FR2789077A1 - PERAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

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

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Derivatives of perazoles. their preparation and their therapeutic use.

dans laquelle, le couple (A, B) représente (N,N), (N,C) ou (C,N), n=0 si A représente un atome d'azote, sinon n=l, m=0 si B représente un atome d'azote, sinon m=l, R1 et R2 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe C1-4 alkyle ou cyclo C3-6 alkyle, Ar1 représente un radical phényle substitué par les groupes R3 et R'3, Ar2 représente un radical phényle substitué par les groupes R4 et R'4, où R3, R'3, R, et R'4 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un atome d'halogène, un groupe hydroxy, C1-4 alcoxy, cyano, trifluorométhyle, C1-4 alkyle ou amino, Dans le cadre de la présente invention, on entend par : - C1-4, une chaîne carbonée pouvant avoir de 1 à 4 atomes de carbone, - alkyle, un groupe aliphatique saturé linéaire ou ramifié; par exemple, un groupe C1-4 alkyle représente une chaîne carbonée de 1 à 4 atomes de carbone, linéaire ou ramifiée, plus particulièrement un radical méthyle, éthyle, propyle, isopropyle, butyle, isobutyle et terbutyle, The subject of the present invention is perazole derivatives (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 = 1, m = 0 if B represents a nitrogen atom, otherwise m = 1, R1 and R2 represent, independently of each other, a hydrogen atom, a C1-4 alkyl or cyclo C3-6 alkyl group, Ar1 represents a radical; phenyl substituted by the groups R3 and R'3, Ar2 represents a phenyl radical substituted by the groups R4 and R'4, where R3, R'3, R and R'4 represent, independently of one another, a hydrogen atom, a halogen atom, a hydroxy group, C1-4 alkoxy, cyano, trifluoromethyl, C1-4 alkyl or amino, In the context of the present invention, the expression: - C1-4, a carbon chain having 1 to 4 carbon atoms; alkyl, a saturated linear or branched aliphatic group; for example, a C1-4 alkyl group represents a carbon chain of 1 to 4 carbon atoms, linear or branched, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl and terbutyl radical,

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 C 3 -C 6 cycloalkyl, a cyclic radical containing 3 to 6 carbon atoms, alkoxy, a linear or branched saturated aliphatic chain alkyloxy group, and halogen atom, a fluorine, a chlorine, a bromine or a iodine.

By leaving group is meant a group that can be easily moved during a substitution reaction.

groupe mésylate (-sotch3) , triflate ou tosylate (-SO2C6H4CH3) et peut être obtenu selon des méthodes connues de l'homme du métier. Such a leaving group is for example a halogen, a

mesylate group (-sotch3), triflate or tosylate (-SO2C6H4CH3) and can be obtained according to methods known to those skilled in the art.

The compounds of general formula (I) may comprise one or more asymmetric carbons. They can therefore exist as enantiomers or diastereoisomers.

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

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

The starting compounds are commercially available or described in the literature, or may be prepared by methods described therein or which are known to those skilled in the art.

The compounds of formula (I) according to the invention may be prepared by processes, illustrated in the following diagrams, the operating conditions of which are conventional to those skilled in the art.

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

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dans laquelle A, B, R1, R2, Ar1, n et m sont tels que définis précédemment et X représente un groupe partant,

avec l'alcoolate d'un composé de formule HO N ~~C Ar2 dans laquelle Ar2 est tel que défini précédemment.

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

with the alkoxide of a compound of formula HO N ~~ C Ar 2 in which Ar 2 is as defined above.

The alkoxide 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.

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

The triazoles of formula (II) in which A = C, B = N, Ar1, R1 and X are as defined above and the triazoles of formula (II) in which A = N, B = C and Ar1 are as defined previously and R2 represents a C1-4alkyl group,

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 are new and part of the invention. Among these compounds, the preferred ones are those for which X represents a mesylate group.

For the tetrazoles, X will preferably be a chlorine atom or a mesylate group.

The triazoles of formula (II, A = C, B = N), wherein X represents a mesylate group, can be prepared according to lanes 1 and 2 shown in Scheme 2.

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

According to route 1, a compound of formula Ar 1 NHHN 2, in which Ar 1 is as defined above, is reacted 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 dimethyl disulphide, thus leading to the compound of formula (IV) in which R 1 represents a hydrogen atom .

