MXPA99010961A - Use of 4-substituted tetrahydropyridines for making medicines acting on tgf-&bgr;1 - Google Patents

Abstract

The invention concerns a compound of formula (I) for preparing pharmaceutical compositions designed to increase the proportions of circulating, cellular and extracellular TGF-&bgr;1.

Description

USE OF TETRAHYDROPYRIDINES 4-YOUR BSTITUIDES TO MAKE MEDICINES THAT ACT ON TGF-B1 DESCRIPTION OF THE INVENTION The present invention relates to the use of certain derivatives of 1, 2,3,6-tetrahydropyridine, and its pharmaceutically acceptable salts and solvates for the preparation of medicaments capable of increasing the levels of TGF-β1 (transforming growth factor-β1). TGF-β1 is a ubiquitous and multifunctional peptide, which is constituted, in its formative, by two identical subunits linked by a disulfide bridge. As illustrated by P.

Bedesse and V. Paradis (Journal of Hepatology, 1995, 22, 37-42), TGF-β1 has been identified as a factor that induces cell growth of transformed fibroblasts, but many other cell functions have been successfully discovered. The application WO 93/09808 describes the use of TGF-β1 for the treatment of damage to the central nervous system. The applications WO 96/34881 and WO 94/17099 claim novel peptides, which have an activity similar to that of TGF-β1, and which can be used for the treatment of several pathologies. TGF-β1 for example is involved in the control of the cell cycle, in angiogenesis, in cell differentiation, in embryogenesis, in tissue repair, as well as in apoptosis. Among these activities, the anti-apoptotic effect of TGF-β1 is very important due to its pharmacological implications. "Apoptosis" or "programmed cell death" indicates all the physiological processes linked to cell death. In its terminal phase, apoptosis is characterized by an activity of endonucleases, which unfold DNA double chain structure in the internucleosomal regions, thus generating mono- and oligo-nucleosomes, which form complex with histones. An enrichment in oligo- and mono-nucleosomes linked to histones is thus observed in the cytoplasm of apoptotic cells. Although this phenomenon is physiological, in contrast to necrosis, it can also be caused by pathological stimulation. D. A. Carson and J. M. Ribeiro reports, (The Lancet 1993, 341, 1251-1254), the role of apoptosis in certain pathologies such as immuno-depression, immune deficiencies in patients presenting with AIDS, cell aging, and degenerative disease. J. Mathieu et al. (Ann. Pharmaceutiques francaises 1996, 54, , 193-201) demonstrated that the pathological effects caused by chemical and physical agents such as free radicals and ionization radiation are caused by the pro-apoptotic effects of these agents. The products of apoptosis regulation were described in the patent application WO 96/21449. The general formula includes tant inhibitors as stimulators of apoptosis. without giving the meaning of distinction between one and the other. It has now been found that certain tetrahydropyridines increase the circulation and cellular and extracellular levels of TGF-β1. In this way, the object of the present invention is the use of 4, 4-substituted 1, 2,3,6-tetrahydropyridine of the formula (I): wherein: -Ri represents a halogen or a CF3, an alkyl group of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; -And represents a nitrogen atom or a CH group; -Z 'and Z "ccaaddaa uunnoo rreepprreesseennttaann hhiiddrróóggeennoo oo uunn ggrruuppoo aallqquuiilloo of 11 to 3 carbon atoms, or one represents hydrogen and the other represents a hydroxy group, or both, together, represent an oxo group; -Z represents * a phenyl radical; * monosubstituted or with a substituent X, X being: a) an alkyl group of 1 to 6 carbon atoms; alkoxy of 1 to 6 carbon atoms; carboxyalkyl of 3 to 7 carbon atoms; alkoxycarbonyl of 1 to 4 carbon atoms-alkyl of 1 to 6 carbon atoms; carboxyalkoxy of 3 to 7 carbon atoms or alkoxy carbonyl of 1 to 4 carbon atoms-alkoxy of 1 to 6 carbon atoms; b) a group selected from the group of cycloalkyl of 3 to 7 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, cycloalkylamino of 3 to 7 carbon atoms and cyclohexenyl, it being possible for said group is substituted with a halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, amino, mono or dialkylamino of 1 to 4 carbon atoms; c) a group selected from phenyl, and phenoxy, phenylamino, n-alkylphenylamino of 1 to 3 carbon atoms, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl, it being possible for said group to be mono- or poly-substituted in the phenyl group with a halogen, CF3, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, amino, mono or dialkylamino of 1 to 4 carbon atoms, acylamino of 1 to 4 carbon atoms, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms , aminocarbonyl, mono or dialkylamino of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; A disubstituted phenyl radical with a substituent R2, R2 being a halogen or a hydroxy group, methyl, ethyl, alkyl of 3 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, or trifluoromethyl, and with a substituent X, X being defined as above: * a 1-naphthyl or 2-naphthyl radical; * a 1-naphthyl or 2-naphthyl radical substituted at positions 5, 6, 7 and / or 8 with 1 or 2 hydroxyl groups, one or two alkoxy groups of 1 to 4 carbon atoms or a 6,7-methylenedioxy group; -o Z "is hydrogen and Z and Z 'represent, each independently, an unsubstituted or mono, di or trisubstituted phenyl group, or one of its pharmaceutically acceptable salts or solvates, for the preparation of pharmaceutical compositions capable of increasing the circulation and cellular and extracellular levels of TGF-β1 According to an advantageous aspect, the object of the invention is the use of a compound of the formula (I), wherein Y is CH and R is o- or m- CF3 According to a preferred aspect, Y is CH, R ^ is o- or m-CF3 and Z 'and Z "are hydrogen. According to another preferred aspect, Y is CH, R ^ is o- or m-CF, Z 'and Z "represent an oxo group and Z is 4-diphenol, In accordance with a further advantageous aspect, the object of The invention is to use the compound of the formula (I), wherein Y is CH, RT is o- or m-CF3, Z 'and Z "are hydrogens, and Z represents a monosubstituted phenyl radical with a substituent X, X being a), b), c) or one of its pharmaceutically acceptable salts or solvates.

According to another preferred aspect, the invention relates to the use of the compound of the formula (1) wherein Y is CH, R2 is o- or / 77-CF3, Z 'and Z "are hydrogen and Z represents either phenyl or monosubstituted radical with a group X ', X' being an unsubstituted phenyl 0 substituted with 1 to 3 halogens, 1 to 3 CF3, 1 to 3 alkyls of 1 to 4 carbon atoms, 1 to 3 alkoxies of 1 to 4 carbon atoms, 1 to 3 cyans, 1 to 3 aminos, 1 to 3 mono or diakylaminos of 1 to 4 carbon atoms, 1 to 3 acylaminos of 1 to 4 carbon atoms, 1 to 3 carboxys, 1 to 3 alkoxycarbonyls of 1 to 4 carbon atoms, 1 to 3 aminocarbonyls, 1 to 3 mono or di-alkylaminocarbonyl of 1 to 4 carbon atoms, 1 to 3 aminoalkyl of 1 to 4 carbon atoms, 1 to 3 hydroxyalkyl of 1 to 4 carbon atoms or 1 to 3 haloalkyl of 1 to 4 carbon atoms; or a phenyl radical disubstituted with a substituent R2, 2 being a halogen or a hydroxy group, methyl, ethyl, alkyl of 3 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms or trifluoromethyl, or with a substituent X ', X 'being as defined above, or one of its pharmaceutically acceptable salts or solvates. According to another preferred aspect, the invention relates to the use of the compound of the formula (I), wherein X is CH, R, is o- or / 77-CF3, Z 'and Z "are hydrogen and Z is a phenyl group substituted at positions 3 and 4 with an alkyl group of 1 to 6 carbon atoms, or a pharmaceutically acceptable salt or solvate thereof According to another preferred aspect, the invention relates to the use of the compound of the formula I), where Y is CH, R ^ is o- or m-CF3, Z "is hydrogen and Z and Z ', identical, each represents a phenyl group; a phenyl group substituted in the 2, 3 or 4 position with a fluorine or chlorine atom or with a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl group , trifluoromethyl, cyano, methoxy, methylthio, methylsulfonyl, ethoxy, ethylthio, ethylsulfonyl, alkoxycarbonyl of 1 to 3 carbon atoms or dialkylaminocarbonium of 1 to 3 carbon atoms; a phenyl group disubstituted at positions 2, 4; 3. 4; 3, 5 or 2, 6 with a chlorine or fluorine atom, or with a methyl, ethyl, trifluoromethyl, cyano or methoxy group; or a triphenyl group disubstituted at positions 2, 4, 5; 2, 4, 5 or 2, 4, 6 with a chlorine or fluorine atom, or with a methyl, ethyl, trifluoromethyl, cyano or methoxy group, or one of its pharmaceutically acceptable salts and solvates.

