MXPA00011152A - 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 addition salts and stereochemically isomeric forms thereof, wherein L represents a radical of formula (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 hydrogen, aryl, Het1, or an optionally substituted C1-6alkyl;each R2 independently represents hydrogen or C1-6alkyl;or in case R1 and R2 are attached to the samenitrogen 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-tetrahydro-naphthalenyl, 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;D represents a trisubstituted 1,3-dioxolane derivative;as antifungals;their processes for preparation, compositions containing them and their use as a medicine.

Description

SOLUBLE AZOLES IN WATER AS WIDE ANTIFUNGICOS OF SPECTRUM The present invention relates to water soluble azoles as broad spectrum antifungals, as well as to 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 Iu | ^ prolonged exposure to antimicrobial agents. The most common fungal infections in man are candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis. Antifungals such as ketoconazole, 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 yet, 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. Mertin 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-phenylpiperzin-1-yl-aryloxy-methyl-1,3-dioxolan-2-yl) -methyl-1 H-imidazoles and 1 -1, 2,4-triazoles useful as antifungal agents.

This 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, [2í- [2a, 4a, 4 (S *)] j, [2S- [2, 4 , 4 (S *)] j and [2S- [2a, 4a, 4 (*)] 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-methyl] -1, 3-dioxolan-2-yl] methyl] -1H-imidazoles and 1H-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 two last publications describe tetrahydrofuran antifungals, which are described as soluble and / or suspensible in an aqueous medium suitable for intravenous administration, which contain substitution groups easily convertible in vivo to hydroxy groups. Saksena et al., In Bioorganic & Medicinal Chemistry Letters (1995), 5 (2), 127-132, discloses some azole antifungals based on tetrahydrofuran such as (3R-c / s) -4- [4- [4- [4 - [[5- (2,4-difluorophenyl) tetrahydro-5- (1H-1, 2,4-triazol-1-ylmethyl) -3-furanyl] methoxy] phenyl] -1-piperazinyl] phenyl] -2- [2- (dimethylamino ) ethyl] -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 an antifungal agent. 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 R2 R2 O -Alk- N- R1 (a): -Alk- N-C-R1 (b); R2 or R2 and R2 I II I II I -Alk- N-C-O-R1 (c); - Alk- N-C-N-R1 (d); wherein each Alk independently represents C-i alkandiyl. optionally substituted with hydroxy or C-M alkyloxy; each n is independently 1, 2 or 3; Y represents O, S or NR2; each R1 independently represents hydrogen, 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 C-? -4 , aryloxy, arylthio, aryl-C1-4alkyloxy, aryl-C1-6alkylthio, cyano, amino, mono- or di (C1-6alkyl) -amino, mono- or di (aryl) amino, mono- or di (arylalkylC? -4) amino, alkyloxycarbonylamino C1-4, benzyloxycarbonylamino, aminocarbonyl, carboxyl, C1-4alkyloxycarbonyl, guanidinyl, aryl or Het2; each R 2 independently represents hydrogen or C 1-6 alkyl, or in the case where R 1 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 may optionally be substituted with C 1-4 alkyl, aryl, Het 2, aryl C 1-4 alkyl, Het 2 C 1-4 alkyl, hydroxyalkyl CM, amino, mono- or di (C 1-4 alkyl) amino, C 1-4 aminoalkyl, mono- or di (C 1 -C 4 alkyl) aminoC 4 alkyl, carboxyl, aminocarbonyl, C 1-4 alkyloxycarbonyl, 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 independently represents hydrogen, hydroxy or C 1-4 alkyloxy; aryl represents phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, indenyl or indanyl; each of said aryl groups may be optionally substituted with one or more substituents selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 4 alkyloxy, nitro, amino, trifluoromethyl, C 1-4 hydroxyalkyl, C 1 alkyloxy, C 1-4 aminoalkyl, mono- or di (C 4 alkyl) aminoalkyl C-; HetVepresents a monocyclic or bicyclic heterocyclic radical; monocyclic heterocyclic radical which is selected from the group consisting of pyridinyl, piperidinyl, homopiperidinyl, pyrazinyl, pyrimidinyl, pipdazinyl, tnazinyl, tnazolyl, pyranyl, tetrahydropyranyl, imidazole, imidazo nyl, imidazohdinyl, pyrazolyl, pyrazyl nyl, pyrazolidinyl, thiazole, thiazolidinyl, isothiazolyl, oxazole, oxazolidyl, isoxazolyl, pyrrole, pyrroleyl, pyrroxydyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, and said bicyclic heterocyclic radical can be selected from the group consisting of quinoline, 1, 2,3,4-tetrahydroquinolmyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazimyl, cinolinyl, chromanyl, thiochromanyl, 2H-chromenyl, 1, 4-benzod? Oxanol, indolyl, isoindole, indolmyl, indazolyl, punnyl, pyrrolopipdinyl, furanopindinyl, thienopindinyl, benzothiazolyl, banzoxazolyl, benzisothiazolyl, benzisoxazole, 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, C1.4 alkyl , hydroxy, C 1-4 alkyloxy, nitro, amino, trifluoromethyl, C 1-4 hydroxyalkyl, C 1-4 alkyloxyC.sub.1, C 1-4 aminoalkyl, monohydric (C? _? alkylo) am? noalkyl? C1-4, anole or C1-4 -lactalkyl, Het2 is equal to Het1 and can also be a monocyclic heterocycle selected from the group consisting of piperazmyl, homopiperazinyl, 1,4-d-oxanol, morpholyl, thiomorpholinyl, which each of said monocyclic heterocycles may be optionally substituted with one or, where possible, more substituents selected from the group consisting of halo, C1.4alkyl, hydroxy, C1-4alkyloxy, nitro, amino, trifluoromethyl, C 1-4 hydroxyalkyl, C 1-4 alkyloxyC 1-4 alkyl, C 1-4 aminoalkyl, mono- or di (C-cycloalkylCM alkyl, aryl or arylalkyl CM; R 6 represents hydrogen or C 1-4 alkyl; R 7 represents hydrogen or C 1-4 alkyl or R6 and R7 together form a bivalent radical of the formula -Rd-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 C1.4, and one or more hydrogen atoms of the radicals (iii) and (iv) can be replaced with an alkyl radical CM; D represents a radical of the formula wherein X is N or CH, R4 is hydrogen or halo; R5 is halo. In the above definitions and thereafter, halo defines fluoro, chloro, bromo and iodo; C1.4 alkyl embraces saturated straight and branched chain hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl and others; C-? 6 alkyl embraces the straight and branched chain saturated hydrocarbon radicals defined for C-M alkyl as well as 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-butanediol , 1, 5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 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 appropriate 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, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- _____________ _! _ methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid and similar acids. Conversely, the salt form can be converted by treatment with an alkali to the free base form. The compounds of the formula (I) containing acidic protons can be converted to their therapeutically active non-toxic metal or amine addition salt forms by treatment with the appropriate organic and inorganic bases. Suitable basic salt forms include, for example, the ammonium salts, alkali metal and alkaline earth metal salts, for example the lithium, sodium, potassium, magnesium, calcium salts and the like, salts such as 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, for example, 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, said mixtures contain all the diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediates described herein, used to prepare the final products of the formula (I). The pure 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 compounds or intermediates having a stereoisomeric excess of at least 80% (ie, a minimum of 90% of an isomer and a maximum from 10% of the other possible isomers) to a stereoisomeric excess of 100% (ie, 100% of an isomer and nothing of the other), more specifically, compounds or intermediates having a stereoisomeric excess of 90% 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% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be interpreted in a similar manner, only with respect to the enantiomeric excess, respectively 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 dioxolane ring of the compounds of the formula (I). For example, when the cis or trans configuration of the dioxolane ring is established in a radical of the formula (Dt), the substituent with the highest priority is considered to be the carbon atom in the 2-position of the dioxolane ring and the substituent with the highest priority over the carbon atom in the 4 position of the dioxolane 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, then 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. For example, the absolute configuration of the asymmetric carbon atoms of compound 86, ie, [2S- [2a, 4a [(R *, S *) (S *)]]] - 4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-yl-methyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] - 1-piperazinyl] phenyl] -2,4-dihydro-2- [2 - [(1-phenylethyl) amino] -1-methylpropyl] -3H-1, 2,4-triazol-3-one, it is as illustrated below. The dioxolane ring in this compound has the cis configuration.

The ring numbering in the dioxolane ring is presented according to the Chemical Abstracts nomenclature for the Di and D radicals that appear immediately below.

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 those cases, the stereoisomeric form isolated in the first place receives the designation "A", the second "B" and if there are more stereogenic forms, the third is "C", the fourth "D" and so on, without further reference to the actual stereochemical configuration. However, the stereogenic forms called "A", "B", "C", "D" and so on can be characterized unequivocally. By example, if "A" and "B" have an enantiomeric relationship, can be unequivocally characterized by their optical rotation. 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 N-oxide forms of the present compounds should encompass the compounds of the formula (I) in which one or several nitrogen atoms are oxidized to the so-called N-oxide. Each time it is used hereafter, the term "compound of formula (I)" must also include its N-oxide forms, its pharmaceutically acceptable addition salts and its stereochemically isomeric forms. Within the scope of the present invention, each of R6 and R7 independently is advantageously hydrogen or methyl; or together they form -R6R7- which is advantageously a radical of the formula (i) to (iv) optionally substituted with Ci ^ alkyl. D is suitably a radical of the formula Di. X is suitably N. R2 is suitably hydrogen, methyl or ethyl. R4 and R5 are advantageously identical, preferably chloro or fluoro. In particular, both R4 and R5 are fluoro.

Aplo is suitably phenyl, 1, 2,3,4-tetrahydro-naphthalene, naphthalenyl or indanyl, said group optionally being substituted with one or more substituents selected from halo, C1.4, hydroxyalkyl C1.4, C1-4, hydroxy, C1-4 aminoalkyl, and mono-di (C1-4 alk) ammonal C1-4 Het1 is advantageously a monocyclic heterocyclic radical, preferably pipdinyl, pipepimel, pyrazinyl, pipmidinyl, pipdazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazole, oxazole, 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, C1_4alkyl hydroxy, alkyloxy Ci ^ nitro, amino, trifluoromethyl, hydroxyalkyl d4, aminoalkyl C1-4 mono od? (most preferably pipdinyl, pipepdinyl or tetrahydrofuranyl Het1 may also be, suitably, chromanyl An interesting group of compounds of the present invention are those compounds of formula (I) in which L represents a radical of formula (a), (b) or (c), especially a radical of formula (a) Another interesting group consists of those compounds of formula (I) in which Alk is C1-C6-alkanoyl, especially 1,2-ethanediol, 1,2-propanediol, 2,3-propanediol. , 2-butanediol, 3,4-butanediol, 2,3-butanediol, 2,3-pentanediol and 3,4-pentanediol, especially 2,3-butanediol Another equally interesting group contains the compounds of the formula (I) in which R1 represents hydrogen, aryl, Het1 or C? _ Alkyl optionally substituted with one, two or three substituents, each of which is independently selected from halo, hydroxy , C 1-4 alkyloxy, aryloxy, aryalkyloxy C 1-4, cyano, amino, mono- or di (C 1) alkyl amino, mono- or di (arylalkyl C? 4) amino, alkyloxycarbonylamino C 1-4, alkyloxycarbonyl C 1-4 , aminocarbonyl, aryl or Het2. R 2 represents hydrogen or C 1-6 alkyl, or if R 1 and R 2 are attached to the same nitrogen atom, it can also be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinium, piperidinyl or piperazinyl; said heterocyclic radical may optionally be substituted with C 1-4 alkyl, aryl C 1-4 arylalkyl, hydroxy C 1-4 amino, mono- or di (alkyl), mono- or di (C 1-4 alkyl) amino C 1-4 alkyl, or C 1-4 alkyloxycarbonylamino, or they can also be taken together to form an azido radical.They are compounds of the formula (I) in which R6 and R7 are taken together to form -R6-R7- which is a radical of the formula (i) or (iii) and D is a radical of the formula Di or D2, where both R4 and R5 are chloro or fluoro and X is N, more specifically, a radical of the formula Di or D2, wherein the The dioxolane ring has the cis configuration Other special compounds are the compounds of the formula (I) in which L represents a radical of the formula (a) in which R 2 is hydrogen, methyl or ethyl and R 1 represents hydrogen, aryl, Het1 or C1-6 alkyl optionally substituted with one, two or three substituents, each of which is independently selected from hydroxy, C 1 -t alkyloxy, aryloxy, arylalkyloxy C 1, cyano, amino, mono- or di (alkyl enamino, mono- or di ( arylalkyl C) amino, aminocarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkyloxycarbonylamino, aryl or Het 2, or R 1 and R 2 together with the nitrogen atom to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; heterocyclic may be optionally substituted with C 1-4 alkyl, aryl, C 1-4 arylalkyl, C 1-4 hydroxyalkyl, amino, mono- or di (C 1 γ) alkyl amino, mono- or di (C 1 -Cylamino alkyl), or alkyloxycarbonylamino C1-4, 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 formula (a) e wherein R1 represents aryl, Het1 or C6.6 alkyl, substituted with at least one of the substituents selected from aryloxy, arylthio, arylalkyloxyC ^, arylalkylC4-4, mono- or di (aryl) amino, mono or di (arylalkyl C? -4) amino, benzyloxycarbonylamino, aryl or Het2; more especially, wherein R 1 represents aryl or C 1-6 alkyl, substituted with at least one of the substituents selected from aryloxy, arylalkyloxy C 1, mono- or di (arylalkyl C 1-4) amino, aryl or Het 2.

