FR2805815A1 - New 4-fluoroalkylated 2-(piperidin-4-ylmethoxy)-1-phenyl-1H-imidazole derivatives, are M3 and 5HT-4 receptor antagonists useful e.g. for treating irritable bowel syndrome or memory or bladder disorders - Google Patents

Abstract

4-Fluoroalkylated 2-(1-substituted piperidin-4-ylmethoxy)-1-phenyl-1H-imidazole derivatives (I) are new. Imidazole derivatives of formula (I) and their salts, N-oxides and hydrates are new: R1 = CnHxFy; n = 1 or 2; x = 0-3; and y = 1-5; provided x + y = 2n + 1; R2 = halo, H or 1-4C alkyl; R = 2-6C alkenyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, imidazolyl or thiazolyl (all optionally substituted by 1-3 R4 groups); R3, R4 = H, halo, 1-4C alkyl, OH, 1-4C alkoxy, CN, NO2, 1-2C perfluoroalkyl, NH2, 1-2C aminoalkoxy, SO2NH2 or CH2OH; and m = 1-3. Independent claims are included for: (i) the preparation of (I); and (ii) new imidazole derivative intermediates of formulae (VI) and (VII). Q = R1 (preferably CF2H) or CHO.

Description

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 The present invention relates to polyfluoroalkylimidazole derivatives, their preparation and their use in therapy.

dans laquelle, R1 est un groupe de formule CnHxFy où n = 1 ou 2, x = 0 à 3, y = 1 à 5 et x+y = 2n+1 et R2 représente un hydrogène, un groupe C1-4 alkyle, un atome d'halogène, R représente un groupe C2-4 alkényle ou un phényle éventuellement substitué par un, deux ou trois groupes R4 ; R3 et R4 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un atome d'halogène, un groupe C1-4 alkyle, hydroxy, C1-4 alcoxy, cyano, nitro, perfluoro-C1-2 alkyle, amino, et ses sels, N-oxydes et hydrates. Consequently, the first subject of the present invention is a compound of general formula (I):

in which, R1 is a group of formula CnHxFy where n = 1 or 2, x = 0 to 3, y = 1 to 5 and x + y = 2n + 1 and R2 represents hydrogen, a C1-4 alkyl group, a halogen atom, R represents a C2-4 alkenyl group or a phenyl optionally substituted by one, two or three R4 groups; R3 and R4 represent, independently of one another, a hydrogen atom, a halogen atom, a C1-4 alkyl, hydroxy, C1-4 alkoxy, cyano, nitro, perfluoro-C1-2 alkyl group , amino, and its salts, N-oxides and hydrates.

Patent application WO99 / 2571 0 discloses compounds of formula (1) in which R1 and R2 represent, independently of one another, hydrogen, a C1-6 alkyl group, or together form a polymethylene group - ( CH2) n-, n can take the values from 3 to 6, as antagonists of the muscarinic M3 and serotonergic 5-HT4 receptors.

However, it has been found that the compounds of the present invention, in which R1 represents a polyfluorinated alkyl group, show a greater affinity for the abovementioned receptors. On the other hand, they exhibit increased inertia in the face of oxidative metabolic mechanisms by microsomes.

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 The preferred compounds according to the present invention are the compounds for which: * R2 represents a hydrogen or halogen atom and / or * R3 represents a hydrogen or halogen atom, a hydroxy or a C1-C4 alkoxy group preferably C1-2 alkoxy and / or * R4 represents a hydrogen atom, a hydroxy or a C1-4 alkoxy group preferably C1-2 alkoxy.

Among these, the particularly preferred compounds are those for which R1 represents a CF3, CF2H or C2F5.

1 : 1-(phénylméthyl)-4-[[[1-phényl-4-(trifluorométhyl)-1H-imidazol-2yl]oxy]méthyl]pipéridine 2 : 1-[(3-méthoxyphényl)méthyl]-4-[[[1-phényl-4-(trifluorométhyl)-9H-imidazol-2- yl]oxy]méthyl] pipéridine 3 : 3-[[4-[[[1-phényl-4-(trifluorométhyl)-1H-imidazol-2-yl]oxy]méthyl]pipéridin-1yl]méthyl]phénol

4 : 4-[[[1-(2-fluorophényl)-4-(trifluorométhyl)-9H-imidazol-2-yl]oxy]méthyl]-1- (phénylméthyl)pipéridine 5 : 4-[[[1-(2-fluorophényl)-4-(trifluorométhyl)-9H-imidazol-2-yl]oxy]méthyl]-1-[(3méthoxyphényl)méthyl]pipéridine 6 : 3-[[4-[[[1-(2-fluorophényl)-4-(trifluorométhyl)-9H-imidazol-2yl]oxy]méthyl]pipéridin-1-yl]méthyl]phénol 7 : 1-[(3-méthoxyphényl)méthyl]-4-[[[1-(3-méthoxyphényl)-4-(trifluorométhyl)-9Himidazol-2-yl]oxy]méthyl]pipéridine 8 : 3-[2-[[ 1-[ (3-hyd roxyphé nyl )méthyl] pi périd in-4-yl] méthoxy]-4-(trifluorométhyl)- 1-/-imidazol-1 -yl]phénol 9 : 4-[[[1-(3-méthoxyphényl)-4-(trifluorométhyl)-lH-imidazol-2-yl]oxy]méthyl]-l- (phénylméthyl)pipéridine 10 : 3-[2-[[1-(phénylméthyl}pipéridin-4-yl]méthoxy]-4-(trifluorométhyl)-9Himidazol-1-yl]phénol 11 : 3-[[4-[[[5-chloro-1-phényl-4-(trifluorométhyl)-lH-imidazol-2yl]oxy]méthyl]pipéridin-1-yl]méthyl]phénol 12 : 3-[[4-[[[5-chloro-1-(2-fIuorophényl)-4-(trifluorométhyl)-1 H-imidazol-2yl]oxy]méthyl]pipéridin-1-yl]méthyl]phénol 13 : 4-[[[5-chloro-1-(2-fluorophényl)-4-trifluorométhyl-9N-imidazol-2- yl]oxy]méthyl]-1-(phénylméthyl)pipéridine By way of example, mention may be made of the following compounds:

1: 1- (phenylmethyl) -4 - [[[1-phenyl-4- (trifluoromethyl) -1H-imidazol-2yl] oxy] methyl] piperidine 2: 1 - [(3-methoxyphenyl) methyl] -4- [ [[1-phenyl-4- (trifluoromethyl) -9H-imidazol-2-yl] oxy] methyl] piperidine 3: 3 - [[4 - [[[1-phenyl-4- (trifluoromethyl) -1H-imidazol- 2-yl] oxy] methyl] piperidin-1yl] methyl] phenol

