MXPA97004667A - 6- [triazolil [3-trifluoromethyl) phenyl] methyl] -2-quinolinones and quinolinotium - Google Patents

Abstract

This invention relates to compounds of formula (I), the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein R 1 is hydrogen, amino or C 1-4 alkyl, R 2 is hydrogen, halogen or C 1-4 alkyl R3 is hydrogen, halogen or C1-4 alkyl, Y is O or S and -X1 = X2- is a bivalent radical having the formula: -N = CH- (a-1) or -CH = N- (a -2), compositions containing the same and methods for preparing these compounds, also refers to their use as medicine, in particular their use as medicine to treat keratinization disorders.

Description

6- [TRINZOLILC3-TRIFLUQROt1ETIL) FENIL3l1ETILl-2-QUINQLINONflS AND QUINOLINOTIONñS DESCRIPTIVE MEMORY OF THE INVENTION The present invention relates to quinolinones and quinolinothiones, compositions containing the same, and methods for preparing these compounds. It also refers to its use as a medicine, and in particular, its use as a medicine to treat keratinization disorders. EP-0,371,564 describes the derivatives of quinoline and quinolinone substituted with lH-azo.l-1-ylmethyl which suppress the elimination of retinoic acids from plasma, filgunos of these compounds which also have the ability to inhibit the formation of androgens from the progestins and / or inhibit the action of the aromatase enzyme complex. The subject matter of the present invention is a select group of quinolinone and quinolinothion derivatives substituted with lH-azol-1-ylmethyl which are invariably substituted with a portion of 3- (trifluoromethyl) enyl. The unexpected superiority of said select group of compounds over the closest compounds according to the prior art lies in their improved ability to suppress the effects of keratinization. Therefore, the present invention relates to compounds of formula pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein: R 1 is hydrogen, amino or a C 1-47 alkyl R 2 is hydrogen, halogen or C 1-4 alkyl; R3 is hydrogen, halogen or C1-4 alkyl; Y is 0 or S and -? I =: 2- is a bivalent radical having the formula -N = CH- (al) or -CH = N- (0-2) As used in the preceding definitions the The term halogen is generic for fluoro, chloro, bromo and iodo.

The term C 1-4 alkyl defines straight and branched saturated hydrocarbons, having 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl and Similar. It is to be understood that the pharmaceutically acceptable addition salts, as mentioned hereinabove, comprise the forms of acid addition salts which can be conveniently obtained by treating the base form of the compounds of formula (I) with suitable acids such as inorganic acids, for example, hydrohalic acid, for example hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and similar acids; or organic acids, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, alic, tartaric, citric, rnetanosulonic, ethanesulonic, benzenesulonic, p-toluenosulonic, cyclic, salicylic, p-aminosalicylic, paoic and similar acids. Conversely, such forms of acid addition salts can be converted to the free base forms by treatment with an appropriate base. The term addition acid salt also comprises hydrates and solvent addition forms which are capable of forming the compounds of formula (I). Some examples of such forms are eg. hydrates, alcoholates and the like. The term "stereochemically isomeric forms" as used herein defines all possible isomeric forms in which the compounds of formula (I) may occur, unless otherwise mentioned or indicated, the chemical designation of the compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all the diastereomers and enantiomers of basic molecular structure. In particular, the compounds of formula (I) and some of the intermediates hereinafter have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration; said notation R and S is used in correspondence with the rules described in Puré Appl. Chem., 1976, 45, 11-30. Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula, it is implied that they are included within the scope of the present invention. For example, compounds of formula (I) in which R 1 is hydrogen can exist in their tautomeric form. Whenever it is used hereinafter, it is implied that the term compounds of formula (I) also includes pharmaceutically acceptable acid addition salts and all stereoisomeric forms. Some particular compounds of the present invention are those compounds of formula (I) in which -? I =? 2- is a bivalent radical of the formula (a-1). Other particular compounds are those compounds of formula (I) in which R2 is substituted in the 5 or 8 portion of the q? Inolin or quinolinothione portion. Of special interest are those compounds in which -X1 = X2- is a bivalent radical of formula (a-l) and Y is 0. Also of special interest are those compounds in which Y is S and R2 is hydrogen. Other interesting compounds are those compounds of formula (I) wherein R, R2 and R3 are hydrogen. Another group of interesting compounds are those compounds of formula (I) for which the free base form has an R configuration. Preferred compounds are those compounds of formula (I) in which -X * = X2- is a bivalent radical of formula (a), R 1 is hydrogen, amino or methyl, R 2 is hydrogen and R 3 is hydrogen, halogen, methyl or ethyl. The most preferred compounds are those preferred compounds in which Y is 0, R1 is hydrogen or methyl and R3 is hydrogen, methyl or ethyl. The still highly preferred compounds are: 6-C1H-1,2,4-triazol-1-ylC 3 -trifluoromethyl) phenylmethyl 3-2 (1H) -quinolinone, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms of the same. Most preferred is still the compound (-) - (R) -6 ~ ClH-1, 2,4-triazol-1-yl): 3- (trifluoromethyl) phenyl] methyl] 2- (1H) -quinolinone and the acid salts of pharmaceutically acceptable addition thereof. The compounds of formula (I) in which Y is 0 can be prepared, said compounds being represented by the formula (1-b), according to the procedures described in EP-0,371,564. The compounds of formula (1-b) can be further converted to compounds of formula (I) in which Y is S, said compounds being represented by the formula (1-c), using transformation reagents known in the art such as , for example, phosphorous pentasulfide.

Such compounds of the formula can be prepared (1-c) by mixing reagents in an inert solvent in the reaction such as, for example, pyridine. The reaction can be carried out suitably at the reflux temperature of the reaction mixture. In this and the following preparations, the reaction products of the reaction medium can be isolated and, if necessary, further purified according to the methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. Compounds of formula (1-b) wherein R 1 is hydrogen can be prepared, said compounds being represented by formula (Ib-1), by reacting a nitrone of formula (II) with a suitable ester forming reagent such as, for example, the anhydride of a carboxylic acid, for example, acetic anhydride, thus forming the corresponding ester in the 2-position of the quinoline moiety. Such a quinoline ester can be hydrolyzed in situ to the corresponding quinolinone using a base such as, for example, potassium carbonate. Agitation and elevated temperatures can increase the speed of the reaction.

