FR2805816A1 - New 4- and/or 5-halogenated 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- and/or 5-halogenated 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, R2 = halo, H or 1-4C alkyl, provided that at least one is halo; R = 2-6C alkenyl, phenyl, naphthyl, thienyl, pyrrolyl or furyl (all optionally substituted by 1-3 R4 groups); R3, R4 = H, halo, OH, 1-4C alkyl, 1-4C alkoxy, CN, NO2, 1-2C perfluoroalkyl, CH2OH or NH2; and n = 1-3. Independent claims are included for: (i) the preparation of (I); and (ii) new imidazole derivative intermediates of formulae (IV), (VII) and (IX): Pg' = protecting group; and R1', R2' = halo.

Description

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

dans laquelle, R1 et/ou R2 représentent un atome d'halogène, et dans le cas où un des substituants R1 ou R2 ne représente pas un halogène celui ci représente un atome d'hydrogène ou un groupe Ci-4 alkyle, R représente un groupe C2-6alkényle ou un phényle éventuellement substitué par un ou deux groupes R4, R3 et R4 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un atome d'halogène, un hydroxy, un groupe C1-4 alkyle, Ci-4 alcoxy, cyano, nitro, C1-2perfluoro alkyle ou amino, ainsi que leurs sels, N-oxydes et hydrates. Accordingly, the present invention firstly relates to haloimidazole derivatives of the general formula (I)

in which, R 1 and / or R 2 represent a halogen atom, and in the case where one of the substituents R 1 or R 2 does not represent a halogen, it represents a hydrogen atom or a C 1-4 alkyl group, R represents a halogen atom, and C2-6alkenyl group or a phenyl optionally substituted with one or two groups R4, R3 and R4 represent, independently of one another, a hydrogen atom, a halogen atom, a hydroxy, a C1-4 group alkyl, C1-4 alkoxy, cyano, nitro, C1-2perfluoroalkyl or amino, as well as their salts, N-oxides and hydrates.

The patent application WO99 / 25710 discloses compounds of formula (I) in which R1 and R2 represent, independently of one another, a hydrogen, a C 1-6 alkyl group, or together form a polymethylene group ( CH2) n-, n being able to take the values of 3 to 6, as muscarinic M3 and serotoninergic 5-HT4 receptor antagonists. It has been found that the compounds of the present invention, in which R1 and / or R2 represents a halogen, exhibit superior affinity for the aforementioned receptors. On the other hand, they exhibit increased inertia in the face of oxidative metabolic mechanisms by microsomes

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The compounds of formula (I) which are preferred according to the present application are the compounds for which
R3 represents a hydrogen atom, a hydroxy or a halogen, preferably a fluorine and / or
R4 represents a hydrogen atom, a hydroxy or a C1-4 alkyl group, preferably C 1-2 alkyl.

 On the other hand when R 1 and / or R 2 is halogen it is preferably chlorine, bromine or iodine.

 Among these subgroups of preferred compounds, the compounds of formula (I) in which R 1 and R 2 represent a halogen, preferably a chlorine or bromine atom, and the compounds where R 1 (or R 2) represents a halogen, and R 2 ( or R1) represents a hydrogen atom or a C1-2 alkyl group are particularly preferred In the context of the present invention, the term - C1-z (or C2-z), where z can take the values of 2 to 6, a carbon chain which may have from 1 (or 2) to z carbon atoms, - alkyl, a saturated aliphatic group, linear or branched, for example, a C 1-4 alkyl group represents a carbon chain of 1 to 4 carbon atoms. carbon, linear or branched, more particularly a methyl, ethyl, propyl, isopropyl, butyl, secbutyl, isobutyl, tertbutyl, preferably a methyl, ethyl, propyl, isopropyl, alkenyl, a mono or polyunsaturated aliphatic group, linear or branched, preferably comprising 1 or 2 i ethylenic unsaturations, - perfluoroalkyl, an alkyl of which all the hydrogens have been substituted by fluors, - alkoxy, a linear or branched saturated aliphatic chain alkyloxy group, and - a halogen atom, a fluorine, a chlorine, a bromine or an iodine A leaving group is understood to mean a group which can be easily cleaved from a molecule, with a departure from 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 mesyl, tosyl, tnflate, acetyl, etc. Examples of leaving groups as well as preparation references are given in

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   Advanced Organic Chemistry, J March, 3rd Edition, Wiley Interscience, 310-316.

By protective group is meant a group that makes it possible to prevent the reactivity of a function or position, during a chemical reaction that may affect it, and that restores the molecule after cleavage according to methods known to those skilled in the art. Examples of protecting groups as well as methods of protection and deprotection are given, inter alia, in Protective groups in Organic Synthesis, Greene et al, 2ndEd. (John Wiley & Sons, Inc., New York).

By functional group is meant a group that 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 standard methods known to those skilled in the art to give other compounds. Such groups are, for example, R 3 and R 4. The compounds of general formula (I) may comprise one or more asymmetric carbons. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and also mixtures thereof, including racemic mixtures. are part of the invention.

The compounds of general formula (I) may be in the form of a free base or addition salts with acids, which are also 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, for example a tartaric acid, a dibenzoyltartnque acid, a mandelic acid or a camphosulfonic acid and those which form physiologically acceptable salts, such as hydrochloride, hydrobromide, citrate, sulfate, hydrogen sulfate, dihydrogenphosphate, maleate, fumarate, pamoate, 2-naphthalenesulphonate, paratoluenesulphonate. Pharmaceutically acceptable salts are preferred, the other salts are part of the present invention. These salts can be prepared according to methods known to those skilled in the art. in the art, for example, by reaction of the compound of formula (1) in base form with the acid in a suitable solvent, such as an alcoholic solution or an organic solvent, and 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 (1) 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 man. It is a second object of the present invention to provide processes for the preparation of the compounds of formula (I). Thus, these compounds can be prepared by processes, illustrated in the following diagrams, the operating conditions of which are conventional for those skilled in the art. .

