MXPA00011155A - Water soluble azoles as broad-spectrum antifungals - Google Patents

Abstract

The present invention concerns novel compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable additonsalts and stereochemically isomeric forms thereof, wherein L represents a radical of formulae (a), (b), (c), (d), (e), or (f);wherein each Alk independently represents an optionally substituted C1-6alkanediyl;n is 1, 2 or 3;Y is O, S or NR2;R1 represents aryl, Het1, or an optionally substituted C1-6alkyl;R2 represents hydrogen;or in case R1 and R2 are attached to the same nitrogen atom, they may be taken together to form a heterocyclic radical;or they may be taken together to form an azido radical;each R3 independently represents hydrogen, hydroxy or C1-4alkyloxy;aryl represents phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, indenyl or indanyl;each of said aryl groups may optionally be substituted;Het1 represents an optionally substituted monocyclic or bicyclic heterocyclic radical;Het2 is the same as Het1 and may also be piperazinyl, homopiperazinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl;R6 represents hydrogen or C1-4alkyl;R7 represents hydrogen or C1-4alkyl;or R6 and R7 taken together form a bivalent radical of formula -N=CH- (i), -CH=N- (ii), -CH=CH- (iii), -CH2-CH2 (iv), wherein one hydrogen atom in the radicals (i) and (ii) may be replaced with a C1-4alkyl radical and one or more hydrogen atoms in radicals (iii) and (iv) may be replaced by a C1-4alkyl radical and;D represents a trisubstituted tetrahydrofuran derivative;as antifungals;their processes for preparation, compositions containing them and their use as a medicine.

Description

AZULES SOLUBLE IN WATER AS ANTIFUNGICQS OF WIDE SPECTRUM The present invention relates to water soluble azoles as broad spectrum antifungals, as well as their preparation; it also refers to the compositions that contain them, and also to their use as a medicine. Systemic fungal infections in man are relatively rare in temperate countries and many of the fungi that can become pathogenic live normally in the body or are common in the environment. In recent decades there has been an increasing incidence of numerous systemic fungal infections with risk to life worldwide and these now represent a significant threat to many susceptible patients, especially those who are already hospitalized. Most of the increase can be attributed to the longer survival of immunocompromised patients and the chronic use of antimicrobial agents. In addition, the typical flora of numerous fungal infections is also changing and this represents an epidemiological challenge of increasing importance. Patients at increased risk include those with impaired immune functioning, either directly as a result of immunosuppression caused by cytotoxic drugs or by HIV infection, or that which occurs as a consequence of other debilitating diseases such as cancer, acute leukemia , aggressive surgical techniques or prolonged exposure to antimicrobial agents. The most common fungal infections in man are candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis. Antifungals such as ketaconazole, itraconazole and fluconazole are used for the treatment and prophylaxis of systemic fungal infections in immunocompromised patients. However, there is growing concern about fungal resistance to some of these agents, especially those with a relatively narrow spectrum, for example fluconazole. Worse, in the medical world it is a recognized fact that approximately 40% of people suffering from severe systemic fungal infections can barely, if they can, receive medication orally. This disability is due to the fact that these patients are in a coma or suffer from severe gastroparesis. Therefore, the use of insoluble or poorly soluble antifungals such as itraconazole, which are difficult to administer intravenously, is extremely difficult in this group of patients. In addition, the treatment of onychomycosis can be facilitated by potent water-soluble antifungals. For some time it has been desired to treat onychomycosis by the transungual route. The problem that arises then is to ensure that antifungal agents penetrate the nail and below it. Ertin and Lippold (J. Pharm. Pharmacol. (1997), 49, 30-34) stated that to trace drugs (drugs) for topical application to the nail plate, attention should be paid primarily to the water solubility of the compound. The maximum flow through the nail is beneficially influenced by the increase in the water solubility of the antifungal. Naturally, the efficacy in the treatment of onychomycosis by the transungual route also depends on the potency of the antifungal agent. Consequently, there is a need to have new antifungals, preferably broad spectrum antifungals, against which there is no resistance and which can be administered intravenously or transungueally. Preferably, the antifungal should be presented in a pharmaceutical composition suitable for oral administration. This allows the doctor to continue the treatment with the same drug once the patient has recovered from the state that justifies the intravenous or transungual administration of said drug. U.S. Patent No. 4, 267,179 describes heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxy-methyl-1,3-dioxolan-2-yl) -methyl-1H-imidazoles and 1H-1, 2,4-triazoles useful as antifungal agents. Said patent covers itraconazole, which is available as a broad spectrum antifungal agent throughout the world. WO 93/19061 describes the stereospecific isomers of itraconazole [2R- [2a, 4a, 4 (R *) j], [2R- [2a, 4a, 4 (S *) j], [2S- [2a, 4a, 4 (S *)]] and [2S [2a, 4, 4 (R *) j], of which it is known that they have greater solubility in water than the respective diastereomeric mixtures thereof.

WO 95/19983, describes derivatives of [[4- [4- (4-phenyl-1-piperazinyl) phenoxy-meth] -1, 3-dioxolan-2-yl] methyl] -1 H -imidazoles and H-1, 2,4-triazoles, which are structurally related to some of the compounds of the present invention, and which are described as water-soluble antimicrobial agents. WO 95/17407 describes tetrahydrofuran antifungals, as well as WO 96/38443 and WO 97/00255. These last two publications describe tetrahydrofuran antifungals, which are described as soluble and / or suspensible in an aqueous medium suitable for intravenous administration, which contain substitution groups readily convertible into hydroxy groups. Saksena et al., In Bioorg. Med. Chem. Lett. (1995), 5 (2), 127-132, describe some azole antifungals based on tetrahydrofuran such as (3R-cis) -4- [4- [4- [4 - [[5- (2,4- difluorophenyl) tetrahydro-5 (1 H-1, 2,4-triazol-1-methyl) -3-furanyl] methoxy] phenyl] -1-piperazinyl] phenyl] -2- [2- (dimethyl) lamino) et? l] -2,4-dihydro-3H-1, 2,4-triazol-3-one. Saksena et al., Stated that said azole, in comparison with SCH 51048, was extremely less active as antifungal. Surprisingly, the compounds of the present invention are potent broad spectrum antifungals with good solubility in water.

The present invention relates to the compounds of the formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein L represents a radical of the formula R2O-Alk-N-R1 (a); - Alk-N-C-R (b); R2 or R2 and R2 -Alk- N- C-O-R1 (c); - Alk- N- C- - R1 (d) ' rc (OHM2? Rl (e); (f); wherein each Alk independently represents C -? - 6 alkanediyl optionally substituted with hydroxy or alkyloxy CM each n is independent 1, 2 or 3; Y represents O, S or NR2 each R1 independently represents hydrogen, aryl Het1 or C-? 6 alkyl optionally substituted with one, two or three substituents each of which is independently selected from halo, hydroxy, mercapto, alkyloxy CM, alkylthio CM, aryloxy, arylthio, arylalkyloxy C 1 - "arylalkylthio C-, cyano, amino, mono- or di (alkyl enamino, mono- or di (aryl) amino, mono- or di (arylalkyl enamino, C1-4 alkyloxycarbonylamino, benzyloxycarbonylamino, aminocarbonyl, carboxyl, alkyloxycarbonyl CH, guanidinyl, aryl or Het2, each R2 independently represents hydrogen, or in the case where R1 and R 2 are attached to the same nitrogen atom, can be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl, said heterocyclic radical can optionally be substituted by C 1-4 alkyl, aryl Het 2, arylalkyl CM, Het 2 alkyl C 1 -4, C 1-4 hydroxyalkyl, amino, mono- or di (C 1-4 alkyl), C 1-4 aminoalkyl, mono- or di (C 1-4 alkyl) C 1-4 aminoalkyl, carboxyl, aminocarbonyl, C 1-4 alkyloxycarbonyl, alkyloxycarbonylamino CM O mono - or di (C 1)) alkyl aminocarbonyl or they can be taken together to form an azido radical, each R 3 represents independently hydrogen, hydroxy or alkyloxy Ci ^; aryl represents phenyl, naphthalenyl, 1, 2, 3,4-tetrahydro-naphthalenyl, indenyl or indanyl; each of said aryl groups may be optionally substituted with one or more substituents selected from halo, C 1 J alkyl, hydroxy, C 1 alkyloxy, nitro, amino, trifluoromethyl, hydroxy C 4 alkyl, C 14, C 1-4 aminoalkyl, mono-di? (alkyl) aminoalkyl C1.4, Het1 represents a monocyclic or bicyclic heterocyclic radical; monocyclic heterocyclic radical which is selected from the group consisting of pyridinyl, piperidinyl, homopiperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, pyrazyl, tetrahydropyranyl, imidazolyl, imidazolidyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, oxazolidinyl, isoxazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl; said bicyclic heterocyclic radical can be selected from the group consisting of quinolinyl, 1, 2,3,4-tetrahydro-quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinolinyl, chromanyl, thiochromanyl, 2H-chromenyl, 1,4-benzodioxanil , indolyl, isoindolyl, indolinyl, ndazolyl, purinyl, pyrrolopyridinyl, furanopyridinyl, thienopyridinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, benzofuranyl, benzothienyl; whereby said mono- or bicyclic heterocycle may be optionally substituted with one or, where possible, more substituents selected from the group consisting of halo, C? _4 alkyl, hydroxy, alkyloxy CM, nitro, amino, trifluoromethyl, hydroxy C1- alkyl , C1-4alkyloxy-C1-4alkyl, C1-4alkyl, mono- or di (C1alkyl, aryl or arylalkyl CM, Het2 is equal to Het1 and may also be a monocyclic heterocycle selected from the group consisting of piperazinyl, homopiperazinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, whereby each of said monocyclic heterocycles can be optionally substituted with one or, where possible, more substituents selected from the group consisting of halo, C 1-4 alkyl, hydroxy, alkyloxy C? _4, nitro, amino, trifluoromethyl, hydroxyalkyl CH, alkyloxyC ^ alkyl C-, aminoalkyl CM, mono- or di (alkyl C?) aminoalkyl CM, aryl or arylalkyl C1-4, R6 represents hydrogen or alkyl CM, R7 represents hydrogen or alkyl CM, O R6 and R7 together they form a bivalent radical of the formula -R6-R7-in which -R6-R7- is: -N = CH- (i), -CH = N- (ii), -CH = CH- (iii), where a hydrogen atom of the radicals (i) and (ii) can be replaced with an alkyl radical CM, and one or more hydrogen atoms of the radicals (ii) and (iv) can be replaced with an alkyl radical C; D represents a radical of the formula (D,) (D2) wherein X is N or CH; R is hydrogen or halo; R5 is halo. In the above definitions and thereafter, halo defines fluoro, chloro, bromo and iodo; C-alkyl embraces straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl and others; Ct.6 alkyl embraces the straight and branched chain saturated hydrocarbon radicals defined for C-alkyl as well as the higher homologs thereof containing 5 or 6 carbon atoms such as, for example, pentyl or hexyl; C6.6-alkanediyl embraces straight and branched chain saturated bivalent hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl , 1,5-pentanediyl, 1, 6-hexanediyl, 1,2-propanediol, 1,2-butanediyl, 2,3-butanediyl, and the like.

