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WO1992017474A1 - Agents fongicides au triazole - Google Patents

Agents fongicides au triazole Download PDF

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Publication number
WO1992017474A1
WO1992017474A1 PCT/EP1992/000697 EP9200697W WO9217474A1 WO 1992017474 A1 WO1992017474 A1 WO 1992017474A1 EP 9200697 W EP9200697 W EP 9200697W WO 9217474 A1 WO9217474 A1 WO 9217474A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
alkyl
oxadiazol
substituted
Prior art date
Application number
PCT/EP1992/000697
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English (en)
Inventor
Roger Peter Dickinson
Original Assignee
Pfizer Limited
Pfizer Inc.
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Filing date
Publication date
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Publication of WO1992017474A1 publication Critical patent/WO1992017474A1/fr

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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
    • 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
    • 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

Definitions

  • This invention relates to triazole derivatives which have antifungal activity.
  • this invention relates to 2-aryl-3-heteroaryl-1-(1H-1,2,4-triazol-1-yl)alkan-2-ols which are useful in the treatment of fungal infections in animals, including human beings.
  • Ihe compounds of the present invention are particularly active as antifungal agents against certain clinically important species of fungus such as Candida spp., Aspergillus spp. or
  • the invention provides triazole antifungal compounds of the formula:-
  • R is phenyl optionally substituted by 1 to 3
  • R 1 is C 1 -C 4 alkyl
  • R 2 is H or C 1 -C 4 alkyl
  • Het is oxazol-2-yl, thiazol-2-yl,
  • halo is fluoro, chloro, bromo or iodo and C 3 and C 4 alkyl groups may be straight or branched chain.
  • the preferred C 1 -C 4 alkyl group is methyl.
  • R examples include 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 2-trifluoromethylphenyl, 2,4-dichlorop ⁇ henyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl,
  • R is phenyl substituted by 1 to 3 halo
  • R is phenyl substituted by 1 or 2 halo substituents.
  • R is phenyl substituted by 1 or 2 substituents each independently selected from fluoro and chloro. Particularly preferred individual embodiments of R include
  • R 1 is C 1 -C 4 alkyl and R 2 is H.
  • R 1 is methyl and R 2 is H.
  • Het is oxazol-2-yl, thiazol-2-yl,
  • Mbst preferably "Het" is 1,3,4-oxadiazol-2-yl or
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts formed from acids which form non-toxic salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, oxalate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
  • a compound of the formula (I) contains one or more chiral centres and as such exists in two or more stereoisomeric forms either as a pair of enantiomers or as two or more
  • the invention includes both the individual stereoisomers of a compound of the formula (I) together with mixtures thereof.
  • An individual enantiomer of a compound of the formula (I) may be prepared from either a corresponding optically pure
  • diastereoisomeric derivatives formed by reacting the racemate with a suitable optically active reagent, for example by fractional crystallisation, chromatography or H.P.L.C, followed by
  • the compounds of the formula (I) provided by the invention may be prepared by the following methods:- 1) A compound of the formula (I) wherein R, R 1 and R 2 are as defined for a compound of the formula (I) and "Het" is 5-substituted-oxazol-2-yl, 4,5-disubstituted-oxazol-2-yl, 5-substituted-thiazol-2-y1, 4,5-disubstituted-thiazol-2-y1, optionally substituted 1,2,4-thiadiazol-5-yl or substituted 1,3,4-thiadiazol-2-yl may be prepared as shown in Scheme 1:-
  • a compound of the formula (II) is deprotonated by the addition of approximately one equivalent of a suitable base, e.g. n-butyllithium or lithium diisopropylamide, and the resulting salt (preferably the lithium, sodium or potassium salt) is reacted in situ with a compound of the formula (I).
  • the reaction is typically carried out at from -80° to 0°C, preferably at from -80°C to -30°C, in a suitable organic solvent, e.g. tetrahydrofuran or diethyl ether, and under an inert
  • a starting material of the formula (II) may be prepared by a conventional procedure in accordance with literature precedents.
  • a starting material of the formula (III) is either known, for example see EP-A-44605, EP-A-69442 or GB-A-1464224, or may be prepared by an analogous method to those used therein.
  • a compound of the formula (I) wherein R, R 1 and R 2 are as defined for a compound of the formula (I) and "Het" is unsubstituted oxazol-2-yl, 4-substituted-oxazol-2-yl, unsubstituted thiazol-2-yl or 4-substituted-thiazol-2-yl may be prepared as shown in Scheme 2:-