According to Scheme 1, the compounds of formula (I) for which R 2 is a halogen atom may be obtained by reaction of an N-halosuccinimide (NXS) for which X is a halogen, with a derivative of formula (II) The reaction may be carried out in a solvent such as tetrahydrofuran or acetonitrile at temperatures ranging from 0 ° C. to the boiling point of these solvents. The meanings of R 1, R 3 and R are as defined for the compounds of formula (I).

 Similarly, when R 1 represents a hydrogen and R 2 does not represent a hydrogen, the reaction according to Scheme 1 can be carried out to give a compound of formula (I) in which R 1 is a halogen. Alternatively, the compounds of formula (I ) for which R2 is a halogen atom, can be obtained as shown in scheme 2 According to this scheme a sulfone of formula (III) is reacted with N-halosuccinimide (NXS) for which X is a halogen in a solvent such as tetrahydrofuran to give derivatives of formula (IV) This latter derivative

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 (IV) is reacted with an alcohol of formula (V-Pg), the nitrogen being protected by a protective group Pg. The reaction can be carried out in the presence of a strong base such as sodium hydride, in a solvent such as anhydrous dimethylformamide or N-methylpyrrolidone, preferably between 20 and 80 ° C., to give compound (VI). As a protecting group, for example, tert-butoxycarbonyl may be used. This protecting group Pg can then be cleaved according to methods known to those skilled in the art, for example in the case where a tert-butyloxycarbonyl was used, the deprotection can be carried out by the action of trifluoroacetic acid in a solvent such as dichloromethane at a temperature preferably ranging from -10 ° C. to 10 ° C. The compound of formula (VII) may then be alkylated, according to methods known to those skilled in the art, for example by the action of a compound of formula RCH2Y, wherein Y represents a leaving group, preferably a halogen, and R is as defined above, in the presence of a proton acceptable amine, such as triethylamine or diisopropylethylamine, or a mineral base such as potassium carbonate and in solvents such as ethanol, dimethylformamide (DMF) or toluene, or by reductive amination by means of an aldehyde of formula RCHO in which R is as defined above, in pre the presence of hydrochloric acid and a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium tetraacetoxyborohydride, or a borane-amine complex, and in methanol or ethanol. The meanings of R 1 and R 3 for the compounds of formula ( III), (IV), (VI) and (VII) are as defined for the compounds of formula (1).

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 Alternatively, the compound of formula (V-Pg) may be replaced by a compound of formula (V-CH 2 -R), in which R is as defined above, and be reacted with the compound of formula (IV ), according to the method described in scheme 2, to give directly the compound of formula (I) The compounds of formula (I) for which R 1 is a halogen atom can also be obtained according to scheme 3.

According to this scheme, the position 5 of the imidazole of the compound of formula (II) in which R 1 represents a hydrogen, is protected by methods known to those skilled in the art. For example, the protective reaction can be carried out by prior formation. of a brominated derivative in position 5 according to the methods described above then exchange of this bromine by a lithium atom, in an anhydrous solvent such as diethylether or tetrahydrofuran at temperatures ranging from -78 C to -50 C to give the lithien which is immediately and in situ reacted with a Pg-Y reagent, or Y represents a leaving group such as halogen and Pg is alkylsilyl or phenylsulfone, in the above solvent at temperatures ranging from -78 ° C to 20 ° C

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The compound (VIII) thus obtained is reacted with an N-halosuccinimide (NXS) under conditions as defined above to give the compound of formula (IX) in which R 1 is a halogen This compound is then deprotected according to methods conventional known to those skilled in the art, for example in the case of a derivative silylated by action of tetrabutylammonium fluoride in a solvent such as tetrahydrofuran (THF)

(I, R1=R2=halogène)
Schéma 4 Dans le cas de composés de formule (I) où R3 et R4 sont des groupes fonctionnels, pouvant être substitués, oxydés, réduits, alkylés ou désalkylés, ces réactions de transformation fonctionnelle peuvent être réalisées par des méthodes classiques connues de l'homme du métier pour donner d'autres composés de formule (1). On the other hand, the compounds of formula (1), for which R 1 and R 2 are both halogen atoms can be obtained directly from derivatives of formula (VIII), according to scheme 4, by reacting the N-halosuccinimide in excess under the conditions as described above Preferably the protecting group for this reaction will be a silylated derivative such as triethylsilyl

(I, R1 = R2 = halogen)
In the case of compounds of formula (I) in which R 3 and R 4 are functional groups which may be substituted, oxidized, reduced, alkylated or dealkylated, these functional transformation reactions may be carried out by standard methods known to man. of the art to give other compounds of formula (1).

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On the other hand, the compounds of formula (II), (IV), (VII) and (IX) in which at least one R1 or R2 group represents a halogen are new and are also part of the invention. They are useful as intermediates in the preparation of the compounds of formula (1).

The starting compounds, in particular the compounds of formula (V-Pg), (V-CH2R), RCHO or RCH2Y, are commercially available or are disclosed in the literature, or can be prepared by methods which are therein or which are known to those skilled in the art.

The starting compounds of formula (II) or (III), in which R 1 represents a hydrogen or a C 1-4 alkyl group, can be obtained according to the methods described in the patent application WO 99/25710.