The above-mentioned pharmaceutically acceptable addition salts should comprise the non-toxic therapeutically active acid addition salt forms which the compounds of the formula (I) can form. The latter can be conveniently obtained by treating the base form with suitable acids such as inorganic acids, for example hydrohalic acids, for example hydrochloric, hydrobromic and the like; sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, for example acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1, 2,3-propanetricarboxylic acid, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and similar acids. Conversely, the salt form can be converted by treatment by an alkali to the free base form. The compounds of the formula (I) containing acidic protons can be converted to their non-toxic therapeutically active metal or amine addition salt forms by treatment with the appropriate organic and inorganic bases. Suitable basic salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example benzathine. ,? / - methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, the salt form can be converted by acid treatment to the free acid form. The term addition salt also includes the hydrates and solvent addition forms that the compounds of the formula (I) can form. Examples of such forms are hydrates, alcoholates and others. The term "stereochemically isomeric forms" used above defines all possible stereoisomeric forms in which the compounds of the formula (I) exist; therefore, all enantiomers, enantiomeric mixtures and diastereomeric mixtures are also included. Unless otherwise mentioned or indicated, the Chemical designation of the compounds denotes the mixture of all possible stereoisomeric forms, mixtures thereof containing all the diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediaries described in this document, used to prepare the final products of the formula (I). The stereoisomeric forms of the compounds and intermediates mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same molecular basic structure of said compounds or intermediates. In particular, the term "stereoisomerically pure", which is equivalent to "chirally pure" refers to intermediate compounds 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 an isomer and nothing of the other), more specifically, the compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular those having a stereoisomeric excess of 94% up to 100% and very particularly those having a stereoisomeric excess of 97% to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be interpreted in a similar manner, only with respect to the enantiomeric excess, respectively to the diastereomeric excess of the mixture in question. The terms cis and trans are used in the present in accordance with the Chemical Abstracts nomenclature and refer to the position of the - '* -' > * "- substituents on a portion of the ring, more specifically on the tetrahydrofuran ring of the compounds of the formula (I). For example, when the cis or trans configuration of the tetrahydrofuran ring is established in a radical of the formula (Di), the substituent with the highest priority is considered on the carbon atom in the 2-position of the tetrahydrofuran ring and the substituent with the highest priority over the carbon atom in the 4-position of the tetrahydrofuran ring (the priority of a substituent is determined 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, the configuration is designated cis; otherwise, the configuration is considered trans. All compounds of the formula (I) contain at least 2 asymmetric centers which may have the R- or S- configuration. In the present, the stereochemical descriptors that indicate the stereochemical configuration of each of the 2 or more asymmetric centers are also in accordance with the Chemical Abstracts nomenclature. The absolute stereochemical configuration of some compounds of the formula (I) and of the intermediates used in their preparation has not been determined experimentally. In these cases, the stereoisomeric form isolated in the first place receives the designation "A", the second "B", without further reference to the actual stereochemical configuration. However, said stereoisomeric forms "A" and "B" can be unambiguously characterized, for example, by their optical rotation in case there is a relationship enantiomeric between "A" and "B". One skilled in the art can determine the absolute configuration of such compounds using methods known in the art such as, for example, X-ray diffraction. If "A" and "B" are stereoisomeric mixtures, they can be further separated, so which the respective first isolated fractions are designated "A1" and "B1" and the second "A2" and "B2", without further reference to the actual stereochemical configuration. The? / -oxide forms of the present compounds should encompass the compounds of the formula (I) in which one or more nitrogen atoms are oxidized to the so-called? / -oxide. Each time it is used hereafter, the term "compounds of the formula (I)" must also include their? / -oxide forms, their pharmaceutically acceptable addition salts and their stereochemically isomeric forms. Within the scope of the present invention, R6 and R7 together form -R6R7- which is advantageously a radical of the formula (ii). D is suitably a radical of the formula D-i. X is suitably N. R2 is suitably hydrogen R4 and R5 are advantageously identical, preferably chloro or fluoro. In particular both R4 and R5 are fluoro. Aryl is suitably phenyl.

Het1 is advantageously a monocyclic heterocyclic radical; preferably pyridinyl, piperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, midazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, tetrahydrofuranyl or thienyl; each of said monocyclic heterocycles may be optionally substituted with one or as far as possible, more substituents selected from halo, C 1 -C 8 alkyl, hydroxy, C 1 alkyloxy, nitro, amino, trifluoromethyl, hydroxyalkyl CM. alkyloxy CMalkyl CM. aminoalkionium CM, mono or di (alkylCM) aminoalkyl C; more preferably pyridinyl, piperidinyl or tetrahydrofuranyl. An interesting group of compounds of the present invention are those compounds of the formula (I) in which L represents a radical of the formula (a), (b) or (c), especially a radical of the formula (a).

Another interesting group consists of those compounds of the formula (I) in which Alk is C6_6 alkanediyl, especially 1,2-ethanediyl, 1,2-propanediyl, 2,3-propanediyl, 1,2-butanediyl, 3, 4-butanediyl, 2,3-butanediyl, 2,3-pentanediyl and 3,4-pentanediyl, especially 2,3-butanediyl, 2,3-pentanediyl and 3,4-pentanediyl. Another equally interesting group contains the compounds of the formula (I) in which L is a radical of the formula (a) in which R 1 represents optionally substituted C 1-6 alkyl with hydroxy or aryl and R 2 represents hydrogen. Special compounds are the compounds of the formula (I) in which R6 and R7 are taken together to form -R6-R7- which is a radical of the formula (ii) and D is a radical of the formula Di, where both R 4 and R 5 are chloro or fluoro and X is N; more specifically, in a radical of the formula D-i, where the tetrahydrofuran ring has the cis configuration. Other specific compounds are the compounds of the formula (I) in which L represents a radical of the formula (a) in which R 2 is hydrogen and R 1 represents aryl or C 1-6 alkyl optionally substituted with one, two or three substituents, each case one of which is independently selected from hydroxy, C-aryloxy, aryloxy, arylalkyloxy CM, cyano, amino, mono- or di (C?-alkyl) amino, mono- or di (arylalkyl) amino, aminocarbonyl , aryl or Het2; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; said heterocyclic radical may be optionally substituted with CM alkyl, aryl, arylalkyl CM, hydroxyalkyl CM, amino, mono- or di (alkyl CM) amino, mono- or di (C C -4 alkyl) aminoalkyl CM, or alkyloxycarbonylamino CM; or R1 and R2 together with the nitrogen atom to which they are attached form an azido radical. Other compounds which are also special are the compounds of the formula (I) in which L represents a radical of the formula (a), (e) or (f), especially a radical of the formula (a) in which R 1 represents aryl, Het1 or substituted d6 alkyl with at least one of the substituents selected from aryloxy, arylthio, arylalkyloxy CM, arylalkylthio CM, mono- or di (aryl) amine, mono- or di (arylalkylCM) amino, benzyloxycarbonylamino, aryl or Het2; more especially where R1 represents aryl or C 1 -β alkyl substituted with at least one of the substituents selected from aryloxy, arylalkyloxy CM, mono- or di (arylalkyl CM) amine, aryl or Het 2. A preferred group of compounds is constituted by the compounds of the formula (I) in which R6 and R7 together form -R6-R7-, which is a radical of the formula (ii); D is a radical of the formula D-i, where both R 4 and R 5 are fluoro and X is N; and L represents a radical of the formula (a) in which R 2 is hydrogen and R 1 represents aryl C 6 alkyl, optionally substituted with one, two or three substituents, each of which is independently selected from hydroxy, alkyloxy CM , aryloxy, arylalkyloxy CM. cyano, amino, mono- or di (alkyl CM) amino, mono- or di (arylalkyl CM) amino, aminocarbonyl, aryl or Het2; or R1 and R2 together with the nitrogen atom to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; said heterocyclic radical may be optionally substituted with CM alkyl, aryl, arylalkyl CM, hydroxyalkyl CM, amino, mono- or di (alkylCM) amino, mono- or di (alkylCM) aminoalkyl CM, or alkyloxycarbonylaminoCM. A more preferred group of compounds are those compounds of the formula (I) wherein R6 and R7 together form -R6-R7- which is a radical of the formula (i); D is a radical of the formula Di wherein both R4 and R5 are fluoro and X is N; and L represents a radical of the formula (a) in which R2 is hydrogen and R1 represents C6.6 alkyl, optionally substituted with hydroxy or aryl.

A particularly preferred group of compounds are the compounds of the formula (I) in which L is a radical of the formula - Alk-N-CH-Z2 (a- |) - Alk-N Z3 (a-2) H 1 1 \ - / in which Alk is as defined above, although preferably 1,2-ethanediyl, 1,2-propanediyl, 2,3-propanediyl, 1,2-butanediyl, 3,4-butanediyl, 2,3-butanediyl, 2,3-pentanediyl or 3,4-pentanediyl; Z1 is aryl, arylmethyl, arylethyl, Het1 or alkylCM, although preferably it is optionally substituted phenyl or optionally substituted phenylmethyl, isopropyl or fer-butyl; Z2 is hydrogen, carboxyl, alkyloxycarbonyl CM, aminocarbonyl or methyl optionally substituted with hydroxy, methoxy, amino or mono- or di (methyl) amino, although preferably it is hydrogen, methyl or hydroxymethyl; or Z1 and Z2 together with the carbon atom to which they are attached form a piperidinyl ring substituted with arylmethyl, arylethyl or CM alkyl.

