MXPA97002060A - Antifungic agents triazoli - Google Patents

Abstract

An antifungal compound of formula (I) :( See Formula), or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable solvate of any entity, wherein X is CH or N; R1 is phenyl substituted with 1 to 3 substituents, selected each independently of halogen and CF3; T2 is C1-C4 hydroxyalkyl, CONH2, S (O) m (C1-C4 alkyl), Ar or Het; m is 1 or 2; Ar is phenyl monosubstituted optionally with halogen or CF3; and Het is a 6-membered nitrogenous aromatic heterocyclic group, attached to a C, containing 1 to 2 nitrogen atoms, or a 5-membered aromatic heterocyclic nitrogen group, attached to a C or an N, containing from 2 to 4 nitrogen atoms, wherein any of said heterocyclic groups is optionally substituted with C 1 -C 4 alkyl or with C 1 -C 4 alkoxy)

Description

TRIANGULIC FLOWER AGENTS MEMORIfi DESCRIPTIVE This invention relates to triazole derivatives having antifungal activity and are useful in the treatment of fungal infections in animals, including humans. Therefore / this invention provides compounds of formula (I): pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvates of any entity, wherein: X is CH or N; R1 is phenyl substituted with 1 to 3 substituents, each independently selected d? halo and CF3; R 2 is hydroxyalkyl Ci -C ", CONH 2, S (0)» (Ci-C alkyl "), Ar or Het; m is 1 or 2; Rr is phenyl, optionally monosubstituted with halo or CF37 Het is a 6-membered nitrogenous aromatic heterocycle, attached to a C, containing 1 or 2 nitrogen atoms, or a 5-membered nitrogenous heterocyclic group, attached to a C or an N , which contains from 2 to 4 nitrogen atoms, wherein said heterocyclic groups are optionally substituted with C 1 -C 4 alkyl or with (C 1 -C 4 alkoxy) rnetyl. In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms may be straight or branched chain; Halo means fluoro, chloro, bromo or iodo. In addition, Het is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl. The compounds of formula (I) contain at least two chiral centers and, therefore, can exist as stereoisomers, that is, as enantiomers or diastereomers and as mixtures thereof. The invention includes the two individual stereoisomers of the compounds of formula (19 together with mixtures thereof) Separation of the diastereomers can be achieved by conventional techniques, for example, by fractional crystallization or chromatography [including high performance liquid chromatography (HPLC )] of a diastereomeric mixture of a compound of formula (19) or a salt or derivative thereof An individual enantiomer of a compound of formula (19) can also be prepared from a corresponding, optically pure intermediate, by HPLC resolution of the racemate using a suitable chiral support or by fractional crystallization of the diastereomeric salts formed by reaction of the racemate with a suitable optically active acid The preferred etheromers of formula (I) have the (2R, 3S) configuration of formula (IA): In addition, the compounds of formula (I) can exist as cis- or trans-alkene isomers and the invention also includes the two separate individual isomers and mixtures thereof. The preferred isomers are the trans isomers. Certain compounds of formula (I) may also exist in tautomeric forms and the invention includes the two separate individual tautuses and mixtures thereof. Also included in the invention are radiolabeled derivatives of compounds of formula (I), which are suitable for biological studies. The pharmaceutically acceptable salts of the compounds of formula (I) are, for example, non-toxic salts, formed by the addition of inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acid, organic carboxylic acids or organic sulfonic acids.

