CN1237173A - 2R, 4S, R, R- and 2S, 4R, R, R-hydroxyitraconazole - Google Patents
2R, 4S, R, R- and 2S, 4R, R, R-hydroxyitraconazole Download PDFInfo
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- CN1237173A CN1237173A CN97199657A CN97199657A CN1237173A CN 1237173 A CN1237173 A CN 1237173A CN 97199657 A CN97199657 A CN 97199657A CN 97199657 A CN97199657 A CN 97199657A CN 1237173 A CN1237173 A CN 1237173A
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Abstract
A method of preparation of optically pure isomers of hydroxyitraconazole, in particular the two cis dioxolane diastereomers of the sec-butyl R,R-isomer, and to phosphate and sulfate derivatives thereof is disclosed. Pharmaceutical compositions containing these compounds and their use for the treatment of fungal infection are also disclosed.
Description
Invention field
The present invention relates to prepare the optically pure isomer of R 63373 (hydroxyitraconazole), particularly sec-butyl (R, R)-two kinds of isomer methods along dioxolane diastereomer and phosphoric acid ester and sulfate derivative.The invention still further relates to pharmaceutical composition that contains these compounds and the purposes that is used for the treatment of fungi infestation thereof.
Background of invention
Itraconazole is a kind of known anti-mycotic agent, it is defined as 4-[4-[4-[4-[[2-(2 in USAN and USP medicine name dictionary, the 4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-the 1-piperazinyl] phenyl]-2,4-dihydro-2-(1-methyl-propyl)-3H-1,2,4-triazole-3-ketone or (±)-1-sec-butyl-4-[be right-[4-[is right-[[(2R
*, 4S
*)-2-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-the 1-piperazinyl] phenyl]-Δ
2-1,2,4-triazoline-5-ketone.The material that can buy is the isomer that is cis on dioxolane, and possible constructions formula I is represented:
Can find that have 3 asymmetric carbons (being represented by asterisk) in the formula I: two in dioxolane, in the tertiary butyl side chain on triazolone.Structure with 3 asymmetric carbons has 8 kinds of possible isomer: (R, R, R), (R, R, S), (R, S, S), (S, S, S), (R, S, R), (S, R, S), (S, R, R) and (S, S, R).Because the itraconazole that can buy is a cis-isomeride, so contain the mixture of isomers that only is cis on dioxolane.If the C-2 that to adopt first specified chiral centre be dioxolane, second C-4 that is dioxolane, the 3rd be agreement in sec-butyl, then commercially available itraconazole be (R, S, S), (R, S, R), (S, R, S) and (S, R, mixture R).Compound of the present invention in dioxolane, have (2R, 4S) and (2S, 4R) configuration.
The hydroxylation of mesomethylene carbon can produce another chiral centre and generate 8 kinds of possible enantiomorphs in the sec-butyl side chain.Compound of the present invention is that two asymmetric centers on tertiary butyl chain are the compound of R (α carbon) and R (β carbon).
What the graphic interpretation of used compound about racemize, ambiscalemic and scalemic or enantiomer-pure adopted in the literary composition is the method for Maehr J.Chem.Ed.62.114-120 (1985): the absolute configuration of representing chiral element with wedge shape solid and interruption; Corrugated line has represented to get rid of the issuable any stereochemistry possibility of key of its representative; Bold line solid and that be interrupted is the geometrical symbol of expression relative configuration but refers to the racemize symbol; The line of wedge profile and point or interruption represents not determine the compound of the enantiomer-pure of absolute configuration.Therefore, in following structural formula, have the structural formula of hollow wedge shape to comprise two kinds of pure enantiomorphs of a pair of enantiomorph, have the structural formula of solid wedge shape comprise single, have shown in the pure enantiomorph of absolute stereo chemistry.
Itraconazole is orally active broad-spectrum antifungals, and its structure and miconazole and clotrimazole are close.This material can weaken the synthetic of ergosterol, and ergosterol is the main sterol of fungal cell membrane.This may cause the increase of permeability and the leakage of cellular content.Under high density, the degeneration of cell within a cell device, the increase and downright bad variation of peroxisome can be taken place.
Behind the oral administration, itraconazole is slowly absorbed.Reach peak plasma concentrations in administration every day after 15 days, the pharmacokinetics of itraconazole is non-linear.This compound is through the R 63373 of biologic activity and final metabolism is the metabolite of multiple non-activity.Metabolism is seemingly finished by liver, in Most patients, do not have metabolite from urine, discharge [referring to, Hardin etc., antiseptic-germicide and chemotherapy (Antimicro.Agents andChemotherapy), 32,1310-1313 (1988)].
The racemic mixture of itraconazole has gone through to be used for blastomycosis and histoplasmosis as anti-mycotic agent.Also studied this compound has been used for aspergillosis, coccidioidomycosis, torulosis, onychomycosis, dermophyte and moniliosis infection.
General fungal disease (systemic mycosis) is by the caused common chronic disease disease of non-pathogenic opportunistic diseases fungi under the normal circumstances, and its development is very slow.But in the time of in it enters the host of being involved by HIV, ionizing rays, reflunomide, immunosuppressor etc. or being involved by situations such as wind-puff, bronchiectasis, diabetes, leukemia, burns, they just become pathogenic.These mycotic symptoms are also not really strong usually, can comprise heating, shiver with cold, apocleisis and body weight reduction, discomfort and dysthymia disorders.Mycosis is confined to typical anatomy usually and distributes, and may relate to the primary lesion at lung, and the more characteristic that can produce specific fungi infestation when fungi when primary lesion is sent out shows.For example, the pathogenetic original form of coccidioides immitis is acute, benign self limiting respiratory disease, develops into chronic, normally fatal skin, lymphoglandula, spleen and liver gradually from former form then and infects.Equally, what blastomycosis related at first is lung, is diffused into skin once in a while.Other infectious diseases such as paracoccidioidomycosis show the different courses of disease with moniliosis, and according to etiologic etiological difference, may show various ways, relate to skin, mucous membrane, lymphoglandula and internal organ.
Shallow fungi infestation is caused by dermophyte or the fungi that relates to skin outer layer, hair or nail.Infection can cause moderate inflammation, causes the alleviation at intermittence and the increasing the weight of of deterioration, decortication and infringement strengthened gradually.Yeast infection comprises moniliosis and oral candidiasis (white mouth), is confined to skin and mucous membrane usually, and its symptom changes with infecting the position.
