EP1150972A1

EP1150972A1 - Triazole and tetrazole derivatives, and their therapeutic use

Info

Publication number: EP1150972A1
Application number: EP00900674A
Authority: EP
Inventors: Jean Bertin; Philippe R. Bovy; Gilles Courtemanche; Olivier Crespin; Gérard Defosse; Eykmar Fett
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1999-02-02
Filing date: 2000-01-28
Publication date: 2001-11-07
Also published as: JP2002539085A; WO2000046220A1; CO5140090A1; FR2789077A1; AU3060400A

Abstract

The invention concerns compounds of formula (I) wherein: the pair (A, B) represents (N, N), (N, C) or (C, N); n = 0 if A represents a nitrogen atom, if not, n = 1; m = 0 if B represents a nitrogen atom, if not m = 1; R1 and R2 independently of each other, represent a hydrogen atom, a C1-C6 alkyl, a C2-C6 alkenyl, or a cyclo C3-C6 alkyl group; Ar1 represents a phenyl radical or a pyridyl radical substituted by the groups R3, R'3 and R''3; Ar2 represents a phenyl radical substituted by the groups R4 and R' 4', wherein R3, R'3, R''3, R4 and R'4, independently of one another, represent a hydrogen atom, a halogen atom, a C1-C4 alkyl, hydroxy, a C1-C4 alkoxy, a cyano, a nitro, a perfluoro C1-C2 alkyl, an amino, a C1-C4 alkylamino, a di-(C1-C4 alkyl)-amino, a C1-C4 alkoxycarbonyl amino, a (C1-C4 alkoxycarbonyl) (C1-C4 alkyl)-amino, aminosulphonyl, a C1-C4 alkyl-aminosulphonyl or a di(C1-C4 alkyl)-aminosulphonyl group; and their salts, N-oxides and hydrates. Said compounds have therapeutic applications.

Description

DERIVATIVES OF TRIAZOLES AND TETRAZOLES, AND THEIR USES IN

THERAPEUTIC

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

Consequently, the first subject of the present invention is derivatives of perazoles (triazoles and tetrazoles) of general formula (I):

in which,

the pair (A, B) represents (N, N), (N, C) or (C, N),

n = 0 if A represents a nitrogen atom, otherwise n = l, m = 0 if B represents a nitrogen atom, otherwise m = l,

R ₂ and R ₂ represent, independently of one another, a hydrogen atom, a group C _l . ₆ alkyl, C ₂ _ ₆ alkenyl or cyclo C ₃ _ ₆ alkyl,

Ar ₂ represents a phenyl radical or a pyridyl radical substituted by the groups R ₃ , R ' ₃ and R " ₃ ,

Ar ₂ represents a phenyl radical substituted by the groups R ₄ and R ' ₄ ,

where R ₃ , R ' ₃ , R " ₃ , R ₄ and R' ₄ represent, independently of one another, a hydrogen atom, a halogen atom, a C ^ alkyl, hydroxy, C ^ alkoxy, cyano, nitro, perfluoro-Cχ- ₂ alkyl, amino, C _x _ ₄ alkyl-amino, d C ^ alkyl) - amino, C -, ..- alkoxycarbonyl-amino, alkoxycarbonyl) (C ... alkyl) -amino, aminosulfonyl, C ^ alkyl-aminosulfonyl or di (Ci. ₄ alkyl) -aminosulfonyl, as well as their salts, N-oxides and hydrates. The preferred compounds according to the invention are chosen from the following subgroups, in which:

R _λ and R ₂ represent, independently of each other, a hydrogen atom, a C ^ alkyl, C ₂ _ ₄ alkenyl or cyclo C ₃ _ ₆ alkyl group, or

R _3ι R ' _{3 <} R " ₃ , R ₄ and R' ₄ represent, independently of one another, a hydrogen atom, a halogen atom, a C ^ alkyl, hydroxy, C ^ alkoxy group , nitro, amino, C _x _ ₄ alkyl-amino, (C ^ alkoxycarbonyl) (C ^ alkyl) -amino, aminosulfonyl, more particularly R ₃ R ' ₃ and R " ₃ represent a hydrogen when Ar _x is a pyridine.

A particularly preferred subgroup of compounds of formula (I) is that in which R _1r R ₂ , R _3, R ' _3, R " ₃ , R ₄ and R' ₄ are as defined above in the sub- groups of preferred compounds and A, B, Ar _: and Ar ₂ are as defined above.

In particular, the following subgroup of compounds is particularly preferred:

R ₂ and R ₂ represent, independently of one another, a hydrogen atom, a methyl, ethyl, propyl, isopropyl, vinyl, a cyclopropyl or cyclobutyl and R _3; R ' ₃ and R " ₃ represent, independently of one another, a hydrogen atom, a halogen atom, a C ^ alkyl group preferably a methyl, ethyl, propyl or isopropyl; hydroxy, _τ . ₂ alkoxy, preferably methoxy, and R ₄ and R ′ ₄ represent, independently of one another, a hydrogen atom, a halogen atom, a hydroxy, a C _x _ ₂ alkoxy, nitro, amino group , (C ₃ _ ₄ alkoxycarbonyl) (C ^ alkyl) -amino, aminosulfonyl.

In the context of the present invention, the following compounds are preferred:

- 4- [[(3-Methyl-1-phenyl-1H-1,2,4-triazol-5-yl) oxy] methyl] -1- (phenylmethyl) piperidine;

- 1- (Phenylmethyl) -4- [[(1-phenyl-ltf-tetrazol-5-yl) oxy] methyl] piperidine; - 3- [[4- [[(1-Phenyl-ltf-tetrazol

-5-yl) oxy] methyl] piperidin-1-yl] methyl] phenol;

- 1- (3-Hydroxyphenyl) -3-methyl-5- [[1- (phenylmethyl) piperidin-4-yl] methoxy] - 1H-1, 2, 4-triazole; - 4- [[[1- (4-Methylphenyl) -1H-tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine;

- 4- [[[1- (4-Fluorophenyl) -1H-tetrazol-5-yl] oxyjmethyl] -1- (phenylmethyl) piperidine;

- 1- (2-fluorophenyl) -3-methyl-5- [[1- [(3-methoxyphenyl) ethyl] -piperidin-4-yl] methoxy] -

1H-triazole;

1- (2-fluorophenyl) -3-methyl-5-

[[1- [(3-hydroxyphenyl) methyl] -piperidin-4-yl] methoxy] -

Iff-triazole; - 1- (2-chlorophenyl) -3-methyl-5-

[[1- [(3-hydroxyphenyl) ethyl] -piperidin-4-yl] methoxy] -

2H-triazole;

- 1-phenyl-3-methyl-5-

[[1- [(3-aminosulphonylphenyl) methyl] -piperidin-4-yl] methoxy] -IH-triazole and

- 1-phenyl-3-methyl-5-

[[1- [3-aminophenylmethyl] -piperidin-4-yl] methoxy] -1H-triazole.