According to a particularly preferred aspect, the invention relates to the use of a compound of the formula (I), wherein Y is CH, Ri is m-trifluoromethyl, Z 'and Z "are hydrogen and Z represents a naphthyl group, 6,7-dimethoxy-2-naphthyl or 6,7-methylenedioxy-2-naphthyl, or one of its pharmaceutically acceptable salts and solvates A particularly advantageous compound according to the present invention can be selected from: -1- ( 2-naphth-2-ylethyl) -4- (3-trif luoromethylphenyl) -1, 2,3,6-tetrahydropyridine; -1- [2- (6,7-dimethoxynaphth-2-yl) ethyl] -4- ( 3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine; -1- [2- (6,7-methylenedioinaphth-2-yl) et il] -4- (3-trif luoromethylphenyl) -1,2, 3,6-tetrahydropyridine; -1- [2- (4-isobutylf in yl) propyl] -4- (3-trif luoromethyl) in i I) -1,2,3,6-tetrahydropyridine; - 1 - [(2S ) -2- (4-isobutylphenyl) propi I] -4- (3-trif luoromethyl) in i I) - 1, 2,3,6-tetrahydropyridine; -1 - [(2R) -2- (4-isobutyl fe ni I) propyl] -4- (3-trif Ioromethyl nil) -1, 2,3,6-tetr ahydropyridine; 1- [2- (4-isobutyl-l-phenyl) -ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; - 1- [2- (4-terbu ti If in il) ethyl] -4- (3-trif-1-uoro-methylf-enyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-isobutyl-phenyl) -2-methyl-1-propyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4-or propylphenyl) ethyl] -4- (3-trifluoromethyl) in I) -1,2,3,6-tetrahydropyridine; -1- [2- (3'-chloro-4-bif on i I I Jet il] -4- (3-trif luoromethyl-phenyl) -1,3,6,6-tetrahydropyridine; (2'-cl or ro-4-bifenyl il) ethyl] -4- (3-trif luoromet ilf enyl) -1,2,3,6-tetrahydropyridine; -1-t2- (4'-chloro-4 -biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine; -1- [2- (4'-f I uoro-4-bif in i I) ethyl] -4- (3-trifluoromethylphenyl) -1,3,6,6-tetrahydropyridine; - 1- [2- (3'-trifluoro-methyl-4-bifen i I) ethyl] -4- (3-trifluoromethyl) in 1) -1, 2,3,6-tetrahydropyridine; -1- [2- (4-cyclohexylphenyl) ethyl] -4- (3-trif luoromethyl) in yl) -1,2,3,6-tetrahydropyridine; -1- [2- (4-biphenyl) -2-ethyl] -4- (4-fluorophenyl) -1, 2, 3, 6 -tet rahidropi ridine; - 1- [2- (4-bifenyl) -2meti I pro pil] -4- (3-trif luoromethylphenyl) -1,2, 2,3,6-tetrahydropyridine; -1- [2- (4-phenoxypynyl) -2-ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4-benzyl) eni I) -2-e t i I] -4- (3-t rif luoromethyl) in i I) -1,2, 3,6-tetrahydropyridine; -1- [2- (4-n-butylphenyl) ethyl] -4- (3-trif luoromethylphenyl) -1,2, 2,3,6-tetrahydropyridine; -1- [2- (4-biphenylyl) ethyl] -4- (3-trif luoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4-n-butoxyphenyl) etiI] -4- (3-t rif luoromethylphenyl) -1,2, 2,3,6-tetrahydropyridine; -1-I2- (3,4-diethylphenyl) ethyl] -4- (3-t rif luoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2 - (3-methyl-4-pentylethyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,6,6-tetrahydropyridine; -1- [2- (4-methyl-3-pentylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (3,4-diethylphene) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; - 1- [2- (2,2-diphenylethyl] -4- (3-t rif luoromethyl) in i I) -1, 2,3,6-tetrahydropyridine; -1- [2, 2- (4, 4 ' -dichlorodif en il) ethyl] -4- (3-trif luoromethyl) en il) -1, 2,3,6-tetrahydropyridine; -1- [2, 2- (3,3'-bistrifluoromethyldifeni) ethyl] - 4- (3-t rif luoromethylphenyl) -1,2,3,6-tetrahydro pyridine; -1- [2,2- (4,4'-dimethoxydiphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1 , 2,3,6-tetrahydropyridine; -1- [2- (4-f luorofenyl) -2-f in ileyl] -4- (3-trif luoromethyl) eni I) - 1,2,3,6-tetrahydropyridine; -1- (3, 3-di-fe-nyl-propyl) -4- (3-t-fluoro-methyl-n-nyl) -1,2,3,6-tetrahydropyridine; -1- [2,2- (4,4; -dichlorodiphenyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; -1- [2- (3'-chloro bife nyl-4-yl) -2-oxoethyl ] -4- (3-tri-fluoro-met-phenyl) -1, 2,3,6-tetrahydropyridine; -1- [2- (2'-clo-robif-enyl-4-yl) -2-oxoetiI] -4- ( 3-trif luoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4'-chlorobi-phenyl-4-yl) -2-oxoethyl] -4- (3-trichloro-methyl-fe nil) -1, 2,3,6-tetrahydropyridine; -1- [2- (4-isobutylphenyl ) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine; -1- [2- (4-benzyl-faith-nyl) -2-oxo-ethyl] -4- (3-t-rifyl-uoro-methyl-phenyl) -1, 2,3,6-tetrahydropyridine; -1 - [2 - (4-cyclohexyl nyl) -2-oxoethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4'-f I uoro bif en il-4-yl) -2-oxoethyl] -4- (3-trif luoromethyl) en i l) -1, 2,3,6-tetrahydropyridine; -1- [2- (4-7-Butylf-enyl) -2-oxoethyl] -4- (3-trifluoromethyl) in i I) -1,2,3,6-tetrahydropyridine; -1- [2- (biphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4-Butylphenyl) -2-oxoethyl] -4- (3-trifluoromethylf eni I) -1,2,3,6-tetrahydropyridine; -1- [2- (4'-trifluorooxy methyl bife nii-4-yl) -2-oxoethyl] -4- (3-trif luoromethyl) en yl) -1,2, 2,3,6-tetrahydropyridine; -1- [2- (2, 3'-Dichloro-4-biphenylyl) ethyl] -4- (3-tri-fluoro-methyl-phenyl) -1, 2,3,6-tetrahydropyridine; -1- [2- (3-Chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (3 ', 5, -dichloro-4-biphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine: -1- [2- (2 , 4, -dichloro-4-biphenylyl) ethyl] -4- (3-trif luoromethyl-enyl) -1,2, 2,3,6-tetrahydropyridine: - 1- [2- (2-chloro-4-bif in ili l) ethyl] -4- (3-t rif luoromethylphenyl) -1,2,3,6-tetrahydropyridine: -1- [2- (3'-chloro-4-b-phenyl) ethyl] -4- ( 3-trifluoromethiifenii) -1,2,3,6-tetrahydropyridine. -1-. { 2- (2-Fluoro-4-biphenylyl) ethyl] -4- (3-trif luoromethylphenyl) -1, 2,3,6-tetrahydropyridine. -1- [2- (4-methoxy-3-bi-phenyl-nilyl) -ethyl] -4- (3-trifluoro-methyl-phe nyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4'-methoxy-4-biphenylyl) ethyl] -4- (3-t rif luoromethyl) in I) -1,2,3,6-tetrahydropyridine; -1- [2- (4'-hydroxy-4-bif in ili I) e t i I] -4- (3-1 rif luoromethyl) in i I) -1,2, 3,6-tetrahydropyridine; -1- [2- (4'-ethoxycarbonylbutoxy-4-byl nyl) ethyl] -4- (3-trifluoromethyl) n-1) -1,2,3,6-tetrahydropyridine; -1 - [2- (3-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydro-pyridine; -1- [2- (3'-Chloro-4'-fluoro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydro pyridine; -1- [2- (2, -trifluoromethyl-4-bif enyl) ethyl] -4- (3-trif luoromethylphenyl) -1,2,3,6-tetrahydropyridine; -1 - [2- (bifenyl-4-yl) ethyl] -4- (2-trif luoromethylphenyl) -1,2,3,6-tetrahydro-pyridine; -1- [2- (4-cyclohexenyl-phenyl-n-ethyl) -4- (3-trifluoromethyl-phenyl) -1,3,3,6-tetrahydropyridine; -1- [2- (3,4-diisobutylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; - 1 - [2 - (3, 4-d i propi If in il) ethyl] -4- (3-trif I uoro methylphenyl) -1,2,3,6-tetrahydropyridine; -1- [2- (4-cyclohexylphenyl) etii] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine: -1- [2- (4-isobutylphenyl) ethyl] - 4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; -1- [2- (2'-trifluoromethyl-phenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3-tetrahydropyridine; -1- [2- (3'-trif Ioromethyl bif in yl-4-yl) -2-oxoethyl] -4- (3-trif luoromethylphenyl) -1,2,3,6-tetrahydropyridine; and its pharmaceutically acceptable salts and solvates. 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine known by its laboratory code, SR 57746 and its pharmaceutically acceptable salts and solvates, especially its hydrochloride (SR 57746A), are particularly preferred compounds for use in accordance with the present invention. Certain compounds of the formula (I) are novel products.