  • R, R 1 and R 2 are as previously defined for this method;
  • X is O or S;
  • Y is CH, C(C 1 -C 4 alkyl) or C(CF 3 ); and
  • Z is a suitable protecting group, preferably a suitable organosilyl group, e.g. trimethylsilyl or tert- butyldimethylsilyl.
  • the deprotection is most conveniently carried out using a suitable source of fluoride ions. Suitable conditions include the use of aqueous hydrofluoric acid in acetonitrile or tetxabutylammoniiim fluoride in tetrahydrofuran. The deprotection is normally carried out at room temperature.
  • a starting material of the formula (IV) wherein Z is a suitable organosilyl group may be prepared as shown in Scheme 3:-
  • R, R 1 , R 2 , X and Y are as previously defined for a compound of the formula (IV).
  • a compound of the formula (V) is deprotonated with approximately one equivalent of a suitable base, e.g. n-butyllithium, and the salt formed is reacted in situ with a suitable chloroorganosilane of the formula Z-Cl.
  • the reaction is typically carried out at from -70° to 0°C, preferably at below -30°C, in a suitable organic solvent, e.g. tetrahydrofuran, and, after addition of the chloroorganosilane, a period of stirring at room temperature is often desirable.
  • the product of the formula (VI) is isolated in a conventional manner.
  • a compound of the formula (VI) is converted to a compound of the formula (IV) by an analogous method to that previously described in method (1) for the preparation of compounds of the formula (I) (see Scheme 1).
  • a starting material of the formula (V) may be prepared by a conventional procedure in accordance with literature precedents, e.g. see Cornforth et al, J. Chem. Sec., 96 (1947) and Metzger et al. Bull. Chim. Soc. France, 4499 (1967). 3) A compound of the formula (I) wherein R, R 1 and R 2 are as defined for a compound of the formula (I) and "Het" is optionally substituted 1,2,4-oxadiazol-5-yl may be prepared as shown in Scheme 4:- Scheme 4
  • R, R 1 and R 2 are as previously defined for this method and R is H, C 1 -C 4 alkyl or -CF 3 .
  • a compound of the formula (VII) is heated, preferably at from 130° to 180°C, and preferably in the absence of solvent, to induce the desired intramolecular condensation reaction.
  • the product of the formula (I) may be isolated by conventional techniques.
  • a starting material of the formula (VII) may be prepared by the route shown in Scheme 5:- Scheme 5
  • R, R 1 , R 2 and R 3 are as previously defined for a compound of the formula (VII) and R 4 is C 1 -C 4 alkyl, preferably methyl or ethyl.
  • an ester of the formula (VIII) is deprotonated with approximately one equivalent of a suitable base, e.g. lithium diisopropylamide, and the salt obtained is reacted in situ with a compound of the formula (III) under analogous conditions to those described in method (1) for the preparation of compounds of the formula (I) (see Scheme 1).
  • the ester of the formula (IX) obtained is hydrolysed to a carboxylic acid of the formula (X) under conventional conditions, e.g. by heating with aqueous potassium hydroxide.
  • the carboxylic acid of the formula (X) is first converted to an activated ester derivative, e.g.
  • R, R 1 and R 2 are as previously defined for this method and R 5 is H, C 1 -C 4 alkyl or -CF 3 .
  • This preparation is based on conventional synthetic methodology, e.g. see lenaers et al, Helv. Chim. Acta, 45, 441 (1962).
  • a starting material of the formula (XII) may be prepared by the route shown in Scheme 7:-
  • R, R 1 , R 2 and R 5 are as previously defined for a compound of the formula (XII) and R 6 is a suitable leaving group, e.g. -OCO(C 1 -C 4 alkyl or -CF 3 ).
  • a nitrile of the formula (XIII) is deprotonated with approximately one equivalent of a suitable base, e.g. n-butyllithium, and the salt obtained is reacted in situ with a compound of the formula (III) under analogous conditions to those described in method (1) for the preparation of compounds of the formula (I) (see Scheme 1) .
  • the nitrile of the formula (XIV) is converted to an amidoxime of the formula (XV) by reaction with hydroxylamine under conventional conditions, e.g. by heating the reactants together in n-butanol at about 40°C.
  • the amidoxime of the formula (XV) is preferably converted to a compound of the formula (XII) by acylation with an acid anhydride of the formula (XVT), the reaction typically being carried out in a suitable solvent, e.g. 1,4-dioxane, at from 0oC to room temperature.
  • a suitable solvent e.g. 1,4-dioxane
  • R, R 1 and R 2 are as previously defined for a compound of the formula (I) and R 7 is H, C 1 -C 4 alkyl or -CF 3 .
  • a compound of the formula (XVII) is heated at above room temperature to provide a compound of the formula (I).
  • the reaction is preferably carried out in a suitable solvent, e.g. toluene, and at the reflux temperature thereof.
  • a suitable solvent e.g. toluene
  • a starting material of the formula (XVII) may be prepared by the route shown in Scheme 9.