Exemple 1 Préparation de 4-[[(5-bromo-1-phényl-1 H-imldazol-2-yl)oxy]méthyl]- 1-(phénylméthyl)pipéndine (formule I, R1 = R3=H, R2 = Br, R = Phényle , selon schéma 1)

Sous atmosphère d'argon, on place 26 g de 4-[[(1-phényl-H-imidazol-2yl)oxy]méthyl]-1-(phénylméthyl)pipéndine en solution dans 375 mL de THF anhydre, et additionne sur 20 minutes, 22 g de N-bromosuccinimide (NBS). On agite le mélange réactionnel durant 1,5 heure, puis le jette 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 repnses par de l'éther éthylique, ce qui entraîne la précipitation de la succinimide, qui est éliminée par plusieurs filtrations successives Cette élimination est parachevée par un traitement acido-basique, puis le brut est purifié par chromatographie flash sur gel de silice, en éluant avec un gradient (de 0 à 5%) de méthanol dans le dichlorométhane, pour fournir 23 g de composé attendu, sous forme de mousse brune The following examples illustrate the methods and techniques used for the preparation of this invention, without however limiting the scope of the claim. The elemental micro-analyzes and the NMR, IR or mass spectra confirm the structures of the compounds obtained.

Example 1 Preparation of 4 - [[(5-bromo-1-phenyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine (Formula I, R1 = R3 = H, R2 = Br , R = Phenyl, according to scheme 1)

Under an argon atmosphere, 26 g of 4 - [[(1-phenyl-2-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine in solution in 375 ml of anhydrous THF are placed, and added to 20 minutes, 22 g of N-bromosuccinimide (NBS). The reaction mixture is stirred for 1.5 hours and then poured onto ice-water and saturated aqueous sodium hydrogencarbonate solution. The aqueous phase is extracted by successive extractions with ethyl acetate. The combined organic phases are concentrated to dryness and treated with ethyl ether, which causes the precipitation of succinimide, which is removed by several successive filtrations. This elimination is completed by an acid-base treatment, then the crude is purified by flash chromatography on silica gel, eluting with a gradient (0 to 5%) of methanol in dichloromethane, to provide 23 g of expected compound, in the form of brown foam

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Exemple 2 : Préparation de 5-chloro-1-{2-fluorophényl)-2-mésyl-4-méthyl-9H- imidazole (formule IV, R1 = CH3, R2 = CI, R3 = 2-F , selon schéma 2)

0,5 g de 1-(2-fluorophényl)-2-mésyl-4-méthyl-H-imidazole est solubilisé dans 10 mL de THF anhydre. On ajoute 0,29 g de N-chlorosuccinimide (NCS), et agite à température ambiante durant 1,5 heure, puis hydrolyse au moyen d'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 Cette élimination est parachevée par un traitement acido-basique, puis le brut est purifié par chromatographie flash sur gel de silice, en éluant avec un gradient d'acétate d'éthyle (de 0 à 25%) dans l'heptane, pour fournir 0,2 g de composé attendu.

Example 2 Preparation of 5-chloro-1- (2-fluorophenyl) -2-mesyl-4-methyl-9H-imidazole (formula IV, R1 = CH3, R2 = Cl, R3 = 2-F, according to Scheme 2)

0.5 g of 1- (2-fluorophenyl) -2-mesyl-4-methyl-H-imidazole is solubilized in 10 mL of anhydrous THF. 0.29 g of N-chlorosuccinimide (NCS) are added and the mixture is stirred at room temperature for 1.5 hours and then hydrolyzed using a mixture of ice and a saturated aqueous solution of sodium hydrogencarbonate. The phase is then used up. aqueous by successive extractions with ethyl acetate. The combined organic phases are concentrated to dryness and taken up with ethyl ether, which causes the precipitation of succinimide, which is removed by several successive filtrations. This elimination is completed by an acid-base treatment, then the crude is purified by flash chromatography on silica gel, eluting with a gradient of ethyl acetate (from 0 to 25%) in heptane, to provide 0.2 g of expected compound.

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Exemple 3 Préparation de 4-[[( 5-chloro-4-méthyl-1-(2-fluorophényl)-1 H- imidazol-2-yl)oxy]méthyl]-1-[(3-méthoxyphényl)méthyl]pipéridine (formule I, R1 = CH3, R2 = CI, R3 = 2-F, R = Phényle, R4 = 3-OCH3, selon schéma 2) Sous atmosphère d'azote, on place 64 mg d'hydrure de sodium en dispersion à 95% dans l'huile, dans 2 mL de diméthylformamide (DMF) anhydre. On ajoute

55 mg de 4-hydroxyméthyl-1-[(3-méthoxyphényl)méthyl]pipéndine en solution dans 4 mL de DMF et porte le mélange réactionnel à 70 C durant 0,75 heure.

Example 3 Preparation of 4 - [[(5-chloro-4-methyl-1- (2-fluorophenyl) -1H-imidazol-2-yl) oxy] methyl] -1 - [(3-methoxyphenyl) methyl] piperidine (formula I, R1 = CH3, R2 = Cl, R3 = 2-F, R = Phenyl, R4 = 3-OCH3, according to scheme 2) Under a nitrogen atmosphere, 64 mg of sodium hydride in dispersion are placed in 95% in the oil, in 2 mL of anhydrous dimethylformamide (DMF). We add

55 mg of 4-hydroxymethyl-1 - [(3-methoxyphenyl) methyl] pipetine dissolved in 4 ml of DMF and the reaction mixture at 70 ° C. for 0.75 hours.

After cooling in an ice-bath, 48 mg of 5-chloro-1- (2-fluorophenyl) -2-mesyl-4-methyl-1H-imidazole, dissolved in 5 ml of DMF are added.