Thus, according to other aspects thereof, the present invention relates to a compound of the formula (I) selected from: 1- [2- (6,7-methylenedioxinaphth-2-yl) ethyl] -4 - (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine, 1 - [2- (4-cyclohexe nil fe ni I) eti l] -4- (3-trifluoromethyl nil) -1, 2,3 , 6-tetrahydropyridine, and 1- [2- (biphenii-4-yl) ethyl] -4- (3-trifluoromethylphenol) -1,2,3,6-tetrahydropyridine, and their pharmaceutically acceptable salts and solvates. Salts with pharmaceutically acceptable bases are, for example, those with alkaline or alkaline earth metals, such as sodium, potassium, calcium, magnesium and those with organic bases, such as amines, basic amino acids (lysine, arginine, histidine), trometamol, N -metüglutamine, etc. Salts with pharmaceutically acceptable acids are, for example, those with mineral acids, such as hydrochloride, hydrobromide, borate, phosphate, sulfate, acid sulfate, acid phosphate, and those with organic acids, such as citrate, benzoate, ascorbate, methyl sulfate, naphthalene-2-sulfonate, picrate, fumarate, maleate, malonate, oxalate, succinate, acetate, tartrate, mesylate, tosylate, isethionate, a-ketoglutarate, cc-glycerophosphate, glucose-1-phosphate, etc. The compounds of the formula (I), wherein Z 'and Z "are hydrogen or an alkyl group having from 1 to 3 carbon atoms are prepared as described in WO 97/01536. The compounds of the formula (I), in where one of Z 'and Z "is hydrogen and the other is a hydroxyl, as well as the compounds wherein Z' and Z" together represent an oxo group, can be prepared as described in WO 93/11107. Formula (I), wherein Z "is hydrogen and Z 'and Z each independently represents an unsubstituted, mono, di or tri-substituted group or phenyl are prepared according to the following method: (a) an aryl- , 2, 3,6-tetrahydropyridine of the formula (II): wherein Y R, as defined above, is allowed to react with an acid of the formula (III): HO - C - CH (lll) \ Z ' wherein Z and Z 'are as defined above, or with one of their functional derivatives, (b) the carbonyl intermediate of the formula (IV): is reduced, and (c) the compound of the formula (I) is isolated and, optionally, transformed to one of its salts or solvates. The reaction step (a) can conveniently be carried out in an organic solvent at a temperature between -10 ° C and the reflux temperature of the reaction mixture; preferably the reaction is carried out at low temperature. The reaction solvent used is preferably a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform and the like, and an alcohol such as methanol or ethanol, but other organic solvents can also be employed which are compatible with the reagents employed, for example, dioxane, tetrahydrofuran or a hydrocarbon such as hexane. The reaction may conveniently be carried out in the presence of a proton acceptor, for example, an alkaline carbonate or a tertiary amine. The pound acid, optionally activated (with BOP, for example), the anhydride, a mixed anhydride, an activated ester or an acid halide, preferably chloride or bromide, can be used as a suitable functional derivative of the acid of the formula (III) . Among the activated esters, the p-nitrophenyl ester is particularly preferred, but the methoxyphenyl, trityl, benzhydryl esters and the like are also suitable. The reduction of step (b) may conveniently be carried out by suitably reducing agents such as aluminum hydrides or a lithium-aluminum complex hydride in an inert organic solvent at a temperature between 0 ° C and the reflux temperature of the mixture. of reaction according to usual techniques. "Inert organic solvent" is understood to be a solvent that does not interfere with the reaction. Such solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. The compound of the formula (I) obtained is isolated according to usual techniques and optionally transformed to one of its addition acid salts or, when an acidic group is present, the amphoteric character of the compound allows the separation of the salts either with acids or bases. The starting amines of the formula (II), wherein Y is CH, are known compounds or can be prepared according to procedures analogous to those used to prepare the known compounds. The starting amines of the formula (II), wherein Y is N, can be prepared through the reaction of a suitable 2-halopyridine of the formula (p): wherein R-i is as defined above, and Hal is a halogen atom, with a 1, 2, 3,6-tetrahydropyridine of the formula (q): wherein p represents a protecting group such as a benzyl group, and Z represents a substituent that allows nucleophilic substitution of the halogen of pyridine. Such substituents are, for example, trialkylstannanes, such as tributylstannane, or Grignard compounds. The 1,2,3,6-tetrahydropyridine is then deprotected by cleaving the protecting group under suitable conditions. The acids of the formula (III) can be prepared according to the Wittig reaction through the reaction of a suitable benzophenone of the formula (r): / O (r) \ Z * wherein Z and Z 'are as defined above, with trimethylsulfoxonium iodide / BF3-Et2O and oxidation of the intermediate aldehyde of the formula (w): -CHO (w) Z ' according to the method described in J. Am. Chem. Soc, 1990. 112 (18): 6690-6695, to obtain the corresponding acid. According to another method, the compounds of the formula (I), wherein Z "is hydrogen can also be prepared through the reaction of an aryl-1, 2,3,6-tetrahydropyridine of the formula (II): wherein R-i and Y are as defined above, with an aldehyde of formula (w) above in the presence of a reducing agent such as sodium cyanoborohydride, according to known techniques. The compounds of the formula (I), wherein R, is m-trifluoromethyl, Y is CH, Z 'and Z "are hydrogen and Z is a naphthyl group substituted with one or more alkoxy groups with a methylenedioxy group, are prepared as described in EP 0 458 697. 1 - (2 -naft-2-ylethyl) -4- (3-t rif luoromethyl) in il) -1, 2,3,6-tetrahydropyridine and its pharmaceutically acceptable salts and solvates, especially the hydrochloride, can be prepared in accordance with EP 0 101 381. An advantageous method provides the reaction of 2- (2-bromoethyl) naphthalene and 4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine and the isolation preferably of 1- (2-naphth-2-hydrochloride -ethyl) -4- (3-trif luoromethylphenyl) - 1,2,3,6-tetrahydropyridine (SR 57746A), which is then crystallized in an ethanol / water mixture by heating and cooling to 5 ° C with a cooling gradient of 10 ° C / hour and a stirring speed of 400 rpm, in order to obtain a mixture of the two crystalline forms in a ratio of approximately 66/34. The 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride is preferably used in a microparticulate form, for example, in an essentially amorphous form obtained through atomization, or in a microcrystalline form obtained through micronization. The effect of the compounds of the formula (I) on the increase of the levels of TGF-β1 was evaluated with the help of tests on lyse muscle cells, as well as on levels in the blood and rat diaphragms after administration in the representative compounds of the invention. Both latent TGF-β1 and active TGF-β1 were determined in lyse muscle cells through incubation with hydrochloric acid. In these tests, representative examples of formula (I) showed an elevation in TGF-β1 levels. The anti-apoptotic activity was measured in the same cells vis-a-vis, the pro-apoptotic activity of a lack in the serum and after the addition of toxic compounds such as vincristine or growth factors such as nerve growth factor (NGF) with the help of a specific ELISA determination kit (assay with enzyme-linked immunosorbent), which detects the presence of oligonucleosomes, the presence of which within the cells is a specific marker of programmed cell death (apoptosis ), according to the method described by Del Bino G. et al., (Experimental Cell Research, 193, 27, 1991 and 195, 485, 1991) or Darzynkiewicz A. and others, (Cytometry, 13, 795, 1992). In all three cases, the representative compounds of the invention, especially: -1- [2- (3,4-diethylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine ( compound A); -1- [2- (biphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (compound B); -1- [2- (biphenyl-4-yl) etl] -4- (3-trifluoromethylphenii) -1, 2,3,6-tetrahydropyridine (Compound C); -1- [2- (6,7-Methylenedioxinaphth-2-ethyl] -4- (3-tri fluoro methyl nyl) -1, 2,3,6-tetrahydropyridine (compound D); -1- [ 2- (4-cyclo-free en-yl) etii] -4- (3-trif luoromethyl-enyl) -1,2,3,6-tetrahydropyridine (compound E); -1- [2- (biphenyl-4 -yl) ethyl] -4- (3-trif luoromethylf eni I) -1, 2,3,6-tetrahydropyridine (compound F), and -1- (2-naphth-2-ylethyl) -4- ( 3-trif luoromethylf eni I) -1, 2,3,6-tetrahydropyridine (SR 57746) and its pharmaceutically acceptable salts, inhibits, as a function of time and dose, the pro-apoptotic effect induced by the lack of the serum or even by the addition of NGF or vincristine Thus, according to a further aspect, the present invention relates to the use of tetrahydropyridines of the formula (I), the advantageous and preferred compounds mentioned above, or their salts and pharmaceutically acceptable solvates for the preparation of a medicament for treating diseases that can be treated by increasing the levels of TGF-.beta.1. pathologies are, for example, diseases related to an abnormal apoptotic activity, ocular diseases such as cataracts or glaucoma, osteoporosis, bone fracture, epidermal lesions, restenosis, conditions related to a proliferation or incorrect migration of hepatic muscle cells, inflammations of the respiratory system, asbestosis, silicosis, lupus erythematosus, Goodpasture's syndrome, granulomatosis, eosinophilic granulomatosis, gastric and duodenal ulcers, oseofagitis, enteritis, gastritis, septicemia, malfunction of hematopoiesis and / or lymphopoiesis, cystic fibrosis. According to a particularly advantageous aspect, the present invention relates to the use of tetrahydropyridines of the formula (I), advantageous and preferred compounds mentioned above, or their pharmaceutically acceptable salts or solvates for the preparation of medicaments capable of inhibiting apoptosis.

By virtue of this anti-apoptotic activity, the compounds of the present invention can be used for the preparation of medicaments for treating cancer and their metastases, infections by antivirus such as HIV and HITV 1 and 2 (human immunodeficiency virus and lymphocyte virus). T human) and the consequences thereof such as ATL (adult cell leukemia), leukemia, myelopathies and arthropathies, hepatitis (C, A, B, F), AIDS, immune deficiencies, cell aging, tissue degeneration phenomenon , inflammation, cell proliferation, infectious diseases, graft rejection, acute or chronic rheumatoid arthritis, ulcerative colitis, thrombocytopenic purpura, autoimmune erythromoclast anemia, juvenile diabetes (Type I) (insulin dependent), myelodysplastic syndrome, Huntington's disease, prion diseases, ARDS, prostatic hypertrophy, asthma, atherosclerosis and its thrombo-embolic complications, kidney diseases, glomerolunephritis, ischemic pathologies such as myocardial infarction, myocardial ischemia, coronary vasospasm, angina and heart failure, chronic pancreatitis, autoimmune gastritis, primary biliary cirrhosis. According to an advantageous aspect, the present invention relates to the use of tetrahydropyridines of the formula (I), to one of the aforementioned advantageous or preferred compounds, or their pharmaceutically acceptable salts or soivates for the preparation of medicaments capable of treating a disease such as graft rejection or acute or chronic rheumatoid arthritis. In accordance with the object of the present invention, "treatment of diseases" is understood to mean both treatment and prevention of diseases, when possible. In this way, for example, when graft rejection is considered, the pharmaceutical compositions can be used in the concept of prevention. According to one more aspect. The invention relates to a method for increasing the circulation and cellular and extracellular levels of TGF-β1. According to another of its aspects, the present invention relates to a method for inhibiting apoptosis, which comprises administration to a mammal with the administration thereof of an effective dose of a compound of the formula (I), from one of the advantageous or preferred compounds mentioned above, or their pharmaceutically acceptable salts and solvates, advantageously SR 57746, or one of their pharmaceutically acceptable salts and solvates. According to a preferred aspect, SR 57746 and its pharmaceutically acceptable salts and solvates are administered in a microparticle form, preferably in a microparticulate form of the hydrochloride. The compounds of the formula (I), one of the advantageous or preferred compounds mentioned above or their pharmaceutically acceptable salts and solvates, are preferably administered orally. The amount of the active substance that will be administered depends on the degree of advancement of the disease, as well as the age and weight of the patient. However, unit doses generally comprise from 0.25 to 700 mg, advantageously from 0.5 to 300 mg, and most preferably from 1 to 150 mg, for example, "between 2 and 50 mg of the active principle." These unit doses are usually administered once or more times a day, preferably 1 to 3 times a day, the total dose in humans ranges from 0.5 to 1400 mg per day, for example from 1 to 900 mg per day, advantageously from 2 to 500 mg per day, and very conveniently 2 to 200 mg per day When the active principle administered is, for example, SR 57746, the unit dose generally comprises 0.5 to 10 mg, advantageously from 1 to 5, and preferably from 1 to 3. mg, for example, 1-1.5-2-2.5-3 mg of the active principle These unit doses are usually administered once or more times a day, preferably 1 to 3 times a day, the total dose in humans varies of 0.5 and 50 mg per day, for example from 1 to 20 mg per day, advantageously from 2 to 10 mg per day. The above doses and amounts refer to the compounds of the formula (I) or to one of the advantageous or preferred compounds mentioned above, in an unsalted form. In the pharmaceutical compositions of the present invention for oral administration, the active ingredient can be administered as unit forms for administration, in a mixture with classical pharmaceutical carriers, to mammals, to animals and to humans for the treatment of the aforementioned diseases. Suitable unit forms of administration comprise, for example, tablets, which are optionally labeled, gelatin capsules, powders, granules and oral solutions or suspensions. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talcum, gum arabic or analogs thereof. The tablets may be coated with sucrose or other suitable materials or may still be treated so as to have a sustained or delayed activity and to continuously release a predetermined amount of the active ingredient. A gelatin capsule preparation is obtained by mixing the active ingredient with a diluent and emptying the obtained mixture into soft or hard gelatin capsules. A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably an acalorific sweetener, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a suitable coloring agent. The powders or granules that can be dispersed in water can contain the active ingredient in a mixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as sweeteners or flavor correctors. The active ingredient can also be formulated in the form of microcapsules, optionally with one or more carriers or diluents.

