MXPA00000362A - 6-azauracil derivatives as il-5 inhibitors - Google Patents

Abstract

The present invention is concerned with the use of compounds of formula (I):the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p represents 0, 1, 2 or 3;q represents 0, 1, 2, 3 or 4;R1 represents hydrogen, C1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, mercapto, C1-6alkylthio, C3-7cycloalkyl, aryl or C1-6alkyl substituted with mono- or di(C1-6alkyl)-amino, C1-6alkyloxy, aryl or Het;R2 represents cyano or a radical of formula -C(=X)-Y-R5;wherein X represents O or S;Y represents O, S, NR6 or a direct bond;R5 represents hydrogen;C3-7cycloalkyl;aryl or optionally substituted C1-6alkyl;and where Y is a direct bond, R5 may also be halo or Het;R3 and R4 each independently represents halo, haloC1-6alkyl, C1-6alkyl, hydroxy, C1-6alkyloxy, C1-6alkylcarbonyloxy, mercapto, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkylsulfinyl, haloC1-6alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di(C1-6alkyl)amino or (C1-6alkylcarbonyl)amino;aryl represents phenyl or substituted phenyl;and Het represents an optionally substituted heterocycle;in the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases. The invention also relates to novel compounds, their preparation and compositions comprising them.

Description

DERIVATIVES OF 6-AZAURACILO AS INHIBITORS OF IL-5 DESCRIPTIVE MEMORY The present invention relates to the use of IL-5 inhibiting 6-azauracil derivatives for the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases. It also relates to certain novel 6-azauracil derivatives, processes for their preparation and compositions comprising them. The influx of eosinophils, the cause of subsequent damage to tissues, is an important pathogenic event in bronchial asthma and allergic diseases. The interleukin-5 (L-5) cytokine, produced mainly by T-lymphocytes in the form of a glycoprotein, induces the differentiation of eosinophils in the bone marrow, primes eosinophils for their activation in the peripheral blood, and sustains its survival in the tissues. As such, IL-5 plays a critical role in the inflammation process of the sinoinfila. Therefore, the possibility that inhibitors of IL-5 production reduce the production, activation and / or survival of eosinophils, provides a therapeutic solution to the treatment of bronchial asthma and allergic diseases such as atopic dermatitis, allergic rhinitis, allergic conjunctivitis , and also other eosinophilic-dependent inflammatory diseases.

Steroids, which strongly inhibit the production of IL-5 in vitro, have been used for a long time as the only drug with remarkable efficacy for bronchial asthma and atopic dermatitis, but they cause several severe adverse reactions such as diabetes, hypertension and cataracts. Therefore, it would be desirable to find non-steroidal compounds which have the ability to inhibit the production of IL-5 in human T-cells and which have few adverse reactions, or none at all. US 4,631,278 discloses alpha-aryl-4- (4,5-dihydro-3,5-dioxo-1, 2,4-triazin-2 (3H) -yl) -benzene acetonitriles, and in US Pat. US 4,767,760 describes 2- (substituted phenyl) -1, 2,4-triazine-3,5 (2H, 4H) -diones, all of which exhibit activity against protozoa, in particular, anti-coccidial activity. Unexpectedly, it has been found that the 6-azauracil derivatives of the present invention, including said 1,4-triazinedione derivatives known in the art, are potent inhibitors of IL-5 production. The present invention relates to the use of compounds of the following formula: MJgJB? ia ^ jgi ^^ - afcA .._ tel_ ~ JSd_t_ _ .... the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: p represents an integer equal to 0, 1, 2, 3 or 4; q represents an integer equal to 0, 1, 2, 3, 4 or 5; R1 represents a hydrogen atom, C? -C6 alkyl, mono- or di (C C β alkyl) amino C C β alkyloxy, mercapto, C C β alkylthio, C 3 -C 7 cycloalkyl, aryl or CrC 6 alkyl substituted by mono- or di (C 1 -C 6 alkyl) amino, C C β alkyloxy, aryl or Het; R 2 represents cyano or a radical of formula -C (= X) -Y-R 5; where: X represents O or S; Y represents O, S, NR6 or a direct link; R5 represents a hydrogen atom; CrC6 alkyl; C3-C7 cycloalkyl; aryl or C1-C6 alkyl substituted by aryl, hydroxy or Het; and if Y is a direct link, R5 can also be halogen or Het; R6 represents a hydrogen atom, Ci-Cβ alkyl, C Cβ alkyloxy or aryl Ci-Cβ alkyl; Each of the R3 independently represents each other, halogen, halogen CrC6 alkyl, CrC6 alkyl, hydroxy, Ci-Cβ alkyloxy, C C β alkylcarbonyloxy, mercapto, Ci-Cß alkylthio, C C 6 alkylsulfonyl, Ci-C β alkylsulfinyl, halogen C C β alkylsulfonyl , aryl, cyano, nitro, amino, mono- and di (Ci-Cß alkyl) amino or (CrC6 alkylcarbonyl) amino; Each of the R4 independently represents each other, halogen, halogen CrC6 alkyl, C? -C6 alkyl, hydroxy, CrC6 alkyloxy, C C? Alkylcarbonyloxy, mercapto, CrC6 alkylthio, Ci-C? Alkylsulfonyl, Ci-C? Alkylsulfinyl, halogen C C? Alkylsulfonyl , aryl, cyano, nitro, amino, mono- and di (C Cß alkyl) amino or (C Cß alkylcarbonyl) amino; Aryl represents phenyl or phenyl substituted by one, two or three substituents selected from the group comprising: halogen, Cr C & alkyl, Ci-Cβ alkyloxy, halogen Ci-Cβ alkyl, hydroxy, mercapto, Ci-Cß-alkylthio, C C β -alkylsulfonyl, CrC 6 alkylsulfonyloxy, CrC 6 alkylsulfinyl, halogen Ci-C β alkylsulfonyl, nitro, cyano, amino, mono- and dι (C C6 alkyl) amino or (Ci-Cß alkylcarbonyl) amino; and Het represents a heterocycle selected from: pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyranyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and thiazole pyridinyl; each of these heterocycles, independently of each other, can be substituted by one, two or three substituents selected from hydroxy, mercapto, C1-C4 alkyl, C? -Calkyloxy, cyano, amino, nitro, mono- or di (C? C4 alkyl) amino, mono- or di (C? -C alkyl) amino, mono- or di (C1-C4 alkyl) amino carbonyl, mono- or di (aryl) amino, halogen, halogen C1-C4 alkyl, C1 -C4 alkyloxycarbonyl, aryl, furanyl, thienyl, pyridinyl, piperidinyl, C1-C4 alkylcarbonylpiperidinyl and C1-C4 alkyl substituted with hydroxy, C1-C4 alkyloxy, aryl, piperidinyl, amino mono- or di (C? -C4alkyl) amino or C3-C7 cycloalkyl; in the manufacture of a drug useful for treating eosinophilic-dependent inflammatory diseases. The compounds of formula (I) are considered as novel, with the proviso that a-aryl-4- (4,5-dihydro-3,5-dioxo-1, 2,4-triazin-2 (3H) -il) ) benzene acetonitriles published in US Pat. No. 4,631,278, and 2- (substituted phenyl) -1,2,4-triazine-3,5 (2H, 4H) -diones published in US 4,767,760 are excluded from the same. Therefore, the invention also relates to novel compounds of the following formula: the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p, q, R1, R2, R3 and R4 are as defined for the compounds of formula (I), with the ^^^ gSaAftfli ** ^ - ^^ condition that the following conditions apply to the variables R3a, R3b, R3c, R4a, R4b, R4c, R1 and R2, in the compounds of the following general structure: a) if R3a, R3, are chloro: R4a is 4-chloro, and R1, R3c, R4b, and R4c are nitrogen; then R2 is not aminocarbonyl, carboxyl, chlorocarbonyl, 1-piperidinylcarbonyl, methoxycarbonyl, methylaminocarbonyl, 1-pyrrolidinylcarbonyl; 4-methyl-1-piperazinylcarbonyl, methylcarbonyl; NH2-C (= S) -, phenylcarbonyl; and b) if R3a is chlorine; R 4a is 4-chloro, and R 1, R 3b, R 3c, R 4b and R 4c are nitrogen; then R3 is not aminocarbonyl, carboxyl, NH2-C (= S) -, chlorocarbonyl, methylaminocarbonyl, (4-methylcarbonyl-1-piperazinyl) carbonyl, (4-phenylmethyl-1-piperazinyl) carbonyl or methyloxycarbonyl; and c) if the combination of R1, R3a, R3b, R3c, R4a and R4c, is one of the following combinations: then R is not cyano. : -; • '. nn As used in the preceding definitions and below, halogen refers generically to fluorine, chlorine, bromine and iodine; C3-C7 cycloalkyl refers generically to propyl cyclo, butyl cyclo, pentyl cyclo, hexyl cyclo and heptyl cyclo; C1-C4 alkyl refers to straight or branched saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylethyl, 2,2-dimethylethyl and the like; Ci-Cß alkyl is intended to include C1-C4 alkyl and higher homologs thereof having 5 or 6 carbon atoms such as for example pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; Halogen C Cß alkyl is defined as CrC 6 substituted polyhalogen alkyl, in particular C C β alkyl substituted with 1 to 6 halogen atoms, more in particular, difluoro- or trifluoromethyl. Het is intended to include all of the isomeric forms of the heterocycles mentioned in the definition of Het, for example, pyrrolyl includes 2H-pyrrolyl; triazolyl includes 1,4-triazolyl and 1,4-triazolyl; Oxadiazolyl includes 1,2-oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl and 1,4-oxadiazolyl; triadiazolyl includes 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, 1, 2,5-thiadiazolyl and 1,4-thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl; thiazolopyridinyl includes thiazole [5,4-b] pyridinyl, thiazole [5,4-c] pyridinyl, thiazole [5,4-d] pyridinyl and thiazo [5,4-e] pyridinyl. The heterocycles represented by Het may be attached to the remainder of the molecule of formula (I) through any carbon ring or heteroatom, as appropriate. Therefore, for example when the heterocyclic is imidazolyl, it can be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is triazolyl, it can be 1, 2,4-triazol-1-yl, 1, 2,4-triazol-3-yl, 1, 2,4-triazol-5-yl, 1,4-triazole -1-yl and 1, 3,4-triazol-2-yl; when it is benzthiazolyl, it can be 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl; when it is thiazolopyridinyl, it can be thiazol [5,4-b] pyridin-2-yl, thiazol [5,4-b] pyridin-4-yl, thiazol [5,4-b] pyridin-5-yl, thiazole [ 5,4-b] pyridin-6-yl, thiazole [5,4-c] pyridin-2-yl, thiazole [5,4-c] pyridin-4-yl, thiazole [5,4-c] pyridine- 5-yl, thiazole [5,4-c] pyridin-7-yl, thiazole [5,4-d] pyridin-2-yl, thiazole [5,4-d] pyridin-4-yl, thiazole [5, 4-d] pyridin-6-yl, thiazole [5,4-d] pyridin-7-yl, thiazole [5,4-e] pyridin-2-yl, thiazol [5,4-e] pyridin-5-yl, thiazol [5,4-e] pyridin-6-yl and thiazole [5,4-e] ] pyridin-7-yl. The aforementioned pharmaceutically acceptable addition salts are intended to include the non-toxic therapeutically active acid addition salt forms, which the compounds of formula (I) are capable of forming. The latter can be comfortably obtained by treating the base form with suitable acids such as inorganic acids, for example hydrohalic acids, for example, hydrochloric, hydrobromic acid, and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic, propanoic, hydroxy acetic, 2-hydroxy propanoic, 2-oxo propanoic, ethane dioic, propane dioic, butane dioic, (Z) -2-buten dioic, (E) -2-buten dioic, 2-hydroxybutane dioic, 2,3-dihydroxybutane dioic, 2-hydroxy-1, 2,3-propane tricaboxylic, methane sulphonic, ethane sulphonic, benzene ____, s_} __ .. í_.i £ _,. ^, ...? ^^ __) sulfonic, 4-methylbenzenesulfonic, cyclohexane sulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic, and similar acids. Conversely, the salt form can be converted by its treatment with alkalis, in the free base form. The compounds of formula (I) having protonic acids can be converted into their non-toxic and therapeutically active metal or amine addition salt forms by their treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, the ammonium salts, the alkali and alkaline earth metal salts, for example the lithium, sodium, potassium, magnesium salts and the like, the salts with organic bases, for example salts of benzathine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1,3-propane-diol, hydrabamine, and salts with amino acids such as for example arginine, lysine and the like, Conversely, the salt form can be converted by its treatment with acid, in the free acid form. The term "addition salt" also comprises the hydrates and the solvent addition forms that the compounds of formula (I) are capable of forming. Examples of such forms are for example hydrates, alcoholates and the like. The N-oxide forms of the compounds herein are intended to include the compounds of formula (I) wherein one or more nitrogen atoms are oxidized to the so-called N-oxide.

