WO1998004546A1 - Benzimidazole derivatives, preparation thereof, and therapeutical uses thereof - Google Patents

Abstract

Compounds of formula (I), wherein A is a nitrogen atom or a CH group; B is a C4-8 cycloalkyl group, a naphthyl group or a group of formula (Y), where n is 0 or 1; X is an oxygen or sulphur atom; Z is a nitrogen atom or a CH group; R2 is a hydrogen atom, a C1-4 alkyl group or a phenyl group; R3 is a C3-6 cycloalkyl group, a phenyl group, benzyl, a furyl group, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, thioazolyl, pyridyl, imidazolyl or benzimidazolyl; and R7 is a hydrogen atom or a straight or branched C1-4 alkyl group; and the therapeutical uses thereof, are disclosed.

Description

 BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATIONS AND THEIR THERAPEUTIC APPLICATIONS

The present invention relates to benzimidazo_e derivatives of general formula (I)

A représente un atome d'azote ou un groupe CH,in

A represents a nitrogen atom or a CH group,

B represents a C ₄ cyclo group. _B alkyl, a naphthyl group or a group of formula (Y) ^

n représente 0 ou 1 ,

n represents 0 or 1,

X represents an oxygen or sulfur atom,

Z represents a nitrogen atom or a CH group,

Ri represents a hydrogen atom, a halogen such as bromine, chlorine or fluorine, or a group C _x . ₄ alkyl, linear or branched, C _1-4 alkoxy, a trifluoromethyl group, a nitro group, an amino group, a C _1-4 alkylsulfonylamino group, a C _1-4 di (alkylsuifonyl) amino group, a C _1- group ₄ alkylamino, a C _1-4 dialkylamino group, a hydroxy group or a C _1-4 alkylcarbonylamino group,

R ₂ represents a hydrogen atom, a C _x _ ₄ alkyl group, or a phenyl group,

R ₃ represents a C ₃ _ ₆ cycloalkyl group, a phenyl, benzyl group, a furyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, pyridyl, imidazolyl or benzimidazolyl group, optionally substituted by one or two R ₆ groups,

R ₄ and R ₅ represent, independently of one another, a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a C _1-4 alkyl group, linear or branched, or a C _1- group ₄ alkoxy, a trifluoromethyl group, R ₆ represents a hydroxy group, a halogen such as fluorine, chlorine or bromine, a C _1-4 alkyl group, linear or branched, an amino group, a C _1-4 alkylsulfonylamino group, a group C_ ₄ di (alkylsulfcnyl) amino, a C _{x 4} alkylammo group, a C _{t 4} dialkylammo group, a fluoromethoxy tr group, a nitro group, a C _{L 4} alkoxy group, or a C _{4 4} alkylcarbonyla mo group, a cyano group , a formyl group, an amino group C, ₂ alkyl, a hydroxy group C ₄ alkyl, an ammocarbonyl group, a group C _{x 4} alkyl -carbonyl, a group -oxy-C ^ ₄ alkylene-oxy-,

R-, represents a hydrogen atom or a C ₄ alkyl group, linear or branched.

The compounds of general formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.

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

The starting materials are directly commercially available, are known in the literature. can be synthesized by conventional methods known to those skilled in the art.

The compounds of the invention can be prepared by methods illustrated by the schemes which follow.

The compounds of the invention for which X represents an oxygen atom can be prepared according to scheme 1 under conditions conventional for a person skilled in the art.

An orthoarylenediamme of general formula (II) in which R, A and B are as defined above is reacted with solvent-free urea at temperatures above 160 ° C. or with phosgene (or its polymers) in solution in a solvent such as dichloromethane or toluene at temperatures between -10 ° C and 110 ° C to give the compound of general formula (III) in which A, B and R _τ are as defined above.

Alternatively the compound of formula (III) is obtained by reaction of a phenyl isocyanate of formula (XVII) with an amme of formula (XIII), in which A, B and R_ are as defined above to give urea of formula (XVIII). The reaction can be carried out in a solvent such as toluene. The urea of formula (XVIII) is then cyclized in the presence of an inorganic base, such as sodium hydroxide, and of sodium hypochlorite in a solvent such as methanol, to give the compound of formula (III) in which A, B and R _x are as defined above.