In the pharmaceutical compositions according to the present invention, the active principle may also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.

The preparations and examples are presented below and better illustrate the invention PREPARATION 1 40,000 hemp muscle cells isolated from the human aorta (provider: CLONETICS) were placed in a 35 mm dish in a medium containing 2 ml of DMEM (medium Eagle modified with Dulbecco containing 4.5 g / l of glucose, 3.7 g / l of NaHCO3 and without containing any of L-glutamine or Na pyruvate). 20% v / v of fetal bovine serum was depleted for 30 minutes at 80 ° C, 4 mM of L-giutamine, 50 U / ml of penicillin and 50 μg / ml of streptomycin were added. The cells were left in this medium for a growth period of 3 days before being tested according to the examples given below.

PREPARATION 2 Cell-containing dishes were prepared as described in Preparation 1. Apoptosis was induced by replacing the medium described in Preparation 1 with the same medium containing only 0.2% of fetal bovine serum. The effect of the compounds of the invention on the levels of latent and active TGF-β1 was measured in the extracellular media after 24 hours of contact with the cells, compared with controls (0.2% of fetal bovine serum and 20% of fetal bovine serum). Active TGF-β1 was determined directly in the culture supernatants, but latent TGF-β1 was determined after activation. For activation, 0.5 ml of the culture supernatant was incubated in the presence of 0.1 ml of 1M HCl for 10 minutes at room temperature. The mixture was then neutralized with 0.1 ml of buffer 0.5 M Hepes, which contains 1.2 M NaOH. Determinations of TGF-β1 were made with the help of a specific ELISA test.

PREPARATION 3 Five Sprague Dawley rats (Ifffa Credo, France) weighing approximately 280 g each day for 3 days were treated with the test compound, which was administered orally. After 24 hours of the last forced feeding, the rats were anesthetized. Blood was taken from the abdominal aorta in EDTA, the samples were centrifuged and the supernatants (platelet-rich plasma) were frozen. The diaphragms were also taken, rinsed several times in cold PBS (saline regulated at pH with phosphate) and centrifuged. After an additional ultracentrifugation, the plugs were collected from the PBS and frozen. Determinations of latent and active TGF-β1 were made in the plasma and ground diaphragms using the technique described in preparation 2. The increase in the circulation of latent TGF-β1 levels was recorded in the rats treated with the compounds of the invention compared to the control rats. The increase in the levels of active TGF-β1 in the diaphragms of the rats treated with the compounds of the invention was also recorded.

PREPARATION 4 Plates containing the cells were prepared as in preparation 1. Apoptosis was induced by three different methods: a) replacing the medium of preparation 1 with the same medium containing only 0.2% fetal bovine serum; b) adding increasing doses of NGF (0.01 ng / ml to 100 ng / ml) to the medium described in preparation 1; c) adding increasing doses of vincristine (0.1 pg / ml to 10 ng / ml) to the medium described in preparation 1. Through an ELISA determination test of the mono- and oligo-nucleosomes associated with cytoplasmic histones after washing and Cell lysis, the effects of the compounds of the invention on apoptosis were measured after 24 hours of contact with the cells compared to the levels of apoptosis obtained in the absence of products (maximum level of apoptosis) or in the presence of 20% serum of fetal bovine (minimum level of apoptosis).

EXAMPLE 1 1- (2,2-difen i I t t I) -4 - (3 - 1 r if luorometilf in il) -1, 2,3,6-tetrahydropyridine and its hydrochloride a / 1 - (a, a-di-f-nylacetyl) -4- (3-trifluoromethyl) n-I) -1, 2,3,6-tetrahydropyridine. 8 g of a, a-diphenylacetyl chloride in 50 ml of methylene chloride were added dropwise to a mixture of 8 g (0.035 mole) of 4- (3-trifluoromethylphenyl) -1,2, 3,6-tetrahydropyridine, 50 ml of methylene chloride and 4.96 ml of triethylamine at a temperature of 0 / + 5 ° C. The stirring was carried out for 1 hour at room temperature, the solvent was evaporated under reduced pressure, the residue was taken up in ethyl ether, the washing was carried out with an aqueous solution at 0.2M hydrochloric acid, with water, with an aqueous solution. of sodium carbonate and then with water. Drying was carried out over sodium sulfate, the solvent was evaporated under reduced pressure. 5 g of the title compound were obtained. 1b / 1- (2,2-diphenylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and its hydrochloride. A solution of 5 g (0.012 mol) of the product from the preceding step in 50 ml of ethyl ether was added dropwise to a mixture of 0.7 g of lithium-aluminum hydride in 10 ml of diethyl ether at 25 ° C. The stirring was carried out at room temperature for 1 hour, then 5 ml of water was added dropwise. Two phases were separated, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. In this manner, 1- (2,2-diphenylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine was obtained. The hydrochloride was prepared with the aid of a saturated solution of hydrochloric acid in diethyl ether. The crystallization was introduced into approximately 150 ml of ethyl acetate. P. f. (207-210 ° C).

EXAMPLE 2 1- [2,2- (4,4'-Dichlorodiphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and its oxalate. 2a / a, a- (4,4'-dichlorodiphenyl) acetaldehyde. 0.75 g (0.025 mole) of 80% sodium hydride was added in portions to a mixture of 5.5 g (0.025 mole) of trimethylsulfoxonium iodide in 10 ml of anhydrous tetrahydrofuran. The mixture was heated at 55 ° C for 6 hours and 6 g (0.025 mole) of 4,4'-dichlorobenzophenone in 10 ml of anhydrous tetrahydrofuran was added thereto. The mixture was allowed to stir at 55 ° C overnight, was emptied into water, extracted with ethyl ether, the organic phase was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 32 ml of toluene and 3 ml of BF3-Et2O was added thereto. The mixture was stirred for 2 minutes and then allowed to stand for 3 minutes. The washing was carried out twice with an aqueous solution of sodium bicarbonate, the organic phase was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. An oil was obtained, which was purified through gel column chromatography eluting with a hexane / ethyl acetate 0 = 9/1 mixture. The title compound was obtained. 2b / 1 - [2, 2- (4,4'-dic lo rod if enyl) ethyl] -4- (3-trifluoromethylf in l) -1,2,3,6-tetrahydropyridine and its oxalate. 1.3 g (0.0045 mol) of the product of the preceding step, 1.2 g (0.0053) or 4- (3-trifluoromethylphenyl) -1, 2.3.6-tetrahydropyridine, 21 ml of methanol, 0.8 ml of glacial acetic acid and 0.5 g were mixed. of anhydrous sodium acetate at the temperature of 0 / + 5 ° C. 0.76 g (0.0121 mole) of sodium cyanoborohydride was added to the mixture at the same temperature, the stirring was carried out for 1.5 hours at low temperature, and then at room temperature overnight. 5 ml of concentrated hydrochloric acid were added dropwise, stirring was continued for 10 minutes, methanol was evaporated and the residue was taken up in a mixture of ethyl acetate / dilute aqueous NH 4 OH solution. The two phases were separated, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. An oil was obtained, which was purified through silica gel column chromatography eluting with a hexane / ethyl acetate mixture = 9/1. The title compound was obtained as a base. The oxalate was prepared with the aid of oxalic acid in isopropanol. P. f. (oxalate) 187-189 ° C.

EXAMPLE 3 1- [2,2- (3,3'-Bistrifluoromethyldi) nyl) ethyl] 4- (3-trifluoro methyl n-nyl) -1,2,3,6-tetrahydropyridine and its oxalate. 3a / a, a- (3,3'-bistrifluoromethyldiphenyl) acetaldehyde. It was continued as in Example 2a /, but using 3,3'-bistrifluoromethylbenzophenone, and thus the title compound was obtained. 3 b / 1- [3,3- (3,3'-Bistrifluoromethyldiphenyl) ethyl] -4- (3-trif-Ioromethylphenyl) -1,2,3,6-tetrahydropyridine and its oxalate. It was continued as described in Example 2b /, but using the product of the preceding step in place of a, a- (4,4'-diciorodiphenyl) acetaldehyde, and the title compound was obtained. P. f. (oxalate) 194-196 ° C.

EXAMPLE 4 1 - [2, 2- (4,4'-dimethoxydi-fe n i I) e t i I] -4- (3-trifluoromethyl nyl) -1, 2,3,6-tetrahydropyridine and its hydrochloride. 4a / a, a- (4,4'-dimethoxydifeniI) acetaldehyde. It was continued as described in Example 2a /, but using 4,4'-d i methoxy benzo-fe-none, and the title compound was obtained. 4b / 1 - [2, 2- (4,4'-dimethoxy dif enyl) eti I] -4- (3-trif luoromethylphenyl) -1,2, 2,3,6-tetrahydropyridine and its hydrochloride. It was continued as described in Example 2b /, but using the product of the preceding step instead of < x, a- (4,4'-dichlorodiphenyl) acetaldehyde, and the title compounds were obtained. P. f. (hydrochloride) 214-216 ° C.