A group of preferred 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 (n) or (m), D is a radical of the formula Di or D2, where both R4 and R5 are fluoro and X is N, L represents a radical of the formula (a) in which R2 is hydrogen or methyl and R1 represents hydrogen, aplo, Het1 or Ci ß alkyl, optionally substituted with one, two or three substituents, each of which is independently selected from hydroxy, C1.4 alkyloxy, aploxy, cycloalkyloxy, cyano, amino, mono-di (monoalkyl) ? C? -4) amino, aminocarbomyl, Ci4alkyloxycarbonyl, alkyloxycarbonylaminoC?, aplo or Het2, or R1 and R2 together with the nitrogen atom to which they are attached form a morphoyl, pyrrolidinyl, pipepdinyl or piperazyl , said heterocyclic radical can be optionally substituted with C 1 4 alkyl, C 1 a, Ci 4 alkylalkyl, C 1 4 hydroxyalkyl, amino, mono-di (ex) amino, mono-or d? (alkyl C? -4) am? noalkyl C1.4, or C1-4 alkyloxycarbonylamino Another group of preferred compounds are those compounds of formula (I) in which R6 and R7 are not hydrogen, said group is represented by the compounds of the formula (V) 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-1) (a-2) H Z l, 1 wherein Alk is as defined above, although it is preferably 1,2-ethanediol, 1,2-propanediol, 2,3-propapodol, 1,2-butane, 3 , 4-butanediol, 2,3-butanediol, 2,3-pentanediol or 3,4-phenytoin, Z 1 is aplo, aplmethyl, aplethyl, Hetl or C 1 -alkyl, although preferably phenyl is optionally substituted or optionally substituted phenylmethyl, isopropyl or re-butyl, Z 2 is hydrogen, carboxyl, C 1 alkyloxycarbonyl, ammocarbonyl or methyl optionally substituted with hydroxy, methoxy, amino or mono-di (methylene) ammon, although it is preferably hydrogen, methyl or hydroxymethyl, or Z1 and Z2 together with the carbon atom to which they are attached form a pipepdinyl ring substituted with aplmethyl, aplethyl or alkyl CH, Z3 is O, N-C1.4 alkyl, or N-aplo more preferred are the following compounds 4-t4- [4- [4 - [[2- (2,4-d? fluorophen? l) -2- (1H-1,2,4-tr? azol-1? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2,4-d? h? dro -2- [2 - [(1-phen? Let? L) am? No] -1 -met? lprop? l] -3 / - / - 1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? fluorophen ?) -2- (1H-1, 2,4-tr? azol-1-? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1- p? peraz? n? l] phen? l] -2,4-d? h? dro-2- [2 - [(2-phen? let? l) am? no] -1 -met? lprop? l ] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1 , 2,4-tpazol-1 -? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2- (4-phen? L-1-p? Peraz? N? L) -1-met? Lprop? L] -3 / - / - 1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2- [ (3-phenolpropyl) amine] -1-methypropyl] -3H-1, 2,4-tr? Azole-3-one, 4- [4- [4- [4- [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4? ] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2- [2 - [[(2-fluorophen? l) met? l] am? no] -1-met ? lprop?] -2,4-d? h? dro-3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4- d? fluorophen?) -2- (1 H-1, 2,4-tpazol-1-? lmet? l) -1, 3-d? oxolan-4? l] methox?] phen? l] - 1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2 - [(phen? Lmet? L) am? No] -1-methyl prop? L] -3H- 1, 2, 4-tr? Azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H-1 , 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2 - [[(2-methox? Phen? L) met? L] am? No] -1-met? Lprop? L] -3 / - / - 1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H-1, 2.4- tr? azol-1-? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2, 4-d? H? Dro-2- [2 - [(2-phenoxy? Et? L) am? No] -1-met? Lprop? L] -3 / - / -1, 2,4-tr? Azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? I) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] - 2,4-d? H? Dro-2- [2 - [(2,3-d? H? Dro-1 H-? Nden-2-? L) am? No] -1-met? Lprop? L ] -3 / - / - 1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H -1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? l] -2- [2 - [[1- (4-fluorophen? l) et? l] am? no] -1-met? lprop? l] -2,4-d? h? dro-3H-1 , 2,4-tr? Azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d? Oxolan-4? I] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [ 2 - [[1- (fen? Lmet? L) -4-p? Pepd? N? L] am? No] -1-met? Lprop? L] -3H-1, 2,4-tpazol-3 ona, 4- [4- [4- [4 - [[2- (2,4-d? fluorophen? l) -2- (1H-1, 2,4-tpazol-1-? lmet? l) - 1,3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N] l] phen? L] -2,4-d? H? Dro-2- [2 - (4-morpholine? -1) -methylpropyl] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- ( 2, -d? Fluorophen?) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4? L] methox?] Phen? ] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2 - [[1- (hydrox? Met? L) -2-fen? let? l] am? no] -1-met? lprop? l] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2, 4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen ? l] -1-p? peraz? n] l] phen? l] -2,4-d? h? dro-2- [2 - [(2-h? drox? -1-phen? l-et ?) am? no] -1-met? lprop? l] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4 -d? fluorophen?) -2- (1 H-1, 2,4-tpazol-1-? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2 - [(2-h? Drox? -2-phen? Let? L) a m? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- (2,4- d? fluorophen?) -2- (1H-1, 2,4-tr? azol-l?? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? Peraz? N] l] phen? L] -2,4-d? H? Dro-2- [2 - [[1- (hydrox? Met? L) -2-met? Lprop ? l] am? no] -1-met? lprop? l] -3 / - / - 1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2 - (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2,4-d? h? dro-2- [2 - [(1-phen? let? l) am? noj-1-methypropyl] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tpazol-1-? Lmet? L) -1 , 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N] l] phen? L] -2,4-d? H? Dro-2- [1- (1-phenol? L) -4-p? Per? D? N? L] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[ 2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d? Oxolan-4-? ] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2,4-d? h? dro-2- [2 - [[1- (hydrox? met? l) -2-met? lpropyl] am? no] -1-met? lpropyl] -3 / -1, 2,4-tr? azol-3-one, 2- [4- [4 - [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 HA, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4- ? l] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2,4-d? h? dro-4- [2 - [(phen? lmet? l) am ? no] -1-met? lprop? l] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? fluorophen ?) -2- (1 H-1, 2,4-tr? azol-1-? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1 -p? peraz? n? l] phen? l] -2,4-d? h? dro-2- [4 - [(phen? lmet? l) am? no] -c? clohex? l] -3H -1, 2,4-tr? Azol-3-one, the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof The most preferred stereochemically pure compounds are n [2S- [2, 4 [(R *, S *) (S *)]]] - 4- [4- [4- [4 - [[2- (2,4-d? fluorophen? l)] -2- (1H-1, 2,4-tpazol-1-? L-met? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz ? n? l] phen? l] -2,4-d? h? dro-2- [2 - [(1-phen? let? l) am? no] -1-met? lprop? l] -3H -1, 2,4-tpazol-3-one, 2S- [2, 4a [(S *, R *)]] - 4- [4- [4- [4 - [[2- (2,4- d? fluorophen?) -2- (1H-1, 2,4-tr? azol-1-? l-met? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n] l] phen? l] -2,4-d? h? dro-2- [2 - [(phen? lmet? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, and [2S- [2, 4 [(R *, S *) (R *)]]] - 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tr? Azol-1-? L-met? L) -1, 3 -d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2.4- dihydro-2- [2 - [[1- (hydroxymethyl) 2-methylpropyl] amino] -1-methylpropyl] -3H-1, 2,4-triazol-3-one. The compounds of the present invention in which Rβ and R7 are not hydrogen, said Rβ 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 alkanesulfonyloxy 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,? /,? / - dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, sulfolane or the like, 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, further purified according to the methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. In particular, stereoisomers can be isolatedchromatographically used 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 N-alkylating an intermediate of the formula (IV) with an intermediate of the formula (V) in which W2 is a suitable leaving group such as, for 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, a C 1-4 alkyloxycarbonyl group, 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 N-alkylation reaction.

+ L-W2 (.) (IV) (V) The compounds of the formula (I ') in which L is a radical of the formula (a), said compounds are represented by the formula (l'-a), 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, naphthylisulfonyloxy 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, it can be used Na 3 as an intermediary of the formula (VII). (fa) 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 Prepare following the reaction procedure illustrated in scheme 1.

^ J SCHEME 1 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 C? _, Or a functional derivative of NP2 such as, for example, a nitro group, with an intermediate of the formula (II) according to the process described for the preparation of the compounds of the formula (I1). The intermediates of the formula (VI 11-b) thus obtained can be deprotected according to deprotection techniques known in the art, thereby 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 alkyl Ci. 4, the amine derivatives of the formula (Vlll-c) can first be reacted with where W4 is a suitable leaving group 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 in L such as primary and secondary amines, if present, are protected with a protecting group P such as, for example, a C 1-4 alkyloxycarbonyl group. Conveniently, the amino reactive group can be deprotected using deprotection techniques known in the art to reach the desired compound of the formula (I ".) The compounds of the formula (I) can also be converted to each other following transformations known in the art. For example, compounds of the formula (I ') in which L is a radical of the formula (b), compounds that are represented by the formula (l'-b), can be prepared using known acylation methods in the technique, for example those described in "Principies of Peptide Synthesis", M. Bodanszky, Springer-Verlag Berlin Heidelberg, 1984.

A special acylation process involves the acylation of a compound of the formula (1-a) in which R 1 is hydrogen, which compound is represented by the formula (1-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 or the like. (f-a-1) (X-b) // \ v / \ - -NA N-Alk- N i.-C ?? ? / - R 'I.

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,? /,? / '- dicyclohexylcarbodiimide, 1- (3-dimethylaminoporyl) -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 intermediate of the formula (X-b), quick couplings can be made without enantiomerization by the addition of hydroxybenzotriazole, benzotriazolyloxytris (d? methylamino) phosphonium hexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate or a functional derivative thereof (D. Hudson, J. Org. Chem., 1988, 53, page 617/1999 Novabiochem catalog &peptide Synthesis Handbook). An acylation process analogous to that of the preparation of the compounds of the formula (l'-b) can be used for the preparation of the compounds of the formula (I ') in which L is a radical of the formula (c) , said compounds are represented by the formula (l'-c). In said analogous reaction procedure, the intermediate of the formula (Xb) is replaced by a carbonate of the formula alk? IC? 4-0-C (= 0) -0-R1 (Xc-1), a chloroformate of the formula CI-C (= 0) -0-R1 (Xc-2) or alkylCM-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) , said compounds are represented by the formula (l'-d). In said analogous reaction process, the intermediate of the formula (Xb) is replaced by an isocyanate of the formula 0 = C = N-R1 (Xd-1), an isothiocyanate of the formula S = C = N-R1 (Xd) -2), a phenylcarbamate of the formula fera / -0-C (= 0) -NR1R2 (Xd-3), a phenylthiocarbamate of the formula phenyl-0-C (= S) -NR R2 (Xd-4) or an intermediate of the formula alkyl ^ SC (= NR2) -NR1R2 (Xd-5).

Reductive N-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) R1b (XI) in which R1a and R1b are defined as Thus, the radical -CHR1aR1b is encompassed by the definition of R1, thus forming the compounds of the formula (l'-a-2). This reductive N-alkylation can be carried out in a solvent inert to the reaction such as, 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 borohydride of tpacetoxy 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 urea-butoxide, calcium oxide, calcium hydride or a titanium (IV) alkoxide, for example titanium (IV) isopropoxide or titanium (IV) n-butoxide. A poison can also be added catalyst, for example, thiophene, butanediol or quinoline-sulfur to the reaction mixture to prevent further harmful hydrogenation of certain functional groups in the reactants and the reaction products. Agitation and, optionally, elevated temperatures and / or pressures may increase the rate of reaction. or AA • ""? f? TO.

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 C1.6 alkyl , 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 (l'-a-1) with an epoxide of the formula (XII) in a solvent inert to the reaction such as, for example, 2-propanol. listener or,,,. II 2 OH 'l - N N -? - N N- Alk- N-CH2-? H \ - * - '^ ß- ¿- substituent (r-a-3) The compounds of the formula (I) which contain an alkyloxycarbonylamino C 1 - moiety can be converted to the compounds of the formula (I) which contain the corresponding amino moiety using techniques _j _? ________ i_l ___? __ i 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 ') which contain a primary amine may 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 employing techniques 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? -oxides following art-known procedures for converting a trivalent nitrogen to its N-oxide form. Said? / -oxidation reaction can be carried out generally by reacting the starting material of the formula (I) with an appropriate 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; suitable organic peroxides 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 ferro-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanes, for example ethanol and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane and mixtures of the mentioned solvents. Some of the intermediates and starting materials used in the said processes can be obtained commercially, or they can be synthesized according to procedures described in other documents, for example US 4,791,111, US 4,931,444 and US 4,267,179. 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 which 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 reductive? -alkylation of the compounds of the formula (l'-a-1) with the intermediaries of the formula (XI).

(XIII) (VII) (III-a) The reaction procedure described can be carried out with chirally pure starting materials, employing stereoselective reaction procedures, to thereby obtain chirally pure intermediates of the formula (III-a). 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 Ci-β 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 get like this intermediates of the formula (III-a) in which R is hydrogen, intermediates that are represented by the formula (III-a-1).

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 the application of procedures known in the art. The 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 one of another by selective crystallization of its 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 will conveniently employ 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 that reason that the chirally pure forms of the intermediates of the formulas (II), (III) and (VI), their forms of? Oxide and its addition salt forms are of particular utility in the preparation of the chirally pure compounds of the formula (I). The enantiomeric mixtures and the diastereomeric mixtures of the intermediates of the formulas (II), (III) and (VI), 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 mixtures and The diastereomers 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 -, and 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-frans) -4,5-dimethyl-2,2-dioxide-1,2,2-dioxathiolane can be carried out in a suitable solvent, preferably a solvent polar aprotic such as, for example, dimethylacetamide or? /,? / - dimethylformamide and in the presence of a base such as, for example, potassium ferc-butanolate, potassium hydroxide or potassium hydride. Next, 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-methylpropyl portion is epimerized, preferably 100% inverted, to obtain the intermediary (SS) (XVII) whereby the 2-amino-1-methylpropyl portion 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 acid methanesulfonic acid, to thereby 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, NaN3, 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 change 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 diethylazodicarboxylate, 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 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 output group O-LG according to what has been described above, to obtain thus 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 means of a SN2-type reaction with a suitable nucleophilic reagent such as, for example, an alcoholate, 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 / - methylpyrrolidone, dimethylimidazolidinone or sulfolane. In case of using an alcoholate or an acetate in the SN2 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. The ester thus obtained can then be hydrolyzed 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 pathways described for the preparation of the intermediates (SS) (XVII) 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 an 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-frans) -4,5-dimethyl-2,2-dioxide-1, 3,2-dioxathiolane include the following chirally pure intermediates. in which LG is an exit group such as, for example, p-toluenesulfonyl. The intermediaries of the formula (III-2) by which the portion 2-hydroxy-1-methylpropyl has the form [R- (R *, R *)], intermediates that are represented by (RR) (III-a-2), can be prepared using the same reaction routes illustrated in scheme 2, although replacing (4R-fraps) -4,5-dimethyl-2,2-dioxide-1, 3,2-dioxathiolane with its enantiomer (4S-frans) -4,5-dimethyl-2,2-dioxide -1, 3,2-dioxatylane.