Alternatively, the triazoles of formula (II, A = C, B = N), in which R 1 represents a C 1-4 alkyl or cyclo C 3-6 alkyl group, are prepared from the compounds of formula (IV), in which R 1 represents a C 1-4 alkyl or cyclo C 3-6 alkyl group, and which are obtained according to route 2.

According to route 2, a compound of formula Ar1NHNH2 in which Ar1 is as defined above is reacted,

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 with an aldehyde of formula R1CHO, in which R1 represents a C1-4 alkyl or C36 alkyl cyclo group, in acidic 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, and a compound of formula (VI) is obtained (Bull Soc Chem 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 giving the compound of formula (IV) in which R 1 represents a C1-4 alkyl or C3-6 cycloalkyl group.

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 moist alumina refluxing chloroform to yield the triazoles of formula (II, A = C, B = N).

Selon le schéma 3, on fait réagir un composé de formule (VII) dans laquelle Ar1 est tel que défini précédemment avec un composé de formule (VIII) dans laquelle R2 est tel que défini précédemment pour obtenir un composé de formule (IX)(J. Het. Chem,17,1077, (1980)). Celui-ci est ensuite The triazoles of formula (II, A = N, B = C), in which X represents a mesylate group, can be prepared according to scheme 3

According to Scheme 3, a compound of formula (VII) in which Ar 1 is as defined above is reacted with a compound of formula (VIII) in which R 2 is as defined above to obtain a compound of formula (IX) (J) Het Chem, 17, 1077, (1980)). This one is then

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 oxidized to sulfone, in the same way as the compounds of formula (IV) described above, to give triazoles of formula (II, A = N, B = C).

The tetrazoles of formula (II, A = N, B = N, X = Cl), in which X represents a chlorine atom, can be prepared according to routes 1,2 and 3 shown in scheme 4.

According to route 1, the amine of formula Ar1NH2 in which Ar1 is as defined above is amidated by formic acid (Organic Synthese, Coll.Vol.3,479-83) to obtain a compound of formula (X). The latter is converted to isonitrile (XI) according to the method described in Synthesis 400-2, (1985), then to chlorotetrazole of formula (II, A = N, B = N, X = C1) according to the method described in J. Org. Chem., 60, 488-9, (1995).

According to route 2, the compounds of formula (II, A = N, B = N, X = C1) are prepared from arylisothiocyanates of formula Ar1NCS in which Ar1 is as defined above according to the method described in Synth. 27 (15), 50 (1997).

According to route 3, the compounds of formula (II, A = N, B = N, X = C1) are prepared from arylisocyanates of formula Ar1NCO in which Ar1 is as defined previously according to the method described in Tetrahedron 42 ( 10), (1986).

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 5.

According to scheme 5, the arylisocyanate of formula Ar 1 CNS 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.

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pour obtenir un composé de formule (XIII) qui est oxydé de la même manière que les composés de formule (IV) précédemment décrits conduisant ainsi à un composé de

formule ( I I , A=N, B=N, X=-SOZCH3) .

to obtain a compound of formula (XIII) which is oxidized in the same manner as the compounds of formula (IV) previously described, thus giving a compound of

formula (II, A = N, B = N, X = -SOZCH3).

On the other hand, the compounds of formula (I), wherein Ar 2 represents a phenyl radical where R 4 and R '4 are a hydrogen atom, can be modified to yield other derivatives of formula (I) as indicated in Figure 6.

According to Scheme 6, the compounds of formula (I), in which A, B, R 1, R 2, Ar 1, n and m are as defined in formula (I) and Ar 2 represents a phenyl radical where R 4 and R '4 are a hydrogen atom, are debenzylated by the action of ammonium formate at reflux of methanol in the presence of a catalytic amount of palladium on charcoal to give the derivatives of formula (XIV).

These compounds of formula (XIV) can then be rebenzylated by the action of a benzyl halide of formula Ar 2 CH 2 X, in which X represents a halogen atom and Ar 2 represents a phenyl radical substituted by at least one R 4 or R 4 group representing a halogen atom, a group

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Les composés de formule (XIV) dans laquelle A, B, R1, R2 Ar1, n et m sont tels que définis précédemment, sont nouveaux et font partie de l'invention. hydroxy, C1-4 alkoxy, cyano, nitrile, trifluoromethyl or a C1-4 alkyl group, in the presence of a proton acceptor amine or a mineral base such as potassium carbonate and in solvents such as ethanol , dimethylformamide (DMF) or toluene, or by reductive amination by means of an aromatic aldehyde of formula Ar 2 CHO in which Ar 2 is as defined above, in the presence of hydrochloric acid and sodium cyanoborohydride and in methanol or ethanol.