EXAMPLE 5 1 - [2 - (4-f Iorofenyl) -2-f-enylethyl] -4- (3-t rif luoromethylphenyl) -1,2,3,6-tetrahydropyridine and its hydrochloride. 5a / a.-4-fluorophenyl-a-phenylacetaldehyde. It was continued as described in Example 2a /, but using 4-fluorobenzophenone, and the title compound was obtained. 5b / 1 - [2, 2- (4-f Iorofenyl) -2-f-enylethyl] -4- (3-trifluoromethyl-phenyl) -1,3,6,6-tetrahydropyridine and its hydrochloride. It was continued as described in Example 2b /, but using the product of the preceding step instead of a, a- (4,4'-dichlorodiphenyl) acetaldehyde, and the title compound was obtained. P. f. (hydrochloride) 206-208 ° C.

EXAMPLE 6 1- (3,3-diphenylpropyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and its hydrochloride. The procedure was continued as described in Example 1b /, but using commercial 3,3-diphenylpropionic acid (Aldrich, reference D21, 165-6) instead of 2,2-diphenylacetic acid, and the title compound was obtained. P.f. (hydrochloride) 176-178 ° C.

EXAMPLE 7 1- [2,2- (4,4'-Dichlorodiphenyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine and its hydrochloride. It was continued as described in Example 2b /, but using 4- (6-chloropyrid-2-yl) -1, 2,3,6-tetrahydropyridine instead of 4- (3-trifluoromethylphenyl) -1, 2, 3 , 6-tetrahydropyridine, the title compound was obtained. P. f. (hydrochloride) 230-232 ° C.

EXAMPLE 8 1 - [2- (3,4-Diethylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. 8a / 1-bromo-2- (3,4-diethylphenyl) ethane. A mixture of 4.4 g (0.033 moles) of 3,4-diethylbenzene, 50 ml of methylene chloride, 8.8 g (0.044 moles) of bromoacetyl bromide was cooled to 0-5 ° C and 5.0 were added thereto. g (0.037 moles) of aluminum trichloride. The mixture was stirred at 0-5 ° C for 1 hour and then allowed to stand overnight at room temperature. It was poured into a water / ice mixture, extracted with methylene chloride, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. 2.9 g (0.011 mole) of the oil thus obtained were mixed with 6 ml (0.057 mole) of trifluoroacetic acid and 6.7 ml (0.057 mole) of triethylsilane and the mixture was heated at 80 ° C for 4 hours. Then a saturated aqueous solution of sodium bicarbonate was added until a basic pH was reached, the extraction was carried out with ethyl ether, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude oil thus obtained was purified through silica gel column chromatography eluting with cyclohexane. The title compound was obtained. 8b / 1 - [2- (3,4-Diethylphenyl) ethyl] -4- (3-trifluoromethyl-p-n-I) - 1, 2, 3,6-tetrahydropyridine hydrochloride. A mixture of 2.6 g (0.001 mole) of 4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine, 60 ml of butanol, 4.1 g (0.025 mole) of anhydrous potassium carbonate in stripes and 2.6 g ( 0.00113 moles) of the product from the preceding step was brought to reflux for 5 hours. The solvent was evaporated under reduced pressure, taken up in ethyl acetate, washed with water, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The oil hydrochloride thus obtained was prepared by treatment with a saturated solution of hydrochloric acid in isopropanol. 1.6 g of the title compound were obtained, P. f. 220-222 ° C.

EXAMPLE 9 > 1 - [2 - (3-methyl-4-pentylphenyl) eti I] -4- (3-trif luoromethylphenyl) -1, 2, 33,6-tetrahydropyridine and 1 [2- (4-methyl-3- pentylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine and its oxalates. 9a / 1-methyl-2-pentylbenzene. 4.7 g (0.035 mole) of phthalic aldehyde were added dropwise to a solution of 50 ml (0.1 mole) of a 2M n-butylmagnesium chloride solution in THF under a nitrogen atmosphere. The mixture spontaneously was heated to 40-45 ° C. The stirring was carried out at room temperature for 1 hourThe mixture was poured into a saturated ammonium chloride solution, extracted with ethyl ether, washed with water, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The oil thus obtained was purified by silica gel column chromatography eluting with a cyclohexane / ethyl acetate = 7/3 mixture.

The product having the highest Rf was isolated. 2.0 g of oil were obtained. The crude reaction mixture was dissolved in 25 ml of ethanol and 1 ml of concentrated sulfuric acid and 0.15 g of 10% Pd / C were added thereto. The hydrogenation was carried out at room temperature for 7 hours. The catalyst was filtered, the solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate. The mixture was washed with an aqueous solution of sodium bicarbonate, dried and the solvent was evaporated under reduced pressure. 1.35 g of the title compound were obtained. 9b / 1-bromo-2- (3-methyl-4-pentylphenyl) ethane and 1-bromo-2- (4- (4-methyl-3-pentyl Ifen i I) ethane A mixture of 1.17 g (0.0054 moles) of the product from the preceding step, 0.62 ml (0.0072 mole) of bromoacetyl bromide was cooled to 0-5 ° C and 0.81 g (0.006 mole) of aluminum trichloride was added thereto. 5 ° C for 1 hour and then for 4 hours at room temperature The mixture was emptied on ice, the two phases were separated, the organic phase was washed with water, dried and the solvent was evaporated under reduced pressure. dissolved in 2.9 ml of trifluoroacetic acid and 3.1 ml (0.0267 mol) of triethylol was added thereto if not and the mixture was heated at 80 ° C. for 5 hours.It was emptied in an aqueous solution of sodium bicarbonate The mixture was extracted with ethyl ether, washed with water and dried over sodium sulfate, obtaining a mixture of the title compounds. 9c / 1- [2- (3-methyl-4-pentylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and 1 - [2- (4-methyl-3-pentylphenyl) ) ethyl] -4- (3-trif I uorometi Ifeni I) -1, 2, 3,6-tetrahydrate and its oxalates. A mixture of 0.7 g (0.0031 mol) of 4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine, 16 ml of butanol, (0.0065 of anhydrous potassium carbonate in bars and the product obtained in the previous step (0.0054 mole theory) was refluxed for 6 hours.The solvent was evaporated under reduced pressure, the residue was taken up in ethyl acetate, washed with water, dried over sodium sulfate and the solvent was evaporated under pressure. The oil thus obtained was purified through silica gel column chromatography eluting with a mixture of cyclohexane / ethyl acetate = 7/3 Two products were isolated having similar Rfs.The product having the highest Rf corresponds to 1 - [2- (3-methyl-4-pentylphenyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine The oxalate was prepared in acetone 0.12 g of the product was obtained. f 140-143 ° C. The product having the lowest Rf corresponds to the isomer 1- [2- (4-methyl-3-pentyl nyl] -4- (3- trifluoro methylphenyl) -1, 2,3,6-tetrahydropyridine. The oxalate was prepared in acetone. The crystallization of the product was carried in acetone. 0.08 g of the product were obtained. P.f. 167-169 ° C.

EXAMPLE 10 1- [2- (3,4-Diethylphenyl) -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine hydrochloride 10a / (1-benzyl 1-1, 2 , 3,6-tetrah id rop i rid-4-il) tributyl stanalate.

A mixture of 15.85 g (0.0837 moles) of 1-benzyl-4-piperidone in 140 ml of anhydrous dimethoxyethane and 25 g (0.0837 moles) of trisylidrazine in 140 ml of anhydrous dimethoxyethane was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was taken up in 420 ml of anhydrous hexane and 420 ml of anhydrous tetramethylene-ethylene diamine were added thereto. The mixture was cooled to -78 ° C and 156 ml of n-butyl (0.25 moles) (1.6M solution in hexane) were added dropwise thereto. After about 30 minutes, the temperature was allowed to reach 0 ° C and the stirring was carried out for 15 minutes. Then, 45 ml (0.167 moles) of tributylstannyl chloride was added to the reaction mixture. After one hour, a water / ice mixture was added with extreme caution. The extraction was carried out with ethyl ether, the organic base was washed with water, dried over sodium sulphate and the solvent was evaporated under reduced pressure. 70 g of the crude product were obtained, which were purified through silica gel column chromatography eluting with a cyclohexane / ethyl acetate = 95/5 mixture. The title compound was obtained with an oil. 'H-NMR (CDCl 3) -d (ppm): 0.84 (9H; m: CH3); 1.19-1.58 (18H; m: chains); 2.31 (2H; m); 2.53 (2H; m); 3.02 (2H; m); 3.56 (2H; s: benzylic methylene); 5.76 (1H; m *); 7.18-7.41 (5H; m: arom.) * Sidebands3Jcis (1H-117Sn) and 3Jcls (1H-119Sn). 10b / 1-benzyl-4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine. 18.5 g (0.04 mole) of the compound of the preceding step was dissolved in 200 ml of anhydrous dimethylformamide under a nitrogen atmosphere. 11.8 g (0.08 mole) of 2,6-diclopyridine, 0.64 g of Pd (ll) (Ph3P) 2- 438 g (0.04 mole) of tetramethylammonium chloride and 2.76 g (0.02 mole) of carbonate were added to the solution. potassium. The mixture was heated at 110 ° C for 6 hours and then emptied into 100 ml of a 5% sulfuric acid solution. The extraction was carried out with ethyl ether, ammonium hydroxide was added to the aqueous phase until a basic pH and the extraction was carried out with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of cyclohexane / ethyl acetate = 1/1. The title compound was obtained. P.f. 100-102 ° C. 10c / 4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine hydrochloride.

A solution of 7.0 g (0.024 mole) of the compound from the preceding step in 110 ml of dichloroethane was cooled to 0-5 ° C and 5.8 ml (0.054 mole) of chloroethyl chloroformate was added thereto. The stirring was carried out for 5 minutes and then refluxed for 1.5 hours. The solvent was evaporated under reduced pressure, the residue was taken up in 100 ml of methanol and heating under reflux was carried out for 1 hour. The solvent was evaporated, the residue was taken up in isopropanol and the solid was filtered. The title compound was obtained, which was crystallized in 90% ethane. P. f. 305-307 ° C. 10d / hydrochloride of 1 - [2- (3,4-d-Iei Ifen i I) etl] -4- (6-chloropyrid-2-i I) -1,2,3,6-tetrahydropyridine We proceeded as described in Example 8B / but using the product of the preceding step in place of 4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine, and the title compound was obtained. P. f. 234-236 ° C.