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), (SR) (Vl-a), (RS) (VI-a) and (RR) (Vl-a), can be prepared using this procedure.

SCHEME 3 optional - < CH3 H_ CH3 H CH3 H CH3 / C .S.CHCH33 ^ c R ^ CCHH33 c - ^^ s CCHH33 x. fC.CH3 \ s HF, OH rs H OH GR H "t) H GA H AH D-W1 (ll) Suitable stereoselective reduction conditions include the use of K-selectride in a suitable solvent such as, for example, dimethylacetamine or tetrahydrofuran; the use of sodium borohydride optionally in combination with CeCl3.7H20, 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 moiety, 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 to thereby obtain an intermediate of the formula (VII-a) or a chirally 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, Aspergillus flavus; Cryptococcus neoformans, Sporothrix schenckii, Fonsecaea spp .; Epidermophyton floccosum, Microsporum canis; Trichophytonn spp .; Fusarium spp .; and several dematiceous hyphomycetes. The activity of some of the present compounds 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 forth below, indicate that the compounds of the formula (I) have a favorable intrinsic inhibitory capacity on the development of 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 sterol in, for example, Candida albicans, also demonstrate their antifungal potential. In addition, in vivo experiments in various models of mice, guinea pigs and rats demonstrate that, after oral as well as intravenous administration, the present compounds are potent antifungals. Another advantage of some of the present compounds is that they are not only fungistatic, like most known azole antifungals, They are also fungicides in 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. The compounds of particular interest are the compounds of the formula (I) which have a water solubility of at least 0.1 mg / ml at a pH of at least 4., preferably, a solubility in water of at least 1 mg / ml at a pH of at least 4 and more preferably a solubility in water of 5 mg / ml at a pH of at least 4. In view of the utility of The compounds of the formula (I) present a method for treating warm-blooded animals, including humans, that suffer from fungal infections. Said method consists of the systemic or topical administration of an effective amount of a compound of formula (I), an N-oxide form, a pharmaceutically acceptable addition salt or a stereisomerically possible form thereof, to warm-blooded animals, 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 fungal treatment. The present invention also presents compositions for treating or preventing fungal infections containing an amount Therapeutically effective of a compound of 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. As Suitable compositions for topical application can be cited all the compositions usually 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 deleterious effect of consideration in 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 reinforced penetration agent that favors the penetration of the antifungal into the keratinized nail layer and through the nail. 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 consists of 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 can be used. For parepheral compositions, other ingredients can be included to contribute to solubility, for example cyclodextrins. Suitable cyclodextrins are a-, β- and β-cyclodextrins or ethers and mixed ethers thereof in which one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with Ci 6 alkyl, especially methyl, ethyl or isopropyl, for example β-CD methylated at random, hydroxyalkyl Ci β, especially hydroxyethyl, hydroxypropyl or hydroxybutyl, C 6 -carboxyalkyl, especially carboxymethyl or carboxyethyl, C 6 -alkylcarbonyl, especially acetyl The β-CDs are noteworthy as complexing agents and / or solubilizers, the randomly-methylated CD-β, the 2,6-dimethyl-β-CD, the 2-hydroxide and the β-CD, the 2-hydroxide and the CD, 2-H? drox? prop? l -? - CD y (2-carbox? metho?) prop? l-β-CD, and especially 2-hydrox? prop? l-β-CD (2- HP-ß-CD) The term mixed ether indicates cyclodextrin derivatives in which at least two hydroxy groups of the cyclodextrin are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. Medium molar substitution (MS) is used as a measure of the average number of moles of alkoxy units for each mole of anhydroglucose The mean substitution degree (DS) refers to the average number of substituted hydroxides for each anhydroglucose unit The MS and DS value can be determined by various analytical techniques such as resonance nuclear magnetic resonance (NMR), mass spectrometry (MS) and spectroscopy - Mftrtt ~ m? i infrared (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. they fluctuate between 0.125 and 10 and the ranges of 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. These particles can then 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) forcing the melt 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 when dissolved in a 2% aqueous solution at 20 ° C. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcellulose, alkali metal salts of carboxyalkylcelluloses, carboxyalkylcelluloses, 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 oxide. Preferred water-soluble polymers are hydroxypropylmethylcelluloses. One or more cyclodextrins can also be used as water-soluble polymers 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 the, β or β? cyclodextrins or pharmaceutically acceptable derivatives thereof.

Substituted cyclodextrins that may 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 C1.6alkyl, C6.6 hydroxyalkyl, C5-carboxyalkyl, or C3-oxycarbonylalkylC1-, or the ethers mixed of them. In particular, those substituted cyclodextrins are ethers in which the hydrogen of one or more hydroxy groups of the cyclodextrin is replaced by C1.3 alkyl, C1-3 hiroxyalkyl or C1-3 carboxyalkyl or more specifically by methyl, ethyl, hydroxyethyl, hydroxypropyl , hydroxybutyl, carboxymethyl or carboxyethyl. Of particular utility 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-cyclodextrin. That type of alkyl ether may consist of a methyl ether with a degree of substitution of about 0.124 to 3, for example from about 0.3 to 2. That hydroxypropylcyclodextrin can be formed, for example from the reaction between β-cyclodextrin and propylene oxide and can have an MS value of about 0.125 to 10, for 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, 1/100 ratios can be applied to 100/1. Interesting ratios of the active ingredient with respect to the 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 be selected, preferably from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Another interesting way of formulating the present compounds includes a pharmaceutical composition by which the antifungals of the present invention are incorporated into hydrophilic polymers and this mixture is applied as a coating film on very small beads, to thereby give a composition which can be elaborated conveniently andwhich 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 antifungal agent, as well as a polymeric layer sealing the coating. The materials suitable for use as cores in the beads 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. Form of unit dosage, term employed in the specification and the claims of the present refers to physically discrete units suitable as unit doses, each of which contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in combination with the vehicle Pharmaceutical necessary. 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-oxopropyl) was hydrogenated -3r--1, 2,4-triazol-3-one (0.05 moles) and (+) - (R) -α-methylbenzenemethanamine (0.1 moles) in THF (500 ml) at 50 ° C for 48 hours with Pd / C 10% (10 g) as 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 uptake 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 H20 (50 ml) was added. The mixture was acidified with a concentrated HCl solution, alkalized with a concentrated NH 4 OH solution and filtered over dicalite. 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] -3- / -1, 2,4-triazol-3-one (interm. b) A mixture of (±) -2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2- (1-methyl-2-oxopropyl) was hydrogenated. ) -3H-1, 2,4-triazol-3-one (0.05 moles) and (-) - (S) -a-methylbenzenemethanamine (0.1 moles) in THF (500 ml) at 50 ° C for 48 hours with Pd / C 10% (3 g) as a catalyst, in the presence of titanium n-butoxide (VI) (28 4 g) and a thiophene solution (3 ml) The catalyst was separated by filtration 10% Pd / C (10 g) and thiophene solution (3 ml) was added again. Hydrogenating was continued for 48 hours at 50 ° C. After the uptake of H 2, the catalyst was separated by filtration and the Evaporated filtrate The residue was stirred in CH2CI2, CH3OH and H2O. The mixture was alkalized with NaOH and filtered with dicalite. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to dryness. give 19 g (74%) of [(R * R *) (S) + (R * S *) (S)] - 2,4-d? h? dro-4- [4- [4- (4 -h? drox? fen? l) -1-p? peraz? n? l] fen? l] -2- [2 - [(1-phen? let? l) am? no] -1-met? lprop ?] -3H-1, 2,4-tpazol-3-one (interm 2) c) A mixture of (±) -2,4-d? h? dro-4- [4- [4- (4 -h? drox? fen?) -1-p? peraz? n? l] phen? l] -2- (1-met? l-2-oxoprop? l) -3H-1, 2 4-tr? azol-3-one (0 018 moles), (S) -a-met? l- l-naphthalenetenenamine (0 0187 mol) and tps (acetate-0) hydroborate (I-) (0 028 mol) in CH 2 Cl 2 (150 ml) was stirred at room temperature overnight A solution of NH OH was added The mixture was stirred for 1 hour The precipitate was separated by filtration, washed with H20 and with CH2CI2 (20 ml) and dried The residue was crystallized with CH3CN The precipitate was separated by dried filtration, to give 3 3 g (32%) from [R- (R *, S *) (S *)] - 2,4-d? h? dro-4- [4- [4- (4-h? drox? phen? l) -1-p ? peraz? n? l] phen? l] -2- [1-met? l-2 - [[1- (1-naphthalene? l) et? l] am? no] prop? l] -3H-1 , 2,4-tr? Azol-3-one (interm 108) d) A mixture of intermediate 5 (0,0049 moles), 3-pipdinocarboxaldehyde (0,0054 moles) and tr? S (acetate-0) hydroborate ( I-) (0 0049 moles) in CH2Cl2 (150 ml) was stirred at room temperature over the weekend. Tris (acetate-0) hydroborate (I-) (0.0022 mol) was added again. The mixture was stirred at room temperature for 2 nights, extracted with CH2Cl2 and washed with H2O. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel (eluent: CH2Cl2 / CH3? H 97/3). The pure fractions were collected and the solvent was evaporated to give 0.8 g of [R- (R *, S *)] - 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl ] pheny] -2- [1-methyl-2 - [(3-pyridinylmethyl) -amino] propyl] -3H-1, 2,4-triazol-3-one (interm 123). e) A mixture of intermediate 5 (0.042 moles) and benzaldehyde (0.042 moles) in tetrahydrofuran (500 ml) was hydrogenated at 50 ° C with palladium on 10% activated carbon (2 g) as a 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 3 OH 98/2, eluent 2: CH 2 Cl 2 / (CH 3 OH / NH 3) 95/5). The desired fraction was 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 - [(phenylmethylJaminojpropilj-SH-l ^^ - triazin-S-one (interm .. 107) Table 1a lists the intermediates which they are prepared according to the previous example A1 a.

TABLE 1a 61 -. 61-NH-CH2- [2- (HO-CH2) -phenyl] CH3 H-62-NH-CH (CH3) - [4-F-phenol] CH3 H [A (R) j; +87.02 @ 24.06; mp 215.4 63-NH-CH (CH 3) - [4-F-phenyl] CH 3 H [B (R)]; +7.62 @ 24.27; mp 171.8 64a -NH-CH [CH (CH3) 2] -CH2-OH CH3 H [R- (R *, R *) (S *) j; +8.93 @ 23.52 64b -NH-CH [CH (CH3) 2] -CH2-OH CH3 H [S- (R *, R *) (S *) J; -10.81 @ 10.18 65a -NH-CH [CH (CH3) 2] -CH2-OH CH3 H [S- (R *, S *) (R *) j; -46.42 @ 25.56 65b -NH-CH [CH (CH3) 2] -CH2-OH CH3 H [R- (R *, S *) (R *)]; +45.42 @ 24.33 66a -NH-CH [CH (CH3) 2] -CH2OH CH3 H [R- (R *, S *) (S *) j; +47.33 @ 23.98 66b -NH-CH [CH (CH3) 2] -CH2OH CH3 H [S- (R *, S *) (S *) j; -49.06 @ 24.36 67a -NH-CH [CH (CH3) 2] -CH2OH CH3 H [S- (R *, R *) (R *) J; -14.03 @ 9.98 67b -NH-CH [CH (CH3) 2] -CH2OH CH3 H [R- (R *, R *) (R *) j; +11.95 @ 24.26 68 -NH-CH2-phenyl CH3 H (R *, R *) 69 -NH-CH2-phenyl CH3 H (R *, S *) 70 CH3 H (B)71 CO CH3 H (A) 72 OO CH3 H 73 -. 73 - JNH¿-CH (CH 3) phenyl H CH 3 [2A (S)]: -46.60 '@ 24.68; p.f. 160.3 74 -NH-CH- (CH 3) (phenol) H CH 3 [2B (R)]; +47.48 ° @ 22.85; PF 161.4 EXAMPLE A2 a) A mixture of intermediate (1) (0.0457 mol) in tetrahydrofuran (400 ml) was hydrogenated at 50 ° C with 10% Pd / C (5 g) as a catalyst. After H2 uptake, H20 and CH2Cl2 were added, then the catalyst was separated by filtration and the filtrate evaporated. The residue was crushed in CH2Cl2, separated by filtration and drying, to give 14 g (75%) of (±) - [(R *, R *) + (R *, S *)] - 2- (2-amino-1-methylpropyl) -2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-pperazinyl] pheny] -3H-1, 2,4-triazol-3-one (interm. . b) A mixture of intermediate (3) (0.025 mol) in acetic anhydride (0.03 mol) in CH2Cl2 (300 ml) was stirred at room temperature. A mixture of NaHCO3 (5 g) in H20 (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 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 *)] -? / - [2- [4,5-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] -phepyl] -5-oxo-1H-1, 2,4-triazol-1-yl] -1-methylpropyllacetamide (interm. 4a) and 2.81 g ( 25%) of [S (R *, R *)] -? / - [2- [4,5-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -5-oxo-1 / - / - 1, 2,4-triazol-1-yl] -1-methylpropyllacetamide (interm 4b). The second fraction was separated into its enantiomers by column chromatography (eluent: hexane / 2-propanol / CH OH30 / 55/15, column: CHIRALPAK AD). Two pure fractions were collected and their solvents were evaporated. The residue was triturated in 2-propapol, separated by filtration and drying to give 0.47 g (4%) of [S (R * S *)] -? / - [2- [4,5-dihydro-4- [4- [4- (4-hydroxyphenyl)) -1-piperazinyl] phenyl] -5-oxo-1H-1, 2,4-triazol-1-yl] -1-methylpropyllacetamide (interm. 4c) and 3.21 g (28%) of [R (R *, S *)] -? / - [2- [4,5-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -5-oxo-1H-1, 2, 4-triazol-1-yl] -1-methylpropyl] acetamide (interm. 4; mp 264.3 ° C); [] D2. = + 10.96 ° @ 20.07 mg / 2 ml in DMF. c) A mixture of intermediate (4) (0.0069 mol) in conc. HCl. (50 ml) was stirred and heated to reflux for 48 hours. The solvent was evaporated and dissolved in H20 (50 ml). The mixture was alkalized with NH OH and extracted with CH2Cl_ / CH3OH 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-hydroxyphenyl) -1-piperazinyl] phenyl] -3 / - / - 1, 2,4-triazol-3-one (intermediate 5; mp 237.2 ° C; ) D20 = + 1.01 ° @ 19.79 mg / 2 me in DMF). d) A mixture of intermediate (5) (0.0061 mol) and bis (1,1-dimethylethyl) bicarbonate (0.008 mol) in CH2Cl2 (500 ml) was stirred and refluxed for 2 hours. Bis (1, 1-dimethylethyl) bicarbonate (0.008 moles) was added again. The mixture was stirred and maintained at reflux for 2 hours. The solvent was evaporated and the residue triturated in DIPE, separated by filtration and dried to give 3.1 g (100%) of [R (R *, S *)] - [2- [4- [4- [4 - (4-hydroxyphenyl) -1-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1H-1, 2,4-triazol-1-yl] -1- 1, 1-d? met? lel methylpropyljcarbamate (intermediate 6, mp 218 3 ° C, [] D20 = + 19 63 ° @ 20 27 mg / 2 ml in DMF) EXAMPLE A3 a) Intermediate (1) (0 53 mol) was separated by HPLC on silica gel (eluent CH2CI2 / 2-propanol 99/1 to 97/3) Five fractions were collected and their solvents were evaporated. A first fraction was ground in DIPE, separated by filtration and dried to give 78.5 g (29%) of [R (R *, R *) (R *)] - 2-4-d? H? Dro-4- [4- [4- (4-H? Drox? Phen?) -1-p? Peraz? N? L] phen? L] -2- [2 - [(1-phen? Lmet? L) am? No] -1-met ? lprop? l] -3 / - / - 1, 2,4-tr? azol-3-one (intermediate 7, [] D20 = + 93 07 ° @ 24 98 mg / 5 ml in DMF) A second fraction was boiled in CH 3 CN The mixture was stirred and then cooled The precipitate was filtered off and dried to give 97 g (35%) of [ S (R *, R *) (S *)] 2-4-d? H? Dro-4- [4- [4- (4-h? Drox? Phen? L) -1-p? Peraz? N ? l] phen? l] -2- [2 - [(1-phen? let? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tpazol-3-one (intermediate 7a) b) A mixture of intermediate (7) (0 00976 moles) in methanol (200 ml) and acetic acid (50 ml) was hydrogenated at 50 ° C with 10% Pd / C (2 g) as a catalyst in the presence of (CH20) n (2 g) and 4% thiophene in methanol (1 ml) After the uptake of H2, the catalyst was separated by filtration and the filtrate evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed With a NaHCO3 solution, dry, filter and evaporate the solvent. 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 2-propanol, separated by filtration and dried, to give 3.8 g (74%) of [R (R *, R *) (R *)] - 2-4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2- [2-methyl (1-phenylethyl) amino] -1-methylpropyl] -3H-1, 2,4-triazol-3-one (intermediate) 8); [α] D20 = 17.69 ° @ 24.31 mg / 5 ml in DMF).