The compounds of formula (XIV) in which A, B, R 1, R 2 Ar 1, n and m are as defined above are new and form part of the invention.

Moreover, in the case where Ar1, respectively Ar2, represent a phenyl radical substituted by the

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 functional groups R3 and R'3, respectively R4 and R'4, which can be oxidized, reduced, alkylated or dealkylated, these functional transformation reactions can be carried out by standard methods known to those skilled in the art.

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

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

25 g of phenylhydrazine and 31.1 g of formamide are refluxed for 15 hours. After cooling, taken up in dichloromethane, washed with water and dried over sodium sulphate, 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 solubilized in 95 ml of anhydrous tetrahydrofuran are cooled to -65 ° C. 35 ml of butyllithium (1.6 N / hexane) are added dropwise and stirred for 1 hour. 5 ml of dimethyl disulphide dissolved in 5 ml of tetrahydrofuran are then added and the mixture is stirred for 2 hours. Allowed to warm to room temperature, hydrolyzed, extracted with ethyl acetate, washed with water and dried over sodium sulfate. After concentration, purify 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

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 solubilized in 200 ml of chloroform. 75 g of Oxone * and 41 g of alumina, moistened with 8.2 ml of water, are added successively. Refluxed 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-dihydro-1H-1,2,4-triazole-3-thiol.

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

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

5-méthyl-2-phényl-2,5-dihydro-1H-1,2,4-triazole-3-thiol sont solubilisés dans 2 L de soude 1N. On fait barboter de l'oxygène durant 5 heures puis acidifie à pH = 1 avec de l'acide chlorhydrique 4N. Le précipité formé est filtré, lavé à l'eau et séché sur pentoxyde de phosphore pour conduire à 8,76 g de solide (Pf = 180 C).

16.3 g of

5-methyl-2-phenyl-2,5-dihydro-1H-1,2,4-triazole-3-thiol are solubilized in 2 L of 1N sodium hydroxide. It is bubbled oxygen for 5 hours and 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.

On 1.32 g of 95% sodium hydride dissolved in 50 ml of dimethylformamide, a solution of 8.7 g of

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 5-methyl-2-phenyl-2,4-dihydro-3H-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 stirring for one hour at room temperature, it is thrown on a mixture of water and ice and extracted with ethyl acetate. It is dried over sodium sulphate and concentrated to give 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 dimethyl acetal are refluxed in 45 ml of dioxane for 1.5 hours. After concentration, purify by flash chromatography on silica gel, eluting with a 98: 2 dichloromethane: methanol mixture. The precipitate obtained is taken up in ethyl ether, triturated, drained and dried in vacuo to yield 5.65 g of crystalline product (mp = 118 ° C.).

Example 8 (Compound No. 12) 4 - [[(3-Methyl-1-phenyl-1H-1,2,4-triazol-5-yl) oxy] methyl] -1- (phenylmethyl) piperidine.

(méthylsulfonyl)-1-phényl-1H-1,2,4-triazole sont ajoutés et le mélange réactionnel est agité durant deux heures. On hydrolyse, extrait à l'acétate d'éthyle et sèche sur sulfate de sodium. Après concentration, on purifie par chromatographie flash sur gel de silice en éluant avec un mélange 97 :3:0.3 dedichlorométhane:méthanol:ammoniaque pour obtenir 4,26 g d'huile (qui est salifiée sous forme de sesquifumarate).

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-1H-1,2,4-triazole are added and the reaction mixture is stirred for two hours. It is hydrolysed, extracted with ethyl acetate and dried over sodium sulphate. After concentration, purify by flash chromatography on silica gel, eluting with a 97: 3: 0.3 dichloromethane: methanol: ammonia mixture to obtain 4.26 g of oil (which is salified in the form of sesquifumarate).

Example 9 (non-compound): 1- (Phenylmethyl) -4 - [[(1-phenyl-1H-tetrazol-5-yl) oxy] methyl] piperidine.