The reaction medium is allowed to return to room temperature and stirring is continued for 2.5 hours. The reaction medium is poured into 50 ml of water and the aqueous phase is extracted by successive extractions with ethyl acetate.

The combined organic phases are washed twice with water and then with brine before being dried over magnesium sulphate. After concentration to dryness, the crude reaction product is purified by flash chromatography on silica gel, eluting with a gradient (from 0.degree. 0.5%) 25% ammonia in ethyl acetate, to provide 0.43 g of the expected compound.

On solubilise 0,43 g de 4-[[(5-bromo-1 phényl-lH-imidazol-2-yl)oxylméthyl]-l -[(3- méthoxyphényl)méthyl]pipéridine dans 10 mL de dichlorométhane (DCM), et ajoute 0,4 mL d'acide chlorhydrique 5N dans l'isopropanol Après concentration à sec, on reprend par 10 mL de DCM et refroidit à -78 C, sous atmosphère d'azote On coule ensuite 0,37 mL de tribromure de bore, et agite 0,5 heure à - 78 C, avant de revenir à -15 C durant 2 heures On jette alors le mélange 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 lavées deux fois à l'eau puis à la saumure avant d'être séchées sur sulfate de magnésium. Après concentration à sec, le brut réactionnel est purifié par chromatographie flash sur gel de silice, en éluant avec un gradient (de 0 à 5%) de méthanol/ammoniaque (10/1) dans le dichlorométhane, pour fournir 0,4 g de composé attendu, sous forme de mousse amorphe blanche Example 4 Preparation of 3 - [[4 - [[[5-chloro-1- (2-fluorophenyl) -4-methyl-7H-imidazol-2-yl] oxy] methyl] piperidin-1-yl] methyl] phenol (formula I, R1 = CH3, R2 = Cl, R3 = 2-F, R = Phenyl, R4 = 3-OH, according to Scheme 2)

0.43 g of 4 - [[(5-bromo-1-phenyl-1H-imidazol-2-yl) oxylmethyl] -1 - [(3-methoxyphenyl) methyl] piperidine is solubilized in 10 ml of dichloromethane (DCM), and added 0.4 ml of 5N hydrochloric acid in isopropanol. After concentration to dryness, it is taken up in 10 ml of DCM and cooled to -78 ° C. under a nitrogen atmosphere. Then 0.37 ml of boron tribromide is poured. and stirred for 0.5 hour at -78 ° C., before returning to -15 ° C. for 2 hours. The reaction mixture is then thrown on a mixture of ice and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous phase is extracted by successive extractions with ethyl acetate. The combined organic phases are washed twice with water and then with brine before being dried over magnesium sulphate. After concentration to dryness, the crude reaction product is purified by flash chromatography on silica gel, eluting with a gradient (from 0 to 5%) of methanol / aqueous ammonia (10/1) in dichloromethane, to give 0.4 g of expected compound, in the form of white amorphous foam

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Exemple 5 Préparation de 4-[[(5-chloro-1-(2-fluorophényl)-4-méthyl-?/-/imidazol-2-yl)oxy]méthyl]-1-fertbutoxycarbonylpipéndine (formule VI, R1 = CH3, R2 = CI, R3 = 2-F, selon schéma 2) Sous atmosphère d'azote, on place 128 mg d'hydrure de sodium en dispersion à 95% dans l'huile, dans 4 mL de diméthylformamide (DMF) anhydre On ajoute

1,05 g de 4-hydroxyméthyl-1-tertbutoxycarbonylpipéndme en solution dans 8 mL de DMF et agite le mélange réactionnel à température ambiante durant 1,5 heure Puis, 1,28 g de 5-chloro-1-(2-fluorophényl)-2-mésyl-4-méthyl-9H- imidazole, en solution dans 10 mL de DMF sont additionnés et on poursuit l'agitation durant 1 heure, avant de porter à 50 C durant 1,5 heure On noie alors le milieu réactionnel dans 100 mL d'eau, et épuise la phase aqueuse par extractions successives avec de l'acétate d'éthyle Les phases organiques réunies sont lavées deux fois à l'eau puis à la saumure avant d'être séchées sur sulfate de magnésium. Après concentration à sec, le brut réactionnel est purifié par chromatographie flash sur gel de silice en éluant avec un gradient (de 0 à 5%) de méthanol dans le dichlorométhane, pour fournir 1,02 g de composé attendu.

Example 5 Preparation of 4 - [[(5-Chloro-1- (2-fluorophenyl) -4-methyl-β-imidazol-2-yl) oxy] methyl] -1-furbutoxycarbonylpiperidine (Formula VI, R1 = CH3 , R2 = Cl, R3 = 2-F, according to scheme 2) Under a nitrogen atmosphere, 128 mg of sodium hydride in a 95% dispersion in oil are placed in 4 ml of anhydrous dimethylformamide (DMF). added

1.05 g of 4-hydroxymethyl-1-tert-butoxycarbonylpipermein in solution in 8 ml of DMF and the reaction mixture is stirred at room temperature for 1.5 hours Then 1.28 g of 5-chloro-1- (2-fluorophenyl) -2-mesyl-4-methyl-9H-imidazole, dissolved in 10 ml of DMF are added and stirring is continued for 1 hour, before raising to 50 ° C. for 1.5 hours. The reaction medium is then drowned in 100 ml of water, and exhausts the aqueous phase 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 crude reaction product is purified by flash chromatography on silica gel, eluting with a gradient (from 0 to 5%) of methanol in dichloromethane, to give 1.02 g of expected compound.