In the context of the present invention, the following definitions are intended:

- C _! _ _z (C ₂ - ₂ or C ₃ _ _z ), where z can take the values from 2 to 6, a carbon chain being able to have from 1 (2 or 3) to z carbon atoms,

- alkyl, a linear or branched saturated aliphatic group; for example, a group C ^ g alkyl represents a carbon chain of 1 to 6 carbon atoms, linear or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, etc; preferably methyl, ethyl, propyl, isopropyl, - perfluoroalkyl, an alkyl in which all the hydrogens have been replaced by fluorines,

cycloalkyl, a cyclic alkyl, for example, a C ₃ _ ₆ cycloalkyl group represents a cyclopropyl, cyclobutyl, cyclopentyl or a cyclohexyl, - alkenyl, a mono or polyunsaturated, linear or branched aliphatic group, preferably comprising 1 or 2 ethylenic unsaturations,

- alkoxy, an alkyloxy group with a saturated, linear or branched aliphatic chain, and

- halogen atom, fluorine, chlorine, bromine or iodine.

The term “leaving group” is intended to mean a group which can be easily cleaved from a molecule, with the departure of an electronic pair, by breaking a heterolytic bond. This group can thus be easily replaced by another group during a nucleophilic substitution reaction for example. Such a leaving group is for example a halogen, a mesylate group (-S0 ₂ CH ₃ ), triflate or tosylate

(-S0 ₂ C ₆ H ₄ CH ₃ ) and can be obtained according to methods known to those skilled in the art. Other examples of leaving groups as well as preparation references are given in "Advanced Organic Chemistry", J. March, 3rd Edition, Wiley Interscience, p. 310-316, p. 587.

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

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

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

A second subject of the present invention is processes for preparing the compounds of formula (I). Thus, these compounds can be prepared by methods, illustrated in the diagrams which follow, the operating conditions of which are conventional for a person skilled in the art.

According to scheme 1, the compounds of formula (I) can be obtained by condensation of a perazole of formula (II)

in which A, B, R _lr R ₂ , Ar _x , n and m are as defined above and X represents a leaving group,

with the alcoholate of a compound of in which Ar ₂ is as defined above. The alcoholate is preformed by the action of a non-nucleophilic base such as sodium hydride, in an organic solvent such as dimethylformamide (DMF) or 1-methyl-2-pyrrolidinone (NMP) and at temperatures between -10 and 120 ° C.

Diagram 1

(II) (l)

For the triazoles of formula (II, A = N, B = C), X will preferably be a mesylate group.

(II, A = N, B = C)

For the triazoles of formula (II, A = C, B = N), X will preferably be a chlorine atom or a mesylate.

(ll, A = C, B = N), A = C, B = N) For tetrazoles, X will preferably be a chlorine atom or a mesylate group.

(ll _I A = N _I B = N, X = CI) (ll, A = N, B = N, X = -S0 ₂ CH ₃ )

The triazoles of formula (II, A = C, B = N), in which X represents a mesylate group, can be prepared according to routes 1 and 2 presented in scheme 2.

The triazoles of formula (II, A = C, B = N), in which R _x represents a hydrogen atom, can be prepared from the compounds of formula (IV) in which R _x represents a hydrogen atom and which are obtained according to channel 1.

According to route 1, a compound of formula is reacted

A ^ NHNI ^, in which Ar _x is as defined above, with formamide according to the method described in Heterocycle, 23 (7), 1645-9, (1985), to obtain a compound of formula (III), which is then thiomethylated by successive action of butyllithium at -78 ° C in tetrahydrofuran (THF) for one hour and dimethyldisulfide, thus leading to the compound of formula (IV) in which R _x represents a hydrogen atom.

Alternatively, the triazoles of formula (II, A = C, B = N), in which R _τ represents a C ₁ _ ₆ alkyl, C ₂ _ ₆ alkenyl or cyclo C ₃ - ₅ alkyl, are prepared from the compounds of formula (IV), in which R _x is as defined above, and which are obtained according to route 2. Diagram 2

TRACK 1 TRACK 2

An-NH-NH, An-NH-NH,

HCI

H NCH0 R CHO NaSCN

oxidation

According to route 2, a compound of formula Ar ₁ NHNH ₂ , in which rj is as defined above, is reacted with an aldehyde of formula RiCHO, in which R _x is as defined above, in an acid medium such as hydrochloric acid and in the presence of sodium thiocyanate, to obtain a compound of formula (V) which is then oxidized by the action of oxygen in the presence of sodium hydroxide, to give a compound of formula (VI) (Bull Soc. Chim. Jpn., 46 (7), 2215-18, (1973)). The compound of formula (VI) is then methylated by successive action of sodium hydride and methyl iodide in dimethylformamide (DMF) at 0 ° C, thus leading to the compound of formula (IV) in which R _x is as defined above.

The compounds of formula (IV) are then oxidized to sulfone by the action of an oxidant such as hydrogen peroxide, metachloroperbenzoic acid (MCPBA) or Oxone® in the presence of wet alumina at the reflux of chloroform to lead to triazoles of formula (II, A = C, B = N).

The triazoles of formula (II, A = C, B = N), in which X represents a chlorine atom, can be synthesized according to scheme 3.

According to this scheme, a nitrile of formula (XV), in which R _α is as defined in formula (I), is reacted with absolute ethanol in the presence of gaseous hydrochloric acid to lead to the alkylimidate of formula (XVI) according to the method described in J. Am. Chem. Soc, 1825, (1942). The alkylimidate of formula (XVI) thus obtained is N-carbethoxylated, according to the method described in J. Med. Chem., 36, 2558, 1993, with ethyl chloroformate in dichloromethane in the presence of triethylamine. This N-carbethoxyalkylimidate is then reacted with a hydrazine of formula (XVIII), in which Ar _x is as defined above, (according to Angel. Chem. 75, 918 (1963)) in toluene at a temperature of approximately 50 ° C and then in the presence of triethylamine at a temperature of approximately 90 ° C to yield the triazolone of formula (XIX). This the latter is heated to reflux of the phosphorus oxychloride in the presence of phosphorus pentachloride to obtain the derivative of formula (II) (II, A = C, B = N, X = C1).