Alternatively, compounds of formula (Ib-1) may be prepared by reacting a nitrone of formula (II) with a sulfonyl containing electrophilic reagent such as, for example, p-toluenesulfonyl chloride in the presence of a base such as, for example, aqueous potassium carbonate. The reaction initially involves the formation of a 2-hydroxyq-inoline derivative which is subsequently tautomerized to the desired quinolinone derivative. Such a reaction can be suitably conducted at room temperature in an inert reaction solvent such as, for example, dichloromethane or toluene. Agitation and application of known conditions in the phase transfer catalysis technique can increase the reaction rate. The compounds of formula (I-b-1) can also be prepared by an intramolecular photochemical rearrangement of the compounds of formula (II). Such rearrangement can be analyzed by dissolving the reagents in a solvent inert in the reaction and irradiating at a wavelength of, for example, 366 nm. It is advantageous to use degassed solutions and conduct the reaction under an inert atmosphere and conduct the reaction under an inert atmosphere such as, for example, argon gas or oxygen-free nitrogen, in order to minimize unwanted side reactions or reduction of the quantum performance.

The compounds of formula (I-b-1) can also be converted to compounds of formula (I-b) wherein R 1 is C 1 -4 alkyl, said compounds being represented by the formula (I-b-2). For example, the compounds of the formula ÍI-b-1) can be N-alkylated with C1-4alkyl wherein L is an exit-reactive group such as, for example, halogen or a sul-onyloxy group, in the presence of a base such as, for example, sodium hydride.

Said N-alkylation can be conveniently carried out by mixing the reactants in an inert solvent in the reaction such as, for example, N, N-dimethylformamide. It may be advantageous to conduct said N-alkylation under an inert atmosphere such as, for example, argon or nitrogen. The compounds of formula (I-b-1) can also be converted to compounds of formula (I-b) wherein R * is amino, said compounds being represented by the formula (I-b-3). For example, the compounds of formula (Ib-3) by N-aminating the compounds of formula (Ib-1) with an ation agent such as, for example, hydroxylamine-O-sulphonic acid at room temperature in a solvent such as, for example, water in the presence of a base such as, for example, sodium hydroxide.

The nitrogens of formula (II) can be prepared by N-oxidizing quinolines of formula (III) with an appropriate oxidizing agent such as, for example, m-chloroperoxybenzoic or phthalic anhydride in combination with hydrogen peroxide. Said N-oxidation can be carried out by mixing reagents at room temperature in an inert solvent in the reaction such as, for example, dichloromethane. Subsequent to the preparation of the intermediates of formula (II), the compounds of formula (I-b) can conveniently be prepared in the manner of an in situ reaction.

(IH) 0D Intermediates of formula (III) can be prepared following the procedures described in EP-0,371,564. A novel approach for preparing the compounds of formula (I ~ b-1) wherein R 3 is hydrogen, said compounds being represented by the formula (I-b-1-a), which involves the process described in scheme (I). The first step involves the protection of a quinolinone of formula (IV-1) wherein halogen represents a halogen atom, in particular, a bromine atom, thus forming a quinoline derivative of formula (IV-2) wherein Z is a protective group such as, for example, methyl, said quinoline derivative is reacted with an organolithium compound such as, for example, n-butyl lithium, in an inert solvent in the reaction such as, for example, tetrahydrofuran , thus replacing the halogen atom in the 6-position of the quinoline portion in the intermediate compounds of formula (IV-2) with a lithium atom. Said liteined quinalin intermediate compound is reacted in situ with 3-trifluoro-benzaldehyde or a functional derivative thereof, thereby forming an intermediate compound of formula (IV-3). The formation of the intermediate compounds of formula (IV-3) from intermediates of formula (IV-2) can be conveniently carried out at low temperatures, preferably at -78 ° C. Intermediates of formula (IV-3) can be oxidized to the corresponding ketones of formula (IV-4) using oxidizing agents known in the art. Said ketones may subsequently be deprotected, thus forming the tautoeric derivatives of quinolinone of formula (IV-5) in the presence of an acid. High temperatures with agitation can increase the speed of the transformation reaction.

SCHEME 1 The compounds of formula (I-b-1-a) can be prepared by reductive alkylation of 1,4-triazole or 1,3,4-triazole with the compounds of formula (IV-5). Said reaction can be conveniently conducted by filtering and heating the reagents in the presence of formic acid and formed as reducing agents optionally in the presence of an acid catalyst such as, for example, hydrochloric acid. If desired, the compounds of formula (I-b-1-a) can be further reacted, according to the methods described hereinabove, to the compounds in formula (I-b) and (I-c). The compounds of formula (I) and their intermediates as prepared in the methods described hereinabove are generally racemic mixtures of enantiomers which can be separated from one another following the resolution procedures known in the art. The racemic compounds of formula (I) or their intermediates can be converted to the corresponding stereoisomeric salt formulas or reaction with suitable chiral acid such as, for example, camphorsulonic acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers thereof are liberated by alkali. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase.

