KR100474454B1 - 5-Phenyl-3-(Piperidin-4-yl)-1,3,4-Oxadiazol-2(3H)-One Derivatives for Use as 5HT4 or H3 Receptor Ligands - Google Patents

Abstract

A compound of formula (I) is disclosed.

Formula I

Wherein R ₁ is a (C _1-4 ) alkyl or (C _3-7 ) cycloalkylmethyl group and X ₁ is a hydrogen or halogen atom or a (C _1-4 ) alkoxy group or OR 1 and X ₁ together are a formula —OCH _{2 O-, -O (CH 2)} 2 -, -O (CH 2) 3 -, -O (CH 2) 2 O- or -O (CH _{2) 3} O- represents a group, X ₂ is a hydrogen atom Or an amino group, X ₃ is hydrogen or a halogen atom, R ₂ is a hydrogen atom or an optionally substituted (C _1-6 ) alkyl group, an optionally substituted phenyl (C _1-4 ) alkyl group on the phenyl ring, phenyl (C _{2- 3} ) alkenyl group, phenoxy (C _2-4 ) alkyl group, cyclo (C _3-7 ) alkylmethyl group, 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-indene Group having the general formula-(CH ₂ ) _n CO-Z, wherein the ₂ -yl group or n is a number 1 to 6 and Z is a piperidin-1-yl or 4- (dimethylamino) piperidin-1-yl group to be. The compounds may also be used to treat or prevent diseases involving 5-HTV and / or H 3 receptors, particularly in the central nervous system, gastrointestinal system, lower urinary system or cardiovascular system.

Description

5-phenyl-3- (piperidin-4-yl) -1,3,4-oxadiazol-2 (3H) -one derivative for use as a 5-HT4 or H3 receptor ligand {5-Phenyl-3 -(Piperidin-4-yl) -1,3,4-Oxadiazol-2 (3H) -One Derivatives for Use as 5HT4 or H3 Receptor Ligands}

The subject of the present invention is a compound corresponding to formula (I).

In the above formula

R 'represents a (C ₁ -C ₄ ) alkyl or (C₃-C ₇ ) cycloalkylmethyl group,

C₁ represents hydrogen or a halogen atom or a (C₁-C₄) alkoxy group, or

OR 'and X' together form of -OCH ₂ O-, -O (CH ₂ ) _2- , -O (CH ₂ ) _3- , -O (CH ₂ ) ₂ O- or -O (CH ₂ ) ₃ O- Represents a group,

X ₂ represents a hydrogen atom or an amino group,

X ₃ represents hydrogen or a halogen atom,

R ₂ is a hydrogen atom or a (C ₁ -C ₆ ) alkyl group or a phenyl (C ₁ -C ₄ ) alkyl group or a phenyl (C ₂ -C ₃ ) alkenyl group or phenoxy (C ₂ -C ₄ ) alkyl group or cyclo (C ₃ -C ₇ ) alkylmethyl group or 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl group or n represents the numbers 1 to 6 and Z is piperi 1-yl or 4- (dimethylamino) piperidin-1-yl group representing the formula - (CH _{2) n} represents a group of the CO-Z.

When R ₂ represents the general formula-(CH ₂ ) _n CO-Z, such groups are 4-oxo-4- (piperidin-1-yl) butyl group, 2- [4- (dimethylamino) piperidine -1-yl] -2-oxoethyl group, 4- [4- (dimethylamino) piperidin-1-yl] -4-oxobutyl group, 5- [4- (dimethylamino) piperidine-1- Il] -5-oxopentyl group or 6- [4- (dimethylamino) piperidin-1-yl] -6-oxohexyl group is preferable.

The compounds of the present invention may exist in the form of free bases or in addition salts with acids. Furthermore, some R ₂ substituents contain asymmetric carbon atoms; Thus the compounds may exist in the form of pure enantiomers or mixtures of enantiomers.

Although the structure is similar to that of the compounds of the present invention and probably has a similar therapeutic effect, the central heterocycle is 1,2,4-oxa instead of 1,3,4-oxadiazole-2 (3H) -one Compounds that are diazoles are described in patent application JP-06 157 518, summarized in CA 121 (23) 280649k.

According to the present invention, the compound of formula I can be prepared by the method shown in the following scheme.

An ester of formula II wherein R ₁ , X ₁ , X ₂ and X ₃ are as defined above and R ₃ is a methyl or ethyl group is reacted in the absence of solvent or with a hydrazine hydrate in a polar protic solvent such as ethanol The hydrazide of formula III is obtained and cyclized to oxidazole of formula IV by phosgene in aprotic solvent, for example dioxane or by phenyl chloroformate in aprotic solvent, for example in toluene. When X ₂ in formula (III) represents an amino group, the latter is reacted with phosgene and the resulting product is esterified with benzyl alcohol so that the amino group is protected by the benzyloxycarbonyl group. The oxadiazole of Formula IV is then reacted in the presence of triphenylphosphine and ethylazodicarboxylate, for example in a nonprotonic solvent such as tetrahydrofuran, R2 is as defined for Formula I but is other than a hydrogen atom. Or else react with a (1,1-dimethylethoxy) carbonyl protecting group piperidin-4-ol of formula (V), and if so, deprotect the nitrogen of the piperidine ring with trifluoroacetic acid and R _{When divalent} hydrogen atom represents the obtained compound, if desired, X is a leaving group or functional group, for example halogen atom, methanesulfonate or 4-methylbenzene, in the presence of triethylamine in an aprotic solvent such as acetonitrile. sulfonate group, or represents a carbonyl functional group R ₂ in the general formula R ₂ -X in the same is other than hydrogen as defined for formula ⅰ It is reacted with a conductor. In a special case where R ₂ represents a 2,3-dihydro-1H-indenyl group, reductive amination is carried out with the indanone corresponding to the compound of formula I in which R ₂ represents a hydrogen atom.

Starting esters of the formula (II) are known and described in particular in patent applications EP-0,231,139, EP-0,234,872, WO-8403281, WO-9316072 and WO-9419344.

Piperidin-4-ols of formula V are known from J. Mol. Pharmacol. , (1992) 41 (4), 718-726 and patent applications WO-9303725 and EP-0,309,043.