The side reaction of using itraconazole comprises the inhibition of drug metabolism in hepatotoxicity and the liver, causes significant disadvantageous drug interaction on the various clinical.[referring to, Gascon and Dayer, European clinical pharmacology magazine (Eur.J.Clin.Pharmacol.) 41,573-578 (1991) (interacting) with the Dormicum; Honig etc., clinical pharmacology magazine (J.Clin.Pharmacol.) 33.1201-1206 (1993) (interacting) with terfenadine; With Neuvonen etc., clinical pharmacology treatment (Clin.Pharmacol.Therap.) 60,54-61 (1996) (interacting) with lovastatin].Also can comprise the rising of liver enzyme level in urticaria and the serum during administration with anaphylaxis.Hepatotoxicity is more rarely but very serious side reaction.Really because the potential serious consequence of the hepatotoxicity of low incidence, do not encourage usually to use oral medicine azole drug (conazoles) as a line anti-mycotic agent [referring to, Lavrijsen etc., lancet (Lancet) 340,251-252 (1992)].
We find that using racemic health azole drug may be with the increase of arrhythmia risk in the research of cavy of exsomatizing and rabbit heart.Although reported excessive irregular pulse-torsades de pointes type chamber speed (Torsades de the Pointes) [Pohjola etc. that can occur a kind of special hypotype during with racemize itraconazole and terfenadine co-administered in the past, Europe clinical pharmacology magazine, 45,191-193 (1993)], but reported never that irregular pulse was the side reaction of itraconazole general administration.Lacking irregular pulse or the unusual clinical report of QT may only be because less relatively patient crowd is only arranged up to now.
Nonpolar relatively and insoluble other two shortcomings of having brought of itraconazole: be difficult to it is mixed with the solution of parenteral admin and is difficult to penetrate hemato encephalic barrier.The result causes multiple needs to reach effective blood concentration rapidly or the treatment indication that enters CNS can't use itraconazole to treat.Specifically, can't use curative effective of Itraconazole in curing maincenter moniliosis (dementia that may be relevant with AIDS is relevant).
Therefore, need especially a kind ofly to have the advantage of itraconazole and do not have the compound of above-mentioned shortcoming.
Summary of the invention
Compound of the present invention and composition have very strong activity in treatment when local and general fungi, yeast and dermophyte infection, avoided simultaneously using itraconazole with adverse effect.Compound of the present invention and composition be also advantageous in that its solubleness in physiological compatibile solution is more much bigger than itraconazole.The preparation first of the independent enantiomorph of R 63373 makes and can prepare very easily molten single enantiomer and derivative thereof.
On the one hand, the present invention relates to pure basically single enantiomer or its salt of following formula: compound,
Wherein, X
1And X
2Be chlorine or fluorine independently of one another, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.There are two kinds of possible single enantiomers in this compound, has formula A and B to represent respectively:
On the other hand, the present invention relates to contain the pharmaceutical composition of above-claimed cpd and pharmaceutically acceptable carrier.Said composition contains and is less than other enantiomorph or the diastereomer that 10% (weight) has the same structure formula.Preferred said composition contains single enantiomorph A or B.
On the other hand, the present invention relates to treat or prevent the method for fungi infestation, this method comprises, to the above-claimed cpd of the administration treatment significant quantity of suffering from (maybe may suffer from) fungi infestation.
On the other hand, the present invention relates to prepare following formula 2, the dibasic 3H-1 of 4-, 2, the method for 4-triazole-3-ketone,
R wherein
1It is the aryl of aryl or replacement.This method comprises, with the 2-aryl-3H-1 of following formula, and 2,4-triazole-3-ketone
With following formula along 4,5-dimethyl-1,2,3-two oxa-tetramethylene sulfides (dioxathiolane) 2, the reaction of 2-dioxide,
Reaction is passed through, in inert solvent, at least one equivalent 1,4,7,10,13,16-six oxygen ring octadecanes (18-hat-6) exist down, form described 2-aryl-3H-1 with excessive potassium hydride KH, 2, the sylvite of 4-triazole-3-ketone adds described two oxa-tetramethylene sulfides down in-5 ℃ to 25 ℃ then.Synthetic for the itraconazole enantiomorph, R
1Be preferably
R wherein
2Be methyl or benzyl.
On the other hand, the present invention relates to prepare the method for the dioxolane tosylate of following formula,
Wherein Ph is the phenyl of phenyl or replacement, and Tos is a tosyl group, R
3It is heterocyclyl methyl.This method comprises following series of steps: (a) with formula R
3The ketone of C (O) Ph and about 1 normal optical activity 1,2-dihydroxypropyl tosylate is dissolved in the inert solvent; (b) temperature is cooled to below 15 ℃; (c) in adding excessive trifluoromethanesulfonic acid below 15 ℃; (d) make the above-mentioned substance reaction generate ketal; (e) under 0 ℃-10 ℃, the solution of described ketal is joined in the aqueous solution of excess base metal carbonate or supercarbonate.
Detailed Description Of The Invention
Compound of the present invention synthesizes by the general route shown in reaction scheme 1,2,3 and 4.
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
Reaction scheme 4
As shown in the reaction scheme 1, from Soviet Union-tosyloxy-1, the 2-propylene glycol turns into obtaining DTTT through acid catalyzed ketal and prepares chirality dioxolane DTTT (3) by literature method.
As shown in reaction scheme 2, by handling, exist under the condition of ruthenium trichloride then with thionyl chloride, prepare two oxa-tetramethylene sulfides 5 with the sulfite of sodium peroxide in-situ oxidation gained from the butyleneglycol of the configuration that suits.
As shown in reaction scheme 3, exist under the crown ether condition, with the potassium hydride KH among the DMF, will be with 2 of embodiment X VII method preparation in the United States Patent (USP) 4267179,4-dihydro-4-[4-[4-(4-p-methoxy-phenyl)-piperazinyl] phenyl]-3H-1,2,4-triazole-3-ketone (6) with by Gaoand Sharpless[J.Am.Chem.Soc.110,7538 (1988)] two oxa-tetramethylene sulfides, 5 reactions of method preparation.By at 100-110 ℃, heat with 48%HBr, gained methoxyl group vitriol is cracked into phenol-alcohol 8.