Said pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. For example, enanti-purely pure forms of the compounds of formula (I) can be prepared from enantio purely forms of the compounds of formula (III). The enantiomerically pure compounds of formula (III) can be prepared using separation techniques known in the art. The compounds of the present invention have superior pharmacological properties compared to those of the closest compounds in the art in that they are more effective in suppressing keratinization effects which can be demonstrated in the "Vaginal Keratinization Test on Ovariectomized Rats" as described below in the present. In view of its activity to suppress the effects of keratinization, the compounds of formula (I) are useful in the treatment and / or prevention of keratinization disorders such as, for example, acne, psoriasis, severe psoriasis, laminar ichthyosis, warts on the soles of the feet, callosities, acanthosis nigricans, lichen planus, olluscum, melasma, corneal epithelial abrasion, geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and keloids, epidermolytic hyperkeratosis, Darier's disease, pityriasis rubra pilaris, erythroderma ictrosi congenita, hyperceratosis palraaris et plantaris and disorders Similar. The compounds of formula (I) also suppress the elimination of retinoids in plasma, such as all-trans-retinoic acid, 13-cis-retinoic acid and its derivatives which result in more sustained tissue concentrations of retinoic acid and improved control of the differentiation and growth of various cell types. The properties of delaying the metabolism of retinoic acid should benefit in several experiments in vitro and in vivo. A particular in vitro procedure is described hereinafter and analyzes the inhibitory activity of the compounds of formula (I) on the metabolism of retinoic acid in cancer cells of the human breast. In view of their ability to delay the metabolism of retinoic acid, the present compounds are useful in the prevention and / or treatment of disorders characterized by proliferation and / or abnormal differentiation of cells, such as cancer and, in particular, disorders. of characterization such as those mentioned hereinabove (Van Wauwe et al., 3. Pharmacol. Exp. Ther. 1992, 261 (2), 773-779). In addition, the compounds of formula (I) are useful in suppressing the metabolism of exogenously and endogenously-formed, 25-dihydroxy-vitamin D3. (calcitriol). The inhibitory activity of the compounds of formula (I) and the metabolic degradation of calcitriol can benefit by measuring the impact of said compounds on the degradation of calcitriol in keratinocytes of the human foreskin, pig kidney cells and hepatic cells. to human In view of its inhibitory effect on the metabolism of the cacitriol, the compounds of the formula (I) can be used in the treatment of vitamin E deficiency states. The "classical" application of the vitamin D compounds is in the field of etabic bone disorders. It has been described that calcitriol. it influences the effects and / or the production of interleukins. In addition, calcitriol is useful in the treatment of diseases characterized by proliferation and / or abnormal cell differentiation, in particular keratinization disorders such as those described hereinabove (Bouillon et al., Endocrine Reviews, 19995, 16 , 200-257). In addition, the compounds of the formula (I) inhibit androgen formation from the progestins and inhibit the action of the aromatase enzyme complex which catalyzes the formation of estrogens from androgenic steroids in mammals. In view of the above described uses of the compounds of formula (I) it is inferred that the present invention provides a method for treating warm-blooded animals suffering from diseases that are characterized by increased proliferation and / or abnormal differentiation of normal preneoplastic cells. or neoplastic, either epithelial or esenchymal; whether they are of ectodermal, endodermal or rnesodermic origin; or if they are dependent on estrogen, dependent on adrogens, or not dependent on estrogen or androgens. Such method comprises the systemic or local demonstration of a therapeutic amount of a compound of formula (I) effective to treat the disorders described above, in particular keratinization disorders, optionally in the presence of an effective amount of a retinoic acid, a derivative or a stereochemically isomeric form thereof. The present invention also relates to a method for treating patients suffering from a pathological condition that can be beneficially influenced by the administration of calcitriol or a prodrug thereof, in particular the disorders of q? Eratinization, said method consisting of patient (a) an efficient amount of calc.itriol or a prodrug thereof and (b) an effective amount of the compound of formula (I). Thus, the present invention also relates to compounds of formula (I) as defined hereinbefore for use as a medicine, in particular, for use as a medicine for treating keratinization disorders. The present invention is further related to compounds of formula (I) as defined hereinbefore in combination with a retinoic acid, a derivative or a stereochemically isomeric form thereof, or in combination with calcitriol or a prodrug thereof, to its use as medicine. The present invention also relates to the use of the compounds of formula (I) and the manufacture of a medicament for the treatment of the disorders described above, in particular, keratinization disorders. For ease of administration, the compounds in question can be formulated by producing various pharmaceutical forms. Suitable compositions may be all of the compositions which are generally used to administer drugs systemically or locally. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, optionally in the form of the acid addition salt, as the active ingredient, is combined in close colloidal aggregate with a pharmaceutically acceptable carrier, which can adopt an extensive variety of forms depending on the form of preparation desired for your administration. These pharmaceutical compositions are desirably in the form of a suitable unit dose, preferably for administration orally, rectally, percutaneously or by parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols or the like, can be employed in the case of oral liquid preparations such as suspensions, syrups, elixirs and solid solutions or vehicles such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like, in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients may be included, for example, to aid in solubility. Injectable solutions can be prepared, for example, in which the vehicle comprises saline solution, glucose solution, or a mixture of saline and glucose. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wettable agent, optionally combined with suitable additives of any nature of minor proportions, additives that do not cause significant deleterious effects in the skin. Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various ways, for example as a transdermal patch, as a spot application or as an ointment. The acid addition salts of the compounds of the formula (I) due to their increased solubility in water on the corresponding base form are obviously more suitable in the preparation of aqueous compositions. Suitable compositions for local application are all the compositions usually used for locally administering drugs, for example creams, jellies, bandages, shampoos, dyes, pastes, ointments, balms, powders and the like. The application of said compositions can be by aerosol, for example with a propellant such as nitrogen, carbon dioxide, freon, or without propellant such as a pump spray, drops, lotions or a semi-solid such as a thickened composition that can be applied with a swab. In the particular compositions, the solid compositions such as balms, creams, jellies, ointments and the like will be conveniently used. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used in the specification and the claims herein refer to physically discrete units as unit doses, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. required. Some examples of such dosage unit forms are tablets (including labeled and coated tablets) capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, spoons and the like, and segregated multiples thereof. Other similar compositions are preparations of the cosmetic type, such as toilet waters, compresses, lotions, milky emulsions for the skin and milky lotions. Said preparations contain, in addition to the active ingredient, components usually employed in such preparations. Some examples of such components are oils, fats, waxes, surfactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, pH regulators, preservatives, perfumes, pigments, lower alkanols and the like. If desired, additional ingredients can be incorporated into the compositions, for example inflammatory agents, bactericides, fungicides, disinfectants, vitamins, sunscreens, antibiotics or other anti-acne agents. In another aspect of the invention particular pharmaceutical and cosmetic compositions comprising an inert carrier, an effective amount of a compound of the formula (I) and an effective amount of a retinoic acid, a derivative thereof or a stereochemically isomeric form of the same. Said compositions containing retinoic acid are particularly useful for treating acne and for retarding the effects of skin aging and generally improving the quality of the skin, particularly the human facial skin. In addition, the invention relates to particular pharmaceutical or cosmetic compositions comprising an inert carrier, an effective amount of a compound of formula (I) and an effective amount of calcitriol or a prodrug thereof. These compositions are particularly useful in the treatment of keratinization disorders. A particular embodiment of the invention relates to a product containing retinoic acid or a derivative thereof and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in dermatological disorders. The invention also relates to a product containing calcitriol or a prodrug thereof and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in disorders beneficially affected by calcitriol. Such products may comprise, for example, a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing calcitriol or a retinoid. Such a product may have the advantage that a physician may select, based on the diagnosis of the patient to be treated, the appropriate amounts of each component and the sequence and perioicity of the administration thereof. Experts in the treatment of keratinization disorders can determine the effective therapeutic daily amount based on the results of the analyzes presented hereinafter. An effective therapeutic daily amount would be from about 0.1 mg / kg to about 40 mg / kg of body weight, most preferably from about 0.3 mg / kg to about 10 mg / kg of body weight. It may be appropriate to administer the therapeutically effective dose once daily or as 2, 3, 4 or more sub-doses and appropriate intervals during the day. Such sub-doses can be formulated as unit dosage forms, for example, containing from 0.1 mg to 500 mg and, in particular, from 0.5 mg to 50 mg of the active ingredient per unit dosage form. The exact dose and frequency of administration depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general condition of the patient in question. particular, as well as other medication that the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount can be decreased or increased depending on the response of the treated patient and / or depending on the evaluation of the physician prescribing the compounds of the present invention. The scales of effective daily amounts mentioned hereinabove are therefore only guidelines. The following examples are intended to illustrate and not limit the scope of the present invention.