The preparation of some compounds according to the present invention is described in detail in the following examples. Component microanalysis and IR and NMR spectra demonstrate the structure of the compounds obtained. The numbers of the compounds shown in parentheses in the title correspond to those in the table given later.

Example 1 (Compound No. 1)

5- (4-amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4-yl) -1,3,4-oxadiazole-2 (3H) -one hydrobromide

1.1. Hydrazide of 4-amino-5-chloro-2-methoxybenzoic acid

51.5 g (0.239 mol) of methyl 4-amino-5-chloro-2-methoxybenzoate in a suspension in 460 ml of ethanol were introduced into a 1 l reactor. 119 g (2.39 mol) hydrazine hydrate were added over 15 minutes and the mixture was heated at reflux for 15 hours. The mixture was cooled using an ice bath and the precipitate was collected by filtration, rinsed with ethanol and dried at 80 ° C. for 2 hours 30 minutes under reduced pressure. This gave 47.5 g of product.

Melting point: 211 ° C.

1.2. Phenylmethyl [2-chloro-5-methoxy-4- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) phenyl] carbamate

37.7 g of hydrazide of 4-amino-5-chloro-2-methoxybenzoic acid in 1200 ml of dioxane in 3 l reactor over 1 hour at room temperature with magnetic stirring of 461 ml (0.875 mol) of 1.93 M phosgene solution in toluene 0.175 mol) in dropwise addition.

The mixture was stirred at rt overnight and then heated at 80 ° C. for 1 h. Excess phosgene was removed by passing argon stream through this temperature for 2 hours. Then 72 ml (0.7 mol) benzyl alcohol were added and heating continued at 100 ° C. for 1 hour. The mixture was cooled, concentrated under reduced pressure and the residue triturated in isopropyl ether. The solid obtained was collected by filtration and dried. This gave 60.3 g of product.

Melting point: 214 ° C.

1.3. Phenylmethyl [2-chloro-4- [4- [1-[(1,1-dimethylethoxy) carbonyl] piperidin-4-yl] -5-oxo-4,5-dihydro-1, 3,4-oxadiazol-2-yl] -5-methoxyphenyl] carbamate

15.03 g (40) in a solution in 200 ml tetrahydrofuran, 13.64 g (52 mmol) triphenylphosphine and 9.66 g 1-[(1,1-dimethylethoxy) carbonyl] piperidin-4-ol mmol) phenylmethyl [2-chloro-5-methoxy-4- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) phenyl] carbamate at 0 ° C. The mixture was introduced into a 500 ml three necked round bottom flask with stirring. 9.76 g (56 mmol) of ethyl azodicarboxylate were introduced and stirring was continued at 0 ° C. for 1 hour and at room temperature for 2 hours 30 minutes.

The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the solution washed several times with water, dried and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column eluting with a 30/70 (volume ratio) mixture of ethyl acetate and hexanes.

15 g of the compound was obtained in the form of a white solid.

Melting point: 140 ° C.

1.4. Phenylmethyl [2-chloro-4- (5-oxo-4- (piperidin-4-yl) -4,5-dihydro-1,3,4-oxadiazol-2-yl) -5- Methoxyphenyl] carbamate

6.52 g (12 mmol) of phenylmethyl [2-chloro-4- [4- [1-[(1,1-dimethylethoxy) carbonyl] piperidin-4-yl in solution in 140 ml dichloromethane ] -5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -5-methoxyphenyl] carbamate and 500 ml of 13.64 g (120 mmol) trifluoroacetic acid Was introduced into a three necked round bottom flask and the mixture was stirred at rt overnight.

Ice, then chloroform, then 25% aqueous ammonia solution was added and the organic phase was separated and the aqueous phase was extracted four times with chloroform. The organic phase was washed with saturated aqueous sodium chloride solution, dried and the solvent was evaporated under reduced pressure.

6.26 g of crude compound were obtained, which was used as such.

Melting point: 180 ° C.

1.5. 5- (4-amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4-yl) -1,3,4-oxadiazole-2 (3H) -one hydrobromide

1 g (2.8 mmol) phenylmethyl [2-chloro-4- (5-oxo-4- (piperidin-4-yl) -4,5-di dissolved in 5.8 ml of 33% hydrobromic acid in acetic acid Hydro-1,3,4-oxadiazol-2-yl) -5-methoxyphenyl] carbamate was placed in a 25 ml round bottom flask and the mixture was stirred at room temperature for 1 hour.

Diethyl ether was added and the precipitate was separated by filtration.

0.67 g of hydrobromide was obtained.

Melting point: 278-280 ℃

0.52 g of free base was recovered by treatment with an aqueous ammonia solution.

Example 2 (Compound No. 5)

5- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (cyclohexylmethyl) piperidin-4-yl] -1,3,4-oxadiazole-2 (3H )-On

2.01 ml (13.92 mmol) trimethylamine, then 0.92 g (5.2 mmol) cyclohexylmethyl bromide in 5 ml acetonitrile under magnetic argon with 1.13 g (3.48 in 40 ml acetonitrile at room temperature under argon atmosphere. mmol) of 5- (4-amino-5-chloro-2-methoxyphenyl) -3- (piperidin-4-yl) -1,3,4-oxadiazol-2 (3H) -one The solution was added continuously and the mixture was stirred at 70 ° C. for 2 days. The solvent was evaporated under reduced pressure, the residue was taken up in chloroform and the solution washed several times with water and dried, the solvent was evaporated under reduced pressure and the residue crystallized from acetone.

0.7 g of a white solid were obtained.

Melting point: 186.5-186.7 ° C.

Example 3 (Compound No. 9)

5- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (2-phenylethyl) piperidin-4-yl] -1,3,4-oxadiazole-2 ( 3H) -on

3.1. Phenylmethyl [2-chloro-5-methoxy-4- [5-oxo-4- [1- (2-phenylethyl) piperidin-4-yl] -4,5-dihydro-1,3, 4-oxadiazol-2-yl] phenyl] carbamate

1.84 g (4 mmol) of phenylmethyl [2-chloro-4- (5-oxo-4- (piperidin-4-yl) -4,5-dihydro-1, in suspension in 40 ml of acetonitrile, 3,4-oxadiazol-2-yl) -5-methoxyphenyl] carbamate and 1.67 ml (12 mmol) of triethylamine were placed in a 100 ml round bottom flask and 0.96 g (5.2 mmol) in 1 ml of acetonitrile. ) (2-bromoethyl) benzene was added and the mixture was heated at 60 ° C. for 3 h and additionally 0.3 ml of (2-bromoethyl) benzene were added and the mixture was heated at 80 ° C. overnight. The solvent was evaporated under reduced pressure, the residue was extracted three times with chloroform, the organic phase was washed several times with water, dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was eluted with an 80/20 (volume ratio) mixture of ethyl acetate and hexane. Purification by chromatography on the column.