Some of the compounds of formula (I) may also exist in their tautomeric forms. Although not explicitly indicated in the above formula, said forms are intended to be included within the scope of the present invention. The term "stereochemically isomeric forms", as used herein, defines all possible stereoisomeric forms in which the compounds of formula (I) may exist. Unless otherwise mentioned or indicated, the chemical designation of the compounds encompasses the mixture of all possible isomeric forms, containing said mixtures, all of the diastereomers and enantiomers of the basic molecular structure. More particularly, the stereogenic centers may have the R-or-S-configuration, used herein in accordance with the Chemical Astracts nomenclature. The stereochemically isomeric forms of the compounds of formula (I), are obviously intended to be included within the scope of this invention. The compounds of formula (I) and some of the intermediate compounds of the present invention contain one or more asymmetric carbon atoms. The isomeric forms pure and stereochemically Mixed compounds of the compounds of formula (I) are intended to be included within the scope of the present invention. Each time it is used in the following, the expression "compounds of formula (I), it is to be understood that it also includes its forms __s £ _s_ | of N-oxide, its pharmaceutically acceptable addition salts, and its stereochemically isomeric forms. The numbering of the phenyl ring carrying the R4 substituent is indicated below, and is used herein as such whenever the position of the substituents R4 on said phenyl ring is indicated, unless otherwise indicated.

The carbon atom carrying the two phenyl rings, and the substituents R1 and R2 will now receive the chiral central designation. A suitable subgroup is that consisting of those compounds of formula (I) or (I '), wherein Het is not pyrrolidinyl. A special group of compounds are those compounds of formula (I) or (I '), wherein R2 is a radical of formula -C (= X) -Y-R5, wherein And it's a direct link and R5 is Het. Another special group of compounds are those compounds of formula (I) or (I '), wherein R 1 is mono- or di (CrC 6 alkyl) amino C C β alkoxy, mercapto, C C β alkylthio or CrC 6 alkyl substituted by mono- or di (C? -C6alkyl) amino, C? -C6alkyloxy or Het.

An interesting group of compounds are those compounds of formula (I) or (I ') wherein the 6-azauracil moiety is connected to the phenyl ring in the the position for or meta with respect to the chiral central carbon atom particularly in the para position. Another interesting group of compounds are those compounds of formula (I) or (I '), wherein R2 is cyano. And another interesting group of compounds, are those compounds of formula (I) or (I '), wherein R 2 is radical of formula -C (= X) -Y-R 5, wherein R 5 is a hydrogen atom, C C β alkyl or aryl, where Y is oxygen, sulfur or NR6, where R6 is a hydrogen atom or CrC6 alkyloxy; or R5 is aryl, d-Cβ alkyl, halogen, Het or C Cß alkyl substituted by aryl, while Y is a direct bond. It is convenient that Het is optionally substituted piperazinyl, imidazolyl, thiazolyl or benzothiazolyl. Another interesting group of compounds are those compounds of formula (I) or (I '), wherein R is a hydrogen atom, aryl, C Cβ alkyl, mono- or di (Ci-Cß alkyl) amino Ci-Cβ alkyl or Het Ci-Cβ alkyl. Particular compounds include those compounds of formula (I) or (I '), wherein R 3 and R 4, independently of one another, are halogen, C Cβ alkyl halogen, hydroxy, Ci-Cβ alkyl, Ci-Cβ alkyloxy, CrC 6 alkylcarbonyloxy or aryl, more in particular, bromine, chlorine, fluorine, trifluoromethyl, methyl, hydroxy, methoxy, methyl carbonyloxy or phenyl. _ __J * »_____ M ____- A____ Other particular compounds are those compounds of formula (I) or (I '), where p is 0, 1 or 2, and q is 0, 1, 2 or 3; more particularly, p and q, independently of each other, are 1 or 2. Preferred compounds include those compounds of formula (I) or (I '), wherein q is 1 or 2 and a substituent of R 4, preferably selected from the group consisting of the group consisting of chlorine, fluorine, methyl, hydroxy, methoxy, methylcarbonyl oxy and phenyl is found in position 4. Other preferred compounds are those compounds of formula (I) or (I '), wherein p is 1 or 2 and the one or two substituents of R 3, preferably selected from the group consisting of bromine, chlorine, methyl, methoxy or trifluoromethyl, are in the ortho position with respect to the chiral central carbon atom. Among the most preferred compounds are those compounds of formula (I) or (I '), wherein the 6-azauracil moiety is in the para position with respect to the carbon atom of chiral symmetry; p is 1 or 2 and one of the substituents of R3 is chloro positioned ortho to the chiral central carbon atom; q is 1 or 2, and one of the substituents of R 4 is chloro in the 4-position. Particularly preferred compounds are those compounds described above as more preferred compounds in which R 2 is cyano or a radical of the formula -C (= X) -Y-R5 where Y is a direct link.

In general terms, the compounds of the present invention can be prepared as described in US-4,631, 278 and US-4,767,760. In particular, the compounds of formula (I ') can be prepared by cyclizing an intermediate compound of formula (II), and removing the E group from the thus obtained dione of formula (III): A suitable way to eliminate the group E, which is for example a carboxyl group, can be to react the compound Intermediary of formula (III) with mercaptoacetic acid or with a functional derivative thereof. The compounds of formula (I ') can also be prepared by removing the protecting group P in the intermediate compounds of formula (IV).

(IV) «» «An appropriate way to eliminate the group P, which is for example an alkyl alkyloxyalkyloxy part, it can be reacting the intermediate compound of formula (IV) with an acid, or with a mixture of acids, such as hydrochloric acid, acetic acid or a mixture thereof. Alternatively, the protecting group P can be removed by reacting an intermediate compound of formula (IV) with a suitable reagent such as, for example, boron tribromide, in a solvent inert to the reaction, such as dichloromethane. The compounds of formula (I '), when R 2 is cyano, said compounds represented by the formula (1-a), can be prepared by converting the hydroxyl function of an intermediate compound of formula (V) to a suitable leaving group W , such as for example a halogen atom or a sulfonyloxy group, said leaving group W subsequently being converted into the intermediate compound thus formed of formula (VI), in a nitrile function.

The compounds of formula (I '), wherein R 1 is a hydrogen atom and R 2 is cyano, said compounds represented by the formula (1-a-1), can be prepared by reacting the carbonyl group in the intermediate compound of formula (VII) with a suitable reagent such as for example 1 - [(isocyanomethyl) sulfonyl] -4-methylbenzene or with a functional derivative thereof.

The compounds of formula (I) can be converted to each other by following the procedures known in the art for the transformation of the functional groups described in US Pat. , 4,767,760. Following are some interesting reactions of transformation of groups, described in the present. In order to simplify the structural representation of the compounds of formula (I '), the group below will be represented by the symbol D. ? sSBk / S ^^^^, ^ n * '* iff | The compounds of formula (1-a) can be partially or completely hydrolyzed, whereby the compounds of formula (I ') are obtained. ), wherein R2 is an aminocarbonyl or carboxyl group, the former represented by the formula (l'-f), and the latter by (l'-b). The compounds of formula (1-f) can also be hydrolyzed to obtain the compounds of formula (1-b). The compounds of formula (1-a) can also be converted into compounds of formula (1-g), wherein R 2 is an aminothioxomethyl group. The acids of formula (1-b) can be converted into the corresponding acyl halides of formula (1-c). Said acyl halides of formula (I-c) can also be derived by HN (R5) (R6) obtaining the corresponding amides of formula (I-d), which in turn can be reacted with a heteroaryl ketone of formula (l'-e) using a metal alkyl such as for example butyl lithium, in a solvent inert to the reaction, such as for example tetrahydrofuran, hexane, diethyl ether, or a mixture thereof. This latter reaction can be comfortably carried out under an inert atmosphere such as for example oxygen-free nitrogen, and at a low reaction temperature, preferably at about -70 ° C. The acyl halides of formula (I-c) can also be reacted with a Grignard reagent, for example RMgX, in which X is a suitable counter-ion such as halogen, and R is C3-C7 cycloalkyl or CrC6 alkyl optionally substituted by aryl or Het, whereby the compounds of formula (l'-h) are obtained.