Certain compounds of formula (I) can also provide pharmaceutically acceptable salts of a metal, in particular non-toxic alkali metal salts, with base. Examples include sodium and potassium salts. For an analysis of suitable pharmaceutical salts, see 3. Pharm. Sci., 1977, 5, 1. A preferred group of compounds of formula (I) is that wherein R * is phenyl substituted by 1 or 2 substituents, each independently selected from F and Cl; R2 is hydroxypropyl, CONH2, SO2CH3, Ar or Het; Ar is fluorophenyl; Het is a pyridyl, pyrazolyl, imidazolyl or triazolyl group, wherein said pyrazolyl group is substituted with methyl and said triazolyl group is optionally substituted with ethoxymethyl; and X is as defined above for formula (I). A more preferred group of compound of formula (I) is that wherein R 1 is 2,4-difluorophenyl; * is C (CH3) 2? H, CONH2, SO2CH3, 4-fluorophenyl, 2-pyridyl, l-methylpyrazol-5-yl, imidozol-1-yl, l, 2,3-triazol-4-yl or l- ethoxy-phenyl-1,2,3-triazol-5-yl; and X is as defined above for formula (I). Particularly preferred compounds of the invention include: trane- (2R, 3S) -1- (1,2,4-triazol-1-yl) -2- (2, -dif luorophenyl) -3- (-C2-) 1-met i lpyrazol-5-yl) ethenyl] phenyl) butan-2-ol; trans- (2R, 3S / 2S, 3R) ~ l- (1, 2,4-triazol-1-yl) -2- (2,4-di fluorophenyl) -3-yC 2- (1-imidazole) -l-il) ethenyl] phenyl) butan-2-ol; and trans- (2R, 3S / 2S, 3R) -l- (1,2,4-triazol-1-yl) -2- (2, 4-di fluorophenyl) -3- (5- C2 -carbamoi leteni Dpi Rid-2-yl] -butan-2-ol and pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvates of any kind In another aspect, the invention provides processes for the preparation of compounds of formula (I), their salts pharmaceutically acceptable and pharmaceutically acceptable solvates of any entity A compound of formula (I) can be prepared from a compound of formula (II): wherein Z is bromine or iodine, and X and R1 are as defined above for formula (I), by treatment with a compound of formula (III): CH2 = CHR2 (III) wherein R2 is as defined above for formula (I), under conditions typical of the Heck reaction. The reaction is generally carried out using an excess of about 20 to about 100% of the required alkene and of an excess of about 50 to about 100% of a tertiary amine, in the presence of about 0.05 to about 0.60 equivalents of a palladium salt and about 0.10 to about 1.10 equivalents of a tertiary aryl foefine, in a suitable solvent, such as acetonitrile or dimethylformamide, at a temperature of about 80 to about 160 ° C. Preferably the tertiary amine is triethylamine, the palladium salt is palladium acetate, the phosphine is tri-o-tolylphosphine or 1,1'-bis (diphenylphosphino) ferrocene and the reaction is carried out in acetonitrile at reflux. A compound of formula (II) can be prepared by a variety of synthesis methods. For example, one such procedure, which is preferred when X eß N, involves the reaction of a compound of formula (IV): wherein R * is as defined above for formula (II), with an organometallic compound of formula (V): - wherein p is a suitable metal (eg, lithium, sodium or potassium) or a halide of a metal (eg, magnesium halide or zinc halide) and X and Z are co or have been defined above for the formula (II). An organometallic compound of formula (V), in which M is a suitable metal, is preferably generated in situ by deprotonation of the corresponding alkane precursor. Cesto is, a compound of formula (V) in which M is hydrogen] with a suitable base, for example, lithium or potassium diisopropylamine or bie (trimethylsilyl) amide lithium, sodium or potassium. An organometallic compound of formula (V), in which N is a halide of a suitable metal, for example, a Grignard reagent or an organosilicate, can be prepared by in situ treatment of the corresponding organometallic compound of formula (V), in that which is lithium, with a halide of a suitable metal, for example, magnesium bromide or zic iodide, or by treatment of the corresponding alkyl halide precursor C, for example, a compound of formula (V) in which chlorine fl ows. , bromine or iodine] with magnesium or zinc respectively, optionally using iodine to promote the reaction. Preferably, the compound of formula (V), wherein M is chlorine, bromine or iodine, is converted into the corresponding zincin in the presence of the compound of formula (IV) in a suitable solvent, at about room temperature and in an inert atmosphere , treating it with zinc in the presence of iodine. This can be achieved in tetrahydrofuran as solvent, using approximately 2.6 equivalents of zinc powder, followed by 0.2 equivalents of iodine, which causes an exothermic reaction. The compounds of formula (IV) are known, see for example EP-A-044605, EP-A-069442 or GB-A-1464224, or can be prepared by procedures similar to those described herein. An alternative synthetic process for preparing a compound of formula (II), which is preferred when X is CH, involves the reduction of a compound of formula (VI): wherein Z, X and R1 are as defined above for formula (II). The reduction is conveniently carried out using a diimide generated in situ. Thus, a precursor of the diimide, such as p-toluenesosulfonyl hydrazide, and a compound of formula (Vi) is combined in a suitable solvent, for example toluene, and the reaction is carried out at the reflux temperature of the reaction medium. The reaction can also be carried out by catalytic hydrogenation, using a suitable catalyst, such as palladium on carbon, in an appropriate solvent, for example, a C 1 -C 3 alkanol. A compound of formula (VI) can be prepared by reaction of an epoxide of formula (VID. wherein Z, X and R * are as defined above for formula (VI), with 1,2,4-triazole in the presence of a base, or with a salt of tetraalkyl onium or alkali metal (preferably the salt sodium) of 1,2,4-triazole in a suitable solvent, such as dimethyl ormamide, methanol or aqueous acetate. The reaction is conveniently carried out using about 50% excess of said sodium salt in dry dimethylformamide, at about 70 ° C. The resulting racemic mixture of 2R and 2S enantiomers can be conveniently resolved in this state, for example, by chromatography, using a chiral stationary phase, and the 2R enantiomer can be reduced as indicated above to give, after its chromatographic resolution, the preferred 2R, 3S enantiomer of a compound of formula (II). A compound of formula (VID) can be prepared by methyleneization of a ketone of formula (VIII): wherein Z, X and R * are as defined above for the formula (VID, under standard conditions of the Wittig or Uittig-Horner reaction) For example, the compound of formula (VIII) is treated with? n about 30% excess of the ylide generated in situ from ethyltriphenylphosphonium bromide and a strong base, for example n-butyl lithium in solution in hexane, in a suitable solvent, such as dry tetrahydrofuran, at a temperature of about -20 ° C at room temperature, in an inert atmosphere A compound of formula (VIII) can be prepared by epoxidation of an alkene of formula (IX): wherein Z, X and R1 are as defined above for formula (VIII). Of the plethora of reagents and oxidation reactions available, a convenient technique is the use of phase transfer catalysts using, for example, a quaternary ammonium salt as a catalyst. Typical conditions are to employ an excess of about 10% of an oxidant, such as 5-butyl hydroperoxide in a suitable solvent, for example toluene, in the presence of about 0.1 equivalents of benzyltrimethylammonium hydroxide in aqueous solution, at about room temperature. A compound of formula (IX) can be prepared by methyleneization of a compound of formula (X): wherein Z, X and R1 are as defined above for formula (IX), using a reaction of the Mannich reaction type, This can conveniently be achieved by treating the compound of formula (X), in the presence of a about 5 times excess of acetic anhydride, with an approximately 50% excess of bis (imethylamino) -methane, at about room temperature. A compound of formula (X) can be prepared by any of a myriad of standard synthesis of α-methyleneketone. For example, a substituted benzyl halide of formula (XI): R1CH2Y (XI) wherein Y is chlorine, bromine or iodine and R * is as defined above for formula (X), it becomes the corresponding Grignard reagent which is then reacted with an excess of about 40% of a derivative of the hydroxamic acid, of formula (XII): wherein Z and X are as defined above for formula (X), in a suitable solvent, such as dry ether, at a temperature of about -70 ° C at about room temperature and in an inert atmosphere. Certain compounds of formula (I), wherein R 1 is a 5-membered nitrogenous aromatic heterocyclic group attached to a C, containing 2 to 4 nitrogen atoms, substituted on a nitrogen atom with C 1 -C 4 alkyl or with ( Ci-C4 alkoxy) methyl, can be prepared by N-alkylation of the corresponding unsubstituted compounds, for example, using the appropriate Ci-C «alkyl halogen or the appropriate C (-C« alkoxy-methyl (for example, chloride or bromide), typically in the presence of an acid acceptor in a suitable solvent. When it is possible tautomeris or in the ring, alkylation can occur on one or more nitrogen atoms, but the resulting product mixture can be separated by chromatography. As an alternative, you can take advantage of the inverse transformation. For example, a compound of formula (I), which carries in R 2 a substituent N- (C 1 -C 4 alkoxy) methyl, can be converted into the corresponding unsubstituted derivative by acid hydrolysis in a suitable solvent. The reaction can be conveniently carried out using dilute hydrochloric acid in aqueous ethanol as solvent, at the reflux temperature of the reaction medium. A compound of formula (III) can be prepared by methyleneization of the corresponding aldehyde (R2CH = 0) by Uittig or Uittig-Horner methodology, in the manner described for the conversion of (VIII) to (VID. The required aldehydes are obtained by formulation, using for example dimethylformamide, of the corresponding (hetero) aryl lithium, under standard reaction conditions: The intermediate alkane and the alkyl halide precursors of 8V) and the intermediates of formulas (III), ( XI) and (XII), when they can not be obtained commercially or as described below, can be obtained by analogy with the procedures described in the "preparations" section or by conventional synthesis procedures, according to standard texts of organic chemistry or of bibliographic precedents, from accessible starting materials using appropriate reagents and appropriate reaction conditions. In addition, those skilled in the art will be aware of variations and alternatives to the procedures described later in the "Examples" sections and "Prepare" to obtain the components defined by the formula (I). The pharmaceutically acceptable salts, by addition of acids, of the compounds of formula (I) can also be prepared in a conventional manner. For example, a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt is isolated by filtration or by evaporation of the reaction solvent or reduced pressure. In an analogous manner, pharmaceutically acceptable base addition salts can be obtained by treating a solution of a compound of formula (I) with the appropriate base. Both types of salt can be formed or interconverted using ion exchange resin techniques. The compounds of formula (I), pharmaceutically acceptable solids and pharmaceutically acceptable solvates of any kind are antifungal agents, useful in the curative or prophylactic treatment of fungal infections in animals, including humans. For example, they are useful for treating superficial fungal infections in humans caused, inter alia, by species of Candida, Trichophyton, ficrosporu or Spider phyton, or mucosal infections caused by Candida albicans (eg, thrush or oral or vaginal candidiasis). and can also be used in the treatment of systemic fungal infections caused, for example, by Candida species (e.g., Candida albicans), Cryptococcus neoformans, Aspergillus Flavue * Aspergillus fu igatus, Coccidioides, Paracoccidioides * Histoplasroa or Blastomyces. They really have a powerful and broad-spectrum antifungal activity, both in vitro and in vivo. It has been found that certain compounds of the invention have unexpectedly good broad spectrum activity, including excellent activity against the important clinical fungi Aspergillus spp. The in vitro evaluation of the antifungal activity of the compounds can be carried out by determining the minimum inhibitory concentration (Cim), which is the concentration of the compound being tested, in a suitable medium, at which no development of the particular microorganism occurs. In practice, a series of plates of agar, or liquid medium in microtiter plates, to which the compound to be tested has been incorporated at a particular concentration, are inoculated with a standard culture, for example, of Cryptococcus neoformans, and each plate is then incubated at 37 ° C for 48 hours. The presence or absence of development of the fungus is then examined on the plates and the appropriate value of the Ci is noted. Other microorganisms used in such assays may include Candida albicans, Aspergillus fumigatus, Trichophyton spp., NicrosporuiTi spp., Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata. The in vivo evaluation of the compounds can be performed at a series of dose levels by intraperitoneal or intravenous injection or by oral administration, to mice or rats that have been inoculated, for example, with a strain of Candida albicans, Aspergillus fumigatus or Cryptococcus neoformans. The activity can be based on the number of surviving animals of a treated group, after the death of an untreated group of mice. In models of infection by Candida spp., The dose level at which the compound provides 50% protection against the lethal effect of infection (PD50) in models of infection by Aspergillus spp., The number of cured mice is also evaluated. of the infection after an established dose allows an additional evaluation of the activity. In models of infection by Cryptococcus spp., The number of existing units that form colonies is evaluated, after an established dose, and compared with a control to determine the efficacy of the compound. A preliminary evaluation of the potential liver toxicity can also be made, based on the increase in liver weight with respect to a control. For use in humans, the antifungal compounds of the invention can be administered alone, although generally they will be administered mixed with a selected pharmaceutical carrier taking into account the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution, which may contain other substances, for example, salts or glucose in sufficient quantity to make the solution isotonic with the blood. The solubility of a compound of formula (I) in an aqueous medium can be improved by formation of a complex with a hydroxyalkyl derivative of a cyclodextrin (see EP-A-0149197) or with a sulfoalkyl derivative of a diclodextrin (cf. UO patent 91/11172) in the preparation of an appropriate pharmaceutical composition. Preferably, the cyclodextrin is a-, β- or t-cyclodextrin. For oral or parenteral administration to human patients, the level of the daily dose of the antifungal compounds of the invention will be 0.01 to 20 mg / kg (in a single dose or in divided doses). Therefore, the tablets or capsules will contain from 5 mg to 0.5 g of active compound, to be administered individually or two or more at a time, as appropriate. In any case, the doctor will determine the actual dose that is most suitable for a particular patient, which will vary with the age, weight and response of the particular patient. The aforementioned doeis are axes after the middle case; Of course, there may be cases in which higher or lower doses are needed and these are within the scope of this invention. Alternatively, the antifungal compounds of the invention can be administered in the form of suppositories or passed through or they can be applied topically in the form of a lotion, solution, cream, ointment or powder to be sprinkled. For example, they can be incorporated into a cream, consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin, or they can be incorporated, at a concentration of 1 to 10%, into an ointment, consisting of a white wax or soft paraffin base. white with the stabilizers and preservatives that may be necessary. Therefore, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of any entity, together with a pharmaceutically acceptable diluent or carrier. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of any entity or a pharmaceutical composition containing any of the aforementioned compounds, for use as a mediating agent. The invention further includes the use of a compound of formula (I) or a pharmaceutically acceptable pharmaceutically acceptable salt thereof or pharmaceutically acceptable salt thereof of any entity or of a pharmaceutical composition containing any of the aforementioned compounds, for the manufacture of a medicament for the curative or prophylactic treatment of fungal infections. In another aspect, the invention provides a method of treating an animal (including a human) to cure or prevent a fungal infection, which comprises treating said animal with an effective amount of a compound of formula (I) or a salt pharmaceutically acceptable thereof or pharmaceutically acceptable solvate of any entity or of a pharmaceutical composition containing any of the aforementioned compounds. The invention also includes any novel intermediates described herein, for example, compounds of formula (II): The synthesis of the compounds of the invention and of the intermediates to be used is illustrated in the following examples and preparations. The nuclear magnetic resonance (RflN) spectra of iH were obtained using a Niclet OE-300 spectrometer or a Bruker AC-300 spectrometer and, in all cases, they were in agreement with the proposed structures. The characteristic chemical shifts (6) are given in parts per million downfield with respect to tetraethylsilane, with conventional abbreviations being used to designate significant peaks, for example: singlet; d, doublet; t, triplet; q, quartet; m, multiplet. The mass spectra (m / z) were obtained with a Trio 1000 spectrometer, from Fisons Instruments, using thermospray ionization. Ambient temperature means 20-25 ° C.

