CN101575330B - Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof - Google Patents
Novel voriconazole broad-spectrum antifungal medicine compound, broad-spectrum antifungal medicine composition and application thereof Download PDFInfo
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Abstract
The invention relates to a novel broad-spectrum antifungal medicine compound, a broad-spectrum antifungal medicine composition, an application of the compound or the composition in the preparation of a broad-spectrum antifungal medicine, and an application of the compound or the composition in the preparation of a medicine used for treating severe invasive infection (comprising Candida krusei) caused by invasive aspergillosis and/or Fluconazole-resistant Monilia and/or severe infection caused by Scedosporium and fusarium. The novel broad-spectrum antifungal medicine compound and the broad-spectrum antifungal medicine composition have extensive and strong antifungal activity and better dynamic property and safety. For deep mycotic infection, the novel broad-spectrum antifungal medicine compound and the broad-spectrum antifungal medicine composition are better than the original voriconazole in the aspects of the antibiotic activity and the medicine resistance and is better than amphotericin B in the aspects of safety and effectiveness; and compared with the formerly applied voriconazole, Fluconazole, itraconazole and amphotericin B, the novel broad-spectrum antifungal medicine compound and the broad-spectrum antifungal medicine composition have reinforced medicine effect, less adverse reaction and good safety.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field.Particularly, the present invention relates to application and said compound or the compsn of a kind of new broad-spectrum antifungal medical compounds, a kind of broad-spectrum antifungal pharmaceutical composition, said compound or compsn in preparation broad-spectrum antifungal medicine and be used for treating that aggressive aspergillosis and/or the microbial bad attack sexuality of the drug-fast beads of fluconazole are dyed (comprising candida krusei) and/or the application of the medicine of the severe infections that caused by Scedosporium and Fusarium in preparation.
Background technology
In view of the serious fungi infestation incidence in the present whole world continues to rise; Especially immunocompromised host crowd's (like tumour patient, AIDS patient, organ transplantation patient etc.) fungi infestation mortality ratio is quite high; Remarkable change has taken place the epidemiology of whole world pathogenic bacteria: Candida is still deep fungal infection most commonly encountered diseases substance at present; Wherein candida albicans infection obviously descends, and non-candida albicans infection increases; The intrinsic Resistant strain of fluconazole---Candida glabrata, gram Rou Shi candidiasis and mould (particularly aspergillus tubigensis) infect obviously and rise; Deep fungal significantly rises to the fluconazole resistant rate year by year, domestic by 10.3% of calendar year 2001 rise to 2004 25.8%.Cause pressing for clinically wide spectrum, imitate by force, safe, economic antimycotic new drug.
The injection Vorionazole (prestige is all) of existing Pfizer is the freeze-dried prepn of Schardinger dextrins after wrapping up, and production cost is higher, expensive price.And according to reported in literature, Schardinger dextrins has certain renal toxicity.
By the original first-generation Vorionazole of producing of beautiful pearl group and more domestic producers, chemical name be " (2R, 3S)-2-(2; the 4-difluorophenyl)-3-(5-fluorine-based-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanols " compound; Narrow antimicrobial spectrum also has drug interaction and problem such as resistance; And be on the rise, especially domestic resistant rate is tangible ascendant trend, considerably beyond external resistant rate.
Original first-generation Vorionazole is following compound:
Chemical name: (2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-fluorine-based-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanols
Chemical structural formula:
Molecular formula: C
16H
14F
3N
5O, molecular weight: 349.32
This compound stability is very poor, and very difficult prolonged preservation is used under the normal temperature state.Cause easily simultaneously untoward reaction (pacify loyal hospital Pneumology Department referring to " Pulmonary Fungal Infections therapeutic advance " Beijing, Gao Yuanming), also relevant for the write up of untoward reaction, its untoward reaction mainly comprises in the injection Vorionazole specification sheets of Pfizer:
1, visual disorder
The visual disorder relevant with Vorionazole is comparatively common.In the clinical trial, vision change, vision enhancing, blurred vision, colour vision change and/or photophobia once appearred in about 30% patient.Visual disorder is generally slightly, rarely causes drug withdrawal person.Visual disorder maybe be relevant with higher Plasma Concentration and/or dosage.