As shown in reaction scheme 4, exist under the condition of DMF solution of potassium hydroxide, the tosyl group ester in the reaction scheme 13 and phenol-alcohol 8 in the reaction scheme 3 are reacted, obtain product 9.
When the R in needing A or B is vitriol, the sequence of steps in the rearrangeable reaction scheme 3 and 4 in case before adding the sec-butyl side chain methoxyl group of cracking 6, perhaps add 3 earlier, add 5 then.
When the R in needing A or B is phosphoric acid salt; at first handle 8 with protection phenol with tert-butyldimethylsilyl chloride thing and diisopropylethylamine; handle with dibenzyl diisopropylphosphoramidite (phosphoramidite) and tert-butyl hydroperoxide according to the method for PCT application WO95/17407 then, so that with pure phosphorylation.Remove the silyl protecting group with anhydrous TBuA muriate, press phosphoric acid ester and the dioxolane tosylate coupling of reaction scheme 3 benzyl protection.Exist under the palladium catalyst condition, by hydrogenolysis cracking benzyl protecting group to obtain the phosphoric acid salt product.
It should be noted that in above-mentioned reaction scheme 3, formed 8 the RR and the racemic mixture of SS enantiomer.Use method well known in the art, chromatogram is easy to the separation of racemic mixture on Chiral Media.Perhaps, can produce single enantiomer by reaction scheme 5,6 and the two kinds of different modifications that reaction scheme 3 is done described in 7:
Reaction scheme 5
Reaction scheme 6
Reaction scheme 7
It is described to press reaction scheme 3, with 2,4-dihydro-4-[4-[4-(4-p-methoxy-phenyl)-piperazinyl] phenyl]-3H-1,2,4-triazole-3-ketone (6) and two oxa-tetramethylene sulfide 5a reaction, but by 45-50 ℃ with 48%HBr heating, the sulfuric ester of hydrolysis gained methoxyl group vitriol and need not be from phenol decomposition of methyl, can obtain alcohol 11.Shown in reaction scheme 6, press the method [Synthesis 1981,1-27] of Mitsunobu and handle alcohol 11, in methyl alcohol, use the potassium hydroxide hydrolysis with di-isopropyl azodicarboxy hydrochlorate, triphenylphosphine and phenylformic acid, obtain 17,8 single enantiomer then with 48%HBr backflow cracking.Perhaps, shown in reaction scheme 7, under the condition that has dimethyl aminopyridine and diisopropylethylamine, handle alcohol 11 with methylsulfonyl chloride, then according to the method [Tet.Lett.34 of Senanyake etc., 2425 (1993)] handle the resulting methanesulfonates 14 of transformation with the propionic acid caesium, obtain propionic ester 16.Before potassium hydroxide and HBr processing, cleavable methoxyl group ester 16 obtains 17.Preparation (-)-(2R, 4S)-2-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-4-tosyloxy methyl isophthalic acid, 3-dioxolane tosylate DTTT (3a tosylate (tosylate salt))
With (R)-tosyloxy-1, the 2-propylene glycol (10.0g, 40mmol) and 1-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazol-1-yl) ethanol ketone (ethanone) (10.0g, toluene suspension 39mmol) (50ml) is cooled to 5 ℃.Slowly add trifluoromethane sulfonic acid (triflic acid) (15mL, 4 equivalents) so that temperature remains on below 15 ℃.After adding fully, reaction mixture (2 phase) was stirred 60 hours at 25 ℃.With (200ml) diluted mixture thing and slowly splash into 5 ℃ K of ethyl acetate (EtOAc)
2CO
3(50g) in the aqueous solution (400ml).Separate organic phase, with EtOAc (150ml) washing water layer.The organic extraction that merges is gone up drying at sodium sulfate (10 gram) also to be filtered.Slowly add (7.6g) ethyl acetate solution of monohydrate (50ml) of toluenesulphonic acids (TsOH) at 25 ℃.After 30 minutes, filter white solid product, washing and drying obtain containing 5% trans suitable DTTT.CH
3Two kinds of crystallizations of CN (400ml) obtain 13.5g pure (2R, 4S)-DTTT (50% productive rate) [a]
D 25=+16.6 ° (c=1, MeOH); Ee=99.6%.Preparation (-)-(2S, 4R)-2-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-4-tosyloxy methyl isophthalic acid, 3-dioxolane tosylate DTTT (3b tosylate)
With (S)-tosyloxy-1, the 2-propylene glycol (14.8g, 60mmol) and 1-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazol-1-yl) ethanol ketone (15.2g, toluene suspension 58mmol) (80ml) is cooled to 5 ℃.Slowly add trifluoromethane sulfonic acid (18mL) so that temperature remains on below 15 ℃.After adding fully, reaction mixture (2 phase) was stirred 60 hours at 25 ℃.Use CH
2Cl
2(300ml) the diluted mixture thing also slowly splashes into 5 ℃ K
2CO
3(30g) in the aqueous solution (300ml).Separate organic phase and be concentrated into about 100ml.(300ml) dilute resistates and with methyl iso-butyl ketone (MIBK) (MIBK) at 25 ℃ of MIBK (100ml) solution that slowly add TsOH (11.0g monohydrate).After 30 minutes, filter white solid product, washing and drying obtain containing 6% trans suitable DTTT.CH
3Two kinds of crystallizations of CN (600ml) obtain 16.6g pure (2S, 4R)-DTTT (44% productive rate).[a]
D 25=-16.6°(c=1,MeOH)；ee=99.6％。Preparation meso-4,5-dimethyl-1,2,3-two oxa-tetramethylene sulfides 2,2-dioxide (5)
In the three neck 500ml round-bottomed flasks that have reflux exchanger and calcium chloride tube, add meso-2, and the 3-butyleneglycol (10.0g, 10.1mL.0.11mol) and tetracol phenixin (20mL).Droppingization sulfuryl chloride under the room temperature (15.98g, 9.8mL, 0.134mol).Gas begins rapidly to discharge.Stirring at room 10 minutes, reflux 30 minutes was to guarantee removing HCl gas fully then with reaction mixture.In ice-water bath, reaction mixture is cooled to 0 ℃, adds acetonitrile (120ml), RuCl respectively
3H
2O (14mg, 0.07mmol), NaIO
4(35.6g, 0.166mol) and water (180ml).Reaction mixture is heated to room temperature and stirred 1.5 hours.Mixture is annotated in the methyl tertiary butyl ether (900ml), added entry to dissolve remaining NaIO