EXAMPLE 11-20 The procedure was continued as described in Example 9, but using the appropriate magnesium halide, and the following compounds were obtained: 1- [2- (3-et i I -4-methylphenyl) ethyl] -4 - (3-t rif luoromet ilf eni I) - 1,2, 3,6-tefrahydropyridine - Ex. 11 1- [2- (4-ethyl-3-methylf eni I) et i I] -4 - (3 - 1 rif luoromethylphenyl) - 1,2, 3,6-tetrahydropyridine - Ex. 12 1- [2- (3-ethyl-4-propylphen i I) ethyl] -4- (3-t rif I uoro methylphenyl) ) - 1, 2,3,6-tetrahydropyridine - Ex. 13 1 - [2- (4-ethyl-3-propylf in ii) eti l] -4- (3-trif luoromethyl in i 1) -1, 2 , 3,6-tetrahydropyridine - Ex. 14 1- [2- (3-butyl-4-met i If in i I) et i I] -4- (3-trifluoromethylmethyl) -1, 2 , 3,6-tetrahydropyridine - Ex. 15 1- [2- (4-Buty! -3-methylphenyl) ethyl] -4- (3-trifluoromethyphenyl) -1,2,3,6-tetrahydropyridine - Ex. 16 1- [2- (3-isobutyl-4-methylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine - Ex. 17 1- [2- (4-isobutyl-3 -methylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine - Ex. 18 1- [2- (3-isobutyl-4-ethylphenyl) ethyl] -4- (3-trifluoromethylphenyl) ) -1, 2,3,6-tetrahydropyridine - Ex. 19 1- [2- (4-isobutyl-3-ethylphenyl) ethyl] -4- (3-trif luoromethylphenyl) -1, 2,3,6- tetrahydropyridine - Ex. 20 EXAMPLE 21 1- [2 - (6-methyl-3-bi-phenyl-n-ethyl) -4- (3-trifluoromethyl-phenyl) -1, 2, 3,6-tetrah id rop i ridine. It was continued as described in Example 9, but using phenyllithium instead of n-butylmagnesium chloride, and the title compound was obtained.

EXAMPLE 22 1 - [2- (3'-Chloro-biphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethyl-p-n-I) -1, 2, 3, 6-tetrahydropyridine hydrochloride. 22a / 1-bromo-2- (3'-chlorobiphenyl-4-yl) ethanone. A mixture of 5 g (0.026 moles) of 3-chlorobiphenyl, 50 ml of methylene chloride, 6.95 g (0.034 moles) of bromoacetyl bromide was cooled to 0-5 ° C and 4 g (0.030) were added thereto. moles) of aluminum trichloride. The stirring was carried out for 1 hour at 5 ° C and then 4 hours at room temperature. The mixture was poured into a water / ice mixture, extracted with methylene chloride, the organic phase was washed with a solution of IN HCl, drying was carried out over sodium sulfate and the residue was evaporated under reduced pressure. 4.5 g of the title compound were obtained. P. f. 63-65 ° C. 22b / 1 - [2- (3'-chlorobiphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride. A mixture of 0.4 g (0.013 moles) of the product from the previous step, 2.95 g (0.013 moles of -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine, 80 ml of ethanol and 2.32 g (0.0167 moles) ) of anhydrous potassium carbonate in bars was brought to reflux for 1 hour.The salts were removed by filtration and the solution was acidified by the addition of a saturated solution of hydrochloric acid in ethanol.The concentration was carried out under pressure reduced until 40 ml of the residue was allowed to stand overnight at 40 ° C. The precipitate was filtered, washed with water and then with isopropanol, 4.9 g of the title compound were obtained, P. f 217-220 ° C. .

EXAMPLE 23 1 - [2- (2'-Chloro-biphen-yl-4-yl) -2-oxoethyl] -4- (3-trifluoromethyl-p-n-I) - 1, 2, 3, 6-tetrahydropyridine hydrochloride. It was continued as described in Example 22, but using 2-chlorobiphenyl instead of 3-chlorobiphenyl, and the title compound was obtained. P. f. 200-202 ° C (crystallized from isopropanol).

EXAMPLE 24 Hydrochloride of. 1 - [2- (4'-Chlorobiphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine. It was continued as described in Example 22 but using 4-chlorobiphenyl instead of 3-chlorobiphenyl, and the title compound was obtained. P. f. 210-215 ° C.

EXAMPLE 25 1 - [2- (4-Isobutylphenyl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. It was continued as described in Example 22 but using 4-isobutylbenzene instead of 3-chlorobiphenyl, and the title compound was obtained. P. f. 224-228 ° C (crystallized from isopropanol).

EXAMPLE 26 1 - [2- (4-Phenoxyphenyl) -2-oxoethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride. It was continued as described in Example 22, but using diphenyl ether instead of 3-chlorobiphenyl, and the title compound was obtained. P. f. 205-210 ° C.

EXAMPLE 27 1- [2- (4-Cyclohexylphenyl) -2-oxoethyl] -4- (3-trifluoromethyl-p-n-i) -1, 2, 3, 6-tetrahydropyridine hydrochloride. It was continued as described in Example 22, but using cyclohexylbenzene instead of 3-chlorobiphenyl, and the title compound was obtained. P. f. 209-213 ° C (crystallized from isopropanol).

EXAMPLE 28 1 - [2- (4'-F-luorobiphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. It was continued as described in Example 22, but using 4-fluorobiphenyl instead of 3-chlorobiphenyl, the title compound was obtained. P. f. 123-125 ° C (crystallized from isopropanol).

EXAMPLE 29 1 - [2- (Biphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride. It was continued as described in Example 22, but using biphenyl instead of 3-chlorobiphenyl, the title compound was obtained. P. f. 145-147 ° C (base); P. f. (240-243 ° C (hydrochloride).

EXAMPLE 30 Hydrochloride 1 - [2- (4-n-butylphenyl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine. The procedure was continued as described in Example 22, but using 4-n-butylbenzene instead of 3-chlorobiphenyl, and the title compound was obtained. P. f. 218-221 ° C.

EXAMPLE 31 1 - [2- (4-t-Butylphenyl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. It was continued as described in Example 22, but using 4-t-butylbenzene instead of 3-chlorobiphenyl, and the title compound was obtained. P. f. 97-99 ° C (base).

EXAMPLE 32 1 - [2- (3,4-Diethylphenyl) -4- (3-trif luoromethylf en il) -1, 2,3,6-tetrahydropyridine hydrochloride was continued as described in Example 22, but using 2, 4-Diethylbenzene in place of 3-chlorobiphenyl, the title compound was obtained, P.F. 232-234 ° C.

EXAMPLE 33 1 - [2 - (2 '-trif Ioromethyl bif in yl-4-yl) -2-oxoethyl) -4- (3-trifluoromethyl-phenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride . 33a / 2- (4-bromophenyl) -2,2-dimethoxyethane. A mixture of 2 g (0.01 mol) of 4-bromoacefenone, 5.6 ml of trimethyl orthoformate, 5.6 ml of methanol and 0.67 g of Amberlite® IR 120 was refluxed for 3 hours. After cooling, it was filtered through Celite® and the filtered solution was evaporated. 2.4 g of the title compound was obtained as an oil. 33b / 2,2-dimethoxy-2- (2'-trifluoromethylbiphenyl-4-yl) ethane.

A mixture of 4.9 g (14 moles) of the product from the preceding step, 2.45 g (16 mmoles) of 2-trifluoromethylbenzeneboronic acid, 63 mg (0.28 mmoles) of palladium acetate, 4.84 g (35 mmoles) of potassium carbonate and 4.5 g (14 mmol) of tetrabutylammonium bromide in 19 ml of water was stirred at 70 ° C for 1 hour. It was allowed to cool and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as an oil. 33c / 4- (2-trifluorophenyl) acetophenone. A solution of 4 ml of trifluoroacetic acid and 4 ml of water was added to a solution of 4.6 g (0.0105 mol) of the product from the preceding step in 4 ml of methylene chloride at 0 ° C. The mixture was stirred at room temperature for 2 hours, poured into water and extracted with methylene chloride. The organic phase was dried, filtered and the solvent was evaporated under reduced pressure. The crude was purified through silica gel column chromatography eluting with a cyclohexane / ethyl acetate = 9/1 mixture. 1.97 g of the title compound were obtained. 33d / -bromo-4- (2-trifluoromethylphenyl) acetophenone. 0.38 ml (7.5 mmol) of bromide was added dropwise to a solution of 1.97 g (7.5 mmol) of the product from the preceding step in 5.4 ml of methanol, at a temperature of 0 ° C. The stirring was carried out at room temperature for 3 hours, the solvent was evaporated and the residue was taken up in water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title product was obtained as an oil. 33e / 1 - [2- (2'-trifluoromethylbiphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride. A solution of 0.74 g (0.0028 moles) of 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, 14 ml of ethanol and 1.27 g (0.0092 mol) of anhydrous potassium carbonate in grid was brought to reflux for 1 hour. A solution of 1.2 g (0.0035 mol) of the oil from the preceding step in 3 ml of ethanol was added thereto and the mixture was left under reflux for 30 minutes. The salts were removed by filtration, and the solution was acidified through the addition of a 1M aqueous hydrochloric acid solution. The solvent was evaporated under reduced pressure, the extraction was carried out with chloroform and the organic phase was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The base was freed with the aid of a concentrated ammonia solution and extracted with ethyl acetate, the product was purified by silica gel column chromatography eluting with a cyclohexane / ethyl acetate = 8/2 mixture. The title compound was obtained. The hydrochloride was prepared with the aid of a saturated solution of hydrochloric acid in isopropanol. P. f. 195-197 ° C.

EXAMPLE 34 1 - (2- (3'-trifluoromethylbifen i-4-yl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. proceeded as described in Example 33, but using 3-trifluoromethylbenzeneboronic acid in place of 2-trifluoromethylbenzeneboronic acid in step 33b / the title compound was obtained.P.F.232-234 ° C.