2.18 g of pure compound was obtained in the form of a white solid.

Melting point: 150 ° C.

3.2. 5- (4-amino-5-chloro-2-methoxyphenyl) -3- [1- (2-phenylethyl) piperidin-4-yl] -1,3,4-oxadiazole-2 ( 3H) -on

2.18 g (3.87 mmol) of phenylmethyl [2-chloro-5-methoxy-4- [5-oxo-4- [1- (2-phenylethyl) dissolved in 7 ml of 33% hydrobromic acid solution in acetic acid Piperidin-4-yl] -4,5-dihydro-1,3,4-oxadiazol-2-yl] phenyl] carbamate was placed in a 100 ml round bottom flask and the mixture was stirred at room temperature for 3 hours. It was.

Diethyl ether was added and the precipitate was isolated by filtration.

1.73 g of hydrobromide were obtained.

The latter was taken up in water and chloroform and the mixture was neutralized by adding sodium hydroxide.

The organic phase was separated and the aqueous phase was extracted and subjected to conventional treatment to afford 1.44 g of compound in the form of a free base.

Melting point: 184.5 ° C.

Example 4 (Compound No. 2)

5- (4-amino-5-chloro-2-methoxyphenyl) -3- (1-methylpiperidin-4-yl) -1,3,4-oxadiazol-2 (3H) -one hydrochloride

4.1. Phenylmethyl [2-Chloro-4- [4- (1-methylpiperidin-4-yl) -5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -5-methoxyphenyl] carbamate

7.5 g of phenylmethyl [2-chloro-5-methoxy-4- (5-oxo-4,5-dihydro-1,3,4-oxadiazole-2- in suspension in 150 ml of tetrahydrofuran I) phenyl] carbamate, 6.82 g (26 mmol) triphenylphosphine and 2.3 g (20 mmol) 1-methylpiperidin-4-ol are placed in a 2.5 l round bottom flask and 4.39 g (28 mmol) Ethyl azodicarboxylate was added with magnetic stirring at 0 ° C. and stirring was maintained for 20 hours. The mixture was concentrated under reduced pressure, the residue was taken up in acetone and cooled to 0 ° C. and the precipitate was isolated by filtration.

5.02 g of the compound was obtained in the form of a white solid.

Melting point: 142 ° C.

4.2. 5- (4-amino-5-chloro-2-methoxyphenyl) -3- (1-methylpiperidin-4-yl) -1,3,4-oxadiazol-2 (3H) -one hydrochloride

2 g (4.23 mmol) of phenylmethyl [2-chloro-4- [4- (1-methylpiperidin-4-yl) -5-oxo-4,5-dihydro-1, dissolved in 20 ml of acetic acid, 3,4-oxadiazol-2-yl] -5-methoxyphenyl] carbamate was placed in a 100 ml round bottom flask and 20 ml of 33% hydrobromic acid in acetic acid was slowly added and the mixture was stirred at room temperature for 18 hours. . Diethyl ether was added and the solid was isolated by filtration.

2 g of hydrobromide was obtained.

It was dissolved in 30 ml of water and the solution was neutralized with sodium hydroxide and the precipitate was separated by filtration, washed with water and dried under reduced pressure.

1.05 g of compound was obtained in the form of a free base.

Melting point: 162 ° C.

Hydrochloride was obtained by treatment with hydrochloric acid in ethanol.

Melting point: 212-218 ° C.

Example 5 (Compound No. 19)

5- [4-amino-5-chloro-2- (cyclopropylmethoxy) phenyl] -3- (1-butylpiperidin-4-yl) -1,3,4-oxadiazole-2 (3H ) -One hydrochloride

5.1. Methyl 4-amino-5-chloro-2- (cyclopropylmethoxy) benzoate

29.1 g (0.120 mol) of 4-amino-5-chloro-2- (cyclopropylmethoxy) benzoic acid and 340 ml of methanol were introduced into a 1 l three necked round bottom flask, the solution was cooled to -40 ° C and 44 ml (0.602 mol) Thionylchloride was added dropwise and the mixture was heated with stirring for 1 h 30 min. The mixture was cooled, the solvent was evaporated, the residue was poured into water and aqueous sodium carbonate solution, extracted with dichloromethane, and the crude product was eluted with a 90/10 (volume ratio) to 80/20 (volume ratio) mixture of n-heptane and ethyl acetate. Purification was carried out by chromatography on a silica gel column.

8.3 g of compound were obtained in the form of a pale yellow solid.

Melting point: 115 ° C.

5.2. Hydrazide of 4-amino-5-chloro-2- (cyclopropylmethoxy) benzoic acid

6.0 g (23.5 mmol) of 4-amino-5-chloro-2- (cyclopropylmethoxy) benzoate and 54 ml of ethanol were introduced into a 250 ml round bottom flask and 118 g (235 mmol) hydrazine hydrate was added at 40 ° C. And the mixture was heated to reflux for 18 hours. The mixture was cooled in an ice bath and the precipitate was isolated by filtration, rinsed with ethanol and dried at 70 ° C. for 4 hours under reduced pressure.

4.7 g of compound was obtained.

Melting point: 172 ° C.

5.3. 5- [4-amino-5-chloro-2- (cyclopropylmethoxy) phenyl] -1,3,4-oxadiazol-2 (3H) -one

Introduce 2.0 g (7.8 mmol) of hydrazide of 4-amino-5-chloro-2- (cyclopropylmethoxy) benzoic acid, 17 ml of toluene and 1.9 ml (8.6 mmol) of phenyl chloroformate into a 100 ml round bottom flask And the mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature. 2.5 ml (16.4 mmol) triethylamine were added and the mixture was heated to reflux for 3 hours, cooled to room temperature, water was added and extraction was performed with chloroform. After the usual treatment and purification by chromatography on a silica gel column eluting with a 98/2 / 0.2 (volume ratio) mixture of aqueous chloroform, methanol and ammonia solution, 0.80 g of white solid was obtained.

