CN1237174A - 2R, 4S, S, R- and 2S, 4R, S, R-hydroxyitraconazole - Google Patents
2R, 4S, S, R- and 2S, 4R, S, R-hydroxyitraconazole Download PDFInfo
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- CN1237174A CN1237174A CN97199658A CN97199658A CN1237174A CN 1237174 A CN1237174 A CN 1237174A CN 97199658 A CN97199658 A CN 97199658A CN 97199658 A CN97199658 A CN 97199658A CN 1237174 A CN1237174 A CN 1237174A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Abstract
A method of preparation of optically pure isomers of hydroxyitraconazole, in particular the two cis dioxolane diastereomers of the sec-butyl (S,R)-isomer, and to phosphate and sulfate derivatives thereof is disclosed. Pharmaceutical compositions containing these compounds and to their use for the treatment of fungal infection are also disclosed.
Description
Invention field
The present invention relates to the optically pure isomer of R 63373 (hydroxyitraconazole), particularly sec-butyl (R, S)-preparation method of two cis dioxolane diastereomers of isomer, with and phosphoric acid ester and sulfate derivative.The invention still further relates to the application of the pharmaceutical composition that comprises these compounds and their treatment fungi infestation.
Background of invention
Itraconazole is a kind of well-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-[p-[4-[p-[((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.Commercially available material is the isomer that is cis in the dioxolane, represents with the structural formula I:
To notice that three asymmetric carbons (representing with asterisk) are arranged in the formula I: two in dioxolane, one on the sec-butyl side chain of triazolone.Have the structure of three asymmetric carbons that eight possible isomer are arranged: (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 commercially available itraconazole is a cis-isomeride, it comprises those and only be the mixture of isomers of cis relation in dioxolane.By convention, the chiral centre of first mark is at the C-2 place of dioxolane, and second at the C-4 place of dioxolane, and the 3rd in sec-butyl, commercially available itraconazole be (R, S, S), (R, S, R), (S, R, S) and (S, R, R) mixture of isomers.Compound of the present invention in dioxolane, have (2R, 4S) and (2S, 4R) configuration.
The methylene radical of sec-butyl side chain is carried out hydroxylation can produce another chiral centre, and produce other eight possible enantiomorphs.Compound of the present invention is that two center of asymmetries in the butyl chain are those compounds of R (at α carbon place) and S (at β carbon place).
Graphic representation at the compound of this used racemize, ambiscalemic, scalemic or enantiomer-pure is taken from Maehr J.Chem.Ed.62,114-120 (1985): solid wedge shape and empty wedge shape are used to represent the absolute configuration of chiral element: the setback line represents that the key of its representative can not produce any stereochemistry connotation; Real thick line and empty thick line are to show relative configuration but geometrical symbol that racemize character is arranged; And wedge profile line and dotted line represent not determine the enantiopure compound of absolute configuration.Therefore, in following structure, those have hollow wedge shape person comprise two should be to pure enantiomorph, those have solid wedge shape person comprise single, have shown in the pure enantiomorph of absolute stereo chemistry.
Itraconazole is a kind of oral, broad spectrum of activity anti-mycotic agent, and is close with clotrimazole (clotrimazole) with miconazole (miconazole) on its structure.It damages the synthetic of ergosterol, and ergosterol is the main sterol of fungal cell membrane.This might cause the perviousness of entocyte and leak increasing.When high density, the degeneration of cell within a cell device, the increase and the necrosis of peroxisome take place.
Behind the oral administration, itraconazole slowly absorbs.Behind 15 days of administration every day, reach peak plasma concentrations, and the pharmacokinetic properties of itraconazole is non-linear.This compound is the metabolite of several non-activities by bioactive R 63373 by final metabolism.Metabolism obviously is by hepatic metabolism mechanism, and in Most patients, does not have metabolite to drain (seeing people such as Hardin, Antimicro.Agents and Chemotherapy 32,1310-1313 (1988)) from urine.
The racemic compound of itraconazole has gone through to be used for the treatment of blastomycosis and histoplasmosis as anti-mycotic agent.Also investigated the effect of this compound in treatment aspergillosis, coccidioidomycosis, torulosis, tinea unguium, dermatophytes and moniliosis infect.