4(about 600ml).Separate mutually also with methyl tertiary butyl ether (2 * 100ml) extraction waters.Water (1 * 50mL), saturated sodium bicarbonate aqueous solution (2 * 50ml) and the saturated sodium chloride aqueous solution (organic phase that 1 * 50ml) washing merges.Dry organic solution is also filtered by the silica gel bed on anhydrous magnesium sulfate, obtains clarifying colourless solution.Solvent removed in vacuo obtains the title compound of 16.20g (96% productive rate).Preparation (4S, 5S)-4,5-dimethyl-1,2,3-two oxa-tetramethylene sulfides 2,2-dioxide (5a)
In the three neck 500ml round-bottomed flasks that have reflux exchanger and calcium chloride tube, add (2S, 3S)-(+)-2, the 3-butyleneglycol (10.0g, 10.1mL.0.11mol) and tetracol phenixin (120mL).Thionyl chloride under the room temperature (16.0g, 9.8mL, 0.13mol).Gas begins rapidly to discharge.Stirring at room 10 minutes, reflux 30 minutes was to guarantee removing HCl gas fully then with reaction mixture.In ice-water bath, reaction mixture is cooled to 0 ℃, adds acetonitrile (120ml), RuCl respectively
3H
2O (14mg, 0.07mmol), NaIO
4(35.6g, 0.144mol) and water (180ml).Reaction mixture is heated to room temperature and stirred 1.5 hours.Mixture is annotated in the methyl tertiary butyl ether (900ml), added entry to dissolve remaining NaIO
4(about 600ml).Separate mutually also with methyl tertiary butyl ether (2 * 100ml) extraction waters.Water (1 * 50mL), saturated sodium bicarbonate aqueous solution (2 * 50ml) and the saturated sodium chloride aqueous solution (organic phase that 1 * 50ml) washing merges.Dry organic phase is also filtered by the silica gel bed on anhydrous magnesium sulfate, obtains clarifying colourless solution.Solvent removed in vacuo obtains the title compound of 16.85g (quantitative yield).Preparation (2R
*, 3R
*)-3-[2,4-dihydro-4-[4-[4-(4-p-methoxy-phenyl)]-the 1-piperazinyl] phenyl]-3H-1,2,4-triazole-3-ketone-2-yl] fourth-2-base vitriolate of tartar (7)
At room temperature, to using hexane (2 * 50mL) N, potassium hydride KH (the 8.53g of dinethylformamide solution (120ml) pre-wash, 74.4mmol, 35% oily dispersion liquid) add in the suspension 18-hat-6 (15.73g, 59.5mmol) and 2,4-dihydro-4-[4-[4-(4-p-methoxy-phenyl)-1-piperazinyl] phenyl] 3H-1,2, and 4-triazole-3-ketone (6) (17.43g, 49.6mmol).With solution be heated to 80-85 ℃ 1.5 hours, in ice-water bath, be cooled to 9 ℃ then.In this solution, add (4R
*, 5S
*)-4,5-dimethyl-1,2,3-two oxa-tetramethylene sulfides 2,2-dioxide (5) (8.00g, 52.6mmol).Reaction mixture heat release to 13 ℃.Be cooled to 0 ℃ again, reaction mixture is heated to room temperature and stirred 18 hours.In mixture impouring 2.5L methyl tert-butyl ether, from solution, filter solid product.Water (1L) is added in the thick solid, then with mixture heating up to 80 ℃ and solids removed by filtration by product.With solid water (400ml) washing, make filtrate be cooled to room temperature.Add saturated potassium chloride solution (50ml), from solution, be settled out product immediately.After the filtration,, obtain the title compound of 13.46g (47% productive rate) with solid vacuum-drying.Preparation racemize 2,4-dihydro-4-[4-[4-(4-hydroxy phenyl)-1-piperazinyl] phenyl]-2-[(1S
*, 2R
*)-2-hydroxyl-1-methyl-propyl)]-and 3H-1,2,4-triazole-3-ketone (8)
To (2R
*, 3R
*)-3-[2,4-dihydro-4-[4-[4-(4-p-methoxy-phenyl)-1-piperazinyl] phenyl]-3H-1,2,4-triazole-3-ketone-2-yl] fourth-2-base vitriolate of tartar (7) (7.00g, 12.9mmol) and S-WAT (480mg, 3.80mmol) the middle 48%HBr (40mL) that adds.With vlil 6 hours, be cooled to room temperature then.Reaction mixture is annotated in the water (100ml), pH is risen to 7-8 with the unsaturated carbonate potassium solution.Filter and collect product and vacuum-drying.(3 * 20mL) extract, and the organic moiety that merges is dry on anhydrous magnesium sulfate, filter and solvent removed in vacuo, obtain white solid with chloroform with filtrate.Combining solid, the title compound that obtains 3.89g (62% productive rate) as and SO
3Adducts.Preparation (2R, 4S)-4-[4-[4-[4-[[2-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-[piperazinyl [phenyl]-2,4-dihydro-2-[(1R
*, 2R
*)-(2-hydroxyl-1-methyl-propyl)]-and 3H-1,2,4-triazole-3-ketone (non-enantiomer mixture that contains A)
To 2,4-dihydro-4-[4-[4-(4-hydroxy phenyl)-1-piperazinyl] phenyl]-2-[(1R
*, 2R
*)-2-hydroxyl-1-methyl-propyl)]-and 3H-1,2,4-triazole-3-ketone SO
3Adducts (8) (1.00g, 2.04mmol) and (-)-(2R, 4S)-2-(2, the 4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl methyl)-4-tosyloxy methyl isophthalic acid, 3-dioxolane tosylate (3a tosylate) (1.52g, 2.32mmol) in add pulverous potassium hydroxide (658mg, 11.7mmol) and N, dinethylformamide (30ml).With reaction mixture be heated to 50-55 ℃ 8 hours, be cooled to room temperature then.Add entry (300ml), and mixture was stirred 30 minutes.(50ml) adds in the mixture with saturated sodium-chloride water solution, mixture stirred also collected crude product, vacuum-drying then by filtering in 1 hour.Use the flash chromatography purifying, with ethyl acetate, chloroform, 98: 2 chloroforms then: methyl alcohol, 95: 5 chloroforms then: methanol-eluted fractions obtains the title compound of 420mg (29% productive rate); [a]
D 25=19.7 ° (c=0.1, MeOH).Preparation (2S, 4R)-4-[4-[4-[4-[[2-(2,4 dichloro benzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-the 1-piperazinyl] phenyl]-2,4-dihydro-2-[(1R
*, 2R
*)-(2-hydroxyl-1-methyl-propyl)-and 3H-1,2,4-triazole-3-ketone (non-enantiomer mixture that contains B)
To 2,4-dihydro-4-[4-[4-(4-hydroxy phenyl)-1-piperazinyl] phenyl]-2-[(1R
*, 2R
*)-2-hydroxyl-1-methyl-propyl)]-3H-1,2, (1.00g is 2.04mmol) with (-)-(2S for 4-triazole-3-ketone (8), 4R)-2-(2, the 4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl methyl)-4-tosyloxy methyl isophthalic acid, 3-dioxolane tosylate (3b tosylate) (1.02g, 1.56mmol) in add pulverous potassium hydroxide (428mg, 7.63mmol) and N, dinethylformamide (22ml).With reaction mixture be heated to 50-55 ℃ 7 hours, be cooled to room temperature then.Add entry (220ml), and collect crude product, vacuum-drying then by filtering.Use the flash chromatography purifying, with 98: 2 chloroforms: methanol-eluted fractions, recrystallization obtains the title compound of 388mg (23% productive rate) from methyl alcohol; [a]
D 25-18.5 ° (c=0.1, MeOH).