EXPERIMENTAL PART A. PREPARATION OF INTERMEDIATE COMPOUNDS EXAMPLE 1 a) A mixture of ethyl 4-amino-2-chlorobenzoate (20 g), glycerol (32.17 g) and sodium 3-nitrobenzenesulphonate (46.73 g) in sulfuric acid (75%) (150 i) was stirred for 3 hours. hours at 100 ° C and for 1 hour at 140 ° C. After the mixture was cooled to 60 ° C and ethanol (200 ml) was added, the mixture was stirred for 16 hours at 60 ° C. The ethanol was evaporated and the residue was emptied in ice water, neutralized with NH0H and extracted with ethyl acetate. The separated organic layer was dried over MgSO4, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / ethylene acetate 97.5 / 2.5). The desired pure fractions were collected and evaporated, yielding 7.56 g (28%) of methyl 5-chlor-6-quinolinecarboxylate (intermediate 1). b) Lithium aluminum hydride (1.66 g) was added portionwise to a solution of intermediate 1 (1.11 g) in tetrahydrofuran (325 ml) at 0 ° C under 2 and the mixture was stirred for 1 hour. Ethyl acetate (70 ml) and water (3 ml) were added to the mixture which was subsequently filtered. The filtrate was dried over pgSO4, filtered and evaporated, yielding 7.9 g (93%) of 5-chloro-6-quinolinemethanol (intermediate 2). c) A mixture of intermediate 2 (7.9g) and manganese dioxide (10.64 g) in CH2C12165n) was stirred for 6 hours at room temperature. The mixture was filtered over celite and the filtrate was stirred again with manganese dioxide (10.64 g) for 24 hours. The mixture was filtered over celite and the filtrate evaporated yielding 7.82 g (100%) of 5-chloro-6-q? Inolinocarboxaldehyde (intermediate 3). Similarly, 6-fluoro-6-quinolinocarboxaldehyde (intermediate compound 4) was prepared.

EXAMPLE 2 a) A solution of l-bromo-3-fluoromethylbenzene (10.67 g) in tetrahydrofunane (15 nl) was added dropwise to a suspension of magnesium burrs (1.15 g) in tetrahydrofuran (15 rnl). The mixture was cooled to 0 ° C and a solution of intermediate 3 (7.57 g) in tetrahydrofuran (90 ml) was added dropwise. The mixture was partitioned between ethyl acetate and a saturated aqueous solution of "C1" NH. The organic layer was separated, dried over MgSO *, filtered 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 combined and evaporated, yielding 10.9 g (81%) of (±) -5-chloro-a- [3- (trifluorornethyl) phenyl) -6-quinolinemethanol (intermediate compound 5). b) Thionyl chloride (8 ml) was added dropwise to a solution of intermediate 5 (8 g) in CH 2 Cl 2 (400 ml) at 0 ° C and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water that was alkalized with a saturated solution of K2CO3. The separated organic layer was dried over MgSO *, filtered and the filtrate was evaporated, yielding 8.4 grams (100%) of (±) -5-chloro-6-C-chloroC3- (trifluoromethyl) phenyl] -rnetillquinoline (intermediate 6) . c) A mixture of intermediate 6 was stirred (8.4 grams), 1,2,4-triasol (4.89 grams) and potassium carbonate (9.78 grams) in acetonitrile (300 L) and refluxed for 12 hours. The solvent was evaporated and the residue was removed between CH2Cl2 and water. The organic layer was dried over MgSO *, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (as follows: CH2Cl2 / CH30H / NH "0H 98.5 / 1.5 / 0.14). The pure fractions were combined and the solvent was evaporated. The residue of the diisopropyl ether / petroleum ether was crystallized, yielding 1.51 g, (32%) of (±) -5-chloro-6-ClH-1, 2,4-triazol-1-ylC3- (trifluoromethyl) phenyl] - methyl] quinoline (intermediate 7; 144.5 ° C). Similarly, the following were prepared: (±) -8-methyl-6-ClH-1, 2,4-t-riazole-1-ylC3-y tri-luoromethyl-1-enyl] -methyl] quinoline (intermediate 8; mp 108.9ßC) and (±) -8-fluoro-6-tlH-l, 2,4-triazol-l-yl [3- (trifluoroethyl) phenylmethyl] quinoline (intermediate 9, mp 146.6 ° C) .