On the other hand, the compounds of formula (I ') can be converted into their corresponding N-oxide forms following the procedures known in the art for converting a trivalent nitrogen atom into its N-oxide form. Said N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, for example sodium peroxide, potassium peroxide; suitable organic peroxides may comprise the peroxy acids such as, for example, benzenecarbon peroxoic acid or halogeno-substituted carboperoxoic acid benzene, for example 3-chlorobenzene peroxoic acid, peroxoalkanoic acids, for example peroxoacetic acid, alkylaldehyde peroxides such as, for example, tert-butyl hydroperoxide . Suitable solvents are for example water, lower alkanols such as for example ethanol and the like, hydrocarbons such as for example toluene, ketones such as for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, and mixtures of said solvents. The pure stereochemically isomeric forms of the compounds of formula (I ') can be obtained by the application of the known procedures. Diastereomers can be separated by physical methods such as selective crystallization and chromatography techniques, for example with a countercurrent distribution, liquid chromatography, and the like. The compounds of formula (I '), as prepared by the methods just described, are generally racemic mixtures of enantiomers that can be separated from each other by methods known in the art. The racemic compounds of formula (I ') which are sufficiently basic or acidic, can be converted into their corresponding diastereomeric salt forms by their reaction with a suitable chiral acid respectively with a suitable chiral base. Said diastereomeric salt forms are subsequently separated, for example by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali or acid. An alternative way of separating the enantiomeric forms of the compounds of formula (I ') involves liquid chromatography by a stationary chiral phase. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction takes place stereospecifically. If a specific stereoisomer is desired, it is preferable that said compound be synthesized by stereospecific preparation methods. It is advantageous that said methods use enantiomerically pure starting materials. An alternative way to separate the enantiomeric forms of the compounds of formula (I) and intermediates, involves liquid chromatography, in particular liquid chromatography wherein a stationary chiral phase is used. A quantity of intermediate compounds and materials of The starting materials for the above-mentioned preparations are commercially available, or they are known compounds which can be prepared following methodologies known in the art for preparing said intermediates, or similar compounds. In particular, the preparation of the intermediate compounds of formula (II), (IV), (V) and (VIII), has been described in the following documents: US-4,631, 278; US-4,767,760; US-3,883,529; and: Carroll et al., in J. Med. Chem. 1983, 26, 96-100. IL-5, also known as a differentiating factor of eosinophils, EDF, or eosinophil colony stimulating factor (Eo-CSF), ayrftffiejjttgiBt is an important factor of survival and differentiation for eosinophils and basophils, which is why it is considered to play a key role in the infiltration of eosinophils in tissues. There is ample evidence that the income flow of eosinophils is an important pathological event in bronchial asthma and in allergic diseases such as cheilitis, irritation of the intestines, eczema, urticaria, vasculitis, vulvitis, winterfeet (winterfeet ), atopic dermatitis, pollinosis, allergic rhinitis and allergic conjunctivitis; and in other inflammatory diseases such as eosinophilic syndrome, allergic angiitis, eosinophilic fasciitis, eosinophilic pneumonia, PIE syndrome, idiopathic eosinophilia, eosinophilic myalgia, Crohn's disease, ulcerative colitis, and similar diseases. The compounds of the present invention also inhibit the production of other chemokines such as the monocyte chemotactic protein, -1 and -3 (MCP-1 and MCP-3). It is known that MCP-1 attracts both T cells, in which it has mainly the production of IL-5, and monocytes, which are known to act synergistically with eosinophils (Carr et al., 1994, Immunology, 91, 3652 -3656). MCP-3 also plays a primary role in allergic inflammation, since it is known to mobilize and activate basophilic and eosinophilic leukocytes (Baggiolini et al., 1994, Immunology Today, 15 (3), 127-133). The compounds of the present have little or no effect on the production of other chemokines such as IL-1, IL-2, IL-3, IL-4, IL-6, IL-10, gamma-interferon (IFN-gamma) and of the granulocyte-macrophage colony stimulating factor (GM-CSF), which indicates that the present inhibitors of IL-5 do not act as broad spectrum immuno-suppressors. The selective inhibitory effect on chemokines by the compounds can be demonstrated by measurements of in vitro chemokines in human blood, whose test results for IL-5 are shown below in the experimental portion. In vivo observations such as the inhibition of eosinophilia in the ear of mice, the inhibition of blood eosinophilia in the mouse model; reduced production of IL-5 protein in serum and splenic expression of IL-5 mRNA, induced by anti-CD3 antibody in mice and inhibition of the influx of eosinophils into the lungs, induced by Sephadex , in the guinea pig, are indicative of the utility of the compounds of the present for the treatment of eosinophilic-dependent inflammatory diseases. The present inhibitors of IL-5 production are orally active compounds. In view of the aforementioned pharmacological properties, the compounds of the present invention can be used in the manufacture of a medicament for treating the aforementioned eosinophilic-dependent inflammatory diseases, in particular, of bronchial asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis. The present invention also involves two groups of novel compounds to be used as a medicament. One such group consists of those compounds of formula (I '), wherein R1 is mono- or di (C? -C6 alkyl) amino dC6 alkyloxy, mercapto, C C alqu alkylthio or Ci-C alqu alkyl substituted by mono- or di (C -C C6 alkyl) amino, C C alquilo alkyloxy or Het, and the other group consists of those compounds of formula (I '), wherein R2 is a radical of formula -C (= X) -Y-R5, where Y is a direct bond and R5 is Het. In view of the utility of the compounds of formula (I), a method is provided for treating warm-blooded animals, including humans, that suffer from eosinophilic dependent inflammatory diseases, in particular bronchial asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis . Said method comprises 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 possible stereoisomeric form thereof, to warm-blooded animals, including Humans. The present invention also provides compositions for treating eosinophilic dependent diseases, comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent, together with instructions for its use for the treatment of an eosinophilic-dependent inflammatory disease. . In particular, the present invention provides compositions for treating eosinophil-dependent inflammatory diseases, comprising a therapeutically effective amount of a compound of formula (I), wherein R2 is a radical of formula -C (= X) -Y-R5, where Y is a direct bond and R5 is Het or a compound of formula (I '), wherein R1 is mono- or di (C? -C6alkyl) amino Ci-C3alkyloxy, mercapto, CrC6alkylthio or C6alkyl substituted by mono- or di (C? -C6alkyl) amino, C-C-alkyloxy or Het, and a pharmaceutically acceptable carrier or diluent. To prepare the aforementioned pharmaceutical compositions, a therapeutically effective amount of the compound in the case, optionally in salt form, as the active ingredient, is combined in an intimate joint mixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms, which depends on the form of preparation desired for administration. It is desirable that the pharmaceutical compositions be in a suitable dosage form, for example for systemic administration such as for example oral, percutaneous or parenteral administration.; or for topical administration such as for example inhalation, nasal spray, eye drops, or by a cream, gel, shampoo or the like. For example, in the preparation of compositions in oral dosage forms, any of the pharmaceutical media such as, for example, water, glycols, oils, alcohols and the like can be used in the case of oral liquid preparations such as suspensions, syrups, elixirs. and the like; or solid carriers such as starches, kaolin, lubricants, binders, disintegrating agents and the like, in the case of powders, pills, capsules and tablets. Given the ease of administration, tablets and capsules represent the most advantageous unit form for oral administration, in which case the vehicles ^ -tíÉÉk. ? & ~ & Solid pharmaceuticals are of obvious use. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although it is possible to use other ingredients, for example to accentuate the solubility. It is possible to prepare, for example, injectable solutions in which the vehicle comprises saline solution, glucose solution or a mixture of saline and glucose. Injectable solutions containing compounds of formula (I), can be formed with an oil, in order to achieve a prolonged action. Suitable oils for this purpose include, for example, peanut oil, sesame oil, cottonseed oil, soybean oil, synthetic esters of glycerol of long-chain fatty acids, and mixtures of said oils and others. Injectable solutions can also be prepared by resorting to suitable liquid carriers, suspending agents, and the like. In the compositions suitable for percutaneous administration, the vehicle optionally comprises an agent that accentuates the penetration and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, whose additives do not cause any damaging effect on the skin. Said additives may facilitate administration to the skin and / or may help to prepare the desired compositions. Said compositions can be administered in various ways, for example as a transdermal patch, as a local application (spot-on) or as an ointment. As compositions suitable for topical application, there may be mentioned all the compositions commonly used in the topical administration of drugs, for example creams, jellies, dressings, shampoos, dyes, pastes, ointments, balms, powders or the like. The application of said compositions can be done by aerosol, for example by a propellant such as nitrogen, carbon dioxide, a freon, or without a propellant such as a rolling pump, drops, lotions, or a semi-solid such as a composition Thickened that can be applied by means of cotton. In particular, semi-solid compositions such as balms, creams, jellies, ointments and the like, will be of convenient use. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage forms, used in the present specification and claims, refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to achieve the desired therapeutic effect in association with the pharmaceutically required vehicle. . Examples of such unit dosage forms include tablets (including corrugated or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, tablespoons, teaspoons and the like, and the separate multiples thereof. . Preferred compositions are those compositions containing a novel compound of formula (I '), wherein R 2 is a radical of formula -C (= X) -Y-R 5, where Y is a direct bond and R 5 is Het, or a compound novel of formula (I '), wherein R1 is mono- or di (C? -C6alkyl) amino CrC6alkyloxy, mercapto, C-C-alkylthio or C-C? alkyl substituted by mono- or di (d-C6alkyl) amino, C ß alkyloxy or Het, and are in a unit dose form, comprising for each dose unit, an effective amount of active ingredient mixed together with suitable carriers. In order to emphasize the solubility and / or the stability of the compounds of formula (I) in pharmaceutical compositions, it may be advantageous to use a-, beta- or gamma-cyclodextrins or their derivatives. Also co-solvents such as alcohols can improve the solubility and / or stability of the compositions of formula (I) in the pharmaceutical compositions. In the preparation of aqueous compositions, the addition salts of the compounds of the present, are obviously more suitable due to their greater solubility in water. Suitable cyclodextrins are the a-, beta-, gamma-cyclodextrins, or the mixed ethers and ethers thereof, wherein one or more of the hydroxy groups of the anhydro glucose units of the cyclodextrin are substituted by C C6 alkyl, particularly methyl, ethyl or isopropyl, for example beta-CD randomly methylated; hydroxy C Cβ alkyl, particularly hydroxy ethyl, hydroxy propyl or hydroxy butyl; carboxy C Cß alkyl, particularly carboxy methyl or carboxy ethyl; C C β alkyl carbonyl, particularly acetyl; CrC6 alkyloxycarbonyl C C6 alkyl or carboxy-C? -6 alkyloxyCi-C? Alkyl, particularly carboxy methoxy propyl or carboxy ethoxy propyl; CI-CT alkylcarbonyloxy C1-6alkyl, particularly 2-acetyloxypropyl. Particularly noteworthy are complex and / or solubilizing formers: beta-CD, randomly methylated beta-CD, 2,6-dimethyl-beta-CD, 2-hydroxyethyl-beta-CD, 2-hydroxyethyl- gamma-CD, 2-hydroxypropyl-gamma-CD and (2-carboxymethoxy) propyl-beta-CD, and in particular 2-hydroxypropyl-beta-CD (2-HP-beta-CD). The term "mixed ether" refers to cyclodextrin derivatives in which at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. Due to their high degree of selectivity as inhibitors of IL-5, the compounds of formula (I) defined above are also useful for labeling or identifying the receptors. For this purpose, the compounds of the present invention have to be labeled, in particular by the partial or complete replacement of one or more atoms in the molecule, by their radioactive isotopes. Examples of interesting labeled compounds are those compounds having at least one halogen which is a radioactive isotope of iodine, bromine or fluorine; or those compounds having at least one 11C atom or one tritium atom. A particular group is that consisting of those compounds of formula (I), wherein R3 and / or R4 are a radioactive halogen atom. In principle, any compound of formula (I) having a halogen atom is prone to be radioactively labeled by the replacement of the halogen atom by an appropriate isotope. The radioactive isotopes of halogen suitable for this purpose are radioactive iodides, for example 122 I, 123 I, 125 I, 131 I; radioactive bromides, for example 75Br, 76Br, 77Br and 82Br, and radioactive fluorides, for example 18F. The introduction of a radioactive halogen atom can be carried out by an appropriate exchange reaction or by the use of any of the above described processes to prepare the halogen derivatives of formula Another interesting way to mark radioactively is by replacing a carbon atom with an 11C atom or replacing a hydrogen atom with a tritium atom. Therefore, said radiolabelled compounds of formula (I) can be used in a method for specifically labeling the receptor sites in a biological material. Said method comprises the following steps: (a) radiolabeling a compound of formula (I); (b) administering this radiolabelled compound to a biological material and subsequently, (c) detecting the emissions from the radiolabelled compound. The term "biological material" is intended to cover all types of material that have a biological origin. More particularly, this term refers to samples of tissues, plasma or body fluids, but also to animals, especially warm-blooded animals or parts of animals, such as their organs. The radiolabelled compounds of formula (I) are also useful as screening agents if a test compound has the ability to occupy or bind to a particular receptor site. The degree to which a test compound will displace a compound of formula (I) from said particular receptor site will show the ability of the test compound to act either as an agonist, antagonist or as a mixed agonist / antagonist of said receptor. When used in in vivo assays, the radiolabelled compounds are administered in a suitable composition to an animal, and the position of said radiolabelled compounds is detected by imaging techniques such as, for example, SPECT (Emission Computed Tomography of Single Photon) or PET (Positron Emission Tomography), and the like. In this way, the distribution of particular receptor sites throughout the body can be detected, and the organs containing said receptor sites can be visualized by the aforementioned imaging techniques. This method of imaging an organ, by administering a radioactively labeled compound of formula (I), and detecting emissions from the radioactive compound, also constitutes part of the present invention.