4: 4 - [[[1- (2-fluorophenyl) -4- (trifluoromethyl) -9H-imidazol-2-yl] oxy] methyl] -1- (phenylmethyl) piperidine 5: 4 - [[[1- ( 2-fluorophenyl) -4- (trifluoromethyl) -9H-imidazol-2-yl] oxy] methyl] -1 - [(3methoxyphenyl) methyl] piperidine 6: 3 - [[4 - [[[1- (2-fluorophenyl ) -4- (trifluoromethyl) -9H-imidazol-2yl] oxy] methyl] piperidin-1-yl] methyl] phenol 7: 1 - [(3-methoxyphenyl) methyl] -4 - [[[[1- (3- methoxyphenyl) -4- (trifluoromethyl) -9Himidazol-2-yl] oxy] methyl] piperidine 8: 3- [2 - [[1- [(3-hyd roxyphé nyl) methyl] pi perid in-4-yl] methoxy ] -4- (trifluoromethyl) - 1 - / - imidazol-1 -yl] phenol 9: 4 - [[[1- (3-methoxyphenyl) -4- (trifluoromethyl) -lH-imidazol-2-yl] oxy] methyl] -1- (phenylmethyl) piperidine 10: 3- [2 - [[1- (phenylmethyl} piperidin-4-yl] methoxy] -4- (trifluoromethyl) -9Himidazol-1-yl] phenol 11: 3- [ [4 - [[[5-chloro-1-phenyl-4- (trifluoromethyl) -1H-imidazol-2yl] oxy] methyl] piperidin-1-yl] methyl] phenol 12: 3 - [[4 - [[[ 5-chloro-1- (2-fluorophenyl) -4- (trifluoromethyl) -1 H-imidazol-2y l] oxy] methyl] piperidin-1-yl] methyl] phenol 13: 4 - [[[5-chloro-1- (2-fluorophenyl) -4-trifluoromethyl-9N-imidazol-2-yl] oxy] methyl] -1- (phenylmethyl) piperidine

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(trifluorométhyl)-9H-imidazol-1-yl]phénol 16 : 4-[[[4-(pentafluoroéthyl)-1-phényl-9N-imidazol-2-yl)oxy]méthyl]-1- (phénylméthyl)pipéridine 17 : 4-[[[4-(difluorométhyl)-1-phényl-9H-imidazof-2-yl)oxy]méthyl]-1- (phénylméthyl)pipéridine Dans le cadre de la présente invention, on entend par : - C1-z (ou C2-z), où z peut prendre les valeurs de 2 à 4, une chaîne carbonée pouvant avoir de 1 ou 2 à z atomes de carbone, - alkyle, un groupe aliphatique saturé, linéaire ou ramifié ; parexemple, un groupe C1-4 alkyle représente une chaîne carbonée de 1 à 4 atomes de carbone, linéaire ou ramifiée, plus particulièrement un méthyle, éthyle, propyle, isopropyle, butyle , isobutyle, secbutyle, tertbutyle, de préférence un méthyle, éthyle, propyle, isopropyle, - alkényle, un groupe aliphatique mono ou poly-insaturé, linéaire ou ramifié, comprenant de préférence 1 ou 2 insaturations éthyléniques, - perfluoroalkyle, un alkyle dont tous les hydrogènes ont été substitués par des fluors, par exemple CF3, - polyfluoroalkyle, un alkyle dont une partie des hydrogènes a été substituée par des fluors, par exemple CF2H, - CnHxFy avec un n, x et y tels que définis ci-dessus, un perfluoroalkyle ou polyfluoroalkyle, tel que, par exemple, -CF3, -CF2H, -CH2F, -CF2CF3, -CFHCF3, ... 14: 3- [5-Chloro-2 - [[1- (phenylmethyl) piperidin-4-yl] methoxy] -4- (trifluoromethyl) - 1H-imidazol-1-yl] phenol 15: 3- [5-Chloro -2 - [[1 - [(3-hydroxyphenyl) methyl] piperidin-4-yl] methoxy] -4-

(trifluoromethyl) -9H-imidazol-1-yl] phenol 16: 4 - [[[4- (pentafluoroethyl) -1-phenyl-9N-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine 17 : 4 - [[[4- (difluoromethyl) -1-phenyl-9H-imidazof-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine In the context of the present invention, the following definitions mean: - C1- z (or C2-z), where z can take the values from 2 to 4, a carbon chain being able to have from 1 or 2 to z carbon atoms, - alkyl, a saturated, linear or branched aliphatic group; for example, a C1-4 alkyl group represents a carbon chain of 1 to 4 carbon atoms, linear or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, preferably methyl, ethyl, propyl, isopropyl, - alkenyl, a mono or polyunsaturated, linear or branched aliphatic group, preferably comprising 1 or 2 ethylenic unsaturations, - perfluoroalkyl, an alkyl in which all the hydrogens have been replaced by fluorines, for example CF3, - polyfluoroalkyl, an alkyl in which a portion of the hydrogens has been substituted by fluorines, for example CF2H, - CnHxFy with an n, x and y as defined above, a perfluoroalkyl or polyfluoroalkyl, such as, for example, -CF3, -CF2H, -CH2F, -CF2CF3, -CFHCF3, ...

- alkoxy, an alkyloxy group with a saturated, linear or branched aliphatic chain, and - halogen atom, a fluorine, a chlorine, a bromine or an iodine.

The term “leaving group” is intended to mean a group which can be easily cleaved from a molecule, with the departure of an electronic pair, by breaking a heterolytic bond. This group can thus be easily replaced by another group during a substitution reaction for example. Such leaving groups are, for example, halogens, or an activated hydroxy group such as a mesyl, tosyle, triflate, acetyl, etc. Examples of leaving groups as well as preparation references are given in Advanced Organic Chemistry, J. March, 3rd Edition, Wiley Interscience, p 310-316.

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The term “protective group” is intended to mean a group which makes it possible to prevent the reactivity of a function or position, during a chemical reaction which may affect it, and which restores the molecule after cleavage according to methods known to those skilled in the art. Examples of protective groups as well as methods of protection and deprotection are given, among others, in Protective groups in Organic Synthesis, Greene et al., 2nd Ed. (John Wiley & Sons, Inc., New York).

The term “functional group” is intended to mean a group which can be oxidized, reduced, substituted, alkylated, dealkylated or undergo any other conventional transformation of organic chemistry. These functional transformation reactions can be carried out by conventional methods known to those skilled in the art to give other compounds. Such groups are for example R3 and R4.

The compounds of general formula (I) may contain one or more asymmetric carbons. They can therefore exist in the form of enantiomers or diastereoisomers.

These enantiomers, diastereoisomers and their mixtures, including racemic mixtures, form part of the invention.

The compounds of general formula (I) can be in the form of free base or of addition salts with acids, which also form part of the invention.