The resulting compound (III) is reacted in the presence of a halogenating agent such as phosphorus oxychloride or phosphorus pentabromide under conditions defined by AM Simonov, Russ. Chem. Rev. , 122, 1996, to give the compound of general formula (IV), in which A, B and R _x are as defined above and Hal represents a halogen such as chlorine or bromine. The substitution of the Hal group of the compound of general formula (IV) by the alcohol of formula (V) in which R ₂ and R ₃ are as defined above, can be carried out in a polar solvent such as dimethylformamide , tetrahydrofuran, or N-methyl-2-pyrrolidinone at a temperature varying between -10 ° C and 80 ° C under the action of a non-nucleophilic base such as sodium hydride, potassium tert-butoxide to give the compound of general formula (I) in which X represents an oxygen atom and R _lt A, B, and R ₂ and R ₃ are as defined above. Diagram 1

The compounds of the invention for which X represents a sulfur atom can be prepared according to scheme 2 under the conditions conventional for a person skilled in the art.

An orthoarylene diamine of general formula (II) in which R _{1 #} A and B are as defined above is reacted with thiourea. The reaction can be carried out in the absence of solvent above a temperature of 180 ° C., to give the compound of general formula (VI) in which R _:, A and B are as defined above. Diagram 2

(I)

The compound of general formula (VI) thus obtained is reacted with an electrophile of general formula (VII) in which R ₂ and R ₃ are as defined above and L represents a leaving group such as a halogen or a esylate. The reaction can be carried out in a polar solvent such as dimethylformamide or tetrahydrofuran in the presence of a non-nucleophilic base such as sodium hydride or potassium tert-butoxide, at temperatures varying between -10 ° C. and 80 ° C.

Alternatively, the compounds of general formula (I) in which X is an oxygen atom or X is a sulfur atom can be prepared according to scheme 3 by reaction of a compound of general formula (VIII) with either a halide d alkyl of general formula (IX), either an aldehyde or a ketone of general formula (X) in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride and optionally in the presence of a Lewis acid such that titanium tetrachloride, or is an acid chloride of general formula (XI), carbonyl being then reduced by a mixed lithium and aluminum hydride in tetrahydrofuran, R ₂ and R ₃ being as defined above.

Diagram 3

¹

The compounds of general formula (I), in which the substituents R ₆ and / or Rj represent a reactive function, these can be modified by conventional reactions, known to those skilled in the art, such as for example reduction, oxidation , hydrolysis or acylation to give new compounds of general formula (I), in accordance with the invention, in which R ₂ R ₃ , A, B and X are as defined above.

For example when R _δ and / or R _x represent a nitro group, this can be reduced to give an amino group. This amino group can be optionally acylated or transformed into an alkylsulfonylamino, di (alkylsuifonyl) amino group, or alternatively into an alkylamino or dialkylamino group, by methods known to a person skilled in the art to give a compound of general formula (I) in which R ₂ , A, B and X are as defined above and R ₆ and / or R _x represent an amino group, a Cj group. ₄ alkylsulfonylamino, a group C ,. ₄ di (alkylsulfonyl) a.nino, a group C _{^ 4} alkylammo, a group C, ₄ dialkylamino, or a group C, ₄ alkylcarbonylamino.

Or, for example, when R ₆ and / or R represent a cyano group, the latter can be hydrolyzed or reduced according to conventional methods known to those skilled in the art, to give for example a formyl, ammomethyl, hydroxymethyl or amino carbonyie.

The starting compounds of general formula (II) in which A, B and R, are as defined above, are obtained, according to scheme 4, by aromatic nucleophilic substitution of an ortho (fluoro or chloro) nitroaryl by a cyclo C _{4 8} alkylamine of general formula (XIII), at temperatures between -30 and 80 ° C, or by an aniline of general formula (XIII), at temperatures between 20 and 180 ° C, giving an intermediate of general formula (XIV), followed by reduction of the nitro group with a sodium sulfide hydrate in methanol in the presence of a base according to the method described by 0. Ozegowski in J. Prakt. Chem. 20, 166, 1963, by catalytic hydrogenation, or by means of a tin chloride hydrate in ethyl acetate at reflux according to methods known to those skilled in the art.

Diagram 4

The compounds of general formula (V), in which R ₂ and R ₃ are as defined above, are commercial or are obtained according to scheme 5 by conventional reaction of N-alkylation with an alkyl halide of general formula ( IX). This halogenation is followed by the reduction of the carbonyl function, either to give the compound of formula (V) directly, or to give the compound of formula (XIX) which is reacted with an organometallic, according to known conventional methods. the skilled person. Alternatively, the compound of formula (V) is obtained by reduction of the carbonyl function on commercially accessible products, as described for example by Lyons in J. Chem. Soc. Chem. Commun., 412.1975.

The compounds of general formula (VII) are obtained, for example, by mesylation or dehydrohalogenation of the compound of general formula (V) according to conventional methods known to those skilled in the art.

Diagram 5

ogene

The compounds of general formula (VIII), in which A, B, X, and R _x are as defined above, are obtained, according to methods known to those skilled in the art, by debenzylation using formate ammonium in palladic catalysis of the compounds of formula (I) for which R ₂ represents a hydrogen and R ₃ represents a phenyl.