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0.82 g of sodium hydride dissolved 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 cooling to room temperature, 5 g of 5-chloro-1-phenyl-1H-tetrazole is added and the reaction mixture is stirred for two hours. It is hydrolysed, extracted with ethyl acetate and dried over sodium sulphate. After concentration, purify by flash chromatography on silica gel, eluting with a 98: 2: 0.2 dichloromethane: methanol: ammonia mixture to obtain 6.5 g of oil (which is salified in the form of sesquifumarate).

Example 10: 4 - [[(1-Phenyl-1H-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 of methanol. 5.8 g of 10% palladium are added to the carbon and refluxed for 1.5 hours. After filtration and concentration, it is basified with 1N sodium hydroxide, extracted with ethyl acetate and dried over sodium sulfate. After concentration, 2.87 g of solid (mp = 105 ° C.) is obtained.

Example 11 (Compound No. 2): 3 - [[4- [(1-Phenyl-1H-tetrazol-5-yl) oxy] methyl] piperidin-1-yl] methyl] phenol.

4- [[(1-phényl-lH-tétrazol-5-yl)oxy]méthyl]pipéridine et 0,8 g de l-chlorométhyl-3-hydroxybenzène sont agités durant 20 heures dans 20 ml de diméthylformamide. Après hydrolyse, extraction à l'acétate d'éthyle, séchage sur sulfate de sodium et concentration, on purifie par chromatographie flash sur gel de silice en éluant avec un mélange dichlorométhane:méthanol:ammoniaque ; 97 :3:0.3. On obtient ainsi 0,72 g de solide (Pf = 140 C). 2.87 g of

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

[ [1- (phénylméthyl) pipér idin- 4 -yl]méthoxy] -1H-1, 2,4- Example 12 (Compound No. 26): 1- (3-Hydroxyphenyl) -3-methyl-5-

[[1- (phenylmethyl) piperidin-4-yl] methoxy] -1H-1,2,4-

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 triazole.

To a solution of 0.43 g of 1- (3-methoxyphenyl) -3-methyl-5- [[1- (phenylmethyl) piperidin-4-yl] methoxy] -1H-1,2,4-triazole (compound 20) in 3 ml of dichloromethane, 0.24 ml of 5N hydrochloric acid in isopropanol is added. The solution is evaporated to dryness and the residue obtained is taken up in 15 ml of dichloromethane. After slow addition at -15 C of 0.42 ml of 99% boron tribromide (BBr3), the solution is stirred at room temperature for 3 hours and 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 mixture of dichloromethane: methanol: ammonia 99: 1: 0.1 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 1-isocyanato-4-methylbenzene in 125 ml of ether is slowly added. After stirring for 3 hours, the mixture is filtered, washed with ethyl acetate and dried at 45 ° C. and under vacuum with phosphorus pentoxide. After purification by column chromatography on silica gel (eluent = dichloromethane: methanol, 95: 5-> 80: 20), 4.31 g of ocher crystals are obtained.

Yield (%) = 13.8.

Example 14 Azide (4-methylphenyl) carbamic acid

Has a suspension of 4.3 g of
N- (4-methylphenyl) hydrazinecarboxamide in 26 ml of 1N hydrochloric acid is slowly added, at 15 C, a solution of 1.82 g of sodium nitrate in 11 ml of water. After
Stirring for 1 hour, filtered, washed with water, dried at 30 ° C.

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Exemple 15 : 5-Chloro-1-(4-méthylphényl)-IH-tétrazole. and under vacuum by phosphorus pentoxide. 4.04 g of ocher crystals are obtained. Yield (%) = 88.2.

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

To a suspension of 1.76 g of (4-methylphenyl) carbamic azide 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, allowed to warm to room temperature, then basified with sodium hydrogencarbonate, extracted with chloroform and dried with sodium sulfate. After purification by column chromatography on silica gel (eluent = heptane: ethyl acetate, 93: 7-> 90: 10), 0.31 g of brown crystals is obtained.

Yield (%) = 16.

Example 16 (Compound No. 4): 4 - [[[1- (4-Methylphenyl) -1H-tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine.

The procedure described in Example 8 is carried out starting from 52 mg of sodium hydride, 0.443 g of 1-phenylmethyl-piperidin-4-ylmethanol and 0.3 g of 5-chloro-1- (4-methylphenyl). ) -LH-tetrazole. After purification by column chromatography on silica gel (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, Pf = 161-162 C).

Yield (%) = 28.2%.