EXAMPLE A4 a) A mixture of 2,4-dihydro-4- [4- [4- (4-methoxy-phenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (0.05 moles) ), Ethyl 2-bromobutanoate (0.055 mol) and Na2CO3 (0.15 mmol) in 1-metll-2-pyrrolidinone (250 ml) was stirred at 75 ° C overnight. Ethyl 2-bromobutoate (0.015 mol) was added again. The mixture was stirred at 75 ° C for 6 hours, at room temperature for 48 hours, poured into H20 and stirred for 30 minutes. The precipitate was separated by filtration and dissolved in CH2Cl2. The solution was filtered. The filtrate was dried, filtered and the solvent was evaporated. The residue was triturated in DIPE and ethyl acetate, separated by filtration and dried to give 10 g (43%) of a-ethyl-4,5-dihydro-4- [4- [4- (4-methoxyphenyl) -1. -piperazinyl] phenyl] -5-oxo-1 H-1, 2,4-triazole-1-acetate (±) -ethyl (interm. 9). b) A mixture of NaHS03 (1 g) in 48% HBr (250 ml) and CH3COOH / HBr (250 ml) was stirred for 15 minutes. Intermediary (9) (0.022 moles) was added. The mixture was stirred and refluxed for 90 minutes The solvent was evaporated. Toluene was added and the solvent was evaporated. The residue was dissolved in CH3OH. The mixture was stirred over an ice bath. SOCI2 (24 g) was added dropwise and the mixture was stirred overnight. The solvent was evaporated and the residue was dissolved in CH2Cl2. The organic solution was washed with a solution of NaHCO 3, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried, to give 6.6 g of -ethyl-4,5-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] -phepil] - 5-oxo-1 H-1, 2,4-triazole-1-acetate (±) -methyl (interm 10). c) A methanesulfonate (ester) mixture of (-) - (2S-c / s) -2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmet) l) -1, 3-dioxolane-4-methanol (0.007 moles), intermediate (10) (0.0068 moles) and NaOH (0.008 moles) in DMF (100 ml) was stirred at 50 ° C under N2 flow overnight , then poured into H20 and stirred for 1 hour. The precipitate was separated by filtration and dissolved in CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH / hexane / ethyl acetate 48/2/20/30). The pure fractions were collected and the solvent was evaporated. The residue was triturated in ethyl acetate, separated by filtration and dried, to give 1.4 g (29%) of (2S-cis) -4- [4- [4- (4 - [[2- (2,4- difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] -phenyl] -1-plperazinyl] phenyl] - ethyl- 4,5-dihydro-5-oxo-1 -1, 2,4-triazole-1-methyl acetate (interm 11) d) A mixture of intermediate (11) (0.009 moles) and NaBH 4 (0.045 moles) ) in dioxane (300 ml) and H20 (100 ml) was stirred at room temperature Atmosphere during the night. A saturated solution of NH CI (100 ml) was added. The mixture was stirred for 3 hours. HCl (10 ml) was added. The mixture was stirred for 48 hours, then neutralized with a Na2CO solution and extracted with CH2Cl2. The organic layer was separated, washed, dried and filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 30 H 96/4). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 4.2 g (68%) of (2S-cis) -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) - 2- (1 / - / - 1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phen l] -1-piperazinyl] phenyl] -2,4-d Hydro-2- [1- (hydroxymethyl) propyl] -3H-1, 2,4-triazol-3-one (interm. 12). e) A mixture of intermediate (12) (0.01 mol) and methanesulfonyl chloride (0.0131 mol) in CH2Cl2 (100 ml) was stirred. N, N-bis (1-methylethyl) ethanamine (3 ml) was added and the mixture was stirred overnight and then poured into H20. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate. The mixture was filtered with dicalite and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated, to give 8.2 g of (2S-cis) -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H- 1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-p yperazinyl] phenyl] -2,4-d, h-d-2-2- [ 1 - [[(Methylsulfonyl) oxy] methyl]) propyl] -3H-1, 2,4-triazol-3-one (interm. 13).

EXAMPLE A5 a) A mixture of (+) - 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazin]] phenyl] -2- (1-methyl-2-oxopropyl) ) -3H-1, 2,4-trilazol-3-one (0.120 moles) in DMF (700 ml) was cooled on ice. Potassium tri-sec-butylborohydride, 1M solution in THF (300 ml) was added dropwise. The mixture was allowed to warm to room temperature, then poured into an aqueous solution of NH 4 Cl. The precipitate was separated by filtration, dried and crystallized with 2-propanol. This fraction was separated into its enantiomers in CHIRALPAC AD [3,5-dimethylphenyl carbamate amylose] purchased from Daicel Chemical Industries, Ltd., Japan] (eluent: 100% methanol). Two groups of pure fractions were collected and their solvent was evaporated. The desired fraction was recrystallized with methanol. The precipitate was separated by filtration and dried to give 0.9 g of [R- (R *, R *)] - 2,4-dihydro-2- (2-hydroxy-1-methylpropyl) -4- [4- [4 - (4-hydroxyphenyl) -1-pperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (intermediate 14a; [a] D20 = + 10.35 ° @ 48.81 mg / 5 ml in DMF) and 0.8 g of [S- (R *, R *)] - 2,4-dihydro-2- (2-hydroxy-1-methyl-propyl) -4- [4- [4- (4-hydroxyphenyl) - 1-piperazinyl] phenyl] -3 / - / - 1, 2,4-triazol-3-one (intermediate 14b). b) Reaction under N2 flow. A mixture of (-) - (2S, c / s) -2- (2,4-difluorophenyl) -2- (1H-1, 2, 4-methylbenzenesulfonate (ester)) was stirred overnight at 70 ° C. , 4-triazol-1-ylmethyl) -1, 3-dioxolan-4-methanol (0.012 moles), intermediate (14a) (0.0109 moles) and NaOH (0.011 moles) in DMF (150 ml). The reaction mixture was cooled and poured into water. The precipitate it was separated by filtration and dried. This fraction was purified by HPLC on Silica Motrex Amicon (20-45 μm, eluent: CI3CCH3 / C2H5OH 90/10). The pure fractions were collected and the solvent was evaporated. The residue was triturated in methanol, separated by filtration and dried, to give 5.3 g of [2S- [2a, 4a (S *, S *)]] - 4- [4- [4- [4 - [[2- 2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] - 2,4-dihydro-2- (2-hydroxy-1-methylpropyl) -3H-1, 2,4-triazol-3-one (interm. 15); [a] D2 _ = - 7.71 ° @ 48.61 mg / 5 ml of DMF). c) A mixture of intermediate (15) (0.0465 moles) in CH2Cl2 (250 ml) and pyridine (200 ml) was stirred on ice. Methanesulfonyl chloride (0.065 moles) was added. The mixture was allowed to warm to room temperature and then stirred overnight. Methanesulfonyl chloride (0.026 moles) was added again. The mixture was stirred overnight. The solvent was evaporated and the residue dissolved in CH2Cl2. The organic solution was washed, the solvent was dried, filtered and evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 34 g (95.5%) of [2S- [2a, 4a (S *, S *)]] - 4- [4- [4- [4- [ [2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-p-piperazinyl ] phenyl] -2,4-dihydro-2- [1-methyl-2 - [(methylsulfonyl) oxy] propyl] -3H-1, 2,4-triazol-3-one (interm.; mp 172.0 ° C; [a] D2. = - 6.96 ° @ 23.69 mg / 5 ml of DMF).

EXAMPLE A6 a) A mixture of (±) -2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2- (1-methyl-2-oxopropyl) -3H- 1, 2,4-triazol-3-one (0.05 moles) and 1- (phenylmethyl) -4-piperidinamine (0.13 moles) in THF (350 ml) was stirred at 140 ° C in an autoclave for 16 hours under pressure of H2 (50 atm) and C02 (10 atm) with Pd / C 10% (3 g) as a catalyst in the presence of a solution of 4% thiophene (3 ml) and CaH2 (0.125 mol). The mixture was cooled. The catalyst was separated by filtration and the filtrate evaporated. The residue was triturated in 2-propanol, separated by filtration and dried. The residue was boiled in CH 3 CN (400 ml). The mixture was cooled for 15 minutes. The precipitate was separated by filtration and dried. The residue was crystallized with CH3CN / 50/50 dioxane. The precipitate was separated by filtration and dried to give 14.8 g (50%) of (±) - (R * S *) - 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1- pperazinyl] phenyl] -2- [2 - [[1- (phenylmethyl) -4-piperazinyl] amino] -1-methylpropyl] -3H-1, 2,4-triazol-3-one ( interm 17a). The combined filtrates were evaporated. The residue was triturated in DIPE, separated by filtration and dried. This fraction was purified by HPLC (eluent: CH 2 Cl 2 / CH 3 OH 100/0 to 95/5, column: AMICON 20 μm). The desired fractions were collected and the solvent was evaporated. The residue was boiled in 2-propanol. After cooling, the precipitate was separated by filtration and dried, to give 7.2 g (24%) of (±) - (R *, R *) - 2,4-dihydro-4- [4- [4- (4 - methoxyphenyl) -1-piperazinyl] phenyl] -2- [2 - [[1- (phenylmethyl) -4-piperazinyl] amino] -1-methylpropyl] -3H-1, 2,4-triazole-3-one (interm 17). b) A mixture of intermediate (17) (0.0119 mol) and Na2SO4 (1 g) in 48% HBr (100 ml) was stirred and refluxed for 5 hours. The solvent was evaporated and the residue neutralized with a solution of NaHC 3. The mixture was extracted with CH2Cl2 / CH3? H. 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 6.1 g (88%) of (+) - (R *, R *) - 2,4-dihydro-4- [4- [4- ( 4-Hydroxyphenyl) -1-piperazinyl] pheny] -2- [2 - [[1- (phenylmethyl) -4-piperazinyl] amino] -1-methylpropyl] -3H-1, 2,4-triazole -3-one (interm. 18).

EXAMPLE A7 a) Reaction under N2 atmosphere. Na2C03 (0.01 mol) was added to a mixture of 2- (2-bromoethyl) -2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] fenll] -3 / - / -1, 2,4-triazole-3-one (0.0054 mol) in 1-methyl-2-pyrrolidinone (25 ml). This mixture was stirred at 60 ° C. A solution of (+) - (R) -a-methylbenzenemethanamine (0.0065 mol) in 1-methyl-2-pyrrolidinone (25 ml) was added dropwise and the resulting solution was stirred overnight at 60 ° C. The reaction mixture was cooled, poured into ice water and the resulting precipitate was separated by filtration, washed with water, then dried. This fraction was recrystallized with 2-propanol, separated by filtration and dried to give 1.98 g (77%) of (R) -2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2- [2 - [(1) phenylethyl) amino] ethyl] -3H-1, 2,4-triazol-3-one (interm 19). b) Reaction under N2 atmosphere. NaH 60% (0.12 mol) was added to 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (0.1 mol) in DMF and stirred for 30 minutes at 50 ° C. A solution of 1-chloro-2-propapo (0.1 mol) in DMF was added dropwise and the resulting reaction mixture was stirred overnight at 50 ° C. The reaction mixture was cooled, poured into ice water and the resulting precipitate was separated by filtration, washed with water and dried. This fraction was recrystallized with CH2Cl2 / CH3OH. The precipitate was separated by filtration and the filtrate evaporated. The residue was crystallized from methanol, separated by filtration and dried. The residue was combined with the crystallized compound, recrystallized with CH_CI2 / CH3OH, separated by filtration and dried to give 0.65 g of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) - 1-piperazinyl] phenyl] -2- (2-oxopropyl) -3H-1, 2,4-triazol-3-one (interm. 20).