Melting point: 153-154 ° C.

5.4. 5- [4-amino-5-chloro-2- (cyclopropylmethoxy) phenyl] -3- (1-butylpiperidin-4-yl) -1,3,4-oxadiazole-2 (3H ) -One hydrochloride

Preparation was carried out according to the method described in Example 4.1 to give the final compound 5- [4-amino-5-chloro-2- (cyclopropylmethoxy) phenyl] -1,3,4-oxadiazole-2 ( From 3H) -one and 1-butylpiperidin-4-ol in base form, treated with a hydrochloric acid solution in ethanol and recrystallized from ethanol to obtain a hydrochloride.

Melting point: 237-238 ° C.

Example 6 (Compound No. 28)

5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- (piperidin-4-yl) -1,3,4-oxa Diazol-2 (3H) -one hydrobromide

6.1. Ethyl 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylate

Slowly introduce 23.5 g (0.198 mol) of thionylchloride into a 2 l three necked round bottom flask containing 772 ml of ethanol cooled to -40 ° C. with stirring, maintaining stirring at this temperature for 1 hour and solution in 100 ml of ethanol 38.6 g (0.198 mol) of 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid was slowly added over 15 minutes and the mixture was returned to room temperature overnight.

The mixture was heated to reflux for 4 hours, the solvent was evaporated under reduced pressure, the residue was taken up in water and sodium carbonate and extraction was performed with chloroform. After washing, drying and evaporating the organic phase, 34.06 g of ester were obtained in the form of a white solid.

Melting point: 112 ° C.

6.2. Ethyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate

37 g (0.165 mol) of ethyl 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylate in a solution in 370 ml dioxane were introduced into a 1 l round bottom flask and 23.2 g (0.174) mol) N-chlorosuccinimide was added with magnetic stirring at room temperature and stirring was maintained overnight.

The mixture was diluted with water, extracted with ethyl acetate and treated with an organic phase to give 42 g of compound which was recrystallized from a mixture of diethyl ether and diisopropyl ether.

Melting point: 105-106 ° C.

6.3. Hydrazide of 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid

38.4 g (0.149 mol) of ethyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate in a suspension in 150 ml ethanol was introduced into a 1 l reactor and 149 g (2.98 mol) hydrazine hydrate was added over 15 minutes and the mixture was heated to reflux for 1 hour.

The mixture was cooled using an ice bath and the precipitate was collected by filtration, washed with ethanol and dried under reduced pressure.

33 g of compound was obtained.

Melting point: 227-231 ° C.

6.4. Phenylmethyl [6-chloro-8- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) -2,3-dihydro-1,4-benzodioxine -5-day] carbamate

32.6 g of hydrazide and 330 ml of dioxane of 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid are added to a 1 l reactor with magnetic stirring at room temperature 310 ml (0.4 mol) of 0.193 M phosgene solution in toluene was added dropwise to the suspension over 1 hour 30 minutes and the mixture was heated at room temperature overnight and refluxed for 5 hours.

Excess phosgene is removed by passing a stream of argon at this temperature for 2 hours and the mixture is cooled and concentrated under reduced pressure, the residue is poured into 200 ml of benzyl alcohol and heated at 100 ° C. overnight, the mixture is cooled and concentrated under reduced pressure and residual Water was triturated in diisopropylether. 52.6 g of compound were obtained after filtration and drying.

Melting point: 230 ° C.

6.5. Phenylmethyl [6-chloro-8- [4- [1-[(1,1-dimethylethoxy) carbonyl] piperidin-4-yl] -5-oxo-4,5-dihydro-1, 3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate

 8.07 g (20 mmol) phenylmethyl [6-chloro-8- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) -2,3-dihydro- 1,4-benzodioxin-5-yl] carbamate, 160 ml of tetrahydrofuran, 6.83 g (26 mmol) triphenylphosphine, 4.83 g (24 mmol) in 1-[(1,1-dimethyl Oxy) carbonyl] piperidin-4-ol, and then 4.52 g (26 mmol) of ethyl azodicarboxylate were introduced into a 250 ml three neck round bottom flask with magnetic stirring at 0 ° C. After stirring for 1 hour at 0 ° C. and 2 hours 30 minutes at room temperature, the mixture was concentrated under reduced pressure and the residue was recrystallized first from diethyl ether and second from ethyl acetate. 5.5 g of compound was obtained in the form of a white solid.

Melting point: 206 캜.

6.6. Phenylmethyl [6-chloro-8- (5-oxo-4- (piperidin-4-yl) -4,5-dihydro-1,3,4-oxadiazol-2-yl) -2, 3-dihydro-1,4-benzodioxin-5-yl] carbamate

5.3 g (9 mmol) of phenylmethyl [6-chloro-8- [4- [1-[(1,1-dimethylethoxy) carbonyl] piperidin-4-yl] -5-oxo-4, 5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate, 100 ml of dichloromethane and 10.3 g ( 90 mmol) of trifluoroacetic acid was introduced into a 250 ml three neck round bottom flask and the mixture was stirred at rt overnight.

The mixture was concentrated under reduced pressure, the residue was triturated in acetone, collected by filtration, washed with diethyl ether, slowly added 17 ml of 25% aqueous ammonia solution and extracted four times with chloroform. After washing with water and then saturated sodium chloride solution, drying and evaporating the solvent, 4.4 g of compound were obtained which was used as such in the next step.

Melting point: 128-130 ° C.

6.7. 5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- (piperidin-4-yl) -1,3,4-oxa Diazol-2 (3H) -one

3.68 g (27.5 mmol) of phenylmethyl [6-chloro-8- (5-oxo-4- (piperidin-4-yl) -4,5-dihydro-1,3,4-oxadiazole- 2-yl) -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate and 35 ml of acetic acid were introduced into a 50 ml round bottom flask and 11 ml of 33% hydrobromic acid in acetic acid were added and the mixture Was stirred at rt for 22 h. Diethyl ether was added to the formed precipitate and the precipitate was collected by filtration. 4 g of hydrobromide was obtained.