EXAMPLE 1 Trans-R2R, 3S) -l- (1,2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-. { 4-C2- (1-methylpyrazol-5-yl) ethyl 3-phenyl} putan-2-ol A stirred solution e (2R, 3S) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluoro-phenyl) -3- was heated at reflux for 1 hour. { 4-iodophenyl) butan-2-ol (preparation 12, 0.5 g, 1.1 mmol), l-methyl-5-vinyl pyrazole (preparation 17, 0.14 g, 1.3 mmol), triethylamine (0.25 ml, 2 mmol), palladium acetate (130 mg, 0.6 mmol) and tri-o-tolylphosphine (340 mg, 1.2 mmol) in acetonitrile (25 ml), and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (50 ml) and then the organic layer was separated, washed with saturated brine (30 ml), dried (Na 2 SO 3) and evaporated to dryness. The crude product was purified by column chromatography on silica gel, using an elution gradient of hexane: propan-2-ol (90:10 to 75:25), to give the title compound (0.31 g) in form of a white solid, mp 81-83 ° C, after crietalization in aqueous ethanol Ca 2SD-55 ° (c = oi ^ CH 3 OH) S (CDCl 3): 1.10 (3H, d), 3.30 (1H, q ), 3.90 and 4.80 (2H, AB system), 3.95 (3H, s), 4.75 £ 1H, s), 6.45 (ÍH, d), 6.80 (2H, m), 7.00 (2H, AB system), 7.50 ( 6H, m), 7.70 (2H, rn).