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

A solution of 15 g of sodium triazide in 45 ml of water is added 1.5 ml of hydrazine hydrate.

After crystallization in acetone, filtration, washing with acetone, drying under vacuum under nitrogen flow, we obtain

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 11.95 g of activated nitrogen triazide.

15.32 g of 1-fluoro-4-isothiocyanatobenzene and 9.75 g of activated sodium triazide in 200 ml of water are refluxed for 6 hours. After one night at ambient temperature, the mixture is filtered and the filtrate is recovered which is acidified with stirring with 35% hydrochloric acid to pH = 3 to 5.2. It is 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. and then 3.92 g of 1- (4-fluorophenyl) -1H-tetrazole-5-thiol are added slowly to 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, filter, wash with water and dry to obtain 4.35 g of white crystals.

 Yield (%) = 100.

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

4,25 g de 1-(4-fluorophényl)-5-(méthylthio)-1H-tétrazole dans 87 ml de chloroforme est additionnée de 37 g d'Oxone# et 21,6 g d'alumine humide. Le mélange est porté sous agitation à 60 C pendant une nuit puis additionné de 37 g d'Oxone#. Après 3 heures et trente minutes d'agitation, le mélange est refroidi à 40 C, puis filtré, lavé au chloroforme et au tétrahydrofurane/méthanol (90/10), concentré. Après purification par chromatographie sur colonne de gel de silice (éluant = dichlorométhane:méthanol ; 100 :0 -> 98 :2 95 :5), obtient 2,342 g de fraction 18 g of alumina are added 3.6 ml of water to form wet alumina. Under argon, a solution of

4.25 g of 1- (4-fluorophenyl) -5- (methylthio) -1H-tetrazole in 87 ml of chloroform is added with 37 g of Oxone # and 21.6 g of wet alumina. The mixture is stirred at 60 ° C. overnight and then 37 g of Oxone # are added. After stirring for 3 hours and 30 minutes, the mixture is cooled to 40 ° C., then filtered, washed with chloroform and tetrahydrofuran / methanol (90:10), concentrated. After purification by column chromatography on silica gel (eluent = dichloromethane: methanol, 100: 0 -> 98: 2 95: 5), 2.36 g of fraction obtained

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 in the form of an orange oil and 1.56 g of fraction in the form of orange crystals.

Example 20 (Compound No. 6): 4 - [[[1- (4-Fluorophenyl) -1H-tetrazol-5-yl] oxy] methyl] -1- (phenylmethyl) piperidine.

de 1-phénylméthyl-pipéridin-4-yl-méthanol dans 17 ml de diméthylformamide sec. Après 40 minutes à 80 C, et refroidissement à 0 C, on ajoute goutte à goutte 2,23 g de 1-(4-fluorophényl)-S-(méthylsulfonyl)-lH-tétrazole dans 17 ml de diméthylformamide et on laisse revenir à température ambiante. Après concentration, le résidu est repris par un mélange d'eau, d'ammoniac concentré et d'acétate d'éthyle, puis après décantation, la phase aqueuse est reprise par de l'acétate d'éthyle, les phases organiques sont regroupées et séchées sur sulfate de sodium et concentrées. Après purification par chromatographie sur colonne de gel de silice (éluant = dichlorométhane:méthanol ; 97 :3), obtient 0,86 g de produit sous forme d'une huile orangée. Under argon, 0.35 g of sodium hydride in 17 ml of dry dimethylformamide are slowly added with 2.26 g

1-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) -S- (methylsulfonyl) -1H-tetrazole in 17 ml of dimethylformamide are added dropwise and the mixture is left to ambient temperature. After concentration, the residue is taken up in a mixture of water, concentrated ammonia and ethyl acetate, and after decantation, the aqueous phase is taken up in ethyl acetate, the organic phases are combined and dried over sodium sulphate and concentrated. After purification by column chromatography on silica gel (eluent = dichloromethane: methanol: 97: 3), 0.86 g of product is obtained in the form of an orange oil.

The following table illustrates the chemical structures and the physical properties of certain compounds of formula (I) according to the invention.