Z3 is O, N-alkyl CM, O N-aryl. An especially preferred group of compounds consists of the compounds of the formula (I) in which L is a radical of the formula - Alk-N-CH- (a-I) H 1 1 wherein Alk is 2,3-butanediyl, 2,3-pentanediyl or 3,4-pentanediyl; Z1 is optionally substituted phenyl or optionally substituted phenylmethyl, isopropyl or re-butyl; Z2 is hydrogen, methyl or hydroxymethyl. The compounds of the present invention in which R6 and R7 are not hydrogen, said R6 and R7 being represented by R6 and R7 'and said compounds represented by the formula (I'), can be prepared by reacting an intermediate of the formula (II) in which W1 is a suitable leaving group such as, for example, a halogen, for example, iodine, an arylsulphonyloxy or an alkan-sulphonyloxy group, for example p-toluenesulfonyloxy, naphthylsulfonyloxy or methanesulfonyloxy, with an intermediate of the formula (III) in a reaction-inert solvent such as, for example, N, N-dimethylformamide, α /, / / - dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, sulfolane or similar, and in the presence of a suitable base such as, for example, sodium hydroxide or sodium hydride.

In this and the following preparations, the reaction products can be isolated from the reaction medium and, if necessary, purified. - - > -, ^ additionally according to the methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. Especially the stereoisomers can be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak, AD (3,5-dimethylphenylcarbamate amylose) or Chiralpak AS, both purchased from Daicel Chemical Industries, Ltd., in Japan. The compounds of the formula (I ') can also be prepared? / - by alkylating an intermediate of the formula (IV) with an intermediate of the formula (V) in which W2 is a suitable leaving group such as, example, a halogen, and in which the reactive amino groups in L such as primary and secondary amines, if present, are protected with a protecting group P such as, for example, an alkyloxycarbonyl group CM. in a solvent inert to the reaction such as, for example, dimethyl sulfoxide, in the presence of a base such as, for example, potassium hydroxide. If L were protected, deprotection techniques known in the art could be employed to reach the compounds of the formula (I ') after the? / -alkylation reaction.

(IV) (V) The compounds of the formula (I ') in which L is a radical of the formula (a), these compounds being represented by the formula (l'-a), ^ * ta «i ^ * ^ J¡MlNa« lÍMh ^ _ ^^^ wriihi can be prepared by the reaction of an intermediate of the formula (VI) in which W3 is a suitable leaving group such as, for example, a halogen, an arylsulfonyloxy group or an alkanesulfonyloxy group, for example p-toluenesulfonyloxy, naphthylsulfonyloxy or methanesulfonyloxy, with an intermediate of the formula (VII) optionally in the presence of a suitable base such as, for example, sodium or potassium carbonate, triethylamine or the like, and optionally in a reaction-inert solvent such as, for example, N , N-dimethylformamide,? /,? / - dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, sulfolane or the like. In case R1 and R2 form, together with the nitrogen atom to which they are attached, an azido radical, NaN3 can be used as an intermediate of the formula (VII).

(VI) (Vil) (r-a) The compounds of the formula (I) in which at least one of R6 or R7 is hydrogen, said R6 and R7 being represented by R6"and R7" and said compounds being represented by the formula (I "), can be prepared following the reaction procedure illustrated in scheme 1.

SCHEME 1 L H- N- Rt (IX) D- O- ('^ - N N- (%) - N- C- N- L (I ") In scheme 1, the reaction of the intermediates of the formula (Vlll-a) in which NP2 is a protected amino group in which P is, for example, an alkyloxycarbonyl group CM, O a functional derivative of NP2 such as, for example, a nitro group, with an intermediate of the formula (II) according to the procedure described for the preparation of the compounds of the formula (I '). The intermediates of the formula (Vlll-b) thus obtained can be deprotected according to deprotection techniques known in the art, thus obtaining an amine derivative of the formula (Vlll-c). In case NP2 is a nitro group, reduction techniques known in the art can be used to obtain amines of the formula (Vlll-c). The amine derivatives of the formula (Vlll-c) can then be reacted with phenyl chloroformate or a functional derivative thereof. To obtain the compounds of the formula (I ") in which R6 is C? -4 alkyl, the amine derivatives of the formula (Vlll-c) can be reacted first with C-W4 alkyl where W4 is a group of a suitable outlet, such as, for example, a halogen, and then reacting them with phenyl chloroformate. The intermediates of the formula (Vlll-e) thus obtained can be reacted with an intermediate of the formula (IX) in which the reactive amino groups of L such as primary and secondary amines, if present, are protected with a protecting group P such as, for example, an alkyloxycarbonyl group CH Conveniently, the amino reactive group can then be deprotected using known deprotection techniques in the art to arrive at the desired compound of the formula (I "). The compounds of formula (I) can also be converted to one another following transformations known in the art. For example, the compounds of the formula (I ') in which L is a radical of the formula (b), compounds which are represented by the formula (l'-b), can be prepared using acylation methods known in the art, for example the descriptive ones in "Principies of Peptide Synthesis", M. Bodanszky, Springer-Verlag Berlin Heidelberg, 1984. A special acylation procedure involves the acylation of a compound of the formula (l'-a) in which R1 is hydrogen, compounds that are represented by the formula (l'-a-1), with an intermediate of the formula (Xb) in which W5 is a suitable leaving group such as, for example, a halogen or a hydroxy group, in the presence of a suitable base such as, for example, sodium bicarbonate or? /,? / - dimethylaminopyridine or a functional derivative thereof, and in a solvent inert to the reaction such as, for example, dichloromethane, dichloroethane, tetrahydrofuran and the like.

(Xb) (fa-1) O p ^ / = IJ R2 or D-0- V XX and - N t \ N - / \ A - NAN- Alk- N i- C ?? - R 11 \ = / \ / \ / ^ Rr (rb) If W5 is hydroxy, it may be convenient to activate the carboxylic acid of the formula (Xb) by the addition of a diimide such as, for example,? /,? / - dicyclohex? Lcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or a functional derivative thereof. On the other hand, the carboxylic acid of the formula (X-b) can be activated by adding carbonyldiimidazole or a functional derivative thereof.

In case of using a chirally pure intermediary of the formula (Xb), quick couplings and without enantiomerization can be performed by the addition of hydroxybenzotriazole, benzotripazoyloxytris (dimethylamino) phosphonium hexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate or a functional derivative of them (D. Hudson, J. Org. Chem., 1988, 53, pp. 617/1999 Novabiochem catalog &peptide Synthesis Handbook). An acylation process analogous to that of the preparation of the compounds of the formula (I-b) can be used for the preparation of the compounds of the formula (I ') in which L is a radical of the formula (c) , these compounds that are represented by the formula (l'-c). In said analogous reaction procedure, the intermediate of the formula (X-b) is replaced by a carbonate of the formula alk? CC? -4-0-C (= 0) -0-R1 (X-c-1), a chloroformate of the formula CI-C (= 0) -0-R1 (Xc-2) or alkyl C? -0-C (= 0) -0-C (= 0) -0-alkyl CM (Xc -3). An acylation process analogous to that of the preparation of the compounds of the formula (I-b) can be used for the preparation of the compounds of the formula (I ') in which L is a radical of the formula (d) , these compounds that are represented by the formula (l'-d). In said analogous reaction procedure, the intermediate of the formula (Xb) is replaced by an isocyanate of the formula 0 = C = N-R1 (Xd-1), an isocyanate of the formula S = C = N-R1 (Xd) -2), a phenylcarbamate of the formula phenyl-O- C (= 0) -NR1R2 (Xd-3), a phenylthiocarbamate of the formula phe // - 0-C (= S) -NR1R2 (Xd-4) or an intermediate of the formula alkylIC4-SC (= NR2 ) -NR1R2 (Xd-5).

The reductive W-alkylation of the compounds of the formula (l'-a-1) can also be carried out with an aldehyde or ketone of the formula R1aC (= 0) R1 (XI) in which R1a and R1 are defined as so that the radical -CHR1aR1b is encompassed by the definition of R1, thus forming the compounds of the formula (l'-a-2). Said reductive alkylation can be carried out in a solvent inert to the reaction such as, for example, toluene, methanol, tetrahydrofuran or a mixture thereof, and in the presence of a reducing agent such as, for example, a borohydride, for example sodium borohydride, zinc borohydride, lithium borohydride, sodium cyanoborohydride or triacetoxy borohydride. In case of using borohydride as a reducing agent, it may be advantageous to use a catalyst such as, for example, titanium (IV) isopropoxide according to that described in J. Org. Chem. 1990, 55, 2552-2554. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium on carbon or platinum on carbon. The formation of a Schiff base in the first step of the reductive N-alkylation can be increased by the addition of a suitable reagent to the reaction mixture, such as for example aluminum ferc-butoxide, calcium oxide, calcium hydride or a titanium (IV) alkoxide, for example titanium (IV) isopropoxide or titanium (IV) n-butoxide. It is also possible to add a suitable catalyst poison, for example, thiophene, butanediol or quinoline-sulfur to the mixture of reaction to prevent further harmful hydrogenation of certain functional groups from the reactants and the reaction products. Agitation and, optionally, elevated temperatures and / or pressures may increase the rate of reaction.