Found: C 64.77; H 5.19; N 15.65. C23H23F2N2O; 0.50 H2O requires C 84.85, - H 5.44; N 15.76%. m / z 436 (M + D +.

EXAMPLE 2 T rans- (2R, 3S / 2S, 3R) -1- (1,2,4-triazol-1-yl) -2- (2, -di luorophenyl) -3- (5-C2- (4-f luoro enyl) ethenyl] pyrid-2-yl.} butan-2-ol A stirred solution of (2R, 3S / 25.3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3- was heated at reflux for 16 hours. { 5-bromopyrid-2-yl) b-tan-2-ol (preparation 3; 0.5 g, 1.22 mmol), 4-fluorostyrene (0.28 mmol, 2.4 mmol), triethylamine (0.28 mL, 2 mmol), palladium acetate ( 15 mg, 0.07 mmol) and tri-o-toylphophylline (40 mg, 0.14 mil i mol) in acetonitrile (20 ml), and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (50 l) and saturated aqueous sodium carbonate solution (50 nl) and then the organic phase was separated, dried (MgSO 4) and evaporated under reduced pressure. The crude product was crystallized from ether to give the title compound (145 mg), m.p. 157-158 ° C. Found: C 66.24; H 4.87; N 12.20. C25H21F3N4O requires C 66.66; H 4.70; N 12.44%.

EXAMPLE 3 Trans- (2R, 3S / 2S, 3R) -1- (1,2, -triazol-1-iD -2- (2, 4-di fluoro-phenyl) -3- C4-C2-wetylsulfonylethyl] -phi Lbutan-2 -ol Obtained from (2R, 3S / 2S, 3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-. { 4-iodophenyl) butan-2-ol (preparation 11) and methylvinylsulfone, by a procedure similar to that described in example 2. P.f. 169-171 ° C. Found: C 58.70; H 5.00; N 9.20. C21H21F2N3O3 S; 0.25 (C2Hs) 2? requires C 58.46; H 5.24; N 9.30%.

EXAMPLE 4 Trans- (2R, 3S / 2S, 3R) -1- (1, 2, -triazol-1-yl) -2- (2,4-difluorophenyl) -3 - [: 4-E2-carboyletenyl) phenyl-3-butan-2 -ol Obtained from the title compound of preparation 1 and acrylamide, edaint a procedure similar to that described in example 2. P.f. 122-124 ° C. Found: C 61. 82; H 5.55; N, 12.53 C21H20F2N4O2; 0.50 H20; 0.33 CH3CO2C2H5 requires C 61.42; H 5.46; N 12.84%.

EXAMPLE 5 Trans- (2R, 3S / 2St3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-. { 4-C2- (iiBidazol-1-yl) ethenyl3-phenyl} butan-2-ol It was obtained from the title compound of preparation 11 and 1-vinyliraidazole, by a procedure similar to that described in example 2. P.f. 225-227 ° C. Found: C 65.34; H 5.24; N 16.39. The C23H2iF2N50 requires C 65. 55; H 5.02; N 16.62%.

EXAMPLE 6 Trans- (2R, 3S / 2S, 3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluoro-enyl) -3-. { 5-E2- (pyrid-2-yl) ethenyl3pyrid-2-yl} putan-2-ol It was obtained from the title compound of preparation 3 and 2-vinylpyridine, by a procedure similar to that described in example 2. P.f. 139-141 ° C.

Found: C 66.51; H 4.94; N 15.98. C24H21F2N5O requires C 66.50; H 4.88; N 16.16%.

EXAMPLE 7 Trans- (2R, 3S / 2S, 3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-di fluoro-phenyl) -3-. { 5-E2-carbarooyletenyl) pyrid-2-yl3butan-2-ol It was obtained from the title compound of preparation 3 and acrylamide, by a procedure similar to that described in example 2. P.f. 170-172 ° C. Found: C 59.74; H 4.63; N, 17.91. C20H19F2N5O2 requires C 60.14; H 4. 79; N 17.54%.