<Desc / Clms Page number 19>

Ari = groupe phényle substitué par R3 et R'3et R'3= H Ar2 = groupe phényle substitué par R, et R', et R', = H

Board

Ari = phenyl group substituted by R3 and R'3et R'3 = H Ar2 = phenyl group substituted by R, and R ', and R', = H

<Tb>
<tb> Point <SEP> of
<tb> N <SEP> A <SEP> B <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> salt <SEP> merge
<tb> (C)
<tb> 1 <SEP> N <SEP> N <SEP> - <SEP> - <SEP> H <SEP> H <SEP> fumarate <SEP> 146
<tb> 2 <SEP> N <SEP> N <SEP> - <SEP> - <SEP> H <SEP> 3-OH <SEP> - <SEP> 140
<tb> 3 <SEP> N <SEP> N- <SEP> - <SEP> 2-CH3 <SEP> H <SEP> fumarate <SEP> 153
<tb> 4 <SEP> N <SEP> N <SEP> - <SEP> - <SEP> 4-CH3 <SEP> H <SEP> fumarate <SEP> 161
<tb> 5 <SEP> N <SEP> N- <SEP> - <SEP> 2-F <SEP> H <SEP> fumarate <SEP> 121
<tb> 6 <SEP> N <SEP> N <SEP> - <SEP> - <SEP> 4-F <SEP> H <SEP> fumarate <SEP> 164
<tb> 7 <SEP> N <SEP> C <SEP> - <SEP> H <SEP> H <SEP> H <SEP> 128
<tb> 8 <SEP> N <SEP> C- <SEP> CH3 <SEP> H <SEP> H <SEP> oxalate <SEP> 85
<tb> 9 <SEP> N <SEP> C- <SEP> H <SEP> H <SEP> 3-OH <SEP> fumarate <SEP> 85
<tb> 10 <SEP> N <SEP> C- <SEP> CH3 <SEP> H <SEP> 3-OH <SEP> oxalate <SEP> 112
<tb> 11 <SEP> C <SEP> N <SEP> H- <SEP> H <SEP> H <SEP> oxalate <SEP> 178
<tb> 12 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> H <SEP> H <SEP> fumarate <SEP> 143
<tb> 13 <SEP> C <SEP> N <SEP> H- <SEP> H <SEP> 3 <SEP> -OH <SEP> - <SEP> 152
<tb> 14 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> H <SEP> 3-OH <SEP> fumarate <SEP> 83
<tb> 15 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> H <SEP> 3-OCH3 <SEP> fumarate <SEP> 148
<tb> 16 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 2-F <SEP> H <SEP> citrate <SEP> 75
<tb> 17 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 3-F <SEP> H <SEP> citrate <SEP> 83
<tb> 18 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 4-F <SEP> H <SEP> citrate <SEP> 80
<tb> 19 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 2-CH3 <SEP> H <SEP> citrate <SEP> 90
<tb> 20 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 3-CH3 <SEP> H <SEP> citrate <SEP> 75
<tb> 21 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 4-CH3 <SEP> H <SEP> Citrate <SEP> 85
<tb> 22 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 2-OCH3 <SEP> H <SEP> Citrate <SEP> 85
<tb> 23 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 3-OCH3 <SEP> H <SEP> citrate <SEP> 80
<tb> 24 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 4-OCH3 <SEP> H <SEP> Citrate <SEP> 80
<tb> 25 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 2-OH <SEP> H <SEP> citrate <SEP> 90
<tb> 26 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 3-OH <SEP> H <SEP> citrate <SEP> 95
<tb> 27 <SEP> C <SEP> N <SEP> CH, <SEP> - <SEP> 4-OH <SEP> H <SEP> Citrate <SEP> 85
<tb> 28 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> - <SEP> 2-OCH3 <SEP> 3-OCH3 <SEP> citrate <SEP> 80
<Tb>

<Desc / Clms Page number 20>

<Tb>
<tb> Point <SEP> of
<tb> N <SEP> A <SEP> B <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R, <SEP> salt <SEP> merge
<tb> (C)
<tb> 29 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 3-OCH3 <SEP> 3-OCH3 <SEP> citrate <SEP> 74
<tb> 30 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 2-OH <SEP> 3-OH <SEP> citrate <SEP> 90
<tb> 31 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 3-OH <SEP> 3-OH <SEP> citrate <SEP> 95
<tb> 32 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 2-F <SEP> 3-OCH3 <SEP> citrate <SEP> 75
<tb> 33 <SEP> C <SEP> N <SEP> CH3 <SEP> - <SEP> 2-F <SEP> 3-OH <SEP> citrate <SEP> 78
<tb> 34 <SEP> C <SEP> N <SEP> CH2CH3 <SEP> - <SEP> H <SEP> H <SEP> Citrate <SEP> 80
<tb> 35 <SEP> C <SEP> N <SEP> CH <SEP> (CH3) <SEP> - <SEP> H <SEP> H <SEP> citrate <SEP> 77
<tb> 36 <SEP> C <SEP> N <SEP> CH (CH2) 2 <SEP> - <SEP> H <SEP> H <SEP> citrate <SEP> 68
<Tb>
CH (CH2) 2 = cyclopropyl