Alternatively, the compounds of formula (VIII), in which A, B, X, and Rj are as defined above, can be prepared by reaction of a compound of formula (IV) with piperidinemethanol, N-protected by a protective group, such as for example a ter-butoxycarbonyl, followed by deprotection according to methods known to those skilled in the art. The following examples illustrate the methods and techniques suitable for the preparation of this invention, without however limiting the scope of the claim. Elementary microanalyses and RN and IR spectra confirm the structures of the compounds obtained.

Example 1: Preparation of compounds of formula (XIV)

Example 1a: N- (2-methoxyphenyl j -2-nιtrobenzenamme

17.2 ml of 2-methoxyaniline and 8 ml of 2-fluoro-nitrobenzene, 0.1 ml of hexamethylphosphotriamide and a few mg of copper (II) chloride are introduced into a flask. It is brought to 160 ° C. for 20 h, then, after returning to ambient temperature, a 1/1 mixture of water / ethyl ether is taken up in 200 ml. The aqueous phase is extracted twice with 50 ml of ether and the combined organic phases are washed with 100 ml of a 9/1 mixture of a saturated aqueous solution of ammonium chloride and of an ammonia solution at 25%. It is dried over magnesium sulfate, filtered through celite and concentrated. Purification is carried out by flash chromatography on silica gel, eluting with a 9/1 mixture of cyclohexane and ethyl acetate. 16 g of product are obtained.

By reproducing the process of Example la, with suitable starting materials, other intermediate compounds of formula (XIV) were prepared. These compounds have been used in particular for the synthesis of the compounds of general formula (I) in accordance with the invention and having the numbers from 1 to 16 in the table below.

Example 1b: N-cyclohexyl-2-nitrobenzenamme 15.8 ml of 2-fluoronitrobenzene in 20 ml of dichloromethane are cooled to 5 ° C. and 46 ml of cyclohexylamine are added slowly. It is brought back to ambient temperature and taken up in 200 ml of a 1/1 water / dichloromethane mixture. The aqueous phase is extracted twice with 50 ml of dichloromethane, dried over sodium sulfate and concentrated. Purification is carried out by flash chromatography on silica gel, eluting with dichloromethane. 31.5 g of product are thus obtained.

By reproducing the process of Example 1b, with suitable starting materials, other compounds of formula (XIV) were prepared. These compounds have been used in particular for the synthesis of the compounds of general formula (I), in accordance with the invention and having the numbers from 19 to 21 in the table below.

Example 2: Preparation of compounds of formula (II)

Example 2a: N- (2-methoxyphenyl) benzene- 1, 2-diamine

16 g of N- (2-methoxyphenyl) -2-nιtrobenzenamine are mixed and

74 g of tin chloride dihydrate in 120 ml of ethyl acetate and the mixture is brought to reflux for 3 h. After returning to room temperature, it is poured onto ice and basified with sodium carbonate. It is extracted with ethyl acetate and dried over sodium sulfate. After concentration, 13 g of product are obtained, used as it is and immediately for the reaction for forming the compounds of formula (III) or (VI).

By reproducing the process of Example 2a, with the appropriate starting materials (XIV), other compounds of formula (II) were prepared. These compounds have been used in particular for the synthesis of the compounds of general formula (I), in accordance with the invention and having the numbers from 1 to 16 in the table below.

Example 2b: N-cyclohexylbenzene-1, 2-diamine

8.8 g of N-cyclohexyl-2-nitrobenzenamine are dissolved in 300 ml of ethanol in a 500 ml Parr bottle, and 0.5 g of 10% palladium on carbon is added. It is left under 345 kPa of hydrogen for 1 h at room temperature, then it is filtered and concentrated. 7.6 g of product are recovered.

By reproducing the process of Example 2b, with suitable starting materials, other compounds of formula (II). These compounds have been used in particular for the synthesis of the compounds of general formula (I) in accordance with the invention and having the numbers from 19 to 21 in the table below.

Example 3: Preparation of compounds of formula (III)

Example 3a: 1- (2-methoxyphenyl) -1, 3 -dihydro-2H-benzimidazol - 2-one 13 g of N- (2-methoxyphenyl) benzene-1, 2-diamine and 11 g of fresh urea are mixed recrystallized and heated to 150 ° C for 5 h. Once it has returned to a temperature below 100 ° C., it is triturated in water, the gum obtained is decanted and then it is triturated in ethyl ether to yield, after drying under vacuum over phosphorus pentoxide, 11.5 g of product. .

By reproducing the process of Example 3a, with the appropriate starting materials (II), other compounds of formula (III) were prepared. These compounds have been used in particular for the synthesis of the compounds of general formula (I), in accordance with the invention and having the numbers from 1 to 17 and from 19 to 21 in the table below.