The compounds of the formula (I ') in which L is a radical of the formula (a) and R1 is a substituent -CH2-CH (OH) in which the substituent belongs to the group of substituents composed of C- alkyl? -6, in the definition of R1, compounds that are represented by the formula (l'-a-3), can be prepared by reacting an intermediate of the formula (I'-a-1) with an epoxide of the formula ( XII) in a solvent inert to the reaction such as, for example, 2-propanol. < - * ^ - - «--- '- * - The compounds of the formula (I) containing an alkylcarbonylamine moiety CM can be converted to the compounds of the formula (I) containing the corresponding amino moiety using techniques known in the art such as, for example, the reaction in dichloromethane and in the presence of trifluoroacetic acid. The compounds of the formula (I ') containing a primary amine can be monomethylated by first protecting the primary amine with a suitable protecting group such as, for example, an arylalkyl group, for example benzyl, and then methylating the secondary amine employed of methylation known in the art such as, for example, the reaction with paraformaldehyde. The tertiary amine thus obtained can be deprotected using deprotection techniques known in the art such as, for example, the reaction with hydrogen in tetrahydrofuran or methanol and in the presence of a catalyst such as, for example, palladium on carbon, to thereby obtain the secondary methylated amine. The compounds of the formula (I) can also be converted to the corresponding forms of A / -oxides following the procedure known in the art for converting a trivalent nitrogen to its? / -oxide form. Said? / -oxidation reaction can be carried out generally by reacting the starting material of the formula (I) with an organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide, organic peroxides • "^ - • - * - suitable may include peroxyacids such as, for example, benzenecarboperoxoic acid or benzenecarboperoxoic acid substituted with halogen, for example 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkylhydroperoxides, for example tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, for example ethanol and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane and mixture of the aforementioned solvents. Some of the intermediaries and initial materials used in the aforementioned procedures can be obtained commercially, or they can be synthesized according to procedures described in other documents, for example E.U.A. 4,791,111, E.U.A. 4,931,444, E.U.A. 4,267,179, WO 95/17407, WO 96/38443, WO 97/00255 and EP-A-0,318,214. Further, in the present document, some methods of preparing the intermediates according to the present invention are described. For example, the intermediates of the formula (III) in which L is a radical of the formula (a), intermediates that are represented by the formula (III-a), can be prepared by reducing amination with a carbonyl-containing intermediate of the formula (XIII) in which Alk = 0 is equal to Alk substituted with an oxo group, with an intermediate of the formula (VII) following the same reaction procedures described for the? / - alkylation reducing the compounds of the formula (l'-a-1) with the intermediates of the formula (XI) or H-O- (V 'V) - N r ~ \ N- (\,) - N A N- Alk = 0 + H- N? // I - I,. R6 R7 R2 (XIII) (VII) O f y -? N-? iA? - NN- Alk- N- R1 R6 'R7' (III-a) The reaction process described can be carried out with chirally pure starting materials, using stereoselective reaction methods, to thereby obtain chirally pure intermediates of the formula (III). to). For example, a stereoselective reductive amination of a chirally pure form of an intermediate of the formula (XIII) with a chirally pure form of the formula (VII) can be a reaction using hydrogen on palladium on carbon as a reducing agent in the presence of a thiophene solution and titanium (IV) isopropoxide. The resulting stereoisomeric forms can be separated using chromatographic or other techniques known in the art. It may also be convenient to carry out the reaction described in the alkylphenoxy derivatives of the intermediates of the formula (XIII). The intermediates of the formula (III-a) in which R1 is an arylalkyl group C-I-T can be reduced using reduction techniques known in the art such as, for example, a reduction with hydrogen in the presence of palladium on activated carbon, to thereby obtain intermediates of the formula (III-a) in which R1 is hydrogen, intermediates which are represented by the formula (III) -a-1).

,, "-V N) - N N-) - N? N.- Alk- N- H \ = ^ jLr (lll-al) Said intermediates of the formula (III-1) can be converted to the intermediates of the formula (III) in which L is a radical of the formula (b), (c) or (d), which are represented by the formula (III-B), (III-C) and (III-D) respectively, using acylation methods known in the art, for example those described in "Principies of Peptide Synthesis", M. Bodanszky, Springer-Verlag Berlin Heidelberg, 1984 and 1999 Novabiochem Catalog & Peptide Synthesis Handbook. In addition, the amides of the formula (III-b) can be hydrolyzed using a suitable acid such as, for example, hydrochloric acid, to thereby obtain the intermediates of the formula (III-a-1). The stereoisomerically pure forms of the compounds and intermediates of the present invention can be obtained by application of procedures known in the art. Diastereomers can be separated by physical separation methods such as selective crystallization and chromatographic techniques, for example liquid chromatography using chiral stationary phases. The enantiomers can be separated from one another by the selective crystallization of their diastereomeric salts with optically active acids. On the other hand, the enantiomers can be separated by chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms can also be obtained from the corresponding pure stereoisomeric forms of the suitable starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound is synthesized by stereoselective or stereospecific methods of preparation. These methods employ, conveniently, chirally pure starting materials. As is evident, the stereoisomeric forms of the compounds of the formula (I) should be considered included within the scope of the present invention. The chirally pure forms of the compounds of the formula (I) form a preferred group of compounds. It is for this reason that the chirally pure forms of the intermediates of the formulas (II), (III) and (VI), their W-oxide forms and their addition salt forms are of particular utility in the preparation of the compounds Chirally pure of the formula (I). The enantiomeric mixtures and the diastereomeric mixtures of the intermediates of the formula (II), (III) and (IV), are also useful for the preparation of the compounds of the formula (I) with the corresponding configuration. Said chirally pure forms and also the enantiomeric and diastereomeric mixtures of the intermediates of the formula (III) are considered novel. A specific way of stereoselectively preparing the intermediates of the formula (III-a) in which R1 and R2 are hydrogen and Alk is -CH (CH3) -CH (CH3) - where both asymmetric carbon atoms have the S configuration -, are represented by the formula (SS) (III-a-2), or the alkoxyphenyl analogs thereof, is the one illustrated in scheme 2a.

SCHEME 2a The reaction of an intermediate of the formula (XIV) with (4R-frar) s) -4,5-dimethyl-2,2-dioxid-1, 3,2-dioxathiolane can be carried out in a suitable solvent, preferably a polar aprotic solvent such as, for example, dimethylacetamide or? /? -dimetílformamída and in the presence of a base such as, for example, potassium urea-butanolate, potassium hydroxide or potassium hydride. Then an acid such as sulfuric acid can be added to the reaction mixture, to thereby obtain an intermediate of the formula (SR) (XV) whereby the 2-hydroxy-1-methylpropyl portion has the erythro form. Then, the carbon atom carrying the alcohol function of said 2-hydroxy-1-methy1propyl portion is epimerized, preferably 100% inverted, to thereby obtain the intermediate (SS) (XVII) whereby the 2-amino portion -1-methylpropyl has the threo form. Two roads are convenient. A first path includes the transformation of the alcohol function into a suitable leaving group O-LG, for example by derivatizing the hydroxy group with an organic acid such as, for example, a sulfonic acid, for example p-toluenesulfonic acid or methanesulfonic acid; to obtain an intermediate of the formula (SR) (XVI). The carbon atom carrying the leaving group in said intermediate (SR) (XVI) can then be epimerized, preferably 100% inverted, by a SN2-type reaction with a nucleophilic reagent such as, for example, NaN, which can then be be reduced to the primary amine of the formula (SS) (XVII). On the other hand, the synthesis of Gabriel, its modification of Ing-Manske or another functional modification thereof can be used to prepare a primary amine of the formula (SS) (XVII). An alternative way to reverse the stereochemistry of the carbon atom that carries the alcohol function is the use of the Mitsunobu reaction. The alcohol function of an intermediate of the formula (SR) (XV) is active with diisopropyl azodicarboxylate or a functional derivative thereof such as diethyl azodicarboxylate, in the presence of triphenylphosphine and in a polar aprotic solvent such as, for example, dimethylacetamide or dimethylformamide. The activated alcohol thus obtained is then reacted with an amide such as, for example, 2,2,2-trifluoroacetamide or a functional derivative thereof. Then the amide thus obtained, whereby the 2-hydroxy-1-methylpropyl portion has been transformed to the threo form can be hydrolyzed using hydrolysis techniques known in the art, to thereby obtain an intermediate of the formula (SS) (XVII). In order to obtain the intermediates of the formula (SR) (XVII), an additional investment step can be introduced as illustrated in scheme 2b.

SCHEME 2b Mitsunobu type investment The intermediaries of the formula (SR) (XV) are converted to an intermediate of the formula (SS) (XV) using two possible paths. A first path includes the transformation of the alcohol function into a suitable outlet group O-LG in accordance as described above; to obtain an intermediate of the formula (SR) (XVI). The carbon atom carrying the starting group in said intermediate (SR) (XVI), preferably 100% inverted, can then be epimerized by a SN2-type reaction with a suitable nucleophilic reagent such as, for example, an alcohol, example a benzyloxy group; a hydroxy salt of an alkali metal, for example sodium hydroxide or potassium hydroxide; an acetate, for example sodium acetate. Said reaction is carried out in a suitable solvent, preferably a polar aprotic solvent such as, for example, dimethylacetamide, α / - methylpyrrolimidone, dimethylimidazolidinone or sulfolane. In case of using an alcohol or an acetate in the Sm reaction the intermediary thus obtained can be deprotected using deprotection techniques known in the art, to thereby obtain an alcohol intermediate of the formula (SS) (XV). Another path consists of Mitsunobu's reaction. The alcohol function of an intermediate of the formula (SR) (XV) is activated in the manner described above. The activated alcohol thus obtained is then reacted with a carboxylic acid such as, for example, 4-nitrobenzoic acid, acetic acid, monochloroacetic acid. Then you can hydrolyze the ester thus obtained using hydrolysis techniques known in the art, to thereby obtain an intermediate of the formula (SS) (XV).

The intermediates of the formula (SS) (XV) can then be reacted to obtain intermediates of the formula (SR) (XVII) using the same reaction routes described for the preparation of the intermediates (SS) (XVII) from from (SR) (XV). Finally, the alkoxyphenyl portion of the intermediates of the formula (SS) (XVII) or (SR) (XVII) can be converted to the phenol portion by the use, for example, of hydrobromic acid or a mixture of hydrobromic acid and acid hydrobromic acid in acetic acid, in the presence of NaHS03, to obtain an intermediate of the formula (SS) (III-2) or (SR) (III-2).