Diagram 3

II, A = C, B = N, X = CI XIX

The triazoles of formula (II, A = N, B = C), in which X represents a mesylate group, can be prepared according to scheme 4.

Diagram 4

H ₃ C ^ O-CH 3

H ₃ C ^N ° - CH, oxidation

(VII) (IX) (II, A = N, B = C)

According to scheme 4, a compound of formula (VII) in which Ar ₂ is as defined above is reacted with a compound of formula (VIII) in which R ₂ is such as defined above to obtain a compound of formula (IX) (J. Het. Chem, 17, 1077, (1980)). This is then oxidized to sulfone, in the same way as the compounds of formula (IV) previously described, to lead to the triazoles of formula (II, A = N, B = C).

The tetrazoles of formula (II, A = N, B = N, X = C1), in which X represents a chlorine atom, can be prepared according to routes 1, 2 and 3 presented in scheme 5.

According to route 1, the amine of formula Ar _x NH ₂ in which Ar _x is as defined above is amidified by formic acid (Organic Syntheses, Coll. Vol. 3, 479-83) to obtain a compound of formula (X). The latter is transformed into isonitrile (XI) according to the method described in Synthesis 400-2, (1985), then into chlorotetrazole of formula (II, A = N, B = N, X = C1) according to the method described in J. Org. Chem., 60,468-9, (1995).

According to route 2, the compounds of formula (II, A≈N, B = N, X = C1) are prepared from arylisothiocyanates of formula ArjNCS, in which Ar _x is as defined above, according to the method described in Synth, common, 27 (15), 2645-50, (1997).

According to route 3, the compounds of formula (II, A = N, B = N, X = C1) are prepared from arylisocyanates of formula Ar _x NCO in which Ar _x is as defined previously according to the method described in Tetrahedron 42 (10), 2677-84 (1986).

Diagram 5

TRACK 1 TRACK 2 TRACK 3

Ai ^ NH _j A ^ NCS A NCO

(ll, A = N, B = N, X = CI) The tetrazoles of formula (II, A = N, B = N, X = -SOCH ₃ ), in which X represents a mesylate group, can be prepared according to scheme 6.

Diagram 6

(ll, A = N, B = N, X = -S0 ₂ CH ₃ )

According to scheme 6, the arylisocyanate of formula Ar _x NCS is reacted with activated sodium triazide, at reflux of water according to the method described in Can. J. Chem., 37 _. , 101-109 (1959), to obtain a compound of formula (XII). The compound of formula (XII) is then methylated by successive action of sodium hydride and methyl iodide in dimethylformamide (DMF) at 0 ° C to obtain a compound of formula (XIII) which is oxidized from the same way as the compounds of formula (IV) previously described thus leading to a compound of formula (II, A = N, B = N, X = -S0 ₂ CH ₃ ).

On the other hand, the compounds of formula (I), in which Ar ₂ represents a phenyl radical as defined for the compounds of formula (I), but preferably where R ₄ or R ′ ₄ represent a hydrogen atom or an electron donor group, can be modified to lead to other derivatives of formula (I) as indicated in scheme 7. According to scheme 7, the compounds of formula (I), in which A, B, R ,, R ₂ , Ar _lr n and m are as defined in formula (I) and Ar ₂ is as defined above, are debenzylated by the action of ammonium formate at the reflux of methanol in the presence of a catalytic amount of palladium on carbon to lead to the derivatives of formula (XIV). Alternatively, the debenzylation reaction can be carried out by the action of hydrogen in a solvent such as methanol or ethanol in the presence of a catalytic amount of palladium on carbon and optionally hydrochloric acid.

These compounds of formula (XIV) can then be rebenzylated, according to methods known to those skilled in the art, for example, by the action of a benzyl halide of formula Ar ₂ CH ₂ X, in which X represents a leaving group, preferably a halogen, and Ar ₂ represents a phenyl radical substituted by at least one group R ₄ or R ′ ₄ different from that of the starting compound, in the presence of a proton-accepting amine, such as a triethylamine or a diisopropylethylamine , or a mineral base such as potassium carbonate and in solvents such as ethanol, dimethylformamide (DMF) or toluene, or else by reductive amination by means of an aromatic aldehyde of formula Ar ₂ CH0 in which Ar ₂ is as defined above, in the presence of hydrochloric acid and sodium cyanoborohydride and in methanol or ethanol.

Diagram 7

(XIV)

(D

The compounds of formula (XIV) in which A, B, R _lr R ₂ ,

Ar _x , n and m are as defined above, are new and form part of the invention.

On the other hand, in the case of compounds of formula (I) where Ar _x and Ar ₂ represent a phenyl radical substituted respectively by the functional groups R ₃ , R ' ₃ and R " ₃ , and R ₄ and R' ₄ , can be oxidized, reduced, alkylated or dealkylated, these functional transformation reactions can be carried out by conventional methods known to those skilled in the art to give other compounds of formula (I).

The starting compounds, in particular the compounds (XV), (XVI) (XVII), (XVIII), Ar _! NH ₂ , Ar ^ NCS, A ^ NCO, Ar ₂ CHO, Ar ₂ CH ₂ X are commercially available or described in the literature, or can be prepared by methods described therein or which are known to man of career. The following examples illustrate the methods and techniques used for the preparation of this invention, without however limiting the scope of the claim. Elementary micro-analyzes and NMR, IR or mass spectra confirm the structures of the compounds obtained.

Example 1: 1-Phenyl-1H-1, 2, 4-triazole

25 g of phenylhydrazine and 31.1 g of formamide are heated at reflux for 15 hours. After cooling, taking up in dichloromethane, washing with water and drying over sodium sulfate, the mixture is concentrated to dryness. The product is distilled at 70 ° C under 10 ^"1 mmHg to yield 7.34 g of crystals.

Example 2: 5- (Methylthio) -1-phenyl-1H-1,2,4-triazole.

7.34 g of 1-phenyl-1H-1,2,4-triazole dissolved in 95 ml of anhydrous tetrahydrofuran are cooled to -65 ° C. 35 ml of butyllithium (1.6 N / hexane) are poured in dropwise and the mixture is stirred for 1 hour. 5 ml of dimethyldisulfide dissolved in 5 ml of tetrahydrofuran are then added and the mixture is stirred for 2 hours. The mixture is left to return to ambient temperature, hydrolysis, extract with ethyl acetate, washing with water and drying over sodium sulfate. After concentration, the mixture is purified by flash chromatography on silica gel, eluting with a 99: 1 mixture of dichloromethane: heptane to obtain 7.8 g of oil.