EXAMPLE 8 Trans- (2R, 3S / 2S, 3R) -1- (1,2, -triazol-1-yl) -2- (2, 4-difluoro-enyl) -3-. { 5-E2- (l-ethoxymethio-l, 2,3-riazol-5-yl) ethenyl) pyrid-2-yl 3 utan-2-ol It was obtained from the title compound of preparation 3 and l-ethoxymethyl-5-vinyl-l, 2,3-triazole (preparation ), by a procedure similar to that described in example 5, except that 0.3 molar equivalents of palladium acetate and also l, l-bis (qyphenyl-phosphino) ferrocene were used. (0.3 molar equivalent) instead of tri-o-tolylphosphine. P.f. 161-163 ° C. Found: 59.73; H 5.31; N 19.77. He C 24 H 2 F 2 N 7 O 2; 0.10 CH3CO2C2H5 requie re C 59.77; H 5.30; N 20.00%.

EXAMPLE 9 Trans- (2R, 3S / 2S, 3R) -l- (1, 2,4-tri-azol-1-yl) -2- (2,4-di fluoro-phenyl) -3-E5-E3-hydroxy- 3-? Netilbut-l-en-l-il) pyrid-2-yl3butan-2-ol It was obtained from the title compound of preparation 3 and 2-methylbut-3-en-2-ol, by a procedure similar to that described in example 2. P.f. 159-161 ° C. Found: C 63.67; H 6.22; N 13.16. C22H24F2N4O2 requires C 63.76; H 5.84; N 13.52%.

EXAMPLE 10 Tranß- (2R, 3S / 2S, 3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-C5-2-Cl, 2, 3 triazol-4-ilJe ei ^ irid ^ - A stirred solution of (2R, 3S / 2S, 3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3- was heated at reflux for 30 minutes. { 5- [2- (1-Ethoxymethyl-1, 2,3-triazol-5-yl) ethenyl] pyrid-2-yl} butan-2-ol (example 8, 0.1 g, 0.21 mmol) in a mixture of hydrochloric acid (2f * 1; 2 ml), water (2 ml) and ethanol (4 ml). Most of the ethanol was evaporated under reduced pressure, the concentrated solution of the reaction was made basic with saturated aqueous sodium carbonate solution and extracted with dichloromethane (4 x 30 ml) and then the combined extracts were dried (Na2SO) and dried. evaporated under reduced pressure to give a brown oil. Trituration of the oil with ether gave a whitish solid which, upon crystallization from hexane: ethyl acetate, gave the title compound (30 mg), m.p. 192-193 ° C Found: C 59.44; H 4.54; N 22.93. He C 21 H 19 F 2 N 7 O requires C 59. 57; H 4 .52; N 23 16% PREPARATION 1 2-Ethyl-5-bromopyridine A solution of ethyl agnesium bromide in dry ether (3M, 100 ml, 0.30 mmol) was added dropwise to a stirred, ice-cooled solution of anhydrous zinc chloride (40.9 g, 0.30 mmol) in dry tetrahydrofuran (500 ml. ) under a nitrogen atmosphere, and the resulting solution was stirred for 1 hour more before sequentially adding tetrakis (triphenylphosphine) palladium (0) (1.0 g, 0.87 mmol) and a solution of 2,5-dibromopynyl (50 g, 0.21). millimoles) in dry tetrahydrofuran (200 ml). The resulting yellow suspension was stirred at room temperature for 18 hours, quenched rapidly by adding water (200 ml) and evaporated under reduced pressure. The residue was partitioned between dichloromethane (500 ml) and a suspension of ethylenediaminetetraacetic acid (200 g) in water (1). The organic phase was separated, combined with an extract (500 ml) of the aqueous phase in dichloromethane, extracted (MgSO 4) and evaporated under reduced pressure. Distillation of the residue under reduced pressure gave the title compound (28.8 g) as a colorless oil, b.p. 123-124 ° C at 8 KPa (60 m Hg). & (CDC13): 1.20 (32H, t), 2.80 (2H, q), 7.10 (IH, d), 7.70 (IH, dd), 8.60 (IH, d).

PREPARATION 2 2- (1-Bromoethyl) -5-bromopyridine A stirred solution of the title compound of Preparation 1 (1.86 g, 10 mmol) and N-bromosuccinimide (1.78 g, 10 mmol) in 1,2-dichloroethane (20 mL) was heated to reflux, added to azobis (isobutyronitrile) (20 mg) and the reaction solution was stirred under reflux for 2 hours. The resulting cold suspension was filtered, the filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using hexane: dichloromethane (1: 1) as eluent, affording the title compound (2.12 g) in form of a pale yellow oil. U (CDC13): 2.05 (3H, d ?, 5.20 (1H, q), 7.35 (IH, d), 7.80 (IH, d), 8.60 (1H, d).

PREPARATION 3 (2R, 3S / 2S, 3R) -l- (1,2, -Triazol-1-yl) -2- (2, -di luo-phenyl) -3- (5-bromopyrid-2-yl) putan-2 ol A solution of the title compound of preparation 2 (1.32 g, 5 mmol) and l- (2,4-difluorophenacyl) -1,4-triazole (1.11 g, 5 mmol) were added dropwise. dry tetrahydrofuran (12 ml) to a stirred suspension of zinc powder (0.85 g, 13 mmol) in dry tetrahydrofuran (8 nm) at rider temperature and under nitrogen atmosphere. Subsequent addition of iodine (0.25 g, 1 millimole) caused an exothermic reaction, after which the reaction mixture was quenched rapidly by sequentially adding glacial acetic acid (1 ml) and water (10 ml), and then adding acetate of ethyl (30 ml) and ethylenediane-tetraacetate disodium dihydrate (3.72 g, 10 mmol). The organic phase was separated, dried (MgSO) and evaporated under reduced pressure and the residue was then purified by column chromatography on silica gel using haxane: ethyl acetate (1: 1) as eluent, followed by trituration with ether. , giving the title compound (0.62 g), m.p. 158-161 ° C. d (CDCl 3): 1.08 (3H, d), 4.05 and 4.78 (2H9, system AB). Found: C 49.81; H 3.55; N 13.45. The Ci7H? SBrF2N? requires C 49.90; H 3.69; N 13.69%. Further elution of the previous column using hexane: ethyl acetate (1: 2) gave the minor, undesired, diastereomeric (2R, 34 / 2S, 3S) pair of enanomers in the form of oil (0.22 g), which crystallized (mp 82-83 ° C) when left at room temperature. 6 (CDI3): 1.50 (3H, d), 4.66 and 480 (2H, AB system). Found C 49.96; H 3.54; N 13.70. The Ci7H? SBrF2? requires C 49.90; H 3.69; N 13.69%.