These salts, according to the present invention, include those with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (1), such as picric acid, oxalic acid or an optically active acid, by example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphosulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, the hydrobromide, the citrate, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the maleate, fumarate, pamoate, 2-naphthalenesulfonate, paratoluenesulfonate. Although the pharmaceutically acceptable salts are preferred, the other salts are part of the present invention. These salts can be prepared, according to methods known to a person skilled in the art, for example, by reaction of the compound of formula (1) in base form with the acid in an appropriate solvent, such as an alcoholic solution or a organic solvent, then separation of the medium which contains it by evaporation of the solvent or by filtration.

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The compounds of general formula (I) can also be in the form of N-oxide derivatives which form part of the present invention. These derivatives are obtained by oxidation reaction of the compound of formula (I) according to methods known to those skilled in the art.

A second subject of the present invention is processes for preparing the compounds of formula (1).

Thus, these compounds can be prepared by methods, illustrated in the diagrams which follow, the operating conditions of which are conventional for a person skilled in the art.

According to scheme 1, the phenylthiourea (II) is transformed into isothiouronium (III) by the method described by J.N. Baxter in J. Chem. Soc., 1956, 663 by the action of iodomethane in a solvent such as acetone or ethanol, preferably at reflux of the latter. The isothiouronium is then reacted with a bromoketone of formula (IV) in an alcohol such as isopropanol and in the presence of a base such as sodium hydrogen carbonate, preferably two equivalents, to lead to the mixture of imidazoline (V) and imidazole (VI). This mixture is then dehydrated according to methods known to those skilled in the art, for example by the action of paratoluenesulfonic acid (APTS) in a solvent such as toluene at reflux to give the compound of formula (VI). This compound is oxidized according to methods known to a person skilled in the art, for example by means of potassium peroxy monosulfate sold under the name Oxone in the presence of wet alumina, in a solvent such as chloroform, at a temperature between 40 and 65 C, to lead to the sulfone (VII). This sulfone is then coupled with a hydroxymethylpiperidine of formula (VIII) in basic medium to give a compound of formula (1). The reaction can be carried out in the presence of a base such as sodium or potassium hydride in a solvent such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP) at a temperature ranging from -10 C to 20 C .

The meanings of R1, R2, R3 and R in the compounds of formula (11), (III), (IV), (V), (VI), (VII) and (VIII) are as defined for the compounds of formula (I).

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 Scheme 1 Alternatively, the compounds of formula (1), in which R1 represents an HF2C- group, can be obtained as indicated in scheme 2.

The isothiouronium (III) is reacted with the bromoketoester (IX) for which A is a C1-4 alkyl group, in the presence of a base such as sodium hydrogencarbonate (2 eq.) In a solvent such as isopropanol, to lead to imidazole (X). The ester function thereof is reduced to alcohol, according to methods known to those skilled in the art, for example, by the action of mixed aluminum and lithium hydride in a solvent such as tetrahydrofuran THF, to lead to the sulfide (XI) which is oxidized by Oxone to sulfone (XII) according to the conditions described above. The alcohol function of the latter is in turn oxidized to aldehyde (XIII). The oxidation reaction can be carried out according to methods known to those skilled in the art, for example by means of manganese oxide activated in a solvent such as chloroform or dichloromethane. The aldehyde is then reacted with diethylaminosulphide trifluoride (DAST) to yield the polyfluoroalkyl derivative (XIV). Finally, as in scheme 1, the derivative (XIV) is reacted with 4-hydroxymethylpiperidine (VIII), to lead to the compounds of formula (1).

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The meanings of R1, R2, R3 and R in the compounds of formula (III), (IV), (X), (XI), (XII), (XIII) and (XIV) are as defined for the compounds of Formula 1).

 Scheme 2 Alternatively, the compounds of formula (1), in which R2 represents a hydrogen atom, can be modified according to scheme 3 to give other compounds of formula (I) in which R2 is a halogen. According to this scheme, a compound of formula (I, R2 = H) is reacted with a Nhalosuccinimide (NXS) for which X is a halogen, preferably chlorine or bromine, in a solvent such as tetrahydrofuran or acetonitrile to lead to a derivative of formula (I, R2 = X).

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 Scheme 3 On the other hand, the compounds of formula (1), for which R is a phenyl, optionally substituted by one or more electron donor groups such as methoxy, can be debenzylated then resubstituted to give other compounds of formula (I ) in which R is a phenyl substituted by another group R4 as defined for the compounds of formula (1). The debenzylation reaction can be carried out according to methods known to those skilled in the art, for example, by the action of hydrogen in the presence of a palladium catalyst, to lead to the derivatives of formula (XV), according to scheme 4. The compounds of formula (XV) can then be substituted, according to methods known to those skilled in the art, for example, by the action of a compound of formula RCH2Y, in which Y represents a leaving group, preferably a halogen, and R is as defined above, in the presence of a proton accepting amine, such as triethylamine or diisopropylethylamine, or of an inorganic base such as potassium carbonate and in solvents such as ethanol, dimethylformamide (DMF) or toluene, or else by reductive amination by means of an aldehyde of formula RCHO in which R is as defined above, in the presence of hydrochloric acid and of a reducing agent such as sodium borohydride, cyanoboroh sodium ydide, sodium triacetoxyborohydride, or a borane-amine complex, and in methanol or ethanol, to lead to new compounds of formula (1).

The meanings of R1, R2 and R3 of the compounds (1) and (XV) of scheme 4 are as defined above for the compounds of formula (1).

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 Scheme 4 On the other hand, in the case of compounds of formula (I) where R3 and / or R4 are functional groups, which can be substituted, oxidized, reduced, alkylated or dealkylated, these functional transformation reactions can be carried out by conventional methods known to a person skilled in the art for giving other compounds of formula (1).

The starting compounds, in particular the compounds of formula (II), (IV), (VIII), (IX), RCHO or RCH2Y, are commercially available or described in the literature, or can be prepared by methods which are described or which are known to those skilled in the art.

The compounds of formula (V), (VI), (VII), (X), (XI), (XII), (XIII), (XIV) and (XV) in which R1, R2, R3 and R4 are such as defined for the compounds of formulas (1), are new and also form part of the invention. They are useful as synthesis intermediates for preparing the compounds of formula (1).

The following examples illustrate the methods and techniques used for the preparation of this invention, without however limiting the scope of the claim. Elementary micro-analyzes and NMR, IR or mass spectra confirm the structures of the compounds obtained.

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Example 1: Preparation of N-phenyl-S-methyl-isothiouronium iodide (formula III; according to scheme 1) 30 g of phenylthiourea are suspended in 500 ml of acetone. 12.3 mL of iodomethane are added while controlling the exothermicity, and the mixture is stirred for 15 hours at room temperature. The reaction mixture is filtered and the filtrate is taken up in 100 ml of ethyl ether. the precipitate formed is drained and washed twice with 50 ml of a 1/1 mixture of ethyl ether and acetone, then dried under vacuum, to give 30 g of N-phenyl-S-methyl iodide isothiouronium (PF = 141 C).