EXAMPLE A8 A mixture of c / s-4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-methylmethyl) -1, 3- phenyl dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] carbamate (0.005 mole), prepared according to the procedure described in EP-A-0,228,125 and 1,1-dimethylethyl [1-methyl-2- (methylamino) propyl] (phenylmethyl) carbamate (0.005 mol) in dioxane (50 ml) was stirred and maintained at reflux overnight. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH / ethyl acetate / hexane 48/2/30/20). The pure fractions were collected and the solvent was evaporated, to give 2.7 g (62.3%) of (2S, c / s) - [2 - [[[[4- [4- [4 - [[2- (2, 4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] amino] carbonyl] methylamino] -1-methylpropyl] (phenylmethyl) carbamate 1,1-dimethylethyl ester (interm 133).

EXAMPLE A9 Reaction under N atmosphere A mixture of intermediate 110 (0.745 mol) in THF (3000 ml) was stirred for 1 hour at 40 ° C. The mixture was allowed to cool to 30 ° C. L2BH 2M in THF (0.800 mol) was added dropwise at 30 ° C. After the addition of 100 ml, the reaction mixture was gradually heated to 60 ° C while the remaining LiBH 4 was added dropwise. Then, the reaction mixture was stirred and maintained at reflux (65 ° C) for + 60 hours. The reaction mixture was cooled. 2-Propanone (500 ml) was added dropwise. Water (800 ml) was added in the course 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 evaporated. The residue was stirred in DIPE (2 I), separated by filtration and dried. This fraction was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH 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-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (interm 104) . 5 EXAMPLE A10 a) A mixture of [S- (R *, R *)] - 2,4-dihydro-2- (2-hydroxy-1-methylpropyl) -4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3 / - / - 1, 2,4-triazol-3-one (0.01 moles), p-toluenesulfonyl chloride (0.012 moles), triethylamine (2 g) and dimethylaminopyridine (0.5 g) in CH2Cl2 (100 ml) was stirred at room temperature for 4 days. The mixture was taken up in CH2CI2 and purified by column chromatography on silica gel (eluent: 100% CH2Cl2). The pure fractions were collected and the solvent was evaporated. The residue was Crushed in methyl isobutyl ketone, separated by filtration and dried to give 4.6 g (79%) of [S- (R *, R *)] - 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2- [1-methyl-2 - [[(4-methylphenyl) sulfonyl] oxy] propyl] -3 / - / - 1, 2,4-triazol-3-one (interm. 134). b) A mixture of intermediate 134 (0.0071 mol) and sodium azide (0.009 mol) in DMF (50 ml) was stirred at 80 ° C for 1 hour, at 100 ° C for 4 hours and cooled. H20 was added and the mixture was allowed to crystallize. The precipitate was separated by filtration, washed with H20 and dissolved in CH2Cl2. The organic solution was dried, filtered and the solvent was evaporated to give 2.8 g (88%) of [S- (R *, R *)] -2- (2-azido-1-methyl-propy) - 2,4- dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3 - / - 1, 2,4-triazol-3-one (interm. 87). c) A mixture of intermediate 87 (0.0062 mol) and triphenylphosphine (0.008 mol) in THF (100 ml) was stirred at 50 ° C / 60 ° C for 24 hours. Water (1 ml) was added. The mixture was stirred at 50 ° C / 60 ° C for 8 hours. The solvent was evaporated. The residue was stirred in H20 (100 ml) and a concentrated HCl solution (5 ml). The mixture was filtered. The filtrate was washed 3 times with CH 2 Cl 2, neutralized with a NaHCO 3 solution and extracted with CH 2 Cl 2 / CH 30 H 90/10. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized with ethanol. The precipitate was filtered off and dried to give 1.36 g (52%) of [S- (R *, R *)] -2- (2-amino-1-methylpropyl) -2,4-dihydro-4- [ 4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl-3H-1, 2,4-triazol-3-one (interm 88). d) A mixture of intermediate 105 (0.049 mol) in THF (300 ml) and water (200 ml) was hydrogenated at room temperature with palladium on activated charcoal 10% (4 g) as a catalyst in the presence of a thiophene 4 solution. % (4 ml). After the uptake of hydrogen, the catalyst was separated by filtration and the filtrate evaporated. The residue was purified on silica gel on a glass filter (eluent 1: CH 2 Cl 2 / CH 0 H 99/1 and eluent 2: CH 2 Cl 2 / CH 30 H / NH 3) 95/5). The pure fractions were collected and the solvent was evaporated to give 18.6 g (90%) of [R- (R *, S *)] -2- (2-amino-1-methylpropyl) -2,4-dihydro-4 - [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazole-3-one (interm 106).

EXAMPLE A11 a) A mixture of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1, 2,4-triazol-3-one (0.1 moles) ) and KOH powder (0.1 mole) in 1,3-dimethyl-2-imidazolidinone (250 ml) and methylbenzene (100 ml) was stirred at 140 ° C under N2 flow for 15 min and then cooled to 80 ° C. 1 - [(4-Methylphenyl) sulfonyl] 4-piperidinol (ester) methanesulfonate (0.12 mol) was added. The mixture was stirred at 140 ° C for 24 hours and cooled. The precipitate was separated by filtration (*). The filtrate was poured on ice and extracted three times with toluene. The combined organic layer was washed twice with H20, dried (MgSO), filtered and the solvent was evaporated. (*) The precipitate was brought to reflux in CH2Cl2 (1000 ml) and CH3OH (500 ml). The precipitate was separated by hot filtration, allowed to crystallize, separated by filtration and dried under vacuum at 60 ° C (yield 8.6 g). Part (1 g) of this fraction was dried under vacuum at 60 ° C for 28 hours. Yield: 4- [4,5-D-Hydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -5-oxo-1H-1, 2,4-triazole- 1-yl] -1 - [(4-methylphenyl) sulfonyl] piperidine (interm 135). b) Intermediate 135 (0.027 mol) was added to a mixture of NaHS03 (2g) in 48% HBr (300 ml) and HBr / CH3OH (150 ml). The mixture was stirred and refluxed for 4 hours and then cooled. The solvent was evaporated. The residue was dissolved in water (300 ml). NH 3 aq. to 28% (50 ml). The precipitate was separated by filtration and dried under vacuum at 75 ° C (yield 7.5 g (66%). Part of this fraction (1 g) was recrystallized with diethyl ether. The precipitate was separated by filtration and dried. Yield: 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2- (4-piperidinyl) -3H-1, 2,4-triazol-3-one (interm. 136).

EXAMPLE A12 a) A mixture of 1,4-dioxaspiro [4.5] decan-8-one (0.115 moles) and hydrazinocarboxaldehyde (0.23 moles) in methanol (300 ml) was hydrogenated at 50 ° C under 100 atm for 16 hours with Pd / C 10% (3 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in CH2Cl2 (750 mL). The organic solution was washed with H20 (100 ml), dried (MgS?), Filtered and the solvent was evaporated. Yield: 19.9 g of 2- (1,4-dioxaspiro [4.5] decan-8-yl) hydrozinecarboxaldehyde (86%) (Example 137). b) A mixture of intermediate 137 (0.0995 moles), 4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] carbamate phenyl (0.09 moles) and? /,? / - dimethyl-4- pyridinamine (0.0995 moles) in methylbenzene (300 ml) was stirred at 80 ° C for 16 hours using a Dean Stark apparatus, then stirred and refluxed for 3 hours and cooled. H20 (200 ml) was added and the mixture was extracted with CH2Cl2. The organic layer was separated, washed once with H20 and once with a saturated solution of NaCl, then dried (MgSO 4), filtered and the solvent was evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and dried. Yield: 32.3 g (73%).

Part of this fraction (3 g) was recrystallized with 2-propanol. The precipitate was separated by filtration and dried. This fraction was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3? H 98.5 / 1.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and dried. Yield: 2- (1,4-dioxaspiro [4.5] decan-8-yl) -2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1 , 2,3-triazol-3-one (interm 138). c) A mixture of intermediate 138 (0.059 moles) in 10% H 2 SO 4 (500 ml) was stirred at 60 ° C for 3 hours and cooled to room temperature. The precipitate was separated by filtration and suspended in H20 (300 ml). The mixture was neutralized with a saturated K2CÜ3 solution. The precipitate was separated by filtration, washed twice with H20 and dried. This fraction was triturated in ethanol / CH 2 Cl 2 1: 1, separated by filtration and dried. This fraction was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dried in vacuo. Performance: 2, 4-dihydro-4- [4- [4- [4-methoxyphenyl) -1-piperazinyl] phenyl] -2- (4-oxocixlohexyl) -3H-1, 2,4-triazol-3-one (interm. 139). d) A mixture of intermediate 139 (0.031 mol) and benzenemethanamine (0.018 mol) in methanol (150 mol) and THF (150 ml) was hydrogenated at 50 ° C with 10% Pd / C (2 g) as catalyst in the presence of a solution of thiophene 4% in DIPE (2 ml). After uptake of H 2 (1 equivalent), the catalyst was removed by filtration and the filtrate evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH 100/0 to 98/2). Two pure fractions were collected and their solvents were evaporated. The residue was dried under vacuum at 60 ° C. Yield: 3.4 g of (+) - c / s-2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-pperazinyl] phenyl] -2- [4 - [(phen Lmethyl) amino] cyclohexyl] -3H-1, 2,4-triazol-3-one (interm.140) and 1.4 g of (±) -_ ans-2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2- [4 - [( phenylmethyl) amino] cyclohexyl] -3H-1, 2,4-triazol-3-one (interm. 144).

EXAMPLE A13 A mixture of intermediate 76 (0.0228 mol) in THF (200 ml) was hydrogenated at 125 ° C for 64 hours with 5% Pt / C (2 g) as a catalyst. After uptake of H 2 (1 equivalent), the catalyst was removed by filtration and the filtrate evaporated. Yield: 10 g of (R) -1- [4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3- [2 - [(1-phenylethyl) amino] 1, 2-dimethylethyl] -2-imidazolidinone (interm.141). Table 1b lists the intermediaries that were prepared analogously to the preceding examples.

TABLE 1b TABLE 1c B. Preparation of the final compounds EXAMPLE B1 a) A methanesulfonate (ester) mixture of (-) - (2S-cis) -2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) - 1,3-dioxolane-4-methanol (0.0071 mol), [R (R *, S *)] - [2- [4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl ] -4,5-dihydro-5-oxo-1 H-1, 2,4-triazol-1-yl] -1-methylpropyl] carbamate 1,1-dimethylethyl (0.0059 moles) and NaOH pellets ( 0.012 moles) in DMF was stirred at 70 ° C under N2 flow for 2 hours and then cooled. DIPE (100 ml) and H20 (400 ml) were added. The mixture was stirred and then allowed to crystallize. The precipitate was separated by filtration, washed with H20 and DIPE and purified on silica gel on a glass filter (eluent: CH2Cl2 / CH3? H 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 3.24 g (69%) of [2S- [2a.4a (S *, R *)]] - [2- [4- [4- [ 4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolane-4-yl] methoxy] phenyl] - 1, 1-dimethylethyl 1-methyl-propyl] -4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl] -1-methylpropyl] carbamate (compound 28, mp 158.3 ° C). b) A mixture of compound 28 (0.0038 mol) in CF3COOH (10 ml) and CH2Cl2 (50 ml) was stirred at room temperature for 4 hours and neutralized with a solution of NaHCO. 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 2.4 g (92%) of [2S- [2, 4a (S *? *)]] - 2- (2-amino-1-methylpropyl) - [4- [4- [4 - [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolane-4-yl] methoxy] phenyl] -1 -piperazinyl] phenyl] -2,4-dihydro-3H-1, 2,4-triazol-3-one (compound 37, mp 168.5 ° C).

EXAMPLE B2 A mixture of compound 37 (0.0034 mole), N - [(1,1-dimethylethoxy) carbonyl] phenylalanine (0.005 mole) and? / '- (ethylcarbonimidoyl) -? /, Was stirred at room temperature for 2 hours. dimethyl-1,3-propanediamine (0.005 mol) in CH2Cl2 (100 ml). The mixture was washed twice with H20, dried, filtered and the solvent evaporated. The residue was triturated in 2-propanol, separated by filtration and dried to give 2.78 g (87%) of [2S- [2, 4 (S *, R *) (R *)]]] - [2- [[2- [4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3 -dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1H-1, 2,4-triazol-1-yl] -1-methylpropyl] amino] -2-oxo-1- (phenylmethyl) ethyl] carbamate 1,1-dimethylethyl ester (compound 124, mp 181.7 ° C).

EXAMPLE B3 Chlorine acetylchloride (0.005 mole) was added to a stirring mixture of [2S- [2a, 4] (R *, R *)]] - 2- (2-amino-1-methylpropyl) -4- [4- [4- [4 - [[2- (2,4-d.fluorophenyl) -2- (1 t7-1, 2,4-triazol-1-ylmethyl) -1, 3-d-oxolane-4 -yl] methoxy] phenyl] -1- __ w_. piperazinyl] phenyl] -2,4-dihydro-3H-1, 2,4-triazol-3-one (0.00436 moles) in CH2Cl2 (100 ml). A mixture of NaHCO 3 (1 g) in water (50 ml) was added. The mixture was stirred at room temperature for 4 hours. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and dried to give 2.8 g (84% of [2S- [2a, 4a (R *, R *)]] - 2-chloro - / .- [2- [4- [4- [ 4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolane-4-yl] methoxy] phenyl ] -1-peperazinyl] -phepil] -4,5-dihydro-5-oxo-1 H-1, 2,4-triazol-1 -yl] -1-methylpropyl-acetamide (compound 33, mp 126.8 ° C).