  • R, R 1 , R 2 and R 7 are as previously defined for a compound of the formula (XVII) and R 4 is as previously defined for a compound of the formula (IX).
  • R, R 1 and R 2 are as previously defined for a compound of the formula (I) and R 8 is C 1 -C 4 alkyl, preferably methyl or ethyl.
  • a compound of the formula (XXI) is heated to provide a compound of the formula (I).
  • the reaction is preferably carried out in a suitable solvent, e.g. toluene, and at the reflux temperature thereof.
  • a compound of the formula (XXI) may be prepared by reacting a hydrazide of the formula (XVIII) with a trialkyl orthoformate of the formula (XX), preferably trimethyl or triethyl orthoformate.
  • Het is substituted 1,3,4-oxadiazol-2-yl may also be prepared as shown in Scheme 11, using conventional synthetic methodology, e.g. see Comprehensive Heterocyclic Chemistry,
  • R, R 1 and R 2 are as previously defined for a compound of the formula (I) and R 9 is C 1 -C 4 alkyl or -CF 3 .
  • a starting material of the formula (XXII) may be prepared by the route shown in Scheme 12:-
  • R, R 1 and R 2 are as previously defined for a compound of the formula (XXII).
  • a compound of the formula (XIV) is treated with tri-n-butyltin azide at about 170°C to provide a tetrazole of the formula (XXIII).
  • the tetrazole of the formula (XXIII) may be acylated to give an acyltetrazole of the formula
  • Hal is halo, preferably chloro, optionally in the presence of a suitable acid acceptor; using an acid anhydride of the formula (R 9 CO) 2 O, wherein R 9 is C 1 -C 4 alkyl or -CF 3 ; or using a carboxylic acid of the formula R 9 COOH, wherein R 9 is C 1 -C 4 alkyl or -CF 3 , in the presence of a suitable dehydrating agent, e.g.
  • Het is optionally substituted 1,3,4-thiadiazol-2-yl may be prepared as shown in Scheme 13 using conventional synthetic methodology, e.g. see H. Eilingsfeld, Chem. Ber., 98, 1308
  • R, R 1 and R 2 are as previously defined for a compound of the formula (I) and R 10 is H, C 1 -C 4 alkyl or -CF 3 .
  • a compound of the formula (XXIV) is treated with a suitable acid, e.g. acetic acid or, preferably, dichloroacetic acid.
  • a suitable acid e.g. acetic acid or, preferably, dichloroacetic acid.
  • the reaction is generally carried out at room temperature but the mixture may be heated if required.
  • the product of the formula (I) is isolated by conventional techniques.
  • a starting material of the formula (XXIV) may be prepared by a route shown in Scheme 14:-
  • R, R 1 and R 2 are as previously defined for a compound of the formula (XXIV).
  • N,N-dimethylformamide diethyl acetal at an elevated temperature, preferably at about the reflux temperature of the acetal.
  • the compound of the formula (XXVI) obtained is treated with hydrogen sulphide in the presence of a suitable acid, e.g. acetic acid, in a sui'table solvent, e.g. N,N-dimethylformamide, at room
  • compositions containing equimolar amounts of the free base and the desired acid are readily prepared by mixing together solutions containing equimolar amounts of the free base and the desired acid.
  • the salt generally precipitates from solution and is collected by filtration, or is recovered by evaporation of the solvent.
  • the compounds of the formula (I) and their salts are antifungal agents, useful in the curative or prophylactic treatment of fungal infections in animals, including humans.
  • they are useful in treating topical fungal infections in man caused by, among other organisms, species of Candida,
  • Trichophyton, Microsporum or Epidermophyton or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). They can also be used in the treatment of systemic fungal infections caused by, for example, Candida albicans,
  • the compounds of the present invention have been found to have particularly good activity against certain clinically important species of fungus such as Candida spp., Aspergillus spp. or Cryptococcus spp.
  • the in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum inhibitory concentration (m.i.c), which is the concentration of the test compounds, in a suitable medium, at which growth of the particular micro-organism fails the occur.
  • m.i.c minimum inhibitory concentration
  • a series of agar plates, each having the test compound incorporated at a particular concentration is inoculated with a standard culture of, for example, Candida albicans, and each plate is then incubated for 48 hours at 37°C.
  • micro-organisms used in such tests can include Aspergillus fumigatus, Cr ⁇ ptococcus spp., Trichophyton spp.,
  • Microsporum spp. Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.
  • the in vivo evaluation of the compounds can be carried out at a series of dose levels by intraperitoneal or intravenous
  • mice which are inoculated with, e.g., a strain of Candida albicans or Aspergillus fumiqatus.