Example 3b: 1- (4-chlorophenyl) -1, 3 -dihydro-2H-benzimidazole- 2-one

1.8 g of N- (4-chlorophenyl) benzene-1,2-diamine are dissolved in 50 ml of methylene chloride and 1 ml of diphosgene is added. There is immediate precipitation. Filtered and 1.9 g of product are recovered.

This compound was used in particular for the synthesis of the compound of general formula (I) in accordance with the invention and having the number 18 in the table below.

Example 3c: 1- (2-methoxyphenyl) -1, 3-dihydro-2H- ,

benzιmιdazole-2-or_ and 1-phenyl -4 -methoxy- 1, 3-dιhydro-2H- benzιmιdazole-2-one

1-phenyl -3 - (2 -methoxyphenyl) urea

13.7 ml of phenyl isocyanate and 15.7 ml of O-anisidme are mixed in 380 ml of toluene under nitrogen and the mixture is heated at 90 ° C. to 100 ° C. for 7 hours. Cool to 0 ° C. The precipitate is filtered, washed with toluene and dried at 40 ° C under reduced pressure to yield 27.1 g of product.

1- (2-methoxyphenyl) -1.3-dιhydro-2H-benzιmιdazole-2-one and 1- phenyl -4 -methoxy-1.3-dιhydro-2H-benzιmιdazole-2-one

To a solution of 26.8 g of 1-phenyl-3- (2-methoxyphenyl) urea in 630 ml of methanol, 8.85 g of sodium hydroxide pellet dissolved in 20 ml of water is added. Cool to 10 ° C and add 194 ml of sodium hypochlorite for 45 mm. After one hour at 15 ° C, the reaction is neutralized with 100 ml of 3N hydrochloric acid. The methanol is evaporated and the residue is taken up in 1 liter of water. The precipitate formed is filtered and dissolved hot in 200 ml of 10% sodium hydroxide solution. The solution is acidified, the precipitate formed is filtered to give 15 g of crude product. The crude product is purified on a silica column, eluting with a dichloromethane / methanol / ammonia mixture (99/1 / 0.1) to give 4.6 g of 1- (2-methoxyphenyl) -1, 3-dιhydro- 2H-benzιmιdazole-2- one and 6.9 g of 1-phenyl -4 -methoxy-1, 3-dehydro-2H- benzimidazole -2-one.

Example 4: Preparation of compounds of formula (VI) 1 -phenyl -1, 3 -dιhydro-2H-benzιmιdazol-2-thιone 18 g of orthophenylenediamme and 15 g of thiourea are heated to 190 ° C. for 3 h. After returning to ambient temperature, the precipitate is washed several times with water and dried over phosphorus pentoxide.

20 g of product are obtained. This method of synthesis with the appropriate starting materials (II) was used for the synthesis of compounds of formula (VI) which can be used for the preparation of the compounds of general formula (I) in accordance with the invention and having the numbers 22 and 23 in the table below.

Example 5: l-benzyl-4-pιpérιdmeméthanol

The mixture is stirred under reflux for 2 hours, a mixture of 31.4 g (0.2 mol) of ¹ ethyl isonipecotate, 55.28 g (0.4 mol) of potassium bicarbonate and 23.79 ml (0, 2 mol) of benzyl bromide in 400 ml of ethanol. The reaction medium is then cooled in an ice-water bath, filtered through Celite and the filtrate is concentrated under reduced pressure. 51.23 g of oily residue are obtained which is suspended in 250 ml of anhydrous tetrahydrofuran, then added to a suspension of 20 g (0.527 mol) of lithium aluminum hydride in 100 ml of anhydrous diethyl ether . The reaction medium is stirred overnight at room temperature and then cooled in an ice-water bath. 20 ml of water are added dropwise, then 20 ml of 20% sodium hydroxide and 60 ml of water. The mixture is stirred for 30 min at room temperature, then filtered through Celite, washed with tetrahydrofuran and a little water and the filtrate is evaporated. 37.2 g of product are obtained in the form of an oil.

Example 6: [1- (Phenylmethyl) pιpérιdm-4-yllmethyl ethanesulfonate according to US patent 5,354,747

0.8 ml of mesyl chloride in 2 ml of dichloromethane is cooled to 5 ° C. and a solution composed of 2.05 g of l-benzyl-4-pipendin-methanol and 1.45 ml of methyl ethylene in 10 ml is added dichloromethane. After 2 h, the mixture is thrown on ice, extracted with methylene chloride, dried over magnesium sulfate and concentrated. 2.8 g of product are recovered which is used as such and rapidly in the synthesis of the compounds of formula (I) in which X represents a sulfur atom. EXAMPLE 7 Preparation of Compounds of Formula (IV) 2-chloro-1- (2-methoxyphenyl) -1H-benzimidazole 11.5 g of 1- (2-methoxyphenyl) -1,3-dihydro-2H-benzimidazol are carried. -2-one and 160 ml of phosphoryl chloride at reflux for 3 h, then the latter is distilled and the residue is thrown on ice. Basified with sodium hydroxide and extracted with ethyl ether. After concentration, it is purified on silica gel, eluting with methylene chloride. This gives 6.6 g of product.