fluorophényl)-4-méthyl-1 H-imidazol-2-yl)oxy]méthyl]-1- tertbutoxycarbonylpipéridine dans 24 mL de dichlorométhane, et refroidit au bain de glace On ajoute 2,9 mL d'acide tnfluoroacétique et agite le mélange réactionnel durant 3 heures à 0 C. Après concentration à sec, le milieu est repris avec 3mL de soude 1 N On épuise la phase aqueuse par extractions successives avec de l'acétate d'éthyle Les phases organiques réunies sont lavées deux fois à l'eau puis à la saumure avant d'être séchées sur sulfate de magnésium Après concentration à sec, on obtient 0,75 g de composé attendu

Exemple 7 Préparation de 4-[[(5-chloro-1-(2-fluorophényl)-4-méthyl-7/-/imidazol-2-yl)oxy]méthyl]-1-(4-méthyl-pent-3-èn-1-yl)pipéndine (formule I, R1 = CH3, R2 = CI, R3 = 2-F, R = 3-méthyl-but-2-èn-1-yl , selon schéma 2) Dans 10 mL de toluène, on ajoute successivement, sous atmosphère d'azote,

0,75 g de 4-[[(5-chloro-1 -(2-fluorophényl)-4-méthyl-IH-imidazol-2-yl)oxy]méthyl]- 1-pipéridine, 0,32 g de carbonate de potassium, et 0,37 mL de 5-bromo-2- Example 6 Preparation of 4 - [[(S-chloro-1- (2-fluorophenyl) -4-methyl-1-heidazol-2-yl) oxy] methyl] -1-piperide (formula VII, R1 = CH3, R2 = CI, R 3 = 2-F, according to scheme 2) 1.01 g of 4 - [[(5-chloro-1- (2-

fluorophenyl) -4-methyl-1H-imidazol-2-yl) oxy] methyl] -1-tertbutoxycarbonylpiperidine in 24 mL of dichloromethane, and cooled in an ice bath 2.9 mL of trifluoroacetic acid are added and the mixture is stirred Reaction for 3 hours at 0 ° C. After concentration to dryness, the medium is taken up with 3 ml of 1N sodium hydroxide. The aqueous phase is extracted by successive extractions with ethyl acetate. The combined organic phases are washed twice with sodium hydroxide. water and then with brine before being dried over magnesium sulphate. After concentration to dryness, 0.75 g of expected compound is obtained.

Example 7 Preparation of 4 - [[(5-Chloro-1- (2-fluorophenyl) -4-methyl-7H-imidazol-2-yl) oxy] methyl] -1- (4-methyl-pent-3) -en-1-yl) piperidine (formula I, R1 = CH3, R2 = Cl, R3 = 2-F, R = 3-methyl-but-2-en-1-yl, according to Scheme 2) In 10 ml of toluene, one adds successively, under a nitrogen atmosphere,

0.75 g of 4 - [[(5-chloro-1- (2-fluorophenyl) -4-methyl-1H-imidazol-2-yl) oxy] methyl] -1-piperidine, 0.32 g of sodium carbonate. potassium, and 0.37 mL of 5-bromo-2-

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Exemple 8 Préparation de 4-[[{1-phényl-5-tnéthylsilyl-9N-imidazol-2yl)oxy]méthyl]-1-(phénylméthyl)pipéndine (formule I, R1 = R3=H, R2 = Si(C2H5)3, R = Phényle , selon schéma 3)

Sous atmosphère d'argon, on place 4,7 g de 4-[[{5-bromo-1-phényl-9H-imidazol- 2-yl)oxy]méthyl]-1-(phénylméthyl)pipéridine (préalablement séché durant deux jours sur pentoxyde de phosphore) dans 54 mL de THF anhydre. Après avoir refroidit à-78 C, on additionne lentement 13,5 mL de buthyllithium 1,6N dans l'hexane, et agite 0,25 heure à cette température avant d'ajouter 3,6 mL de chlorotnéthylsilane On revient à température ambiante en deux heures, et jette sur un mélange de glace et de soude 1 N. La phase aqueuse est épuisée par extractions successives avec de l'acétate d'éthyle Les phases organiques réunies sont lavées deux fois à l'eau puis à la saumure avant d'être séchées sur sulfate de magnésium Après concentration à sec, le brut réactionnel est purifié par chromatographie flash sur gel de silice en éluant avec un gradient (de 0 à 1 %) d'ammoniaque à 25% dans l'acétate d'éthyle, pour fournir 1,5 g de composé attendu

Exemple 9 . Préparation de 4-[[(4-chloro-1-phényl-5-tnéthylsilyl-fH-imidazol-2yl)oxy]méthyl]-1-(phénylméthyl)pipéndme (formule I, R1 = CI, R2 = Si (C2Hs)3, R3=H, R = Phényle ; selon schéma 3) Sous atmosphère d'argon, on refroidit à 0 C, une solution de 0,42 g de 4-[[(1-

phényl-5-triéthylsilyl-9H-imidazol-2-yl)oxy]méthyl]-1-{phénylméthyl)pipéridme dans 5 mL de THF anhydre, et ajoute 0,133 g de N-chlorosuccinimide Après 15 heures, on jette 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 methylpent-2-ene, then heated at 80 ° C. for 40 hours. After returning to ambient temperature, it is hydrolyzed with a saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase is extracted by successive extractions with ethyl acetate, and after an acid-base treatment, the crude reaction product is purified by flash chromatography on silica gel, eluting with a gradient (from 0 to 5%) of methanol in dichloromethane, to provide 0.12 g of the expected compound

Example 8 Preparation of 4 - [[{1-phenyl-5-methylsilyl-9N-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine (formula I, R1 = R3 = H, R2 = Si (C2H5)) 3, R = Phenyl, according to Scheme 3)