A suitable therapeutically effective daily amount would be from 0.01 mg / kg to 50 mg / kg of body fat, in particular from 0.05 mg / kg to 10 mg / kg of body weight. A method of treatment may also include the administration of the active ingredient based on a regimen of between two and four ingestions per day.

EXPERIMENTAL PART A. Preparation of intermediate compounds In the following, "THF" represents tetrahydrofuran, "RT" represents room temperature, "DIPE" is diisopropyl ether, "EtOAc" is ethyl acetate and "DMF" is N, N-dimethylformamide.

EXAMPLE A.1 a) A solution of 4-chloro-3- (trifluoromethyl) benzene acetonitrile (0.114 mol) in THF (100 ml) was added dropwise at room temperature to a solution of 1,2,3-trichloro-5-nitrobenzene ( 0.114 mol) and N, N, N-triethylbenzene ethanamminium chloride (3 g) in NaOH (150 ml) and THF (100 ml). The mixture was stirred at room temperature for two hours, then poured onto ice, acidified with a concentrated solution of HCl and extracted with CH 2 Cl 2. The organic layer was separated, dried, filtered, and l _ »^^ __ ______ É ___ ___? The solvent was evaporated. The residue was crystallized from DIPE. The precipitated material was removed by filtration, and dried, yielding 40.4 g (86.5%) of (+/-) 2,6-dichloro-a- [4-chloro-3- (trifluoromethyl) phenyl] -4-nitrobenzene acetonitrile ( intermediate compound 1). 5 b) A mixture of (3,4-dichlorophenyl) acetonitrile (0.149 mol) in DMF (100 ml) was subjected to stirring at 0 ° C under nitrogen flow. An amount (0.223 mol) of sodium hydride was added in portions. The mixture was subjected to stirring at 0 ° C under a nitrogen flow for one hour. A mixture of 2-methoxy-1,3-dimethyl-5-nitrobenzene (0.149 mol) in DMF10 (100 ml) was added dropwise at 0 ° C under a nitrogen flow. The mixture was stirred at room temperature for 6 hours, then cooled, hydrolyzed with water and with 3N HCl and extracted with EtOAc. The organic layer was separated, washed several times with water, dried, filtered, and the solvent was evaporated. The residue was crystallized from of DIPE. The precipitated material was removed by filtration, and dried, yielding 43.4 g (87%) of (+/-) - a- (3,4-dichlorophenyl) -3-, 6-dimethyl-4-nitrobenzene acetonitrile (intermediate compound 48). c) A solution of intermediate compound 1 (0.0466 mol), idomethane (0.0606 mol), KOH (0.1864 mol) and N, N, N-triethyl benzene chloride metanaminium (0.0466 mol) in toluene (200 ml), was subjected to stirring at 50 ° C for 2 hours. The mixture was poured into water, acidified with HCl (3N) and extracted with CH2Cl2. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by chromatography of * column on silica gel (eluent: hexane cycle (EtOAc 90/10) .The pure fractions were recovered, and the solvent was evaporated, yielding 11 g (55%) of (+/-) - 2,6-dichloro-a - [4-chloro-3- (trifluoromethyl) phenyl] - alpha-methyl-4-nitrobenzene acetonitrile (intermediate compound 2) 5 EXAMPLE A.2 a) A mixture of intermediate compound 2 (0.0259 mol) in methanol (200 ml) was hydrogenated at 40 ° C overnight with platinum on Activated carbon (1%, 1 g) in the form of a catalyst in the presence of thiophene (10% in ethanol, 1 ml). After incorporation of the hydrogen, the catalyst was filtered through Celite, washed with CH3OH, and the filtrate was evaporated, yielding 10 g (98%) of (+/-) 4-amino-2,6-dichloro- alpha- [4-chloro-3- (trifluoromethyl) phenyl] -alpha-methyl benzene acetonitrile (compound intermediary s). b) A mixture of intermediate compound 1 (0.138 mol) in methanol (300 ml) was hydrogenated at room temperature under a pressure of 3 bar for one hour with Raney nickel (50 g) as a catalyst in the presence of a thiophene solution. to 10% in ethanol (5 ml). After the After incorporation of the hydrogen, the catalyst was filtered through Celite, washed with CH3OH and CH2Cl2, and the filtrate was evaporated, yielding 49.5 g (94%) of (+/-) - 4-amino-2,6-dichloro -alpha- [4-chloro-3- (trifluoromethyl) phenyl] benzene acetonitrile (intermediate compound 46). _ -. - £ _ "# ~ * '. * £ fe *? Í'fl_ c) A solution of TiCl3 in water (0.13 mol) was added dropwise at room temperature to a solution of (+/-) - 2.6 -dibromo-alpha- (4-chlorophenyl) -4-nitrobenzene acetonitrile (0.026 mol) in THF (200 ml) The mixture was stirred at room temperature for 2 hours, poured into water and extracted with CH 2 Cl 2. The organic material was separated, washed with water and with 10% K2CO3, dried, filtered, and the solvent was evaporated.A part of this residue (2 g) was crystallized from diethyl ether.The precipitated material was removed by filtering and drying , obtaining 1.3 g of (+ / -) - 4-amino-2,6-dibromo-alpha- (4-chlorophenyl) benzene acetonitrile (intermediate compound 47).