EXAMPLE 35 1 - [2- (4'-trifluoromethylbiphenyl-4-yl) -2-oxoethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. It was continued as described in Example 33, but using 4-trifluoromethylbenzeneboronic acid in place of 2-trifluoromethylbenzeneboronic acid in step 33b /, and the title compound was obtained. P. f. 245-247 ° C.

EXAMPLE 36 A mixture of 12.5 g of 2- (2-bromoethyl) naphthalene, 14 g of 4- (3-tpfluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, 4.34 g of sodium hydroxide, 135 ml of Water and 95 ml of 35% ethanol was heated for 5 hours under reflux, and the reaction mixture was allowed to cool overnight at room temperature. The mixture ^ cooled below 25 ° C. and then filtered, the product thus isolated was washed with water and then dried under vacuum at 50 ° C. The base 1- [2- (2-naphthyl) ethyl] -4- (3-tri fluoro methyl n-nyl) -1.2, 3,6-tetrahydro pyridine was thus obtained in a yield of 90% calculated on the 4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine hydrochloride starting material.

EXAMPLE 37 A mixture of 19.5 g of crude 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, 95 ml of absolute ethanol and 4.65 ml of 35% hydrochloric acid was heated under reflux with stirring until complete dissolution, and then allowed to cool while stirring was continued. When the first crystals began to form (around 63 ° C) the stirring was stopped and the reaction mixture was kept at 0-5 ° C overnight. After filtration, the product was swelled twice in 30 ml of absolute ethanol, and then dried overnight at 40 ° C under vacuum. Under these conditions, 12.8 g of Form I of 1- [2- (2-naphthyl) ethyl] -4- (3-trif luoromethyl-phenyl) -1,2,3,6-tetrahydroxy-pyridine hydrochloride were obtained. . The differential calorimetric analysis of Form I obtained from this preparation shows a solid-solid transition temperature of 148-149 ° C, a transition enthalpy of 26.4 J / g.

EXAMPLE 38 A mixture of 70 g of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 1 liter of absolute ethanol was brought to reflux in a Mettier RC1 calorimeter reactor equipped with an impeller with a diameter of 8 cm until the dissolution of the product is complete. The solution thus obtained was cooled with a cooling rate of 80 ° C per hour and an agitation speed of 500 r.p.m. at 10 ° C. The precipitate thus obtained is filtered and dried overnight at 45 ° C under vacuum. Under these conditions, Form II of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride was obtained. The differential calorimetric analysis of Form II obtained in this preparation shows a solids-solid transition temperature of 153-155 ° C and a transition enthalpy of 24.1 J / g.

EXAMPLE 39 A mixture of 2 g of 1 - [2- (2-naphthyl) ethyl] -4- (3-trif luoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 50 ml of dimethylsulphoxide was carried at reflux until complete dissolution, allowed to cool overnight, and then the crystalline product was recovered and dried under vacuum at 45 ° C overnight. Under these circumstances, Form lll of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylf en il) -1, 2, 3, 6-tet rahidropi ridine hydrochloride was obtained. The differential calorimetric analysis of Form III obtained in this preparation shows: - a solid-solid transition temperature of 141-142 ° C, a transition enthalpy of 17.6 J / g.

EXAMPLE 40 A mixture of 100 g of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride in 1 liter of an ethanol / water mixture , 90/10, was brought to reflux with stirring until the dissolution of the product was completed. The product thus obtained was cooled from the reflux temperature to 5 ° C under impeller stirring at 400 rpm at a cooling rate of 10 ° C / hour. The crystalline product thus obtained was filtered and dried at 45 ° C under vacuum overnight. Under these conditions, 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -112,3,6-tetrahydropyridine hydrochloride was obtained as a mixture of Form l / Form III , in a ratio of 65.7 / 34.3. The differential calorimetric analysis of Form l / lll obtained in this preparation shows a thermogram, which presents only the two characteristic peaks corresponding to Forms I and 111.

EXAMPLE 41 A solution of 3 g of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride in 300 ml of ethanol was atomized in an apparatus of "Büchi mini Spray Dryer" according to the principle of atomization through a parallel current pipe, to regulate the flow rate of the pump, the suction, the heating and the current flow in order to obtain a temperature input of 172 ° C, an outlet temperature of 107 ° C and a depression of 40 mbar. Under these conditions, a broad DSC monopic product was obtained with the maximum at 145 ° C. The particles obtained are spherical and the very homogeneous population did not exceed an average size of 5 micrometers.

EXAMPLE 42 24 kg of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride, Form I / MI, described in Example 40, introduced into the micronization chamber (diameter of 200 mm) of an Alpine 200 AS micronizer at a rate of 25 kg / hour and a working pressure of 6.5 bar and the product thus micronized was recovered in 1 filter sleeve. In this way a micronized product was obtained, which had a particle distribution according to which all the particles have a size smaller than 20 microns and 85% of the particles have a size smaller than 10 microns. The differential calorimetric analysis of the micronized product thus obtained shows that the transition temperatures are not affected by micronization. These transitions are of the solid-solid type. The compound degrades before melting, which starts at 250 ° C.

EXAMPLE 43 A pharmaceutical composition containing, as an active principle, the Form I / III of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride (micronized) according to Example 42 : Active ingredient 1,192 mg Maize starch 141,208 mg Microcrystalline cellulose 26,000 mg Colloidal silica Anhydrous 0,200 mg Magnesium stearate 0.400 mg The active substance was sieved to 0.2 mm, and then premixed with the excipients. This mixture was sieved at 0.315 mm, mixed again and then sieved again at 0.315 mm. After final mixing, the composition was filled into No. 3 gelatin capsules, at a rate of 170 mg of the composition containing an amount of 1 - [2- (2-naphthyl) ethyl] -4- hydrochloride ( 3-trifluoromethyl faith or I) - 1, 2, 3, 6-tetrahydropyridine-Form l / lll, corresponding to 2 mg of base 1- (2- (2-naphthyl) ethyl] -4- (3- tri fl uoromethyl faith nyl) -1, 2, 3, 6-tetrahydropyridine.

EXAMPLE 44 Cell-containing dishes were prepared as in preparation 1. The levels of TGF-β1 were measured as described in preparation 2. The levels of active TGF-β1 were measured in the extracellular media in the presence of SR 57746A after 1 , 3, 14, 24 and 48 hours and 7 days of contact with the cells, compared with the controls (0.2% of fetal bovine serum, and 20% of fetal bovine serum) through the method described in preparation 2 SR 57746 induces a significant increase in the levels of TGF-β1 activated in the extracellular medium after 14 hours of contact with the cells.

EXAMPLE 45 Cell-containing dishes were prepared as in preparation 1, and apoptosis was induced as in preparation 4 according to method a). The anti-apoptotic effects of SR 57746 and compounds A, B, C, D, E, and F were measured after 1, 2, 14, 24, 48 hours and 7 days of contact with the cells compared to controls (0.2% fetal bovine serum and 20% fetal bovine serum) through the method described in preparation 4. The tested compounds significantly inhibit apoptosis induced by serum deprivation after 24 hours of contact with the cells and for 7 days at least.

EXAMPLE 46 Plates containing cells were prepared as in preparation 1. Apoptosis was induced according to method b). From preparation 4. The levels of apoptosis were measured after 24 hours of contact with the cells through the method described in preparation 4; the same controls as in preparation 4, were used. SR 57746, as well as A, B, C, D, E, and F significantly inhibited the pro-apoptotic effect of NGF.

EXAMPLE 47 Cell-containing dishes were prepared as described in preparation 1. Apoptosis was induced according to method c) of preparation 4. The levels of apoptosis were measured after 24 hours of contact with the cells through the method described in Preparation 4; the same controls were used as in preparation 4. SR 57746 and compounds A, B, C, D, E and F significantly inhibit the pro-apoptotic effect of vincristine.

EXAMPLE 48 1-1- [2- (6,7-Methylenedioxinaphth-2-yl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride. 1.1 g (0.0048 mole) of 2- (6,7-dimethoxynaphth-2-yl) acetic acid, 20 ml of methylene chloride, 2 ml (0.0144 mole) of triethylamine, 1.35 g (0.0048 mole) were stirred at room temperature. of 4- (3-trifluoromethylphenyl) -4-piperodonol and 2.15 g (0.0048 moles) of BOP. The washing was carried out with a 1N HCl solution, and then with a saturated solution of NaHCO3 and then with water. The drying was carried out over sodium sulphate and the solvent was evaporated under reduced pressure. The oil thus obtained, 1.5 g, was dissolved in 18 ml of THF. The mixture was heated to reflux and a solution of 0.97 ml (0.0102 mole) of dimethyl sulfide / borane in 12 ml of THF was added dropwise thereto. The mixture was refluxed for 4 hours, cooled to 0 ° C and 15 ml of methanol was added. Again, it was refluxed for 30 minutes, and then evaporated under reduced pressure. The residue was taken up in ethyl acetate, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oil obtained was dissolved in 22 ml of glacial acetic acid and 1.2 ml of concentrated sulfuric acid was added thereto, and the mixture was heated at 60 ° C for 4 hours. This was poured into an ice / NaOH mixture and extracted with ethyl acetate. The hydrochloride was prepared with the aid of isopropanol saturated with HCl to obtain the title compound P. f. 277-280 ° C.

EXAMPLE 49 49a / 4- (2-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine hydrochloride. A mixture of 2 g (0.0071 mol) of 4- (2-trifluoromethylphenyl) -4-piperidinol (prepared from benzylpiperidone, 2-bromo-1-trifluoromethylbenzene and magnesium and successive hydrogenation), 12 ml of glacial acetic acid and 3 My concentrated sulfuric acid was heated at 100 ° C for 2 hours. It was poured into an ice / NaOH mixture and extracted with methylene chloride. The organic phase was dried and evaporated under reduced pressure. The hydrochloride was prepared with the aid of isopropanol saturated with hydrochloric acid. P. f. 213-215 ° C. 49b / 1 - [2- (biphenyl-4-yl) etl] -4- (2-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. It was continued as described in Example 8b, but using the product of the preceding step in place of 4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine and 1-bromo-2-biphenylylethane in place of the product of the Step 8a, and the title compound was obtained. P. f. 273-275 ° C.