Under argon atmosphere, 4.7 g of 4 - [[{5-bromo-1-phenyl-9H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine (previously dried for two days on phosphorus pentoxide) in 54 mL of anhydrous THF. After having cooled to-78 ° C., 13.5 ml of 1.6N buthyllithium in hexane are slowly added and the mixture is stirred for 0.25 hours at this temperature before adding 3.6 ml of chlorothymethylsilane. two hours, and cast on a mixture of ice and sodium hydroxide 1 N. 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 After being concentrated to dryness, the crude reaction product is purified by flash chromatography on silica gel, eluting with a gradient (from 0 to 1%) of 25% ammonia in ethyl acetate. to provide 1.5 g of expected compound

Example 9. Preparation of 4 - [[(4-chloro-1-phenyl-5-methylsilyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidme (Formula I, R1 = Cl, R2 = Si (C2Hs)) 3, R 3 = H, R = Phenyl, according to Scheme 3) Under an argon atmosphere, a solution of 0.42 g of 4 - [[(1-

phenyl-5-triethylsilyl-9H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidin in 5 mL of anhydrous THF, and 0.133 g of N-chlorosuccinimide are added. After 15 hours, the reaction medium is discarded. a mixture of ice and a saturated aqueous solution of sodium hydrogencarbonate The aqueous phase is extracted by successive extractions with ethyl acetate The combined organic phases are concentrated to dryness and taken up with ethyl ether, which precipitates succinimide, which is removed by several successive filtrations After concentration, the crude is purified by

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Exemple 10 . Préparation de 4-[[(4-chloro-1-phényl-H-imidazol-2- yl)oxy]méthyl]-1-(phénylméthyl)pipéridine (formule I, R1 = CI, R2 = R3=H, R = Phényle , selon schéma 3)

On solubilise 0,29 g de 4-[[(4-chloro-1-phényl-5-triéthylsilyl-'//-/-imidazol-2- yl)oxy]méthyl]-1-(phénylméthyl)pipéridine dans 6 mL de THF, et additionne 0,3 g de fluorure de tétrabutylammonium Après 15 heures d'agitation à température ambiante, on jette le milieu réactionnel sur un mélange de glace et de soude 1 N. flash chromatography on silica gel, eluting with ethyl acetate, to provide 0.29 g of the expected compound

Example 10 Preparation of 4 - [[(4-chloro-1-phenyl-3-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine (formula I, R 1 = Cl, R 2 = R 3 = H, R = Phenyl, according to diagram 3)

0.29 g of 4 - [[(4-chloro-1-phenyl-5-triethylsilyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine is solubilized in 6 ml. THF, and added 0.3 g of tetrabutylammonium fluoride After stirring for 15 hours at room temperature, the reaction mixture is thrown on a mixture of ice and 1N sodium hydroxide.

Exemple 11 ' Préparation de 4-[[(4,5-dichloro-1-phényl-'//L/-imidazol-2- yl)oxy]méthyl]-1-(phénylméthyl)pipéndine (formule I, R1 = CI, R2 = CI, R3=H, R = Phényle ; selon schéma 4) Sous atmosphère d'argon, on refroidit à 0 C, une solution de 0,5 g de 4-[[(1-

phényl-5-triéthylsilyl-1H-imidazol-2-yl)oxy]méthyl]-1-(phénylméthyl)pipéridine dans 6 mL de THF anhydre, et ajoute 0,32 g de N-chlorosuccinimide. Après 15 heures, on jette 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 repnsess 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 0,24 g de composé attendu The aqueous phase is extracted by successive extractions with ethyl acetate. The combined organic phases are washed twice with water and then with brine before being dried over magnesium sulphate. After concentration, the crude is purified by chromatography. flash on silica gel, eluting with a 60/40 mixture of ethyl acetate and heptane, to provide 0.11 g of expected compound

Example 11 Preparation of 4 - [[(4,5-dichloro-1-phenyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine (Formula I, R1 = Cl , R2 = Cl, R3 = H, R = Phenyl, according to diagram 4) Under an argon atmosphere, a solution of 0.5 g of 4 - [[(1-

phenyl-5-triethylsilyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine in 6 mL of anhydrous THF, and 0.32 g of N-chlorosuccinimide are added. After 15 hours, the reaction mixture is poured into a mixture of ice and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous phase is extracted by successive extractions with ethyl acetate. The combined organic phases are concentrated to dryness and dried. This is followed by ethyl ether, which causes the precipitation of succinimide, which is removed by several successive filtrations. After concentration, the crude is purified by flash chromatography on silica gel, eluting with a gradient of methanol (from 0 to 2.5%) in dichloromethane, to provide 0.24 g of expected compound

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

1. R = Ph

1. R = Ph

<Tb>
<tb> Input <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> salt <SEP> PF <SEP> (C)
<tb> 1 <SEP> H <SEP> Br <SEP> H <SEP> H <SEP> fumarate <SEP> 182
<tb> 2 <SEP> CH3 <SEP> Br <SEP> H <SEP> H <SEP> Hydrobromide <SEP> 170
<tb> 3 <SEP> CH3 <SEP> Cl <SEP> H <SEP> H <SEP> fumarate <SEP> 170
<tb> 4 <SEP> CH3 <SEP> CI <SEP> H <SEP> 3-OH <SEP> fumarate <SEP> 140
<tb> 5 <SEP> CH3 <SEP> CI <SEP> 3-OH <SEP> 3-OH <SEP> - <SEP> 200
<tb> 6 <SEP> CH3 <SEP> CI <SEP> 2-F <SEP> H <SEP> fumarate <SEP> 175
<tb> 7 <SEP> CH3 <SEP> CI <SEP> 2-F <SEP> 3-OH <SEP> fumarate <SEP> 165
<tb> 8 <SEP> CI <SEP> H <SEP> H <SEP> H <SEP> fumarate <SEP> 150
<tb> 9 <SEP> Br <SEP> Br <SEP> H <SEP> H <SEP> fumarate <SEP> 195
<tb> 10 <SEP> CI <SEP> Cl <SEP> H <SEP> H <SEP> fumarate <SEP> 190
<Tb>