Example 2 Preparation of 2-methylthio-1-phenyl-4- (trifluoromethyl) -1 Himidazole (formula VI; according to scheme 1) 10 g of Nphenyl-S-methyl iodide are successively added to 500 ml of isopropanol -isothiouronium, 6 g of sodium hydrogen carbonate and 5 ml of 1-bromo-3,3,3-trifluoroacetone, and heats at 70-80 C for 15 hours. After concentration to dryness, the residue is taken up in 200 ml of water and the aqueous phase is exhausted with ethyl acetate. The combined organic phases are washed successively with water and brine before being dried over magnesium sulfate, filtered and concentrated to dryness. The crude reaction product is then taken up in 50 ml of toluene, and 0.15 g of paratoluenesulfonic acid (APTS) is added, then brought to reflux for 5 hours. After returning to ambient temperature, neutralization is carried out using a saturated aqueous solution of sodium hydrogencarbonate, and the aqueous phase is exhausted with ethyl acetate. The combined organic phases are washed successively with water and brine before being dried over magnesium sulfate, filtered and concentrated to dryness. Purification is carried out by flash chromatography on silica gel, eluting with an 85/15 mixture of heptane and ethyl acetate, to isolate 4 g of the expected compound.

phényl-4-(trifluorométhyl)-7/-/-imidazole, 28 g d'Oxone, et 15 g d'alumine (préalablement hydratée avec 3 mL d'eau). On porte le mélange réactionnel à 60 C durant 20 heures, puis le filtre à chaud, et lave deux fois le précipité avec Example 3: Preparation of 2-mesyl-1-phenyl-4- (trifluoromethyl) -9H-imidazole (formula VI I; according to scheme 1) In 85 ml of chloroform, 3.9 g of 2-methylthio- are successively added 1-

phenyl-4- (trifluoromethyl) -7 / - / - imidazole, 28 g of Oxone, and 15 g of alumina (previously hydrated with 3 ml of water). The reaction mixture is brought to 60 ° C. for 20 hours, then the filter is hot, and the precipitate is washed twice with

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40 mL of hot chloroform. The filtrate is concentrated to dryness and then triturated in diisopropyl ether, drained and dried under vacuum, to yield 3.35 g of the expected compound.

avant d'ajouter 3,35 g de 2-mésyl-1-phényl-4-(trifluorométhyl)-9H-imidazole en solution dans 25 mL de DMF anhydre. Après une heure d'agitation à température ambiante, le milieu réactionnel est hydrolysé avec 150 mL d'eau. La phase aqueuse est épuisée à l'acétate d'éthyle. Les phases organiques réunies sont lavées successivement à l'eau et à la saumure avant d'être séchées sur sulfate de magnésium, filtrées et concentrées à sec. On purifie par chromatographie flash sur gel de silice en éluant avec un mélange 95/5 de dichlorométhane et de méthanol, pour isoler 4,4 g de composé attendu.

Example 4: Preparation of 4 - [[[I-phenyi-4- (trifluoromethyl) -1H-imidazol-2-yl] oxy] methyl] -1 - [(3-methoxyphenyl) methyl] piperidine Formula (I); R1 = CF3, R2 = R3 = H, R = phenyl, R4 = 3-OCH3, according to diagram 1 Under a nitrogen atmosphere, 0.69 g of sodium hydride is placed (in 60% dispersion in oil ), and adds 20 mL of anhydrous dimethylformamide (DMF), then 3.53 g of 4-hydroxymethyl-1 - [(3-methoxyphenyl) methyl] piperidine in solution in 25 mL of anhydrous DMF. The reaction mixture is brought to 50 ° C. until the evolution of hydrogen is completed, then cooled in an ice bath.

before adding 3.35 g of 2-mesyl-1-phenyl-4- (trifluoromethyl) -9H-imidazole in solution in 25 mL of anhydrous DMF. After one hour of stirring at room temperature, the reaction medium is hydrolyzed with 150 ml of water. The aqueous phase is exhausted with ethyl acetate. The combined organic phases are washed successively with water and brine before being dried over magnesium sulfate, filtered and concentrated to dryness. Purification is carried out by flash chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol, to isolate 4.4 g of the expected compound.

Example 5: Preparation of 4-ethylcarboxylate-2-methylthio-1-phenyl-H-imidazole (formula X; according to scheme 2) In 1.25 L of isopropanol, 25 g of N-phenyl-S- iodide are mixed methylisothiouronium, 15 g of sodium hydrogen carbonate and 13.4 ml of ethyl bromopyruvate, and brings the reaction mixture to 80 ° C. for 20 hours. After concentration to dryness, the residue is taken up in 250 ml of water and the aqueous phase is exhausted by successive extractions with ethyl acetate. The combined organic phases are washed successively with water and brine before being dried over magnesium sulfate, filtered and concentrated to dryness. Purification is carried out by flash chromatography on silica gel, eluting with a 75/25 mixture of heptane and ethyl acetate, to isolate 12.5 g of the expected compound (PF = 55 C).

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Exemple 6 : Préparation de 4-hydroxyméthyl-2-méthylthio-1-phényl-9H- imidazole (formule XI; selon schéma 2) Sous atmosphère d'azote, on recouvre 2 g d'hydrure mixte de lithium et d'aluminium par 100 mL de THF anhydre, et refroidit le mélange à -15 C. On coule lentement 12,5 g de 4-éthylcarboxylate-2-méthylthio-1-phényl-1Himidazole, préalablement solubilisés dans 140 mL de THF anhydre, et agite à température ambiante durant 1,5 heure. On refroidit le mélange réactionnel à 0 C et additionne successivement 2 mL d'eau, 2 mL de soude aqueuse à 15%, puis trois fois 2 mL d'eau. On agite à température ambiante durant 15 heures et empâte avec de la cellite. Après concentration à sec, on dépose cette pâte sur un gel de silice et élue avec un gradient de méthanol (de 0 à 2,5%) dans le dichlorométhane, pour conduire à 5,6 g de composé attendu (PF = 122 C).