General fungal disease (whole body mycosis) normally chronic, development illness very slowly, bring out by the fungi of opportunistic diseases, this fungi under normal circumstances is not pathogenic.But when they enter infringements such as suffering HIV, ionizing rays, reflunomide, immunosuppressor, during the host that perhaps damaged by for example illnesss such as pulmonary emphysema, bronchiectasis, diabetes, white thin disease, burn, they become pathogenic.The symptom of these fungal diseases is not serious usually, can comprise that fever, shiver with cold, apocleisis and body weight reduce, uncomfortable and depression.Fungal disease often is confined to typical anatomy and distributes, and many illnesss relate to the primary lesion in lung, when fungi when primary lesion spreads, show as more distinctive concrete fungi infestation.For example, the initial stage of coccidioidomycosis is a respiratory disease acute, benign, self limiting, develops into PD from former form, and it shows as the chronic infection of skin, lymph gland, spleen and liver, and this infection is normally fatal.Similarly, the blastomycosis initial stage relates to lung, and extends to skin sometimes.Other infectious diseases such as moniliosis then have different pathogenic processes with Brazilian blastomycosis, and can show as several forms according to etiology, wherein relate to skin, mucous membrane, lymphoglandula and internal.
Surface fungi infestation is by dermatophytes or relate to the outer field fungi of skin, hair or nail and cause.This infection can form slight inflammation, and causes discontinuity recurrence and deterioration that enlarge gradually, lepidiod, the projection damage.The yeast infection that comprises moniliosis, oral candidiasis (mycodermatitis) is confined on skin and the mucous membrane usually, and its symptom changes with infecting the position.
The side effect relevant with oral itraconazole comprises liver toxicity and suppresses the metabolism of medicine in liver, cause tangible on the various clinical, disadvantageous drug interaction (to be seen: Gascon and Dayer, Eur.J.Clin.Pharmacol.41,573-578 (1991) (interacting) with midazolam (midazolam); People such as Honing, J.Clin.Pharmacol.33,1201-1206 (1993) (interacting) with terfenadine (terfenadine); And people such as Neuvonen, Clin Pharmacol.Therap.60,54-61 (1996) (interacting) with lovastatin (lovastatin)).Comprise that urticaria is also relevant with this medicine of administration with the anaphylaxis that the serum liver enzyme raises.Liver toxicity is uncommon, but severe side effect more.Really, do not encourage usually to orally use the health azole drug as first-selected anti-mycotic agent, this is (for example see, people such as Lavrijsen, Lancet 340,251-252 (1992)) because the hepatotoxic potential serious consequence of low incidence.
We study in cavy of exsomatizing or rabbit heart, confirm that the dangerous increase of racemic health azole drug of administration and arrhythmia is relevant.At present do not report that arrhythmia is the side effect of itraconazole general administration, but existing produce an ARR special paratype when reporting itraconazole of administration racemize at the same time and terfenadine--torsades de pointes type chamber speed (Torsades de Pointes) (people such as Pohjola, Eur.J.Clin.Pharmacol.45,191-193 (1993)).Lacking the unusual clinical report of relevant arrhythmia or QT can think simply owing to present patient's comparatively small amt.
Nonpolar relatively and insoluble two other defective of generation of itraconazole: it is difficult for being formulated in the solution of parenteral administration, and can not see through hemato encephalic barrier.Consequently, many treatment indications need reach effective haemoconcentration fast or need enter CNS, therefore can not treat with itraconazole.Maincenter moniliosis in particular to the dementia relevant with AIDS just can not be treated with itraconazole.
Therefore, the special compound of wishing to find to have the advantage of itraconazole but not having above-mentioned defective.
The invention summary
Compound of the present invention and composition have potent activity to treating part and general fungi, yeast and dermatophytid infection, and have avoided the side effect relevant with the administration itraconazole simultaneously.Compound of the present invention and composition also have special advantage: more be soluble in the physiological compatibile solution than itraconazole.The preparation of the independent enantiomorph of R 63373 makes and can make the very single diastereomer and the derivative thereof of processable for the first time.
In one aspect, the present invention relates to pure basically single enantiomer or its salt of following structural formula compound:
X wherein
1And X
2Be chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.At this two these possible single enantiomers are arranged, represent with following structural formula A and B respectively:
In one aspect of the method, the present invention relates to comprise the pharmaceutical composition of acceptable carrier on above-claimed cpd and the pharmacology.Said composition comprises and is lower than other enantiomorphs or the diastereomer that 10 weight % have the same structure formula.Preferably, described composition comprises single enantiomorph A or B.
