MXPA00000453A - 2,4,4-trisubstituted-1,3-dioxolane antifungals - Google Patents

Abstract

The present invention concerns novel compounds of formula (I), a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein n is zero, 1, 2 or 3;X is N or CH;each R1 independently is halo, nitro, cyano, amino, hydroxy, C1-4alkyl, C1-4alkyloxy or trifluoromethyl;R2 is hydrogen;C3-7alkenyl;C3-7alkynyl, aryl;C3-7cycloalkyl;optionally substituted C1-6alkyl;R3 and R4 each independently are hydrogen, C1-6 alkyl, C3-7cycloalkyl or aryl;or R3 and R4 taken together form a bivalent radical -R3-R4- of formula (a), (b), (c), (d), or (e), wherein R5a, R5b, R5c, R5d each independently are hydrogen, C1-6alkyl or aryl;and aryl is optionally substituted phenyl;as antifungals;their preparation, compositions containing them and their use as a medicine.

Description

ANTIFUNGALES 1.3-DIOXOLANO 2.4,4-TRISUSTITUIDOS The present invention relates to novel 1,3,4-trisubstituted 1,4-dioxolane antifungals and their preparation; it also refers to the compositions comprising them, as well as to their use as medicine. European patent A-0,118,138 discloses 2,4,4-trisubstituted 1,3-dioxolane having antimicrobial properties and which are effective in inhibiting the development of Candida albicans. The compounds of the present invention differ from each other structurally by the substitution pattern on the 1,3-dioxolane ring. WO 88/05048 describes 2,4,4-trisubstituted 1,4-dioxolane derivatives which are said to have antifungal activity. The present compounds differ structurally thereof by the nature of the substituent on the 4- (4-phenylpiperazinyl) phenoxymethyl portion at the 2-position on the 1,3-dioxolane ring. It was found that the present compounds are active against a wide variety of fungi, in particular against dermatophytes. The present invention relates to new compounds of formula ^ f * to the N-oxide forms, to the pharmaceutically acceptable acid addition salts and to their stereochemically isomeric forms in which n is 0, 1, 2, or 3; 10 X is N or CH; each R 1 is independently halo, nitro, cyano, amino, hydroxy, C 4 alkyl, C 0 O alkyloxy trifluoromethyl; R2 is hydrogen, C3-7 alkenyl, C3-7 alkynyl, aryl; C3-7 cycloalkyl, C-? 6 alkyl, or C? -6 alkyl substituted with hydroxy, C- alkyloxy, C3-7 cycloalkyl, or aryl; R3 and R4 are each independently hydrogen, C6-6 alkyl, C3-7 cycloalkyl or aryl; R3 and R4 taken together form a divalent radical - R3 and R4 - having the formula: R5a 0 0 R5a R5a R5c O R5a OOOI II II III II II II II H - c - c - c - c - c - c- - cc - c- or - cc - c- R5b R5b R5b R5d R5b p5a (a) (b) (c) (d) (e) wherein R5a, R5b, R5c and R5d are each independently hydrogen, C6-6 alkyl or aryl; and aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, nitro, cyano, amino, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy or trifluoromethyl. In the preceding definitions and in those which are given below, the term halo defines fluorine, chlorine, bromine and iodine; C 1-4 alkyl, defines straight and branched chain saturated hydrocarbon radicals having from one to four carbon atoms such as for example methyl, ethyl, propyl, 1-methylethylthio, butyl, 2-butyl, 2-methylpropyl, 2,2 -dimethylethyl and similar; C? -6 alkyl, includes C- alkyl, and their higher homologs having 5 or 6 carbon atoms such as for example pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C3-6 alkyl, defines straight and branched chain saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as for example propyl, 1-methylethyl, butyl, 2-methylpropyl, 2,2-15 dimethylethyl, pentyl, 2- methylbutyl, hexyl, 2-methylpentyl and the like; C3-7 alkenyl defines straight or branched chain hydrocarbon radicals having a double bond having from three to seven carbon atoms such as for example 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-methyl- 2-butenyl, 2-hexenyl, 2-heptenyl and the like, and the carbon atom of said C3- alkenyl 7 is connected to the nitrogen atom is preferably saturated; C3-7 alkynyl, defines straight or branched chain hydrocarbon radicals having a triple bond and having from 3 to 7 carbon atoms such as for example 2-propinyl, 3-butinyl, 2-butinyl, 2-pentynyl, 3- methyl-2- butynyl, 2-hexenyl, 2-heptynyl and the like, and the carbon atom of said C3-7 alkynyl which is connected to the nitrogen atom is preferably saturated; C3-7 cycloalkyl is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The pharmaceutically acceptable acid addition salts mentioned above comprise the non-toxic therapeutically active acid addition salt forms which the compounds of formula (I) can form. The latter can be conveniently obtained by treating the basic form with suitable acids such as inorganic acids for example hydrohalic acids, for example hydrochloric, hydrobromic, and the like.; sulfuric acids; nitric acid, phosphoric acid and the like; or organic acids, for example acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic (Z) -2-butenedioic, (E) -2-butenedioic, 2-hydroxybutanedioic, 2,3- dihydroxybutanedioic, 2-hydroxy-1, 2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and similar acids. Conversely, saline can be converted by alkali treatment to the free base form. The term addition salt also comprises hydrates and solvent addition forms which the compounds of formula (I) are capable of forming. Examples of such forms are for example hydrates, alcoholates and the like.

The N-oxide forms of the present compounds comprise the compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called N-oxide. Whenever used in the following, the term "compound of formula (I)" will also include its N-oxide forms, its pharmaceutically acceptable acid addition salts, and its stereochemically isomeric forms. An interesting group of compounds consists of those compounds of formula (I) to which one or more of the following 10 conditions can be applied: 1) n is 1 or 2; 2) R1 is halo; 3) R 2 is C 3-7 cycloalkyl or C 1 -β alkyl; 4) R3 is hydrogen or C-? 6 alkyl; and R4 is hydrogen or C-i-β alkyl, or R3 and R4 form a divalent radical -R3 -R4 having the formula (a), (b), (c), (d) or (e), wherein R5 is hydrogen or C-? -6 alkyl. Interesting compounds are compounds of formula (I) wherein n is 1 or 2 and each R1 independently is halo and more particularly where n is 2 and both R1 are fluorine, especially when the fluorine atoms are attached at the 2-position. and 4 of the phenyl ring. Also interesting are compounds of formula (I) in which X is N.

A - ^^ «s» toi-¿sai », ^? «.aj» »tofc»? »'Ate - - - Other interesting compounds are those compounds of formula (I) in which R3 and R4 form a divalent radical -R3-R4 having the formula (a), (b) , (c), (d) or (e) wherein R5a, R5b, R5c and R5d are each independently hydrogen, C-? 6 alkyl, in particular -R3-R4- is a radical of formula (c) wherein both R5a and R5 are hydrogen and R5c and R5d are each independently hydrogen and alkyl CIT; Or a radical of formula (d) wherein both R5a and R5b are C6-alkyl; or a radical of formula (e) wherein R5a is C-? -6 alkyl. Another interesting group of compounds consists of those compounds of formula (I) in which R2 is C3-7 cycloalkyl or Ci-β alkyl in particular those in which R2 is alkyl d-6 preferably those in which R2 is C3-alkyl 6 whereby the alkyl chain is branched at position a. Said preferred alkyl chains include for example 1-methylethyl and 1-methylpropyl. A group of preferred compounds consists of those compounds of formula (I) in which the phenyl ring attached at the 4-position of the 1,3-dioxolane ring is a 2,4-difluoromethyl ring; and R3 and R4 form a divalent radical-R3-R4 of formula (c) wherein both R5a and R5b are hydrogen and R5c and R5d are amD0S hydrogen or both are C-i-β alkyl; and R2 is Ci-β alkyl. Also preferred are those compounds of formula (I) in which the substituents on the 1,3-dioxolane ring have the cis configuration, especially the enantiomerically pure cis isomers. > Most preferred are those compounds of formula (I) in which the phenyl ring attached at the 4-position of the 1,3-dioxolane ring is a 2,4-difluorophenyl ring; and R3 and R4 form a divalent radical -R3-R4 of formula (c) where R5a, R5b, R5c and R5d are hydrogen, and R2 is methyl, ethyl, propyl, -butyl, 1-methylethyl or 1-methylpropyl, especially 1-methylethyl. Most preferred are 1- [4- [4- [4 - [[4- (2,4-difluorophenyl) -4- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3- dioxolan-2-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -3- (1-methylethyl) -2-imidazolidinone; the N-oxide forms, the pharmaceutically acceptable acid addition salts and their stereochemically isomeric forms. In the following paragraphs, different ways of preparing the compounds of formula (I) are described. In order to simplify the structural formulas of the compounds of formula (I) and the intermediates of formula (I) and the intermediates involved in their preparation, the 2,4,4- to trisubstituted portion involved in their preparation, 2,4,4-trisubstituted portion will be represented by the symbol T given below.