X wherein
1And X
2The compound that is fluorine can make from suitable 3 by similar mode, and described 3 press shown in the reaction scheme 1 by condensation from suitable 2, and 4-dihalogenated phenyl ethanol ketone makes.
Term used herein " pure basically single enantiomer " refers to exist other enantiomer that is lower than 10% (weight).Described composition contains the R 63373 or derivatives thereof, and wherein at least 90% (weight) R 63373 has shown suitable dioxolane of above-mentioned stereochemistry and sec-butyl side chain.
Available microorganism and pharmaceutical research are determined the relative potentiality and the specificity figure of optical purity enantiomer, as the racemic mixture of the itraconazole of the broad-spectrum antifungals of anti-multiple fungi, yeast and dermophyte.
With regard to the antimicrobial acivity of aforesaid compound, draw useful antimicrobial acivity figure with selected test, and do not limit the present invention in any way, comprise the scope of sensitive microbial.Can assess in the ability of anti-multiple fungi of external antimycotic health azole drug and bacterium several concentration (in μ l/mL).(referring to Van Cutsem, Chemotherapy38 Suppl1,3-11 (1992) and Van Cutsem etc., Rev.Infec.Dis.9Suppl 1, S15-S32 (1987)).With 16 * 160mm developmental tube, finish the test that suppresses fungi at Sha Shi liquid (every 100ml distilled water contains the new peptone of 1g (neopeptone) Difco and 2g glucose Difco), each pipe contains 4.5mL 5 minutes liquid nutrient medium of sterilization in 120 ℃ of pressure kettle.Test compound is dissolved in 50% ethanol with the initial concentration of 20mg/ml.Dilute the concentration that this solution reaches 10mg/ml with sterile distilled water subsequently.Carry out continuous decimal system dilution with distilled water.To contain and add the 0.5mL drug solution in the pipe of 4.5mL Sha Shi liquid nutrient medium, obtain the substratum that concentration is 1000,500,100,10 and 1 μ g/mL thus.Prepare control tube by 0.5mL distilled water is added in the 4.5mL substratum, add ethanol and obtain and the identical concentration of pipe that contains 1000 and 500 μ g medicines.At 25 ℃, filamentous fungus is cultivated 2-3 week in sabouraud's agar.Piece with 2 * 2 * 2mm is seeded in the substratum then.All cultures all are incubated 14 days in duplicate and at 25 ℃.In the Sha Shi meat soup that contains 10% deactivation bovine serum, the itraconazole anti-mycotic activity is improved, and described activity depends on used test medium.With Sabouraudites lanosus (Microsporum canis), trichophyton mentagrophytes (Trichophyton mentagrophytes), Candida albicans (Candida albicans), sporotrichum schenckii (Sporothrix schenckii), Brazil's class coccidioides immitis (Paracoccidioides brasiliensis), Blastomyces dermatitidis (Blastomyces dermatitides), Histoplasma (Histoplasma spp.), Eurotium (Aspergillus spp.) and other fungi and bacterium can be observed the complete or significant growth-inhibiting effect in Sha Shi meat soup after 14 days of cultivating.
The effective saccharomyces albicans that picks from the pure culture flat board of 10ml that will contain 4ml Sha Shi dextrose meat soup falls to inoculating.This bacterial strain is ordered from American type culture collection (ATCC).Organism was vibrated with 150RPM 30 ℃ of growths simultaneously in 4 hours.When biology growing, the non-enantiomer mixture 9 usefulness DMSO of hydroxyl itraconazole A and B are dissolved as the concentration of 10mg/ml.Then each sample was diluted to obtain 1mg/ml or 1000 μ g/ml samples with 1: 10.Then these samples are obtained containing the sample of 1000,500,250,125,62.5,31.25,15.6 μ g/ml by 2 times of dilutions of series.Obtain 96 hole microtitre wares with 98 μ L liquid growth mediums, in each test holes, contain 1 μ L R 63373 solution.In the time of 4 hours, Candida albicans is diluted to the 0.5McFarland standard in growth, represents about 10
5-10
6Cell/mL, and the described inoculum of 1 μ L is placed in each test holes of microtitre ware.Then this ware is covered and cultivated 16 hours at 30 ℃.The MIC that contains the mixture of A and B is lower than 0.156 μ g/mL.