<Desc / Clms Page number 21>

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

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

CHO cell membranes, in solution in 10 mM TRIS-HCl buffer, 2 mM EDTA pH 7.2, expressing the human muscarinic M3 receptor subtype were provided by Receptor Biology (Baltimore, USA).

10 to 30 g of membranes were incubated in a phosphate buffer, pH 7.4 (Sigma, St. Louis, MO) in the presence of 0.5 nM of [3 H] N-methyl-scopolamine (NEN-Dupont, the Ulis, France), and a compound of the invention, in a total volume of 1 ml. The non-specificity of the binding was determined by 0.5 M atropine (Sigma, St Louis, Mo).

Incubation (60 min at 25 C) was stopped by rapid filtration on Whatmann GF / B filters by a Brandel filtration device. The filters were washed three times with 4 ml 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% (ICso) was used to calculate the Ki values according to the ChengPrusoff equation. The efficiency of each product studied is expressed by the negative logarithm of their Ki (pKi).

The pKi of the compounds of the invention with respect to M3 receptors are between 6 and 8.

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

Female rabbits (New Zealanders, 3-4Kg, ESD provider) approximately 20 weeks old were sacrificed by

<Desc / Clms Page number 22>

 cervical dislocation then exsanguineous. After opening the abdomen, the bladders were removed and then quickly placed in a Krebs bicarbonate solution of composition (mM): NaCl: 114; KCl: 4.7; CaCl2: 2.5; MgSO4. 1,2; KH2PO4: 1.2; NaHCO3. 25,; ascorbic acid: 1.1; glucose: 11.7. Propranolol (1M), methylsergide (1M), ondansetron (1M), GR113808 (1M) were added to Krebs to respectively inhibit P-adrenergic receptors and the different serotonin 5HT1 receptor subtypes. The bladders were cleaned, degreased and each face was cut into two longitudinal flaps about 4 mm wide and 15 mm long.

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

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

After an equilibration period of 30 minutes, an initial contraction to carbachol (1M), a potent muscarinic agonist, was achieved. The tissues were then rinsed abundantly and after a further equilibration period of 30 minutes, the tissues were incubated for 30 minutes in the presence or absence of a compound of the invention to be studied (concentration 0.1 or 1 M) before Achieving a carbachol concentration-response range at intervals of half a log unit.

The concentrations producing half of the maximal effect (EC50 (M)) were calculated for each range (absence or presence of the compound to be studied), then the power of the

<Desc / Clms Page number 23>

 The compound to shift the carbachol response curve was determined by a calculation of the affinity of the antagonist (apparent pKb or pA2) according to the method of Furchgott (Handbook of Experimental Pharmacology, 1972, 283-335).

The pKb of the compounds of the invention are between 7 and 9.5.

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

Guinea pigs (Hartley, Charles River) were euthanized from 300 to 400 g and their brain removed. The striata are excised and frozen at -80 ° C. On the day of the experiment, the tissue is thawed at +4 ° C. in 33 volumes of 50 mM Hepes-NaOH buffer (pH = 7.4 at 20 ° C.) and homogenize using a Polytron # grinder. The homogenate is centrifuged for 10 minutes at 48,000xg, the pellet is recovered, resuspended and centrifuged again under the same conditions. The final pellet is suspended in HepesNaOH 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 Hepes-2 buffer. NaOH (50 mM, pH = 7.4), in the absence or in the presence of the test compound. The incubation is stopped by filtration on Whatman GF / B filters, previously treated with 0.1% polyethyleneimine, each tube is rinsed with 4 ml of buffer at 0 ° C. and filtered again. The radioactivity retained on the filters is measured by liquid scintigraphy. Nonspecific binding is determined in the presence of 30 M serotonin.

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

For each concentration of compound studied, the percentage inhibition of the specific binding of the

<Desc / Clms Page number 24>

 [3H] GR118808 then the concentration of test compound which inhibits 50% of specific binding (IC50).