Melting point> 260 ° C.

The compound was recovered in the form of free base by treatment with sodium hydroxide.

Melting point: 213-215 ° C.

Example 7 : (Compound No. 37)

5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- [1-[[4- (trifluoromethyl) phenyl] methyl] Piperidin-4-yl] -1,3,4-oxadiazole-2 (3H) -one

60 ml of aceto at room temperature with magnetic stirring of 0.88 g (5.68 mmol) of 4- (trifluoromethyl) benzylbromide in a solution in 1.58 ml (11.38 mmol) of triethylamine and 5 ml of acetonitrile under an argon stream 1 g (2.84 mmol) of 5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- (piperidin-4-yl in nitrile The solution was added continuously to a solution of) -1,3,4-oxadiazole-2 (3H) -one and the mixture was stirred for 2 hours.

The solvent was evaporated under reduced pressure, the residue was taken up in chloroform and the solution washed several times with water, dried and the solvent was evaporated under reduced pressure.

The residue was crystallized from acetone to give 1.14 g of white solid.

Melting point: 198 ° C.

Example 8 (Compound No. 32)

5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- [1- (4,4,4-trifluorobutyl) piperi Din-4-yl] -1,3,4-oxadiazol-2 (3H) -one

8.1. Phenylmethyl [6-chloro-8- [5-oxo-4- [1- (4,4,4-trifluorobutyl) piperidin-4-yl] -4,5-dihydro-1,3 , 4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate

2 g (4.1 mmol) of phenylmethyl [6-chloro-8- (5-oxo-4- (piperidin-4-yl) -4,5-dihydro-1,3,4-oxadiazole-2 -Yl) -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate, 40 ml of acetonitrile and 2.3 ml (16 mmol) of triethylamine were introduced into a 100 ml round bottom flask and 1 ml 1.5 g (6.67 mmol) of 4,4,4-trifluorobutyl bromide in acetonitrile was added and the mixture was heated at 80 ° C. overnight.

The solvent was evaporated under reduced pressure and the residue was extracted three times with chloroform and the organic phase was washed, dried and evaporated. The residue was purified by chromatography on a silica gel column eluting with a 97/3 / 0.3 (volume ratio) mixture of dichloromethane, methanol and aqueous ammonia solution to give 2.4 g of the compound in the form of a white solid.

Melting point: 158 ° C.

8.2. 5- (8-amino-7-chloro-2, 3-dihydro-1, 4-benzodioxin-5-yl) -3- [1- (4, 4,4-trifluorobutyl) piperi Din-4-yl] -1,3,4-oxadiazol-2 (3H) -one

1.72g (2.88 mmol) phenylmethyl [6-chloro-8- [5-oxo-4- [1- (4,4,4-trifluorobutyl) piperidin-4-yl] -4,5 -Dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate and 17 ml of acetic acid in a 100 ml round bottom flask 5 ml of 33% hydrobromic acid in acetic acid was added and the mixture was stirred at room temperature for 7 hours. Diethyl ether was added to the formed precipitate and 1.8 g of hydrobromide was collected by filtration.

This was added to water and chloroform and sodium hydroxide was added to release basicity, and 1.19 g of compound was obtained after the usual treatment of the organic phase.

Melting point: 188 ° C.

Example 9 (Compound No. 29)

5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- (1-methylpiperidin-4-yl) -1,3, 4-oxadiazole-2 (3H) -one hydrobromide

9.1. Phenylmethyl [6-chloro-8- [4- (1-methylpiperidin-4-yl) -5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate

6.27 g (15.53 mmol) of phenylmethyl [6-chloro-8- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) in 80 ml of tetrahydrofuran in suspension ) -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate, 6.12 g (23.3 mmol) triphenylphosphine and 2.24 g (19.4 mmol) 1-methylpiperidine- 4-ol was introduced into a 250 ml round bottom flask and 4.06 ml (23.3 mmol) of ethyl azodicarboxylate was added slowly at 0 ° C. with stirring and the mixture was stirred for 48 h.

The mixture was concentrated under reduced pressure, the residue was poured into water, 1.6 ml of 37% hydrochloric acid, 60 ml of ethyl acetate was added, the mixture was stirred for 1 hour, and then extracted four times with ethyl acetate. The solvent was evaporated under reduced pressure, the residue was treated with aqueous ammonia solution up to pH = 10 and the precipitate was collected by filtration.

3.16 g of compound was obtained in the form of a white solid.

Melting point: 177 ° C.

9.2. 5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- (1-methylpiperidin-4-yl) -1,3, 4-oxadiazole-2 (3H) -one hydrobromide

1.71 g (3.41 mmol) of phenylmethyl [6-chloro-8- [4- (1-methylpiperidin-4-yl) -5-oxo-4,5-dihydro- in 30 ml of solution in acetic acid 1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate was introduced into a 100 ml round bottom flask and 33% hydrobromine in acetic acid. 3 ml of acid was added slowly and the mixture was stirred for 5 hours. Diethyl ether was added to the formed precipitate and the latter was collected by filtration.

1.72 g of hydrobromide were obtained.

Melting point: 248 ° C.

Example 10 (Compound No. 31)

5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- (1-butylpiperidin-4-yl) -1,3, 4-oxadiazole-2 (3H) -one hydrochloride

10.1. Phenylmethyl [8- [4- (1-butylpiperidin-4-yl) -5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -6-chloro -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate

Phenylmethyl [6-chloro-8- (5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) -2,3-dihydro-1,4-benzodioxine Preparation was carried out from -5-yl] carbamate and 1-butylpiperidin-4-ol as described in Example 9.1.

10.2. 5- (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl) -3- (1-butylpiperidin-4-yl) -1,3, 4-oxadiazole-2 (3H) -one hydrochloride

Phenylmethyl [8- [4- (1-butylpiperidin-4-yl) -5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -6-chloro Preparation was performed from -2,3-dihydro-1,4-benzodioxin-5-yl] carbamate and hydrobromic acid as described in Example 9.2 and treated with hydrochloric acid in ethanol to form hydrochloride. .

Melting point: 280-283 ° C.