The Kirby-Bauer test
Active grown culture by above-mentioned preparation Candida albicans, novel Cryptococcus (Cryptococcus neoformens) and yeast saccharomyces cerevisiae (Saccharomyces cerevisiae).Culture is diluted to the 0.5McFarland standard and swabs on 150mm Sha Shi dextrose agar flat board.With dull and stereotyped skimmer paper plane (7mm) is placed on the agar plate.Then pipetting 10 each R 63373 sample solution of μ l 10mg/ml is placed on each paper plane.At 30 ℃, flat board was cultivated 16 hours subsequently.Measure the inhibitory area with mm then.Data are summarized as follows.
| Compound | The white candiyeast | Novel Cryptococcus | Yeast saccharomyces cerevisiae |
| Diastereomer A | 23 | 34 | 23 |
| Diastereomer B | 27 | 32 | 25 |
| ± itraconazole | 17 | 22 | 15 |
Data represented inhibitory area in millimeter.
Relatively R 63373 and derivative are to tentative dermatocandidiasis of cavy and the oidiomycotic activity in vivo of rat vagina.Assess the activity in vivo of described compound by in the Wistar of oophorectomize and hysterectomy rat (100g), bringing out vaginal infection, use the described rat of estradiol undecane acid esters subcutaneous treatment in the 100 μ g sesame oil weekly for vaginal candidiasis with Candida albicans.Candida albicans salt solution intravaginal with fixed concentration infects the animal that is in false oestrus (pseudooestms).In the metainfective set time, assess infection or cure contrast by getting vaginal smear.With to be assessed and chemoprophylaxis or therapeutic administration relatively, judge effectiveness by the ratio of total number of animals in more negative animal and each the medicine group in mg/kg then.In similarly studying, provide comparison basis to the oidiomycotic activity of guinea pig skin (Van Cutsem etc., Chemotherapy17,392 (1972)).
Compound of the present invention can be treated fungi infestation, can avoid the side effect relevant with itraconazole simultaneously.Term " side effect " includes, but are not limited to cause increase, the drug interaction of rhythm disturbance, liver toxicity and serum liver enzyme, and anaphylaxis comprises urticaria, feels sick, vomiting, stomachache, headache, dizziness etc.
By detecting the R 63373 isomer potentiality that promote rhythm disturbance are assessed in the action potential and the inotropic influence of people, dog and rabbit heart.Torsades de pointes type chamber speed is the side effect that causes that anti-rhythm disturbance medicine that the heart repolarization prolongs is known, and described medicine is Quinidine, sotolol and acetylprocainamide for example.All these medicines can both be blocked and be called the cell potassium channel that delays rectifier (IK), it has been generally acknowledged that this induces the ability of torsades de pointes type chamber speed syndrome relevant with it on mechanism.(referring to Cardiovascular Drugs Ther. such as Zehender, 5,515-530 (1991)).
Therefore, cause the rhythm disturbance effect with the exsomatize cavy or the QT phase of the rabbit heart and the increase explanation of action potential phase.With containing 0.0; 1.0; 5.0; 10.0 or the Tyrode ' s solution of the oxidation of the 30.0 μ M racemize itraconazoles perfusion heart.Measure QT phase and action potential phase (APD) from heart electrode.
To act in order observing in the body, to detect with the mongrel anesthesia of the arbitrary sex of body weight 5-20kg and with blood pressure and EKG standard technique.The solid state sensor of dP/dT is placed on left ventricle, and inserts epicardial lead.With the dosage infusion test compound that raises gradually, the dosage of beginning is 1 μ g/kg/ minute, infusion 15-30 minute, and increase gradually up to cardiovascular breaking taken place.The parameter of measuring is: blood pressure, heart rate, dP/dT and QT-are at interval.Hemodynamics and electroactive measurement comprise QT
cUndertaken by response at interval, and this is compared test compound.
Personnel selection hepatomicrosome, people liver lymphocyte and the external assessment of other cell culture systems promote the potentiality of hepatotoxicity.Hepatomicrosome prepares from the people liver.Tissue is melted, then with the 0.15M KCl homogenate of Polytron homogenizer.Homogenate is centrifugal and with 0.15M KCl resuspension, and then homogenate.To wait duplicate samples freezing and be stored in-70 ℃.Aseptic separation of human lymphocyte from fresh heparinization human blood.With blood usefulness Eagle ' s minimum medium dilution and at the Ficoll-Paque higher slice.Sample is centrifugal, remove lymphocyte from moisture-Ficoll interface then, be suspended in then substratum (15mM HEPES, pH7.4) in.With cell centrifugation, wash once resuspension with the HEPES substratum then.
By with 3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene tetrazolium drone bromide (MTT) is transformed into purple first .In microwell plate, finish the transformation of MTT to dyestuff.After the preparation, in moistening insulation can, 37 ℃ is that the test compound of 1-400 μ M is incubated with hepatomicrosome or lymphocyte separately or with concentration.After the insulation, with containing 5% albuminous HEPES-buffered medium washing microsome/cell and resuspension.Then, this microsome/cell in moistening insulation can 37 ℃ of insulations.After the insulation, 125 μ gMTT are added in each hole.Flat board is also centrifugal 37 ℃ of insulations.After centrifugal, add 100 μ L Virahols, after the insulation, determine optical density(OD) with automatic dull and stereotyped reading apparatus.
In the management of acute or chronic disease, the prevention of R 63373 or derivative or therapeutic dose with the severity of disease to be treated with route of administration and different.Dosage, and may also have dose frequency also with age, body weight and the reactions change of individual patient.In a word, total dose range every day of the R 63373 of disease described herein or derivative is from the about 1200mg of about 50mg-, can be single dose or packing dosage.Preferably, the dosage range of every day should can be single dose or packing dosage, and most preferably, the dosage range of every day should be a packing dosage between the about 400mg of about 200mg-between the about 800mg of about 100mg-.In treatment patient's process, treatment should roughly be the about 200mg of about 100mg-from less dosage, then, according to patient's general reaction, is increased to about 400mg or bigger dosage.Also recommend the patient of children, over-65s and the patient of kidney or liver dysfunction, accept low dose during beginning, described dosage can be determined according to individual reaction and blood levels.In some cases, need to use these scopes dosage in addition, this is conspicuous for those skilled in the art.In addition, it should be noted that how and when clinician or treatment doctor should know to interrupt, adjusts or finish according to the reaction of individual patient treats.Be enough to alleviate or preventing infection but be not enough to cause that the amount of side effect is included by above-mentioned dosage and administration frequency scheme.