^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ) O-alkylation of the appropriately substituted phenol of formula (III) can be conveniently prepared with an alkylating reagent of formula (II). In formula (II) and then W represents an appropriate reactive leaving group 5 such as for example halo or a sulfonyloxy group. di) (lll) Said O-alkylation reaction may conveniently be carried out in an appropriate solvent inert to the reaction in the presence of an appropriate base and optionally under an inert atmosphere such as for example oxygen free argon or nitrogen gas. Suitable solvents are, for example, hydrocarbons, halogenated hydrocarbons, alkanols, ethers, ketones, esters, dipolar aprotic solvents, or mixtures of said solvents. The acid that is released during the course of the reaction can be collected by an appropriate base such as for example sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydride and the like; or an amine, for example triethylamine. In some cases it can be advantageous Converting the substituted phenol (III) first into a metal salt thereof, for example the sodium salt by reaction of (III) with a metal base such as for example sodium hydride and the like and using said metal salt subsequently in the reaction with (II). The reaction mixture can be stirred, heated in order to improve the rate of the reaction. In this and in the following preparations, the reaction products can be isolated from the medium and if necessary can be further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. Alternatively, said O-alkylation can be carried out by applying known conditions in the reaction art of phase transfer catalysis. Said conditions comprise stirring the reactants with an appropriate base and optionally under an inert atmosphere as defined above, in the presence of an appropriate phase transfer catalyst. Somewhat elevated temperatures may be appropriate to improve the rate of the reaction. The compounds of formula (I) can also be prepared by transacetallating an acetal of formula (V) with 1,2-diol of formula (IV) by stirring the reagents in an appropriate solvent inert to the reaction in the presence of an appropriate acid catalyst.

In formula (V) and below, each R independently represents an alkyl group or both radicals taken together can also form a divalent alkanediyl radical such as for example 1,2-ethanediyl, 1,3-propanediyl, 2,2-dimethyl- 1,3-propanediyl and the like. Suitable acid catalysts are, for example, hydrochloric and hydrobromic acid, sulfuric acid and the like or a sulfonic acid. Suitable solvents inert to the reaction are, for example, aromatic hydrocarbons, halogenated hydrocarbons, ethers or a mixture thereof. Said transacetallation reaction can conveniently be carried out at temperatures ranging from about 0 ° C to about room temperature. In some cases, however, the reaction can be carried out at a somewhat elevated temperature in order to shift the equilibrium to the acetal of formula (I). The alcohol or diol that is read during the course of the transacetalation reaction may be removed from the reaction mixture following procedures well known in the art such as for example distillation. The compounds of formula (I) can also be obtained by cyclizing an intermediate of formula (VI) or (IX) with respectively an amine of formula (VII) or (VIII). ^^^^^^^^^ &S ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (VIII) (IX) Said cyclization reaction can be conveniently carried out by mixing the reactants optionally in a reaction-inert solvent such as for example water, an aromatic solvent, an alkanol, an acetone, an ether, a dipolar aprotic solvent or a mixture of said solvents. The addition of an appropriate base such as for example sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide and the like or a Organic base such as for example triethylamine, can optionally be used to collect the acid that is formed during the course of the reaction. In some cases the addition of an iodide salt for example potassium iodide; or a crown ether for example 1, 4,7, 10,13, 16-hexaoxacyclooctadecane may be appropriate. Stirring and slightly elevated temperatures can improve the rate of reaction.

The compounds of formula (I) can also be obtained by N-alkylation of a compound of formula (X) with an alkylating reagent of formula R2-W (XI) wherein R2- and W are: (X) The compounds of formula (I) wherein R 4 is hydrogen, and which are represented by formula (Ia), can be prepared by the reaction of an intermediate of formula (XVll) with an isocyanate R2-N = C = O in a solvent inert to the reaction such as for example dichloromethane.

(XVll) (ka) Compounds of formula (I) wherein R 4 is selected from hydrogen, C 1 -C 6 alkyl, C 3 cycloalkyl and aryl, wherein said R 4 is represented by R 4, and said compounds are represented by the formula (Ib) can be prepared by the reaction of an intermediate of formula (XVlll) where L is an appropriate leaving group such as for example phenoxy, trichloromethoxy, chloro or midazolyl, with an NHR2R4 intermediate in a reaction-inert solvent, such as for example tetrahydrofuran or dichloromethane, in the presence of an appropriate base such as for example triethylamine. The reactive amino groups in R2, if present, are They are protected with a protecting group P such as, for example, a C 1-4 alkyloxycarbonyl group. Conveniently, the reactive amino group can be again deprotected using deprotection techniques known in the art to arrive at the desired compound of formula (1-b).

(XVlll) (l-b) The compounds of formula (I) can also be converted to one another following known transformations. The compounds of formula (I) can also be converted to the corresponding N-oxide forms following art-known procedures for converting trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can be carried out generally by reacting a starting material of formula (I) with an organic peroxide or inorganic appropriate. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metals, for example sodium peroxide, potassium peroxide; suitable inorganic peroxides may also comprise peroxyacids such as, for example, carboperoxoic benzene acid or benzene acid Halo-substituted carboperoxoic, for example carboperoxoic 3-chlorobenzene, peroxoalkanoic acids for example peroxoacetic acid, alkylhydroperoxide, for example terbutilic hydroperoxide. Suitable solvents are for example water, lower alkanols, for example ethanol and the like, t * i * a ^ i * fe ^ 1 & Hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons for example dichloromethane and mixtures of said solvents. A variety of intermediates and starting materials used in the foregoing preparations are known compounds while others may be prepared according to methodologies known in the art to prepare said compounds or similar compounds. The preparation of intermediates (II) (has been described in WO88 / 05048, the preparation of (III), (VII) and (IX) has been described in U.S. Patent No. 4,619,931, U.S. Patent No. 4,861. 879 and / or European patent EP-A-0,331,232 In particular, the intermediates of formula (II) can be prepared from the intermediates of formula (IV) and the acetals of formula (XII) following the transacetalization procedures described above for the preparation of the compounds of formula (I) from (IV) and (V) The diastereoselectivity of the acetalization can be improved by favoring the cis isomer in the case where W represents a hydroxy portion.

(IV) (ii) áÁ ^^? M ^^^ ,. TO? The intermediates of formula (IV) can be obtained from an acetal (XIII) by N-alkylation with 1 H-imidazole or with 1, 2,4-triazole, followed by hydrolysis of the acetal (XIV) in an aqueous acidic medium. Alternatively, hydrolysis of the acetal (XIII) can be carried out before N-alkylation with 1 H-imidazole or with 1, 2,4-triazole.

(XIII) (XIV) The intermediate (XIII) can be prepared in turn from a 2-propanone derivative of formula (XV) by treatment with an optionally substituted Grignard reagent of formula (XVI) followed by formation of Hephoxide and followed by base and acetalation with a ketone in the presence of a Lewis acid, such as for example tin (IV) chloride.

(XV) The intermediates of formula (XVll) wherein R3 is hydrogen, and said intermediates being represented by the formula (XVII-a) can be prepared by the reaction of an intermediate of formula XlX-a) where Mgag ^^^ ifi ^^ É g SAj g? ^^^^^ yiíg ^^ jj? ^? ^ NP2 is a protected amino group where P is for example a C? -4 alkyloxycarbonyl group or a functional derivative of NP2 such such as for example a nitro group, with an intermediate of formula (II) analogous to the procedure descr for the reaction of the intermediate (II) with the intermediate (III). The intermediates thus obtained of formula (XlX-b) can be deprotected according to deprotection techniques known in the art. In the case where NP2 is a nitro group, reduction techniques known in the art such as for example reduction using hydrogen in the presence of a catalyst such as for example palladium on activated carbon, can be used for obtain the intermediates of formula (XVI I-a). The intermediates of formula (XVll) wherein R 3 is C 1-6 alkyl, C 3-7 cycloalkyl or aryl, said R 3 represented by R 3, and said intermediates being represented by the formula (XVII-b), can be prepared by the reaction of a formula intermediary (XVI Ia), with an intermediate W-R3, or in the case that R3, is Methyl, with a functional derivative thereof such as paraformaldehyde together with sodium metalonate in a reaction-inert solvent such as for example methanol and in the presence of an appropriate reducing agent such as for example sodium borohydride.