EXAMPLE A.3 a) A solution of sodium nitrite (0.0243 mol) in water (10 ml) was added dropwise at 5 ° C to a solution of intermediate 3 (0.0243 mol) in acetic acid (75 ml) and concentrated HCl ( 20 ml). The mixture was stirred at 0 ° C for 35 minutes and then added dropwise to a solution of ethyl (cyanoacetyl) carbamate (0.0326 mol) and sodium acetate (112 g) in ice water (1300 ml). The mixture was subjected to stirring at 0 ° C for 45 minutes. The precipitated material was separated, washed with water, dried, filtered, and the solvent was evaporated, yielding 15.2 g of (+/-) - ethyl 2-cyano-2 - [[3,5-dichloro-4- [1- [4-chloro-3- (trifluoromethyl) phenyl] -1-cyanoethyl] phenyl] hydrazono] -1-oxoethylcarbamate (intermediate compound 4). b) A mixture of intermediate compound 4 (0.0271 mol) and potassium acetate (0.0285 mol) in acetic acid (150 ml), it was subjected to agitation and reflux for three hours and then poured on ice. The precipitated material was filtered off, washed with water and recovered in EtOAc. The organic layer was separated, washed with water, dried, filtered, and the solvent was evaporated, yielding 12 g of (+/-) - 2- [3,5-dichloro-4- [1- [4-chloro-3 - (trifluoromethyl) phenyl] -1-cyanoethyl] phenyl] -2,3,4,5-tetrahydro-3,5-dioxo-1, 2-4-triazine-7-carbonitrile (intermediate compound 5). c) A mixture of intermediate compound 5 (0.0223 mol) in HCl (40 ml) and acetic acid (150 ml) was stirred and refluxed for three hours and then poured into ice water. The precipitated material was removed by filtration, washed with water and recovered in CH 2 Cl 2 and CH 3 OH, washed with water, dried, filtered, and the solvent was evaporated, obtaining 11.4 g of acid (+/-) -2- [3,5- dichloro-4- [1- [4-chloro-3- (trifluoromethyl) phenyl] -1-cyanoethyl] phenyl] -2,3,4,5-tetrahydro-3,5-dioxo-1, 2,4 -triazine-6-carboxylic acid (intermediate compound 6). The following intermediates were prepared according to the procedures described in Example A.3.

TABLE i fifteen EXAMPLE A.4 20 a) A mixture of (+/-) - 4-chloro-alpha- [2-chloro-3- (4,5-dihydro-3,5-dioxo-1, 2,4-triazin- 2- (3H) -yl) phenyl] -3- (trifluoromethyl) benzene acetonitrile (0.00542 mol), 1- (chloromethoxy) -2-methoxyethane (0.006 mol) and triethylamine (0.0065 mol) in 4_ £ ft_a_ THF (15 ml) was stirred at room temperature for 2 hours. The mixture was poured into water, and extracted with EtOAc. The organic layer was separated, dried, filtered, and the solvent was evaporated, yielding 3.4 g of (+/-) - 4-chloro-alpha-p-chloro-S - ^. D-dihydro ^ - ^ - methoxyethoxyJmeti ^ - Sd-dioxo-l ^^ -triazin-2 (3H) -yl] phenyl] -3- (trifluoromethyl) benzene acetonitrile (intermediate compound 22). (+/-) - 2-Chloro-alpha- (4-chlorophenyl) -4- [4,5-dihydro-4 - [(2-methoxyethoxy) methyl] -3,5-dioxo-1, 2,4 -triazin-2 (3H) -yl] benzene acetonitrile was prepared analogously (intermediate compound 39). b) An amount (0.0193 mol) of potassium salt of 2-methyl-2-propanol was added in portions at 0 ° C under a nitrogen flow to a solution of intermediate compound 22 (0.00642 mol) and methane iodine (0.0321 mol) ) in DMF (10 ml). The mixture was stirred at 0 ° C for 2 hours and then poured into ice water, and extracted with diethyl ether. The organic layer was separated, washed with water, dried, filtered, and the solvent was evaporated. The residue was subjected to chromatography on silica gel (eluent: cidohexane / EtOAc 50/50 to 35/65). The pure fractions were pooled, and the solvent was evaporated, yielding 2.07 g (60%) of (+/-) - 4-chloro-alpha-3- [4,5-dihydro-4 - [(2-methoxyethoxy) methyl] ] -3,5-dioxo-1, 2,4-triazin-2 (3H) yl] phenyl] -alpha-methyl-3- (trifluoromethyl) benzene acetonitrile (intermediate compound 23). (+/-) - 4-Chloro-alpha- [2-chloro-5- [4,5-dihydro-4- (2-methoxyethoxy) methyl] -3,5-d -oxo-1, 2,4 -triazin-2 (3H) -l] phenyl] -alpha-methyl-3- (trifluoromethyl) -benzene-acetonitrile was prepared analogously (intermediate compound 24).

EXAMPLE A.5 a) A solution of 4-bromo-1-chloro-1-chloro-2- (trifluoromethyl) benzene (0.165 mol) in THF (30 ml) was added dropwise under a stream of nitrogen to a suspension of Mg ( 0.181 mol) and a crystal of 12 in THF (20 ml). The mixture was subjected to stirring at 30-35 ° C for 2.5 hours and then cooled to 10 ° C. The mixture was added dropwise at 5 ° C under nitrogen flow to a solution of N- (2-chloro-3-formylphenyl) acetamide (0.0788 mol) in THF (500 ml). The mixture was stirred at room temperature for 3 hours, poured onto ice and NH 4 Cl, and extracted with EtOAc. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH 2 Cl 2 / CH 3 OH 98.5 / 1.5). The pure fractions were pooled, and the solvent was evaporated, yielding 22.2 g (74%) of (+/-) - N- [2-chloro-3 - [[4-chloro-3- (trifluoromethyl) phenyl] hydroxymethyl] phenyl] acetamide (intermediate compound 25). b) A mixture of intermediate 25 (0.0587 mol) and manganese oxide (IV) (0.587 mol) in CH2Cl2 (400 ml) was stirred at room temperature for 24 hours and filtered on Celite. The solvent was evaporated, yielding 19.21 g (87%) of N- [2-chloro-3- [4-chloro-3- (trifluoromethyl) -benzoyl] phenyl] acetamide (intermediate compound 26). c) A mixture of intermediate 26 (0.0511 mol) in HCl (6N, 200 ml) was subjected to stirring and reflux for 5 hours. The mixture was cooled, poured into ice, basified with NH 4 OH and extracted with CH 2 Cl 2. The organic layer was dried, filtered, and the solvent was evaporated, yielding 17.1 g (100%) of (3-amino-2-chlorophenyl) [4-chloro-3- (trifluoromethyl) phenyl] methanone (intermediate compound 27). d) 2- [2-Chloro-3- [4-chloro-3- (trifluoromethyl) benzoyl] phenyl] -2,3,4,5-tetrahydro-3,5-dioxo-1, 2,4- acid triazine-6-carboxylic acid was prepared according to the procedures described in examples A2.a), A2. b), and A2. c) (intermediate compound 28). e) A mixture of intermediate 28 (0.0207 mol) in mercaptoacetic acid (10 ml), it was heated at 160 ° C for 3 hours. The solution was cooled and poured on ice. EtOAc was added, and the mixture was basified with NaHCO3. The organic layer was separated, dried, filtered, and the solvent was evaporated. 0.8 g of the residue were crystallized from 2-propanol / DIPE. The precipitated material was filtered and dried, obtaining 0.5 g (93%) of 2- [2-chloro-3- [4-chloro-3- (trifluoromethyl) benzoyl] phenyl] -1, 2,4-triazin-3, 5 (2H, 4H) -dione (intermediate compound 29). 2- [4-Chloro-3- [4-chloro-3- (trifluoromethyl) benzoyl] phenyl] -1,2,4-triazine-3,5 (2H, 4H) -dione was prepared in accordance with procedures described in Examples A.5 a) to A.5 e) (intermediate compound 30).

EXAMPLE A.6 A) A mixture of 2- [4- (4-chlorobenzoyl) phenyl] -1,4,4-triazine-3,5- (2H, 4H) -dione (0.05 mol), ethanol (150 ml), water ( 150 ml) and NaOH (50%, 10 ml) was stirred at 10 ° C. A mixture of NaBH 4 (0.05 mol), water (50 ml) and NaOH (50%, 2 ml) was added dropwise over 15 minutes. After being stirred for 3 hours, 300 ml of ice were added. The mixture was acidified with concentrated HCl. The product was extracted with CHCl3, obtaining 5.8 g of 2- [4 - [(4-chlorophenyl) hydroxymethyl] hydroxymethyl] phenyl] -1, 2,4-triazine-3,5- (2H, 4H) -dione (compound intermediary 31). The organic layer was dried, filtered, and evaporated. The residue was crystallized with 2-propanol. The product was subjected to filtering, washing with 2,2'-oxybispropane and drying, obtaining a second fraction of 5.5 g of intermediate 31. 31. b) A mixture of intermediate 31 (0.053 mol), thionyl chloride (50 ml) and CHCl3 (200 ml), was subjected to stirring and refluxing for 2 hours. The solvent was evaporated. After the addition of toluene, the solvent was again evaporated, yielding 18.4 g of 2- [4- [chloro- (4-chlorophenyl) methyl] phenyl] -1,2,4-triazine-3,5- (2H, 4H) -dione (intermediate compound 32). ÍÍ_d £ ú ______ S ^ & _ ____t > > .? - EXAMPLE A.7 a) An amount of NaH (0.042 mol, 80% in oil) was added in portions at 10 ° C under a flow of nitrogen to a solution of intermediate compound 39 (0.0325 mol) in DMF (90 ml). The mixture was stirred for 15 minutes. A solution of 1-bromo-3-chloro-propane (0.065 mol) in DMF (20 ml) was added dropwise. The mixture was subjected to stirring at room temperature for 24 hours. Water (250 ml) was added. The mixture was filtered on Celite, washed with water, 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: CH 2 Cl 2 / EtOAc 85/15). The pure fractions were pooled, and the solvent was evaporated, yielding 7.5 g (43%) of (+/-) - 2-chloro-alpha- (4-chlorophenyl) -alpha- (3-chloropropyl) -4- [4 , 5-dihydro-4 - [(2-methoxy-ethoxy) methyl] -3,5-dioxo-1, 2,4-triazin-2 (3H) -l] benzene acetonitrile (intermediate compound 40). b) A mixture of intermediate 40 (0.0132 mol), dimethylamine (0.066 mol) and potassium carbonate (0.066 mol) in acetonitrile (100 ml), was subjected to stirring and reflux for 12 hours and then allowed to cool to room temperature . Water was added. The mixture was 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: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97.5 / 2.5 / 0.5). * &• The pure fractions were pooled, and the solvent was evaporated, yielding 2.5 g (35%) of (+/-) - 2-chloro-alpha- (4-chlorophenyl) -4- [4,5-dihydro] -4 - [(2-methoxyethoxy) -methyl] -3,5-dioxo-1, 2,4-triazin-2 (3H) -yl] -alpha- [3- (dimethylamino) propyl] -benzene acetonitrile (compound intermediary 41).