PREPARATION 4 N, 0-dimethyl-4-vodobenzenehydroxamic acid A solution of pyridine (104 g, 1.32 mol) in dichloromethane (150 ml) was added dropwise to a stirred and ice-cooled suspension of 4-iodobenzoyl chloride (251 g, 0.94 mol) and N, 0- hydrochloride. dimethylhydroxy-amine (97 g, 0.94 mol) in dichloromethane (850 ml). The mixture was allowed to warm to room temperature and was then stirred for a further 18 hours. The resulting solution was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (11) and this solution was then washed sequentially with hydrochloric acid (2M, 3 x 400 ml) and saturated aqueous sodium bicarbonate solution (300 ml). , dried (a2S0) and evaporated under reduced pressure. The residue was purified by distillation under reduced pressure to give the title compound (241 g) as a yellow oil, bp. 130 ° C to 13.3 Pa (0.1 mm Hg). d (CDCl 3 ?: 3.32 (3H, s ?, 3.50 (3H, s), 7.40 (2H, d), 7.72 (2H, d).) PREPARATION 5 1- (-phenyl mode) -2- (2, -dif luorophenyl) ethanone 2,4-di-fluorobenzyl bromide was added dropwise (23.7 ml, 0.114 moles) was added to a stirred mixture of magnesium chips (8.1 g, 0.183 mol) in dry ether (300 ml) under nitrogen atmosphere. Initially the mixture was heated until the start of the reaction took place and then the aforementioned bromide was added at such a rate that it was kept under gentle reflux. After 1 hour, the resulting solution of the Grignard sß reagent was added dropwise to a solution of the title compound of preparation 4 (45.71 g, 0.157 mol) in dry ether (300 ml) at about -70 ° C and let the mixture warm to room temperature overnight (18 hours). The resulting mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate and then the organic phase was separated, taken out (MgSO 4) and evaporated under reduced pressure to give the title compound (38.71 g) as a a white solid, d (CDCI3J: 4.23 (2H, s), 6.83 (2H, m), 7.17 (ÍH, dt, 3 = 7.0 and 8.15 Hz), 7.72 (2H, d, 3 - 9.0 Hz), 7.84 ( 2H, d, 3 -9.0 Hz).

PREPARATION 6 1- (4-Iodophenyl) -2- (2, -difluorophenyl) prop-2-enone Bis (imethylaminoymethane (8.78 ml, 0.075 mol) was added dropwise to a stirred suspension of the title compound of preparation 5 (17.73 g, 0. 0495 mol) in acetic anhydride (23.1 ml., 0.248 moles) at room temperature. There was an exothermic reaction, raising the temperature of the mixture to approximately 60 ° C. After the end of the addition, the mixture was stirred at room temperature for 35 minutes and then ice water was added to hydrolyze the excess acetic anhydride. After a further 30 minutes, the organic material was extracted into ethyl acetate and the combined extracts were sequentially washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried (M S04) and evaporated at reduced pressure to give the title compound. title (17.03 g) in the form of a solid balnco. d (CDCI3 ?: 6.90 (ÍH, s), 6.14 (ÍH, s), 6.84 (ÍH, ddd, 3 = 2.0 and 12 Hz), 6.95 (ÍH, dt.J = 2 and 8 Hz), 7.390 (ÍH) , dt.3 = 7 and 9 Hz), 7.59 (2H, d, J. = a Hz =, 7.38 (2H, d, 3 = 9 Hz).

PREPARATION 7 (2R, 2S) -2- (2,4-Di fluorophenyl) -2- (4-iodobenzoyl) oxy rano Benzyltrimethylammonium hydroxide (40% aqueous solution, 3.44 ml, 8.2 mmol) was added in one portion to a solution of the title compound of preparation 6 (37.3 g, 100.8 mmol) and t-butyl hydroperoxide (3M in tri ethyl pentane; 36.6 ml, 109 mmol) in toluene (550 ml) at room temperature. After 2 hours, the mixture was washed with water (2 x 500 ml), dried (MgS?) And evaporated under reduced pressure to give the title compound (37.46 g) as a white solid, d (CDCl 3) : 3.22 (ÍH, d, 3 = 5 Hz), 3.42 (ÍH, d, 3 = 5 Hz), 6.80 (ÍH, ddd, 3 = 2.8 and 12 Hz), 6.93 (ÍH, dt, 3 = 2 and 8 Hz), 7. 47 (ΔH, 7 = 7 and 9 Hz), 7.70 (2H, d, 3 - 9 Hz), 7.77 (2H, d, J = 9 Hz).

PREPARATION 8 (2R, 2S,) - 2- (2,4-Difluorophenyl) -2-El- (4-vodofßnil) ethenyl-3-ylorane N-butyllithium (2.5f1 in hexane, 50 ml, 125 mmol) was added dropwise to a stirred suspension of methyltri phenylphosphonium bromide (45.0 g, 126 mmol) in dry tetrahydrofuran (6700 ml) in 15 minutes. ) at about -70 ° C under nitrogen atmosphere. The mixture was allowed to warm to -20 ° C in 20 minutes and a solution of the title compound of preparation 7 (37.46 g, 97 mmol) in dry tetrahydrofuran (200 ml) was then added over 5 minutes. This mixture was allowed to warm to room temperature, stirred for a further 84 hours, treated with 10% aqueous ammonium chloride solution (500 ml) and concentrated under reduced pressure. The organic material was extracted into ethyl acetate and the combined extracts were dried (M S0) and evaporated under reduced pressure. The resulting solid residue was treated with boiling hexane (3 x 500 ml) and the remaining solid was added. discarded. The combined hexanes were filtered through a short pad of silica gel and evaporated at reduced pressure to give the title compound (34.3 g) as a yellow oil, d (CDCl 3): 3.13 (1H, d, 3 - 5 Hz), 3.17 (HH, d, 3 = 5 Hz), 5.45 (2H, m), 6.72 (HH, m), 6.80 (HH, m), 7.14 (2H, d, 3 = 9Hz), 7.39 (ÍH, dt, 3 - 7 and 9 Hz), 7.60 (2H, d, 3 = 9 Hz).