As if though the site of action of Vorionazole mainly is confined to retina, its mechanism of action is still unclear.In the research, be that object has been studied the Vorionazole treatment influence to retinal function in 28 days, find that these article can reduce the amplitude of retina electric wave waveform, reduced field of view and change colour vision with healthy volunteer.Electroretinogram ERG is generally used for detecting the current conditions in the retina.Electroretinogram ERG, the visual field and colour vision in 14 days promptly recover normal after the drug withdrawal.Vorionazole can take place in medication the influence of vision in early days, and continues to be present in during the whole medication.Evidence suggests that visual disorder is relevant with multiple dosing.
2, skin reaction
In the clinical trial, skin reaction person is comparatively common for the generation of Vorionazole treatment group.The mechanism of these skin adverse events is still unclear.But these patients also suffer from other serious underlying diseases simultaneously usually, need accept multiple treatment simultaneously.In clinical trial, the fash incidence relevant with Vorionazole is 6% (86/1493).Most fash is light to moderate, comprises Stevens-Johnson syndromes, Lyell syndrome and erythema multiforme.In case fash appears in the patient, must carry out tight observation, if decreasing, increases the weight of skin, then must drug withdrawal.The report that photosensitization is also arranged, photosensitized reaction comparatively in the patient of long-term treatment more to be seen.Serious skin reaction is seldom seen.Have to avoid the direct projection of intensive sight during the Vorionazole treatment.
Summary of the invention
Go through the preparation and the use of the various embodiments of the present invention below, but should be appreciated that, the invention provides many suitable inventive concepts, it can be embodied on the various concrete aspects.The specific embodiments of this paper discussion only is preparation and uses illustrating of concrete mode of the present invention, do not limit the scope of the invention.
One object of the present invention is, a kind of medical compounds of new broad-spectrum antifungal is provided.Another object of the present invention is, a kind of pharmaceutical composition of broad-spectrum antifungal is provided.Another object of the present invention is, the application in preparation broad-spectrum antifungal medicine of said compound or compsn is provided.Another object of the present invention is, provides said compound or compsn to be used for treating that aggressive aspergillosis and/or the microbial bad attack sexuality of the drug-fast beads of fluconazole are dyed (comprising candida krusei) and/or the application of the medicine of the severe infections that caused by Scedosporium and Fusarium in preparation.
To the foregoing invention purpose, the present invention provides following technical scheme:
On the one hand, the present invention provides a kind of following formula (formula 1) compound or its pharmacy acceptable salt:
Formula 1
Its chemical name is: (2R, 3S)-(2-5-is fluorine-based-4-pyrimidine, 4-fluorophenyl)-3-(5-fluorine-based-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanols
Its molecular formula is: C
16H
16F
3N
7O
Preferably; Said pharmacy acceptable salt is selected from vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, a hydrogen orthophosphate, dihydrogen orthophosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate, oxalate, malonate, SUMATRIPTAN SUCCINATE, suberate, sebacate, fumarate, PHENRAMINE MALEATE, butine-1; 4-diformate, hexin-1,4-diformate, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulphonate, xylenesulfonate, phenylacetic acid salt, phenylpropionic acid salt, phenylbutyric acid salt, Citrate trianion, lactic acid salt, gamma hydroxybutyrate, glycol hydrochlorate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulphonate, naphthalene-2-sulfonic acid salt and mandelate.
On the other hand, the present invention provides a kind of pharmaceutical composition, and said pharmaceutical composition comprises formula 1 compound or its pharmacy acceptable salt, and preferably, said composition also comprises one or more pharmaceutically acceptable carrier and/or vehicle.
Preferably, the concrete formulation of pharmaceutical composition according to the invention is injection or oral prepns, and further preferably, said injection is powder injection or injection liquid, and said oral prepns is tablet or capsule.