By reproducing the process of Example 7, with suitable starting materials (III), other compounds of formula (IV) were prepared. These compounds have been used in particular for the synthesis of the compounds of general formula (I), in accordance with the invention and having the numbers from 1 to 21 in the table below.

EXAMPLE 8 Preparation of Compounds of Formula (I) (X represents an oxygen atom) 1- (2 -methoxyphenyl) -2- [[1- (phenylmethyl) piperidin-4 - yl] methoxy] -1H-benzimidazole

360 mg of sodium hydride and 2.84 g of 1-benzyl-4-piperidinemethanol are gradually heated to 70 ° C. in 20 ml of dimethylformamide until the evolution of hydrogen is completed. It is then cooled to 0 ° C. and 3 g of 2-chloro-1- (2-methoxyphenyl) -1H-benzimidazole added in solution in 30 ml of dimethylformamide are added. The temperature is allowed to slowly rise to room temperature and 50 ml of water are added. It is extracted with ethyl acetate and prepurified by acid-base treatment. After concentration, chromatography on silica gel eluting with a gradient of methanol in dichloromethane from 1/99 to 5/95. 2.5 g of product are recovered.

By reproducing the process of Example 8, with the appropriate starting materials, other compounds of general formula (I) were prepared, in accordance with the invention and in particular some indicated in the table below.

Example 9 Preparation of compounds of formula (I) (X represents a sulfur atom) 1 -phenyl -2- [[1- (phenylmethyl) pιpérιdιn-4 -yl] methylsulfanyl] - 1H-benzimidazole

In 5 ml of dimethylformamide is successively added 440 mg of sodium hydride in dispersion at 60% in oil then 2.25 g of 1-phenyl-1,3-d hydro-2H-benzιmιdazol-2 -thione. The temperature is brought to 45 ° C. to complete the deprotonation, then it is cooled to 0 ° C. and 2.8 g of freshly prepared [1- (phenylmethyl) pιpéridm-4-yl] methyl methanesulfonate are added and the temperature is allowed to slowly rise to the ambient. Thrown on ice and extracted with methylene chloride. It is dried over magnesium sulphate and concentrated. Purification is carried out by chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. 0.6 g of product is recovered.

The process of Example 9, with the appropriate starting materials, made it possible to prepare the compounds of general formula (I) in which X represents a sulfur atom and having the numbers 22 and 23 in the table below.

Example 10 Preparation of Compounds of Formula (VIII) 1 -phenyl -2- (piperidin-4-ylmethoxy) -lH-benzimidazole 450 mg of l-phenyl-2- [[1- (phenylmethyl) pιpéridm-4- yl] methoxy] -lH-benzimidazole are suspended in 10 ml of methanol and successively added with 700 mg of ammonium formate and 350 mg of 10% palladium on carbon. It is brought to boiling for 45 minutes, then the catalyst is filtered and concentrated under vacuum. It is taken up in normal soda, extracted with dichloromethane and dried over sodium sulfate. After concentration, 260 mg of product is recovered. Example 11: Preparation of compounds of formula (I) 2- [[1- [(3-chlorophenyl) methyl] pιpérιdm-4 -yl] methoxy] - 1 - phenyl - IH-benzimidazole

Stirred for 2 hours, 500 mg of 1-phenyl -2 - (pιpérιdm-4 - ylmethoxy) -IH-benzimidazole, 240 mg of potassium carbonate and 0.21 ml of 3-chlorobenzyl bromide in 5 ml of dimethylformamide, then 30 ml of water are added and the mixture is extracted three times with 20 ml of ethyl acetate. The combined organic phases are washed with water (2 x 20 ml), and with brine. It is dried over sodium sulfate and concentrated. Purification is carried out by chromatography on silica gel, eluting with a mixture of dichloromethane, methanol and 25% ammonia 97/3 / 0.3.

By reproducing the process of Example 11, with the appropriate starting materials (VIII), other compounds of general formula (I) were prepared in accordance with the invention.