PREPARATION 9 (2R, 2S,) -! - (!, 2,4-Triazol-l-yl) -2- (2,4-difluorophenyl) -3- (4-iodophrysil) but-3-ßn-2-ol Sodium 1,2,4-triazole (12.15 g, 133 mmol) was added to a solution of the title compound of Preparation 8 (34.3 g, 89 mmol) in dry dimethylformamide (350 mmol) at about 70 ° C under an nitrogen. The resulting mixture was stirred for 5 hours and then allowed to cool and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in ether (800 ml) and the solution was washed with water (2 x 500 ml), dried (rigS04) and treated with silica gel (60-200 u, 75 g). The ether was evaporated under reduced pressure and the residual solid was applied to a column of silica gel (40-60 um 300 g? Elution with a solvent gradient of ethyl hexanocacetate (100: 0 to 25:75), followed by evaporation under reduced pressure of the required fractions of the eluate afforded the title compound (23.8 g) as a white foam, d (CDCl 3): 4.55 (H, d, 3 = 15 Hz), 4.90 (H, D) , 3 = 15 Hz), 5.16 (HH, s), 5.25 (2H, s), 6.70 (2H, m), 7.03 (2H, d, 3 = 9 Hz), 7.43 (HH, dt, 3 = 7 and 9 Hz), 7.58 (2H, d, J = 9 Hz), 7.79 (HH, s), 7.80 (HH, s).

PREPARATION 10 (2R) and (2S,) -! - (!, 2, -triazol-l-yl) -2- (2,4-difluorofßnil) -3- (4-iodophenyl) but-3-ßn-2-ol The title compound of preparation 9 was resolved by chiral HPLC using a column "Chiralpak AD" R and hexane: ethanol (95: 5) as eluent. The fractions containing each enantiomer were combined and evaporated under reduced pressure and then the residues were further purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent, followed by trituration with ether. Analytical HPLC indicated > 99% ee for each antiomer. For (A), the required (2R) enantiomer (peak 2): p.f. 111-112 ° C and Ca] 2S0 -49o (c = 0.1, CH 3 OH). Found: C 47.52; H 2.97; N 9.09. C18H1 F2N3O requires C 47.70; H 3.11; N 9.27%. For (B), the (2S) enantiomer (peak 1): p.f. 110-111 ° C and Ca] 25D + 41 ° (c = o.i, CH 3 OH). Found: C 47.88; H 3.02; N 9.29. C18H1 F2IN3O requires C 47.70; H 3.11; N 9.27%.

PREPARATION 11 (2R, 3S / 2S, 3R) -1- (1, 2, 4-Triazol-1-yl) -2- (2, -di fluorophenyl) -3- (4-iodophrysil) butan-2-ol A stirred solution of the title compound of preparation 9 (1.0 g, 2.2 mmol) and p-toluenesulfonihydrazide (4.1 g, 22 mmol) in toluene (30 ml) was allowed to reflux for 3 hours, allowed to cool to room temperature, it was diluted with ethyl acetate (30 ml) and washed with aqueous sodium hydroxide solution (2M, 2 x 30 ml). The combined aqueous liquids from the washings were washed with ethyl acetate and then the combined organic solutions were washed with saturated brine (30 ml), extracted (MgSO) and evaporated at reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of hexane: ethyl acetate (3: 1 to 1: 3), whereby the first diastereomeric pair eluting was the title compound (0.30. g), obtained in the form of a white solid, mp 169-171 ° C. after triturating with hexane containing traces of ethyl acetate, d (CDCl 3): 1-10 (3H, d), 3.30 (1H, q), 3.80 6 4.80 (2H, AB system), 4.90 (1H, s) , 6.80 (2H, m), 7.30 (2H,), 7.45 (1H, m), 7.70 (4H, m). Found: C 47.66; H 3.55; N 9.29. The C22H25F C1N5 O3 requires C 47.49; H 3.54; N 9.23%.

PREPARATION 12 (2R, 2S,) -! - (!, 2,4-triazol-1-yl) -2- (2,4-di fluorophenyl) -3- (4-iodophenyl) butan-2-ol Obtained from the title compound of preparation 10A, by a procedure similar to that described in Preparation 11 followed by crystallization from aqueous ethanol, m.p. 104 ° C and (oc) 2SD -44o (c = 0.1, CH 3 OH). Found: C 47.42; H 3.64; N 9.11. The C22H2SF3CINSO3 requires C 47.49; H 3.54; N 9.23%. m7z 456 (M + D +.

PREPARATION 13 1-Ethoxymethyl-1,2,3-triazole Chloromethylethylether (125 g, 1.32 mol) was added dropwise to a cooled, quenched 1,2,3-triazole suspension (91.4 g, 1.32 mol) and potassium carbonate ahydrous (183 g, 1.32 g. moles) in acetone (1.5 1). The mixture was then allowed to warm to room temperature and stirred for a further 18 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in water (11) and the aqueous solution was extracted with dichloromethane (3 x 300 ml). The combined extracts were washed with saturated brine (3 x 300 rnl), dried (a2S04) and evaporated under reduced pressure to give pale yellow oil. The distillation under reduced pressure of the oil initially gave 2-ethoxymethyl-l, 2,3-triazole (57 g), p.b. < 90 ° C a 0. 4 KPa (3 mm Hg). d (CDC13): 1.17 (3H, t), 3.60 (2H, q), 5.70 (2H, s), 17.70 (2H, s). found: C 47.36; H 7.23; N 32.62. C5H9N3O requires C 47.19; H 7.14; N 33.05%. The continued distillation gave the title compound (73 g), p.eb. 92-93 ° C at 0.4 KPa (3 mm Hg). d (CDCI3): 1.15 (3H, t), 3.56 (2H, q), 5.70 (2H, s), 7.77 (ÍH, s). Found: C 46.30; H 7.52; N 33.29. C5H9N3O requires C 47.19; H 7.14; N 33.05%.