In one aspect of the method, the present invention relates to treat or prevent the method for fungi infestation, it comprises the above-claimed cpd to the Mammals drug treatment significant quantity of suffering from fungi infestation (or fungi infestation danger is arranged).
In one aspect of the method, the present invention relates to prepare 2 of following formula, the dibasic 3H-1 of 4-, 2, the method for 4-triazole-3-ketone:
Wherein: R
1Be aryl or the aryl that is substituted.Described method comprises the 2-aryl-3H-1 that makes following formula, 2, and 4-triazole-3-ketone
Trans 4 with following formula, 5-dimethyl-1,2,3-sulphur dioxide generation penta ring (dioxathiolane) 2, the reaction of 2-dioxide,
Wherein, in inert solvent, at least 1 equivalent 1,4,7,10,13,16-six oxygen ring octadecanes (18-hat-6) exist down, make described 2-aryl-3H-1,2,4-triazole-3-ketone and the excessive corresponding sylvite of potassium hydride KH reaction formation add described sulphur dioxide generation penta ring down at-5 ℃ to 25 ℃ then.When the enantiomorph of synthetic itraconazole, R
1Preferably
R wherein
2Be methyl or benzyl.
In one aspect of the method, the present invention relates to prepare the method for the dioxolane methanesulfonates of following formula:
Wherein, Ph is phenyl or the phenyl that is substituted, and Tos is a tosyl group, and R
3It is heterocyclic methyl.Described method comprises the step of following order: (a) with formula R
3The ketone of C (O) Ph and about 1 normal optically active 1,2-dihydroxypropyl methanesulfonates is dissolved in the inert solvent; (b) be cooled to and be lower than 15 ℃ temperature; (c) add excessive trifluoromethanesulfonic acid down at＜15 ℃; (d) make the above-mentioned substance reaction form ketal; (e) is introduced into the ketal in solution in the excessive alkaline carbonate or bicarbonate aqueous solution down at 0-10 ℃ then.Detailed description of the Invention
Compound of the present invention is to come synthetic by the conventional route shown in following synthetic route 1,2,3 and 4:
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
Reaction scheme 4
Shown in reaction scheme 1, chirality dioxolane DTTT (3) according to the stereospecificity literature method from R-3-tosyloxy-1,2-propylene glycol or S-3-tosyloxy-1, the 2-propylene glycol prepares by acid catalyzed ketal reaction, produces the RR or the SS-DTT of enantiomer-pure respectively.
Shown in reaction scheme 2, handle with thionyl chloride, exist under the condition of ruthenium trichloride then, with the cyclic sulfite of sodium periodate in-situ oxidation gained, the butyleneglycol from suitable configuration prepares described sulphur dioxide generation penta ring 5 thus.
Shown in reaction scheme 3, in the presence of crown ether, with the potassium hydride KH among the DMF, will be according to United States Patent (USP) 4,267, in 179 2 of the method preparation of embodiment X VII, 4-dihydro-4-[4-[4-(p-methoxy-phenyl)-piperazinyl] phenyl]-3H-1,2,4-triazole-3-ketone (6) and sulphur dioxide generation penta ring 5 reactions according to the preparation of the method for Gao and Sharpless (J.Am.Chem.Soc.110,7538 (1988)).Under 100-110 ℃,, thus gained methoxyl group sulfuric acid is cracked into phenol-alcohol 8 with the 48%HBr heating.
Shown in reaction scheme 4, in the presence of the DMF of potassium hydroxide solution,, obtain the product 9 of enantiomer-pure basically with the phenol in tolylsulfonyl ester in the reaction scheme 13 and the reaction scheme 3-alcohol 8 reactions.