EXAMPLE A.8 a) A mixture of (+/-) - 4-amino-2,6-dichloro-alpha- [4-chloro-3- (trifluoromethyl) phenyl] -alpha-methylbenzene acetonitrile (0.08 mol) in acetic acid (250 ml ) and concentrated hydrochloric acid (0.24 mol), was subjected to stirring at +/- 10 ° C. A solution of sodium nitrite (0.08 mol) in water (15 ml) was added dropwise during 30 minutes at +/- 10 ° C. The mixture was stirred for one hour. An amount of sodium acetate (0.24 mol) and carbamic acid (1,3-dioxo-1,3-propanediyl) -bis-, diethyl ester (0.088 mol) was added in one portion. The resulting reaction mixture was subjected to stirring for two hours at room temperature. The mixture was poured into ice water, and the resulting precipitated material was removed by filtration, washed with water, and then dissolved in CH 2 Cl 2. The organic solution was dried, filtered, and the solvent was evaporated. A sample of the residue (2 g) was purified on silica gel on a glass filter (eluent: CH 2 Cl 2 / CH 3 OH 99/1). The desired fractions were pooled, and the solvent was evaporated. The residue was subjected to stirring in DIPE, filtering, washing and drying, obtaining 0.95 g of (A) -N, N '- [2 - [[3,5-dichloro-4- [1- [4-chloro-3 - * 3_í. (trifluoromethyl) phenyl] -1-cyanoethyl] phenyl] hydrazone] -1,3-dioxo-1,3-propanediyl] diethyl dicarbamate (intermediate compound 42; [alpha] D2o = + 37.83 ° ® 20.3 mg / 2 ml in methanol). b) A solution of intermediate 42 (0.08 mol) and potassium acetate (0.08 mol) in acetic acid (350 ml) was subjected to stirring and refluxing for 4 hours. The solvent was evaporated, yielding (A) - [[2- [3,5-dichloro-4- [1- [4-chloro-3- (trifluoromethyl) phenyl] -1-cyanoethyl] phenyl] -2.3, Ethyl 4,5-tetrahydro-3,5-dioxo-1, 2,4-triazin-6-yl] carbonyl] carbamate (intermediate compound 43). c) A solution of intermediate 43 (0.08 mol) in concentrated hydrochloric acid (100 ml) and acetic acid (350 ml) was subjected to stirring and refluxing overnight. The reaction mixture was poured into ice water, and the resulting precipitated material was filtered, washed with water, and then dissolved in CH 2 Cl 2 / CH 3 OH 98/2). The organic solution was dried, filtered and the solvent was evaporated, yielding (A) -2- [3,5-dichloro-4- [1- [4-chloro-3- (trifluoromethyl) phenyl] -1-cyanoethyl] phenyl] -2,3,4,5-tetrahydro-3,5-dioxo-1, 2,4-triazine-6-carboxylic acid (intermediate compound 44; [alpha]% = + 33.76 @ 20-38 mg / 2 ml in methanol). The acid (B) -2- [3,5-dichloro-4- [1 - [4-chloro-3- (trifluoromethyl) phenyl] -1-cyanoethyl] phenyl] -2,3,4,5-tetrahydro- 3,5-dioxo-1, 2,4-triazine-6-carboxylic acid, was obtained in a similar manner (intermediate compound 45).

EXAMPLE B.1 A mixture of intermediate 6 (0.044 mol) in mercaptoacetic acid (23 ml) was subjected to stirring at 175 ° C for 2 hours. The mixture was cooled, poured on ice, basified with K2CÜ3 and extracted with EtOAc. The organic layer was separated, 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 99.5 / 0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitated material was filtered and dried, obtaining 3.7 g (17.2%) of (+) - 2,6-dichloro-alpha- [4-chloro-3- (trifluoromethyl) phenyl] -4- (4,5- dihydro-3,5-dioxo-1, 2,4-triazin-2 (3H) -yl) -alpha-methylphenol acetonitrile (compound 1.7).

EXAMPLE B.2 An amount of boron tribromide (0.01932 mol) was added dropwise at -70 ° C to a solution of intermediate 23 (0.00322 mol) in CH2Cl2 (20 ml). The mixture was stirred at -70 ° C for 5 hours, then poured into ice water, basified with K2CO3 and extracted with CH2Cl2. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by chromatography W íníiíi]. f? ^ a -? '--- ^ -' 'column on silica gel (eluent: CH2Cl2 / CH3OH 9t¿52>). The pure fractions were recovered and the solvent was evaporated. The residue was dried, yielding 0.30 g of (+) - 4-chloro-alpha- [2-chloro-3- (4,5-dihydro-3,5-dioxo-1, 2,4-triazin-2 (3H ) -yl) phenyl] -alpha-methyl-3- (trifluoromethyl) benzene acetonitrile (compound 1.36).

EXAMPLE B.3 An amount of potassium salt of 2-methyl-2-propanol (0.0428 mol) was added in one portion at 10 ° C under nitrogen flow to a mixture of 1 - [(isocyanomethyl) sulfonyl] -4-methylbenzene (0.0155 mol) in DMSO (19 ml). The mixture was stirred for 10 minutes. Intermediate compound 29 (0.0019 mol) and methanol (0.9 mol) were added. The mixture was stirred at room temperature for 4 hours, then poured into water, neutralized with HCl (3N) and extracted with EtOAc. The organic layer was separated, washed with water, dried, filtered, and the solvent was evaporated. The solvent was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 / CH 3 OH 99/1). The pure fractions were pooled, and the solvent was evaporated, yielding 2.39 g (46%) of (+) - 4-chloro-alpha- [2-chloro-3- (4,5-dihydro-3,5-dioxo- 1, 2,4-triazin-2 (3H) -yl) phenyl] -3- (trifluoromethyl) -benzene acetonitrile (compound 1.38).

EXAMPLE B.4 A mixture of intermediate 32 (18.4 g) and copper cyanide (I) (6.7 g) was stirred for 30 minutes at 180 ° C. After cooling, the reaction mixture was recovered in a mixture of CHCl3 / CH3OH (90:10). The whole was filtered, and the filtrate was evaporated. The residue was crystallized from a mixture of CHCl3 / CH3OH (98: 2). The product was filtered, washed with 2,2'-oxybispropane and dried, yielding 6.7 g (37.3%) of alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1,2). , 4-triazin-2- (3H) -yl) benzene acetonitrile; (compound 1.41, melting point 206.3 ° C).

EXAMPLE B.5 A mixture of 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1, 2,4-triazin-2 (3H) -yl) -alpha-methylbenzene acetonitrile (0.01 mol) and triethylamine (0.01 mol) in pyridine (115 ml), was heated to 60 ° C. H2S was bubbled through the mixture for 5 hours. The mixture was then subjected to stirring for 16 hours at 60 ° C. H2S was bubbled through the mixture again for 8 hours, and the mixture was then subjected to stirring for 48 hours at 60 ° C. H2S was bubbled through the mixture for 3 days. The solvent was evaporated and the residue was taken up in CH 2 Cl 2, washed with HCl (3N) and with water, 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 97/3). The pure fractions were pooled, and the solvent was evaporated, yielding 1.5 g (36%) of (+) - 2-chloro-alpha- (4-chlorophenyl) -alpha-methyl-4- (4,5-dihydro-3) , 5-dioxo-1, 2,4-triazin-2 (3H) -yl) -benzene diamide (compound 1.21).

EXAMPLE B.6 a) An amount of compound 2.8 (0.00474 mol) was added dropwise to sulfuric acid (5 ml), acetic acid (5 ml) and water (5 ml). The mixture was subjected to stirring at 140 ° C for 14 hours and then poured into water. The precipitated material was filtered, washed with water, recovered in ethyl acetate, washed with water, dried, filtered, and the solvent was evaporated. The residue was crystallized from ethyl acetate and diethyl ether. The precipitated material was filtered and dried, obtaining 0.7 g (33%) of (+) - 2,6-dichloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1) , 2,4-triazin-2 (3H) -yl) -alpha-methyl benzene acetonitrile (compound 1.11). b) A mixture of 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1, 2,4-triazin-2 (3H) -yl) -alpha- methyl benzene acetonitrile (0.026 mol) in sulfuric acid (75 ml), acetic acid (75 ml) and water (75 ml) was stirred at 140 ° C for 24 hours. Sulfuric acid (25 ml) and acetic acid (25 ml) were added again. The mixture was subjected to stirring and refluxing for 18 hours and then poured on ice. The precipitated material was filtered, recovered in ethyl acetate, washed, with water, dried, filtered, and the solvent was evaporated. The residue was taken up in CH 2 Cl 2, washed with water, dried, and the solvent was evaporated. Part of this residue (1 g) was recovered in water and 3N NaOH, treated with activated carbon, filtered on Celite, extracted with CH2Cl2 and separated in its layers. The aqueous layer was acidified with 3N HCl and extracted with CH2Cl2. The combined organic layer was washed with water, dried, filtered, and the solvent was evaporated, obtaining 0.56 g of (+) - 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3) acid. , 5-dioxo-1, 2,4-triazin-2 (3H) -yl) -alpha-methyl benzene acetic (compound 1.12).

EXAMPLE B.7 a) A mixture of 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3-, 5-dioxo-1, 2,4-triazin-2 (3H) -yl) benzene acetic acid (0.0178 mol) in thionyl chloride (30 ml) was subjected to stirring and refluxing for 2 hours. The mixture was cooled, and the solvent was evaporated, yielding 6.5 g of (+) - 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-) chloride. 1, 2,4-triazin-2 (3H) -yl) benzene acetyl (compound 1.5). b) A mixture of compound 1.56 (0.0038 mol) in thionyl chloride (11 ml) was subjected to stirring and refluxing for 2 hours. The solvent was evaporated, yielding (+) - 2,6-dichloro-alpha- [4-chloro-3- (trifluoromethyl) phenyl] -4- (4,5-dihydro-3,5-dioxo-1) chloride, 2,4-triazin-2 (3H) -yl] -benzene acetyl (compound 1.57).