Example 3: 5- (Methylsulfonyl) -1-phenyl-1H-1,2,4-triazole.

7.8 g of 5- (methylthio) -1-phenyl-1H-1,2,4-triazole are dissolved in 200 ml of chloroform. Are successively added 75 g of Oxone ^® and 41 g of alumina previously moistened with 8.2 ml water. The mixture is brought to reflux for 16 hours and filtered. The precipitate is washed twice with chloroform and then taken up with a 9: 1 mixture of tetrahydrofuran: methanol and drained. The combined filtrates are concentrated and purified by flash chromatography on silica gel, eluting with a 99: 1 mixture of dichloromethane: heptane to obtain 5.16 g of a crystalline solid (Mp = 111 ° C).

Example 4: 5-Methyl-2-phenyl-2,5,5-dihydro-lf-1,2,4-triazole -3-thiol.

Protected from light, we add successively in

550 ml of 0.25M hydrochloric acid, 20 g of phenylhydrazine hydrochloride and 11.2 g of sodium thiocyanate. 6.1 g of acetaldehyde are poured in slowly and the mixture is stirred for 16 hours. After filtration and washing with water, 16.3 g of a white precipitate are obtained which are immediately used in the oxidation step (Example 5).

Example 5: 5-Methyl-2-phenyl-2,4,4-dihydro-3H- 1,2,4-triazole

-3-thione.

16.3 g of

5-methyl-2-phenyl-2, 5-dihydro-lf-1,2,4-triazole-3-thiol are dissolved in 2 L of IN sodium hydroxide. Oxygen is bubbled for 5 hours then acidified to pH = 1 with 4N hydrochloric acid. The precipitate formed is filtered, washed with water and dried over phosphorus pentoxide to yield 8.76 g of solid (Mp = 180 ° C).

Example 6: 3-Methyl-5- (methylthio) -1-phenyl-1H-1,2,4-triazole.

To a solution of 1.32 g of 95% sodium hydride in 50 ml of dimethylformamide, a solution of 8.7 g of 5-methyl-2-phenyl-2,4-dihydro-3H is added at 0 ° C. -1,2,4-triazole-3-thione in 50 ml of dimethylformamide. After completion of the evolution of hydrogen, 6.8 g of methyl iodide in solution in 15 ml of dimethylformamide are added. After one hour of stirring at room temperature, we throw on 11 a mixture of water and ice and extracted with ethyl acetate. Dried over sodium sulfate and concentrated to obtain 9.5 g of oil.

Example 7: 3-Methyl-5- (methylthio) -4-phenyl-4H-1,2,4-triazole.

8 g of N-phenylhydrazinecarbothioamide and 15 g of N, N-dimethyl acetamide dimethylacetal are heated to reflux in 45 ml of dioxane for 1.5 hours. After concentration, it is purified by flash chromatography on silica gel, eluting with a 98: 2 mixture of dichloromethane: methanol. The precipitate obtained is taken up in ethyl ether, triturated, drained and dried under vacuum to yield 5.65 g of crystalline product (mp = 118 ° c).

Example 8 4- [[(3-Methyl-1-phenyl-1H-1,2,2,4-triazol-5-yl) oxy] methyl] -1- (phenylmethyl) piperidine.

0.94 g of sodium hydride in solution in 25 ml of dimethylformamide and 3.2 g of 1-phenylmethyl-piperidin-4-yl-methanol are heated at 75 ° C for one hour. After returning to room temperature, 3.5 g of 3-methyl-5- (methylsulfonyl) -1-phenyl-ltf-1, 2, 4-triazole are added and the reaction mixture is stirred for two hours. Hydrolyzed, extracted with ethyl acetate and dried over sodium sulfate. After concentration, purification is carried out by flash chromatography on silica gel, eluting with a 97: 3: 0.3 mixture of dichloromethane: methanol: ammonia to obtain 4.26 g of oil (which is salified in the form of sesquifumarate). Example 9 1- (Phenylmethyl) -4- [[(1-phenyl-1H-tetrazol-5-yl) oxy] methyl] piperidine N

0.82 g of sodium hydride in solution in 25 ml of dimethylformamide and 2.8 g of 1-phenylmethyl-piperidin-4-yl-methanol are heated at 75 ° C for one hour. After returning to ambient temperature, 5 g of 5-chloro-1-phenyl-1fl ^" -tetrazole are added and the reaction mixture is stirred for two hours. The mixture is hydrolyzed, extracted with ethyl acetate and dried over sodium sulfate. After concentration, it is purified by flash chromatography on silica gel, eluting with a 98: 2: 0.2 mixture of dichloromethane: methanol: ammonia to obtain 6.5 g of oil (which is salified in the form of sesquifumarate).

Example 10: 4- [[(1-Phenyl-ltf-tetrazol-5-yl) oxy] methyl] piperidine.

6.5 g of 1- (phenylmethyl) -4- [[(1-phenyl-1H- tetrazol-5-yl) oxy] methyl] piperidine and 12 g of ammonium formate are cooled to 0 ° C in 130 mL methanol. 5.8 g of 10% palladium in charcoal are added and the mixture is brought to reflux for 1.5 hours. After filtration and concentration, the mixture is basified with 1Ν sodium hydroxide, extracted with ethyl acetate and dried over sodium sulfate. After concentration, 2.87 g of solid is obtained (mp = 105 ° C.).

Example 11 3- [[4- [[((1-Phenyl-1H-tetrazol -5-yl) oxy] methyl] piperidin-1-yl] methyl] phenol.

2.87 g of

4- [[(1-phenyl-1H-tetrazol-5-yl) oxy] methyl] piperidine and 0.8 g of l-chloromethyl-3-hydroxybenzene are agitated during 20 hours in 20 ml of dimethylformamide. After hydrolysis, extraction with ethyl acetate, drying over sodium sulphate and concentration, the mixture is purified by flash chromatography on silica gel, eluting with a dichloromethane: ethanol: ammonia mixture; 97: 3: 0.3. 0.72 g of solid is thus obtained (mp = 140 ° C.).

Example 12 1- (3-Hydroxyphenyl) -3-methyl-5- [[1- (phenylmethyl) piperidin-4-yl] methoxy] - 1H-1, 2, 4-triazole.