When the R in needing A or B is sulfuric ester, the sequence of steps in the rearrangeable reaction scheme 3 and 4 so that 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 ester; at first handle 8 with protection phenol with tert-butyldimethylsilyl chloride and diisopropyl ethyl amine; handle with dibenzyl diisopropylphosphoramidite and tertbutyl peroxide according to the method for PCT application WO95/17407 then, so that with pure phosphorylation.Remove the silyl protecting group with anhydrous tetrabutyl ammonium fluoride, press phosphoric acid and the dioxolane tosylate coupling of reaction scheme 3 then benzyl protection.Exist under the condition of palladium catalyst, by hydrogenolysis cracking benzyl protecting group to obtain phosphate product.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 (3a benzene methanesulfonic acid ester 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) ketene (10.0g, 39mmol) suspension in toluene (50ml) is cooled to 5 ℃.Slowly add trifluoromethane sulfonic 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.At 25 ℃ of ethyl acetate solutions (50ml) that slowly add toluenesulphonic acids (TsOH) (7.6g monohydrate).After 30 minutes, filter white solid product, washing and drying obtain containing 5% trans suitable DTTT.Use CH
3CN (400ml) carries out recrystallization, 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 (3b benzene methanesulfonic acid ester salt)
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) ketene (15.2g, 58mmol) suspension in toluene (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 ℃.With methylene dichloride (300ml) diluted mixture thing and slowly splash 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 add down slowly TsOH (11.0g monohydrate).After 30 minutes, filter white solid product, washing is also dry, obtains containing 6% trans suitable DTTT.Use CH
3CN (600ml) carries out recrystallization, obtain 16.6g pure (2S, 4R)-DTTT (44% productive rate).[a]
D 25=-16.6°(c=1,MeOH)；ee=99.6％。Preparation (4R, 5R)-4,5-dimethyl-1,2,3-sulphur dioxide generation penta ring 2,2-dioxide (5)
In the three neck 500ml round-bottomed flasks that have reflux exchanger and calcium chloride dry test-tube, add (2R, 3R)-(+)-2,3-butyleneglycol (4) (10.0g, 10.1ml, 0.11mol) and tetracol phenixin (120mL).Thionyl chloride under the room temperature (16.0g, 9.8ml, 0.13mol).Gas is emitted rapidly.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 and and extract water (2 * 100ml) with methyl tertiary butyl ether.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 16.01g (quantitatively property productive rate).Preparation (2R, 3S)-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)
In room temperature, to using the hexane (potassium hydride KH (530mg of 2 * 50ml) pre-wash, 4.6mmol, 35wt% oil dispersion liquid) at N, (980mg is 3.7mmol) with 2 to add 18-hat-6 in the suspension in the dinethylformamide (37ml), 4-dihydro-4-[4-[4-(4-p-methoxy-phenyl)-1-piperazinyl] phenyl] 3H-1,2, and 4-triazole-3-ketone (6) (1.09g, 3.3mmol).With solution be heated to 80-85 ℃ 1.5 hours, in frozen water, be cooled to 0 ℃ then.In this solution, add (4R, 5R)-4,5-dimethyl-1,2,3-sulphur dioxide generation penta ring 2,2-dioxide (5) (500mg, 3.3mmol).Reaction mixture heat release to 4 ℃.Be cooled to 0 ℃ again, then reaction mixture be heated to room temperature and stirred 21 hours.Mixture is annotated in 150ml toluene and the 400ml methyl tert-butyl ether, from mixture, filtered white depositions.Solid is dry under vacuum, obtains the title compound of 1.70g (quantitative yield) and 87: 13 mixtures (HPLC) of triazolone initiator.The partial confounding compound carries out pure system with flash chromatography (95: 5 chloroforms: methyl alcohol is to the gradient of methyl alcohol) and is used for characterizing.Preparation 2,4-dihydro-4-[4-[4-(4-hydroxy phenyl)-1-piperazinyl] phenyl]-2-[(1S, 2R)-2-hydroxyl-1-methyl-propyl]-3H-1,2,4-triazole-3-ketone (8)
To (2R, 3S)-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 sulfuric ester potassium (7) (1.50g, 2.98mmol) and S-WAT (84mg, 0.67mmol) in adding 48%HBr (6.0ml).With solution be heated to 110-115 ℃ 7 hours, be cooled to room temperature then.Reaction mixture is annotated in the wide-mouth beaker, slowly added solid carbonic acid potassium pH is risen to 7.Add water (100ml), filter and collect product and vacuum-drying.Crude product is carried out the pure system of flash chromatography, and with chloroform to 95: 5 chloroforms: the gradient elution of methyl alcohol obtains 1.03g (70% productive rate) title compound and SO
3The product of addition.Preparation (2S, 4R)-4-[4-[4-[4-[[2-(2, 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-[(1S, 2R)-(2-hydroxyl-1-methyl-propyl)]-and 3H-1,2,4-triazole-3-ketone (B)
To 2,4-dihydro-4-[4-[4-(4-hydroxy phenyl)-1-piperazinyl] phenyl]-2-[(1S, 2R)-(2-hydroxyl-1-methyl-propyl)]-3H-1,2,4-triazole-3-ketone SO
3Affixture (8) (420mg, 0.86mmol) and (-)-(2S, 4S)-2-(2, the 4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl methyl)-4-tosyloxy methyl isophthalic acid, 3-dioxolane tosylate (3b benzene methanesulfonic acid ester) (637mg, 0.97mmol) in add the potassium hydroxide powder (277mg, 4.94mmol) and N, dinethylformamide (15ml).With reaction mixture be heated to 50-55 ℃ 8 hours, be cooled to room temperature then.Add entry (150ml), collect crude product, vacuum-drying then by filtering.Use purification by flash chromatography, with ethyl acetate, chloroform, 98: 2 chloroforms then: methyl alcohol, 95: 5 chloroforms: methanol-eluted fractions, recrystallization obtains the title compound of 320mg (52% productive rate) from methyl alcohol; [a]
D 25=-22.0 ° (c=0.1, MeOH).