Example 6 Preparation of 4-hydroxymethyl-2-methylthio-1-phenyl-9H-imidazole (formula XI; according to scheme 2) Under a nitrogen atmosphere, 2 g of mixed lithium aluminum hydride are covered per 100 mL of anhydrous THF, and the mixture is cooled to -15 C. 12.5 g of 4-ethylcarboxylate-2-methylthio-1-phenyl-1Himidazole, slowly dissolved in 140 mL of anhydrous THF, are slowly poured in and stirred at room temperature for 1.5 hours. The reaction mixture is cooled to 0 ° C. and 2 ml of water, 2 ml of 15% aqueous sodium hydroxide are added successively, then 2 ml of water three times. The mixture is stirred at room temperature for 15 hours and pasted with cellite. After concentration to dryness, this paste is deposited on a silica gel and eluted with a methanol gradient (from 0 to 2.5%) in dichloromethane, to yield 5.6 g of the expected compound (PF = 122 C) .

hydroxyméthyl-2-méthylthio-1-phényl-9N-imidazole, 27 g d'Oxone@, et 14,6 g d'alumine (préalablement hydratée avec 2,9 mL d'eau). On porte le mélange réactionnel à 50 C durant 16 heures, puis le filtre à chaud, et lave deux fois le précipité avec 20 mL d'un mélange 9/1 de THF et de méthanol. Le filtrat est concentré à sec puis purifié par chromatographie flash sur gel de silice en éluant avec de l'acétate d'éthyle pour conduire à 2,13 g de composé attendu.

Example 7: Preparation of 4-hydroxymethyl-2-mesyl-1-phenyl-9H-imidazole (formula XII; according to scheme 2) In 73 ml of chloroform, 3.22 g of 4- are successively added

hydroxymethyl-2-methylthio-1-phenyl-9N-imidazole, 27 g of Oxone @, and 14.6 g of alumina (previously hydrated with 2.9 mL of water). The reaction mixture is brought to 50 ° C. for 16 hours, then the filter is hot, and the precipitate is washed twice with 20 ml of a 9/1 mixture of THF and methanol. The filtrate is concentrated to dryness and then purified by flash chromatography on silica gel, eluting with ethyl acetate to yield 2.13 g of the expected compound.

A 2,13 g de 4-hydroxyméthyl-2-mésyl-1-phényl-9H-imidazole, en solution dans 42 mL de dichlorométhane, on ajoute 0,74 g d'oxyde de manganèse activé, et porte au reflux durant 1 heure. On ajoute à nouveau 0,74 g d'oxyde de manganèse activé, et porte au reflux durant 1 heure. Cette addition est répétée cinq fois. Après filtration et concentration, on purifie par chromatographie flash sur gel de silice en éluant avec un mélange 1/1 de cyclohexane et de l'acétate d'éthyle pour conduire à 1,8 g de composé attendu. Example 8 Preparation of 4-formyl-2-mesyl-1-phenyl-? N-imidazole (formula XIII; according to scheme 2)

To 2.13 g of 4-hydroxymethyl-2-mesyl-1-phenyl-9H-imidazole, dissolved in 42 ml of dichloromethane, 0.74 g of activated manganese oxide is added, and the mixture is brought to reflux for 1 hour . 0.74 g of activated manganese oxide is again added and the mixture is brought to reflux for 1 hour. This addition is repeated five times. After filtration and concentration, the mixture is purified by flash chromatography on silica gel, eluting with a 1/1 mixture of cyclohexane and ethyl acetate to yield 1.8 g of the expected compound.

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Exemple 9 : Préparation de 4-(difluorométhyl)-2-mésyl-1-phényl-9N-imidazole (formule XIV; selon schéma 2) A 2,32 g de 4-formyl-2-mésyl-1-phényl-1H-imidazole, solubilisés dans 110 mL de dichlorométhane, on ajoute, sous atmosphère d'azote, 3,7 mL de trifluorure de diéthylaminosulfure (DAST) en solution dans 20 mL de dichlorométhane. Après trois heures d'agitation à température ambiante, on additionne à nouveau 3,7 mL de DAST en solution dans 20 mL de dichlorométhane, et poursuit l'agitation trois autres heures. On jette le milieu réactionnel sur un mélange de glace et d'hydrogénocarbonate de sodium et épuise la phase aqueuse par extractions successives au dichlorométhane. Les phases organiques réunies sont lavées successivement à l'eau et à la saumure avant d'être séchées sur sulfate de magnésium, filtrées et concentrées à sec. On purifie par chromatographie flash sur gel de silice en éluant avec un gradient d'acétate d'éthyle (de 0 à 20%) dans le cyclohexane, pour isoler 2. g de composé attendu.

Example 9 Preparation of 4- (difluoromethyl) -2-mesyl-1-phenyl-9N-imidazole (formula XIV; according to scheme 2) A 2.32 g of 4-formyl-2-mesyl-1-phenyl-1H- imidazole, dissolved in 110 ml of dichloromethane, 3.7 ml of diethylaminosulphide trifluoride (DAST) dissolved in 20 ml of dichloromethane are added under a nitrogen atmosphere. After three hours of stirring at room temperature, 3.7 ml of DAST dissolved in 20 ml of dichloromethane are again added, and stirring is continued for another three hours. The reaction medium is thrown onto a mixture of ice and sodium hydrogencarbonate and the aqueous phase is exhausted by successive extractions with dichloromethane. The combined organic phases are washed successively with water and brine before being dried over magnesium sulfate, filtered and concentrated to dryness. Purification is carried out by flash chromatography on silica gel, eluting with a gradient of ethyl acetate (from 0 to 20%) in cyclohexane, to isolate 2. g of the expected compound.

d'ajouter 0,12 g de 4-(difluorométhyl)-2-mésyl-1 -phényl- 1H-imidazole en solution dans 3 mL de DMF anhydre. Après 2 heures d'agitation à 45 C, le milieu réactionnel est hydrolysé avec 30 mL d'eau. La phase aqueuse est épuisée par extractions successives à l'acétate d'éthyle. Les phases organiques réunies sont lavées successivement à l'eau et à la saumure avant d'être séchées sur sulfate de magnésium, filtrées et concentrées à sec. On purifie par chromatographie flash sur gel de silice en éluant avec un gradient (0 à 5%) de méthanol dans le dichlorométhane, pour isoler 0,11g de composé attendu. Example 10: Preparation of 4 - [[[4- (diftuoromethyl) -1-phenyl-1 H-imidazol-2-yl] oxy] methyl] -1- (phenylmethyl) piperidine Formula (1), R1 = CF2H, R = phenyl, R2 = R3 = R4 = H; according to diagram 2 Under a nitrogen atmosphere, 16 mg of sodium hydride (95% dispersion in oil) are placed, and 1 ml of anhydrous dimethylformamide (DMF) is added, then 0.13 g of 4-hydroxymethyl -1- (phenylmethyl) piperidine in solution in 2 mL of anhydrous DMF. The reaction mixture is brought to 60 C until completion of the evolution of hydrogen, then cooled in an ice bath before

add 0.12 g of 4- (difluoromethyl) -2-mesyl-1-phenyl- 1H-imidazole in solution in 3 mL of anhydrous DMF. After 2 hours of stirring at 45 ° C., the reaction medium is hydrolyzed with 30 ml of water. The aqueous phase is exhausted by successive extractions with ethyl acetate. The combined organic phases are washed successively with water and brine before being dried over magnesium sulfate, filtered and concentrated to dryness. Purification is carried out by flash chromatography on silica gel, eluting with a gradient (0 to 5%) of methanol in dichloromethane, to isolate 0.11 g of the expected compound.