To a solution of 0.43 g of 1- (3-methoxyphenyl) -3-methyl-5- [[1- (phenylmethy1) piperidin-4-y1] methoxy] -liï-1, 2, -triazole (compound n 23) in 3 ml of dichloromethane, 0.24 ml of 5N hydrochloric acid in isopropanol is added. The solution is evaporated to dryness, then the residue obtained is taken up in 15 ml of dichloromethane. After the slow addition at -15 ° C of 0.42 ml of 99% boron tribromide (BBr ₃ ), the solution is stirred at room temperature for 3 hours, then poured into ice water. The pH of the solution obtained is brought to 8 with 1M sodium hydrogen carbonate. After extraction with ethyl acetate, washing with water, drying over magnesium sulphate, filtration, and evaporation, the mixture is purified by chromatography on silica gel, eluting with a gradient of the dichloromethane: methanol: ammonia mixture of 99: 1: 0.1 to 98: 2: 0.2. 0.33 g of solid is thus obtained.

Example 13: N- (4-Methylphenyl) hydrazinecarboxamide,

To a solution of 10.15 g of hydrazine monohydrate in emulsion in 125 ml of ether, a solution of 24.3 g of l-isocyanato-4-methylbenzene is slowly added in

125 ml of ether. After 3 hours of stirring, filtered, washed with ethyl acetate and dried at 45 ° C and under vacuum with phosphorus pentoxide. After purification by chromatography on a silica gel column (eluent = dichloromethane: methanol; 95: 5 -> 80: 20), 4.31 g of ocher crystals are obtained.

Example 14: Azide (-methylphenyl) carbamic.

To a suspension of 4.3 g of

N- (4-methylphenyl) hydrazinecarboxamide in 26 ml of IN hydrochloric acid, a solution of 1.82 g of sodium nitrate in 11 ml of water is slowly added at 15 ° C. After 1 hour of stirring, it is filtered, washed with water, dried at 30 ° C. and under vacuum with phosphorus pentoxide. 4.04 g of ocher crystals are obtained.

Example 15: 5-Chloro-1- (4-methylphenyl) -2f-tetrazole.

To a suspension of 1.76 g of azide (4-methylphenyl) carbamic acid in 5 ml of trichlorethylene, a suspension of 2.59 g of phosphorus pentachloride in 5 ml of trichlorethylene is rapidly added. After stirring overnight at 55 ° C., it is allowed to return to ambient temperature, then it is made alkaline with sodium hydrogen carbonate, extracted with chloroform and dried with sodium sulfate. After purification by chromatography on a silica gel column (eluent = heptane: ethyl acetate; 93: 7 -> 90: 10), 0.31 g of brown crystals is obtained.

Example 16 4- [[[1- (4-Methylphenyl) -1H-tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine.

The procedure described in Example 8 is carried out using 52 mg of sodium hydride, 0.443 g of l-phenylmethyl-piperidin-4-ylmethanol and 0.3 g of 5-chloro-1- (4-methylphenyl ) -2H-tetrazole. After purification by chromatography on a silica gel column (eluent = dichloromethane: methanol; 97.5: 2.5), 0.158 g of product is obtained in the form of an orange oil (which is salified in the form of ^" fumarate, mp = 161-162 ° C.).

Example 17: 1- (4-Fluorophenyl) -liT-tetrazole-5-thiol.

A solution of 15 g of sodium triazide in 45 ml of water is added with 1.5 ml of hydrazine hydrate. After crystallization from acetone, filtration, washing with acetone, drying under vacuum under a stream of nitrogen, 11.95 g of activated nitrogen triazide are obtained.

15.32 g of 1-fluoro-4-isothiocyanatobenzene and 9.75 g of activated sodium triazide in 200 ml of water are brought to reflux for 6 hours. After overnight at room temperature, the mixture is filtered and the filtrate is recovered, which is acidified with stirring using 35% hydrochloric acid until pH = 3 to 5.2. Filtered again, washed with water, and dried with phosphorus pentoxide to obtain 17.38 g of white crystals (Mp = 159-160 ° C).

Example 18: 1- (4-Fluorophenyl) -5- (methylthio) -1H- tetrazole.

Under argon, 0.555 g of 95% sodium hydride in 10 ml of dry dimethylformamide are cooled to 0 ° C., then slowly added with 3.92 g of

1- (4-fluorophenyl) -lϋf-tetrazole-5-thiol in 15 ml of dry dimethylformamide. The mixture is then slowly added with 3.12 g of methyl iodide and left at room temperature with gentle stirring. After precipitation with water, it is filtered, washed with water and dried to obtain 4.35 g of white crystals.

Example 19: 1- (4-Fluorophenyl) -5- (methylsuifonyl) -1H-tetrazole.

18 g of alumina are added with 3.6 ml of water to constitute wet alumina. Under argon, a solution of 4.25 g of 1- (4-fluorophenyl) -5- (methylthio) -ltf-tetrazole 37 g of Oxone® and 21.6 g of wet alumina are added to 87 ml of chloroform. The mixture is brought to 60 ° C. with stirring overnight and then added with 37 g of Oxone®. After 3 hours and thirty minutes of stirring, the mixture is cooled to 40 ° C, then filtered, washed with chloroform and tetrahydrofuran / methanol (90/10), concentrated. After purification by chromatography on a silica gel column (eluent = dichloromethane: methanol; 100: 0 -> 98: 2 -> 95: 5), 2.342 g of fraction are obtained in the form of an orange sulfone oil and 1, 56 g of fraction in the form of orange crystals of tallow oxide.

Example 20 4- [[[1- (-Fluorophenyl) -ltf- tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine,

Under argon, 0.35 g of sodium hydride in 17 ml of dry dimethylformamide is slowly added with 2.26 g of l-phenylmethyl-piperidin-4-yl-methanol in 17 ml of dry dimethylformamide. After 40 minutes at 80 ° C., and cooling to 0 ° C., 2.23 g of 1- (4-fluorophenyl) -5- (methylsulfonyl) -ltf-tetrazole in 17 ml of dimethylformamide are added dropwise. return to room temperature. After concentration, the residue is taken up in a mixture of water, concentrated ammonia and ethyl acetate, then after decantation, the aqueous phase is taken up in ethyl acetate, the organic phases are combined and dried over sodium sulfate and concentrated. After purification by chromatography on a silica gel column (eluent = dichloromethane: methanol; 97: 3), 0.86 g of product is obtained in the form of an orange oil.