(XVII-b) (XViμa) Intermediates of formula (XVlll) can be prepared by the reaction of an intermediate of formula (XVll) with a chloroformate such as for example phenyl chloroformate or trichloromethyl chloroformate, bis (trichloromethyl) carbonate, or with a functional derivative thereof such as for example 1, 1'-carbonylbis-1 H -amidazole.

Cl- C- L (XVlll) It may be convenient to prepare the intermediates of formula (XVlll) and the subsequent compounds of formula (1-b) in the same reaction mixture. The term "stereochemically isomeric forms" as used below defines all possible isomeric forms that the compounds of the formula (I) may possess. From the formula (I) it is clear that the compounds of this invention have at least two asymmetric carbon atoms in their structures ie those which are located in the 2 and 4 position of the dioxolane nucleus. Depending on the nature of the substituents R1 to R5, the compounds of formula (I) may also contain a third or more asymmetric carbon atoms. Accordingly, the compounds of the formula (I) can exist under different stereochemically isomeric forms. Unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, containing said mixtures all diastereomers and enantiomers of the basic molecular structure. The pure stereoisomeric forms of the compounds and intermediates mentioned herein are defined as isomers that are substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" refers to compounds or intermediates having a stereoisomeric excess of at least 80% (ie a minimum of 90% of an isomer and a maximum of 10% of the other possible isomers). ) to a 100% stereoisomeric excess (ie 100% of one isomer and none of the other), more particularly compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more particularly having a stereoisomeric excess of 94% up to 100% and more particularly still having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar manner, but taking into account that the enantiomeric excess respectively of the diastereomeric excess of the mixture in question. The absolute configuration of each asymmetric center can be indicated by the stereochemical descriptors R and S, this annotation R and S corresponding to the rules described in Puré Appl. Chem. 1976, 45, 11-30. The terms cis and trans are used herein in accordance with the nomenclature of Chemical Abstracts (J. Org. Chem. 1970, 35 (9), 2849-2867), and refer to the position of the substituents in the ring portion further particularly in the dioxolane ring in the compounds of the formula (I). For example when the cis or trans configuration of the dioxolane ring is established, the substituent with the highest priority at the carbon atom at the 2-position of the dioxolane ring and the substituent with the highest priority at the carbon atom at the 4-position of the dioxolane ring are considered (determining the priority of a substituent according to the rules of the Cahn-Ingold-Prelog sequence). When said two substituents with the highest priority are on the same side of the ring then the configuration is designated cis, and if not, the configuration is designated trans. For example, the absolute configuration of the asymmetric carbon atoms of compound 51 described in example B.3 below, ie (2S-cis) -1 - [4- [4 [4 [[4- (2,4 -difluorophenyl) -4- (1 H-1, 2,4-triazoM -ylmethyl) -1, 3-dioxolane-2-yl] methoxy] phenyl-1-piperazinyl + phenyl-3 (1-methylethyl) - 2-imidazolidinone as will be described below. Therefore the carbon atom number 2 of the dioxolane ring in this compound has the configuration S and the carbon atom 4 have the configuration R.

The pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained by the application of methods known in the art. For example, the enantiomers can be separated from one another by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, the enantiomers can be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms can also be derived from the corresponding stereochemically isomeric pure forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if it is desired to obtain a specific stereoisomer, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. The stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of the invention. The diastereomeric racemates of (I) can be obtained separately by conventional methods. Suitable physical separation methods that can be used advantageously are for example crystallization and selective chromatography for example column chromatography. Because the stereochemically configuration is already fixed in an amount of intermediates for example in the intermediates of formula (II), (VI), (VIII) and (X) and in some of their respective precursors it is also possible to separate the forms cis and trans in one of these stages. The separation of the cis and trans forms of said intermediates can be carried out by conventional methods as mentioned above for the separation of the cis and trans forms of the compounds of formula (I). The corresponding diastereomeric forms of (I) can then be derived in the manner previously indicated. It is evident that the cis and trans racemates can be further resolved into their optical isomers cis (+) and cis (-), respectively and trans (+) and trans (-) by the application of methodologies known in the art. In case additional asymmetric centers are present in the intermediates and / or the aforementioned compounds, the resulting mixtures of the stereoisomers can be further separated by the previously indicated methodologies. Preferably, if it is desired to obtain a specific stereochemical form, said compound will be synthesized by stereoselective preparation methods which will advantageously employ enantiomerically pure starting materials. The compounds of formula (I), the pharmaceutically acceptable addition salts and the stereochemically isomeric forms and the same are useful agents for combating fungi in vivo. The present compounds are active against a wide variety of fungi such as Candida spp., For example Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida kefyr, Candida tropicalis, Aspergillus spp., For example Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenc ii, Epidermophyton floccosum; Microsporum canis; Trichophyton spp., For example Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum; and several dematiaceous hypomycetes. The compounds of the present invention show enhanced antifungal activity against some fungal isolates and have good oral availability. In vitro experts such as the determination of the fungal susceptibility of the present compounds for, for example, Candida and the determatophytic isolates and the determination of the effects of the present compounds or of the synthesis of sterol in for example Trichophyton mentagrophytes, demonstrate their potency antifungal Likewise, in the in vivo experiments in several mouse models, guinea pig and rats for example the oral administration of a test compound or mice infected with Trichophyton quinckeanum or Microsporum canis, shows that the present compounds are potent antifungal. The following example demonstrates the in vitro antifungal activity of the present compounds versus Candida kefyr and Trichophyton rubrum. In view of the usefulness of the compounds of the formula (I) a method is provided for treating warm-blooded animals including humans suffering from fungal infections. Said methods comprise the systemic administration of an effective amount of a compound of formula (I), of an N-oxide form, and a pharmaceutically acceptable acid addition salt or of a possible stereoisomeric form thereof, to animals of hot blood including humans. Therefore the compounds of formula (I) are provided to be used as a particular medicament the use of a compound of formula (I) for the manufacture of a medicament that is useful for treating fungal infections. In general it has been contemplated that a therapeutically effective daily amount would be from 0.05 mg / kg to 20 mg / kg of body weight. The present invention also provides compositions for treating or preventing fungal infections comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. In view of their useful pharmacological properties, the present compounds can be formulated into various pharmaceutical forms for administration or topical purpose. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of a particular compound in its addition or base salt form as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may have a variety of form depending on the the form of preparation desired for administration. These pharmaceutical compositions are conveniently given in an appropriate unit dosage form, preferably for oral, rectal, percutaneous administration or by parenteral injection.

