro antifungal activities of compounds(MIC
90, μ gmL
-1)
By In Vitro Bacteriostasis test experiments result as seen, the invention compound all has inhibition to a certain degree active to 8 kinds of pathomycetes, and especially the activity of chemical compounds I-4, I-6 and I-9 even surpasses the first-selection of clinical treatment fungi but the larger medicine amphotericin B of toxicity.Part of compounds has stronger external activity to the most common clinically monilial infection with producing resistance on a large scale.This class new compound has wide spectrum, highly active advantage, has further further investigation and is worth.
Embodiment
Below in conjunction with embodiment, the present invention is described further, embodiment is only indicative, means that never it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1H NMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Embodiment1: intermediate II-1 synthetic
Add chloroacetyl chloride 1.47g(1.3 * 10 in the reaction flask that stirring, condenser, thermometer are housed
-2Mol), then add the 10mL methylene dichloride that it is diluted, add the Anhydrous potassium carbonate 2.76g(2 of grinding * 10 under stirring
-2Mol).With (2,3-dichlorophenyl) piperazine 2.31g(1.0 * 10
-2Mol) be dissolved in the 20ml methylene dichloride, and slowly be added dropwise to reaction system under-10 ℃.Add, be warming up under 15 ℃ continue stirring reaction 3.5h(flaggy show react completely).With 3 * 30mL saturated aqueous common salt washing reaction liquid, divide and get dichloromethane layer, fully dry with anhydrous sodium sulphate; filter, methylene dichloride is to the greatest extent steamed in decompression, gets colorless oil product 1-chloracetyl-4-(2; the 3-dichlorophenyl) piperazine crude product 2.8g, purity 81.3%(HPLC, lower same).Rf=0.75[developping agent: sherwood oil: ethyl acetate=1:1].
Embodiment 2:Synthesizing of intermediate II-2
Add chloroacetyl chloride 1.47g(1.3 * 10 in the reaction flask that stirring, condenser, thermometer are housed
-2Mol), then add the 15mL trichloromethane that it is diluted, add the sodium hydroxide 0.8g(2 of grinding * 10 under stirring
-2Mol).With the 1-(2-pyridyl) piperazine 1.63g(1.0 * 10
-2Mol) be dissolved in the 25ml trichloromethane, and slowly be added dropwise to reaction system under-5 ℃.Add, be warming up under 25 ℃ continue stirring reaction 4h(flaggy show react completely).With 3 * 40mL saturated aqueous common salt washing reaction liquid, divide and get the trichloromethane layer, fully dry with anhydrous sodium sulphate; filter, trichloromethane is to the greatest extent steamed in decompression, gets colorless oil product 1-chloracetyl-4-(2-pyridyl) piperazine crude product 2.1g; purity 84.9%(HPLC, lower same).Rf=0.73[developping agent: sherwood oil: ethyl acetate=1:1].
With reference to the method in embodiment 1 and 2, those skilled in the art all can conveniently make compound ii-3～II-16.Its physicochemical constant sees Table 2.
Table 2 compound ii-3～II-16
Embodiment 3: the preparation of chemical compounds I-1
Add 3.1g(1 * 10 in the reaction flask that stirring, condenser, thermometer are housed
-2Mol) dilute it with the 30mL methylene dichloride intermediate II-1, adds triethylamine 4.0g(4 * 10 under stirring
-2Mol), with 4,5,6, the 7-tetramethylene sulfide hydrochloride 1.76g(1 of [3,2-c] pyridine * 10 also
-2Mol) add reaction system in batches.Add, show in the lower continuation reaction 6h(flaggy that refluxes to react completely).with 3 * 30mL saturated aqueous common salt washing reaction liquid, divide and get dichloromethane layer, fully dry with anhydrous sodium sulphate, filter, methylene dichloride is to the greatest extent steamed in decompression, get colorless oil, combiflash companion gradient separations [eluent: v (sherwood oil): v (ethyl acetate)] gets white solid product 1-(2, the 3-dichlorophenyl)-4-(((4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-5-yl) ethyl) carbonyl) piperazine (I-1) 2.6g, yield 63.4%, purity 99.5%, Rf=0.41[developping agent: v (sherwood oil): v (ethyl acetate)=1:1].
1H?NMR(DMSO-d6，400MHz)δ：2.786(s,4H),2.937～2.943(d,J=2.4,4H),3.404(s,2H),3.550(s,2H),3.620(s,2H),3.705(s,2H),6.776～6.789(d,J=5.2,1H),7.096～7.120(m,J=9.6,1H),7.248～7.268(m,J=8,1H),7.289～7.304(m,J=6,2H)，ESI-MS{[M+H]
+}m/z：410.0862。
Embodiment 4: the preparation of chemical compounds I-2
Add 2.4g(1 * 10 in the reaction flask that stirring, condenser, thermometer are housed
-2Mol) dilute it with the 35mL trichloromethane intermediate II-2, adds pyridine 3.2g(4 * 10 under stirring
-2Mol), with 4,5,6, the 7-tetramethylene sulfide hydrochloride 1.76g(1 of [3,2-c] pyridine * 10 also
-2Mol) add reaction system in batches.Add, show in the lower continuation reaction 8h(flaggy that refluxes to react completely).with 3 * 40mL saturated aqueous common salt washing reaction liquid, divide and get the trichloromethane layer, fully dry with anhydrous sodium sulphate, filter, trichloromethane is to the greatest extent steamed in decompression, get yellow oil, combiflash companion gradient separations [eluent: v (sherwood oil): v (ethyl acetate)] gets light yellow solid product 1-(2-pyridyl)-4-(((4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-5-yl) ethyl) carbonyl) piperazine (I-1) 2.1g, yield 61.7%, purity 99.3%, Rf=0.39[developping agent: v (sherwood oil): v (ethyl acetate)=1:1].