Further preferably, injection liquid according to the invention is formula 1 compound of 2-5mg/ml or the aqueous solution of its pharmacy acceptable salt.
Further preferably, powder injection according to the invention adopts sodium chloride injection or glucose injection to dilute use.
Further preferably, the content of tablet Chinese style 1 compound according to the invention or its pharmacy acceptable salt is the 0.1-0.5g/ sheet; Preferably, be the 0.15-0.4g/ sheet; Further preferably, be the 0.2-0.3g/ sheet.
On the other hand, the present invention provides a kind of formula 1 compound or the application of its pharmacy acceptable salt in preparation broad-spectrum antifungal medicine.
On the other hand, the present invention provides a kind of formula 1 compound or its pharmacy acceptable salt to be used for treating that aggressive aspergillosis and/or the microbial bad attack sexuality of the drug-fast beads of fluconazole are dyed (comprising candida krusei) and/or the application of the medicine of the severe infections that caused by Scedosporium and Fusarium in preparation.
On the other hand, the present invention provides the application of described pharmaceutical composition in preparation broad-spectrum antifungal medicine.
On the other hand, the present invention provides described compsn to be used for treating that aggressive aspergillosis and/or the microbial bad attack sexuality of the drug-fast beads of fluconazole are dyed (comprising candida krusei) and/or the application of the medicine of the severe infections that caused by Scedosporium and Fusarium in preparation.
The following specifically describes each technical scheme of the present invention and preferred implementation.
Formula 1 compound of the present invention is white or off-white powder, is a kind of triazole species new compound with antifungic action of wide spectrum, and its indication specifically comprises: treatment aggressive aspergillosis; Treatment is dyed (comprising candida krusei) to the microbial bad attack sexuality of the drug-fast beads of fluconazole; The severe infections that treatment is caused by Scedosporium and Fusarium.Be mainly used in progressive among the treatment immunodeficient patient, the life-threatening infection of possibility.
Formula 1 compound or its salt of the present invention can parenteral admin mode such as injection system administration.
These article can adopt solvent dissolving, redilution to 2～5mg/ml earlier when intravenous drip.
Experiment showed, formula 1 compound or its salt of the present invention with the oral way administration through drug metabolism, its bioavailability very high (can reach 96%) is so intravenous drip and oral two kinds of route of administration can be exchanged use when clinical indication is arranged.
No matter be intravenous drip or oral administration, all should give loading dose first in first day during first administration, so that its Plasma Concentration promptly approached Css in first day in administration.
The preferred dosage of table 1. formula 1 compound
Intravenous drip and oral administration can also carry out sequential therapy, and this moment, oral administration need not to give loading dose, because intravenous drip administration has before this made the Vorionazole Plasma Concentration reach stable state.
Preferred dosage when 1 compound intravenous drip of table 2. formula and oral administration sequential therapy
Annotate:
*Oral maintenance dose: body weight>=40kg person, per 12 hours 1 time, each 0.2g; The adult patients of body weight＜40kg, per 12 hours 1 time, each 0.1g.
Oral administration: if patient treatment reaction is not good enough, the maintenance dose of oral administration can be increased to every day 2 times, each 0.3g; Body weight is adjusted into every day 2 times, each 0.15g less than the patient dose of 40kg.If the patient can not tolerate above-mentioned higher dosage, the maintenance dose of oral administration can subtract 50mg at every turn, reduces to every day 2 times gradually, each 0.2g (body weight is reduced to every day 2 times, each 0.1g less than the patient of 40kg).
According to the present invention one preferred embodiment, during with the injection system administration, be 2～5mg/mL with formula 1 diluted chemical compound to final concentration.Preferably, can adopt following injection liquid dilution: 0.9% sodium chloride injection or 5% glucose injection.