In order to prepare the compositions in an oral dosage form, any of the usual means in pharmacy such as for example water, glycols, oils, alcohols and the like can be used in the case of liquid preparations. oral substances such as suspensions, syrups, elixirs and suspensions or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Due to its easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case obviously solid pharmaceutical carriers will be employed. Suitable compositions for topical application are all the compositions which are usually used to administer drugs topically, for example cream, gels, bandages, shampoos, dyes, pastes, ointments, dressings, powders and the like. In particular, the present compounds can be formulated in topical compositions especially adapted to be released into the nail. In compositions that are suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or an appropriate wetting agent, optionally combined with appropriate additives of any nature in minor proportions whose additives do not cause a significant detrimental effect to the skin . Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various forms, for example as a transdermal spot-on patch, as an ointment. For the ^^ | ^ g ¡| ^^ = áÉÉ parenteral compositions the carrier will usually comprise water sterilized at least for the most part. Injectable solutions can be prepared, for example, in which case the carrier comprises saline solution, glucose solution or a mixture of saline and glucose. Injectable solutions can also be prepared in which case suitable carriers, suspending agents and the like can be employed. In order to improve the solubility and / or the stability of the compounds of formula (I) in the pharmaceutical compositions, it may be advantageous to employ a - β- or β-cyclodextrin or its derivatives. Also, co-solvents, such as alcohols can improve the solubility and / or stability of the compounds of formula (I) in the pharmaceutical compositions. In the preparation of aqueous compositions, the addition salts of the present compounds will obviously be more appropriate due to their increased solubility in water. Suitable cyclodextrins are α- or β-cyclodextrin or ethers and ethers thereof where one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C alquilo?-6 alkyl, particularly ethyl, methyl or isopropyl. , for example ß-CD randomly methylated; hydroxyC6 alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; C 1 -C 6 carboxyalkyl, particularly carboxymethyl carboxyethyl; C? -6 alkylcarbonyl, particularly acetyl; C 1 - 6 alkyloxycarbonyl, C 1 --6 alkyl, or C 1 --6 carboxy - alkyloxy, C 6 --6 alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkyl, particularly 2-acetyloxy propyl. Especially valuable as complexing and / or solubilizing agents are β-CD, randomly methylated CD-β, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl- ? -CD and (2-carboxymethoxy) propyl-β-CD, and in particular 2-hydroxypropyl-β-CD (2-HP-β-CD). The term "mixed ether" denotes cyclodextrin derivatives in which at least two hydroxycyclodextrin groups are etherified with different groups such as for example hydroxypropyl and hydroxyethyl. The average molar substitution (S.M.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The value M.S. it can be determined by various analytical techniques such as nuclear magnetic resonance (NMR) mass spectrometry (MS) and infrared spectrometry (IR). Depending on the technique used, slightly different values may be obtained for a given cyclodextrin derivative. Preferably, measured by mass spectrometry, the SM will be between 0.125 to 10. The degree of substitution G.S. refers to the average number of substituted hydroxyl per unit of anhydroglucose. The value G.S. it can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared (IR) spectroscopy. Depending on the technique used, slightly different values may be obtained for a given cyclodextrin derivative. Preferably measured by mass spectrometry, G.S. will be between 0.125 to 3. sdg S ^^^ S 7 An interesting way of formulating the present compounds in combination with the cyclodextrin or a derivative thereof has been described in the European patent EP-A-721337 (equivalent to the Argentine patent application No. 329,617). The formulations described therein are particularly suitable for oral administration and comprise an antifungal as an active ingredient, a sufficient amount of a cyclodextrin or a derivative thereof as a solubilizer, an aqueous acidic medium as a liquid mass carrier and an alcoholic co-solvent that greatly simplifies the preparation of the composition. These formulations can become also in tastier formulations by the addition of pharmaceutically acceptable sweeteners and / or flavors. Other convenient ways to improve the solubility of the compounds of the present invention in the pharmaceutical compositions have been described in WO-94/05263 (equivalent to the patent application Argentine N °. 325,899) and PCT application No. PCT / EP98 / 01773. European Patent EP-A-499,299 and WO97 / 44014 (equivalent to the Argentine patent application No. P 97 01 02113). More particularly, the present compounds can be formulated in a pharmaceutical composition comprising an amount Therapeutically effective of particles consisting of a solid dispersion comprising (a) a compound of formula (I), and (b) one or more pharmaceutically acceptable water soluble polymers. ^^^^^^^^ m ^ M ^^^ i. . ^.

The term "solid dispersion" defines a system in the solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one of the components is dispersed more or less uniformly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogeneous in its entirety or consists of a phase as defined in thermodynamics such as a solid dispersion is referred to as a "solid solution". Solid solutions are preferred physical systems because the components thereof are usually readily bioavailable to the organisms to which they are administered. The term "solid dispersion" also includes dispersions that are less homogeneous throughout all solid solutions. Said dispersions are not chemically and physically uniform in their entirety or comprise more than one phase. The water-soluble polymer in the particle is a polymer that has an apparent viscosity of 1 to 100 mPa.s. when dissolved in a 2% aqueous solution to a solution at 20 ° C. Preferred water soluble polymers are hydroxypropylmethylcellulose or HPMC. HPMC having a degree of methoxy substitution of from about 0.8 to about 2. 5 and a hydroxypropyl molar substitution of from about 0.05 to about 3.0, are generally soluble in water. The degree of methoxy substitution refers to the average number of methyl ester groups that are present for each anhydroglucose unit of the cellulose molecule. The hydroxypropyl molar substitution refers to the number of moles of propylene oxide that have reacted with each anhydroglucose unit of the cellulose molecule. The particles defined above can be prepared by first preparing a solid dispersion of the components, and then optionally grinding or milling this dispersion. There are several techniques for preparing solid dispersions including melt extrusion, spray drying and solution evaporation, with the melt extrusion being preferred. It may further be convenient to formulate the present antifungal azole in the form of nanoparticles having a surface modifier absorbed onto the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. It is believed that useful surface modifiers include those that physically adhere to the surface of the antifungal agent but do not chemically adhere to the antifungal agent. Suitable surface modifiers can preferably be selected from pharmaceutical organic and inorganic excipients with oxides. Said excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Another interesting way of formulating the present compounds involves a pharmaceutical composition in which the antifungal agents are incorporated in hydrophilic polymers and this mixture is applied as a coating film on many small granules, obtaining in this way a composition with good bioavailability that can be conveniently manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said granules comprise (a) a spherical or central round core, (b) a coating film of a hydrophilic polymer and an antifungal agent and (c) a polymeric layer that seals by coating. The materials to be used as cores in the granules are many, with the proviso that said materials are pharmaceutically acceptable and have the appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances and saccharides and derivatives thereof. The cores in said granules may have a diameter of approximately 60 mesh corresponding to approximately 250 μm, or more. Particular granules having a 25-30 mesh core (600-710 μm) have been described in WO-94/05263 (equivalent to Argentine patent application No. 325,899). PCT / EP98 / 01773 discloses granules whose core has a diameter of about 250 to about 600 (30-60 mesh).

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in a unit dosage form to facilitate the administration and uniformity of the dosage. The unit dosage form used in the present claims and claims refers to 5 physically discrete units which are suitable as unit dosages containing each unit a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored tablets or tablets). coated), capsules, pills, powder packets, seals, injectable solutions or suspensions, tea spoons, table spoons and the like and segregated multiples thereof. It may also be convenient to combine the present antifungal compounds with other antifungals such as for example antifungals containing azole, for example bifoconazole, crococonazole, clotrimazole, eberconazole, econazole, fenticonazole, fluconazole, flutrimazole, isoconazole, itroconazole, ketoconazole, lanoconazole, miconazole, neticonazole, omoconazole, oxiconazole, saperconazole, SCH 39304, sertaconazole, solconazole, thioconazole , voriconazole; or antifungals that are not diazol, for example amorolfine, butenafine, cyclopirox, cioteronel, naftidine, isotretinoin, rimoprogin, terbinafine. It is particularly useful to combine the present compounds with other determatological antifungals. ^ £ g ^^^ jjj? G j | gj ^ | ^^^^^^^^^^^ j ^^^^^^^ The combination of an antifungal compound and a compound of formula (I) can be used as a medicine. Therefore, the present invention also relates to products containing (a) a compound of formula (I) and (b) another antifungal compound, in the form of a combined preparation for simultaneous, separate or sequential use in the antifungal treatment. The different drugs of said products can be combined in a single preparation in conjunction with pharmaceutically acceptable carriers. Alternatively said products may comprise for example an equipment comprising a container with an appropriate composition containing a compound of formula (I) and another container with a composition containing another antifungal. Said product may have the advantage that a physician may select based on the patient's diagnosis that he must treat the appropriate amounts of each component and the sequence and time of administration thereof. The following examples are intended to illustrate the invention.

EXPERIMENTAL PART Of some compounds of the formula (I), the absolute stereochemical configuration of the stereogenic carbon atoms was not determined experimentally. In those cases in which the stereochemically isomeric form was isolated, they were first designated as "A" and ^ S ^ j ^^ g ^^^^^^^ j? G ^ & g ^^^ * ^ seconds as "B", without further reference to the actual stereochemical configuration. As used below, "DMF" is defined as N, N-dimethylformamide, "EtOAc" is defined as ethyl acetate, "DIPE" is defined as diisopropyl ether.

A. PREPARATION OF THE INTERMEDIATES EXAMPLE A-1 a) To a stirred and cooled mixture (-78 ° C) of 2-chloro-1 (2,4-difluorophenyl) -1-ethanone (30 g), chloroiodomethane (56.4 g), and tetrahydrofuran ( 267 ml) was dripped to a 6% solution of a methyllite-lithium bromide complex in diethyl ether (215 ml). The reaction mixture was slowly heated to room temperature and then hydrolyzed with NH CI. Aqueous NaOH was added and the mixture was stirred for one hour. The organic layer was separated, washed, dried and filtered and the solvent was evaporated. The residue was purified on silica gel (eluent: hexane / CH 3 COOC 2 H 5 98/2). The solvent of the desired fraction was evaporated obtaining 11 g (16.8%) of 2- (chloromethyl) -2- (2,4-difluorophenyl) oxirane (intermediate 1). b) A mixture of intermediate (1) (22 g), 2-propanone (158 ml) and a catalytic amount of trifluor [1,1'-oxybis [ethane]] boron was stirred overnight at room temperature. The reaction mixture was poured into an aqueous solution of NaHCO3 and the product was extracted with CH2Cl2. The extract AIABÉ? ISßA was washed with water, dried, filtered and the solvent was evaporated. The residue was purified on silica gel (eluent: hexane). The solvent of the desired fraction was evaporated obtaining 21 g (74.3%) of 4- (chloro-methyl) -4- (2,4-difluorophenyl) -2,2-dimethyl-1,3-dioxolane (intermediate 2). ). In a similar manner, there were prepared: 4- (chloromethyl) -4- (4-fluorophenyl) -2,2-dimethyl-1,3-d-oxolane (intermediate 3); and 4- (chloromethyl) -4- (4-chlorophenyl) -2,2-dimethyl-1,3-dioxolane (intermediate 4).