For the R 63373 or the derivative of significant quantity are provided to the patient, can use any suitable route of administration.For example, can use form of medication such as mouth, rectum, gi tract outer (subcutaneous, intramuscular, intravenously), transdermal, part.Formulation comprises tablet, lozenge, dispersion agent, suspension agent, solution, capsule, patch, ointment, emulsifiable paste, shampoo etc.
Pharmaceutical composition hydroxyl itraconazole of the present invention or derivative are as activeconstituents, and perhaps its pharmacologically acceptable salt also can contain pharmaceutically acceptable carrier, and when needing, also can contain the other treatment composition.
Term " pharmacologically acceptable salt " or " its pharmacologically acceptable salt " refer to from the salt of pharmaceutically acceptable non-toxicity acid that comprises inorganic bronsted lowry acids and bases bronsted lowry and organic bronsted lowry acids and bases bronsted lowry or alkali preparation.Because oxy-compound of the present invention is alkaline, so can be from comprising inorganic and the pharmaceutically acceptable non-toxicity acid preparation salt of organic acid.The pharmaceutically acceptable acid additive salt of suitable The compounds of this invention comprises acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid, fumaric acid, gluconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, two hydrogen naphthoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Phosphoric acid and sulfuric acid can be used for preparing the salt and the inner salt of alkali as acid.The suitable pharmaceutically acceptable base addition salt of The compounds of this invention comprises from the metal-salt of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc preparation or from Methionin, N, the organic salt of N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumine (N-methylglucosamine) and PROCAINE HCL, PHARMA GRADE preparation.
The present composition comprises the composition as suspension agent, solution, elixir, vapour sol and solid dosage.Carrier such as starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc. are usually used in oral solid formulation (as powder, capsule and tablet), and oral solid formulation is preferable over oral liquid.Most preferred oral solid formulation is a tablet.
Owing to be easy to administration, tablet and capsule have been represented best oral dosage form, wherein can use the solid medicinal carrier.If desired, can pass through standard aqueous or the agent of non-aqueous techniques peridium patch.
Second kind of preferred route of administration is topical, and for this approach, emulsifiable paste, ointment, shampoo etc. suit.
Except that above-mentioned listed regular dosage form, also can use The compounds of this invention by controlled release method and/or transfer device, because its solubleness, also available gi tract outer solution, for example intravenous administration.
Be applicable to that oral pharmaceutical composition of the present invention can be used as discrete units and provides, as capsule, cachet or tablet or vapour colloidal sol sprays, per unit contains the activeconstituents of predetermined amount, as powder or particle, or the solution in liquid, aqueous or suspension, non-liquid, aqueous, O/w emulsion or water-in-oil liquid emulsion.Can prepare described composition by any method of pharmacy, but all methods include with activeconstituents with constitute the carrier that one or more must composition and carry out associating step.In a word, by activeconstituents is evenly compactly mixed with liquid vehicle or thin solid carrier or two kinds of carriers, then, product can be made required shape if desired and prepare described composition.
For example, optionally can prepare tablet by compacting or one or more ancillary components of mold pressing.Optionally prepare the tablet of compacting with suitable machine by compacting with the free-flowing form of tackiness agent, lubricant, inert diluent, tensio-active agent or dispersant such as powder or particulate activeconstituents.The mold pressing tablet can prepare with the wetting powder compounds mixture of inert liquid diluent by mold pressing with suitable machine.Needed is that each tablet contains the activeconstituents of 100mg to about 300mg of having an appointment.Most preferably, tablet, cachet or capsule contain one of following three kinds of dosage: about 50mg, about 100m or about 200mg activeconstituents.
For topical application, can be used as non-sprayable form, sticking or semifixed or solid form uses, described form contains and adapts with topical application and dynamic viscosity is better than the carrier of water.Suitable preparation comprises, but be not limited to solution, suspension agent, emulsion, emulsifiable paste, ointment, powder agent, liniment, ointment, vapour colloidal sol etc., if desired, described preparation available secondary auxiliary agent such as sanitas, stablizer, wetting agent, the damping fluid that influences osmotic pressure or salt etc. are stable or mix.For topical application, also available sprayable vapour colloidal sol goods wherein preferably with activeconstituents, are preferably packed with compression bottle with solid or liquid inert support material or normally gaseous propellant such as freonll-11 mix with the compression volatile matter.
With reference to following present composition preparation method with and uses thereof the embodiment of detailed description further define the present invention.It will be apparent for a person skilled in the art that and to carry out many modifications and not depart from purpose of the present invention material and method.
Embodiment 1
Oral preparations-capsule
| Prescription | Amount in every capsule (mg) | ||
| A | B | C | |
| R 63373 | 50 | 100 | 200 |
| Lactose | 380 | 330 | 230 |
| W-Gum | 65 | 65 | 65 |
| Magnesium Stearate | 5 | 5 | 5 |
| Pressing weight | 500 | 500 | 500 |
Activeconstituents R 63373 or derivative are sieved also and mixed with excipients.With suitable machine mixture is filled in two glutoid of suitable size.By changing filling dose, if desired and change the big I of capsule and prepare other dosage.
Embodiment 2
Oral preparations-tablet
| Prescription | Amount in every tablet (mg) | ||
| A | B | C | |
| R 63373 | 50 | 100 | 200 |
| Lactose | 109 | 390 | 209 |
| W-Gum | 30 | 30 | 30 |
| Water (per thousand tablets) * | 300mL | 300mL | ?300mL |
| W-Gum | 60 | 60 | 60 |
| Magnesium Stearate | 1 | 1 | 1 |
| Pressing weight | 250 | 500 | 500 |
*In preparation process, the water evaporation.
Activeconstituents is mixed with lactose up to forming uniform mixture.To mix with water to form corn cream than W-Gum in a small amount.Then corn cream is mixed with uniform mixture up to forming uniformly wet material and adding remaining W-Gum, mix up to forming homogeneous granules.With 1/4 " stainless steel mesh is by the suitable runner milling particle that sieves.The particle of milling is also milled by the suitable machine of milling in suitable drying oven drying again.Then Magnesium Stearate is mixed and the mixture of gained is pressed into the tablet of required shape, thickness, hardness and disintegrating property.
Claims (18)
1. pure basically single enantiomer or its salt of following formula: compound:
X wherein
1And X
2Be respectively chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
2. the compound that has the claim 1 of following structural:
3. the compound that has the claim 1 of following structural:
4. the compound of each of claim 1-3, wherein R is a hydrogen.