EXAMPLE 50 1 - [2- (4-Cyclohexenylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. A mixture of 1 g (0.005 mole) of 2- (4-bromophenyl) ethanol, 0.7 g (0.0055 mole) of 1-cyclohexanboronic acid, 25 mg of palladium acetate, 1.73 g (0.0012 mole) of potassium carbonate and 1.61 g (0.005 mole) of tetrabutylammonium bromide in 7 ml of water was stirred at 70 ° C for 3 hours. It was allowed to cool and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The reaction crude was purified by silica gel column chromatography, eluting with a cyclohexane / ethyl acetate = 7/3 mixture. The title compound was obtained as an oil. A solution of 1.35 g (6.67 mmoles) of the product from the preceding step, 0.93 ml (6.67 moles) of mesyl chloride and 0.5 ml of methylene chloride was cooled to 0.5 ° C. The mixture was stirred at 0 ° C for 30 minutes and then overnight at room temperature. The mixture was poured into water and extracted with methylene chloride. The organic phase was dried and the solvent was evaporated under reduced pressure. The residue was taken up in 8 ml of isopropanol, and 0.64 ml (4.6 mmol) of triethylamine and 0.45 g (1.7 mmol) of 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine were added thereto. The mixture was refluxed for 4 hours, the solvent was evaporated and washed with water. It was extracted with methylene chloride, the organic phase was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a cyclohexane / ethyl acetate = 8/2 mixture. The hydrochloride was prepared with the aid of isopropanol saturated with HCl. In this manner, the title compound was obtained. P. f. 244-245 ° C.

Claims (1)

1. CLAIMS The use of a compound of the formula (I): wherein: -Ri represents a halogen or a CF3, an alkyl group of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; -And represents a nitrogen atom or a CH group; -Z 'and Z "each represent hydrogen or an alkyl group of 1 to carbon atoms, or one represents hydrogen and the other represents a hydroxy group, or both, together, represent an oxo group; -Z represents: * a radical phenyl; * monosubstituted with a substituent X, X being: a) an alkyl group of 1 to 6 carbon atoms; alkoxy of 1 to carbon atoms; carboxy alkyl of 3 to 7 carbon atoms; alkoxycarbonyl of 1 to 4 atoms carbon-alkyl of 1 to carbon atoms, carboxyalkoxy of 3 to 7 carbon atoms, alkoxy carbonyl of 1 to 4 carbon atoms-alkoxy of 1 to carbon atoms, b) a group selected from the group of cycloalkyl of 3 to atoms carbon, cycloalkyloxy of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 7 carbon atoms, ciloalquilamino 3 to 7 carbon atoms and cyclohexenyl, it being possible for said group to be substituted by a halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, carboxy, alkoxycarbonyl from 1 to 4 át carbon, amino, mono or dialkylamino of 1 to 4 carbon atoms; one group selected from phenyl, and phenoxy, phenylamino, n-alkylphenylamino 1 to 3 carbon atoms, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl or styryl, it being possible for said group to be mono- or poly-substituted in the group phenyl with a halogen, CF3, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, amino, mono or dialkylamino of 1 to 4 carbon atoms, acylamino of 1 to 4 carbon atoms, carboxy alkoxycarbonyl of 1 to 4 carbon atoms, aminocarbonyl, mono- or dialkylamino of 1 to 4 carbon atoms, aminoalkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; * A phenyl radical disubstituted with R2 substituent, R2 being a halogen or a hydroxy, methyl, ethyl, alkyl of 3 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, or trifluoromethyl, and with a substituent X, X being defined as above: * a 1-naphthyl or 2-naphthyl radical; * a 1-naphthyl or 2-naphthyl radical substituted at positions 5, 6, 7 and / or 8 with 1 or 2 hydroxyl groups, one or . • two alkoxy groups of 1 to 4 carbon atoms or a 6,7-methylenedioxy group; -o Z "is hydrogen and Z and Z 'represent, each independently, an unsubstituted or mono, di or trisubstituted phenyl group, or one of its pharmaceutically acceptable salts or solvates, for the preparation of pharmaceutical compositions capable of increasing the circulation and cellular and extracellular levels of TGF-β1 2. The use according to claim 1, wherein said compound of formula (I), Y is CH and RT is o- or m-CF3. - The use according to claim 2, wherein Z 'and Z "are hydrogen 4. The use according to claim 2, wherein Z 'and Z" together form an oxo group and Z is 4-biphenyl. 5. The use according to claim 3, wherein Z represents a 2-naphthyl, 6,7-dimethoxy-2-naphthyl or 6,7-metlenedioxy-2-naphthyl group. 6. The use according to claim 3, wherein Z represents a monosubstituted phenyl radical with a substituent X, X being as defined in claim 1. 7. The use according to claim 3, wherein Z represents a phenyl radical monosubstituted with a group X ', X' being an unsubstituted or substituted by 1 to 3 halogens, 1 to 3 is CF3, 1 to 3 alkyl of 1 to 4 carbon atoms, phenyl 1 to 3 alkoxys of 1 to 4 carbon atoms, 1 to 3 cyans, 1 to 3 amines, 1 to 3 mono or diakylaminos of 1 to 4 carbon atoms, 1 to 3 acylaminos of 1 to 4 carbon atoms, 1 to 3 carboxis, 1 to 3 alkoxycarbonyl of 1 to 4 carbon atoms, 1 to 3 aminocarbonilos, 1 to 3 mono- or dialkylamino carbonyl 1 to 4 carbon atoms, 1 to 3 aminoalkyl of 1 to 4 carbon atoms, 1 to 3 hydroxyalkyl of 1 to 4 carbon atoms of carbon or 1 to 3 haloalkyl groups of 1 to 4 carbon atoms; or a disubstituted phenyl radical with a substituent R2, R2 being as defined in claim 1 and with a substituent X ', X' being as defined above. 8. The use according to claim 3, wherein Z is a phenyl group disubstituted at positions 3 and 4 with a methyl, ethyl, alkyl group of 3 to 6 carbon atoms. 9. The use according to claim 2, wherein Z "is hydrogen and Z and Z ', each one representing a phenyl group, a phenyl group substituted at the 2, 3 or 4 position with a fluorochloro atom or with methyl, ethyl, n-propyl, i-butyl, n-butyl, i-butyl, s-butyl, t-butyl, trichloromethyl, cyano, methoxy, methylthio, methylsulphonyl, ethoxy, ethylthio, ethylsulphonyl, alkoxycarbonyl group 1 3 carbon atoms dialkylaminocarbonyl of 1 to 3 carbon atoms, a phenyl group disubstituted in positions 2,4, 3,4, 3,5 or 2,6 with a chlorine or fluorine atom, or with a methyl, ethyl group , trifluoromethyl, cyano or methoxy, or a phenyl group trisubstituted at the 3,4,5, 2,4,5 or 2,4,6 positions with a chlorine or fluorine atom, or with a methyl, ethyl, trifluoromethyl group, cyano or methoxy 10. The use according to claim 3, wherein the compound of the formula (I) is 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) - hydrochloride 1,2,3,6-tetrahydropyr 11. The use according to claim 10, wherein the hydrochloride of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoro-methyl-en-I) -1,3, 6-tetrahydropyridine is atomized or micronized. 12. The use according to claim 10, wherein the hydrochloride of 1 - [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine is a mixture micronized crystalline forms I and III in a ratio of approximately 66/34. 13. The use according to one of claims 1 to 12, wherein the pharmaceutical compositions are indicated for the treatment of diseases that can be treated by increasing the circulation and cellular and extracellular levels of TGFßl. 14. The use according to claim 3, wherein the pharmaceutical compositions are indicated for the treatment of diseases selected from pathologies related to an abnormal apoptotic activity; eye diseases such as cataracts or glaucoma; osteoporosis; Bone fracture; epidermal lesions; restenosis; conditions related to incorrect proliferation or migration of smooth muscle cells; inflammations of the respiratory system; asbestosis; silicosis; lupus erythematosus; Goodpasture syndrome; granulomatosis; eosinophilic granulomatosis; gastric and duodenal ulcers; oseophagitis; enteritis; gastritis; septicemia; malfunctioning of hematopoiesis and / or lymphopoiesis; cystic fibrosis. 15. The use according to claim 13, wherein the pharmaceutical compositions are indicated for the treatment of pathologies related to an abnormal apoptotic activity. 16. The use according to claim 15, wherein the pharmaceutical compositions are indicated for the treatment of a disease selected from cancer and its metastasis; infections by antivirus such as HIV and HITV 1 and 2 and its consequences such as ATL; leukemia; leukemia; myelopathies and arthropathies; hepatitis (C, A, B, F); AIDS; immune deficiencies; cell aging; tissue degeneration phenomenon; inflammation; cell proliferation; infectious diseases; rejection of grafts; acute or chronic rheumatoid arthritis; Ulcerative colitis; thrombocytopenic purpura; autoimmune erythromoclast anemia; juvenile diabetes (Type I) (insulin dependent); myelodysplastic syndrome, Huntington's disease; prion diseases; ARDS; prosthetic hypertrophy; asthma; atherosclerosis and its thrombo-embolic complications; kidney diseases; glomerolunephritis; chronic pancreatitis, autoimmune gastritis, and primary biliary cirrhosis. 17. The use according to claim 16, wherein the pharmaceutical compositions are indicated for the treatment of graft rejection or acute or chronic rheumatoid arthritis. 18. The use according to claim 15, of a compound of the formula (I), other than the compounds wherein Z 'and Z "each represents hydrogen and Z represents 1-naphthyl or 2-naphthyl for the preparation of a drug capable of treating myocardial infarction, myocardial ischemia, coronary vasospasm, angina and heart failure 19.- A compound selected from 1- [2- (6,7-methylenedioxinaphth-2-yl) ethyl] -4- (3-trifluoromethyl nyl) -1, 2,3,6-tet rahydropyrinium, 1- [2- (4-cyclohexenylphenyl) -ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6- tetrahydropyridine and 1- [2- (b-fe nyl-4-yl) ethyl] -4 - (3-trifluoromethyl-phenyl I) -1, 2,3,6-tetrahydropyridine, and their pharmaceutically acceptable salts or solvates.