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A 1,6 g de 4-[[[l-phényl-4-(trifluorométhyl)-lH-imidazol-2-yl]oxy]méthyl]-I-[(3- méthoxyphényl)méthyl]pipéridine, en solution dans 20 mL de THF anhydre, on ajoute sous azote 2,16 g de N-chlorosuccinimide (NCS), et chauffe le milieu réactionnel à 60 C durant 6 heures. On jette alors le milieu réactionnel sur un mélange de glace et d'une solution aqueuse saturée en hydrogénocarbonate de sodium. On épuise la phase aqueuse par extractions successives avec de l'acétate d'éthyle. Les phases organiques réunies sont concentrées à sec et reprises par de l'éther éthylique, ce qui entraîne la précipitation de la succinimide, qui est éliminée par plusieurs filtrations successives. Après concentration, le brut est purifié par chromatographie flash sur gel de silice, en éluant avec un gradient de méthanol (de 0 à 2,5%) dans le dichlorométhane, pour fournir 0,73 g de composé attendu.

Example 11: Preparation of 4 - [[[5-chloro-1-phenyl-4- (trifluoromethyl) -1H- imidazol-2-yl] oxy] methyi] -1 - [(3-methoxyphenyl) methyl] piperidine Formula ( 1), R1 = CF3, R2 = CI, R3 = H; R = phenyl, R4 = 3-OCH3, according to scheme 3

To 1.6 g of 4 - [[[1-phenyl-4- (trifluoromethyl) -1H-imidazol-2-yl] oxy] methyl] -I - [(3-methoxyphenyl) methyl] piperidine, in solution in 20 mL of anhydrous THF, 2.16 g of N-chlorosuccinimide (NCS) is added under nitrogen, and the reaction medium is heated at 60 ° C. for 6 hours. The reaction medium is then thrown onto a mixture of ice and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous phase is exhausted by successive extractions with ethyl acetate. The combined organic phases are concentrated to dryness and taken up in ethyl ether, which causes the precipitation of the succinimide, which is eliminated by several successive filtrations. After concentration, the crude is purified by flash chromatography on silica gel, eluting with a methanol gradient (from 0 to 2.5%) in dichloromethane, to provide 0.73 g of the expected compound.

Example 12: Preparation of 3 - [[4 - [[[5-chloro-1-phenyl-4- (trifluoromethyl) -7 / - / imidazol-2-yl] oxy] methyl] piperidin-1-yl] methyl] phenol Formula (1), R1 = CF3, R2 = CI, R3 = H; R = phenyl, R4 = 3-OH 0.9 g of 4 - [[[5-chloro-1-phenyl-4- (trifluoromethyl) -9H-imidazol-2-yl] oxy] methyl] -1- is dissolved. [(3-methoxyphenyl) methyl] piperidine in 20 mL of dichloromethane (DCM), and add 3.75 mL of 3.5N hydrochloric acid in isopropanol. After concentration to dryness, the residue is taken up in 20 ml of DCM and cooled to -78 ° C., under a nitrogen atmosphere. Then poured 0.53 ml of boron tribromide, and stirred 0.25 hour at -78 C, before returning to -15 C for 1.75 hours. The reaction mixture is then thrown onto a mixture of ice and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous phase is exhausted by successive extractions with ethyl acetate.

The combined organic phases are washed twice with water and then with brine before being dried over magnesium sulfate. After concentration to dryness, the reaction crude is purified by flash chromatography on silica gel, eluting with a gradient (from 0 to 5%) of methanol in dichloromethane, to provide 0.63 g of the expected compound, in the form of foam beige amorphous.

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The compounds described in the following table were prepared according to the methods described above.

R=Ph entrée R1 R2 R3 R4 sel PF ( C)
1 CF3 H H H fuma rate 170
2 CF3 H H 3-OCH3 chlorhydrate 171
3 CF3 H H 3-OH chlorhydrate 196
4 CF3 H 2-F H chlorhydrate 173
5 CF3 H 2-F 3-OCH, chlorhydrate 155
6 CF3 H 2-F 3-OH chlorhydrate 190 7 CF3 H 3-OCH3 3-OCH3 chlorhydrate 150
8 CF3 H 3-OH 3-OH
9 CF3 H 3-OCH3 H chlorhydrate 151 10 CF3 H 3-OH H 11 CF3 CI H 3-OH fumarate 130
12 CF3 Cl 2-F 3-OH
13 CF3 CI 2-F H 14 CF3 Cl 3-OH H
15 CF3 CI 3-OH 3-OH
16 C2F5 H H H 17 CF2H H H H fumarate 150
18 CF3 CI H 3-OCH3

R = Ph input R1 R2 R3 R4 salt PF (C)
1 CF3 HHH fuma rate 170
2 CF3 HH 3-OCH3 hydrochloride 171
3 CF3 HH 3-OH hydrochloride 196
4 CF3 H 2-FH hydrochloride 173
5 CF3 H 2-F 3-OCH, hydrochloride 155
6 CF3 H 2-F 3-OH hydrochloride 190 7 CF3 H 3-OCH3 3-OCH3 hydrochloride 150
8 CF3 H 3-OH 3-OH
9 CF3 H 3-OCH3 H hydrochloride 151 10 CF3 H 3-OH H 11 CF3 CI H 3-OH fumarate 130
12 CF3 Cl 2-F 3-OH
13 CF3 CI 2-FH 14 CF3 Cl 3-OH H
15 CF3 CI 3-OH 3-OH
16 C2F5 HHH 17 CF2H HHH fumarate 150
18 CF3 CI H 3-OCH3

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 The compounds of the invention, of formula (1), have been the subject of pharmacological tests which have shown their interest as active substances in therapy.

In particular, they have been tested for their inhibitory effects on the binding of [3H] -N-methyl-scopolamine with human M3 muscarinic receptors transfected into CHO (chinese hamster ovarian cells) cells (Buckley et al., Mol. Pharmacol. 35: 469-476, 1989).

Membranes of CHO cells, in solution in a 10 mM TRIS-HCl buffer, 2 mM EDTA pH 7.2, expressing the human muscarinic receptor subtype M3 were supplied by the company Receptor Biology (Baltimore, USA).