EXAMPLE A-2 a) A mixture of intermediate 2 (55 g), methanol (395 ml), water (100 ml) and hydrochloric acid (6.35 ml) was stirred overnight at reflux temperature. After cooling, the reaction mixture was neutralized with NaHCO3 and the solvent was evaporated. The residue was taken up in ethyl acetate and this solution was washed with NaCl, dried, filtered and the solvent was evaporated obtaining 45 g (96.5%) of 3-chloro-2- (2,4-difluorophenyl) -1, 2-propanediol (intermediate 5). b) A mixture of 1 H-1, 2,4-triazole (1.37 g), a dispersion of sodium hydride in mineral oil (50%) (0.6 ml) DMF (47 ml) was stirred for three hours at 80 ° C. C. Intermediate (5) (1.5 g) was added and the mixture was stirred at 80 ° C for one hour. The solvent was evaporated and the residue & j ^ ^^^^^^^^^^^^ a ^^^^^^ ^^^^ purified on silica gel (CH ^^ CH3OH 98/2). The solvent of the desired fraction was evaporated obtaining 0.7 g (40.9%) of 2- (2,4-difluorophenyl) -3- (1 H-1, 2,4-triazol-1-yl) -1,2-propanediol (intermediate 6, mp 132.3 ° C). c) A mixture of the intermediate nt 6 (0.16 mole) in methanesulfonic acid (100 ml) and CH2CL2 (1000 ml) was stirred in an ice bath. Drill 1-bromo-2,2, -dietoxyethane (0.2 ml) was added dropwise at 10 ° C. The mixture was allowed to warm to room temperature, stirred overnight, poured into a saturated aqueous NaHCO3 solution and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified on silica gel (eluent: CH 2 Cl 2 / CH 3 OH from 100/0 to 98/2) The desired fractions were collected and the solvent was evaporated.This residue was combined with the residue obtained from the same reaction carried out separately, this combined residue was further purified, separated into its enantiomers by chiral column chromatography on Chiralcel OD (eluent: hexane / ethanol 75/25) The groups of pure fractions were collected and their solvent was evaporated obtaining 45.4 (2R-cis) -1 - [[2- (bromomethyl) -4- (2,4-difluorophenyl) -1, 3-dioxolan-4-yl] -1 H-1, 2,4-triazole; aD20 = -4.26 ° (c = 28.2 mg / 3 ml in DMF) (intermediate 7) and 36.3 g (2S-cis) -1 - [[2- (bromomethyl) -4- (2,4-difluorophenyl) -1 , 3-dioxolan-4-yl] methyl] -1 H-1, 2,4-triazole, aD2o = + 5.83 ° (c = 16.46 mg / 2 ml in DMF) (intermediate 8) EXAMPLE A-3 a) To a stirred mixture of a dispersion of 50% sodium hydride in diethyl ether (25 ml) and in DMF (900 ml) was added dropwise a solution of 1 H-1, 2,4-triazole (40 ml). g) in DMF (225 ml). Stirring was continued for three hours at 60 ° C. A solution of intermediate 3 (50 g) in DMF (225 ml) was added drop by drop at 130 ° C and the mixture was stirred overnight. The solvent was evaporated and the residue was purified on silica gel (eluent: CHCl3 / CH3OH 98/2). The pure fractions were collected and the solvent was evaporated obtaining 78 g (68.5%) of 1 - [[4- (4-fluorophenyl) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl] -1 H-1, 2,4-triazole (intermediate 9). b) A mixture of the intermediate (99 g (38 g), methanol (320 ml), water (200 ml) and concentrated hydrochloric acid (60 ml) was stirred overnight at reflux temperature. The reaction was poured into an aqueous solution of NaHCO.sub.3 The solvent was evaporated and the residue was stirred in ethyl acetate.The precipitate was separated by filtration and the filtrate was dried, filtered and evaporated to obtain 25.5 g (78.4% of 2- ( 4-fluorophenyl) -3- (1 H-1, 2,4-triazol-1-yl) -1,2-propanediol (intermediate 10) c) A mixture of intermediate 10 (25 gr9, 2-bromo-1) , 1-diethoxyethane (20.6 g) and methanesulfonic acid (225 g) was stirred for two hours at room temperature The reaction mixture was added dropwise to an aqueous solution of NaHCO 3 The mixture was extracted with CHCl 3. with water, dried, filtered and the solvent was evaporated. ^^ a ^ UH ^ u ^^ purified on silica gel (eluent: CHCl3 / ethyl acetate / hexane 50/30/20). The desired fraction was collected and the solvent was evaporated. The residue was converted to the hydrochloride salt in 4-methyl-2-pentanone. The salt was separated by filtration and dried to obtain 7 g (17.6%) of cis-1 - [[2- (bromo-methyl) -4- (4-fluorophenyl) -1,3-dioxolan-4-yl monohydrochloride. ] -methyl] -1 H-1, 2,4-triazole (intermediate 11). In a similar manner, there were prepared: cis-1 - [[2- (bromomethyl) -4- (4-chlorophenyl) -1,3-dioxolan-4-yl] methyl] -1H-1, 2,4-triazole ( intermediary 12). cis-1 - [[2- (bromomethyl) -4- (4-dichlorophenyl) -1,3-dioxolan-4-yl] methyl] -1 H-1,2,4-triazole (intermediate 13). cis-1 - [[2- (bromomethyl) -4- (4-chlorophenyl) -1, 3-dioxolan-4-yl] methyl] -1 H-1, 2,4-imidazole (intermediate 14); and cis-1 - [[2- (bromomethyl) -4- (4-fluorophenyl) -1,3-dioxolan-4-yl] methyl] -1H-1, 2,4-imidazole (intermediate 15).