2. R=C2-6alkényle

2. R = C2-6alkenyl

<Tb>
<tb> Input <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R
<tb> 11 <SEP> CH3 <SEP> CI <SEP> 2-F <SEP> 3-methyl- <SEP> fumarate <SEP> 155
<tb> but-2-in-1-yl
<Tb>

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 The compounds of the invention of formula (I) have been the subject of pharmacological tests which have shown their interest as therapeutically active substances. In particular, they have been tested for their inhibitory effects on the binding of [3H] - N-methyl scopolamine with human M3 muskin receptors transfected into CHO cells (Buckley et al., Mol Pharmacol 35: 469-476, 1989) CHO cell membranes, in solution in a 10 mM TRIS-HCl buffer, 2 mM EDTA pH 7.2, expressing the human muscarinic M3 receptor subtype were provided by 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, the Ulis, France), and a compound of the invention, in a total volume of 1 mL The non-specificity of the binding was determined by 0.5 M atropine (Sigma, St. Louis, Mo) 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. (glittering Ultima Gold). The concentration of compound displacing the specific binding by 50% (IC50) was used to calculate the Ki values according to the Cheng-Prusoff equation. The efficiency of each product studied is expressed by the negative logarithm of their Ki (pKi). .

The pKi of the compounds of the invention with respect to 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, M3 receptors Female rabbits (New Zealanders, 3-4Kg, ESD provider) approximately 20 weeks old were sacrificed by cervical dislocation and then exsanguinated After opening the abdomen, the bladders were removed and then rapidly Krebs bicarbonate solution of composition (mM) NaCl 114, KCl -4.7, CaCl2.2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25, ascorbic acid 1.1, glucose: 11.7. Propranolol (1M), methylsergide (1M), ondansetron (1M), GR113808 (1M) were added to Krebs to inhibit β-adrenergic receptors and the various

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 Serotonin 5-HT 1/5-HT 2, 5-HT 3 and 5-HT 4 receptor subtypes The bladders were cleaned, degreased and each side cut into two longitudinal flaps about 4 mm wide and 15 mm long. .

The tissues were then placed in 20 mL vats thermostatically controlled at 37 ° C. under carbogenic aeration (95% O 2, 5% CO 2) and subjected to a basal tension of 1 g. The tension was measured by means of gauges. isometric (Hugo Sacks, type 351) connected to couplers (Gould) that transform and amplify the responses that will be plotted on 4-track potentiometric recorders (Gould) and connected to a data acquisition system (Jad, Notocord). An equilibration time of about 45 minutes was observed during which the Krebs was renewed and the basal tension rectified. After an equilibration period of 30 minutes, an initial contraction to carbachol (1 M), a potent muscarinic agonist, was observed. The tissues were then rinsed abundantly and after a further equilibration period of 30 minutes, the tissues were incubated for 30 minutes in the presence or absence of a compound of the invention to be studied (0.1 or 1 M concentration). prior to completion of a carbachol concentration-response range at an interval of half a log unit.

Concentrations producing half of the maximal 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 carbachol response curve 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 pKb of the compounds of the invention are between 7 and 10 The compounds of the The invention has also been studied with respect 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) were euthanized from 300 to 400 g and their brain 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 Hepes-NaOH buffer (pH = 7.4 at 20 ° C.) and homogenized using a Polytron mill The homogenate is centrifuged for 10 minutes at 48,000 × g,

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 The pellet is recovered, resuspended and centrifuged again under the same conditions. The final pellet is suspended in hepes NaOH buffer (30 mg of fresh tissue / ml). This membrane suspension is used as it is. membrane suspension 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-NaOH buffer (50 mM, pH = 7.4), in the absence or in the presence of the test compound 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. 0 C and filtered again. The radioactivity retained on the filters is measured by liquid scintigraphy. The non-specific binding is determined in the presence of 30 M serotonin. 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 then the concentration of the test compound which inhibits 50% of the specific binding (Cl 50) The Cl 50 of the compounds of the invention are between 0.1 and 350 nM Finally, the compounds of The invention has been studied with regard to their antagonistic effects on 5-HT4 receptors in the rat esophagus. Sprague-Dawley male rats weighing 300 to 450 g are used. A fragment of about 1 is rapidly removed. 5 cm from the end part of the esophagus, the muscular layer is removed, the internal muscular mucous membrane is opened longitudinally and mounted in an isolated organ container containing a solution of Krebs-Henseleit at 32 C oxygenated by a carbogen stream (95% O2 and 5% CO2), and connected to an isometric transducer at a basal tension of 0.5 g The compounds are studied at a concentration of 1 M. Their ability to shift the relaxation introduced by 5-HT (at 0.1nM concentrations) of the esophageal tissue preconcerted to the P 1M substance is measured.

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 M3 and serotoninergic 5HT4 muscular receptors. The involvement of the 2D6 isoform of human cytochromes P450 (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 protein / ml) in the presence of a regenerative system of reduced equivalents (NADP, 3mM, MgSO4, 10mM, G-6P , 60mM, UDPGA, 8.6mM) at 37 ° C. and in the presence or absence of quinidine (3uM) (according to M BOURIE, V MEUNIER, Y. BERGER, G FABRE, Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catal ysed by human liver microsomes, Journal of Pharmacology and Experimental Therapeutics, 1995, Vol, 277, No. 1, p321-336) in a total volume of 1 ml. An aliquot of the incubation medium (100 μl) is taken at different times between 0. and 20 minutes after the beginning of the incubation, the reaction is stopped by the addition of 100 l of acetonitrile. After centrifugation and recovery, the supernatant is then analyzed in LC / MS. The unchanged compound is assayed using a range of external calibration treated under the same conditions as the incubations The results are expressed as percentage of involvement of CYP2D6 in the biotransformation of the compounds.