PREPARATION 14 l-Ethoxymethyl-5-formyl-l, 2,3-triazole N-butyl lithium (2.5H in hexane, 11.3 ml, 28.3 mmol) was heated dropwise to a stirred solution of the title compound of preparation 13 (3.0 g, 23.6 mmol) in dry tetrahydrofuran (100 ml) at approximately -70 ° C under nitrogen atmosphere. The band suspension was stirred for a further 30 minutes, and then a solution of dry dimethylformamide (3.66 ml, 47.2 mmol) in dry tetrahydrofuran (3 ml) was added dropwise. The resulting solution was allowed to warm to room temperature, stirred for a further 30 min? And treated with saturated aqueous ammonium chloride solution (20 ml) and water (30 ml). The organic phase was separated, combined with extracts (2 x 50 ml) of the aqueous phase in dichloromethane, dried (a2S? 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gdl, using an elution gradient of hexane: ethyl acetate (3: 1 to 2: 1), giving the title compound (1.0 g) as an oil. colorless, d (CDCl 3): 1.15 (3H, t), 3.60 (2H, q), 6.00 (2H, s), 8.25 (H, s), 10.16 (1H, s). m / z 156 (M + l) *.

PREPARATION 15 l-Ethoxymethyl-5-vinyl-l, 2,3-triazole Obtained as a colorless oil, from the title compound of preparation 14, by a procedure similar to that described in preparation 8. d (CDCI3J: 1.15 (3H, t), 3.50 (2H, q), 5.55 (HH, d), 5.70 (2H, s), 5.90 (HH, d), 6.70 (HH, dd), 7.80 (HH, s ).

PREPARATION 16 l-Hethyl-5-formylpyrazole It was obtained from 1-methyl pyrazole by a procedure similar to that described in preparation 14. d (CDCl 3): 4. 20 (3H, s), 6.90 (H, s), 7.55 (H, s), 9.85 (H, s).

PREPARATION 17 l-Methyl-5-vinylpyrazole It was obtained from the title compound of preparation 16 by a procedure similar to that described in preparation 8. d (CDCl 3): 3.90 (3H, s), 5.35 (1H, d), 5.70 (1H, d), 6.40 Í1H, d), 6.60 (ÍH, dd), 7.40 (ÍH, d).

BIOLOGICAL ACTIVITY The following table illustrates the in vivo activity against acute systemic candidiasis in immunologically normal mice, from a solution of the compounds of the invention. The mice were infected intravenously with Candida albicans in order to establish a systemic infection (all untreated control mice died 2 days after infection). The efficiency of the compound was evaluated based on survival after oral dosing (0.1-5 mg / kg, 1, 4 and 24 hours after infection was measured as the dose that protects 50% of the mice on day 2 after the infection.

PICTURE PROFILE OF SAFETY The compounds of the invention were not found to exhibit overt signs of toxicity. For example, in a 7-day toxicity study in rats (dosed at 30 mg / kg orally), the compound of Example 1 caused no adverse effects.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of any entity, wherein: X is CH or N; R1 is phenyl substituted with 1 to 3 substituents, each independently selected from halo and CF3; R 2 is C 1 -C 4 hydroxyalkyl CONH 2, S (0) * (C 1 -C alkyl), Ar or Het, m is 1 or 2; Ar is phenyl, monosubstituted optionally with halo or CF3; and Het is a 6-membered nitrogenous aromatic heterocyclic group, attached to a C, having 1 or 2 nitrogen atoms, or a 5-membered nitrogenous aromatic heterocyclic group, attached to a C or an N, containing from 2 to 4 nitrogen atoms, wherein any of said heterocyclic groups is optionally substituted with Ci-C4 alkyl or with (Ci-C) alkoxymethyl.

2. A compound according to claim 1, wherein R1 is phenyl substituted by 1 or 2 substituents, each independently selected from R and Cl; R is hydroxypropyl, CONH2, SO2CH3, Ar or Het; Ar is fl orophenyl; and Het is a pyridyl, pyrazolyl, imidazoyl or triazolyl group, in which the cyanate pyrazolyl group is substituted as methyl and the said triazolyl group is optionally substituted with β-methoxyphenyl.

3. A compound according to claim 2, wherein Rl is 2,4-fluorophenyl and R2 is C (CH3) 2? H, CONH2, SO2CH3, 4-fluorophenyl, 2-pyridyl, l-methylpyrazol-5-yl, imidazol-1-yl, 1,2,3-triazol-4-yl or l-ethoxymethyl-1,2,3-triazole-5- ilo.

4. A compound according to any one of claims 1 to 3, which is the (2R, 3S) enantiomer of formula (IA):

5. - A compound according to any one of claims 1 to 4, which is the trans-alkene isomer.

6. A compound according to claim 5, which is selected from: trans- (2R, 3S) -l- (1, 2,4-triazol-1-yl) -2- (2,4-difluorophenyl) -3-. { 4-C2- (1-methylpyrazol-5-yl) ethenyl] -phenyl} butan-2-ol; trans- (2R, 3S / 2S, 3R) -l- (1, 2,4-triazol-1-yl) -2- (2, 4-di fluorophenyl) -3-. { 4-C2- (imidazol-1-yl) ethenyl] phenyl} butan-2-ol; trans- (2R, 3S / 2S, 3R) -l- (1, 2,4-triazol-1-yl) -2- (2,4-di fluorophenyl) -3-. { 5-C2-carbamoyletenyl) pyrid-2-yl] b? Tan-2-ol; and pharmaceutically acceptable salts thereof and pharmaceutically acceptable solvates of any entity.

7. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof or a pharmaceutically acceptable solvate of any entity, according to any one of claims 1 to 6, together with a pharmaceutically acceptable diluent or carrier.

8. A pharmaceutical composition according to claim 7, wherein the compound of formula (I) is complexed with a hydroxyalkyl- or suslfoalkyl- derivative of a cyclodextrin.

9. A pharmaceutical composition according to claim 8, wherein the cyclodextrin is an α-, β- or t-cyclodextrin.

10. A compound of formula (I) or a pharmaceutically acceptable salt of the same or pharmaceutically acceptable solvate of any entity or a pharmaceutical composition containing any of the aforementioned compounds, according to any one of claims 1 to 9. , for use as a medicine.

11. The use of a compound of formula (I) or of a pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate of any entity or of a pharmaceutical composition containing any of the aforementioned compounds, according to any one of the claims 1 to 9, for the manufacture of a means for the curative or prophylactic treatment of a fungal infection.

12. A compound of formula (II): wherein Z is bromine or iodine, and X and R1 are as defined above for formula (I) in claim 1.