EXAMPLE A-4 a) 2,2-Dimethylmalonyl chloride (0.057 mol) was added to a solution of N- [4 [4- (4-methoxyphenyl) -1-piperazinyl + phenyl + urea (0.057 mol) in tetrahydrothiophene, 1, 1- dioxide (200 ml). After stirring for 15 minutes the reaction mixture was heated at 40 ° C for three hours and at 50 ° C for two hours. The reaction mixture was allowed to stand overnight at 25 ° C. The product was precipitated with diethyl ether and crystallized by trituration. The product was recrystallized from 2-propanol, yielding 20.1 g of 1- [4 [4- (4-methoxyphenyl) -1-piperazinyl) phenyl] -5,5-dimethyl-2,4,6 (1 H, 3H, 5H) -pyrimidinatrione (intermediate 16). 5 b) 80% NaH (0.0174 mol) was washed to get rid of the oil with hexane. DMF (70 ml) was added under argon atmosphere. Intermediate (16) (0.0166 mol) was added and the mixture was stirred for thirty minutes. Iodoethane (0.0182 mol) was added and the mixture was heated for three hours at 80-90 ° C. The reaction mixture was poured into water and the product was extracted with CH2Cl2. The residue was purified over AI2O3 (eluent: CH2Cl2). The pure fraction was collected and the solvent was evaporated. The residue was crystallized from ketonitrile to obtain 3.0 g of 1-ethyl-3- [4 [4- (4-methoxyphenyl) -1-pperazinyl] phenyl] -5,5-dimethylpyrimidine-2,4,6 - (1 H, 3 H, 5 H) trione (intermediate 17) c) A solution of the intermediate (17) (0.0068 mol) in HBr (60) ml; 48%) and acetic acid (30 ml) was refluxed for five hours. The reaction mixture was poured into a K2CO3 solution and the product was extracted with CH2Cl2. The extract was dried, filtered and the solvent was evaporated. The residue was crystallized from acetonitrile, 2-propanone and further purified on silica gel (eluent: CH 3 OH / CH 2 Cl 2/98). The residue crystallized from acetonitrile to yield 1.2 g (40%) of 1-ethyl-3- [4- [4- (4-hydroxyphenyl) -1- piperacin¡l] phenyl] -5,5-dimethylpyrimidine-2,4,6 ( 1 H, 3H, 5H) trione (intermediate 18). ^^^^^ ¿& ^ S ^ ¡^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ a) A mixture of intermediate 8 (0.048 mol) in 1,3-dimethyl-2-imidazolidinone (200 ml) was stirred under a flow of N2 for 15 minutes. HE added NaOH (3 ml, 50). The mixture was stirred for thirty minutes. 4- [4 - [(4-Nitrophenyl) -1-piperazinyl] phen] (0.04 mol) and then NaOH (2.4 g, solid) were added. The mixture was stirred at 70 ° C under an N 2 flow for 9 hours and at room temperature overnight and then poured into N 2 O and stirred for one hour. The precipitate was separated by filtration and dissolved in CH2CI2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / EtOAc / hexane 48/2/30/20.) The pure fractions were collected and the solvent was evaporated, The residue was crystallized from EtOAc. The precipitate was separated by filtration and dried to obtain 9 g of (2S-cis) -1 - [4 [[4- (2,4-difluorophenyl) -4- (1 H-1, 2,4-triazoM -ylmethyl) -1, 3-dioxolan-2-yl] methoxy] phenyl] -4- (4-nitrophenyl) piperazine (intermediate 19). b) A mixture of intermediate 19 (0.0155 mol) in tetrahydrofuran (250 ml) was hydrogenated at 50 will ° C with palladium on activated carbon (2 g; 10%) as a catalyst in the presence of a thiophene solution (1 ml). After uptake of H 2 (3 equiv.) The catalyst was removed by filtration and the filtrate was evaporated. The residue was triturated in 2-propanol. The precipitate was separated by filtration and dried to obtain 8 g (94%) of (2S-cys) -4- [4- [4 - [[4- (2,4-difluorophenyl) -4- ( 1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-2-yl] - ^^^^ ¿^ Ú ^^^^^^^ tó ^^^^^^^^^^^^^ gj ^^^^^^ methoxy] phenyl] -1-piperazinyl] benzenamine (intermediate 20; mp -180 ° C; aD20 = + 20.45 ° (c = 26.16 mg / ml in DMF)) .- c) A mixture of intermediate 20 (0.0033 mol), paraformaldheid (0.0066 mol) and NaOCH3 (0.022 mol) in methanol ( 50 ml) was stirred and refluxed for 4 hours. NaBH 4 (0.008 mol) was added. The mixture was stirred and refluxed for one hour and then cooled. H2O was added. The precipitate was filtered off and dried. The residue was purified over silica gel on a glass filter: (eluant: CH 2 Cl 2 / CH 3 OH / EtOAc / n-hexane 48/2/30/20.) The pure fractions were collected and the solvent was evaporated. in 2-propanol, filtered off and dried to give 1.2 g (64% of (B-cis) -4- [4- [4 - [[4- (2,4-difluorophenyl) -4- (1 H- 1, 2,4-triazol-1-methylmethyl) -1, 3-dioxolan-2-yl] methoxy] phenyl] -1-piperazinyl] benzenamine (intermediate 21, mp 181 ° C, aD20 = + 20.63X (c = 24.96 mg / 5 ml in DMF)).

B. PREPARATION OF A COMPOUND OF FORMULA fl) EXAMPLE B.1 A mixture of intermediate 18 (0.0114 mol) in DMF (50 ml) was stirred at room temperature under N2 flow. Bis (trimethylsilyl) amide sodium (0.012 mol) was added. The mixture was stirred for 10 minutes. The intermediate (7) (0.015 mol) was added. The mixture was stirred at 60 ° C for 6 hours, then cooled, poured into H2O and extracted with CH2Cl2. The organic layer was separated, washed with H2O, dried, filtered and then the solvent was evaporated. He The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / EtOAc / n-hexane 49/1/30/20. The residue was crystallized from ethanol, the precipitate was separated by filtration and dried to obtain 2.2 g of 5 (2R-cis) -1-ethyl-3- [4 [4- [4 - [[4- (2,4-difluorophenyl) -4- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3- dioxolan-2-yl] methoxy] phenyl] -1-piperazinyl ] phenyl-5,5-dimethyl-2,4,6 (1 H, 3 H, 5 H) -pyrimidinatrione (27%), a D 20 = + 13.92 ° (c = 20.11 mg / 2 ml in DMF)). (Compound 48, mp 126.1 ° C).

EXAMPLE B.2 1-ethyl-3- [4- [4 - [(4-hydroxyphenyl) -1-piperazinyl] -5-propyl-1, 3,5-triazone 2,4,6 (1 H, 3 H, 5 H) was dissolved -trione (0.011 mol) under N2 flow in DMF (40 ml) and toluene (10 ml). Sodium hydride (0.011 mol) was added. The mixture stirred at room temperature and then added dropwise at 70 ° C to a mixture of intermediate 8 (0.015 mol) in DMF (20 ml). The mixture was stirred at 70 ° C for 5 hours and then cooled by pouring into water and extracted with CH2Cl2. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on gel Silica (eluent: CH2Cl2 / CH3OH / EtOAc / n-hexane 49/1/30/20). The pure fractions were collected and the solvent was evaporated. The residue crystallized from ethanol. The precipitate was separated by filtration, and dried to obtain 3.28 g (40%) of (2S-cis) -1-ethyl-3- [4 [4- [4 - [[4- (2,4-difluorophenyl) - 4- (1 H-1, 2,4-triazole-1 - ylmethyl) -1,3-dioxolan-2-yl] methoxy] fél ^] - 1-piperazinyl] phenyl] -5-propyl-1, 3,5-triazine-2,4,6 (1 H, 3 H, 5 H ) -trione aD2o = + 15.73 ° (c = 19.96 mg / 2 ml in DMF)) (Compound 47; mp 158.8 ° C).

EXAMPLE B.3 a) A mixture of 1- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3- (1-methylethyl) -2-imidazolidinone (0.037 mol) and sodium hydroxide (0.165 mol) in DMF (500 ml) was stirred at 50 ° C molar under N 2 flow for one hour. HE added a mixture of intermediate (8) (0.055 mol) in DMF (100 ml). The mixture was stirred at 50 ° C under N 2 flow overnight. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified twice by column chromatography on silica gel (eluent CH2Cl2 / hexane / EtOAc 50/20/30). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and EtOAc, filtered and dried to obtain 14.97 g (62.5%) of (2S-cis) -1- [4 [4- [4 - [[4- (2,4-difluorophenyl) - 4- (1 H-1, 2,4-triazol-1-ylmethyl) -1,3-dioxolan-2-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -3- (1-methyl-ethyl) -2-imidazolidinone; aD2o = + 17.54 ° (c = 25.37 mg / 5 ml in DMF)). (Compound 51; p.f. 177.8 ° C). b) Compound (51) (0.0045 mol) was dissolved in boiling 2-propanol (200 ml). HCl in 2-propanol (0.0048 mol) was added and the mixture was concentrated to 100 ml in volume and then allowed to crystallize. The precipitate is ^^^^^ ^ j ^^ jg ^^^^^ j ^^^ separated by filtration and dried to obtain 1.5 g (48%) of (2S-cis) -1- [4 [4 - [4 - [[4- (2,4-difluorophenyl) -4- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-2-yl] methoxy] phenyl] - piperazinyl] phenyl] -3- (1-methylethyl) -2-imidazolidinone; (eleven ) (Compound 52).

EXAMPLE B.4 cis-1 - [4 [4- [4 - [[4- (2,4-difluorophenyl) -4- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-2 -yl] methoxy] phenyl] -1-piperazinyl] phenyl] -3- (1-methylpropyl) -2-imidazolidinone was prepared in a manner similar to that described in example B.3 but additionally using a catalytic amount of potassium iodide (Comp 21 pf 155.1 ° C).

EXAMPLE B.5 Isopropyl isocyanate (0.008 mol) was added to a stirred mixture of intermediate 20 (0.0055 mol) in CH 2 Cl 2 (100 ml). The mixture was stirred for one hour. Isopropyl isocyanate (0.114 mol) was added again. The mixture was stirred for four hours. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent CH2Cl2 / CH3OH 99/1 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was boiled in ethanol. The mixture was cooled. The precipitate was separated by filtration and dried to obtain 2.6 g (74%) of (2S-cis) -N- St μμ-μ-tμ ^^ - difluorophenylH-ít ^^^ - triazol-l-ilmeti-I. S-dioxolan ^ -yl] methoxy] phenyl] -1-piperazinyl] phenyl] -N '- (1-methylethyl) ) urea D20 = + 18.64 ° (c = 24.68 mg / 5 ml in DMF)). (Compound 53; p.p. 196 ° C).