10 to 30 g of membranes were incubated in a phosphate buffer, pH 7.4 (Sigma, St Louis, MO) in the presence of 0.5 nM of [3 H] N-methyl-scopolamine (NEN-Dupont, Les Ulis, France), and of a compound of the invention, in a total volume of 1 ml. The non-specificity of the binding was determined by 0.5 M of atropine (Sigma, St Louis, Mo). The incubation (60 min at 25 ° C.) was stopped by rapid filtration on Whatmann GF / B filters by a Brandel filtration device. The filters were washed three times with 4 ml of cold phosphate buffer, dried and the radioactivity was measured by liquid scintillation (scintillant Ultima Gold). The concentration of compound displacing 50% the specific bond (ICso) was used to calculate the Ki values according to the ChengPrusoff equation. The effectiveness of each product studied is expressed by the negative logarithm of their Ki (pKi).

The pKi of the compounds of the invention vis-à-vis the M3 receptors are between 7 and 10.

The compounds of the invention have also been studied as to their antagonistic effects with respect to the contractions of the female rabbit detrusor, mediated by the M3 receptors.

Female rabbits (New Zealanders, 3-4 kg; ESD supplier) aged around 20 weeks were sacrificed by cervical dislocation and then bloodless.

After opening the abdomen, the bladders were removed and then quickly placed in a bicarbonated Krebs solution of composition (mM): NaCl: 114; KCI: 4.7; CaCl2: 2.5; MgSO4: 1.2; KH2PO4: 1.2; NaHC03: 25,; ascorbic acid: 1.1; glucose: 11.7. Propranolol (1 pM), methylsergide (1 M), ondansetron (1 M), GR113808 (1 M) were added to Krebs in order to inhibit the receptors!] - adrenergic and the different

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 5-HT1 / T-HT2, 5-HT3 and 5-HT4 serotonergic receptor subtypes. The bladders were cleaned, degreased and each side was cut into two longitudinal flaps about 4 mm wide and 15 mm long.

The tissues were then placed in 20 ml tanks thermostatically controlled at 37 C under carbogenic aeration (95% O2, 5% CO2) and were subjected to a basal tension of 1 g.

The voltage was measured using isometric gauges (Hugo Sacks, type 351) connected to couplers (Gould) which transform and amplify the responses which will be traced on 4-track potentiometric recorders (Gould) and connected to a system of data acquisition (Jad, Notocord). A balancing time of approximately 45 minutes was observed during which the Krebs is renewed and the basal tension rectified.

After a 30-minute equilibration period, an initial contraction to carbachol (1 pM), a potent muscarinic agonist, was performed. The tissues were then rinsed thoroughly and then after a new equilibration period of 30 minutes, the tissues were incubated for 30 minutes in the presence or not of a compound of the invention to be studied (concentration 0.1 or 1 M) before performing a concentration-response range for carbachol at intervals of half a logarithm.

The concentrations producing half of the maximum effect (EC50 (μM)) were calculated for each range (absence or presence of the compound to be studied), then the power of the compound to shift the response curve to carbachol was determined by a calculation of the affinity of the antagonist (pKb or apparent pA2) according to the method of Furchgott (Handbook of Experimental Pharmacology, 1972, 283-335).

The pKbdes compounds of the invention are between 7 and 10.

The compounds of the invention have also been studied as to their affinity for 5-HT4 receptors in the guinea pig striatum, according to the method described by Grossman et al., In Br. J. Pharmacol., 109, 618-624 (1993).

Guinea pigs (Hartley, Charles River) weighing 300 to 400 g are euthanized and their brains removed. The striata are excised and frozen at -80 C. On the day of the experiment, the tissue is thawed at + 4 ° C. in 33 volumes of 50 mM HepesNaOH buffer (pH = 7.4 at 20 ° C.) and it is homogenize using a Polytron mill. The homogenate is centrifuged for 10 minutes at 48000xg,

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 collect the pellet, resuspend it and centrifuge again under the same conditions. The final pellet is suspended in HépèsNaOH buffer (30 mg of fresh tissue / mL). This membrane suspension is used as it is.

100 L of the membrane suspension are incubated at 0 ° C. for 120 minutes, in the presence of 0.1 nM of [3 H] GR113808 (specific activity: 80-85 Ci / mmol), in a final volume of 1 ml of Hepes buffer. NaOH (50 mM, pH = 7.4), in the absence or in the presence of the compound to be tested. The incubation is stopped by filtration on Whatman GF / B # filters, previously treated with 0.1% polyethyleneimine, each tube is rinsed with 4 ml of buffer at 0 ° C. and filtered again. The radioactivity retained on the filters is measured by liquid scintigraphy. Nonspecific binding is determined in the presence of serotonin 30 M.

The specific binding represents 90% of the total radioactivity recovered on the filter.

For each concentration of compound studied, the percentage of inhibition of the specific binding of [3H] GR118808 is determined, then the concentration of the compound tested which inhibits 50% of the specific binding (Cl50).

The IC50 values of the compounds of the invention are between 0.1 and 350 nM.

Finally, the compounds of the invention were studied as to their antagonistic effects with respect to the 5-HT4 receptors in the rat esophagus.

Male Sprague-Dawley rats weighing 300 to 450 g are used. We quickly remove a fragment of about 1.5 cm from the end part of the esophagus, we eliminate the muscular layer, we open the inner muscular mucous membrane longitudinally, we mount it in a tank with isolated organ containing a Krebs solution -Henseleit at 32 C oxygenated by a carbogenic current (95% O2 and 5% CO2), and it is connected to an isometric transducer under a basal voltage of 0.5 g.

The compounds are studied at a concentration of 1 M. We measure their capacity to displace the relaxation introduced by 5-HT (at concentrations of 0.1 nM) from the esophageal tissue pre-contracted to the substance P 1 M.

The compounds of the invention are active in this test.

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The results of the biological tests show that the compounds of the invention are antagonists of the muscarinic M3 and serotonergic 5HT4 receptors.

The involvement of the 2D6 isoform of human cytochromes (CYP2D6) in the microsomal metabolism of the compounds of the invention was evaluated after determination of the biotransformation of the compounds in the absence or presence of a specific inhibitor of CYP2D6 after incubation with human microsomes.

The compounds of the invention are incubated at a concentration of 1 M (in phosphate buffer, pH 7.4) with human microsomes (pool of human biopsies, 6 donors, 0.5.1 or 2 mg of proteins / mL) in the presence of a regenerator system of reduced equivalents (NADP, 3mM; MgSO4, 10mM; G-6P, 60mM, UDPGA, 8.6mM) at 37 C and in the presence or not of quinidine (3pM) (according to: M.BOURIE, V.MEUNIER, Y. BERGER, G. FABRE, Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes, Journal of Pharmacology and Experimental Therapeutics, 1995, Vol. 277, n 1 , p321-336.) in a total volume of 1 mL.

An aliquot of the incubation medium (100 l) is taken at different times between 0 and 20 minutes after the start of the incubation; the reaction is stopped by the addition of 100 μl of acetonitrile. After centrifugation and recovery, the supernatant is then analyzed by LC / MS. The unchanged compound is assayed using an external calibration range treated under the same conditions as the incubations.