Suitable alternatives for (4R-fraps) -4,5-dimethyl-2,2-dioxid-1, 3,2-dioxathiolane include the following chirally pure intermediates: in the limes LG is an exit group such as, for example, p-toluenesulfonyl. The intermediates of the formula (III-a-2) by which the 2-hydroxyl-1-methylprop1 portion has the form [R- (R *, R *)], intermediates that are represented by (RR) (lll-a-2) can be prepared using the same reaction routes illustrated in scheme 2, although replacing (4R-frans) -4,5-dimethyl-2,2-dioxide-1, 3 , 2-dioxathiolane with its enantiomer (4S-frans) -4,5-dimethyl-2,2-dioxide-1, 3,2-dioxathiolane. The intermediates of the formula (VI) can be prepared by reducing an intermediate of the formula (XIII) and then introducing an output group W3. Especially, the intermediates of the formula (VI) in which Alk is -CH (CH 3) -CH (CH 3) -, intermediates that are represented by the formula (V 1-a), can be prepared according to the reaction scheme illustrated in scheme 3. Optionally, the chirally pure intermediates of the formula (Vl-a), represented by (SS) (Vl-a), (RS) (Vl-a) and (RR) (VI-a), they can be prepared using this procedure.

SCHEME 3 optional < O (Vkajo DO- N N- N A N- Alk-W3 (RR) (VI-a), (RS) (Vμa), R6 'ht (SR) (VI-a) or (SS) (VI-a) Suitable stereoselective reduction conditions include the use of K-selectride in a suitable solvent such as, for example, example, dimethylacetamine or tetrahydrofuran; the use of sodium borohydride optionally in combination with CeCI3.7H20, ZnCl2 or CaCl2.2H20 in a suitable solvent such as, for example, dimethylacetamide, dimethylformamide, methanol or tetrahydrofuran. Said reduction conditions favor the threo form of the 2-hydroxy-1-methylpropyl portion, that is, the way in which the two asymmetric carbon atoms have identical absolute configuration. The recrystallization of the intermediate of the formula (XVIII) obtained after the stereoselective reduction can further improve the threo / erythro ratio in favor of the threo form. The desired stereoisomeric forms of the intermediates of the formula (XVIII), which are (RR) (XVIII), (SS) (XVIII), (RS) (XVIII) and (SR) (XVIII), can then be isolated by chromatography using a chiral stationary phase such as, for example, Chiralpak AD (3,5-dimethylphenylcarbamate amylose) purchased from Daicel Chemical Industries, Ltd. of Japan. The intermediary of the formula (XVIII) or one or more of its stereoisomeric forms can then be further reacted with an intermediate of the formula (II) according to that described above for the general preparation of the compounds of the formula ( I '). Finally, the hydroxy group of the intermediates thus obtained of the formula (XIX) or a chirally pure form thereof can be converted to the appropriate leaving group W3, for example by derivatization of the hydroxy group with an organic acid such as, for example, a sulfonic acid, for example, p-toluenesulfonic acid or methanesulfonic acid for thus obtain an intermediate of the formula (Vl-a) or a purely pure form thereof. The compounds of the formula (I), the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof are useful agents for combating fungi in vivo. The present compounds are broad spectrum antifungals. They have activity 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, flavus, Cryptococcus neoformans; Sporothrix schenckii; Fonsecaea spp; Epidermophyton floccosum, Microsporum canis, Trichophyton spp; Fusariun spp and several dematiáceos hyphomycetes. The activity of some of those present against Fusarium spp. Is very interesting. The in vitro experiments, which include the determination of the fungal susceptibility of the present compounds according to that described in the pharmacological example set out below, indicate that the compounds of the formula (I) have an intrinsic inhibitory capacity on the development of the fungi, for example in Candida albicans. Other in vitro experiments, such as the determination of the effects of the present compounds on the synthesis of esteral in, for example, Candida albicans, also demonstrate their antifungal potency. In addition, in vivo experiments in various models of mice, guinea pigs and rats demonstrate that, after oral administration, as well as intravenous, the present compounds are potent antifungals. An additional advantage of some of the present compounds is that they are not only fungistatic, like most known azole antifungals, but are also fungicides at acceptable therapeutic doses against numerous fungal isolates. The compounds of the present invention are chemically stable and have good oral availability. The solubility profile in aqueous solutions of the compounds of the formula (I) makes them suitable for intravenous administration. Compounds of particular interest are the compounds of the formula (i) having a solubility in water of at least 0.01 mg / ml at a pH of at least 4, preferably a water solubility of at least 0.1 mg / ml at a pH of at least 4, and more preferably a solubility in water of at least 1 mg / ml at a pH of at least 4 The most preferred are compounds having a water solubility of 5 mg / ml or more, at a pH of at least 4. In view of the utility of the compounds of the formula (I), a method for treating warm-blooded animals, including humans, suffering from fungal infections is presented. Said method consists of the systemic or topical administration of an effective amount of a compound of the formula (I), a form of / V-oxid, a pharmaceutically acceptable addition salt or a stereisomerically possible form thereof, to animals of warm blood, including humans. Therefore, compounds of the formula (I) are presented for use as a medicament, especially the use of a compound of the formula (I) in the preparation of a medicament used for the treatment of fungal infections. The present invention also features compositions for treating or preventing fungal infections containing a therapeutically effective amount of a compound of the formula (I) and a pharmaceutically acceptable carrier or diluent. By virtue of their advantageous pharmacological properties, the compounds in question can be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of the present invention, a therapeutically effective amount of a particular compound, in the form of a base or addition salt, is combined as an active ingredient, intimately mixed with a pharmaceutically acceptable carrier, vehicle which can take a wide variety of forms according to the form of preparation desired for administration. These pharmaceutical compositions are conveniently presented in unit dosage form suitable, preferably, for administration orally, rectally, topically, percutaneously, transungueally or by parenteral injection. For example, when preparing the compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like can be employed in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid vehicles such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and others in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous unit oral dosage form, in which case, solid pharmaceutical carriers are obviously employed. Suitable compositions for topical application are all the compositions commonly used to administer drugs topically, for example creams, gels, compresses, shampoos, tinctures, ointments, salves, balsams, powders and others. In compositions suitable for percutaneous administration, the carrier optionally includes a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any kind in minor proportions., additives that do not cause a significant deleterious effect on the skin. Said additives can facilitate administration to the skin and / or serve to prepare the desired compositions. These compositions can be administered in various ways, for example in the form of a transdermal patch, as a local topical or in an ointment. The transungual compositions are presented in the form of a solution and the vehicle optionally contains a penetration enhancing agent that favors the penetration of the antifungal into the keratinized nail layer of the nail therethrough. The solvent medium consists of water mixed with a cosolvent such as an alcohol with 2 to 6 carbon atoms, for example ethanol.

For parenteral compositions, the carrier usually consists of sterile water, at least in large part. For example, injectable solutions may be prepared in which the vehicle sews in saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be used. For parenteral compositions, other ingredients may be included to contribute to solubility, for example cyclodextrins. Suitable cyclodextrins are the α-, β- and β-cyclodextrins or mixed ethers and ethers thereof in which one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C alquilo ?. alquilo alkyl, especially methyl, ethyl or isopropyl, for example, randomized methylated CD-β; C6-6 hydroxyalkyl, especially hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl C -? 6, especially carboxymethyl or carboxyethyl; C 1 - β alkylcarbonyl, especially acetyl. It is worth mentioning as β-CD complexing and / or solubilizing agents, the randomly-mixed β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl -? - CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy) propyl-β-CD, and especially 2-hydroxypropyl-β-CD (2-HP-β-CD). The term "mixed ether" refers to cyclodextrin derivatives in which at least two hydroxy groups of the cyclodextrin are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per moles of anhydroglucose. The degree of average substitution (D.S.) refers to the average number of substituted hydroxyls per each anhydroglucose unit. The value M.S. and D.S. can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, different values can be obtained for a given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the ranges of M.S. fluctuate between 0.125 s 10 and the D.S. they range from 0.125 to 3. Other compositions suitable for oral or rectal administration contain particles which are obtained by melt extrusion of a mixture consisting of a compound of the formula (I) and an appropriate water soluble polymer and then milling said mixture extruded in fusion. Next, such particles can be formulated by conventional techniques to prepare pharmaceutical dosage forms such as tablets and capsules. Said particles consist of a solid dispersion constituted by a compound of the formula (I) and one or more pharmaceutically acceptable water soluble polymers. The preferred technique for preparing solid dispersions is the melt extrusion process which includes the following steps: a) mixing a compound of the formula (I) with an appropriate water-soluble polymer, b) optionally mixing the additives with the mixture thus obtained, c) heating the mixture thus obtained to obtain a homogeneous melting, d) force the fusion thus obtained through one or more nozzles and e) cool the melt until it solidifies. The solid dispersion product is ground or milled to obtain particles with a size of less than 600 μm, preferably less than 400 μm and most preferably less than 125 μm. The water-soluble polymers included in the particles are polymers having an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20 ° C. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectins, chitin derivatives, polysaccharides, polyacrylic acids and salts thereof, polymethacrylic acids and the salts thereof, copolymers of methacrylate, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides and copolymers of ethylene oxide and propylene. Preferred water-soluble polymers are hydroxypropylmethylcelluloses. One or more cyclodextrins can also be used as the water soluble polymer in the preparation of the mentioned particles, as described in WO 97/18839. Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more specifically those, β or β? cyclodextrins or pharmaceutically acceptable derivatives thereof. Substituted cyclodextrins that can be used include the polyethers described in U.S. Patent No. 3,459,731. Other substituted cyclodextrins are the ethers in which the hydrogen of one or more hydroxy groups of the cyclodextrin is replaced by C ^ alkyl, C6-6 hydroxyalkyl, C6.6 carboxyalkyl, or C6-6alkyloxycarbonyl Ci-b. , or the mixed ethers thereof. In particular, those substituted cyclodextrins are ethers in which the hydrogen of one or more hydroxy groups of the cyclodextrin is replaced by C? _3 alkyl, C hidro ?. hidro hydroxyalkyl or C carbox-carbox carboxyalkyl or more specifically by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl. Especially useful are the β-cyclodextrin ethers, for example, dimethyl-β-cyclodextrin, as described in Drugs of the Future, Vol. 9, No. 8, p. 577-578 by M. Nogradi (1984) and polyethers, for example hydroxypropyl β-cyclodextrin and hydroxyethyl β-c ?clodextrin. That type of alkyl ether may consist of a methyl ether with a degree of substitution of about 0.125 to 3, for example of about 0.3 to 2. That hydroxypropylcyclodextrin can be formed, for example from the reaction between β-cyclodextrin or propylene oxide and can have an MS value of about 0.125 to 10, per example of about 0.3 to 3. A newer type of cyclodextrins is that of sulfobutylcyclodextrins. The ratio of active ingredient to cyclodextrin can vary widely. For example, ratios of 1/100 to 100/1 can be applied. Interesting ratios of active ingredient with respect to cyclodextrin are in the range of about 1/10 to 10/1. The most interesting ratios of active ingredient with respect to cyclodextrin are in the range of about 1/5 to 5/1. It may also be convenient to formulate the azole antifungals of the present invention in the form of nanoparticles consisting of a surface modifier adsorbed on 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 bind to the antifungal agent. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and agents surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Another interesting way of formulating the present compounds includes a pharmaceutical composition by which the antifungals of the present invention are incorporated into hydrophilic polymers and this mixture is applied in the form of a coating film on very small beads, to thereby give a composition which can be conveniently prepared and that is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads are composed of a central, rounded or spherical core, a coating film of a hydrophilic polymer and an anti-fungal agent, as well as a sealed polymeric coating layer. The materials suitable for use as cores in the pearls are multiple, provided that said materials are pharmaceutically acceptable and have the appropriate dimensions and firmness. Examples of such materials include polymers, organic substances, inorganic substances and saccharides and derivatives thereof. The pharmaceutical compositions mentioned above may also contain an antifungally effective fungicidal amount such as active compounds for the cell wall. The term "active compound for the cell wall" used herein means any compound that interferes with the cell wall of the fungus and includes compounds such as papulacandins, echinocandins and aculeacins, as well as inhibitors of the cell wall of the fungus such as nikkomicins, for example nikkomicin K and others described in U.S. Patent No. 5,006,513, but not limited thereto . It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, term employed in the specification and the claims herein refers to physically discrete units suitable as unit doses, each of which contains a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in combination with the necessary pharmaceutical vehicle. Examples of such unit dosage forms are represented by tablets (including scored or coated tablets), capsules, pills, powder packets, stamps, injectable solutions or suspensions, tea spoons, soup spoons and the like, as well as segregated multiples of the same. Those skilled in the art of treating warm-blooded animals suffering from diseases caused by fungi could easily determine the therapeutically effective daily amount from the results of the tests presented herein. In general, it is considered that a therapeutically effective daily amount would be from about 0.05 mg / kg to 20 mg / kg of body weight.