Example 21: 5-Methyl-2-phenyl-2,4-dihydro-3tf-1,2,4-triazole -3-one.

1) 29g (234 mmol) of ethyl acetimidate hydrochloride are dissolved in 600mL of dichloromethane and cooled to -15 ° C. 68mL (491 moles) of triethylamine are then added dropwise, then 23.6mL (246mmoles) of ¹ ethyl chloroformate. The reaction medium is stirred at room temperature for 15 h and then filtered. The precipitate is washed with pentane, which causes a second precipitation. The operation is repeated until there is no precipitation. The filtrate is concentrated to yield 27.2 g of a colorless oily liquid carbethoxymetylimidate.

2) To 8.1 g (49.8 mmol) of 2-fluorophenylhydrazine hydrochloride in suspension in 50 ml of chloroform, 0.1N sodium hydroxide is added until basic pH (8-9). After decantation and extraction with chloroform, dried over sodium sulfate, and concentrated in vacuo. This gives 6.3g of a bister oil which crystallizes quickly. 15 ml of toluene are added under a nitrogen atmosphere, and 8.75 g (55 mmol) of the carbethoxymetylimidate previously obtained, dissolved in 30 ml of toluene, are added slowly. The reaction mixture is heated at 50 ° C for 2 h 45 min (dark red coloration). 7.6 ml (55 mmol) of triethylamine are then added, and the temperature is maintained at 65 ° C. for 16 h. After returning to ambient temperature, the reaction medium is concentrated to one third and taken up in 15 ml of pentane. After trituration, the precipitate formed is drained, washed with pentane, and dried under vacuum. There is thus recovered 7.07 g of an orange powder (Mp = 174-178 ° C).

Example 22: 5-chloro-3-Methyl-1-phenyl-ltf-1,2,4-triazole.

7g (36.2 mmol)

5-Methyl-2-phenyl-2,5-dihydro-ltf-1,2,4-triazole-3-one and 9 g (43.4 mmol) of phosphorus pentachloride are heated to reflux of 270 mL of oxychloride of phosphorus for 4 hours. After concentration, the reaction mixture is cooled in an ice bath, hydrolyzed with a water / ice mixture, and made alkaline at pH = 8-9. The aqueous phase is exhausted with ethyl acetate, and the organic phases combined dried over sodium sulfate, filtered and concentrated. 6.8 g of a brown oil are thus recovered.

Example 23: 1- (2-fluorophenyl) -3-methyl-5- [[1- [(3-methoxyphenyl) ethyl] -piperidin-4-yl] methoxy] - Itf-triazole.

11.3g (48mmol) of

1- [(3-methoxyphenyl) methyl] -4-hydroxymethyl-piperidine are cooled, under an inert atmosphere, in an ice bath in 60 ml of anhydrous dimethylformamide. 2.3 g (57.6 mmol) of sodium hydride (60% in oil) are added per portion, and the mixture is stirred at room temperature for 1 h. 6.8 g (32 mmol) of 5-chloro are then poured

3-Methyl-1-phenyl-ltf-1, 2, 4-triazole dissolved in 50 mL of dimethylformamide, and stirred at room temperature for 1 hour. The reaction medium is then neutralized using a saturated aqueous solution of ammonium chloride. The aqueous phase is exhausted with ethyl acetate, and the combined organic phases dried over sodium sulfate, filtered and concentrated. The crude is purified by chromatography on silica gel, eluting with a methanol gradient of 2 to 10% in dichloromethane. After concentration and drying under vacuum, 9.33 g of oil are thus recovered.

Example 24: 1- (2-fluorophenyl) -3-methyl-5-

[[1- [(3-hydroxyphenyl) methyl] -piperidin-4-yl] methoxy] - ltf-triazole.

To 9.2 g (22 mmol) of the methoxylated derivative of Example 23 dissolved in 70 ml of dichloromethane, 4.4 ml of a 0.1N hydrochloric acid solution in 1 isopropanol. After having stirred for a few minutes, it is concentrated to dryness (elimination of the alcohol), taken up in 220 ml of dichloromethane, and cooled in an ice bath, before slowly adding 10.4 L (110 mmol) of boron tribromide. Stirring is continued at room temperature for 2 hours, the reaction mixture is thrown on a mixture of water, ice and salt, and basified with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous phase is exhausted with ethyl acetate, and the combined organic phases washed with water, with brine, dried over sodium sulfate, filtered and concentrated. The crude is purified by chromatography on silica gel, eluting with a methanol gradient of 5 to 10% in dichloromethane. After concentration and drying under vacuum, 6.93 g of oil are thus recovered.

Example 25: 1- (2-fluorophenyl) -3-methyl-5- [[1- [(3-hydroxyphenyl) methyl] -piperidin-4-yl] methoxy] - ltf-triazole hydrochloride

6.92 g (17.45 mmol) of base are dissolved in 3.7 ml of hydrochloric acid (5-6 N) in isopropanol. After having stirred for a few minutes, 25 ml of diethyl ether are added, which causes precipitation of 1- (2-fluorophenyl) -3-methyl-5- [[1- [(3-hydroxyphenyl) methyl] -piperidin-4 hydrochloride]. -yl] methoxy] - ltf-triazole. (mp: 142 ° C)

Likewise, according to Examples 21 to 25, 1- (2-chlorophenyl) -3-methyl-5- [[1- [(3-hydroxyphenyl) ethyl] -piperidin-4-yl] methoxy] hydrochloride - ltf-triazole can be obtained. (mp: 168 ° C) Example 26: 1-phenyl-3-methyl-5-

[[1- [(4-aminosulphonylphenyl) methyl] -piperidin-4-yl [methoxy] -ltf-triazole.

2 ml of a solution of buthyllitiu in hexane (2.5 ml) are added dropwise to a solution of 1.6 mg of 1-phenyl-3-methyl-5-

[[1- [(4-bromophenyl) methyl] -piperidin-4-yl] methoxy] -ltf-triazole in 5 ml of tetrahydrofuran at -70 ° C. The reaction mixture is stirred for 1 hour then gaseous sulfoxide, dried by passage through sulfuric acid, is bubbled through this mixture until saturation. The white precipitate thus formed is filtered and washed with heptane and then with ethyl acetate. The residue is taken up in 40 ml of water and 1.3 g of sodium acetate and then 0.8 g of NH ₂ SO ₃ H is added. The reaction mixture is stirred overnight then extracted with ethyl acetate. The aqueous phase is made alkaline and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate and concentrated. The crude product is purified by chromatography on silica gel, eluting with ethyl acetate / methanol / ammonia 99 / 0.5 / 0.5.