Example 12: Preparation of compounds of general formula (I) 2- [[1- [(3-amιnophenyl) methyl] pιpéndιn-4-yl] methoxy] -1- phenyl - IH-benzimidazole

3.49 g of 2 - [[1 - ((3-nitrophenyl) methyl] pιpérιdm-4-yl] methoxy] - 1 -phenyl -1H- benzimidazole are dissolved in 300 ml of ethanol and 3 tips of spatulas are added of Raney nickel. Leave for one hour under 345 kPa of hydrogen at ambient temperature then filter and concentrate to dryness. 2.26 g of product is recovered. Purify by flash chromatography on silica gel, eluting with dichloromethane. 1.54 g of product are obtained.

The derivatives of general formula (I), in accordance with the invention and having the numbers from 35 to 37 in the table below, were obtained by this method of preparation. EXAMPLE 13 Preparation of Compounds of General Formula (I 2- [[1- [(3 -acetylammophenyl) methyl] pιpéπdιn-4-yl] methoxy] -1- phenyl-1H-benzimidazole

0.5 g of 2 - [[1 - [(3-aminophenyl) methyl] pιpéπdιn-4-yl] methoxy] - 1 -phenyl -1H-benzimidazole and 1.2 g of pyr dme are introduced into a flask. We put under nitrogen. 0.13 ml of acetic anhydride is added. The mixture is left to stir at ambient temperature for 12 hours. The reaction is treated by adding water and 1M sodium bicarbonate until a basic pH is obtained. Extracted with ether, then after washing with water is dried over sodium sulfate. It is filtered and evaporated to dryness. Purification is carried out by flash chromatography on silica gel, eluting with a mixture of dichloromethane / methanol / ammonia (97/3 / 0.3). 0.34 g of product of general formula (I) and having the number 40 in the table below is obtained.

Example 14 Preparation of Compounds of Formula (I)

2- [[1- [(3 -methylsuifonylaminophenyl) methyl] pιpérιdm-4- yl] methoxy] - 1-phenyl -IH-benzimidazole and 2 - [[l ~ [(3- di ethylsulfonylaminophenyl) methyl] pιpérιdm-4 - yl] methoxy] -1 - phenyl - IH-benzimidazole

0.8 g of 2 - [[1 - [(3-acetylammophenyl) methyl] pιpérιdιn-4 -yl] methoxy] - 1 -phenyl -1H- benzimidazole in 6 ml ether and 0.44 ml of is introduced into a flask tπethylamme. Cool to -30 ° C and add 0.23 ml of mesyl chloride to the syringe dropwise. After 20 minutes, the solution is treated. Dichloromethane, water and sodium hydroxide are added. Extraction is carried out with dichloromethane. Wash with water and dry over sodium sulfate. It is filtered and evaporated to dryness. Purification is carried out by flash chromatography on silica gel, eluting with a mixture of dichloromethane / methanol / ammonia (96/4 / 0.4). 0.33 g of methylsulfonyl and 0.15 g of dimethylsulfonyl are obtained, corresponding respectively to the compounds of general formula (I), in accordance with the invention and having the numbers 41 and 42 in the table below. Example 15: 1 -phenyl -2- [[1- (3 -aminocarbonyl - phenylmethyl) pιpérιdιn-4 -yl] methoxy] - 1H-benzimidazole In a 50 ml flask, place 600 mg of l-phenyl-2 - [ [1- (3 - cyano-phenylmethyl) pιpérιdm-4 -yl] methoxy] -1H-benzimidazole with 0.28 g of 85% potassium hydroxide in 5 ml of tert-butanol. Heated from 80 ° C to 92 ° C for 2 hours. We add water. Extraction is carried out with ethyl acetate. The organic phases are washed with brine and water. It is dried over sodium sulfate and evaporated to dryness. Purification is carried out by chromatography on silica gel, eluting with a mixture of dichloromethane / methanol / ammonia (97/3 / 0.3). 0.58 g of product is recovered.

Example 16: Preparation of compounds of formula (I) l-phenyl-2- [[1- (3-furylmethyl) pιpérιdm-4-yl] methoxy] -1H- benzimidazole

0.6 g of 1 -phenyl -2- (pιpéndm-4 -ylmethoxy) -IH-benzimidazole with 6.5 ml of a 0.1 N hydrochloric acid solution in 1 is placed in a 50 ml flask 'isopropanol. It is evaporated to dryness. The residue is taken up in 6 ml of methanol. 0.34 ml of 3-furaldehyde and 0.244 g of sodium cyanoborohydride are added to the syringe. The mixture is stirred for 12 hours. Hydrolysis is carried out by adding water. Extraction is carried out with dichloromethane. The organic phases are combined and dried over sodium sulfate. It is filtered and evaporated to dryness. After concentration, 0.54 g of product is recovered.