Compared with prior art, the present invention has following obvious advantage:
Formula 1 compound is a kind of new triazole antifungal agent, compares former Vorionazole class medicine, and this formula 1 compound has extensive and powerful anti-mycotic activity, and its pharmacokinetic property and security are better.For deep fungal infection, formula 1 compound is being superior to amphotericin B being superior to original Vorionazole compound aspect anti-microbial activity and the resistance aspect security and the validity; The Vorionazole of using, fluconazole, itraconazole, amphotericin B not only drug effect strengthen, and untoward reaction is less, and security is good.
The inventor is through verification experimental verification; Formula 1 compound can be killed aspergillus tubigensis clinically; Candida albicans to anti-fluconazole has fabulous anti-microbial activity; Lower 10～100 times to the oidiomycetic minimal inhibitory concentration of white (MICs) than fluconazole; The saccharomycetic anti-microbial activity of pathogenicity bo is higher than fluconazole, confirmed fluconazole to filamentous fungus invalid (MIC90＞512mg/L), however formula 1 compound but all has excellent external activity to pathogenic filamentous fungus (comprising the rare mould Pseudomonas of sufficient branch, Fusarium, Histoplasma capsulatum, Blastomyces dermatitidis and cryptococcus neoformans etc.) widely.Such fungi of treatment cryptococcal meningitis clinical discovery has produced resistance to fluconazole, and (MIC >=64ug/mg), formula 1 compound is strong than fluconazole to the activity of such fungi, and persistent, is a more promising antimycotic new compound.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention., these embodiment are not used in restriction scope of the present invention but only limiting to the present invention is described.The experimental technique of unreceipted concrete experiment condition in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
The preparation and the test of embodiment 1, formula 1 compound
Step 1, in the 500ml three-necked bottle, add 2-chloro-2,4 difluorobenzene ethyl ketone (27.3g, 0.14mol), 3; 5 two bromo-1H-[1,2,4] triazole (34g; 0.15mol), salt of wormwood (27.6g, 0.2mol), four butyl bromation amine (2.0g) and methylene dichloride 300ml, refluxing and stirring 8 hours.Cooling is filtered, and filter residue is used CH
2Cl
2Washing merges organic layer, washing, and drying is concentrated into driedly, and (1/1,200ml) recrystallization must light yellow solid 35.0g, and the gained solid product is not purified directly to be used for next step reaction with sherwood oil/ethyl acetate.
Step 2, (2R, 3S/2S, 3R)-pure the synthesizing of 3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3,5-two bromo-1H-[1,2,4]-triazol-1-yl) fourth-2-
(80ml 0.2mol) joins in the three-necked bottle, and ice-water bath drips diisopropylamine (20g down with the ethane solution of 2.5M n-Butyl Lithium under nitrogen; 0.2mol) THF 100ml solution; Stirred 30 minutes, cooling drips 4-chloro-5-fluoro-6-ethyl-pyrimidine (32.1g; 0.2mol) THF 300ml, stirred under this temperature 3 hours.(76.2g, THF 500ml 0.2mol) stirred 2 hours down in-60 ℃ to add 1-(2,4 difluorobenzene base)-2-(3,5-two bromo-1H-[1,2,4]-triazole-1-yl) ethyl ketone; Be cooled to-50 ℃, the aqueous solution that adds glacial acetic acid 12g makes the reaction all standing, is warming up to room temperature, tells organic layer, extracts water layer with ETHYLE ACETATE 100ml, merges organic layer, and drying concentrates purification by silica gel column chromatography.Collection isomer A (2R, 3S/2S, 3R, 22.7g); Continue wash-out, and collection isomer B (2R, 3R/2S, 3S, 7.5g).
Step 3, (2R, 3S/2S, 3R)-pure the synthesizing of 3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-[1,2,4]-triazol-1-yl) fourth-2-
Isomer A is dissolved in ethanol 250ml, add salt of wormwood (17.4g, 0.126mol), 10%Pd/C (2.3g), in 40 ℃ down logical H-H reaction filter to fully, with ethanol 50ml filter wash slag, be concentrated into dried, adding CH
2Cl
2(150ml), water 150ml, regulate pH value to 11 with 40%NaOH, layering, water layer is used CH
2Cl
2(100ml) extract, merge organic layer, washing 100ml is dry, concentrates, and adds Virahol 20ml, and heating makes its dissolving, stirs cooling, filters, and obtains white solid 11.4g, and the gained solid product is not purified directly to be used for next step reaction.