Example 27: 1-phenyl-3-methyl-5- [[1- [3-aminophenylmethyl] -piperidin-4-yl] methoxy] -ltf-triazole.

To a solution of 1.2 g of 1-phenyl-3-methyl-5- [[1- [3-nitrophenylmethyl] -piperidin-4-yl] methoxy] -ltf-triazole is added a Raney nickel spatula at 50% in water then the reaction mixture is subjected to a hydrogen pressure of 50 psi (3300 HectoPascal) at room temperature in a Parr apparatus. After three hours of stirring, the reaction mixture is filtered through sodium sulfate and then celite. The filtrate is then concentrated to dryness. The crude product is purified by chromatography on silica gel, eluting with a gradient of methanol in ethyl acetate. 0.52 g is recovered in the form of a solid (mp: 108-110 ° C).

Example 28: 1-phenyl-3-methyl-5- [[1- [2,3-dihydroxyphenylmethyl] -piperidin-4-yl] methoxy] -ltf-triazole.

To a solution of 0.8 g 4- [[(1-Phenyl-3-methyl-ltf-triazol-5-yl) oxy] methyl] piperidine in 7 ml of methanol is added a solution of 0.1 hydrochloric acid N in isopropanol up to a pH 5-6 then 0.33 g of 2,3-dihydroxybenzaldehyde and 0.16 g sodium cyanoborohydride. The reaction mixture is stirred overnight at room temperature and then concentrated to dryness The residue is taken up in dichloromethane, washed twice with water. The organic phase is dried over sodium sulfate, concentrated in vacuo then the crude is purified by chromatography on silica gel, eluting with a gradient of methanol in ethyl acetate. The solid thus obtained is triturated in an ethyl acetate / ether mixture. 0.357 g is recovered in the form of a solid (mp: 150 ° C).

The following table illustrates the chemical structures and physical properties of certain compounds of formula

(I) according to the invention. These compounds were prepared according to the methods described above. Board

Ar _x = phenyl group (or pyridyle when indicated by "*" next to the number) substituted by R ₃ , R ' ₃ and R "₃;

R ' ₃ and R " ₃ are hydrogen atoms unless otherwise indicated in parentheses,

Ar ₂ = phenyl group substituted with R ₄ and R '₄; R ' ₄ is a hydrogen atom unless otherwise indicated in parentheses

In this table :

CH (CH ₂ ) ₂ = cyclopropyl, fum. = fumarate cit. = citrate ox. = oxalate chl. = hydrochloride

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

They have in particular been tested for their inhibitory effects on the binding of [ ³ H] -N-methyl-scopolamine with human M ₃ muscarinic receptors transfected into CHO (chinese hamster ovarian cells) cells (Buckley et al ., Mol. Pharmacol. 35: 469-476, 1989). Membranes of CHO cells, in solution in 10 m TRIS-HC1 buffer, 2 mM EDTA pH 7.2, expressing the human muscarinic receptor subtype 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 0.5 nM of [ ³ H] N-methyl-scopolamine (NEN-Dupont, Les Ulis , France), and of a compound of the invention, in a total volume of 1 ml. The non-specificity of the binding was determined by 0.5 μM of atropine (Sigma, St Louis, Mo). Incubation (60 min at 25 ° C) was stopped by rapid filtration on hatmann GF / B filters by a Brandel filtration device. The filters were washed three times with 4 ml of cold phosphate buffer, dried and the radioactivity was measured by liquid scintillation (scintillant Ultima Gold). The concentration of compound displacing 50% the specific bond (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 pKi of the compounds of the invention vis-à-vis the M ₃ receptors are between 6 and 9.5.

The compounds of the invention have also been studied as to their antagonistic effects with respect to the contractions of the female rabbit detrusor, mediated by the M ₃ receptors. Female rabbits (New Zealanders, 3-4 kg; ESD supplier) aged around 20 weeks were sacrificed by cervical dislocation and then bloodless. After opening the abdomen, the bladders were removed and then quickly placed in a bicarbonate solution of Krebs 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 (lμM), methylsergide (lμM), ondansetron

(lμM), GR113808 (lμM) were added to Krebs in order to inhibit the β-adrenergic receptors and the different serotonergic receptor subtypes 5- HT ₁ /5-HT ₂ , 5-HT ₃ and 5- respectively HT ₄ . The bladders were cleaned, degreased and each side was cut into two longitudinal flaps about 4 mm wide and 15 mm long. The tissues were then placed in 20 ml tanks 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 linked to a data acquisition system (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 performing a concentration-response range for carbachol at intervals of 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 ₂ ) 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 9.5.

The compounds of the invention have also been studied as regards their affinity with respect to 5-HT ₄ receptors in the guinea pig striatum, according to the method described by Grossman et al., In Br. J. Pharmacol., 109, 618-624 (1993). Guinea pigs (Hartley, Charles River) weighing 300 to 400 g are euthanized and their brains removed. The striata are excised and frozen at -80 ° C. 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 minutes 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. The incubation is stopped by filtration on hatman GF / B® filters, previously treated with 0.1% polyethyleneimine, each tube is rinsed with 4 ml of buffer at 0 ° C. and filtered again. The radioactivity retained on the filters is measured by liquid scintigraphy. The non-specific binding is determined in the presence of 30 μM 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 [ ³ H] GR118808 is determined, then the concentration of the compound tested which inhibits 50% of the specific binding (IC ₅₀ ).

The IC ₅₀ values of the compounds of the invention are between 1 and 3500 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-Da ley rats weighing 300 to 450 g are used. We quickly remove a fragment of about 1.5 cm from the end part of the esophagus, we eliminate the muscular layer, we open the inner muscular mucous membrane longitudinally, we mount it in a tank with isolated organ containing a Krebs solution -Henseleit at 32 ° C oxygenated by a carbogenic current (95% 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) from the esophageal tissue pre-contracted to the P μM substance. 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 muscarinic M ₃ and serotonergic 5-HT ₄ receptors.

They can therefore be used in the treatment of pathologies where a 5-HT ₄ and M ₃ receptor antagonist provides a therapeutic benefit. For example, they can be used in the treatment of irritable bowel syndrome, memory impairment, airway obstruction and bladder instability, especially emergency urinary incontinence.