(2S, 4R)-4-[4-[4-[4-[[2-(2, 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-[(1S, 2R)-(2-hydroxyl-1-methyl-propyl)]-and 3H-1,2,4-triazole-3-ketone (A) can be according to preparing with the similar method of dioxolane tosylate 3b.
Wherein X1 and X2 are that the compound of fluorine can make by similar method by suitable 3, described 3 press shown in the reaction scheme 1 by condensation by suit 2,4-phenyl-dihalide ethyl ketene makes.
Term used herein " pure basically single enantiomer " refers to exist other enantiomorph that is lower than 10% (weight).Described composition contains the R 63373 or derivatives thereof, and wherein at least 90% R 63373 has above-mentioned stereochemical cis dioxolane and sec-butyl side chain.
Available microorganism and pharmaceutical research are determined the relative utility and the specificity figure of optical purity enantiomorph, and the racemic mixture of the itraconazole of the broad-spectrum antifungals of conduct anti-multiple fungi, yeast and dermatophytes.
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 antifungal property health azole drug and bacterium several concentration (in μ l/ml).(referring to Van Cutsem, Chemotherapy 38 Suppl 1,3-11 (1992); And Van Cutsem etc., Rev.Infec.Dis.9 Suppl 1, S15-S32 (1987)).With 16 * 160mm test tube, finish the antifungal test at Sabouraud ' s liquid (every 100ml distilled water contains the neopeptone Difco of 1g and the glucose Difco of 2g), each test tube 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.In the test tube that contains 4.5ml Sabouraud ' s liquid nutrient medium, add the 0.5ml drug solution, obtain the substratum that concentration is 1000,500,100,10 and 1 μ g/mL thus.0.5ml distilled water is added in the 4.5ml substratum, add ethanol and obtain and the identical concentration of test tube that contains 1000 and 500 μ g medicines, thus preparation contrast test tube.At 25 ℃, filamentous fungus is cultivated 2-3 week in Sabouraud 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 Sabouraud liquid nutrient medium that contains 10% deactivation bovine serum, the itraconazole extracorporeal antifungal activity is improved, and described activity depends on used test medium.With Sabouraudites lanosus (Microsporum canis), trichophyton mentagrophytes (Trichophyton mentagrophytes), white candiyeast (Candidaalbicans), sporotrichum schenckii (Sporothrix schenckii), Brazil's class coccidioides immitis (Paracoccidioides brasiliensis), Blastomyces dermatitidis (Blastomycesdeermatitides), Histoplasma (Histoplasma spp.), Eurotium (Aspergillusspp.) and other fungi and bacterium can be observed the complete or significant growth-inhibiting effect in the Sabouraud liquid nutrient medium after 14 days of cultivating.
The 10ml test tube that will contain 4ml Sabouraud dextrose liquid nutrient medium uses a saccharomyces albicans that picks from the pure culture flat board to fall to inoculating.This bacterial strain is ordered from U.S. typical case culture collection center (ATCC).Make this organism 30 ℃ of growths 4 hours, vibrate with 150RPM simultaneously.When biology growing, the sample of R 63373 A and B is dissolved as the concentration of 10mg/ml with DMSO.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, white candiyeast is diluted to 0.5 McFarland standard in growth, this standard represents about 10
5-10
6Cell/mL and 1 μ L are placed on the described inoculum in each test holes of microtitre ware.Then this ware is covered and cultivated 16 hours at 30 ℃.The MIC of A and B is respectively 0.625 and be lower than 0.156 μ g/mL.