Experimental part Hereinafter, "DMF" is defined as? /,? / - dimethylformamide, "THF" is defined as tetrahydrofuran and "DIPE" is defined as diisopropyl ether.

A. PREPARATION OF INTERMEDIARIES EXAMPLE A1 a) A mixture of (±) -2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2- (1-methyl-2-oxopro? il) was hydrogenated. ) -3H-1, 2,4-triazol-3-one (0.05 moles) (prepared in accordance with that described in EP-A-0,228,125) and (+) - (R) - -methylbenzenemethanamine (0.1 moles) in THF (500 ml) at 50 ° C during 48 hours with Pd / C 10% (10 g) as a catalyst, in the presence of titanium (IV) p-butoxide (28.4 g) and a thiophene solution (10 ml). The catalyst was separated by filtration. Pd / C 10% (10 g) was added again. Hydrogenating was continued for 48 hours at 50 ° C. After the capture of H2, the mixture was cooled, then the catalyst was removed by filtration and the filtrate was evaporated. The residue was stirred in CH2Cl2 (500 ml) and added H20 (50 ml). The mixture was acidified with a concentrated solution of HCl, alkalized with a concentrated NH 0 H solution and filtered with dícalite.

The organic layer was separated, dried, filtered, and the solvent was evaporated.

The residue was triturated in DIPE, separated by filtration and dried, to give 23. 5 g (91%) of [(R *, R *) (R) + (R *, S *) (R)] - 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1- piperazinyl] phenyl] -2- [2 - [(1-phenylethyl) amino] -1-methylpropyl] -3H-1, 2,4-triazol-3-one (interm. b) A mixture of intermediate (1) (0.0457 mol) in THF (400 ml) was hydrogenated at 50 ° C with 10% Pd / C (5 g) as a catalyst. After uptake of H2, H20 and CH2Cl2 were added, then the catalyst was separated by filtration and the filtrate evaporated. The residue was triturated in CH2Cl2, separated by filtration and dried, to give 14 g (75%) of (+) - [(R ', R *) + (R *, S *)] - 2- (2-amino) -1-methy1propyl) -2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (interm. ). b) A mixture of intermediate (2) (0.0025 mol) and acetic anhydride (0.03 mol) in CH2Cl2 (300 ml) was stirred at room temperature. A mixture of NH 4 HCO 3 (5 g) in H 2 O (100 ml) was added. The mixture was stirred for 2 hours and CH3OH was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by HPLC on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 97/3 to 90/10). Two pure fractions were collected and their solvents were evaporated.

A first fraction was separated into its enantiomers by column chromatography (eluent: ethanol / 2-propanol 50/50, column: CHIRALPAK AS). Two pure fractions were collected and their solvents were evaporated. The residue was triturated in 2-propanol, separated by filtration and dried, to give 0.37 g (3.2%) of [R (R *, R *) - N- [2- [4,5-dihydro-4- [4 - [4- (4-Hydroxyphenyl) -1-piperazinyl] phenyl] -5-oxo-1 H-1, 2,4-triazol-1 -ü] -1 - methylpropyllacetamide (interm 3a) and 2.81 g (25%) of [S (R *, R *)] - N- [2- [4,5-dihydro-4- [4- [4- (4-hydrox? phen.l) -1-piperazinyl] phenyl] -5-oxo-1 H-1, 2,4-triazol-1-yl] -1-methylpropyllacetamide (interm 3b).

The second fraction was separated into its enantiomers by column chromatography (eluent: hexane / 2-propanol / CH3OH 30/55/15, column CHIRALPAK AD). Two pure fractions were collected and their solvents were evaporated. The residue was triturated in 2-propanol, separated by filtration and dried to give 0.47 g (4%) of [S (R *, S *)] - N- [2- [4,5-dihydro-4- [4 - [4- (4-Hydroxyphenyl) -1-piperazinyl] phenyl] -5-oxo-1 H-1, 2,4-triazol-1-yl] -1-methylpropyllacetamide (interm. 3c) and 3.21 g (28%) of [R (R *, S *)] - N- [2- [4,5-dhydro-4- [4- [4- (4-hydroxyphenyl) - 1-pperazinyl] phenyl] -5-oxo-1 H-1, 2,4-tr? Azole-1-yl] -1-methylpropyl-acetamide (interm. 3d, mp 264.3X); [a] D2o = + 10.96 ° @ 20.07 mg / 2 ml in DMF. c) A mixture of the intermediate (3d), (0.0069 mmoles) in conc. HCl. (50 ml) was stirred and heated to reflux for 48 hours. The solvent was evaporated and the residue was dissolved in H20 (50 ml). The mixture was alkalized with NH OH and extracted with CH 2 Cl 2 / CH 3 OH 80/20 (500 mL). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in 2-propanol, separated by filtration and dried to give 2.6 g (92%) of [R (R ", S *)] -2- (2-amino-1-methylpropyl) - 2,4-dihydro-4- [4- [4- (4-hydroxy-phenyl) -1-pperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (intermediate 4; mp 237.2 ° C; [a] D20 = + 1.01 ° @ 19.79 mg / 2 ml in DMF). d) A mixture of intermediate Kt (4) (0.042 moles) and benzaldehyde (0.042 moles) in THF (500 ml) was hydrogenated at 50 ° C with palladium on 10% activated carbon (2 g) as catalyst in the presence of a solution of 4% thiophene (1 ml). After uptake of hydrogen (1 equivalent), the catalyst was removed by filtration and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent 1: CH 2 Cl 2 / CH 30 H 98/2, eluent 2: CH 2 Cl 2 / (CH 3 OH / NH 3) 95/5). The desired fractions were collected and the solvent was evaporated. The residue was triturated in 2-propanol, separated by filtration and dried to give 15 g (71%) of [R (R *, S *)] - 2,4-dihydro-4- [4- [4- (4- hydroxyphenyl) -1-piperazinyl] phenyl] -2- [1-methyl-2 - [(phenylmethyl) amino] propyl] -3H-1, 2,4-triazin-3-one (intermediate 5).

EXAMPLE A2 It was separated into its enantiomers [(R ", R *) (S) + (R *, S *) (S)] - 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1 -piperazinyl] phenyl] -2- [2 - [(1-phenylmethyl) amino] -1-methylpropyl] -3H-1, 2,4-triazin-3-one (intermediate 6) (0.51 mol), prepared in a manner Analogous to intermediate 1, by HPLC on silica gel (eluent 1: CH 2 Cl 2/2-propanol 95/5 to 90/10, eluent 2: CH 2 Cl 2 / CH 3 OH 90/10) Two desired fractions were collected and their solvents were evaporated. The first fraction was crushed in CH3CN, separated by filtration and dissolved in CH2Cl2, the mixture was extracted with a dilute HCl solution and separated in its layers.

NaHC? 3 and extracted with CH2C. The combined organic layer was dried, filtered, and the solvent was evaporated. The residue was triturated in CH 3 CN, separated by filtration and dried to give 54.4 g of [S (R *, R *) (R *)] - 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl ) -1-piperazinyl] phenyl] -2- [1-methyl-2 - [(1-phenylethyl) amino] propyl] -3H-1, 2,4-triazol-3-one (intermediate 7a). The second fraction was stirred in CH3CN. The precipitate was separated by filtration and dried to give 9.5 g of monohydrochloride of [R (R *, S *) (S *)] - 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl ) -1-piperazinyl] phenyl] -2- [1-methyl-2 - [(phenylmethyl) amino] propyl] -3H-1, 2,4-triazol-3-one (intermediate 7b) .