5. each compound of claim 1-3, wherein R is a phosphoric acid ester.
6. each compound of claim 1-3, wherein R is a sulfuric ester.
7. the pharmaceutical composition that contains following formula: compound:
Described composition contains other enantiomer or diastereomer or its salt and pharmaceutically acceptable carrier, the wherein X of the described compound that is less than 10% (weight)
1And X
2Be respectively chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
8. the pharmaceutical composition of claim 7 contains the single enantiomer of described compound and less than other enantiomer of the described compound of 10% (weight).
9. treat the method for fungi infestation, described method comprises the following formula: compound to the administration treatment significant quantity of suffering from described fungi infestation:
Described compound contains other enantiomer or its salt, the wherein X of the described compound that is less than 10% (weight)
1And X
2Be respectively chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
10. prevent the method for fungi infestation, described method comprises to the following formula: compound that the administration treatment significant quantity of suffering from described fungi infestation danger is arranged:
Described compound contains other enantiomer or its salt, the wherein X of the described compound that is less than 10% (weight)
1And X
2Be respectively chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
11. the method for claim 9 or 10 comprises the single enantiomer of the pure basically described compound of other enantiomer that is less than the described compound of 10% (weight) containing of administering therapeutic significant quantity.
12. the method for claim 9 or 10 comprises and uses following formula: compound:
13. the method for claim 9 or 10 comprises and uses following formula: compound:
14. the method for claim 9 or 10, wherein said fungi infestation are the maincenter moniliosis.
15. preparation following formula 2, the dibasic 3H-1 of 4-, 2, the method for 4-triazole-3-ketone,
R wherein
1Be the aryl of aryl or replacement, this method comprises, with the 2-aryl-3H-1 of following formula, and 2,4-triazole-3-ketone
Anti-4 with following formula, 5-dimethyl-1,2,3-two oxa-tetramethylene sulfides 2, the reaction of 2-dioxide,
Be by, in inert solvent, at least one equivalent 1,4,7,10,13,16-, six oxygen ring octadecanes (18-hat-6) exist down, form described 2-aryl-3H-1 with excessive potassium hydride KH, 2, the sylvite of 4-triazole-3-ketone adds described two oxa-tetramethylene sulfides down in-5 ℃ to 25 ℃ then.
16. the method for claim 15, wherein R
1Be
R wherein
2Be methyl-benzyl, and described two oxa-tetramethylene sulfides be (4S, 5S)-4,5-dimethyl-1,2,3-two oxa-tetramethylene sulfides 2,2-dioxide.
17. the method for the dioxolane tosylate of preparation following formula,
Wherein Ph is the phenyl of phenyl or replacement, and Tos is a tosyl group, R
3Be heterocyclyl methyl, this method comprises:
(a) with formula R
3The ketone of C (O) Ph and about 1 normal optical activity 1,2-dihydroxy phenyl tosylate is dissolved in the inert solvent;
(b) temperature is cooled to below 15 ℃;
(c) in adding excessive trifluoromethanesulfonic acid below 15 ℃;
(d) make the above-mentioned substance reaction generate ketal; With
(e) under 0 ℃-10 ℃, the solution of described ketal is joined in the aqueous solution of excess base metal carbonate or supercarbonate.
18. the method for claim 17, wherein R
3Be (1,2,4-triazole-2-yl) methyl, Ph is the 2,4 dichloro benzene base, described optical activity 1, and 2-dihydroxy phenyl tosylate is the S configuration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2999296P | 1996-11-12 | 1996-11-12 | |
| US60/029,992 | 1996-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1237173A true CN1237173A (en) | 1999-12-01 |
Family
ID=21851969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97199657A Pending CN1237173A (en) | 1996-11-12 | 1997-11-12 | 2R, 4S, R, R- and 2S, 4R, R, R-hydroxyitraconazole |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0938484A1 (en) |
| JP (1) | JP2001504466A (en) |
| CN (1) | CN1237173A (en) |
| AU (1) | AU5251398A (en) |
| CA (1) | CA2269622A1 (en) |
| WO (1) | WO1998021205A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105582012A (en) * | 2016-02-29 | 2016-05-18 | 扬州艾迪生物科技有限公司 | Application of 3'-hydroxyitraconazole |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6147077A (en) * | 1999-04-29 | 2000-11-14 | Sepracor Inc. | 2R,4S-hydroxyitraconazole isomers |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69330248T2 (en) * | 1992-03-18 | 2002-03-21 | Janssen Pharmaceutica N.V., Beerse | ITRACONAZOLE AND SAPERCONAZOLE STEREOISOMERS |
| ZA9410142B (en) * | 1993-12-21 | 1996-05-02 | Schering Corp | Tetrahydrofuran antifungals |
| WO1995019983A1 (en) * | 1994-01-24 | 1995-07-27 | Janssen Pharmaceutica N.V. | Watersoluble azole antifungals |
| ES2112151B1 (en) * | 1995-03-17 | 1999-09-16 | Menarini Lab | NEW HOMOQUIRAL COMPOUNDS FOR THE PREPARATION OF KETOCONAZOLE, THERONAZOLE AND RELATED ANTIFUNGICS, PROCEDURE FOR THEIR MANUFACTURE AND USE OF THEM. |
-
1997
- 1997-11-12 CN CN97199657A patent/CN1237173A/en active Pending
- 1997-11-12 WO PCT/US1997/020462 patent/WO1998021205A1/en not_active Ceased
- 1997-11-12 AU AU52513/98A patent/AU5251398A/en not_active Abandoned
- 1997-11-12 CA CA002269622A patent/CA2269622A1/en not_active Abandoned
- 1997-11-12 JP JP52272598A patent/JP2001504466A/en active Pending
- 1997-11-12 EP EP97947428A patent/EP0938484A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105582012A (en) * | 2016-02-29 | 2016-05-18 | 扬州艾迪生物科技有限公司 | Application of 3'-hydroxyitraconazole |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001504466A (en) | 2001-04-03 |
| CA2269622A1 (en) | 1998-05-22 |
| EP0938484A1 (en) | 1999-09-01 |
| AU5251398A (en) | 1998-06-03 |
| WO1998021205A1 (en) | 1998-05-22 |
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