The Kirby-Bauer test
Active grown culture by above-mentioned preparation white candiyeast, novel Cryptococcus (Cryptococcusneoformens) and cereuisiae fermentum (Saccharomyces cerevisiae).Culture is diluted to 0.5 McFarland standard and swabs on 150mm Sabouraud 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.Under 30 ℃, flat board was cultivated 16 hours then.Be that the inhibitory area is measured by unit then with mm.Data are summarized as follows.
Data represented inhibitory area in millimeter.
| Compound | The white candiyeast | Novel Cryptococcus | Cereuisiae fermentum |
| Diastereomer A | ??????22 | ??????28 | ????22 |
| Diastereomer B | ??????25 | ??????25 | ????20 |
| ± itraconazole | ??????17 | ??????22 | ????15 |
Relatively R 63373 and derivative are to tentative dermatocandidiasis of cavy and the oidiomycotic activity in vivo of rat vagina.In the Wistar of oophorectomize and hysterectomy rat (100g), bring out vaginal infection with white candiyeast, assess the activity in vivo of described compound thus, wherein use the described rat of estradiol undecylate subcutaneous treatment in the 100 μ g sesame oil weekly for vaginal candidiasis.White candiyeast salt brine solution intravaginal with fixed concentration infects the animal that suffers from virtual genus fly (pseudooestrus).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, (Van Cutsem etc., Chemotherapy 17,392 (1972)) provide comparison basis to the oidiomycotic activity of guinea pig skin.
Compound of the present invention can be treated fungi infestation, can avoid the side effect relevant with itraconazole simultaneously.Term " side effect " include but not limited to cause rhythm disturbance (arrhythmo-genicity), liver toxicity and serum liver enzyme rising, drug interaction, comprise urticarial anaphylaxis, feel sick, vomiting, stomachache, headache, dizziness etc.
Detect action potential and the inotropic influence of R 63373 isomer to people, dog and the rabbit heart, assessment promotes the potentiality of rhythm disturbance thus.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 quinine, sotolol and acetyl PROCAINE HCL, PHARMA GRADE for example.All these medicines can both be blocked and be called the cell potassium channel (I that delays rectifier
K), 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 Zehender etc., Cardiovascular Drugs Ther., 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 the oxygenation Tyrode ' s solution perfusion heart that comprises 0.0,1.0,5.0,10.0 or 30.0 μ M racemize itraconazoles.Measure QT phase and action potential phase from heart electrode.
Act in order to observe in the body, with the mongrel anesthesia of arbitrary sex of body weight 5-20kg and with blood pressure and the detection of 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.The Hemodynamics of determination test compound and control compounds and electroactive comprises QT
cAt interval.
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, use the homogenate in 0.15M KCl of Polytron homogenizer then.Homogenate is centrifugal and suspend again with 0.15M KCl, 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 Ficoll-Paque upper berth layer.Sample is centrifugal, remove lymphocyte from moisture-Ficoll interface then, be suspended in then substratum (15mM HEPES, pH7.4) in.With cell centrifugation, with the washing of HEPES substratum once, and suspend again then.
By with 3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene Thiazolyl blue tetrazolium bromide (MTT) is transformed into formazan.In micropore, finish the transformation of MTT to dyestuff.After the preparation, in moistening insulation can, under 37 ℃, be that the test compound of 1-400 μ M is incubated separately or with concentration with hepatomicrosome or lymphocyte.After the insulation, with containing 5% albuminous HEPES buffered substratum washing microsome/cell and resuspension.After the insulation, 125 μ g MTT are added in each hole.Insulation is also centrifugal down at 37 ℃ with flat board.After centrifugal, add 100 μ l Virahols, after the insulation, determine optical density(OD) with automatic dull and stereotyped reading apparatus.
In the processing 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 to change with patient's age, body weight and individual reaction.Generally, 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 haemoconcentration.In some cases, need to use these scopes dosage in addition, this is conspicuous for those skilled in the art.In addition, should notice how and when clinician or treatment doctor should know to interrupt, regulates 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, parenteral route (subcutaneous, intramuscular, intravenously), transdermal, part.Formulation comprises tablet, lozenge, dispersion agent, suspensoid, solution, capsule, patch, ointment, emulsifiable paste, shampoo etc.