Step 4, (2R, 3S)-(2-5-is fluorine-based-4-pyrimidine, 4-fluorophenyl)-3-(5-fluorine-based-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanols synthetic
(42g 0.12mol) is dissolved in acetone 900ml, adds to be dissolved with R-(-)-10-camphorsulfonic acid (28.3g will to go up step gained solid; 0.12mol) methyl alcohol 300ml, mixture is back to whole dissolvings, stir and to be chilled to 20 ℃; The granulation of spending the night obtains white solid 30.4g, fusing point 176-177 ℃.This white solid is dissolved in CH
2Cl
2(300ml), add water 300ml, regulate pH value to 11 with 40%NaOH, layering, water layer is used CH
2Cl
2(200ml) washing, organic layer is dry, concentrates, and gets solid, adds Virahol 15ml, and heating makes its dissolving, stirs cooling, separates out white solid.Filter, drying, solid 17g, the solid that finally obtains is formula 1 compound: (2R 3S)-(2-5-is fluorine-based-4-pyrimidine, 4-fluorophenyl)-3-(5-fluorine-based-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanols, is 171 ℃ through detecting its fusing point.
Embodiment 2, comprise the injection liquid preparation of formula 1 compound
As activeconstituents, process injection liquid with formula 1 compound by following prescription and preparation technology:
2.1 specification: every bottle contains new Vorionazole 0.1g.
2.2 the composition of injection liquid and prescription:
New Vorionazole (formula 1 compound) 100g
Ethanol 4L
Water for injection 20L
Process 1000
2.3 the preparation technology of injection liquid:
In between aseptic technique, take by weighing new Vorionazole raw material (formula 1 compound) 100g, add 4L ethanol, stir and make dissolving, add the 30g gac, stir after 30 minutes, filtering decarbonization with the no mycoderm of filtrating through 0.22 μ m, gets in 100 grades of clean grooves; Slowly in above-mentioned solution, add water for injection (hiding through refrigerator and cooled) 20L, the limit edged stirs, and adds to continue to stir 30 minutes, leaves standstill crystallization after 2 hours, suction filtration, filter cake washs with water for injection, the gained solid under 50 ℃ of conditions, drying under reduced pressure 6 hours.Be sub-packed in after the assay was approved in the 10ml cillin bottle, every bottle of 0.1g, the moulding plug rolls aluminium lid, labels, finished product inspection, packing promptly gets.
The untoward reaction rate simultaneous test of embodiment 3, formula 1 compound and former Vorionazole compound
Under two kinds of different administering modes (A oral administration/B intravenous drip); Give earlier new Vorionazole compound (200 example) shown in the formula 1 of the present invention and existing product (former Vorionazole compound respectively to 391 routine acute aggressive aspergillosis patients; 191 examples) treatment; Sequential afterwards with other antifungal drug of having permitted treatments, and estimated formula 1 compound (180 example) and the oidiomycotic untoward reaction contrast of former Vorionazole (196 example) treatment esophagus.The laboratory result of treatment of formula 1 compound and former Vorionazole compound is approaching basically, but untoward reaction difference is huge.Concrete contrast and experiment is as shown in the table:
The untoward reaction rate simultaneous test of table 3. formula 1 compound and former Vorionazole compound
Wherein, former Vorionazole is that chemical name is that (2R, 3S)-compound of 2-(2,4 difluorobenzene base)-3-(5-fluorine-based-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanols, new Vorionazole compound is formula 1 compound of the present invention.
Embodiment 4, formula 1 compound are at the preventive trial of acute myelocytic leukemia chemotherapy induction period
Present embodiment is a double blinding simultaneous test at the new Vorionazole compound shown in the acute myelocytic leukemia chemotherapy induction period prophylactic application formula 1 of the present invention.