EXAMPLE 3 The racemic mixture of 6-C1H-1, 2,4-triazol-1-ylC3- (trifluoromethyl) phenyl] -methyl] quinoline (10 g), described and exemplified in EP-371,564 was separated to its pure enantiomers on a column Chiracel ODR (eluent: ethanol / hexanes 1/1). The fractions of the first eluted peak were pooled, combined and the solvent was evaporated, yielding 3.6 g of (±) - (S) -6-ClH-1, 2,4-triazol-1-ylC3- (trifluoromethyl) phenyl] -methyl] quinoline (intermediate compound 10). The pure fractions of the second eluted peak were pooled, combined and selected with diethyl ether. The separated organic layer was filtered and the solvent was evaporated yielding 3.48 g of (-) - (R) 6-ClH-1, 2,4-triazol-1-ylC3- (trifluoromethyl-phenyl] -methyl] quinoline (intermediate compound 11) EXAMPLE 4 Iodomethane (8.8 mL) was added to a stirred mixture of (±) 6-ClH-1, 2,4-triazol-1-ylC3- (trifluoromethyl-phenyl] -methyl] q-inolin (10 g) and N, N-dimethylformamide (100 mL) at 0 ° C under N2 was added in portions of potassium butoxide (9.5%) and the mixture was stirred for 2 hours at room temperature The mixture was partitioned between ice water and CH2Cl2.

The separated organic layer was washed with water, dried over MgSO *, filtered and the filtrate was evaporated. The oily residue was purified by column chromatography on silica gel (eluent: toluene / 2-propanol 94/6). They met and the pure fractions evaporated. The residue was converted to the nitric acid salt (1: 2) in CH 3 OH and crystallized from 2 propane / diethyl ether, yielding 1.15 g (9%) of (±) -6-ClH-1 dinitrate, 2.4 -triazol-l-ylC3- (trifluoromethyl) phenyl-methyl] -quinoline (intermediate 12, mp 1.16.4 ° C). Similarly, (±) -6-C1H-1,2,4-triazol-1-ylC3- (tri fluoromethyl) phenyl] -profyl] -quinoline (intermediate 13) was prepared; (±) -6-ClH-1,2,4-triazol-l-ylC3- (trifluoromethyl) phenyl] -methyl-propyl] quinoline (intermediate 14); and (±) -6-ClH-1,2,4-triazol-1-ylC3- (trifluoroethyl) phenyl] -pentyl] -quinoline (intermediate 15).

EXAMPLE 5 Potassium t-butoxide (0.975 g) was added to a stirred mixture of (±) 6-ClH-1, 2,4-triazol-1-ylC3- (trifluoromethyl) phenyl] methyl] quinoline (2.7 g) in N, N-dimethylformamide a (80 mL) at 0 ° C under N2. The mixture was stirred for 30 minutes at 0 ° C and N-fluorosultam (2.43 g) described in Helv. Chim. Minutes 72 p. 1248 (1989). Subsequently the mixture was stirred at 0 ° C for one hour and at room temperature for one hour. A few rnl of water were added and the solvent evaporated. The residue was partitioned between water and ethyl acetate. The separated organic layer was washed with water, dried over MgSO *, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH30H 98/2). They met and the pure fractions evaporated. The residue was converted to the ethanedioic acid salt (1: 1) in 2-propanone / diethyl ether, yielding (±) -6-1. fluoro of (lH-1, 2,4-triazol-1-ylC3- (tri-fluoromethyl) phenyl] rnethyl] quinoline (intermediate 16, mp 142.6 ° C).

EXAMPLE 6 3-Chloro-peroxibensic acid was added in portions (49 g) to a solution of intermediate 11 (50.3 g) and CH2Cl2 (50.0 ml) and the mixture was stirred for one hour at room temperature. The mixture was sectioned with a 10% solution of NaHCOß. The separated organic layer was washed with a saturated solution of NaCl, dried over MgSO.j, filtered and the filtrate was evaporated, yielding (-) - (R) (±) -6-ClH-1, 2 oxide, 4-triazol-1-yl E3- (tri fluoromethyl) phenyl] methyl] quinoline (intermediate 17, mp 123.2 ° C). Similarly, the following intermediate compounds were prepared.

EXAMPLE 7 a) Butyl lithium (12.5 ml) was added dropwise at -78 ° C to a solution of 6-bromo-2-methoxyq-inoline (4 g in tetrahydrofuran (160 ml). Mix at -78 ° C for 15 minutes, a solution of 3- (trifluoromethyl) -benzaldehyde (3.51 g) in tetrahydrofuran (40 rnl) was added dropwise and the mixture was stirred at -78 ° C for 30 minutes, then it was quenched with water (50 ml) and extracted with ethyl acetate. The organic filtrate was separated, washed with saline, dried (1 g <0>, filtered and the solvent was evaporated) The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3 OH 97/3) The pure fractions were combined and the solvent was evaporated, yielding 3.7 g, (66%) of (±) -2-methoxy-aC-3- (trifluoromethyl) phenyl] -6-quniline-methanol (intermediate 28). b) A mixture of intermediate 28 (1 g) and HCl (25 ml) was stirred.; 3N) and refluxed for 2 hours. The solution was basified with NaOH and extracted with CH2Cl2. The organic layer was separated, washed with saline, dried over MgSO4, filtered and the solvent was evaporated, yielding 1.8 g of (±) -6-ChydroxyC3- (tri fluoromethyl) phenyl] methyl] -2 (1H ) -quinoline (intermediate 29). c) Thionyl chloride (12.3 rnl) was added dropwise at 0 ° C to a solution of intermediate 29 (12.3 g) in CH 2 Cl 2 (900 ml) and the mixture was stirred for 1 hour. Thionyl chloride (12.3 ml) was added dropwise again at 0 ° C and the mixture was stirred at room temperature for 1 hour. Thionyl chloride (12.3 ml) was added dropwise again to 1 ° C and the mixture was stirred at room temperature for 1 hour.

The mixture was emptied on ice and extracted. The organic layer was dried over MgSO *, filtered off and the solvent was evaporated, yielding 13 g (100%) of (±) -6-Chlorot3- (trifluoromethyl) phenyl] methyl] -2- (lH) -q? inolin (intermediate compound 30).