  • Activity is based on the survival of a treated group of mice after the death of an untreated group of mice.
  • the dose level at which the compound provides 50% protection against the lethal effect of the infection (PD 50 ) is noted.
  • PD 50 The dose level at which the compound provides 50% protection against the lethal effect of the infection
  • the number of mice cured of the infection after a set dose allows further assessment of activity.
  • the antifungal compounds of the formula (I) and their salts can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents.
  • They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the daily dosage level of the antifungal compounds of the formula (I) and their salts will be from 0.01 to 20 mg/kg (in single or divided doses) when administered by either the oral or parenteral route.
  • tablets or capsules of the compounds will contain from 5 mg to 0.5 g of active ccsipound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the antifungal compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be
  • an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention yet further provides a compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament.
  • the invention also provides the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or
  • composition thereof for the manufacture of an antifungal agent.
  • the invention yet further provides a method of treating an animal (including a human being) to cure or prevent a fungal infection, which comprises treating said animal with an effective amount of a compound of the formula (I), or with, as appropriate, a pharmaceutically acceptable salt or composition thereof.
  • the invention also includes the novel intermediates of the formulae (XVII), (XXI) and (XXIV).
  • the following Examples illustrate the preparation of the compounds of the formula (I) :-
  • part (ii) (4.80g) was added to a solution of sodium hydroxide (1.20g) in water (15ml), and sufficient methanol was added to give a homogeneous solution.
  • the solution was allcwed to stand for 2 hours, evaporated to a small volume and then acidified to pH3 with 2N hydrochloric acid.
  • the solution was continuously extracted with dichlorcauethane for 18 hours. The extract was dried
  • n-Butyllithium (11.0ml of 1.6M solution in hexane) was added to a solution of the product of part (iv) (1.70g) in dry tetrahydrofuran (40ml) at from -50° to -30°C under an atmosphere of dry nitrogen. The solution was stirred at -50°C for 30 minutes and then chlorotrimethylsilane (2.28g) was added dropwise. The cooling bath was removed and the mixture was allowed to warm to room temperature. Sodium bicarbonate solution and ether were added and the organic layer was separated, washed with brine and dried (Na 2 SO 4 ). Evaporation of the solvent gave an oil which was distilled to give the title compound (1.90g), b.p. 66°-68°C @ 15mm.
  • n-Butyllithium (6.3ml of a 1.6M solution in hexane) was added dropwise to a stirred solution of the product of part (v) (1.70g) in dry tetrahydrofuran (40ml) at -50°C under an atmosphere of dry nitrogen. The orange solution was stirred at -50°C for 30 minutes and then a solution of
  • Example 1(vi) 1-(2-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone according to the method of Example 1(vi) gave two diastereoisomeric pairs of enantiomers.
  • the pairs of enantiomers were separated and individually deprotected with hydrofluoric acid as described in Example 1(vi) to provide:- a) the title compound, enantiomeric pair A (less polar) ,
  • n-Butyllithium (93.75ml of a 1.6M solution in hexane) was added to a stirred solution of diisopropylamine (15.18g) in dry tetrahydrofuran (525ml) at -70°C under an atmosphere of dry nitrogen. The solution was stirred at -70°C for 10 minutes, followed by 10 minutes at 0°C and then it was re-cooled to -70°C. Ethyl propanoate (15.32g) was added dropwise and stirring was continued at -70°C for 30 minutes. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (33.48g) in dry tetrahydrofuran
  • N,N-dimethylformamide diethyl acetal (10ml) was heated under reflux for 1.5 hours and then evaporated. The solid was triturated with ether and filtered to give the title compound as a single enantiomeric pair, (2.01g), m.p.
  • dichloroacetic acid (6ml) was stirred at about 90°C for 30 minutes to give a clear solution. The solution was allowed to stand at room temperature for 18 hours and then
  • part (iii) was heated at 160°C for 45 minutes and cooled. Ihe coloured impurity was removed by passage through a short column of silica gel using a mixture of dichlorometiiane/methanol/concentrated aqueous ammonia (100:5:1) as solvent. Evaporation of the eluate gave an amorphous foam which was dissolved in ether and treated with an ethereal solution of oxalic acid. The solid was filtered off, washed with ether and dried to give the title compound as a single enantiomeric pair as the oxalate salt (0.18g), m.p. 145-6°C.