4.1 purpose:
Invasive infections with fungi is the frequently-occurring disease and dead common cause that long-term grain lacks patient; Use as original Vorionazole " (2R; 3S)-2-(2; the 4-difluorophenyl)-3-(5-fluorine-based-4-pyrimidine)-1-(1H-1,2,4-triazol-1-yl)-2-butanols " such patient broad-spectrum antifungal medicine that can tolerate can cause the arguement about antifungal therapy treatment Best Times.We have carried out a clinical trial, are intended to analyze and estimate validity and the security that the new Vorionazole compound shown in the formula 1 of the present invention soaks in acute myelocytic leukemia chemotherapy induction period prevention lung.
4.2 method:
This be a prediction of in the acute myelocytic leukemia chemotherapy patient in inducer remission stage, carrying out, at random, the three phases test of double blinding, placebo control, the new Vorionazole compound shown in twice oral 200mg patient's every day formula 1 of the present invention is until checking out that lung soaks into or agranulocytosis finishes just now.Main level of signification is the sickness rate that chemotherapy begins lung's infiltration in back 21 days.Less important index is the incidence of infection, hospital stays, antifungal therapy time, the security of fever time and medicine first.
4.3 result:
Amount to 25 patient's random packet and accept new Vorionazole compound (n=10) shown in the formula 1 of the present invention and placebo (n=15) administration.Sickness rate test group to lung's infiltration in 21 days is 0 (0%); Control group is 5 (33%) (P=0.06), and the average hospital days test group is slightly short, the new Vorionazole compound group (median 31.9 days) shown in the formula 1 of the present invention; Placebo (median 37.3 days, P=0.09).4 in the patient of placebo following up a case by regular visits to around thereafter quilt diagnosed out liver spleen moniliosis (P=0.01).Adverse events in two groups and toxicity indifference.
4.4 conclusion:
New Vorionazole compound shown in preventative oral twice on the one 200mg of the acute myelocytic leukemia chemotherapy induction period formula 1 of the present invention can lower lung and soak into and the oidiomycotic sickness rate of liver spleen.Present embodiment has shown that the new Vorionazole compound shown in the formula 1 of the present invention is safety and better tolerance.
Claims (17)
1. a following formula: compound or its pharmacy acceptable salt:
Formula 1.
2. the described compound of claim 1 or its pharmacy acceptable salt; It is characterized in that; Said pharmacy acceptable salt is selected from vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, a hydrogen orthophosphate, dihydrogen orthophosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate, oxalate, malonate, SUMATRIPTAN SUCCINATE, suberate, sebacate, fumarate, PHENRAMINE MALEATE, butine-1; 4-diformate, hexin-1,4-diformate, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulphonate, xylenesulfonate, phenylacetic acid salt, phenylpropionic acid salt, phenylbutyric acid salt, Citrate trianion, lactic acid salt, gamma hydroxybutyrate, glycol hydrochlorate, tartrate, mesylate, propanesulfonic acid salt, naphthalene-1-sulphonate, naphthalene-2-sulfonic acid salt and mandelate.
3. a pharmaceutical composition is characterized in that, said pharmaceutical composition comprises claim 1 or 2 described compounds or its pharmacy acceptable salt.
4. the described pharmaceutical composition of claim 3 is characterized in that, said composition also comprises one or more pharmaceutically acceptable carrier and/or vehicle.
5. claim 3 or 4 described pharmaceutical compositions is characterized in that, said pharmaceutical composition is injection or oral prepns.
6. the described pharmaceutical composition of claim 5 is characterized in that, said injection is powder injection or injection liquid, and said oral prepns is tablet or capsule.
7. the described pharmaceutical composition of claim 6 is characterized in that, said injection liquid is the aqueous solution, wherein contains the described compound of claim 1 or its pharmacy acceptable salt of 2-5mg/ml.
8. the described pharmaceutical composition of claim 6 is characterized in that, said powder injection dilutes through sodium chloride injection or glucose injection and uses.