The process of Example 16, with the appropriate starting materials, made it possible in particular to prepare the compounds of general formula (I) having the numbers 53 and 62 to 68 in the table below. The following table illustrates the chemical structures and physical properties of some compounds according to the invention.

In the table, "B", unless otherwise specified, represents "Y", "Phe" represents a phenyl group, "-" indicates that the phenyl group (R ₃ ) is not substituted and iC ₃ H ₇ represents an iso -propyle. The last column of the table indicates whether the compound is in the form of a salt, "Ox" represents an oxalate, "Fu" represents a fu arate. The compounds of the invention 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 [ ³ H] -N-methyl-scopolamine with type ₁ muscle receptors ₍ human M ₂ and M ₃ transfected into CHO cells (chmese hamster ovarian cells). ) (Buckley et al., Mol. Pharmacol. 35: 469-476, 1989). Membranes of CHO cells, in solution in buffer

10 mM TRIS-HCl, 2 mM EDTA pH 7.2, expressing the 3 human muscle receptor M ₁ subtypes _; M ₂ , M ₃ were supplied by the company Receptor Biology (Baltimore, USA). 10 to 30 μg of membranes were incubated in a phosphate buffer, pH 7.4 (Sigma, St Louis, MO) in the presence of [ ³ H] N-methyl-scopolamme (NEN-Dupont, Les Ulis, France), 0 , 49 nM for M _: and 0.5 nM for M ₂ and M ₃ , and of a compound of the invention, in a total volume of 1 ml. The non-specificity of the binding was determined by 1 μM of atropine (Sigma, St Louis, Mo) for the M ₁ receptors ₍ M ₂ and 0.5 μM for M _3. 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

(scintillating Ultima Gold). The concentration of compound displacing the specific binding by 50% (IC ₅₀ ) was used to calculate the Ki values according to the Cheng-Prusoff equation. The effectiveness of each product studied is expressed by the negative logarithm of their Ki (pKi).

The IC ₅₀ values of the compounds of the invention vis-à-vis the M ₃ receptors are between 1 and 800 nM.

The IC ₅₀ values of the compounds of the invention vis-à-vis the M _x and M ₂ receptors are higher by a factor of 1 to 126. The compounds of the invention have also been studied as to their antagonistic effects with respect to contractions of the female rabbit detrusor, mediated by the M ₃ receptors. Female rabbits (New Zealanders, 3-4 kg; ESD supplier) aged about 20 weeks were sacrificed by cervical dislocation and then bloodless. After opening the abdomen, the bladders were removed and then quickly placed in a bicarbonate Krebs solution of composition (mM): NaCl: 114; KC1: 4.7; CaCl ₂ : 2.5; MgSO ₄ : 1.2; KH ₂ P0 ₄ : 1.2; NaHCO ₃ : 25,; ascorbic acid: 1.1; glucose: 11.7. Propranolol (1 μM), methysergide (1 μM), 1 ondansetron (1 μM), GR113808 (1 μM) were added to Krebs in order to respectively inhibit the β-adrenergic receptors and the various subtypes of serotomnergic receptors 5 - HT / 5-HT ₂ , 5-HT ₃ and 5-HT ₄ The bladders were cleaned, degreased, then each face was cut into two longitudinal strips about 4mm wide and 15mm long. The tissues were then placed in 20 ml tanks thermostated at 37 ° C under carbogenic aeration (95% 0 ₂ , 5% C0 ₂ ) 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 with carbachol (1 μM), a powerful 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 μM) before the realization of a concentration-response range to carbachol per interval half a logarithm.

The concentrations producing half of the maximum effect (EC ₅₀ (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 (pK _B or apparent pA _^ ) according to the method of Furchgott (Handbook of Experimental Pharmacology, 1972, 283-335).

The pK _b of the compounds of the invention are between 6 and 9.

The compounds of the invention have also been studied as to their affinity for 5-HT ₄ receptors in the guinea pig striatum, according to the method described by Grossman et al., In Br. J. Phar acol. , 109, 618-624 (1993).

Guinea pigs (Hartley, Charles River) weighing 300 to 400 g are euthanized and their brains removed. The stπata are excised and frozen at -80 ° C. 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 it is homogenized using a grinder. Polytron ^® . The homogenate is centrifuged for 10 min at 48000 × g, the pellet is recovered, it is resuspended and it is again centrifuged 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.

100 μl 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 buffer Hepes-NaOH (50 mM, pH = 7.4), in the absence or in the presence of the test compound. Incubation was stopped by filtration on Whatman GF / B ^®, pretreated with 0.1% polyéthylèneimme, rinsed tuoe each with 4 ml of buffer at 0 ° C and filtered again. The radioactivity retained on the filters is measured by liquid scigraphy. The non-specific binding in the presence is determined 30 μM serotonin.