1H?NMR(DMSO-d6，400MHz)δ：2.780(s,4H),3.401(s,2H),3.474～3.485(d,J=4.4,4H),3.547(s,4H),3.648(s,2H),6.624～6.654(m,J=12,1H),6.772～6.785(d,J=5.2,1H),6.804～6.826(d,J=8.8,1H),7.242～7.255(d,J=5.2,1H),7.500～7.543(m,J=17.2,1H),8.095～8.107(m,J=4.8,1H)，ESI-MS{[M+H]
+}m/z：343.1590。
With reference to the method for embodiment 3 and 4, those skilled in the art all can conveniently make chemical compounds I-3～I-16.Its physicochemical constant and analytical data see Table 3, table 4.
Table 3 chemical compounds I-3～I-16
The NMR of table 4 chemical compounds I-3～I-16 and ESI-MS data
Embodiment 5: chemical compounds I-4 one-tenth hydrochloride
Get I-4 solid product 2.0g, be dissolved in the 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 ℃, drip 18% hydrochloric acid diethyl ether solution to pH be 2, continue at stir about 1h under ice-water bath.Filter, get yellow solid.
Embodiment 6: chemical compounds I-6 one-tenth Citrate trianion:
Get I-6 oily product 2.5g, be dissolved in the 15mL dehydrated alcohol.Add after being heated to reflux and wait mole citric acid, continue at the approximately 3h of time stirring reaction that refluxes.React complete, standing 24h under room temperature.Filter, get yellow solid.
Embodiment 7: chemical compounds I-9 one-tenth vitriol
Get I-9 oily product 2.0g, be dissolved in the 15mL anhydrous methanol.Ice-water bath is cooled to 5 ℃, drip concentrated sulfuric acid solution to pH be 1, continue at stir about 2h under ice-water bath.Filter, get white solid.
For the pharmaceutical composition of piperazine derivative of the present invention is described more fully, the below provides following FORMULATION EXAMPLE, and described embodiment only is used for explanation, rather than is used for limiting the scope of the invention.Described preparation can use any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 3～7.
Embodiment 8:
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieve three times, add appropriate 10% polyvidone ethanol (95%) solution softwood processed, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the 16 whole grains of mesh sieve, are packed in hard gelatin capsule.
Embodiment 9:
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.First with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in 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 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross 16 mesh sieves and arrange, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 10:
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and propylene glycol, add medicinal basic to regulate pH value to 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 11:
The preparation of injection lyophilized powder:
The Citrate trianion 50mg of chemical compounds I-6
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-80%
Preparation method: get activeconstituents and add water for injection, regulate pH value to 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, filtrate is carried out packing, adopts freeze-drying, makes loose block, sealing, and get final product.
Claims (8)
1. the compound or its pharmacy acceptable salt that have formula I structure:
Wherein:
R
1Be (1)
R wherein
2, R
3, R
4, R
5Be hydrogen at the same time or separately, C
1～C
4Alkyl, halogen, nitro, cyano group, trifluoromethyl;
(2)
R wherein
6, R
7Be hydrogen at the same time or separately, halogen, trifluoromethyl;
(3)
R wherein
8Be hydrogen.
2. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1 is selected from following compound:
3. compound or its pharmacy acceptable salt with formula I structure as claimed in claim 1 or 2, its pharmacy acceptable salt is: the salt that formula I compound becomes with mineral acid, organic acid.
4. the compound or its pharmacy acceptable salt that have as described in claim 3 formula I structure; its pharmacy acceptable salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate.
5. the preparation method with compound of formula I structure as claimed in claim 1 or 2, it is characterized in that: chloroacetyl chloride and substituted-piperazinyl are in methylene dichloride, trichloromethane, toluene, ethanol or acetone solvent, under acid binding agent existed ,-10 ℃～85 ℃ reactions made the intermediate II; Also the hydrochloride of [3,2-c] pyridine is in methylene dichloride, trichloromethane, acetonitrile or toluene for intermediate II and 4,5,6,7-tetramethylene sulfide, and under acid binding agent existed ,-10 ℃～105 ℃ reactions made chemical compounds I,
R wherein
1Definition as claimed in claim 1.
6. preparation method as claimed in claim 5, wherein said acid binding agent is triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide.
7. pharmaceutical composition, it comprises compound or its pharmacy acceptable salt and one or more pharmaceutical excipients with formula I structure as claimed in claim 1 or 2 for the treatment of significant quantity.
8. compound or the application of its pharmacy acceptable salt aspect the preparation antifungal drug with formula I structure as described in any one in claim 1～2.
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2013
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| CN101701020A (en) * | 2009-11-04 | 2010-05-05 | 天津药物研究院 | Amide derivate, preparation method and application thereof |
| CN101817834A (en) * | 2010-05-13 | 2010-09-01 | 天津药物研究院 | Pyrazole derivatives and preparation method and application thereof |
| CN102002054A (en) * | 2010-10-25 | 2011-04-06 | 天津药物研究院 | Pyrazole type compound and preparation method and application thereof |
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