EXAMPLE B.8 A mixture of compound 1.5 (0.00158 mol), 0, N-dimethylhydroxylamine (0.0237 mol) and triethylamine (0.0521 mol) in CH2Cl2 (150 ml) was stirred at room temperature for 12 hours. The mixture was washed with K2CO3 (10%) and with water, dried, filtered, and the solvent was evaporated. The residue was taken up in CH 2 Cl 2, washed with HCl (3N) and with water, 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 pooled, and the solvent was evaporated. The residue was recrystallized from CH3CN and diethyl ether. The precipitated material was filtered and dried, obtaining 2.15 g (34%) of (+) - 2-chloro-alpha- (4-chlorophenyl) -N-methoxy-N-methyl-4- (4,5-dihydro-3) , 5-dioxo-1, 2,4-triazin-2 (3H) -yl) benzene acetamide (compound 1.6).

EXAMPLE B.9 A solution of (+) - 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1, 2,4-triazin-2 (3H) chloride -yl) -alpha-methylbenzene acetyl (0.007 mol) in CH2Cl2 (20 ml) was added at room temperature to 40% methanamine in water (0.015 mol). The mixture was stirred at room temperature for 4 hours, poured into water, acidified with HCl (3N) 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: CH 2 Cl 2 / CH 3 OH 97/3). The pure fractions were pooled, and the solvent was evaporated, yielding 1.25 g (43%) of (+) - 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo) -1, 2,4-triazin-2 (3H) -yl) -alpha, N-dimethyl benzene acetamide (compound 1.14).

EXAMPLE B.10 An amount of n-butyl lithium (solution of 1.6 M in hexane, 0.0575 mol) was added at -70 ° C under nitrogen flow to a solution of benzothiazole (0.0575 mol) in THF (150 ml), and the mixture was subjected to stirring at -70 ° C for 30 minutes. Compound 1.6 (0.0115 mol) in THF (100 ml) was added dropwise, the mixture was stirred at -70 ° C for three hours, poured into water and extracted with ethyl acetate. 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 99/1). The pure fractions were collected and the solvent was evaporated. The residue (1.7 g) was crystallized from 2-propanone. The precipitated material was filtered and dried, obtaining 1.35 g of (+) - 2- [4- [2- (2-benzothiazolyl) -1- (4-chlorophenyl) -2-oxoethyl] -3-chlorophenyl] -1, 2,4-triazin-3,5 (2H, 4H) -dione (compound 1.20).

EXAMPLE B.11 An amount of ammonium salt of acetic acid (3 g) was added at room temperature to a solution of (+) - 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-) chloride. 3,5-dioxo-1, 2,4-triazin-2 (3H) -yl) -alpha-methyl-benzene acetyl (0.007 mol) in 2-propanone (30 ml). The mixture was subjected to stirring at room temperature for 5 hours. An amount of ammonium salt of acetic acid was filtered, and the solvent was evaporated. The residue was taken up in CH 2 Cl 2, washed with water, 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 97/3). The pure fractions were recovered and the solvent was evaporated, obtaining 1.6 g (57%) of (+) - 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo- 1, 2,4-triazin-2 (3H) -yl) -alpha-methyl benzene acetamide (compound 1.18).

EXAMPLE B.12 A mixture of intermediate 1.68 (0.031 mol) in HBr in acetic acid (110 ml, 33% solution) and Hbr (65 ml, 48% aqueous solution) was stirred and refluxed overnight and then poured into frozen water. The precipitated material was filtered, washed with water and recovered in CH2Cl2 and a small amount of CH3OH. The organic solution was dried, filtered, and the solvent was evaporated, yielding 13.6 g of (+) - 2,6-dichloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-1, 2, 4-triazin-2 (3H) -yl-alpha-methylbenzene acetic acid (compound 1.69).

EXAMPLE B.13 A mixture of the intermediate compound (41) (0.00457 mol) in concentrated HCl (25 ml) and acetic acid (44 ml) was subjected to stirring and refluxing overnight. The mixture was allowed to cool to room temperature, poured into ice, basified with K2CO3 and extracted with CH2Cl2 and a small The amount of CH3OH: The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue (2.1 g) was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH / NH4OH 90/10/1 and 70/30/1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ethyl acetate and 2-propanone. The precipitated material was filtered and dried, obtaining 0.95 g (45%) of (+) - 2-chloro-alpha- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1, 2 , 4-triazin-2 (3H) -yl) -alpha- [3- (dimethylamino) propyl] -benzene acetonitrile; melting point 140 ° C (Kofler) (compound 1.58).

EXAMPLE B. 14 A mixture of compound 1.5 (0.05 mol) in THF (350 ml) was subjected to stirring at -75 ° C. A solution of chlorine (phenylmethyl) magnesium (0.1 mol; 2M / THF) in THF (50 ml) was added dropwise for one hour at -75 ° C. The mixture was stirred at -75 ° C for 4 hours, then the temperature was raised to -20 ° C, and a saturated solution of NH 4 Cl (50 ml) was added dropwise over 15 minutes. Water was added, and the layers were separated. The organic layer was evaporated. The residue was dissolved in CH 2 Cl 2 / CH 3 OH 90/10. The organic layer was dried, filtered, and the solvent was evaporated. The residue was subjected to stirring in CH2Cl2. The solid was filtered, the filtrate was evaporated and the residue was filtered on silica gel, using a mixture of CH2Cl2 / CH3OH as eluent. The fraction of the desired final product was recovered, obtaining 4.3 g of (+) - 2- [3-chloro-4- [1- (4-chlorophenyl) -2-oxo-3-phenylpropyl] phenyl] -1, 2, 4-triazine-3,5 (2H, 4H) -dione (compound 1.67). The following compounds 2 to 5 list the compounds of formula (I) that were prepared according to one of the preceding examples (example column No.) TABLE 2 5 TABLE 3 TABLE 4 TABLE 5 Table 6 lists the values of the elemental analysis, both the experimental ones (column with the heading "Exp") and the theoretical ones (column with the heading "theory"), corresponding to carbon (C), hydrogen (H) and nitrogen (N), of the compounds prepared in the preceding experimental part.

TABLE 6 C. Pharmacological Example EXAMPLE C.1 In vitro inhibition of IL-5 production in human blood Stimulation in whole human blood Peripheral blood was extracted from healthy male donors in heparinized syringes (12.5 U heparin / ml). The blood samples were diluted 1: 3 in an RMPI 1640 medium (Life Technologies, Belgium), supplemented with 2 mM L-glutamine, 100 IU / ml penicillin and 100 μg / ml streptomycin, and 300 μl fractions were distributed on 24-disc multi-disc plates. Blood samples were pre-incubated (60 minutes at 37 ° C) in a 6% humidified CO2 atmosphere with 100 μl of drug solvent (final concentration: 0.02% DMSO in RPMI) or with 100 μl of a suitable dose of test compound before being stimulated by the addition of 100 μl of phytohaemagglutinin HA17 (Murex, UK) to a final concentration of 2 μg / ml. After 48 hours, the supernatant fluids free of cells were collected by centrifugation and ? ^^ | i ^ m ^ i ^ ^ stored at -70 ° C until submitted »* test to verify the presence of IL-5.

Measurements of IL-5 Measurements of IL-5 were made as described in Van Wauwe et al. (1996, Inflamm Res., 45, 357-363), on p. 358, using ELISA test. Table 8 lists the percentage inhibition of IL-5 production (column "% inhibition" with a test dose of 1 x 10 ~ 6 M, or in the case where the percent inhibition is marked with a " * "1 x 10" 5 M, for the compounds of the present invention, which includes the compounds of formula (I) which have been described in US 4,631, 278 (Ref. A), or US 4,767,760 (Ref. B), as summarized in table 7.

TABLE 7 TABLE 8 D. Examples of Compositions In the following formulations, typical pharmaceutical compositions suitable for systemic or topical administration to animal and human subjects are exemplified, in accordance with the present invention. As used in the following examples, the term "active ingredient" (I.A.) refers to a compound of formula (I), or a pharmaceutically acceptable addition salt thereof.

Example D1 Tablets coated with a film Preparation of the core of the tablets A mixture of LA. (100 g), lactose (570 g) and starch (200 g), was well mixed and then moistened by a solution of sodium dodecyl sulfate (5 g) and polyvinyl pyrrolidone (10 g) in approximately 200 ml of water. The mixture, a dry powder, was sieved, dried and sieved again. Next, microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g) were added. The whole was well mixed and compressed into tablets, obtaining 10,000 tablets, each of which contained 10 mg of the active ingredient.

Coating To a solution of methyl cellulose (10 g) in denatured ethanol (75 ml), a solution of ethyl cellulose (5 g) in dichloromethane (150 ml) was added. Then dichloromethane (75 ml) and 1,2,3-propanetriol (2.5 ml) were added. Polyethylene glycol (10 g) was added, and it was dissolved in dichloromethane (75 ml). This last solution was added to the previous one, and then magnesium octadecanoate (2.5 g), polyvinylpyrrolidone (5 g) and a concentrated color suspension (30 ml) were added, and the whole was homogenized. The cores of the tablets were coated with the mixture thus obtained, in a coating apparatus.

Example D2 Topical cream at 2% To a solution of hydroxypropyl beta-cyclodextrin (200 mg) in purified water, I.A. (20 mg) is added under stirring. Hydrochloric acid was added until complete dissolution and then sodium hydroxide was added until pH = 6.0. During stirring, glycerol (50 mg) and polysorbate 60 (35 ml) are added, and the mixture is heated to 70 ° C. The resulting mixture is added to a mixture of mineral oil (100 mg), stearyl alcohol (20 mg), cetyl alcohol (20 mg), glycerol monostearate (20 mg) and sorbate (15 mg), which have a temperature of 70 ° C, while mixing slowly. After cooling to below 25 ° C, the remainder of the purified water is added to a sufficient quantity of 1 g, and the mixture is combined until homogeneous.

Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of formula: an N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein: p represents an integer equal to 0, 1, 2, 3 or 4; q represents an integer equal to 0, 1, 2, 3, 4 or 5; R 1 represents a hydrogen atom, C C β alkyl, mono- or di (Ci-C β alkyl) amino CrC 6 alkyloxy, mercapto, d-C β alkylthio, C 3 -C cycloalkyl, aryl or C C β alkyl substituted by mono- or di (C C 6 alkyl) amino, C C β alkyloxy, aryl or Het; R 2 represents cyano or a radical of formula -C (= X) -Y-R 5; where: X represents O or S; Y represents O, S, NR6 or a direct link; R5 represents a hydrogen atom; C Cß alkyl; C3-C cycloalkyl; aryl or C Cβ alkyl substituted by aryl, hydroxy or Het; and if Y is a direct link, R5 can also be halogen or Het; R6 represents a hydrogen atom, Cr C6 alkyl, C? -C6 alkyloxy or aryl CrC6 alkyl; each of the R3 independently represents each other, halogen, C1-C6 halogen alkyl, CCβ alkyl, hydroxy, CrC6 alkyloxy, C Cß alkylcarbonyloxy, mercapto, C C6 alkylthio, Ci-Cß alkylsulfonyl, d-Cß alkylsulfinyl, halogen C C 1 alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di (CrC 6 alkyl) amino or (C C β alkylcarbonyl) amino; each of the R4 independently represents each other halogen, Ci-Cβ alkyl halogen, C C β alkyl, hydroxy, C C β alkyloxy, C C 6 alkylcarbonyloxy, mercapto, Ci-C β alkylthio, C C β alkylsulfonyl, C α -C 6 alkylsulfinyl, halogen C 1 -C 6 alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di (CrC 6 alkyl) amino or (C C β alkylcarbonyl) amino; Aryl represents phenyl or phenyl substituted by one, two or three substituents selected from the group comprising: halogen, C C6 alkyl, Ci-Cβ alkyloxy, halogen Ci-Cβ alkyl, hydroxy, mercapto, C?-C6-alkylthio, Ci -Cß-alkylsulfonyl, C?-C6 alkylsulfonyloxy, Ci-Cß alkylsulfinyl, halogen C C6 alkylsulfonyl, nitro, cyano, amino, mono- and di (C?-C6 alkyl) amino or (Ci-Cß alkylcarbonyl) amino; and Het represents a heterocycle selected from: pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyranyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and thiazole pyridinyl; each of these heterocycles, independently of each other, can be substituted by one, two or three substituents selected from hydroxy, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, cyano, amino, nitro, mono- or di (C C 4 alkyl) amino, mono- or di (C 1 -C 4) alkylamino, mono- or di (C 1 -C 4 alkyl) aminocarbonyl, mono- or di (aryl) amino, halogen, C 1 -C 4 halogen alkyl, C 1 -C 4 alkyloxycarbonyl, aryl, furanyl, thienyl, pyridinyl, piperidinyl, C 1 -C 4 alkylcarbonylpiperidinyl and C 1 -C 4 alkyl substituted with hydroxy, C 1 -C 4 alkyloxy, aryl, piperidinyl, amino mono- or di (CrC 4 alkyl) amino or C 3 -C 7 cycloalkyl; in the manufacture of a drug useful for treating eosinophilic-dependent inflammatory diseases.

2. The use of the compound according to claim 1, wherein the eosinophilic-dependent inflammatory disease is bronchial asthma.

3. The use of the compound according to claim 1, wherein the eosinophilic-dependent inflammatory disease is atopic dermatitis.

4. The use of the compound according to claim 1, wherein the eosinophilic-dependent inflammatory disease is allergic rhinitis.

5. The use of the compound according to claim 1, wherein the eosinophilic-dependent inflammatory disease is allergic conjunctivitis.

6. The use of the compound according to any of claims 1 to 5, wherein the 6-azauracil moiety is in the para position with respect to the central chiral carbon atom; p is 1 or 2, and one of the substituents R3 is chloro positioned ortho to the central chiral carbon atom; q is 1 or 2, and one of the substituents R 4 is chloro at the 4-position.

7. A compound of the formula: an N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein p, q, R1, R2, R3 and R4 are as defined in claim 1, with the proviso that the following conditions apply to the variables R3a, R3b, R3c, R4a, R4b, R4c, R1 and R2, in the compounds of the following general structure: a) if R3a, R3b, are chlorine: R4a is 4-chloro, and R1, R3c, R4b and R4c are nitrogen; then R2 is not aminocarbonyl, carboxyl, chlorocarbonyl, 1-piperidinylcarbonyl, methoxycarbonyl, methylaminocarbonyl, 1-pyrrolidinylcarbonyl, 4-methyl-1-piperazinylcarbonyl, methylcarbonyl; NH2-C (= S) -, phenylcarbonyl; b) if R3a is chlorine; R 4a is 4-chloro; and R1, R3, R3c, R4b and R4c are hydrogen; then R3 is not aminocarbonyl, carboxyl, NH2-C (= S) -, chlorocarbonyl, methylaminocarbonyl, (4-methylcarbonyl-1-piperazinyl) carbonyl, (4-phenylmethyl-1-piperazinyl) carbonyl or methyloxycarbonyl; and c) if the combination of R1, R3a, R3b, R3c, R4a, R4a and R4c, is one of the following combinations: then R2 is not cyano.

8. The compound according to claim 7, further characterized in that R 2 is cyano or a radical of formula -C (= X) -Y-R 5, wherein R 5 is hydrogen, C C β alkyl or aryl, while Y is O, S o

NR 6, where R 6 is hydrogen or C C alkyloxy; or R 5 is aryl, C C β alkyl, halogen, Het or C C β alkyl substituted with aryl, where Y is a direct bond. 9. The compound according to claim 7 or 8, further characterized in that R3 and R4 independently of each other, are halogen, halogen C Cß alkyl, hydroxy, C C β alkyl, Ci-C β alkyloxy, Cr C 6 alkylcarbonyloxy or aryl.

10. The compound according to any of claims 7 to 9, further characterized in that the 6-azauracil moiety is in the para position with respect to the central chiral carbon atom; p is 1 or 2, and one of the substituents R3 is chloro positioned ortho to the central chiral carbon atom; q is 1 or 2, and one of the substituents R 4 is chlorine at the 4-position.

11. The compound according to claim 7, further characterized in that R 2 is a radical of the formula -C (= X) -Y-R 5 , where Y is a direct link and R5 is Het.

12. The compound according to claim 7, further characterized in that R1 is mono- or di (CrC6 alkyl) amino Ci-Cβ alkyloxy, mercapto; C C β alkylthio or C C β alkyl substituted with mono- or di (Ci-C β alkyl) amino, C α -C 6 alkyloxy or Het.

13. - A process for preparing a compound of formula (I ') according to claim 7, characterized in that it comprises: a) cyclizing an intermediate compound of formula (II), and eliminating group E from the dione thus obtained of formula (III) ): ion b) eliminating the group P in the intermediary compounds of formula (IV); c) converting the function of an intermediate compound of formula (IV) into a suitable leaving group W, such as for example a halogen atom or a sulfonyloxy group, subsequently converting said leaving group W into the intermediate compound thus formed of formula (VI) ), in a nitrile function; whereby a compound of formula (l'-a) is formed: d) reacting the group in an intermediate compound of formula (VII) with a suitable 1 - [(isocyanomethyl) sulfonyl] -4-methylene benzene reagent or with a functional derivative thereof; e) converting the compounds of formula (I ') to each other following the procedures known in the art for transformation and, further, if desired, converting the compounds of formula (I') to a non-toxic acid addition salt, therapeutically effective, by treatment with an acid, or in a non-toxic, therapeutically effective basic addition salt, by treatment with a base, or conversely, converting the acid form of addition salt to the free base by treatment with alkali, or converting the Basic salt of addition in the free acid by acid treatment; and, if desired, preparing the stereochemically isomeric forms of the N-oxide forms thereof.

14. A composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as claimed in claims 11 or 12.

15. A compound comprising a pharmaceutically acceptable carrier and, as an active ingredient. , a therapeutically effective amount of a compound of formula (I) defined in claim 1, together with instructions for its use for the treatment of an eosinophil-dependent inflammatory disease.

16. The compound according to claims 11 or 12, to be used as a medicine.

17. A method for marking a receiver, characterized in that it comprises the following steps: (a) radioactively labeling a compound as defined in claim 1; (b) administering said radiolabelled compound to a biological material; and (c) detect emissions from the radiolabelled compound.

18. - A method for imaging an organ, characterized by the administration of a sufficient amount of a radioactively labeled compound of formula (I) in a suitable composition, and the detection of emissions from the radioactive compound. SUMMARY OF THE INVENTION The present invention relates to the use of the compounds of the following formula: the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p represents 0, 1, 2 or 3; q represents 0, 1, 2, 3, or 4; R 1 represents a hydrogen atom, C C β alkyl, mono- or di (CrC 6 alkyl) amino C C β alkyloxy, mercapto, C C 6 alkylthio, C 3 -C cycloalkyl, aryl or C C β alkyl substituted by mono- or di (C C β alkyl ) amino, CrC6 alkyloxy, aryl or Het; R 2 represents cyano or a radical of formula -C (= X) -Y-R 5; where X represents O or S; Y represents O, S, NR6 or a direct link; R5 represents a hydrogen atom; C3-C cycloalkyl; aryl or C Cβ alkyl optionally substituted, and wherein Y is a direct bond, R5 may also be halogen or Het; R3 and R4 are each, independently of each other, halogen, halogen C, C, alkyl, CrC6, alkyl, hydroxy, CrC6, alkyloxy, C, C6, alkylcarbonyloxy, mercapto, CrC6, alkdffio, CI-CT, alkylsulfonyl; C? -C6 alkylsulfinyl, halogen CrC6 alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di (C C6 alkyl) amino or (C C? Alkylcarbonyl) amino; aryl represents phenyl or substituted phenyl; and Het represents an optionally substituted heterocycle; for the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases; The invention also relates to novel compounds, their preparation and the compositions comprising them. MG P99 / 1582F.