EXAMPLE B.6 a) 1, 1'-carbonylbis-1 H-imidazole (0.006 mol) was added to a stirred mixture of intermediate 20 (0.0055 mol) in tetrahydrofuran (100 ml). The mixture was stirred at room temperature for two hours. N-methyl-2-propanamine (0.0073 mol) and triethylamine (0.01 mol) were added. The mixture was stirred at room temperature overnight. N2O was added. The precipitate was filtered off and dried. The residue was purified by column chromatography on silica gel (eluent CH 2 Cl 2 / CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was boiled in ethanol. The mixture was cooled. The precipitate was separated by filtration and dried to obtain 1.8 g (50%) of (B-cis) -N- [4 [4- [4 - [[4- (2, 4-difluorophenyl) -4- (1 H-1, 2,4-triazoM -ylmethyl) -1, 3-dioxolan-2-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -N '- (1 - methylethyl) urea aD2o = + 18.27 ° (c = 24.08 mg / 5 ml in DMF)). (Compound 54; p.f. 186 ° C). b) (B-cis) -N- [4 [4- [4 - [[4- (2,4-difluorophenyl) -4- (1 H-1, 2,4-triazol-1-ylmethyl) -1 , 3-dioxolan-2-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -N-N'-dimethyl-N '- (1-methylethyl) urea (compound 56) which is prepared analogously but was used ^^^^ tej ^ gá? y ^? & ^^^^^^ & a ^^^^^^ - ^^^^^^ trichloromethyl chloroformate in CH2Cl2 instead of 1, 1 '-carbonylbis- 1 H- imidazole in tetrahydrofuran. The compounds listed in Table 1 were prepared in a manner similar to that of the previously mentioned examples.

TABLE 1 7 TABLE 2 ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿? EXAMPLE C.1 Measurement of in vitro antifungal activity 5 The test compounds were dissolved in a concentration of 10-2M in dimethyl sulfoxide (DMSO) and diluted in CYG broth (Odds, FC Antimicrobial Agents and Chemotherapy 1992; 36: 1727-1737) to give a final concentration of 25 μM and in most trials it is 5 μM.

For some compounds the tests were carried out at 100, 10, 1.0 and 0.1 μM. The cultures were inoculated with Candida Kefyr to an initial concentration of 104 / ml and with Trichophyton rubrum to an equivalent concentration determined by turbidity measurement. The cultures were incubated in the plate wells for microdilution at 37 ° C for 48 hours (C. Kefyr) and 30 ° C for 5-7 days. { T.rubrum). Well development containing the test compounds was estimated in a turbidimetric manner as the percentage of development in the compound-free controls, and the lowest concentration of compound that inhibited the development of an isolate below 35% of the development of control was recorded as the lowest active dose (LAD). - r- - • -jfiBi * MÉ-lM.tiE ^ -í * a; i »iiaa? ^ Yt > j ^ V-a '^ ^ ^ fe Étí ^ ¡^^^ ^ w ^ te ^^ TABLE 2 D. EXAMPLES OF COMPOSITION "Active ingredient" (LA) refers to a compound of formula (I) to a pharmaceutically acceptable addition salt or to a stereochemically isomeric form thereof.

EXAMPLE D.1 Suspension in Nanoparticles A solution of water for injection and Pluronic ™ F108 (540 g) was prepared. The grinding media, ZrO stabilized with magnesia, and the I.A. in the form of particles (540 g). The resulting suspension was dispersed at room temperature using a rotary mill for 14 days and the grinding media was separated from the suspension which was then diluted with water for injection to a total volume of up to 54 liters. All manipulations were carried out aseptically in accordance with the rules of the FD and the European guidelines.

EXAMPLE D.2 Tablet extruded by fusion A mixture of 40/60 (w / v) LA. (21.74 kg) and hydroxypropylmethylcellulose 2910 5 mPa.s (1) or HPMC 2910 5 mPa.s (32.11 kg) were sieved and mixed in a planetary mixer until the mixture was homogeneous. 1500 gr of this mixture were charged to a twin screw fusion extruder of the APV-Baker MP19 L / D 15 type that had the following operating parameters: The temperature of the first compartment was 245 ° C, the temperature of the second compartment was 265 ° C. ° C, and the double screw had a rate of 20-300 revolutions per minute and was extruded for 120 minutes. The extruded product was transferred to a hammer mill of the Fitzmill type, for a 0.125 inch mesh screen and the speed of revolution was 1640 revolutions per minute. The crushed extruded product was again passed to a hammer mill this time, with a 0.063 inch mesh screen and a speed of 1640 revolutions per minute. Subsequently, microcrystalline cellulose (351 g, 21% (w / w)), Crospovidone (117 g, 7% (w / w)), Aerosil (colloidal silicon dioxide) (5 g 0.3% (w / w) were screened. )) and Sterotex (8 g, 0.5% (w / w)) and mixed together with the ground extruded product (1169 g, 71% 10 (w / w)) using a planetary mixer until a homogeneous mixture was obtained. This mixture was used to obtain the oval biconvex semi-cracked tablets.

EXAMPLE D.3 15 Oral solution 100 ml of propylene glycol was treated with 3.76 ml of concentrated HCl, stirred and warmed slightly. 10 g of A. were added and stirring was continued until homogeneous. In a separate vessel, 400 g of hydropropyl beta-cyclodextrin was dissolved in 400 ml of distilled water. The LA solution was slowly added to the cyclodextrin solution with stirring. A non-crystallizable solution of isorbitol (70%) 190 ml was added and stirred until homogeneous. Sodium saccharin was dissolved (0.6 gr) in 50 ml of paraffined water and added to the mixture. The pH of the mixture was adjusted with a 10 N NaOH solution to pH 2.0 ± 0.1. The resulting solution was diluted with distilled water to a final volume of one liter. A pharmaceutical dosage form was obtained by filtering the previous solution and introducing it into suitable containers, for example in 100 ml glass bottles with a screw cap.

EXAMPLE D.4: 2% TOPICAL GEL A solution of hydroxypropyl β-cyclodextrin (200 mg) in purified water was added to A. (20 mg) while stirring. Hydrochloric acid was added until the solution was complete and sodium hydroxide was added until the pH was equal to 6.0. This solution was added to a dispersion of carrageenan PJ (10 mg) in propylene glycol (50 mg) while mixing. While mixing slowly the mixture was heated to 50 ° C and allowed to cool to about 35 ° C after which ethyl alcohol (95%, 50 mg) was added. Purified water was added to complete one gram and then the mixture was mixed until homogeneous.

EXAMPLE D.5.2% CREAM Stearyl alcohol (75 mg, cetyl alcohol (20 mg), sorbitan monostearate (20 mg) and isopropyl myristate (10 mg) were added TOSS & ^^^^ w «? ^ ~ 2jSi a double-walled lined container and heated until the mixture was completely melted. This mixture was added to a mixture prepared separately from purified water propylene glycol (200 mg) and polysorbate 60 (15 mg) having a temperature of 70 to 75 ° C while using a homogenizer for the liquids. The resulting mixture was allowed to cool to below 25 ° C while mixing continuously. Then a LA solution was added. (20 mg), polysorbate 80 (1 mg) and purified water until complete and 1 g of an anhydrous sodium sulfite solution (2 mg) in purified water, to said emulsion while mixing continuously. The mixture was homogenized and introduced into suitable tubes.

EXAMPLE D.6 2% CREAM A mixture of LA. mocrofine (2 g) phosphatidyl choline (20 g), cholesterol (5 g) and ethyl alcohol (10 g) was stirred and heated to 55-60 ° C until the solution was complete and a solution of methyl paraben (0.2 g) was added. , propyl paraben (0.02 gr), disodium edetate (0.15 g) and sodium chloride (0.3 g) in purified water (added up to 100 g) while homogenizing. Hydroxypropylmethylcellulose (1.5 g) was added in purified water and the mixture was continued until the dilation was complete.