EXAMPLE B4 a) A mixture of compound (37) (0.0043 mol) and (S) -phenyl oxirane (0.005 mol) in 2-propanol (50 ml) was stirred and refluxed overnight. S-phenyl oxirane (0.005 moles) was added again. The mixture was stirred and maintained at reflux for 3 hours. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 99/1). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 1.6 g (47%) of [2S- [2a, 4a (S *, R *) (R *)]]] - 4- [4- [4 - [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] - 1-piperazinyl] phenyl] -2,4-dihydro-2- [2 - [(2-hydroxy-2-phenylethyl) amino] -1-methylpropyl] -3H-1, 2,4-triazol-3-one (compound 81). b) A mixture of (R) -phenyl oxirane (0.016 mol) in ethanol (50 ml) was stirred. Diethylamine was bubbled through the mixture for 2 hours. The solvent was evaporated. The residue was dissolved in a mixture of triethylamine (0.08 mol) in diethyl ether (30 ml). The mixture was stirred on ice. Methanesulfonyl chloride (0.015 mol) was added dropwise. The mixture was stirred at room temperature for 30 min. Compound 37 (0.0027 mol) was dissolved in DMF (20 ml) and H20 (4 ml) and then added to the reaction mixture. The mixture was stirred overnight, poured into H20 and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH30H / NH3) 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and ethyl acetate, separated by filtration and dried to give 1.1 g (45.8%) of [2S- [2alpha, 4alpha [(S *, R *) (S *)]]] - 4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4- il] methoxy] phenyl] -1-piperazinyl] phenyl] -4- [2 - [[2- (dimethylamino) -1-phenylethyl] amino] -1-methylpropyl] -2,4-dihydro-3H-1 , 2,4-triazol-3-one (compound 172).

EXAMPLE B5 a) A mixture of [2S- [2a, 4a [(S *, S *)]] - 4- [4- [4- [4 - [[2- (2,4-d-fluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] pheny] -2,4-dihydro-2- [1 -methyl- [2 - [(methylsulfonyl) oxy] propyl] -3H-1, 2,4- triazol-3-one (0.0039 mol) and NaN3 (0.005 mol) in DMF (50 ml) was stirred at 85 ° C for 48 hours, poured into H20 and stirred for 30 minutes. The precipitate was separated by filtration and dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3? H 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 to give 1.1 g (41%) of [2S- [2, 4a (R *, S *)]] - 2- (2-azido). -1-methylpropyl) -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3 -dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-3 - / - 1, 2,4-triazol-3-one (compound 19). b) A mixture of (2S-c / _) - 4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazole -methyl) -1,3-d-oxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- [2 - [(methylsulfonyl) oxy] ] ethyl] -3H-1, 2,4-triazol-3-one (0.0093 moles), (-) - (S) - -methyl-benzenemethanamine (0.015 moles) and Na2C03 (0.02 moles) in 1-methyl-2 pyrrolidinone (50 ml) was stirred for 5 hours at 100 ° C and then cooled. Water was added. 2-propanol was added. The mixture was allowed to crystallize. The precipitate was separated by filtration, washed with water and dried. The residue was purified on silica gel on a glass filter (eluent: CH 2 Cl 2 / CH 3 OH (1) 99/1, (2) 98/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and dried to give 4.6 g (64%) of [2S- [2a, 4a [(R *)]] - 4- [4- [4- [4 - [[2- (2, 4-d-fluorophenyl) -2- (1 tf-1, 2,4-triazol-1-ylmethyl) -1, 3- dioxolan-4-yl] methoxy] phenyl]] - 1-piperazinyl] phenyl] -2,4-dihydro-2- [2 - [(1-phenylethyl) amino] etl] -3H-1, 2 , 4-triazol-3-one (compound 115; mp 110.2 ° C). c) A mixture of (2S-cis) -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) ) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- [1-methyl-2 - [(methylsulfonyl) oxy] ethyl] -3H- 1, 2,4-triazol-3-one (0.0016 mol) in (+) - (R) -a-methylbenzenemethanamine (20 ml) was stirred at 140 ° C for 4 hours in an autoclave, then cooled and purified on gel of silica in a glass filter (eluent: CH2CI2 100%).). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with DIPE and 2-propanol. The precipitate was separated by filtration and dried to give 0.52 g (42%) of [2S- [2, 4a [R * (S *)]]] + [2S- [2a, 4a (S *)]]] - 4- [4- [4- [4 - [[2- (2,4-d.fluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4 -yl] methoxy] phenyl] -1-p¡perazinyl] phenyl] -2,4-dihydro-2- [2 - [(1-phenylethyl) amino] -1-methylethyl] -3H-1, 2, 4-triazol-3-one (compound 118: mp 114.9 ° C). d) A mixture of (2S-cis) -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) ) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- [1-methyl-2 - [(methylsulfonyl) oxy] ethyl] -3H- 1, 2,4-triazol-3-one (0.00093 mol) and (-) - (S) -methylbenzenemetnamine (0.0099 mol) in 1,3-dimethyl-2-imidazolidinone (20 ml) was stirred at 140 °. C under N2 flow for 6 hours, then cooled and poured into ice water. The precipitate was separated by filtration and recrystallized with DIPE and 2-propanol. The precipitate was separated by filtration and dried, 0.31 g (43%) of [2S- [2a, 4a [R * (R *)]]] + [2S- [2a, 4cc [S * (R *)]] ] -4- [4- [4- [4 - [[2- (2,4-d.fluorophenyl) -2- (1 H-1, 2,4-triazoM -ylmethyl) - 1,3-dioxolan-4-yl] methoxy] phenyl] -1-p-piperazinyl] phenyl] -2,4-dihydro-2- [2 - [(1-phenylethyl) amino] -1-methylethyl] -3H-1, 2,4-triazol-3-one (compound 119).

EXAMPLE B6 a) A mixture of [2S- [2a, 4a (R *, S *)]] + [2S- [2a, 4a (S *, R *)]] - 4- [4- [4- [4- [[2- (2,4-d.fluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl ] phenyl] -2,4-dihydro-2- [2 - [[1-phenylmethyl) -4-piperidinyl] amino] -1-methylpropyl] -3H-1, 2,4-triazole-3- One (0.0046 moles) in methanol (100 ml) was hydrogenated at room temperature for 72 hours with Pd on 10% activated carbon (2 g) as a catalyst. After uptake of H2, the catalyst was separated by filtration and the filtrate was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH2Cl2 / (CH30H / NH3) 95/5 to 90/10).). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 3 g (84%) of diisopropyl ether (1: 1) of [2S- [2a, 4a (R * S *)]] - 4- [4- [ 4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy ] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- [2- (4-piperidinylamino) -1-methylpropyl] -3H-1, 2,4-triazol-3-one (compound 63). b) A mixture of [2S- [2a, 4a (R * S *]] + [2S- [2a, 4 (S *, R *)]] - 4- [4- [4- [4 - [[ 2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-d-oxolan-4-yl] methoxy] phenyl] -1-plperazinyl] phenyl ] -2,4-Dihydro-2- [2 - [[1- (phenylmethyl) -4-piperidinyl] amino] -1-methylpropyl] -3 - / - 1, 2,4-triazole-3-one (0.006 moles) in THF (250 ml) was hydrogenated for 3 days with Pd on 10% activated carbon (2 g) as a catalyst. Then paraformaldehyde (0.006 mole) and a 4% thiophene solution (2 ml) were added. Hydrogenation proceeded at 50 ° C. After uptake of H2, the mixture was cooled. The catalyst was separated by filtration and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / (CH30H / NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and dried to give 3.2 g (68%) of [2S- [2a, 4a (R *, S *]] + [2S- [2a, 4a (S *, R *)]] - 4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl ] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-d? hydro-2- [2 - [(1-methy1-4-piperidinyl] amino] -1-methylpropyl] -3H- 1, 2,4-triazol-3-one (compound 64).

EXAMPLE B7 A mixture of [2S- [2a, 4a [(R *, R *) (R *)]]] - [2 - [[2- [4- [4- [4- [4 - [[2- ( 2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-p-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1H-1, 2,4-triazol-1-yl] -1-methylpropyl] amino] -2-oxo-1- (phenylmethyl) ethyl] carbamate of 1,1-d-methylethyl (0.0058 mol) in HCl / 2-propanol 6 N (20 ml) and methanol (80 ml) was stirred at room temperature overnight. After evaporation, the residue was triturated in CH 3 CN, separated by filtration and dried. The residue was taken up in toluene (200 ml). The mixture was stirred and refluxed for 8 hours using a water separator and then cooled. The precipitate was separated by filtration, washed with toluene, ground in a mortar and dried. This fraction was taken up in toluene (200 ml). The mixture was stirred and maintained at reflux using a water separator. H20 (20 ml) was added slowly by dropwise. Once all the H20 was removed, the mixture was cooled and stirred. The precipitate was separated by filtration, ground in a mortar and dried. This fraction was converted to the free base with a solution of NaHCO 3 and CH 2 Cl 2 and then purified on silica gel on a glass filter (eluent: CH 2 Cl 2 / CH 3 D 96/4 H). The pure fractions were collected and the solvent was evaporated. The residue was dried dissolved in CH 2 Cl 2 and converted to the hydrochloric acid salt (1: 1) with HCl / 2-propanol. The solvent was evaporated. The residue was recrystallized with 2-propanol. The precipitate was separated by filtration and dried. This fraction was dissolved in CH 2 Cl 2 and converted to the hydrochloric acid salt (1: 1) with HCl / 2-propanol. The solvent was evaporated. The residue was boiled in 2-propanol. The mixture was cooled. The precipitate was separated by filtration and dried to give 2.44 g (48%) of [2S- [2, 4 [(R * R *) (R *)]]] - - amino -? / - [2- [4 - [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4- il] methoxy] phenyl] -1-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1 H-1, 2,4-triazol-1-yl] -1-methylpropyljbenzenepropanamide, monohydrochloride (compound 134 ).

EXAMPLE B8 A mixture of [2S- [2a, 4 [A (R *)]]] - 4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H- 1, 2,4-triazol-1-yl-methyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- [2 - [( 2-hydroxy-1-phenylethyl) amino] -1-methylpropyl] -3H-1, 2,4-trilazol-3-one (0.0052 mol) in THF (100 ml). NaH 60% (0.01 mol) was added. The mixture was stirred for 15 minutes. Iodomethane (0.01 mol) was added. The mixture was stirred for 1 hour. NaH was added back to 60% (0.01 moles). The mixture was stirred at room temperature overnight, then poured into H20 and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified on silica gel on a glass filter (eluent: CH 2 Cl 2 / CH OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and dried to give 3.4 g (79%) of [2S- [2a, 4a [A (R *)]]] - 4- [4- [4- [4 - [[2- ( 2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-yl-methyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-p yperazinyl] phenyl ] -2,4-dihydro-2- [2 - [(2-methoxy-1-phenylethyl) amino] -1-methylpropyl] -3a-1, 2,4-triazol-3-one (compound 113).

EXAMPLE B9 A mixture of [2S- [2, 4a (R * R *)]] - 2-chloro -? / - [2- [4- [4- [4- [4 - [[2- (2,4- difluorophenyl) -2- (1W-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolane-4-yl] methoxyjiphenyl] -1- pperazinyl] phenyl] -4,5-dihydro-5-oxo-1 H-1, 2,4-triazol-1-yl] -1-methylpropyl] acetamide (0.004 mol) in? / - ethylethanamine ( 4 ml) and DMF (50 ml) was stirred at room temperature for 2 hours. H20 and NaHCO3 were added. The precipitate was separated by filtration, washed with H20 and dried. The residue was purified on silica gel on a glass filter (eluent: CH2Cl2 / CH3? H 98/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with 2-propanol. The precipitate was separated by filtration and dried to give 2.56 g (80%) of [2S- [2a, 4a (R *, R *)]] 2-diethylamino -? / - [2- [4- [4- [ 4- [4 - [[2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1 H-1, 2,4-triazol-1-yl] -1-methylpropyl] acetamido (compound 36, mp 196.6 ° C).

EXAMPLE B10 A mixture of compound 37 (0.0029 moles) and benzaldehyde (0.0029 mol) in methanol (250 ml) was hydrogenated at 50 ° C with palladium on 10% activated charcoal (2 g) as a catalyst in the presence of a thiophene solution (2 ml). After uptake of hydrogen, the catalyst was separated by filtration and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 0 H 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 to give 1.1 g (48%) of [2S- [2a, 4a (S *, R *)]] - 4- [4- [ 4- [4 - [[2- (2,4-difluorophenyl) -2- (1 H-1, 2.4- triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-2- [2 - [(phenylmethyl) amino] -1 -meti-propyl] -3H-1, 2,4-triazol-3-one (compound 106, mp 154.3 ° C).

EXAMPLE B11 a) A mixture of benzaldehyde (0.0094 mol) and trimethylsilanecarbonitrile (0.01 mol) in CH2Cl2 (50 ml) was stirred for 20 minutes. Compound 37 (0.0022 moles) was added. The mixture was stirred overnight. The solvent was evaporated, to give 2 g of [2S- [2, 4 (S *, R *)] ja - [[2- [4- [4- [4- [4 - [[2- (2, 4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -4, 5-dihydro-5-oxo-1H-1, 2,4-triazol-1-yl] -1-methylpropyljaminoj-benzeneacetonitrile (compound 122). b) Methanol (100 ml) was saturated with HCl. Compound 122 (0.0025 moles) was added. The mixture was stirred for 2 hours while HCl was bubbled through it, then it was poured into a Na2C03 solution and extracted with CH2CI2. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2CI_ / CH3OH 98/2). The fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 0.5 g of [2S- [2, 4a (S *, R *)]] - a - [[2- [4- [4- [4- [ 4 - [[2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-tr! Azo! -1 - ilmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -4,5-dihydro-5-oxy-1 H-1, 2,4-triazol-1-yl ] -1-methylpropyl] amino] -benzeneacetamide (compound 123). c) A mixture of compound 122 (0.003 mol) in CH3OH / NH3 (200 ml) was hydrogenated overnight with Raney nickel (1 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was removed by filtration and the filtrate evaporated. The residue was triturated in DIPE and 2-propanol, separated by filtration and dried. The residue was purified by HPLC (eluent: (0.5% ammonium acetate in H20 / CH3CN 90/10) / CH3CN 90/10 at 0/100, column: HYPERPREP C18 BDS 8 μm). Two pure fractions were collected and their solvents were evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 0.45 g of [2S- [2a, 4a (S *, R *) (A)]]] - 2- [2 - [(2-amino-1 phenylethyl) amino] -1-methylpropyl] -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1 / - / - 1, 2,4-triazole- 1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-3H-1, 2,4-triazol-3-one (18.7% ) (compound 174) and 0.37 g of [2S- [2a, 4a (S *, R *) (B)]]] - 2- [2 - [(2-amino-1-phenylethyl) amino] - 1-methylpropyl] -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3 -dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-3H-1, 2,4-triazol-3-one (15.4%) (compound 178). d) Methanol (150 ml) was saturated with HCl on ice. Compound 122 (0.0025 moles) was added. The mixture was stirred and refluxed for 6 hours while HCl was bubbled through it, then cooled and stirred at room temperature over the weekend. The solvent was partially evaporated. The concentrate was poured in a Na2C03 solution and extracted with CH2Cl2. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 98/2). The pure fractions were collected and the solvent was evaporated to give 1 g (60%) of [2S- [2a, 4 (S *, R *)]] -? / - [2- [4- [4- [4 - [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1H-1, 2,4-triazol-1-yl] -1-methylpropyl] -2-phenylglycine (compound 170).