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Abstract

L'invention concerne des agents fongicides de formule (I), ainsi que leurs sels pharmaceutiquement acceptables, où R est phényle éventuellement substitué par 1 à 3 substituants, chacun étant choisi indépendamment parmi halo et CF3; R1 est alkyle C¿1-4; R?2 est H ou alkyle C¿1-4?; et 'Het' est oxazol-2-yle, thiazol-2-yle, 1,2,4-oxadiazol-3 ou 5-yle, 1,2,4-thiadiazol-5-yle, 1,3,4-oxadiazol-2-yle ou 1,3,4-thiadiazol-2-yle, tous pouvant éventuellement être substitués par alkyle C1-4 ou CF3. On décrit également des compositions pharmaceutiques contenant lesdits composés, et des procédés et intermédiaires utilisés pour leur préparation.
PCT/EP1992/000697 1991-04-04 1992-03-26 Agents fongicides au triazole WO1992017474A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9107055.7 1991-04-04
GB919107055A GB9107055D0 (en) 1991-04-04 1991-04-04 Triazole antifungal agents

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WO1992017474A1 true WO1992017474A1 (fr) 1992-10-15

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IE (1) IE921059A1 (fr)
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0617031A1 (fr) * 1993-03-15 1994-09-28 J. URIACH & CIA. S.A. Dérivés d'azole oralement actifs
EP0670315A1 (fr) * 1994-02-04 1995-09-06 Mochida Pharmaceutical Co., Ltd. Dérivés de triazole oxime avec une activité antimycotique
WO1997001552A1 (fr) * 1995-06-26 1997-01-16 Pfizer Research And Development Company, N.V./S.A. Agents antifongiques au triazole
EP0753513A3 (fr) * 1995-07-08 1997-01-22 Nihon Nohyaku Co., Ltd. Dérivés de triazole optiquement actifs, procédé pour leur préparation et leur utilisation
US5648372A (en) * 1994-02-07 1997-07-15 Eisai Co., Ltd. Antifungal agents, and compositions
WO1999045008A1 (fr) * 1998-03-06 1999-09-10 F. Hoffmann-La Roche Ag Derives 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol possedant une activite antifongique
US6319933B1 (en) 2000-04-17 2001-11-20 Basilea Pharmaceutica Ag Azole derivatives
WO2003002498A1 (fr) * 2001-06-26 2003-01-09 Basilea Pharmaceutica Ag Derives halophenyle intermediaires et utilisation de ceux-ci dans un processus de preparation de derives azole
WO2003042188A1 (fr) * 2001-11-15 2003-05-22 Meiji Seika Kaisha, Ltd. Derive de triazole, et composition medicamenteuse renfermant ce derive
CN102690240A (zh) * 2012-06-07 2012-09-26 郑州大学 三氮唑烯醚类、肟醚类化合物及其制备方法与应用
US20120329802A1 (en) * 2011-06-23 2012-12-27 Viamet Pharmaceuticals, Inc. Metalloenzyme inhibitor compounds
WO2014023623A1 (fr) 2012-08-07 2014-02-13 Basilea Pharmaceutica Ag Procédé pour la fabrication d'isavuconazole ou ravuconazole
CN105801500A (zh) * 2014-12-31 2016-07-27 四川科伦药物研究院有限公司 拆分艾沙康唑中间化合物消旋体的方法
TWI646088B (zh) * 2012-03-16 2019-01-01 維愛美製藥公司 金屬酶抑制劑化合物