B. PREPARATION OF FORMULA COMPOUNDS (I) EXAMPLE B A solution of 10% K2CO3 (700 mL) and p-toluenesulfonyl chloride (36.8 g) was added to a solution of intermediate 17 (52.5 g) in CH2Cl2 (700 mL) and the mixture was stirred at room temperature for 1 hour. hour. The mixture was washed with a saturated NaCl solution, the separated organic layer was dried over MgSO4, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH 96.5 / 3.5). They met and the pure fractions evaporated. The residue of methyl ethyl ketone / isopropyl ether was crystallized, yielding 15.3 g (29%) of (-) - (R) -6-t: iH-1, 2,4-triazol-1-ylC3- (tri-fluoromethyl) phenyl] methyl] -2 (lH) -quinoline (compound 1; mp 192.8 ° C; [a] 20"= -41.05 ° (c = 99.87 mg / lDml tanol)).

EXAMPLE 9 Alternatively, compound 1 was prepared by stirring a solution of intermediate 17 (1.2 g) in acetic anhydride (10 ml) for 12 hours at 140 ° C. The excess acetic anhydride was evaporated, the mixture was made alkaline with a 10% K2SO3 solution and extracted with CH2Cl2. The separated organic layer was washed with a saturated solution of NaCl, dried over M S ?4, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent CH 2 Cl 2 / CH 3 OH 95/5). The pure fractions were combined, evaporated and further purified by column chromatography over Chiracel ADR (eluent: n-hexane / ethanol 90/10). The pure fractions were pooled and evaporated, yielding 0.235 g (33.7%) of compound 1 (mp 176.0 ° C, Ca] 2 D = -45.62 ° (c = 10.96 rng / 10 ml methanol) The above reaction procedure was repeated a number of times and a mixture of the resulting fractions in ethyl methyl ketone was dissolved ( 300 ml) and warmed to complete the dissolution The mixture was filtered while being moderately hot The filtrate was allowed to stand for 18 hours, allowing the compound to recrystallize The precipitate was separated by filtration, washed with isopropyl ether (100 ml) and dried, yielding 118 g (90.8%) of compound 1. This fraction was dried again, yielding 109.5 g (64.2%) of compound 1 (mp 195ßC; Ca] 20 D = -42.12 ° (c = 99.23 mg / 10 ml nithanol).

EXAMPLE 10 The mixture of intermediate 30 (0.846 g), 1,2,4-triazole (0.346 g) and potassium carbonate (0.7 g) in CH 3 CN (30 ml) was stirred and refluxed for 2 hours. The solvent was evaporated and the residue was taken up in water and extracted with CH2Cl2. The organic layer was dried over rlgSO ^, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 / CH3OH / NH4OH 98/2 / 0.1) and the solvent was evaporated from the desired fraction, yielding 0.25 g (27%) of (±) -6- ClH-1, 2,4-triazol-1-ylC3- (tri-luomomethyl) phenyl-3-methyl-3- (1H) -quinoline (compound 3). The following table lists that they were prepared in a manner similar to one of the examples mentioned above.

EXAMPLE 11 A mixture of compound 3 (10 g) in N, N-dimethylformamide (100 ml) is stirred at room temperature under N2. Sodium hydroduro proportions (0.51 g) were added and the mixture was stirred for 15 minutes. The mixture was cooled, iodomethane was added dropwise and the reaction mixture was stirred for 12 hours. The solvent was evaporated and the residue was partitioned between CH2 and Cl2 and water. The separated organic layer was dried over MgSO4, filtered and the filtrate was evaporated. The oresidue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 98/2 / 0.1). The pure fractions were combined and the solvent was evaporated. The residue of methyl ethyl ketone / diethyl ether was crystallized, yielding 2.9 g (28%) of (±) -l-methyl-6-ClH-1, 2,4-triazol-1-ylC3- (tri fluoromethyl) phenyl3-methyl3-2 ( lH) -quinolinone (compound 12; p, f, 186. 7 ° C). Similarly, the following compounds were prepared: EXAMPLE 12 A mixture of compound 3 (7.3 g) and NaOH was stirred (4.12 g) in water (200 ml) at room temperature for 15 minutes. Hydroxylamine-O-sulphonic acid proportions (6.3 g) were added and the mixture was stirred for 12 hours. The filtrate was separated by filtration and crystallized from 2-propanol, yielding 2.3 g of (±) - (1-amino-6-lH-1, 2,4-triazol-1-yl-C3- (tri fluoromethyl) phenyl3methyl -2 (lHl) -quinilinone (compound 20; mp 222.3 ° C).

EXAMPLE 13 A mixture of compound 12 (7 g) and pentasulfido foephorus (8.1 g) and pyridine (100 ml) was stirred and refluxed for 4 hours. The solvent was evaporated, the residue between water and CH2Cl2 was desiccated. The separated organic layer was dried over MgSO 4, filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 99/1 / 0.1). They met and the pure fractions evaporated. The residue of diisopropyl ether / ethyl ethyl ketone / 2-propanone was recrystallized, yielding 1.4 g (20% of (±) -l-methyl-6-ClH-1, 2,4-triazol-1-ylC 3- (tri fluoromethyl] phenyl] -2 (lH) -quinolinothione (compound 21; mp 143.7 ° C.) Similarly, (±) -6-ClH-1, 2,4-triazol-1-ylC 3- (tri fluoromethyl) was prepared. phenyl] -2 (lH) -quinolinothione (compound 22).

EXAMPLE 14 Compound 1 (3.7 g) was dissolved in ethanol (50 ml). HBr bubbles (gas) are selected through the mixture for 2 minutes. The solvent was evaporated and the residue was dissolved in CH3CH / C2H-5OH 80/20. The solvent was evaporated and the residue triturated in roethyl isobutyl ketone. The precipitate was separated by filtration and dried. This fraction of ethanol was recrystallized in a closed chamber, saturated with 2-propanol. The liquid was washed and the crystals dried, yielding 0.74 g (16.4%) of (R) -6-ClH-l, 2,4-triazol-1-ylC3- (trifluoromethyl) enylmethyl] -2- (1H) monohydrobromide. ) -quinolinone (1: 1) (compound 23; mp 220 ° C).