EXAMPLE B12 A mixture of 4- (2-chloroethyl) morpholine hydrochloride (1.9 g), c / s-4- [4- [4- [4- [2- (2,4-dichlorophenyl) -2- (1 H-lmidazolyl) -1-ylmethyl) -1,3-dioxolan-4-? L-methoxy] phenyl] -1-piperazinyl] phenyl] -2,4-dihydro-5-methyl-3H-1, 2,4-triazole-3 -one (5 g), potassium hydroxide (2 g) in dimethyl sulfoxide (100 ml) was stirred for 24 hours at room temperature. The reaction mixture was poured into water and then extracted with dichloromethane. The organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCls / methanol 99/1). The pure fractions were collected and the eluent was evaporated. The residue was crystallized with 4-methyl-2-pentanone, to give 1.4 g (24%) of c / s-4- [4- [4- [4 - [[2- (2,4-dichlorophenyl) -2 - (1 / - / - imidazolyl-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1- piperazinyl] phenyl] -2,4-dihydro-5-methyl- [2- (4-morpholinyl) ethyl] -3H-1, 2,4-triazol-3-one (compound 1; mp 157.6 ° C) .

EXAMPLE B13 Intermediate 110 (0.0037 mol) in DMF (50 ml) was stirred under N2 flow. 60% NaH (0.004 moles) was added. The mixture was stirred at 50 ° C for 1 hour. (-) - (2S-c / s) -2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3 (methanesulfonate) was added. -dioxolan-4-methanol (0.0045 moles). The mixture was stirred at 80 ° C for 5 hours and then cooled. H20 was added. The mixture was allowed to crystallize. The precipitate was separated by filtration and dried. The residue was purified over silica gel on a glass filter (eluent 1: CH2Cl2 / CH OH / ethylacetate / hexane 49/1/30/20 and n-eluent 2: CH2CI / CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with ethanol. The precipitate was separated by filtration and dried to give 1.73 g (57%) of [2S- [2a, 4a [A (R ")]]] -? / - [2- [4- [4- [4- [ 4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazole-1-methylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] - 1-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1 H-1, 2,4-triazol-1-yl] -1-methylpropyl-jvaline (compound 154).

EXAMPLE B14 A mixture of compound 37 (0.0044 mol) and ester 1, 1-dimethylethyl [(1S) -1-Fortnil-2-fenilet¡l] -carbám¡co (0.0044 mol) in CH2CI2 (50 ml) was stirred at room temperature. Sodium tris (acetate-O) borohydrate (I-) (0.007 mol) was added. The mixture was stirred for 2 hours. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH 99/1 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 3.2 g (79%) of [2S- [2, 4 [(S *, R *)]]] - [[[2- [4- [4 - [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] fenilj-1-piperazinyl] phenyl] -4,5-dihydro-5-oxo-1 - / - 1, 2,4-triazol-1-yl] -1-methylpropyl] amino] methyl] (phenylmethyl) carbamate 1 , 1-dimethylethyl (compound 141).

EXAMPLE B15 a) A mixture of c / s- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-d¡oxolan-4-¡l] methoxy] phenyl] -1-piperazin¡l] phenyl] carbamate (0.005 moles) prepared according to the procedure described in EP-a-0,228,125 and (S) -1, 2-dimethyl-? - (1-phenylethyl) ethanediamine (0.005 mol) in dioxane (50 ml) was stirred for 3 hours. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was crystallized with diethyl ether. The precipitate was filtered off and dried to give 1.8 g (41%) of [2S- [2a, 4 [2 (1 R *)]]] -? / - [4- [4- [4- [ [2- (2,4-difluorophenyl) -2- (1 H-1, 2,4-triazaol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenol] -1-piperazinyl ] phenyl] -? / '- [1-methyl-2 - [(1-phenylethyl) amino] propyl] urea monohydrate (compound 197). b) Trifluoroacetic acid (15 ml) was added dropwise to a stirred mixture of intermediate 133 (0.0025 mol) in CH 2 Cl 2 (150 ml). The mixture was stirred for 4 hours, was poured into H20 and neutralized with Na2CO3. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl_ / CH 3 OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, separated by filtration and dried to give 1.42 g (74.7%) of (2S-cis) -? / - [4- [4- [4 - [[2- (2, 4-D-fluoro-phenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazyl] phenyl] -? / - methyl -? / '- [1-methyl-2 - [(phenylmethyl) amino] propyl] urea (compound 198).

EXAMPLE B16 A mixture of compound 204 (0.0014 mol) and acetophenone (0.042 mol) in toluene (100 ml) was hydrogenated at 150 ° C for 16 hours with 10% Pd / C (1 g) as catalyst in the presence of 1 - butanediol (1 ml, 4% solution in DIPE). After uptake of H 2 (1 equivalent), the catalyst was removed by filtration and the filtrate evaporated. The residue was triturated in DIPE, separated by filtration and recrystallized with 2-propanol. The precipitate was filtered off and dried to give 0.51 g (46%) of (2S-c / s) -4- [4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl) phenyl] -2,4-dihydro-2- [1 - (1-phenylethyl) -4-piperidinyl-3 / -1-, 2,4-triazol-3-one (compound 199).

EXAMPLE B17 A mixture of compound 195 (0.0013 mol) in THF (100 ml) was hydrogenated at 125 ° C (100 atm.) For 16 hours with 5% Pd / C (0.5 g) as a catalyst. After uptake of H 2 (1 equivalent), the catalyst was removed by filtration and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, separated by filtration and dried to give 0.28 g (28%) of (2S-c / s) -1- [4- [4- [4 - [[2- (2,4-difluorophenyl) ) -2- (1 H-1, 2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl) phenyl] -4- [2- [(phenylmethyl) amino] -1-methylethyl] -2-imidazolidinone (compound 196). Tables 2 to 8 list compounds of the formula (I) which illustrate the present invention and are prepared according to one of the examples shown.

TABLE 2 TABLE 3 TABLE 4 TABLE 5 fifteen twenty TABLE 6 TABLE 7 TABLE 8 TABLE 9 TABLE 10 TABLE 11 C. Pharmacological examples EXAMPLE C1 A panel of 8 Candida spp isolates (panel 1) was analyzed. The panel included a strain of C. albicans resistant to azoles. A panel of 6 more fungi (panel 2) composed of 3 isolated dermatoflts and simple isolates of Aspergillus fumigatus, Cryptococcus neoformans and Sporothrix schenckii. To screen these two panels, a series of solutions of the test compounds in dimethylsulfoxide (DIVISO) was prepared. The DMSO solutions were then diluted 100-fold in CYG broth (Odds, FC, Antimicrobial Agents and Chemotherapy, 1992, 36, 1727-1737) and inoculated with yeast cells at an initial concentration of 104 / ml and with other fungi a an equivalent concentration determined by turbidimetry. 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. The development in the receptacles containing the test compounds were estimated turbidimetrically in terms of percent growth in the controls without test compound and the lowest concentration of the test compound that inhibited the development of an isolate below 35% was recorded. of control development as the lowest active dose (LAD).

Compounds Nos. 1 to 4, 6 to 19, 21 to 29, 31, 34, 35, 40, 41, 43 to 47, 49, 50, 52 to 62, 64, 66, 68, 71 to 79, 81 a 86, 93 to 98, 100 to 109, 114 to 121, 130 to 132, 134 to 153, 155 to 190, 197 and 198 had a geometric mean of the minimum inhibitory concentration (MIC) value that ranged between 0.01 and 1.0 μM pair the Candida spp. The other compounds were not analyzed or had a MIC of more than 1 μM. Compounds Nos. 1 to 4, 6 to 31, 34, 35, 40, 41, 43 to 50, 52 to 62, 64 to 69, 71 to 86, 91 to 98, 100 to 123, 130, 132, 134 to 139, 142 to 156, 158, 160 to 178, 180 to 182, 184 to 190 and 198 had a MIC in the order of 0.01 to 1.0 μM for the other fungi. The other compounds were not analyzed or had a MIC of more than 1 μM.

EXAMPLE C2 A panel of 24 Candida isolates was used, 8 isolates from Aspergillus spp. 8 dermatophytes, 10 Zygomycetes, 10 Fusarium spp., 2 Cryptococcus neoformans and 8 dematiáceos hyphomycetes. The inocula were prepared as in Example C1, except that the culture medium used in this test was RPMI 1640 with MOPS buffer, with 2% glucose (Odds, FC, Antimicrobial Agents and Chemotherapy, 1995, 39, 2051 -2060). 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 incubation times and temperatures were the same as in Example C1. Once the microdilution plates were read spectrophotometrically to determine development turbidity, samples of the material from the test cultures were removed to inoculate 10μl volumes on Sabouraud glucose agar plates. The plates were incubated at 37 ° C for 48 hours in the case of the yeasts and with other times and temperatures for other species. The geometric mean of the minimum fungicidal concentrations in μM determined at the lowest concentrations of the test compound that will completely or substantially eliminate the reappearance of fungal growth in the Sabouraud plates for Candida spp. ranged from 1 to 10 μM for compounds Nos. 5, 8 to 10, 14 to 18, 20 to 22, 38 to 52, 54, 55, 59 to 63, 65, 66, 68, 71 to 86, 91 to 120 , 123, 138 to 143, 145 to 148, 150 to 154, 163 to 165, 167 to 178, 185 to 189, 191, 193, 194, 197, 199 and 203; for Aspergillus spp. it ranged from 0.1 to 10 μM for compounds Nos. 5, 8 to 10, 14 to 18, 20 to 22, 38 to 52, 54 to 56, 59 to 86, 91 to 120, 123, 138 to 143, 145 to 148, 150 to 153, 163 to 165, 167 to 178, 185 to 189, 191, 193, 194, 199 and 203; for Dermatophytes, ranged between 0.1 and 10 μM for compounds Nos. 5, 8 to 10, 14 to 18, 20 to 22, 41, 43 to 47, 49, 50, 52, 54 to 56, 59 to 62, 66 , 68, 71 to 83, 85, 86, 92 to 120, 123, 138 to 143, 145, 163 to 165, 167 to 174, 185 to 188, 193 and 199; for Zygomycetes, ranged between 0.1 and 10 μM for compounds Nos. 43, 51, 74, 77, 79, 83, 86, 93, 95, 96, 98, 100 to 102, 107, 108, 120, 138, 143, 146, 163 to 165, 170, 171, 175, 176, 185 to 187, 193, 194 and 203; for Fusarium spp., ranged between 0.1 and 10 μM for the 5 compounds Nos. 43 to 46, 54, 60, 61, 73, 74, 77, 79, 83, 86, 100 to 107, 109, 116, 117, 120 , 138, 143, 145, 146, 148, 151, 163, 165, 168, 175 to 177, 186 to 188, 193, 194, 199 and 203; and for other fungi, ranged between 0.1 and 10 μM for compounds Nos. 5, 8 to 10, 14 to 18, 20 to 22, 38 to 52, 54 to 56, 59 to 86, 91 to 93, 95 to 120, 10 123, 138 to 143, 145 to 148, 150 to 153, 163 to 165, 167 to 178, 185 to 189, 191, 193, 194, 197, 199 and 203. The numbers of compounds not mentioned were not analyzed or had a geometric mean of minimum fungicidal concentrations of more than 10 μM. 15 D. Physico-chemical example 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. Compounds Nos. 9, 10, 15 to 18, 21, 38, 39, 42, 49, 51, 52, 55, 61, 63, 65, 68, 70, 71, 73, 74, 81 to 86, 93, 100 to 102, 106, 107, 109, 114, 115, 139, 140, 142, 143, 147, 149 to 152, 155 to 159, 172, 174 to 179, 181 to 184, 187, 189 to 191, 193, 194, 197, 198, 200, 201 and 203 demonstrated a solubility of more than 0.1 mg / ml. The other compounds were not analyzed or exhibited a solubility less than 0.01 mg / ml.

E. Example of composition 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, amount necessary until obtaining 1 I, to give a solution with a content of 4 mg / ml of the active ingredient. The solution was sterilized by filtration and packaged in sterile containers.