EXAMPLE A3 a) A mixture of 2,5-anhydro-1, 3,4-trideoxy-2-C- (2,4-difluorophenyl) -4- (hydroxymethyl) -1 - (1 H-1, 2,4-triazole -1-) pentitol (0.044 moles) (prepared according to the procedure described in WO 89/04829) and 4-dimethylaminopyridine (0.5 g) in triethylamine (16 ml) and CH2Cl2 (75 ml) was stirred at room temperature. 2-Naphthalenesulfonyl chloride (0.05 moles) was added under N2 and the mixture was stirred overnight. The mixture was poured into water and extracted with CH2Cb. The organic layer was evaporated and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane / CH 2 Cl 2 1/12). The pure fractions were collected and evaporated to give 6 g of 2-naphthalenesulfonate of (±) -c / s- [5- (2,4-d-fluorophenyl) tetrahydro-5- (1 H-1, 2 , 4-triazol-1-ylmethyl) -3-furanyl] methyl (interm. and a second residue. A sample (1.1 g) of the second residue was triturated in 2-propanol, to give (±) -frans- [5- (2,4-difluorophenyl) tetrahydro-5- (1 H-1, 2-naphthalenesulfonate, 4-triazol-1-methylmethyl) -3-furanyl] methyl (interm 8b). Intermediate 8a (0.015 mol) was separated into two enantiomers by chiral column chromatography on AD phase (eluent: 100% ethanol). Two groups of pure fractions were collected and their solvent was evaporated to give 3.8 g of residue I and 4.1 g of residue II. The residue I was stirred in DIPE (50 ml), separated by filtration and dried to give 3.45 g of 2-naphthalenesulfonate of (2S-c / s) - [5- (2,4-difluorophenyl) tetrahydro-5- (1 H-1, 2,4-triazol-1-ylmethyl) -3-furanyl] methyl (interm .. 9a). The residue II was stirred in DIPE (50 ml), separated by filtration and dried to give 3.54 g of 2-naphthalenesulfonate of (2R-c / sH5- (2,4-difluoropheni!) Tetrahydro-5- (1H-1) , 2,4-triazol-1-ylmethyl) -3-furanyl] methyl (interm .. 9b).

EXAMPLE A4 a) Reaction under N2 flow. A mixture of (±) -2,4-dihydro-4- [4- [4- (4-hydroxy-phenyl) -1-piperazinyl] phenol] -2- (1-methyl-2-oxopropyl) - 3H-1, 2,4-triazol-3-one (0.590 mol) in CH2Cl2 (6000 ml) with triethylamine (60 g) was stirred for 30 min. S-valine hydrochloride ethyl ester (0.3165 moles) was added. Tris (acetate-0) sodium borohydride (I-) (0.3185 mol) was added and the mixture was stirred for 2 hours at room temperature. More S-valine ethyl ether hydrochloride (0.3165 moles) and tris were added (acetate-O) sodium borohydrate (I-) (0.3185 mol) and the reaction mixture was stirred overnight at room temperature. Additional S-valine ethyl ether hydrochloride (13 g) and sodium tris (acetate-O) borohydrate (I-) (28 g) were added in portions over a period of one hour and the resulting reaction mixture was stirred for the night at room temperature. Water was added (2 I). The reaction mixture was stirred for 2 hours. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, separated by filtration and dried to give 315 g of [A (S)] - N- [2- [4,5-dihydro-4- [4- [4- (4-hydroxyphenyl) - 1-Piperazinyl] phenyl] -1 H-1, 2,4-triazol-1-yl] -1-methylpropyl] valine ethylene (interm. b) Reaction under N2 atmosphere. A mixture of intermediate 10 (0.745 moles) in THF (3000 ml) was stirred for 1 hour at 40 ° C. The mixture was allowed to cool to 30 ° C. 2 M LHBH 4 in THF (0.800 mol) was added dropwise over the course of one hour at 30 ° C. After adding 100 ml, the reaction mixture was gradually heated to 60 ° C while the remainder of LiBH4 was added dropwise. Then, the reaction mixture was stirred and maintained at reflux for about 60 hours. The reaction mixture was cooled. 2-Propanone (500 ml) was added dropwise over a period of 2 hours. Water (800 ml) was added in a period of 1.5 hours. More water was added (2 I). A solution of NH CI (350 g) in water (1.5 I) was added and the mixture was stirred for 2 hours. The layers were separated. The organic layer was dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, separated by filtration and dried. The residue was purified by chromatography Column on silica gel (eluent: CH2Cl2 / CH3OH 95/5). The desired fractions were collected and the solvent was evaporated to give 120 g (32.6%) of [B (S)] -2,4-dihydro-2- [2 - [[1- (hydroxymethyl) -2 -methylpropyl] amino] -1-methylpropyl] -4- [4- [4- (4-hydroxyphenyl) -1-p-perazinyl] phenol] -3H-1, 2,4-triazole- 3-ona (interm.

EXAMPLE A5 a) A mixture 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (0.05 mol) prepared from according to that described in EP-A-0,006,711, 3-bromo-2-pentanone (0.073 mol) and K2C03 (10 g) in DMF (200 ml) and toluene (200 ml) was stirred and maintained at reflux overnight using a water separator The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and the filtrate evaporated. The residue was triturated in DIPE, separated by filtration and dried, to give 4.6 g of (+) - 2- (1-ethyl-2-oxopropyl) -2,4-dihydro-4- [4- [4- (4 -methoxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (interm. 12). b) A mixture of NaHS03 (0.5 g) in 48% HBr (50 ml) was stirred for 15 min. Intermediate 12 (0.01 mol) was added.

The mixture was stirred and maintained at reflux for 2 hours. The solvent was evaporated. The residue was dissolved in H20. The solution was neutralized with Na 2 CO 3 and extracted with CH 2 Cl 2. The organic layer was separated, separated, washed, ^^ Uiitá ^ aaß u ^ filtered and the solvent evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 2.7 g (64%) of (±) -2- (1-ethyl-2-oxo-propyl) -2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (interm. 13). c) A mixture of intermediate 13 (0016 moles), benzenemethanamine (0.028 moles) and palladium on carbon 10% (2 g) in a solution of thiophene 4% (2 ml) and THF (300 ml) was stirred at 140 °. C under a pressure of 100 atm., For 16 hours, then cooled and filtered. The filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH30H 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, separated by filtration and dried. The residue was separated by HPLC in C18 (eluent: (5% ammonium acetate in H20 / CH3CN 90/10) / CH3OH 40/60, 0/100 and 40/60). The desired fraction was collected and the solvent was evaporated. The residue was purified once more by HPLC on silica gel (eluent: CH 2 Cl 2 / hexane / CH 3 OH / ethyl acetate 40/42/8/10). The desired fraction was collected and the solvent was evaporated to give 1.3 g (90%) of (B) -2- [1-ethyl-2 - [(phenylmethyl) amino] propyl] -2,4-dihydro -4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (interm. 14).

B. PREPARATION OF FINAL COMPOUNDS EXAMPLE B1 a) A mixture of intermediate 9b (0.0026 moles), intermediate 14 (0.0025 moles) and NaOH (00078 moles) in DMF (50 ml) was stirred at 80 ° C under N2 flow for 4 hours and then at room temperature for a period of 48 hours, after which it was poured into H2O and stirred for 30 min. The precipitate was separated by filtration and dissolved in CH2Cl2. The organic solution was dried, filtered and the solvent was evaporated. The residue was triturated in 2-propanol, separated by filtration and dried to give 1.27 g (63.5%) of [2R- [2a, 4 (B) J] -4- [4- [4- [4 - [[5 - (2,4-d? Fluorophenyl) tetrahydro-5- (1 H-1, 2,4-triazol-1-ylmethyl) -3-furanyl] methoxy] phenyl-1-piperazonyl] phenyl] -2- [1-ethyl-2 - [(phenylmethyl) amino] propyl] -2,4-dihydro-3H-1, 2,4-triazol-3-one (compound 4). Table 1 lists compounds of the formula (I) which are prepared analogously to the procedure described in example B1.

C. PHARMACOLOGICAL EXAMPLES EXAMPLE C1 A panel of 24 Candida isolates, 8 Aspergillus spp. Isolates, 10 Zygomycete isolates, 10 Fusarium spp., 2 Cryptococcus neoformans and 8 Dematiáceous hyphomycetes were used. A series of solutions of the test compounds in dimethyl sulfoxide (DMSO) was prepared. Then the solutions of DSO 100 times in RPMI 1640 broth regulated with MOPS, with 2% glucose (Odds, FC, Antimícrobial Agents and Chemotherapy, 1995, 39, 2051-2060) and inoculated with yeast cells at an initial concentration of 104 / ml and with other fungi at an equivalent concentration determined by turbidimetry. The test compounds were added to the medium from the DMSO solutions to give final concentrations in the order of 10, 3.2, 1.0, 0.32, 0.10, 0.032, 0.010, 0.0032 and 0.0010 μM. The cultures were incubated in the receptacles of the microdilution plates at 37 ° C for 48 hours for the yeasts or for other periods and at other temperatures for other fungi. After reading the microdilution plates spectrophotometrically to determine development turbidity, samples were removed from the test cultures to inoculate 10 μl volumes on Sabouraud glucose agar plates. The plates were incubated at 37 ° C for 48 hours in the case of yeast and with other times and temperatures for other species. Table 2 lists, for each of the species analyzed, the geometric mean of the minimum fungicidal concentrations in μM determined as the lowest concentrations of the test compound that will completely or substantially eliminate the reappearance of the growth of the fungi in the plates. Sabouraud.

TABLE 2 Comp. Candida Aspergillus Zygomycetes Fusarium Other No. spp. spp. spp. mushrooms 1 2.3 0.87 7.5 > 10 2.7 2 1.9 1.0 3.2 > 10 2.7 D. PHYSICAL EXAMPLES EXAMPLE D1 Solubility in water An excess of compound was added to the water regulated with 0.1 M citric acid and 0.2 M Na2HP04 in a proportion of 61.5 / 38.5 (pH = 4). The mixture was stirred for 1 day at room temperature. The precipitate was separated by filtration. The concentration of the compound was measured by UV spectroscopy and is shown in Table 3.