9. the described pharmaceutical composition of claim 6 is characterized in that, the content of the described compound of claim 1 or its pharmacy acceptable salt is the 0.1-0.5g/ sheet in the said tablet.
10. the described pharmaceutical composition of claim 6 is characterized in that, the content of the described compound of claim 1 or its pharmacy acceptable salt is the 0.15-0.4g/ sheet in the said tablet.
11. the described pharmaceutical composition of claim 6 is characterized in that, the content of the described compound of claim 1 or its pharmacy acceptable salt is the 0.2-0.3g/ sheet in the said tablet.
12. claim 1 or 2 described compounds or its pharmacy acceptable salt application in preparation broad-spectrum antifungal medicine.
13. claim 1 or 2 described compounds or its pharmacy acceptable salt are used for treating the aggressive aspergillosis and/or the microbial bad attack sexuality of the drug-fast beads of fluconazole is dyed and/or the application of the medicine of the severe infections that caused by Scedosporium and Fusarium in preparation.
14. the described application of claim 13 is characterized in that, said candidiasis is a candida krusei.
15. the application of each described compsn in preparation broad-spectrum antifungal medicine among the claim 3-11.
16. each described compsn is used for treating the aggressive aspergillosis and/or the microbial bad attack sexuality of the drug-fast beads of fluconazole is dyed and/or the application of the medicine of the severe infections that caused by Scedosporium and Fusarium in preparation among the claim 3-11.
17. the described application of claim 16 is characterized in that, said candidiasis is a candida krusei.
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| CN101758337B (en) | 2009-12-03 | 2012-02-15 | 湖南阿斯达生化科技有限公司 | Non-halogen active agent for scaling powder |
| US20150087657A1 (en) * | 2011-12-06 | 2015-03-26 | Basf Se | Multicomponent crystalline system of voriconazole with fumaric acid |
| CN103724342B (en) * | 2014-01-11 | 2016-03-02 | 珠海海滨医药生物科技有限公司 | Antifungal drug compounds, its composition and purposes |
| CN103864775A (en) * | 2014-02-12 | 2014-06-18 | 珠海海滨医药生物科技有限公司 | 3-methyl-1-[[6-(1H-pyrryl)-2-methylsulfonyl-1-phenyl] benzothiazole]-1H-pyrrole-2-alcohol crystal form and preparation method thereof |
| CN109535091B (en) * | 2018-12-04 | 2022-05-13 | 淮安国瑞化工有限公司 | Method for synthesizing cyproconazole by using 1- (4-chlorphenyl) -2- (1H-1,2, 4-triazole-1-yl) ethanone |
| CN113384570B (en) * | 2021-07-13 | 2022-08-26 | 山东省妇幼保健院 | Application of caffeic acid methyl ester and triazole composition in preparation of antifungal products |
| CN115785072A (en) * | 2021-09-10 | 2023-03-14 | 北京新康哌森医药科技有限公司 | Voriconazole impurity compound and preparation method and application thereof |
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| CN1053787A (en) * | 1990-02-02 | 1991-08-14 | 美国辉瑞有限公司 | Triazole antifungal agent |
| CN1195346A (en) * | 1995-08-05 | 1998-10-07 | 辉瑞研究开发公司 | Preparation of triazoles by organometallic addition to ketones and intermediates therefor |
| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
| WO2006004795A2 (en) * | 2004-06-25 | 2006-01-12 | The Johns Hopkins University | Angiogenesis inhibitors |
-
2008
- 2008-05-05 CN CN 200810094145 patent/CN101575330B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1053787A (en) * | 1990-02-02 | 1991-08-14 | 美国辉瑞有限公司 | Triazole antifungal agent |
| CN1195346A (en) * | 1995-08-05 | 1998-10-07 | 辉瑞研究开发公司 | Preparation of triazoles by organometallic addition to ketones and intermediates therefor |
| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
| WO2006004795A2 (en) * | 2004-06-25 | 2006-01-12 | The Johns Hopkins University | Angiogenesis inhibitors |
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