The IC50's of the compounds of the invention are between 1 and 3500 nM.

Finally, the compounds of the invention have been studied for their antagonistic effects against 5-HT4 receptors in the rat esophagus.

Male Sprague-Dawley rats weighing 300 to 450 g are used. A fragment of about 1.5 cm from the end part of the esophagus is rapidly removed, the muscular layer is removed, the inner muscular mucous membrane is opened longitudinally and mounted in an isolated organ vessel containing a Krebs solution. -Henseleit at 32 C oxygenated by a carbogenous current (95% O2 and 5% CO2), and connected to an isometric transducer at a basal tension of 0.5 g.

The compounds are studied at a concentration of 1M. Their ability to displace the relaxation introduced by 5-HT (at concentrations of 0.1 nM) from the esophageal tissue pre-packed to the P 1 M substance is measured.

The compounds of the invention are active in this test.

The results of the biological tests show that the compounds of the invention are muscarinic M3 and serotoninergic 5-HT4 receptor antagonists.

They can therefore be used in the treatment of irritable bowel syndrome, memory problems, airway obstruction and bladder instability, especially urinary incontinence.

The compounds of the invention, in combination with suitable pharmaceutically acceptable excipients, may be presented in any form suitable for oral, vaginal, rectal or parenteral administration, such as tablets, dragees, capsules, capsules, suppositories, suspensions or solutions. drinkable or

<Desc / Clms Page number 25>

 injectable, and dosed to allow administration of 0.1 to 50 mg / kg per day.

Claims (7)

 in which the pair (A, B) represents (N, N), (N, C) or (C, N) n = 0 if A represents a nitrogen atom, otherwise n = 1, m = 0 if B represents a nitrogen atom, otherwise m = 1, R 1 and R 2 represent, independently of one another, a hydrogen atom, a C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl group, Ar 1 represents a phenyl radical substituted by the R 3 and R '3 groups, Ar 2 represents a phenyl radical substituted by the groups R 1 and R' 4, where R 3, R '3, R and R' represent, independently of one another, a hydrogen atom , a halogen atom, a hydroxy, C1-4 alkoxy, cyano, trifluoromethyl, C1-4 alkyl or amino group, and optionally in the form of an enantiomer, a diastereoisomer, or a mixture of these different forms, including a mixture of as well as addition salts with pharmaceutically acceptable acids and N-oxide derivatives of one of these forms.

 Claims 1. Compound of formula (I) 2. 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. <Desc / Clms Page number 27>  hence, Ho-CN - Ar 2 with the alkoxide of a compound of formula wherein Ar 2 as defined in claim 1.

 wherein A, B, R 1, R 2, Ar 1, n and m are as defined in claim 1 and X represents a group

3. Compound of formula (II)

 in which A = C, n = 1, B = N, m = 0, R1 represents a hydrogen atom, a C1-4 alkyl or C3-6 cycloalkyl group and X represents a leaving group, or in which A = N, n = 0, B = C, m = 1, R2 represents a C1-4 alkyl group and X represents a leaving group. 4. Process for the preparation of a compound of formula (I) according to claim 1, in which A, B, R1, R2, Ar1, n and m are as defined in claim 1 and Ar2 represents a substituted phenyl radical. by at least one R4 or R'4 group representing a halogen atom, a hydroxy, C1-4 alkoxy, cyano, nitrile, trifluoromethyl or a C4-4 alkyl group, characterized in that a compound of formula (XIV) <Desc / Clms Page number 28>  wherein A, B, R1, R2, Ar1, n and m are as defined in claim 1, with a benzyl halide of the formula Ar2CH2X, wherein X is a halogen atom and Ar2 is a phenyl radical substituted by at least one R4 or R'4 group representing a halogen atom, a hydroxy, C1-4 alkoxy, cyano, nitrile or trifluoromethyl group or a C1-4 alkyl group, or a reductive amination of said compound of formula (XIV) using an aromatic aldehyde of formula Ar 2 CHO wherein Ar 2 is as defined above.

5. Compound of formula (XIV)

 wherein A, B, R 1, R 2, Ar 1, n and m are as defined in claim 1. 6. Medicinal product characterized in that it contains a compound according to claim 1. 7. Pharmaceutical composition characterized in that it contains a compound according to claim 1 in association with any pharmaceutically acceptable excipient.