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

For each concentration of compound studied, it is determined the percentage of ¹ inhibition of specific binding of ^[3 H] GR118808 and then the concentration of test compound which inhibits 50% of specific binding (IC _50).

The IC ₅₀ values of the compounds of the invention are between 1 and 800 nM.

Finally, the compounds of the invention were studied as regards their antagonistic effects with respect to the 5-HT ₄ receptors in the rat esophagus. Male Sprague-Dawley rats weighing from 300 to

450 g. We quickly take 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% 0 ₂ and 5% C0 ₂ ), 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 μM. We measure their ability to displace the relaxation introduced by 5-HT (at concentrations of 0.1 nM to 10 μM) from the esophageal tissue pre-contracted to substance P lμM. The compounds of the invention are active in this test.

The results of the biological tests show that the compounds of the invention are antagonists of the muscanic receptors M ₃ and serotonmergic 5-HT ₄ .

They can therefore be used in the treatment of irritable bowel syndrome, memory problems, airway obstruction and bladder instability, in particular emergency urinary incontinence. The compounds of the invention, in combination with suitable, pharmaceutically acceptable excipients, can be presented in any form suitable for oral or parenteral administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions, and dosages to allow administration of 0.1 to 50 mg / kg per day.

Claims

claims 1. Compound of general formula (I)

in which: A represents a nitrogen atom or a CH group, B represents a C ₄ cyclo group. ₈ alkyl, a naphthyl group or a group of formula (Y) n represents 0 or 1,

X represents an oxygen or sulfur atom, Z represents a nitrogen atom or a CH group, R _j represents a hydrogen atom, a halogen such as bromine, chlorine or fluorine, or a C _1-4 alkyl group, linear or branched, C _1-4 alkoxy, a trifluoromethyl group, a nitro group, an amino group, a C _1-4 alkylsulfonylamino group, a C _1-4 di (alkylsuifonyl) amino group, a C _1-4 alkylamino group, a C _x _ ₄ dialkylamino group, a hydroxy group or a C-_ ₄ alkylcarbonylamino group, R ₂ represents a hydrogen atom, a C _1-4 alkyl group, or a phenyl group, R ₃ represents a group C ₃ . ₆ cycloalkyl, a phenyl, benzyl, a furyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, pyridyl, imidazolyl or benzimidazolyl group, optionally substituted by one or two R ₆ groups, R ₄ and R ₅ represent, independently of one another, a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a C _1-4 alkyl group, linear or branched, or a C _1- group ₄ alkoxy, a trifluoromethyl group, R ₆ represents a hydroxy group, a halogen such as fluorine, chlorine or bromine, a group C _,. . ,, alkyl, linear or branched, an amino group, a C_ group. ₄ alkylsulfonylamino, a group C _1-4 di (alkylsulfonyl) amino, a group C ,. ₄ alkylamino, a group C _1-4 dialkylamino, a group trifluoromethoxy, a group nitro, a group C _1-4 alkoxy, or a group C, _ ₄ alkylcarbonylamino, a group cyano, a formyl group, an amino group C _{1- 2} alkyl, a hydroxy group C _1-4 alkyl, an aminocarbonyl group, a group C ^ ,, alkyl -carbonyl, a group -oxy-C _l-4 alkylene-oxy-, R ₇ represents a hydrogen atom or a linear or branched C _1-4 alkyl group, in the form of an enantiomer, a diastereoisomer, or a mixture of these different forms, including a racemic mixture and their addition salts to pharmaceutically acceptable acids or N-oxide derivatives. 2. Process for the preparation of the compounds according to claim 1, characterized in that a compound of formula (IV) is reacted

in which R _α A and B are as defined in claim 1 and Hal represents a halogen such as chlorine or bromine, with a compound of formula (V)

in which R ₂ and R ₃ are as defined in claim 1, or else a compound of formula (VI) is reacted

in which R ,, A and B are as defined in claim 1, with a compound of formula (VII)

in which R ₂ and R ₃ are as defined in claim 1 and L represents a leaving group or else a compound of general formula (VIII) is reacted

in which R _1; A, B, and X are as defined in claim 1, with either a halide alkyl d ¹ of the general formula (IX) or an aldehyde or ketone of general formula (X) in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride and optionally in the presence of a Lewis acid such as titanium tetrachloride, or either an acid chloride of general formula (XI), the carbonyl then being reduced by a mixed hydride of lithium and aluminum in tetrahydrofuran, in which R ₂ and R ₃ are as defined above,

(IX) (X) (XI) in which R ₂ and R ₃ are as defined in claim 1. 3. Medicament, characterized in that it consists of a compound according to claim 1. 4. Pharmaceutical composition characterized in that it comprises a compound according to claim 1 and one or more suitable excipients.