Pharmaceutical composition hydroxyl itraconazole of the present invention or derivative are as activeconstituents, and perhaps acceptable salt on its pharmacology also can contain acceptable carrier on the pharmacology, and when needing, also can contain the other treatment composition.
Term " acceptable salt on the pharmacology " or " acceptable salt on its pharmacology " refer to the salt of from the pharmacology that comprises inorganic bronsted lowry acids and bases bronsted lowry and organic bronsted lowry acids and bases bronsted lowry acceptable non-toxicity acid or alkali preparation.Because oxy-compound of the present invention is alkaline, thus can from comprise inorganic and organic acid pharmacology on acceptable non-toxicity acid preparation salt.Acceptable acid salt comprises acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, vinyl sulfonic acid, formic acid, gluconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, mandelic acid, methylsulfonic acid, mucic acid, nitric acid, pounces on acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc. on the pharmacology of suitable The compounds of this invention.Phosphoric acid and sulfuric acid can be used for preparing the salt and the inner salt of alkali as acid.The appropriate drug of The compounds of this invention goes up acceptable base addition salt and 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 non-aqueous techniques coated tablet.
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 parenteral route solution, for example intravenous administration.
Be applicable to that oral pharmaceutical composition of the present invention can be used as single cell and provides, as capsule, cachet or tablet or vapour colloidal sol sprays, every unit contains the activeconstituents of predetermined amount, described activeconstituents can be powder or particle, or solution or suspension in liquid, aqueous, non-liquid, aqueous, oil-in-water or the water-in-oil.Can prepare described composition by any method of pharmacy, but all methods include with activeconstituents with constitute the associating step of carrier that one or more must composition.In a word, activeconstituents is evenly fully mixed with liquid vehicle or thin solid carrier or two kinds of carriers, then, product can be made required shape if desired, can prepare described composition thus.
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.Wish every activeconstituents that comprises about 100mg-300mg.Most preferably, tablet, cachet or capsule contain the activeconstituents of one of following three kinds of dosage: about 50mg, about 100mg or about 200mg.
For topical application, can non-sprayable formulation, sticking or semifixed or solid dosage uses, described formulation contains and adapts with topical application and dynamic viscosity is better than the carrier of water.Suitable formulation includes but not limited to: solution, suspensoid, emulsion, ointment, ointment, powder agent, liniment, salve, vapour sol etc., if desired, described formulation can or be mixed with sterilization such as assistant agent such as sanitas, stablizer, wetting agent, the damping fluid that influences osmotic pressure or salt.For topical application, also available sprayable vapour sol preparation, wherein preferably activeconstituents is packed with compression bottle with solid or liquid inert support material or with the compression volatile matter normally gaseous propellant freonll-11 mix.
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
*In preparation process, the water evaporation.
| 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) * | ????300mL | ????300mL | ????300mL |
| W-Gum | ????60 | ????60 | ????60 |
| Magnesium Stearate | ????1 | ????1 | ????1 |
| Pressing weight | ????500 | ????500 | ????500 |
Activeconstituents is mixed with lactose up to forming uniform mixture.To mix with water to form cornmeal mush than W-Gum in a small amount.Then cornmeal mush 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 " the runner milling screening particle of stainless steel mesh by suiting.With the suitable drying oven drying of particle of milling, and mill by the suitable machine of milling again.Then Magnesium Stearate is mixed and the mixture of gained is pressed into 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 chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
2, compound as claimed in claim 1, it has following structural:
3, compound as claimed in claim 1, it has following structural:
4, as the described compound of one of claim 1-3, wherein, R is a hydrogen.
5, as the described compound of one of claim 1-3, wherein, R is a phosphoric acid ester.
6, as the described compound of one of claim 1-3, wherein, R is a sulfuric ester.
7. the pharmaceutical composition that contains following formula: compound:
Described composition contains acceptable carrier, wherein X on other enantiomorph of the described compound that is less than 10% (weight) or diastereomer or its salt and the pharmacology
1And X
2Be chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
8, pharmaceutical composition as claimed in claim 7, it contains the single enantiomer of described compound and less than other enantiomorph of the described compound of 10% (weight).
9, the method for treatment fungi infestation, its method comprises the following formula: compound to the Mammals drug treatment significant quantity of suffering from described fungi infestation:
Described compound comprises other enantiomorph or its salt, the wherein X of the described compound that is less than 10% (weight)
1And X
2Be chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
10, the method for prevention fungi infestation, it comprises to the following formula: compound that the Mammals drug treatment significant quantity of suffering from described fungi infestation danger is arranged:
Described compound contains other enantiomorph or its salt, the wherein X of the described compound that is less than 10% (weight)
1And X
2Be chlorine or fluorine independently, R be hydrogen ,-P (O) (OH)
2Or-SO
3H.