C. PHARMACOLOGICAL EXAMPLES EXAMPLE 15 Inhibition of metabolism of retinoic acid (RA) MCF-7 human breast cancer cells were cultured as strain cultures according to the protocols known in the art. One day before the experiment, RA was added to the strain cultures to stime RA metabolism. At the beginning of the experiment, suspensions of cells were incubated in a tissue culture medium containing 3H-RA as a substrate. Different concentrations of the test compound (dissolved in 1% DMSO) were added to the mixing mixtures and at the end of the incubation the unmetabolized RA is separated from its polar metabolites. The fraction containing the polar metabolites labeled with 3H was pooled and counted in a centillion counter. For each experiment, a control and an indistinct in parallel were conducted. The ICso values listed in Table 1 are the concentrations needed to reduce the amount of metabolites to 50% of the control.

EXAMPLE 16 Vaginal keratinization test in rats undergoing ovariectomy Rats subjected to ovariectomy were injected subcutaneously with a solution of sesame oil containing 10 micrograms of oestradiol undecylate of 0.1 ml volume per 100 g of body weight and the control animals were injected with sesame oil. On days 1, 2 and 3, the test animals were treated once per day with a per os dose of the test compound and control animals with the drug vehicle (PEG 200). One day after the last treatment, the animals were sacrificed and their vaginas were processed for a histological evaluation according to the method described in 3. Pharmacol. Exp. Ther. 261 (2), 773-779 (1992). A dose in which 50% of the rats examined show complete suppression of the keratinization effects induced by the estradiol undecylate, is defined as active dose. The minimum active dose (LAD) for the compounds of the present invention is listed in Table 1. The expected superiority of the compounds of the present invention over the closest other compounds known in the art is shown in Table 2. In said table, the keratinization effect in the present compound number 3 is compared with the structurally closest compounds known in the art, describing being the last in EP-0,371,564.

TABLE 2 D. EXAMPLES OF COMPOSITION The following formulations exemplify typical pharmaceutical compositions suitable for systemic or local solubilization to animal and human individuals in accordance with the present invention. "Active ingredient" (A.l.) as used in all of these examples refers to a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

EXAMPLE 17 Oral solution 9 g of methyl 4-hydroxybenzoate were dieced and 1 g of propyl 4-hydroxy-benzoate in 4 1 of purified water in boiling. In 3 1 of this solution, 10 g of 2,3-hydroxybutanedioic acid were first dissolved and then 20 g of A.l. 1 and / or 0.2 g of A.l. 2 . The last solution of the excess part of the previous solution was combined and 12 1 of 1,2,3-propane-triol and 3 1 of 70% sorbitol solution were added to the honeycomb. 40 g of sodium saccharin were dissolved in 0.5 1 of water and 2 ml of raspberry essence and 2 ml of wild gooseberry essence were added. The last solution was combined with the first water was added as much as was sufficient to a volume of 20 1 providing an oral solution comprising 5 mg of A.l. 1 and / or 0.05 rng of A.l. 2 per teaspoon (5 mi). The resulting solution was emptied into suitable containers.

EXAMPLE 18 Oral drops 500 g of A.l. in 0.5 1 of 2-hydroxy-propanoic acid and 1.5 1 of polyethylene glycol at 60-80 ° C.

After cooling to 30-40 ° C, 35 1 of polyethylene glycol was added and the mixture was stirred well. A solution of 1750 g of sodium saccharin in 2.5 1 of purified water was then added and while stirring 2.5 1 of cocoa flavoring and polyethylene glycol was added as was sufficient to a volume of 50 1, providing a solution of oral drops comprising 10 mg / ml Al The resulting solution was emptied into suitable containers.

EXAMPLE 19 Capsules g of A.l. were stirred vigorously with each other. 1 and / or 0.2 g of A.l. 2. 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide and 1.2 g of magnesium stearate. The resulting mixture was subsequently emptied into 1000 suitable capsules of hardened gelatin, each containing 20 mg of A.l. 1 and / or 0.2 mg of A.l. 2.

EXAMPLE 10 Injectable solution 0.5 mg of A.l. 1 and / or 0.5 (n of A.l. 2, 50 mg of anhydrous glucose and 0.332 ml of concentrated hydrochloric acid with 0.8 ml of water for injections. Sodium hydroxide was added until pH = 3.2 ± 0.1 and water was added to 1 ml. The solution was sterilized and emptied into sterile containers.

EXAMPLE 21 Film coated tablets Preparation of the core of the tablet A mixture of 100 g of AI, 570 g of lactose and 200 g of starch was mixed well and then a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinyl pyrrolidone was moistened (Kollidon-K 90 CR ) in approximately 200 ml of water. The wet powder mixture was sieved and dried and sieved again. Afterwards, 100 g of microcrystalline cellulose (Avicel (R) and 15 g of hydrogenated vegetable oil (Sterotex < R >) were added, and the whole was compressed into tablets, giving 10000 tablets, each one 10 mg of the ingredient Active coating To a solution of 10 g of methylcellulose (Methocel 60 HG <r> in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose (Ethocel 22 cps < R) in 150 ml of dichloromethane. Then 75 ml of dichloromethane were added in 2.5 ml of 1,2,3-propane-triol, 10 g of polyethylene glycol were dissolved in 75 ml of dichloromethane, the last solution was added to the first and then 2.5 was added. g of magnesium octadecanoate, 5 g of polyvinyl pyrrolidone and 3 ml of concentrated dye suspension (Opaspray Kl-2109 (R)) and the whole was homogenized The tablet cores were coated with the mixture thus obtained in a coating apparatus.

EXAMPLE 22 2% cream 75 ml of stearyl alcohol are introduced, 2 mg of cetyl alcohol, 20 mg of sorbital monostearate and 10 mg of isopropyl iristate to a double walled lined vessel and heated until the mixture is completely melted. The mixture is added to a mixture prepared separately from purified water, 200 mg of propylene glycol and 15 mg of polysorbate 60 having a temperature of 70 to 75 ° C while a homogenizer for liquids is used. The resulting emulsion is allowed to cool to below 25 ° C while mixing continuously. A solution of 20 mg of A.I., 1 mg of polysorbate 80 and purified water and a solution of 2 mg of anhydrous sodium sulfide in purified water to the emulsion is added immediately while mixing continuously. The mixture, 1 g of A.l. It is homogenized and emptied into suitable tubes.