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EP0115400A1 (fr) * 1983-01-21 1984-08-08 Pfizer Limited Agents antifongiques triazoliques
EP0106515B1 (fr) * 1982-09-30 1988-12-28 Pfizer Limited Dérivés du triazole comme agents antifongiques
EP0311892A1 (fr) * 1987-10-14 1989-04-19 Bayer Ag Carbinols azolylméthyl substitués
JPH01249755A (ja) * 1988-03-29 1989-10-05 Toyama Chem Co Ltd 新規な２−アゾリル−１−シクロプロピルエタノール誘導体およびその塩
EP0357241A1 (fr) * 1988-08-13 1990-03-07 Pfizer Limited Triazoles comme agents antifongiques

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Publication number Priority date Publication date Assignee Title
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JP2006124397A (ja) * 1993-03-15 2006-05-18 J Uriach & Cia Sa 新規な経口活性を有するアゾール誘導体
EP0617031A1 (fr) * 1993-03-15 1994-09-28 J. URIACH & CIA. S.A. Dérivés d'azole oralement actifs
US5646294A (en) * 1993-03-15 1997-07-08 J. Uriach & Cia. S.A. Orally active azole derivatives
EP0670315A1 (fr) * 1994-02-04 1995-09-06 Mochida Pharmaceutical Co., Ltd. Dérivés de triazole oxime avec une activité antimycotique
US5792781A (en) * 1994-02-07 1998-08-11 Eisai Co., Ltd. Antifungal agents, processes for the preparation thereof, and intermediates
EP1231210A3 (fr) * 1994-02-07 2002-12-04 Eisai Co., Ltd. Dérivés azole fongicdes, procédé pour leur préparation et intermédiaires
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US5789429A (en) * 1994-02-07 1998-08-04 Eisai Co., Ltd. Antifungal agents, processes for the preparation thereof, and intermediates
AU696640B2 (en) * 1994-02-07 1998-09-17 Eisai R&D Management Co., Ltd. Antifungal agents, processes for the preparation thereof, and intermediates
EP0667346A3 (fr) * 1994-02-07 1998-04-29 Eisai Co., Ltd. Dérivés d'azole fongicides, leur préparation et des produits intermédiaires
US6015825A (en) * 1995-06-25 2000-01-18 Pfizer Inc. Triazole antifungal agents
AU697405B2 (en) * 1995-06-26 1998-10-08 Pfizer Research And Development Company, N.V./S.A. Triazole antifungal agents
WO1997001552A1 (fr) * 1995-06-26 1997-01-16 Pfizer Research And Development Company, N.V./S.A. Agents antifongiques au triazole
EP0753513A3 (fr) * 1995-07-08 1997-01-22 Nihon Nohyaku Co., Ltd. Dérivés de triazole optiquement actifs, procédé pour leur préparation et leur utilisation
US6300353B1 (en) 1998-03-06 2001-10-09 Basilea Pharmaceutica Ag, A Swiss Company Azoles for treatment of fungal infections
WO1999045008A1 (fr) * 1998-03-06 1999-09-10 F. Hoffmann-La Roche Ag Derives 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol possedant une activite antifongique
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WO2003002498A1 (fr) * 2001-06-26 2003-01-09 Basilea Pharmaceutica Ag Derives halophenyle intermediaires et utilisation de ceux-ci dans un processus de preparation de derives azole
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WO2003042188A1 (fr) * 2001-11-15 2003-05-22 Meiji Seika Kaisha, Ltd. Derive de triazole, et composition medicamenteuse renfermant ce derive
WO2012177725A1 (fr) 2011-06-23 2012-12-27 Viamet Pharmaceuticals, Inc. Composés inhibiteurs de métalloenzymes
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