TABLE 3 E. COMPOSITION EXAMPLE EXAMPLE E.1 Injectable solution 1.8 grams of methyl 4-hydroxybenzoate and 0.2 grams of sodium hydroxide were dissolved in approximately 0.5 I of boiling water for injection. After cooling to about 50 ° C, 0.05 grams of propylene glycol and 4 grams of the active ingredient were added while stirring. The solution was cooled to room temperature and supplemented with water for injection, necessary amount until obtaining 1 I, to give a solution with a content of 4 mg / ml of active ingredient. The solution was sterilized by filtration and packaged in sterile containers.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula a N-ox form, a pharmaceutically acceptable addition salt or a stereochemically possible form thereof, wherein L represents a radical of the formula R2 R2 O -Alk- -N- R1 i ?? 1 (a); - Alk- N- C- R (b); R2 O R2 and R2 I II -Alk- -N- C- -O- R (c); -Alk- J I, I -_A II C_- N, _- RD? (d); wherein each Alk independently represents C6-6 alkanediyl optionally substituted with hydroxy or C1-4alkyloxy; each n is independently 1, 2 or 3; Y represents O, S or NR2; each R1 represents independently aryl, Het1 or C6-6 alkyl optionally substituted with one, two or three substituents each of which is independently selected from halo, hydroxy, mercapto, C1.4 alkyloxy, alkylthio CM, aryloxy, arylthio, arylalkyloxy C1.4 , aryl-C 1-4 alkyl, cyano, amino, mono- or di (C 1-4 alkyl) amino, mono- or di (aryl) amino, mono- or di (arylalkyl C) amino, alkyloxycarbonylamino CM, benzyloxycarbonylamino, aminocarbonyl, carboxyl, C1-4 alkyloxycarbonyl, guanidinyl, aryl or Het2; each R2 independently represents hydrogen, or in the case where R1 and R2 are attached to the same nitrogen atom can be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl; said heterocyclic radical may optionally be substituted with alkyl CM, aryl, Het2, arylalkyl C1-4, He alkyl C1.4, hydroxyalkyl C1.4, amino, mono- or di (alkyl enamino, aminoalkyl Ci. 4, mono- or di- (C C ^ alkyl) C 1-4 aminoalkyl, carboxyl, aminocarbonyl, alkyloxycarbonyl &M, C 1-4 alkyloxycarbonylamino or mono- or di (C 1-4 alkyl) aminocarbonyl, or can be taken together to form an azido radical; each R 3 represents independently hydrogen, hydroxy or alkyloxy CM, aryl represents phenyl, naphthalenyl, 1, 2,3,4-tetrahydro-naphthalenyl, indenyl or indanyl, each of said aryl groups may be optionally substituted with one or more substituents selected from halo, alkyl C ^, hydroxy, alkyloxy CM, nitro, amino, trifluoromethyl, hydroxyC1-4alkyl, CM, aminoalkyl C-1-4, mono- or dialkylC? ^) aminoalkyl C1.4; Het1 represents a monocyclic or bicyclic heterocyclic radical; monocyclic heterocyclic radical which is selected from the group consisting of pyridinyl, piperidinyl, homopiperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, pyranyl, tetrahydropyranyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, oxazolidinyl , isoxazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, said bicyclic heterocyclic radical can be selected from the group consisting of quinolinyl, 1, 2,3,4-tetrahydroquinoline, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinolinyl, chromanyl, thiochromanyl, 2H-chromenyl, 1,4-benzodioxanyl, indolyl, isoindole, indolinyl, indazolyl, purinyl, pyrrolopyridinyl, furanopyridinyl, thienopyridinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, benzofuranyl, benzothienyl; whereby each of said mono- or bicyclic heterocycles may be optionally substituted with one or, where possible, more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, hydroxy, C 1 -4 alkyloxy, nitro, amino, trifluoromethyl , hydroxyalkyl CM, alkyloxy C ?. 4CM alkyl, aminoalkyl CM, mono- or di (C1-4alkyl, aryl or arylalkyl CM; Het2 is equal to Het1 and can also be a monocyclic heterocycle selected from the group consisting of piperazinyl, homopiperazinyl, 1,4- dioxanyl, morpholinyl, thiomorpholinyl, whereby each of said monocyclic heterocycles may be optionally substituted with one or, where possible, more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, hydroxy, C 1 -4 alkyloxy, nitro, amino, trifluoromethyl, hydroxyalkyl CM, alkyloxy CM alkyl, C 1-4 aminoalkyl, mono- or di (C 1-4 alkyl, aryl or arylalkyl C, R 6 represents hydrogen or alkyl CM; R 7 represents hydrogen or CH alkyl; or R 6 and R 7 together form a bivalent radical of the formula -R6-R7- in which -R6-R7-is: -N = CH- (i), CH = N- (ii), -CH = CH- (iii), -CH2-CH2 - (iv) where a hydrogen atom of the radicals (i) and (ii) can be replaced with an alkyl radical CH, and one or more hydrogen atoms of the radicals (ii) and (iv) can be replaced with an alkyl radical CM; D represents a radical of formula wherein X is N or CH; R4 is hydrogen or halo; R5 is halo.

2. The compound according to claim 1 in which D is a radical of formula D-i.

3. The compound according to claim 1 or 2 wherein L is a radical of formula (a).

4. The compound according to claim 1 in any of claims 1 to 3 wherein Alk is 1,2-ethanediyl, 1,2-propanediyl, 2,3-propanediyl, 1,2-butanediyl, 3,4-butanediyl, 2,3-butanediyl, 2,3-pentanediyl or 3,4-pentanediyl.

5. The compound as claimed in any of claims 1 to 4 wherein R1 represents aryl, Het1 or Ci-β alkyl optionally substituted with one, two or three substituents, each of which is selected from hydroxy , alkyloxy CM, aryloxy, arylalkyloxyC 1-4, cyano, amino, mono- or di (alkylCM) amino, mono- or di (arylalkyl), alkyloxycarbonylaminoCM, aminocarbonyl, aryl or Het2; R2 represents hydrogen or alkyl CI.

B or if R1 and R2 are attached to the same nitrogen atom, they can also be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl, said heterocyclic radical optionally being substituted with C1.4alkyl, aryl, arylalkyl C-, hydroxyalkyl CM, amino, mono- or di (alkyl Ci ^ amino, mono- or di (alkyl CM, O alkyloxycarbonylamino CM; or R1 and R2 can also be taken together to form an azido radical. co as set forth in any one of claims 1 to 4 wherein L is a radical of the formula - Alk-N-CH-Z2 (a.,) H 1 wherein Alk is 2,3-butanediyl, 2,3-pentanediyl or 3,4-pentanediyl; Z1 is optionally substituted phenyl or optionally substituted phenylmethyl, isopropyl or fer-butyl, Z2 is hydrogen, methyl or hydroxymethyl.

7. The compound according to any of claims 1 to 6 which is stereochemically pure.

8. The compound according to any of claims 1 to 7 for use as a medicine.

9. The use of a compound as claimed in any of claims 1 to 7 in the preparation of a medicament for the treatment of fungal infections.

10. A pharmaceutical composition containing a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7.

11. A process for the preparation of a compound of the formula (I) in which D and L are as defined in claim 1 and R6 and R7 are as defined in claim 1 except that they are not hydrogen, where said R6 and R7 are represented by R6 'and R7' and said compound is represented by the formula (I '), which is characterized by including: a) the reaction of an intermediate of the formula (II) in which W1 is a suitable leaving group with an intermediate of the formula (III) in a solvent inert to the reaction and in the presence of a suitable base; b) the? / - alkylation of an intermediate of the formula (IV) with an intermediate of the formula (V) in which W2 is a suitable leaving group and where the primary and secondary amines present in L are protected, in case of present, with a protecting group P consisting of a C 1 -C 15 alkyloxycarbonyl group, in a solvent inert to the reaction and in the presence of a base; and if L was protected, then deprotection of L using deprotection techniques known in the art. (iv) (V) c) the reaction of an intermediate of the formula (VI), in which W3 is a suitable leaving group, with an intermediate of the formula (VII) or NaN3 optionally in the presence of a suitable base and optionally in a solvent inert to the reaction, to thereby obtain a compound of the formula (I ') in which L is a radical of the formula (a); (VI) (Vil) D-O- < ') - N- v / > - N. l? N ~ l.- Alk- 7., 2? 'R6 R7 R and, if desired, converting the compounds of the formula (γ) to each other following transformations known in the art and further, if desired, converting the compounds of formula (I') to an acid addition salt non-toxic and therapeutically active by treatment with an acid or, conversely, converting the acid addition salt to the free base by treatment with an alkali; if it is also desired to prepare the stereochemically isomeric forms or forms of? / - oxides thereof. SUMMARY OF THE INVENTION The present invention relates to novel compounds of the formula the? / -oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein L represents a radical of the formula R2 R2 OR I II. -Alk- N- R1 (a); -Alk- N-C-R1 (b); R2 OR R2 AND R2 II II (d); -Alk- N-C-O-R (c); - Alk- N-C-N- R wherein, each Alk independently represents an optionally substituted C 1 _6 alkanoyldyl; n is 1, 2 or 3; And it is O, S or NR2; R1 represents aryl, Het1 or an optionally substituted C? _6 alkyl; each R2 represents hydrogen; or if R1 and R2 are attached to the same nitrogen atom, they can be taken together to form a heterocyclic radical or to form an azido radical; each R3 independently represents hydrogen, hydroxy or alkyloxy C-; aryl represents phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, indenyl or indanyl; each of said aryl groups may be optionally substituted; Het1 represents an optionally substituted monocyclic or bicyclic substituted heterocyclic radical; Het2 is equal to Het1 and may also be piperazinyl, homopiperazinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl; R6 represents hydrogen or C-M alkyl; R7 represents hydrogen or CM alkyl; or R6 and R7 together constitute a bivalent radical of the formula -N-CH- (i), -CH = N- (i), -CH = CH- (iii), -CH2-CH2 (iv), where one atom of hydrogen of the radicals (i) and (ii) can be replaced with a C 1-4 alkyl radical and one or more hydrogen atoms of the radicals (iii) and (iv) can be replaced by a C alkyl radical; D represents a trisubstituted tetrahydrofuran derivative; as antifungals; with processes for its preparation, with compositions that contain them and with its use as a medicine JANSSEN / PM / cgm * osu * mmr * kra * jvc * gas * sff * aom * eos * mvh * P00 / 1197F