11, as claim 9 or 10 described methods, it comprises the single enantiomer of the pure basically described compound of other enantiomorph that is less than the described compound of 10% (weight) containing of drug treatment significant quantity.
12, as claim 9 or 10 described methods, it comprises the administration following formula: compound:
13, as claim 9 or 10 described methods, it comprises the administration following formula: compound:
14, as claim 9 or 10 described methods, wherein, described fungi infestation is the maincenter moniliosis.
15,2 of the preparation following formula, 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, makes the 2-aryl-3H-1 of following formula, 2, and 4-triazole-3-ketone
Trans 4 with following formula, 5-dimethyl-1,2,3-sulphur dioxide generation penta ring 2, the reaction of 2-dioxide,
Wherein, in inert solvent, at least one equivalent 1,4,7,10,13,16-six oxygen ring octadecanes (18-hat-6) exist down, with excessive potassium hydride KH with described 2-aryl-3H-1,2,4-triazole-3-ketone forms sylvite, adds described sulphur dioxide generation penta ring down in-5 ℃ to 25 ℃ then.
16, method as claimed in claim 15, wherein, R
1Be
R wherein
2Be methyl or benzyl, and described sulphur dioxide generation penta ring is that (4R, 5R)-4,5-dimethyl-1,2,3-sulphur dioxide encircle 2 for penta, the 2-dioxide.
17, the method for the dioxolane tosylate of preparation following formula,
Wherein Ph is the phenyl of phenyl or replacement, Tos 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 equivalent are optically active 1, and 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, method as claimed in claim 17, wherein, R
3Be (1,2,4-triazole-2-yl) methyl, Ph is the 2,4 dichloro benzene base, and described optically active 1,2-dihydroxy phenyl tosylate is the S configuration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2999896P | 1996-11-12 | 1996-11-12 | |
| US60/029,998 | 1996-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1237174A true CN1237174A (en) | 1999-12-01 |
Family
ID=21851995
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97199658A Pending CN1237174A (en) | 1996-11-12 | 1997-11-12 | 2R, 4S, S, R- and 2S, 4R, S, R-hydroxyitraconazole |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0942907A1 (en) |
| JP (1) | JP2001504464A (en) |
| CN (1) | CN1237174A (en) |
| AU (1) | AU5251298A (en) |
| CA (1) | CA2269616A1 (en) |
| WO (1) | WO1998021203A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112521378A (en) * | 2019-12-26 | 2021-03-19 | 上海英诺富成生物科技有限公司 | Antifungal water-soluble prodrug and preparation method thereof |
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 |
|---|---|---|---|---|
| PT631578E (en) * | 1992-03-18 | 2001-11-30 | Janssen Pharmaceutica Nv | STEREOISOMERS OF ITRACONAZOLE AND SAPERCONAZOLE |
| WO1995017407A1 (en) * | 1993-12-21 | 1995-06-29 | Schering Corporation | Tetrahydrofuran antifungals |
| ES2141329T3 (en) * | 1994-01-24 | 2000-03-16 | Janssen Pharmaceutica Nv | AZOLIC ANTIFUNGALS SOLUBLE IN WATER. |
| 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 AU AU52512/98A patent/AU5251298A/en not_active Abandoned
- 1997-11-12 JP JP52272398A patent/JP2001504464A/en active Pending
- 1997-11-12 CA CA002269616A patent/CA2269616A1/en not_active Abandoned
- 1997-11-12 WO PCT/US1997/020460 patent/WO1998021203A1/en not_active Application Discontinuation
- 1997-11-12 EP EP97947427A patent/EP0942907A1/en not_active Withdrawn
- 1997-11-12 CN CN97199658A patent/CN1237174A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112521378A (en) * | 2019-12-26 | 2021-03-19 | 上海英诺富成生物科技有限公司 | Antifungal water-soluble prodrug and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001504464A (en) | 2001-04-03 |
| CA2269616A1 (en) | 1998-05-22 |
| WO1998021203A1 (en) | 1998-05-22 |
| AU5251298A (en) | 1998-06-03 |
| EP0942907A1 (en) | 1999-09-22 |
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