The results are expressed as a percentage of involvement of CYP2D6 in the biotransformation of the compounds.

The involvement of human CYP2D6 in the microsomal oxidative metabolism of the compounds of the invention is low.

They can therefore be used in the treatment of pathologies where a 5-HT4 and M3 receptor antagonist provides a therapeutic benefit. For example, they can be used in the treatment of irritable bowel syndrome, memory impairment, airway obstruction and bladder instability, especially emergency urinary incontinence.

The use of the compounds according to the invention for the preparation of a medicament intended to treat the pathologies mentioned above forms an integral part of the invention.

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According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention.

Thus, these pharmaceutical compositions contain an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt, N-oxide or hydrate thereof, and one or more suitable pharmaceutical excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, its salt or hydrate, if any, can be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, subcutaneous, intramuscular or intravenous administration and forms of rectal or vaginal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.1 mg and 50 mg per kg of body weight per day. Although these dosages are examples of an average situation, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.

Each unit dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg, of active ingredient in combination with one or more excipients

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 pharmaceutical. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 0.5 to 2500 mg.

For example, when preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative, or other materials. The tablets can be produced by different techniques, direct compression, dry granulation, wet granulation or hot melting.

According to a second example, a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.

The present invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of a compound according to the invention or one of its salts, N-oxides or hydrates.

Claims (13)

R3 and R4 represent, independently of one another, a hydrogen atom, a halogen atom, a C1-4 alkyl, hydroxy, C1-4 alkoxy, cyano, nitro, perfluoro-C1-2 alkyl group , amino, and its salts, N-oxides and hydrates. R represents a C2-4 alkenyl group or a phenyl optionally substituted by one, two or three R4 groups, R2 represent a hydrogen, a C1-4 alkyl group, a halogen atom,  in which, R1 is a group of formula CnHxFy where n = 1 or 2, x = 0 to 3, y = 1 to 5 and x + y = 2n + 1 and

 Claims 1. Compound of formula (I): 2. Compound according to Claim 1, characterized in that: * R2 represents a hydrogen or halogen atom and / or * R3 represents a hydrogen or halogen atom, a hydroxy or a C1-2 alkoxy group and / or * R4 represents a hydrogen atom, a hydroxy or a C1-2 alkoxy group. 3. Compound according to claim 1 or 2, characterized in that: * R1 represents a group CF3, C2F5 or CF2H. 4. Compound according to claim 1 characterized in that it consists of:

 1- (phenylmethyl) -4 - [[[1-phenyl-4- (trifluoromethyl) -H-imidazol-2yl] oxy] methyl] piperidine 1 - [(3-methoxyphenyl) methyl] -4 - [[[1- phenyl-4- (trifluoromethyl) -9H-imidazol-2yl] oxy] methyl] piperidine 3 - [[4 - [[[1-phenyl-4- (trifluoromethyl) -1 H-imidazol-2-yl] oxy] methyl ] piperidin-1yl] methyl] phenol 4 - [[[1- (2-fluorophenyl) -4- (trifluoromethyl) -7H-imidazol-2-yl] oxy] methyl] -1- (phenylmethyl) piperidine <Desc / Clms Page number 23>  wherein R1, R2 and R3 are as defined in claim 1.

 (trifluoromethyl) - '/ H-imidazol-1 -yljphenol 4 - [[[4- (pentafluoroethyl) -1-phenyl-9H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine 4- [ [[4- (difluoromethyl) -1-phenyl-9H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine 5. Compound of formula (VII)

 4 - [[[1- (2-fluorophenyl) -4- (trifluoromethyl) - / - / - imidazoi-2-yf] oxy] methyt] -1 - [(3methoxypheny () methyl] piperidine 3 - [[4- [[[1 - (2-fluorophenyl) -4- (trif! Uoromethyl) - # / H-imidazol-2yl] oxy] methyl] piperidin-1-yi] methyl] phenol 1 - [(3-methoxyphenyl) methyl] -4 - [[[1- (3-methoxyphenyl) -4- (trifluoromethyl) -1Himidazol-2-yl] oxy] methyl] piperidine 3- [2 - [[1 - [{3-hydroxyphenyl) methyl] piperidin- 4-yl] methoxy] -4- (trifluoromethyl) -9Himidazol-1-yl] phenol 4 - [[[1- (3-methoxyphenyl) -4- (trifluoromethyl) - '// - / - imidazol-2-yl ] oxy] methyl] -1- (phenylmethyl) piperidine 3- [2 - [[1- (phenylmethyl) piperidin-4-yl] methoxy] -4- (trifluoromethyl) -9H-imidazol-1yl] phenol 3 - [[ 4 - [[[5-chloro-1-phenyl-4- (trifiuoromethyl) -1 H-imidazol-2yl] oxy] methyl] piperidin-1-yl] methyl] phenol 3 - [[4 - [[[5- chloro-1- (2-fluorophenyl) -4- (trifluoromethyl) -9H-imidazol-2yl] oxy] methyl] piperidin-1-yl] methyl] phenol 4 - [[[[5-chloro-1- (2-fluorophenyl ) -4-trifluoromethyl-TH-imidazol-2-yl] oxy] methyl] -1- (phenylmethyl) pi peridine 3- [5-Chloro-2 - [[1- (phenylmethyl) piperidin-4-yl] methoxy] -4- (trifluoromethyl) -1H ~ imidazol-1-yl] phenol 3- [5-Chloro-2- [[1 - [(3-hydroxyphenyl) methyl] piperidin-4-yl] methoxy] -4-

<Desc / Clms Page number 24> 6. compound of formula (VI)

 wherein R1, R2 and R3 are as defined in claim 1. 7. Compound of formula (XIV)

 wherein R2 and R3 are as defined in claim 1. 8. Compound of formula (XIII)

 wherein R2 and R3 are as defined in claim 1. 9. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 4 in which a compound of formula (VII) is reacted

<Desc / Clms Page number 25>  wherein R is as defined in claim 1.

 in which R1, R2 and R3 are as defined in claim 1, with a compound of formula (VIII) 10. Pharmaceutical composition characterized in that it contains a compound of formula (I) according to one of claims 1,2, 3 or 4 in combination with one or more pharmaceutically acceptable excipients. 11. Use of a compound of formula (1) according to any one of claims 1,2, 3 or 4 for the preparation of a medicament intended to treat a pathology where a 5HT4 and M3 receptor antagonist brings a therapeutic benefit . 12. Use of a compound of formula (I) according to claim 11 characterized in that the pathology consists in the treatment of irritable bowel syndrome, memory disorders, obstruction of the airways and bladder instabilities. 13. Use according to claim 12, characterized in that the bladder instability is emergency urinary incontinence.