Example 11 (Compound No. 62)

5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -3- (piperidin-4-yl) -1,3,4-oxadiazol-2 (3H) -one hydrochloride

11.1. Hydrazide of 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid

57.3 ml (1.18 mol) of hydrazide hydrate is added to 25.14 g (0.118 mol) of methyl 5-chloro-2,3-dihydrobenzofuran-7-carboxylate in a suspension in 300 ml of methanol and the mixture is 4 Heated under reflux for hours.

The mixture was cooled using an ice bath and the precipitate was collected by filtration, washed with ethanol and dried under reduced pressure.

24.34 g of compound were obtained.

Melting Point: 182 ℃

11.2. 5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -1,3,4-oxadiazol-2 (3H) -one

24.34 g (0.115 mol) of hydrazide of 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid and 500 ml of dioxane are introduced into a 1 l reactor with magnetic stirring at room temperature and 0.193 in toluene. 178 ml (0.343 mol) of M phosgene were added with a dropping funnel and the mixture was stirred at room temperature for 24 hours and then refluxed for 4 hours to remove excess phosgene.

The solvent was evaporated under reduced pressure and the residue was taken up in diethyl ether and collected by filtration and dried.

27 g of compound was obtained.

Melting point: 270 ° C.

11.3. 5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -3- [1-[(1,1-dimethylethoxy) carbonyl] piperidin-4-yl] -1, 3,4-oxadiazol-2 (3H) -one

20 g (0.08 mol) of 5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -1,3,4-oxadiazole-2 (3H) in a suspension in 250 ml tetrahydrofuran 10.06 g (0.05 mol) of 1-[(1,1-dimethylethoxy) carbonyl] piperidine- was introduced into a 500 ml three necked round bottom flask, cooled to 0 ° C. and placed under magnetic stirring. 4-ol, 18.36 g triphenylphosphine and 14.81 g (0.085 mol) ethyl azodicarboxylate were added and the mixture was stirred at rt for 4 h.

The mixture was concentrated under reduced pressure and the residue was recrystallized from a mixture of dichloromethane and diethyl ether.

14.7 g of a beige solid were obtained.

Melting point: 203 캜.

11.4. 5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -3- (piperidin-4-yl) -1,3,4-oxadiazol-2 (3H) -one hydrochloride

14.7 g (0.035 mol) 5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -3- [1-[(1,1-dimethylethoxy) carbonyl] piperidine- 4-yl] -1,3,4-oxadiazole-2 (3H) -one is dissolved in 150 ml of dichloromethane in a 500 ml round bottom flask, 26.8 ml of trifluoroacetic acid is added at 0 ° C. and the mixture is Stir at room temperature for 3 hours. 200 ml of water and 47 ml of 30% sodium hydroxide in 300 ml of water were added and the mixture was extracted with chloroform, the organic phase was dried and the solvent was evaporated under reduced pressure.

10.8 g of base were obtained in the form of a white solid.

Melting point: 180 ° C.

3.5 g of hydrochloride was obtained by treating 5 g of base with a solution of hydrochloric acid, a gas in ethanol.

Melting point:> 260 ° C.

Example 12 (Compound No. 67)

5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -3- [1- (2-phenylethyl) piperidin-4-yl] -1,3,4-oxadiazole -2 (3H) -one hydrochloride

2.5 g (7.77 mmol) of 5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -3- (piperidin-4-yl)-in a solution in 50 ml of butan-2-one 1,3,4-oxadiazole-2 (3H) -one was introduced into a 250 ml three necked round bottom flask, 2.87 g (15.5 mmol) of phenylethyl bromide and then 2.36 g (23.3 mmol) triethylamine were added. And the mixture was stirred at reflux for 20 hours. The precipitate formed was collected by filtration, the filtrate was evaporated under reduced pressure, the residue was poured into water and extracted twice with chloroform and the organic phase was evaporated under reduced pressure.

The residue was dissolved in a solution of hydrochloric acid, a gas in ethanol, diethyl ether was added and the precipitate was collected by filtration and recrystallized from ethanol. 2.0 g hydrochloride was obtained.

Melting point: 255-257 ° C.

Example 13 (Compound No. 65)

5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -3- (1-butylpiperidin-4-yl) -1,3,4-oxadiazole-2 (3H) -On

2.38 g (0.01 mol) of 5- (5-chloro-2,3-dihydrobenzofuran-7-yl) -1,3,4-oxadiazole-2 (3H in suspension in 80 ml of tetrahydrofuran) ) -One was introduced into a 250 ml three necked round bottom flask, cooled to 0 ° C. and under magnetic stirring 1.57 g (0.01 mol) of 1-butylpiperidin-4-ol, 3.41 g (0.013 mol) triphenyl Phosphine 2.44 g (0.014 mol) of ethyl azodicarboxylate were then added and the mixture was stirred at room temperature for 3 hours and then at 40 ° C. for 3 hours. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted five times with diethyl ether. The organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a silica gel column eluting with an 80/20 (volume ratio) mixture of ethyl acetate and heptane.

3 g of compound was obtained.

Melting point: 133.8-134 ° C.

Example 14 (Compound No. 71)

5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- (piperidin-4-yl) -1,3,4-oxadiazole-2 (3H) -Warm hydrochloride

14.1. Hydrazide of 6-chloro-3,4-dihydro-2H-benzopyran-8-carboxylic acid

72.8 ml (1.5 mol) of hydrazide hydrate is added to 34 g (0.15 mol) of methyl 6-chloro-3,4-dihydro-2H-benzopyran-8-carboxylate in a solution in 250 ml of ethanol and the mixture Heated at reflux for 8 h.

It was cooled using an ice bath and the precipitate was collected by filtration, washed with ethanol and dried under reduced pressure.

31 g of compound was obtained.

Melting point: 149 ° C.

14.2. 5- (6-Chloro-3,4-dihydro-2H-benzopyran-8-yl) -1,3,4-oxadiazol-2 (3H) -one

31 g (0.137 mol) of hydrazide of 6-chloro-3,4-dihydro-2H-benzopyran-8-carboxylic acid and 500 ml of dioxane are introduced into a 1 l reactor with magnetic stirring at room temperature and in toluene 212.7 ml (0.411 mol) of 0.139 M phosgene was added to the dropping funnel and the mixture was heated to reflux for 2 hours.

The precipitate was collected by filtration and dried.

26 g of compound was obtained.