EXAMPLE 23 2% local gel To a solution of 200 mg of hydroxypropyl-b-cyclodextrin in purified water, 20 mg of A.l. while stirring. Hydrochloric acid is added until the solution is complete and then eondiohydroxide is added, pH 6.0. This solution is added to a dispersion of 10 mg of carrageenan PJ in 50 mg of propylene glycol while mixing. While mixing slowly, heat the mixture to 50 ° C and allow it to cool to about 35 ° C on top of which 50 mg of 95% (v / v) ethyl alcohol is added. The rest of the purified water is added as much as possible and the homogeneous mixture is mixed.

EXAMPLE 24 Local cream 25% To a solution of 200 mg of hydroxypropyl-b-cyclodextrin in purified water is added 20 mg of A.l. while stirring. Hydrochloric acid is added until the solution is complete and then sodium hydroxide is added to a pH of 6.0. While stirring, 50 mg of glycerol and 35 mg of polysorbate 60 are added and the mixture is heated to 70 ° C. The resulting mixture is added to a mixture of 100 ng of mineral oil, 20 mg of stearyl alcohol, 20 mg of cetyl alcohol, 20 mg of glycerol monostearate and 15 mg of sorbate 60 having a temperature of 60 ° C while mixing slowly. After cooling to a temperature of 25 ° C, the reaction of the purified water is added as much as 1 g and the mixture is mixed until it is homogeneous.

EXAMPLE 25 Formulation of the 2% liposome A mixture of 2 g of A.l. microfine, 20g of foefatidil choline, 5g of coleeterol and 10 g of ethyl alcohol and heated to 55-60 ° C until the solution is complete and a solution of 0.2g of methyl paraben, 0.02g of propyl paraben, 0.15 is added g of disodium edetate and 0.3 g of sodium chloride in purified water while homogenizing. 0.15g of hydroxypropyl methylcellulose in purified water is added at 100g and mixing is continued until the expansion is complete.

EXAMPLE 26 Formulation of 2% liposome A mixture of lOg of phosphatidyl choline and lg of cholesterol in 7.5 g of ethyl alcohol is stirred and heated to 40 ° C until this is complete. Dissolve 2g of A.l. microfine in purified water by mixing while heating at 40 ° C. The alcohol solution is slowly added to the aqueous solution while it is homogenized for 10 minutes. 1.5g of hydroxypropylmethylcellulose is added in purified water while mixing until the expansion is complete. The resulting solution is adjusted to a pH of 5.0 with 1 N sodium hydroxide and diluted with the remainder of the purified water to lOOg.

Claims (14)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of formula a pharmaceutically acceptable addition acid salt to a stereochemically isomeric form thereof, wherein: l is hydrogen, amino or C?-alkyl; R 2 is hydrogen, halogen or C 1-4 alkyl; R3 is hydrogen, or halogen or C1-4 alkyl; And it is O or S; and -Xi =? 2- is a bivalent radical having the formula -N = CH- (a-1) or -CH = N- (a-2).
2. 2. A compound in accordance with the claim 1, further characterized in that - ?? = X2- is a bivalent radical of formula a-1.
3. 3. A compound in accordance with the claim 2, characterized further because Y is 0. 4.- A compound in accordance with the claim 3, further characterized in that R * is hydrogen or methyl, R2 is hydrogen and R3 is hydrogen, methyl or ethyl. 5. A compound according to claim 1, further characterized in that the compounds are 6-ClH-l, 24-triazol-1-ylC3- (trifluoromethyl] phenyl3methyl] -2 (lH) -quinolinone, especially (-) - (R) -6-ClH-1, 2,4-triazol-1-ylCtrifluoromethyl] phenyl] methyl] -2 (1H) -quinolinone, or pharmaceutically acceptable acid addition salts thereof. comprises a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as claimed in any of claims 1 to 5. 7. A composition comprising a pharmaceutically acceptable carrier and, as active ingredients, a) an effective amount of retinoic acid, a derivative or a stereochemically isomeric form thereof; and b) a therapeutically effective amount of a compound as claimed in any one of claims 1 to 5. 8. A composition comprising a pharmaceutically acceptable carrier and , as active ingredients, a) an effective amount of calcitriol or a prodrug thereof, and b) a therapeutically effective amount of a compound as claimed in any of claims 1 to 5. 9. A process for preparing a composition as claimed in any of claims 6 to 8, further characterized in that a pharmaceutically acceptable carrier is intimately mixed with the active ingredients. 10. A compound as claimed in any of claims 1 to 5 for use as a medicine. 11. - A compound as claimed in any of claims 1 to 5 for use as a medicine for treating keratinization orders. 12. The use of a compound as claimed in claims 1 to 5 in the manufacture of a medicament for the treatment of keratinization disorders. 13.- An intermediate compound of formula where R, R3 and - ?? =? 2- are defined as in claim 1, an acid addition salt to a stereoisomeric form of the ism. 14. A process for preparing a compound as claimed in claim 1, further characterized in that: a) a nitrone of formula wherein R2, R3 and -? i =? 2- are defined as in claim 1, are reacted with a suitable ester-forming reagent or as an electrophilic reagent containing sulfonyl, or dissolved in an inert solvent in the reaction and radiates, thus obtaining a compound of formula b) a compound of formula wherein R2, R3 and -? i =? 2- are defined by claim 1, is N-alkylated with C1-4 alkyl where L is an exit reactive group, thereby obtaining a compound of formula Cμ. rent c) a compound of formula wherein R2, R3 and -? i =? 2- are defined as in claim 1, is reacted with an amination agent, thereby obtaining a compound of formula d) a compound of formula wherein *, R, R3 and -? i =? 2 - are defined as in claim 1, is converted using transformations known in the art to a compound of formula e) a compound of formula wherein and -? i =? 2- are defined as in claim 1, reacted with 1,2,4-triasol or 1,3,4-triazole in the presence of a reducing agent and optionally in the presence of an acid catalyst , to the compound of formula and further, if desired, converting the compounds to formula (I) to an acidic addition salt by treatment with an appropriate acid or, conversely, converting the acid addition salt to the free base by treatment with alkali; and / or preparing the stereochemically isomeric forms thereof.