EXAMPLE D.7. FORMULATION OF GRANULES A stainless container with methylene chloride (375 kg) and denatured ethanol (250 kg) was charged through a filter (5 μ). They added while the LA was shaking. (21.74 kg) and hydroxypropylmethyl cellulose 2910 5 mPas. (32.61 kg). Stirring was continued until a complete solution was obtained. A separate stainless steel vessel was charged with methylene chloride (21.13 kg) and polyethylene glycol 20,000 (3,913 kg) while stirring. Denatured ethanol (14.09 kg) was added and the spray solution was stirred until homogeneous. A fluidized bed granulator equipped with an 18-inch Wurster insert (inner tray) was charged with 25-30 (600-700 μm) (41.74 kg) sugar spheres. The spheres were heated with dry air at 50 ° -55 ° C. The volume of fluidized air was controlled by opening the air exhaust valve up to approximately 50% of its maximum at the beginning, increased up to 60% at the end of the spraying process. The previously prepared spray solution was then sprayed onto the spheres by moving them in the apparatus at an initial delivery rate of about 600 to 700 g.min -1 at an atomizing pressure of about 3.5 kg / cm2 (0.343 MPa). After releasing approximately 30% of the spray solution, the rate of release was increased to 700-800 g / min. Once the spraying process was complete the coated spheres were dried, further providing dry air at 50 ° -55 ° C for about 10 minutes. The coated spheres were then cooled in the apparatus by supplying dry air at 20-25 ° C for about 10 to 20 minutes. d) Expanded The coated spheres were placed in a vacuum-shake dryer and dried for at least 24 hours, preferably about 36 hours at a temperature of about 80 ° C and at a pressure of about 200-300 mbar 10 (20-7). 30 kPa). The shaker dryer operated at its minimum rotation speed (2 to 3 rpm). The dried coated spheres were sieved with a Sweco S24C sieve; sieve with a mesh width of 1,145 mm). e) Sealing procedure by coating 15 The dried coated spheres were reintroduced into the fluidized bed granulator equipped with the Wurster insert and heated with dry air of 50-55 ° C. The pre-prepared sealed spray coating solution was then sprayed onto the coated spheres that moved into the apparatus. The solution was sprayed to a delivery rate of approximately 400 to 500 g.min-1 at an atomizing air pressure of approximately 2.5 bar (0.25 MPa). When the spraying procedure was completed the granules were further dried by supplying dry air of 50-55 ° C for 10 minutes. The Coated spheres were then cooled in the apparatus by supplying dry air at 20-25 ° C for about 5 to 15 minutes. The granules were extracted from the apparatus and stored in appropriate containers. * .t¡ & »~ .j« «aa-BB & fefiafe ..,« &KA, »^ A jga ^^^^^ tfl ^

Claims (14)

1. NOVELTY OF THE INVENTION
3. Having thus specially described and claimed the nature of the present invention and the way of carrying it out, it is declared to claim as property and exclusive right: 1. A compound having the formula to the N-oxide forms, to the pharmaceutically acceptable acid addition salts and to their stereochemically isomeric forms in which n is 0, 1, 2 or 3; X is N or CH; each R 1 is independently halo, nitro, cyano, amino, hydroxy, C 1 - alkyl, C 1 O alkyloxy trifluoromethyl; R2 is hydrogen, C3-7 alkenyl, C3-7 alkynyl, aryl; C3-7 cycloalkyl, C-i-β alkyl or C-? 6 alkyl substituted with hydroxy, C? -4 alkyloxy, C3-7 cycloalkyl or aryl; R3 and R4 are each independently hydrogen, C-? -6 alkyl > C3-7 aryl cycloalkyl; R3 and R4 taken together form a divalent radical -R3 and R4- having the formula:
4. R5a 0 OR R5a R5a R5c 0 R5a 0 0 0 1 II II 1 1 II 1 II II II c-c- -c-c- 1 -c-c-c- 0 -c-c | -c- R5b R5b R5b R5d R5b R5a (a) (b) (c) () (e)
5. Wherein R5a, R5b, R5c and R5 are each independently hydrogen, C6-6 alkyl or aryl; and aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, nitro, cyano, amino, hydroxy, C- alkyl, C 1-4 alkyloxy or trifluoromethyl. 2. A compound of compound according to claim 0 1 or 2 wherein each R1 is independently halo. 3. A compound according to any of claims 1 or 2 wherein each R3 and R4 are independently hydrogen or C6-6 alkyl or -R3 and R4- form a divalent radical -R3 and R4 of formula (a), ( b), (c), (d) or (e). 4. A compound according to any of claims 1 to 3 wherein R2 is C3-7 cycloalkyl or Ci-β alkyl. 5. A compound according to any of claims 1 to 4 wherein the substituents on the 1,3-dioxolane ring have a cis configuration.
6. 6. A compound according to any of claims 1 to 5 of the phenyl ring attached in position 4 of the ring, 1,3-dioxolane is a 2,4-difluorophenyl ring; R3 and R4 form a divalent radical -R3 ^ g ^ ua? aa ^^^^^^^^ »i ^ g || ^^^ a and R4 of formula (c) where R5a, R5b, R5c and R5d are hydrogen, and R2 is methyl, ethyl, propyl, Butyl, 1-methylethyl or 1-methylpropyl.
7. 7. A compound according to any of claims 1 to 6 which is used in medicine.
8. 8. Use of a compound according to any of claims 1 to 6 for the manufacture of a medicament for treating fungal infections.
9. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound according to any of claims 1 to 6.
10. 10. A method for preparing a compound according to claim 1 characterized because it comprises: a) O-alkylating an appropriately substituted phenol of formula (III) with an alkylating reagent of formula (II) where W represents an appropriate reactive leaving group and n, X, R1 to R4 are as defined in claim 1 in a solvent inert to the appropriate reaction in the presence of an appropriate base and optionally under an inert atmosphere; b) transacetalizing an acetal of formula (V) with 1,2-diol of formula (IV) by stirring the reagents in a solvent inert to the appropriate reaction in the presence of an appropriate acid catalyst, (IV) where R represents an alkyl group or both R radicals taken together they can also form a divalent alkanediyl radical and n, X, R1 to R4 are as defined in claim 1; c) cycling a intermediary of formula (VI) or (IX) with respectively an amine of formula (VII) or (VIII) optionally in a solvent inert to the reaction and optionally in the presence of a base, (HIV) (IX) where W represents an appropriate reactive leaving group and n, R1 to R4 are as defined in claim 1; d) alkylating a compound of formula (X) with an alkylating reagent of formula R2-W (XI) (X) where W represents an appropriate reactive leaving group and n, X, R1 to R4 are as defined in claim 1; e) reacting an intermediate of formula (XVll) with an isocyanate R2 = N = C = 0 in a solvent inert to the reaction, thereby obtaining a compound of formula (I-a); (I-a) where n, X, R1 to R3 are as defined in claim 1; thereby obtaining a compound of formula (I-a). f) reacting an intermediate of formula (XVlll) with an intermediate NHR2R4 where L is an appropriate leaving group, n, X, R1 to R3 are as defined in claim 1, R4 'is defined as hydrogen, alkyl mt ^ mimi É ák C -? - 6, C3-7 cycloalkyl, and aryl in a solvent inert to the reaction and in the presence of an appropriate base; and wherein the amino reactive groups in R2, if present, are protected with a protecting group P and subsequently, if necessary, deprotected using deprotection techniques known in the art; thereby obtaining a compound of formula (1-b); and if desired, converting the compounds of formula (I) to one another following transformations known in the art; and further, if desired, converting the compounds of the formula (I), into a non-toxic therapeutically active acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form to the base free by treatment with alkali and, if desired, preparing the stereochemically isomeric forms or the N-oxide forms thereof.
11. 11. The combination of a compound of formula (I) as defined in claim 1 and another antifungal compound.
12. 12. A combination according to claim 11 which is used in medicine. Y
13. 13. A product containing a) a compound of formula (I) as defined in claim 1 and (b) another antifungal compound in the form of a combined preparation for simultaneous, separate or sequential use for an antifungal treatment.
14. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier as an active ingredient (a) a compound of formula (I) as defined in claim 1, and (b) another antifungal compound. _-i-AiMÉIH SUMMARY OF THE INVENTION The present invention relates to new compounds of formula a form of N-oxide, a pharmaceutically acceptable acid addition salt and a stereochemically isomeric form thereof where n is 0, 1, or 3; X is N or CH; each R1 is independently halo, nitro, cyano, amino, hydroxy, C1-4alkyl, dyalkyloxy or trifluoromethyl; R2 is hydrogen, C3,7 alkenyl; C3-7 alkynyl, aryl; C3-7 cycloalkyl, optionally substituted d-6 alkyl, R3 and R4 are each independently hydrogen, C-βalkyl, C3-7cycloalkyl or aryl; or R3 and R4 taken together form a divalent radical -R3 and R4- having the formula: fc "." c5a_ 5.c. .. 0 0 R5a 0 0 R5a 0 R5a 0 I II I I I II I II II II c-c- -c-c- -c C- -c-c-c- -C-N C- R5b R5b R5b R5d R5b R5a (a) (b) (c) (d) (e) wherein R5a, R5b, R5c and R5d are each independently hydrogen, C-? -6 alkyl or aryl; and aryl is optionally substituted phenyl; as anti-illegal; its preparation, compositions that contain them and their use in medicine. JANSSEN / All P99 / 1722F ÜÜahatH ^ iiiB