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

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention. Thus, these pharmaceutical compositions contain an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt, N-oxide or hydrate thereof, and one or more suitable pharmaceutical excipients.

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

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

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

Each unit dose can contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of active ingredient in combination with one or more pharmaceutical excipients. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 0.5 to 2500 mg.

For example, when preparing a solid composition in 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 can be produced by different techniques, direct compression, dry granulation, wet granulation or hot melting.

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

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

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

Claims

claims

1. Compound of formula (I)

in which the pair (A, B) represents (N, N), (N, C) or (C, N), n = 0 if A represents a nitrogen atom, otherwise n = l, m = 0 if B represents a nitrogen atom, otherwise m = l,

R _x and R ₂ represent, independently of one another, a hydrogen atom, a Cι_ ₆ alkyl group, C ₂ . ₆ alkenyl or cyclo C ₃ _ ₅ alkyl,

Ar _x represents a phenyl radical or a pyridyl radical substituted by the groups R ₃ , R ' ₃ and R " ₃ ,

Ar ₂ represents a phenyl radical substituted by the groups

R ₄ and R ₄ , where R ₃ , R ' _3, R " ₃ , R ₄ and R' ₄ represent, independently of one another, a hydrogen atom, a halogen atom, a group C ₁ _ ₄ alkyl, hydroxy, C ^ alkoxy, cyano, nitro, perfluoroCχ. ₂ alkyl, amino, C ₁ _ _i alkyl-amino, di (C ^ alkyl) - amino, Cχ- ₄ alkoxycarbonyl-amino, (C ^ alkoxycarbonyl ) (C ^ alkyl) -amino, aminosulfonyl, C ^ alkyl-aminosulfonyl or di (Cχ- ₄ alkyl) -aminosulfonyl, as well as its salts, N-oxides and hydrates.

2. Compound according to Claim 1, characterized in that R _x and R ₂ represent, independently of one another, a hydrogen atom, a C ^ alkyl, C ₂ _ ₄ alkenyl or cyclo C ₃ - _{6 group.} alkyl, and

R ₃ _ R '_3; R " ₃ , R ₄ and R ' ₄ represent, independently of each other, a hydrogen atom, a halogen atom, a C _x _ ₄ alkyl, hydroxy, C _x _ ₄ alkoxy, nitro group , amino, C ^ alkyl-amino, (C ^ alkoxycarbonyl) {C _τ . _A alkyl) -amino, aminosulfonyl.

3. Compound according to one of claims 1 to 2, characterized in that:

R _λ and R ₂ represent, independently of one another, a hydrogen atom, a methyl, ethyl, propyl, isopropyl, vinyl, a cyclopropyl or cyclobutyl and

R _{3 /} R ' ₃ and R " ₃ represent, independently of each other, a hydrogen atom, a halogen atom, a C ^ alkyl group preferably a methyl, ethyl, propyl, isopropyl, hydroxy , C _x _ ₂ alkoxy preferably methoxy, and R ₄ and R ' ₄ represent, independently of one another, a hydrogen atom, a halogen atom, a hydroxy, a C ^ alkoxy, nitro group , amino, C _x _ ₂ alkyl-amino, (C ₃ _ alkoxycarbonyl) (C _x _ ₂ alkyl) -amino, aminosulfonyl.

4. Compound according to one of claims 1 to 3 characterized in that it consists of:

- 4- [[(3-Methyl-1-phenyl-ltf-1,2,4-triazol-5-yl) oxy] methyl] -1- (phenylmethyl) piperidine;

- 1- (Phenylmethyl) -4- [[(1-phenyl-ltf-tetrazol-5-yl) oxy] methyl] piperidine;

- 3- [[4- [[(1-Phenyl-ltf-tetrazol

-5-yl) oxy] methyl] piperidin-1-yl] methyl] phenol;

- 1- (3-Hydroxyphenyl) -3-methyl-5- [[1- (phenylmethyl) piperidin-4-yl] methoxy] -ltf-1, 2, 4-triazole;

- 4- [[[1- (4-Methylpheny1) -1tf-tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine;

- 4- [[[1- (4-Fluorophenyl) -ltf- tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine;

- 1- (2-fluorophenyl) -3-methyl-5-

[[1- [(3-methoxyphenyl) methyl] -piperidin-4-yl] methoxy] - ltf-triazole;

1- (2-fluorophenyl) -3-methyl-5- [[1- [(3-hydroxyphenyl) methyl] -piperidin-4-yl] methoxy] - ltf-triazole;

- 1-phenyl-3-methyl-5-

[[1- [(4-aminosulphonylphenyl) methyl] -piperidin-4-yl] methoxy] -ltf-triazole or

- 1-phenyl-3-methyl-5-

[[1- [3-aminophenylmethyl] -piperidin-4-yl] methoxy] - ltf-triazole.

5. Compound of formula (XIV)

wherein A, B, R _lf R ₂ , Ar _x , n and m are as defined in claim 1.

6. Process for the preparation of a compound according to claim 1, characterized in that the condensation of a compound of formula (II) is carried out

in which A, B, R _lr R ₂ , Ar _x , n and m are as defined in claim 1 and X represents a leaving group,

with the alcoholate of a compound of

wherein Ar ₂ as defined in claim 1

7. A method of preparing a compound of formula (I), according to claim 1, wherein A, B, R _x , R ₂ , Ar _x , Ar ₂ , n and m are as defined in claim 1 characterized in that a compound of formula (XIV) is reacted

in which A, B, R _:, R ₂ , Ar _τ , n and m are as defined in claim 1, with a benzyl halide of formula Ar ₂ CH ₂ X, in which X represents a leaving group and Ar ₂ represents a phenyl radical as defined in claim 1, or a reductive amination of the said compound of formula (XIV) is carried out by means of an aromatic aldehyde of formula Ar ₂ CHO in which Ar ₂ is as defined above.

8. Pharmaceutical composition characterized in that it contains a compound of formula (I) according to one of claims 1 to 4 in combination with one or more pharmaceutically acceptable excipients.

9. Use of a compound of formula (I) according to any one of claims 1 to 4 for the preparation of a medicament intended to treat a pathology where a 5HT ₄ and M ₃ receptor antagonist provides a therapeutic benefit.

10. Use of a compound of formula (I) according to one of claims 1 to 4, for the preparation of a medicament intended for the treatment of irritable colon, memory disorders, obstruction of the airways and bladder instabilities.

11. Use according to claim 10, characterized in that the bladder instability is emergency incontinence.