EXAMPLE E.2 Transunqueal composition 0.144 g of KH2P04, 9 g of NaCl, 0.528 g of Na2HP0 were added. 2H20 to 800 ml of H20 and the mixture was stirred. The pH was adjusted to 7.4 with NaOH and 500 mg of NaN3 was added. Ethanol (42% v / v) was added and the pH was adjusted to 2.3 with HCL. 15 mg of the active ingredient was added to 2.25 ml of PBS / Ethanol (42%, pH 2.3) and the mixture was stirred, which was treated with ultrasound. 0.25 ml of PBS / Ethanol (42%, pH 2.3) was added and the mixture was continued stirring and treating with ultrasound until the total active ingredient was dissolved, to give the desired transungual composition.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula a form of? / -oxide, a pharmaccally acceptable addition salt or a sterechemically isomeric form thereof, wherein L represents a radical of the formula R2 R2 O ll. -Alk- N- R (a); - Alk- N- C- R1 (b); R2 0 R2 and R2 1 11 Alk- N-C-O-R1 -N i-C ?? - N i (c); - Alk - R1 (d); wherein each Alk independently represents Ci-β alkanediyl optionally substituted with hydroxy or C1-4 alkyloxy; each n is independently 1, 2 or 3; Y represents O, S or NR2; each R1 represents independently hydrogen, anole, Het 1 or C 1-6 alkyl optionally substituted with one, two or three substituents each of which is independently selected from halo, hydroxy, mercapto, C 1-4 alkyloxy, C 1-4 alkylthio, aploxy, apthio, aplalkyloxy Ci ^, arylalkylthio C? _, Cyano, ammo, mono-di? (Alkyl C? _t) -am? No, mono-di? (Ar? L) am? No, mono- or di (arylalkyl Ci) -) ammonium, C1.4alkyloxycarbonylamino, benzyloxycarbonylamino, aminocarbonyl, carboxyl, alkyloxycarbonyl CM, guanidinyl, anole or Het2, each R2 independently represents hydrogen or C1 6alkyl, or in the case where R1 and R2 are attached to the same atom of nitrogen can be taken together to form a heterocyclic radical selected from morpholinyl, pyrro-dynyl, pipendinyl, homopipepdynyl or piperazinyl, said heterocyclic radical can optionally be substituted with C 1-4 -alkyl, -anol, Het 2, C1-C1-alkyl, Het2-alkyl C1 .4, C1-4 hydroxyalkyl, amino, mono-od? (C1-4 alkyl) ammon, am Ci ^ inoalquilo, mono- or d? (alk? l C? _t) am? noalqu? I C1.4, carboxyl, aminocarbonyl, C ^, C1.4 alkyloxycarbonylamino or mono- or d? (alk? l C1 4) am? nocarbon? it, or can be taken together to form an azido radical, each R3 independently represents hydrogen, hydroxy or alkyloxy C1 4, aplo represents phenyl, naphthalenyl, 1, 2,3,4-Tetrah? dro-naphthalen? I, Indenyl or indanyl, each of said aplo groups may be optionally substituted with one or more substituents selected from halo, C1.4alkyl, hydroxy, C1-4alkyloxy, nitro, amino, trifluoromethyl, hydroxyalkylC? _ ?, alkylox ? C? _talqu? I C? _4, aminoalkyl C1 4 mono- or d? (alk? l C? _t) am? noalqu? I C1.4, Het1 is a heterocyclic radical or bicycles co monocíchco, radical monochrome heterocyclic which is selected from the group consisting of pipdinyl, pipepdmilo, homopipepdinil, pyrazinyl, pinmidinyl, pindazinyl, tpazmyl, tpazo lo, pyranyl, tetrahydropyranyl, imidazolyl, imidazolinyl, imidazo-dynil, pyrazolyl, pyrazolinyl, pyrazolidin, thiazole, thiazolidinyl , isothiazolyl, oxazole, oxazo-dynyl, isoxazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, said heterocyclic bicyclic radical can be selected from the group consisting of quinolinyl, 1, 2,3,4- tetrahydroquinone, isoquinolinyl, qumoxalmyl, quinazolinyl, phthalazimyl, cinolinyl, chromanyl, thiochromanyl, 2H-chromenyl, 1,4-benzodioxanyl, indole, isomdole, indolinyl, indazole, punnyl, pyrrolopindinyl, furanopipdinyl, thienopindinyl, benzothiazole, benzoxazole, benzisothiazole, benzisoxazole, benzimidazolyl, benzofuranyl, benzothienyl, whereby each of said mono- or bicyclic heterocycles icos may optionally be substituted with one or, as far as possible, more substituents selected from the group consisting of halo, alkylCal, hydroxy, C? _4alkyloxy, nitro, amino, tnfluoromethyl, hydroxyalkyl C? ^ "alkyloxyCi 4alkyl C1 4, ammoalkyl C? _ ?, mono-od? (Alk? C? _?) Am? Noalk? Ci 4, anlo or aplalkyl CiJt, Het2 is equal to Het1 and can also be a monocyclic heterocycle selected from a group consisting of piperazinyl, homopiperazinyl, 1,4-d-oxanol, morpholinyl, thiomorpholinyl, whereby each of said monocyclic heterocycles can be optionally substituted with one or, where possible, more substituents selected from the group consists of halo, C1.4 alkyl, hydroxy, C1.4 alkyloxy, nitro, amino, trifluoromethyl, C 1-4 hydroxyalkyl, C 1-4 alkyloxy C 1-4 alkyl, C 1-4 aminoalkyl, mono- or di (C 1-4 alkyl, aryl or arylC 1-4 alkyl, R 6 represents hydrogen or C alkyl, R 7 represents hydrogen, alkyl, or R 6 and R7 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), wherein a hydrogen atom of the radicals (i) and (ii) can be replaced with a C1.4 alkyl radical, and one or more hydrogen atoms of the radicals (iii) and (iv) can be replaced with a C 1-4 alkyl radical, D represents a radical of the formula wherein X is N or CH; R is hydrogen or halo; R is halo.

2. The compound according to claim 1 wherein D is a radical of the formula Di.

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

4. The compound according to claims 1 to 3 wherein Alk is 1,2-ethanediyl, 1-2-propanediyl, 2,3-propanediol, 1,2- ________________ • butanediyl, 3,4-butanediyl, 2,3-butanediyl, 2,3-pentanediyl or 3,4-pentanediyl.

5. The compound according to claims 1 to 4 wherein R1 represents hydrogen, aryl, Het1 or Ci_alkyl, optionally substituted with one, two or three substituents, each of which is selected from halo, hydroxy, C 1-4 alkyloxy, aryloxyl, aryl C 1-4 alkyloxy, cyano, amino, mono- or di (C 1-4 alkyl), amino, mono- or di (arylalkyl C? .4) amino, C 1-4 alkyloxycarbonylamino, aminocarbonyl, aryl or Het2; R 2 represents hydrogen or C 1-6 alkyl; 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 may optionally be substituted with C 1 -4 alkyl, arylalkyl, hydroxyalkyl C 1 _t, amino, mono- or di (alkyl enamino, mono- a di (C 1 .4 alkylamino) C 1-4 alkyl, or C1.4alkyloxycarbonylamino, or R1 and R2 can also be taken together to form an azido radical

6. The compound according to claims 1 to 5 wherein L is a radical of the formula - Alk-N-CH-Z2 (a-1) - Alk-N Z3 (a-2) H | _ / Zl in which Alk is defined as in claim 1; Z1 is aryl, arylmethyl, arylethyl, Het1 or C? _t alkyl; Z2 is hydrogen, carboxyl, C1.4 alkyloxycarbonyl, aminocarbonyl or methyl optionally substituted with hydroxy, methoxy, amino or mono-od? (met? l) am? no, or Z1 and Z2 together with the carbon atom to which they are attached form a pipepdmyl ring substituted with aplmethyl, anlethyl or C? _t alkyl, Z3 is O, N-alkyl Ci 4, or N-aplo 7 - A compound according to claim 1 in which the compound is 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) - 2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? l] phen? l] -2,4-d? h? dro-2- [2 - [(1-phen? let? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tr? Azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2.4 -tpazol-1 -? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n] l] phen? l] -2.4 -d? h? dro-2- [2 - [(2-phen? let? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3 ona, 4- [4- [4- [4 - [[2- (2,4-d? fluorophen? l) -2- (1H-1, 2,4-tr? azol-1-? lmet? l ) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2- (4-phenol-1-p? Peraz? N? L) -1-met? Lprop? L] -3H-1, 2,4-tr? Azol-3-one, 4- [4 - [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3 -d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n ? l] phen? l] -2,4-d? h? dro-2- [2 - [(3-phen? lprop? l) am? no] -1-met? lprop? l] -3H-1 , 2,4-tr? Azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2, 4-tr? Azole-1-α-lime? -1) -1,3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] - 2- [2 - [[(2-fluorophen? L) met? L] am? No] -1-met? Lprop? L] -2,4-d? H? Dro-3H-1, 2,4- tr? azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? fluorophen? l) -2- (1 / - / - 1, 2,4-tr Azole-1-? lmet? l) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n] l] phen? l] -2.4 -d? h? dro-2- [2 - [(fen? lmet? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2- [ [(2-methox? Phen?) Met? L] am? No] -1-met? Lprop? L] -3H-1, 2,4-tr? Azol-3-one, 4- [4- [ 4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d ? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2,4- d? h? dro-2- [2 - [(2-phenoxy? et? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tpazol-3-one, 4 - [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2- [ (2,3-d? H? Dro-1 H-? Nden-2-? L) am? No] -1-met? Lprop? L] -3H-1, 2,4-tpazol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tr? Azol-1-? Lmet? L) - 1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N] l] phen? L] -2- [2 - [[1- (4-fluorophen? l) et? l] am? no] -1-met? lprop?] -2,4-d? h? dro-3H-1, 2,4-tpazol-3-one, 4- [4- [ 4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d ? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n] l] phen? l] -2,4-d? h? dro-2- [2 - [[1- (fen? lmet? l) -4-p? pepd? n? l] am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1 , 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N] l] phen? L] -2,4-d? H? Dro-2- [2- (4-morpholine? -1) -methylpropyl] -3H-1, 2,4-tr? Azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen ? l] -1-p? peraz? n? l] phen? l] -2,4-d? h? dro-2- [2 - [[1- (hydrox? met? l) -2- phen? let? l] am? no] -1-met? lpropyl] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2 - (2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] phen? l] -1-p? peraz? n? l] phen? l] -2,4-d? h? dro-2- [2 - [(2-h? drox? -1-phen? l- et? l) am? no] -1-met? lprop? l] -3H-1,2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- ( 2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? l] -1-p? peraz? n? l] phen? l] -2,4-d? h? dro-2- [2 - [(2-h? drox? -2-phen? let? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- (2,4- d? fluorophen?) -2- (1 H-1, 2,4-tr? azol-l?? lmet? l) -1, 3-d? oxolan-4? l] methox?] phen? ] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2 - [[1- (hydrox? Met? L) -2-met? lprop? l] am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- ( 2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] fen? l] -1-p? peraz? n? l] fen? l] -2,4-d? h? dro-2- [2 - [(1-phen? Let? L) am? No] -1-met? Lprop? L] -3H-1, 2,4-tr? Azol-3-one, 4- [4- [4 - [4 - [[2- (2,4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d? oxolan-4-? l] methox?] phen? l] -1-p? peraz? n] l] phen? l] -2,4-d? h? dro-2- [1- (1-phen? let? l) -4-p? pepd? n? l] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- (2, 4-d? Fluorophen? L) -2- (1 H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-dioxolan-4? L] methox?] Phen? L ] -1-p? Peraz? N? L] phen? L] -2,4-d? H? Dro-2- [2 - [[1- (hydrox? Met? L) -2-met? lprop? l] am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, 2- [4- [4- [4 - [[2- ( 2,4-d? Fluorophen? L) -2- (1H-1, 2,4-tpazol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? l] -1-p? peraz? n] l] phen? l] -2,4-d? h? dro-4- [2 - [(phen? lmet? l) am? no] -1-met? lprop? l] -3H-1, 2,4-tr? azol-3-one, 4- [4- [4- [4 - [[2- (2,4-d? fluorophen? l) -2- (1H-1, 2,4-tr? Azol-1-? Lmet? L) -1, 3-d? Oxolan-4-? L] methox?] Phen? L] -1-p? Peraz? N? l] phen? l] -2,4-d? h? dro-2- [4 - [(fen? lmet? l) am? no] -c? clohex? l] -3H-1, 2.4- tr? azol-3-one, the forms of / -oxide, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms of the smos 8 - The compound according to any of claims 1 to 7 which is stereoisome purely 9 - The compound according to any of claims 1 to 8 for use as a medicament 10 - The use of a compound as claimed in claims 1 to 8 for the manufacture of a medicament for treating fungal infections 11 - A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as an active ingredient an amount Therapeutically effective of a compound as defined in any of claims 1 to 8. 12.- An intermediate of the formula wherein L is as defined in claim 1 and R6 'and R7 are the same as R6 and R7 as defined in claim 1 but different from hydrogen. 13. A process for preparing a compound of the formula (I) wherein D and L are as defined in claim 1 and R6 and R7 are as defined in claim 1 but are not hydrogen, said R6 and R7 are represented by R6 and R7 and said compound is represented by the formula (I '), characterized in that a) an intermediate of formula (II) is reacted wherein W1 is a suitable leaving group, with an intermediate of formula (III) in a solvent inert to the reaction and in the presence of a suitable base; b) se? / - alkyl an intermediate of the formula (IV) with an intermediate of the formula (V) in which W2 is an appropriate leaving group and wherein the primary and secondary amines in L, if present, are protected with a protecting group P such as, for example, an alkyloxycarbonyl group Ci-4, in a solvent inert to the reaction in the presence of a base, and if L is protected , deprotection techniques known in the art could be employed; (iv) (V) c) reacting an intermediate of formula (VI) wherein W is a suitable leaving group, with an intermediate of formula (VII) or NaN3 optionally in the presence of a suitable base and optionally in a solvent inert to the reaction; thereby obtaining a compound of formula (I1) wherein L is a radical of formula (a); and, if desired, converting the compounds of the formula (I ') to each other following transformations known in the art; and further, if desired, converting the compounds of the formula (I ') to a non-toxic acid addition salt. therapeutically active by treatment with an acid, or conversely, converting the acid addition salt form to the free base by treatment with an alkali; and, if desired, preparing stereochemically isomeric forms or? / -oxide forms thereof. SUMMARY OF THE INVENTION The present invention relates to novel compounds of the formula (I) the? / -oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein L represents a radical of the formula R2 R2 or - Alk- N- R1 (a); - Alk- - C- R1 (b); R2 O R2 and R2 I II I II I -Alk- N- C- O- R1 (c); - Alk- N- C- N- R1 (d); wherein each Alk independently represents an optionally substituted C-β alkanediyl; n is 1, 2 or 3; And it is O, S or NR2; R1 represents hydrogen, anole, Het1, or an optionally substituted C6-6 alkyl; each R2 independently represents hydrogen or C? -6 alkyl; or in case R1 and R2 are attached to the same nitrogen atom can be taken together to form a heterocyclic radical; or they can be taken together to form an azido radical, each R 3 independently represents hydrogen, hydroxy or C 1 δ alkyloxy; aryl represents phenol, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl, indenyl or indanyl; each aryl group can be optionally substituted; Het1 represents an optionally substituted monocyclic or bicyclic heterocyclic radical; Het2 is equal to Het1 and may also be piperazinyl, homopiperazinyl, 1,4-dioxanyl, mofolinyl, thiomorpholinyl; R6 represents hydrogen or C ^ alkyl; R7 represents hydrogen or C1.4alkyl; or R6 and R7 together form a bivalent radical of the formula -N = CH- (i), -CH = N- (ii), -CH = CH- (ii), -CH2-CH2- (iv) where a hydrogen atom of the radicals (i) and (ii) can be replaced with a C 1-4 alkyl radical and one or more hydrogen atoms in radicals (ii) and (iv) can be replaced by an alkyl radical CM; D represents a trisubstituted 1,3-dioxolane derivative; as antifungals; its procedures for its preparation, compositions that contain them and their use as a medicine. JANSSEN / PM / kra * / avc * jtr * sff * aom * eos * yac * pbg * jtc * igp * rcp * osu * cgm * P00 / 1478F