Melting point: 246 ° C.

14.3. 5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- (piperidin-4-yl) -1,3,4-oxadiazole-2 (3H) -Warm hydrochloride

20 g (0.08 mol) of 5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -1,3,4-oxadiazole-2 in a suspension in 300 ml of tetrahydrofuran (3H) -one was introduced into a 500 ml three necked round bottom flask, cooled to 0 ° C. and placed under magnetic stirring to 15.94 g (0.08 mol) of 1-[(1,1-dimethylethoxy) carbonyl] piperi Din-4-ol, 35.36 g (0.134 mol) triphenylphosphine and 21.1 ml (0.134 mol) ethyl azodicarboxylate were added and the mixture was stirred at rt for 4 h. The mixture was concentrated under reduced pressure and the residue was dissolved in 250 ml of dichloromethane, the solution was cooled to 0 ° C. and 100 ml of trifluoroacetic acid was added and the mixture was stirred at rt for 2 h.

It was concentrated under reduced pressure, 100 ml of 1N aqueous hydrochloric acid solution was added, and the precipitate was collected by filtration and dried.

19 g of hydrochloride were obtained.

Melting point: 297 ° C.

Example 15 (Compound No. 77)

5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- [1- [4- [4- (dimethylamino) piperidin-1-yl] -4- Oxobutyl] piperidin-4-yl] -1,3,4-oxadiazole-2 (3H) -one hydrochloride

1 g (2.68 mmol) of 5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- (piperidin-4-yl)-in 50 ml of acetonitrile 1,3,4-oxadiazole-2 (3H) -one hydrochloride was introduced into a 250 ml three neck round bottom flask and 1.24 ml (5.36 mmol) of 1- (4-chloro-1-oxobutyl) -N, N -Dimethylpiperidin-4-amine and 1.12 ml (8 mmol) triethylamine were added and the mixture was stirred at rt overnight. The mixture was evaporated under reduced pressure and the residue was taken up in water and extracted three times with chloroform. The organic phase is dried over magnesium sulphate, filtered, the solvent is evaporated under reduced pressure and the residue is 98/2 (volume ratio) of dichloromethane and methanol, then 95/5 (volume ratio) and then silica gel eluting with a 90/10 (volume ratio) mixture Purification by chromatography on the column. A white solid was obtained, which was treated in a solution of hydrochloride, a gas in ethanol, recrystallized from ethanol, and finally 0.22 g of hydrochloride was isolated.

Melting point: 193 ° C.

Example 16 (Compound No. 74)

5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- [1- (1-methylethyl) piperidin-4-yl] -1,3,4- Oxadiazole-2 (3H) -one hydrochloride

0.5 g (1.34 mmol) of 5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- (piperidin-4-yl) -1,3,4-oxa Preparation was carried out as described in Example 15 from Diazol-2 (3H) -one hydrochloride and 0.378 g (1.34 mmol) of 1-bromo-1-methylethane to afford 0.33 g of compound.

Melting point: 241 ° C.

Example 17 (Compound No. 81)

5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- [1- (2,3-dihydro-1H-inden-2-yl) piperidine-4 -Yl] -1,3,4-oxadiazole-2 (3H) -one hydrochloride

1.0 g (2.68 mmol) of 5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- (piperidin-4-yl) -1,3,4-oxa Diazol-2 (3H) -one hydrochloride was added to a solution of 1.13 g (8.60 mmol) in 15 ml of methanol containing 0.169 ml of acetic acid and 0.709 g (1.13 mmol) of sodium cyanoborohydride at a temperature of 5 ° C. Was added and the mixture was stirred for 18 h.

15 ml of aqueous hydrochloric acid solution was added and stirred for 30 minutes before the mixture was neutralized with 2M aqueous sodium hydroxide solution.

The mixture was extracted with dichloromethane, the organic phase was separated, dried and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with a 98/2 (volume ratio) mixture of dichloromethane and methanol.

White solids were obtained, the hydrochlorides of which were prepared by conventional methods. 0.8 g of salt was isolated.

Melting point: 283-284 ° C.

Example 18 (Compound No. 75)

5- (6-chloro-3,4-dihydro-2H-benzopyran-8-yl) -3- [1- [5- [4- (dimethylamino) piperidin-1-yl] -5- Oxopentyl] piperidin-4-yl] -1,3,4-oxadiazole-2 (3H) -one fumarate (1: 2)

2.0 g (5.37 mmol) of 5- (6-chloro-3,4-dehydro-2H-benzopyran-8-yl)-in 75 ml of acetonitrile containing 2.24 ml (16 mmol) triethylamine 1.44 g (5.37 mmol) of 1- (5-chloro-1-oxopentyl)-with 3- (piperidin-4-yl) -1,3,4-oxadiazole-2 (3H) -one hydrochloride The suspension of N, N-dimethylpiperidin-4-amine was heated at reflux for 2 hours.

2.88 g (10.74 mmol) of additional 1- (5-chloro-1-oxopentyl) -N, N-dimethylpiperidin-4-amine were added and heating was maintained for 18 hours.

The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted with chloroform. After drying the organic phase the residue was purified by chromatography on a silica gel column eluting with a 98/2 (volume ratio) to 90/10 (volume ratio) mixture of dichloromethane and methanol. 0.4 g of product was obtained in the form of a base and its difumarate was prepared in a conventional manner.

Melting point: 127 ° C.

The chemical structures and physical properties of some compounds according to the invention are shown in the following table. In columns R ₁ and R ₂ , cC ₃ H ₅ represents a cyclopropyl group, cC ₆ H ₁₁ represents a cyclohexyl group, C ₆ H ₅ represents a phenyl group, and C ₆ C ₄ -nX is substituted with X in the n-position. A phenyl group, C ₆ H ₃ -m, nX ₂ is a phenyl group substituted with X at the m- and n-positions, and 1-C ₉ H ₉ is a 2,3-dihydro-1H-inden-1-yl group , 2-C ₉ H ₉ is a 2,3-dihydro-1H-inden-2-yl group, NC ₅ H ₁₀ is a piperidin-1-yl group, and NC ₅ H ₉ -4-N (CH ₃ ) ₂ represents a 4- (dimethylamino) piperidin-1-yl group.