The involvement of human CYP2D6 in the microsomal 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 may be used in the treatment of irritable bowel syndrome, memory disorders, airway obstruction and bladder instability, particularly emergency unintentional incontinence. invention for the preparation of a medicament for treating the above mentioned pathologies is 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 a pharmaceutically acceptable salt, N-oxide or hydrate thereof, and one or more suitable pharmaceutical excipients. Said excipients are selected 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 ingredient of formula (I) ci above its salt or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. appropriate administration include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intranasal, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms. For topical application, the compounds according to the invention may be used in creams, ointments or lotions. In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle may vary between 0.1 mg and 50 mg per kg. of body weight and per day. Although these assays are examples of average conditions, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. In accordance with the usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode 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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 pharmaceuticals. This unit dose can be administered 1 to 5 times per 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 tablet form, 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 may be made by different techniques, direct compression, dry granulation, wet granulation or hot melt. According to a second example, a preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into capsules. soft or hard.

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

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 a salt thereof, N-oxides or hydrates

Claims (11)

1. Compound of formula (I) in which R1 and / or R2 represent a halogen atom, and in the case where one of the substituents R1 or R2 does not represent a halogen, it represents a hydrogen atom or a hydrogen atom. C1-4 alkyl group, R represents a C2-6alkenyl group or a phenyl optionally substituted with one or two groups R4, R3 and R4 represent, independently of one another, a hydrogen atom, a halogen atom, hydroxy, C1-4alkyl, C1-4alkoxy, cyano, nitro, C1-2perfluoroalkyl or amino, as well as its salts, N-oxides and hydrates. 2. Compound according to claim 1 characterized in that R3 represents a hydrogen atom, a hydroxy or a halogen and / or R4 represents a hydrogen atom, a hydroxy or a C1-4 alkyl group. 3. Compound according to claim 2 characterized in that R1 and R2 represent a halogen, or R1 (or R2) represents a halogen and R2 (or R1) represents a hydrogen atom or a C1-2alkyl group. 4. Compound according to claim 1 characterized in that it consists of the.

 4 - [[(5-bromo-1-phenyl-N-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine; 4 - [[(5-bromo-4-methyl-1-phenyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine; 4 - [[(5-Chloro-4-methyl-1-phenyl-1H-midazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine - [- 4- [ [(5-chloro-4-methyl-1-phenyl-N-imidazol-2-yl) oxy] methyl] pipet-1-yl] methyl] phenol; <Desc / Clms Page number 22>

 3 - [[4 - [[[5-chloro-1- (3-hydroxyphenyl) -4-methyl-1H-imidazol-2-yl] oxy] methyl] piperidin-1-yl] methyl] phenol, 4- [ [[5-Chloro-1- (2-fluorophenyl) -4-methyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine, 3 - [[4 - [[[5-chloro]] 1- (2-fluorophenyl) -4-methyl-TH-imidazol-2-yl] oxy] methyl] piperid-1-yl] methyl] phenol, 4 - [[(4-chloro-1-phenyl-1H-imidazole) 2-yl) oxy] methyl] -1- (phenylmethyl) piperidine, 4 - [[(4,5-dibromo-1-phenyl-1H-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) pipetine, 4 - [[(4,5-dichloro-1-phenyl-3-imidazol-2-yl) oxy] methyl] -1- (phenylmethyl) piperidine, and 4 - [[[5-chloro-1- (2-fluorophenyl) -4-methyl-2-imidazol-2-yl) oxy] methyl] -1- (4-methyl-pent-3-en-1-yl) piperidine 5. Process for the preparation of a compound of formula (I) wherein R2 represents a halogen according to claim 1 by reaction of a compound of formula (II)

 in which R1 and R3 are as defined in claim 1 with a Nhalosuccinimide 6. A process for the preparation of a compound of formula (I) according to claim 1 wherein R1 and optionally R2 represent a halogen by reaction and a compound of formula (VIII)

<Desc / Clms Page number 23>  wherein R3 and R are as defined in claim 1 and Pg is a protecting group, with N-halosuccinimide. 7. Compound of formula (IX)

 (IX) wherein R1 represents halogen, Pg a protecting group and R and R3 are as defined in claim 1. 8. Compound of formula (II)

 wherein R 1 is halogen and R and R 3 are as defined in claim 1. 9. Compound of formula (VII)

 wherein R2 is halogen and R, R1 and R3 are as defined in claim 1. <Desc / Clms Page number 24> 10. Compound of formula (IV)

 wherein R2 is halogen and R1 and R3 are as defined in claim 1. 11. Pharmaceutical composition characterized in that it contains a compound of formula (I) according to one of claims 1 to 4 in association with one or more pharmaceutically acceptable excipients. 12. Use of a compound of formula (I) according to any one of claims 1 to 4 for the preparation of a medicament for treating a pathology where a 5-HT4 and M3 receptor antagonist provides a therapeutic benefit. 13. Use of a compound of formula (I) according to one of claims 1 to 4, for the preparation of a medicament for the treatment of irritable bowel syndrome, memory disorders, obstruction of the pathways. aerial and bladder instabilities. 14. Use according to claim 13, characterized in that the bladder instability is emergency urinary incontinence.