In salt heat-indicates base, HBr indicates hydrobromide, HCl indicates hydrochloride, 2HCl indicates (1: 2) hydrochloride, fum. Indicates fumarate, 2fum. Indicates (1: 2) fumarate, tar Indicates tartrate.

M.p. In column (° C), (d) indicates the melting point with decomposition.

The compounds of the present invention were tested to demonstrate their benefits as substances with therapeutic activity.

So the compounds of the invention are described in Grossman et al. in Br. J. Pharmacol. , (1993) 109 , 618-624, their affinity for 5-HT ₄ receptors in guinea pig striatum was studied according to the methods described.

Guinea pigs weighing 300-400 g (Hartley, Charles River, France) were euthanized, brains removed, striatal sections dissected and frozen at -80 ° C.

On the day of the experiment, the tissues were thawed in 33 volumes of HEPES-NaOH buffer (50 mM, pH = 7.4 at 20 ° C.), homogenized using PolytronR mill and centrifuged at 48,000 g for 10 minutes. The pellet was recovered and resuspended and recentrifuged under the same conditions and the final pellet was resuspended in HEPES-NaOH buffer at a rate of 30 mg tissue per ml. 100 μl of this membrane suspension was added to the final volume of 1 ml of HEPES-NaOH buffer (50 mM, pH = 7.4) in the presence or absence of the test compound [ ³ H] GR113808 (ligand described in the cited paper, specific activity 80-85). Incubated at 0 ° C. for 120 minutes in the presence of Ci / mmol). Incubation was stopped by filtration through a Whatman GF / B filter pretreated with 0.1% polyethyleneimine, rinsed each tube with 4 ml of buffer at 0 ° C., filtered again and radioactivity retained on the filter was measured by liquid scintography. .

Nonspecific binding was determined in the presence of 30 μM serotonin. Specific binding showed 90% of the total radioactivity recovered on the filter.

For each concentration of study compound, the percent inhibition of specific binding of [ ³ H] GR113808, followed by IC ₅₀ , the concentration of test compound that inhibits 50% of specific binding.

IC ₅₀ values of the most active compounds are between 0.1 and 10 nM.

Compounds of the invention are also described in Baxter et al. in Naunyn schmied. Arch. Pharmacol ., (1991) 343 , 349, were studied by evaluating their agonist or antagonist effects on 5-HTV in the esophagus of rats. Male Sprague-Dawley rats weighing 300-450 g were used. Rapidly remove the 1.5 cm fragment from the distal end of the esophagus, remove the muscle layer, open the medial mucosal layer longitudinally and remove the Krebs-Henseleit solution at 32 ° C. oxygenated by carbogen streams (95% O ₂ and 5% CO ₂ ). It was placed in an isolated organ container containing and connected to an isotonic converter under a basic tension of 0.5 g. Tissue shrinkage was induced by the addition of 0.5 μΜ carbacol, waited until the contraction stabilized (15 min) and then the preparation was exposed to serotonin (1 μΜ) to quantify maximum relaxation. Tissues were washed and after a period of 20 minutes 0.5 μM carbacol was added again and the preparations were exposed to increasing additional concentrations of test compound from 0.1 to 1 μM. Compounds that induce relaxation are considered 5-HTG agonists.

For compounds that did not induce relaxation, the preparation was exposed to increasing additional concentrations of serotonin from 0.1 nM up to the concentration that induces maximum relaxation, and then a relaxation curve by serotonin in the presence of the study compound was made in the absence of the compound. Comparison with the control curve. If its presence causes a shift in the curve towards the right, the study compound is considered to be a 5-HTV antagonist.

The results of these two biological tests indicate that the compounds of the present invention are potent ligands for the 5-HTV type serotonin receptor and they act on this receptor as agonists or antagonists.

Finally, the compounds of the present invention are essentially Korte A. et al., Biochem. Phys. Res. Commun. , (1990) 168 , 979-986 and West RE et al., Mol. In vivo studies were conducted on their affinity for H 3 histamine receptors in the rat brain, as described in Pharmacol ., (1990) 38 , 610-613.

Male Sprague-Dawley rats (OFA, Iffa Credo, France) weighing 250-300 g were euthanized and their brains removed. Tissues were homogenized using PolytronTM mill (position 7, 20 sec) in 20 volumes of Tris-HCl buffer (50 nM, pH 7.4 at 22 ° C.). Homogenate was centrifuged at 1000 g for 10 minutes and then the supernatant was further centrifuged at 45,000 g for 20 minutes at 4 ° C. The pellet was then resuspended in buffer, washed by homogenization and centrifugation. The final pellet was resuspended in buffer at a rate of 100 mg of starting tissue per milliliter and then divided into 11 ml aliquots frozen at -80 ° C. On the day of the experiment, membrane supernatant (100 μl, 300-400 μg protein) was added to 0.5 nM of [ ³ H] Nα-methylhistamine (specific activity 75) in 500 μl of Tris-HCl buffer with or without test compound. Incubated at 30 ° C. for 60 minutes in the presence of 80 Ci / mmol, New England Nuclear, Du Pont de Nemours, Boston, USA). Incubation was stopped by filtration through Whatman GF / BTM filter pretreated with polyethyleneimine (0.4%). Each reaction tube was rinsed three times with 4 ml of cold (0 ° C.) Tris-HCl buffer. The filter was dried in an oven at 120 ° C. for 5 minutes. Radioactivity retained on the filter was determined by liquid scintography. Nonspecific binding was determined in the presence of 10 μM of thioperamine (N-cyclohexyl-4- (1H-imidazol-4-yl) piperidine-1-carbothioamide.

For each concentration of study compound, the percent inhibition of specific binding of [ ³ H] Nα-methylhistamine was calculated and then the concentration IC ₅₀ of the compound that inhibited 50% of the binding was determined.

The largest active compound of the present invention in this test has an IC ₅₀ of 5 nM order.

The results of various biological tests performed on the compounds of the present invention indicate that they are ligands for the 5-HTV receptor and / or the H 3 receptor.

These results suggest that this compound can be used to treat or prevent diseases involving 5-HTV and / or H₃ receptors, particularly at the central nervous system, gastrointestinal, lower urinary tract or cardiovascular levels.

At the central nervous system level, this disease and its disorders are particularly composed of neurological and mental disorders such as cognitive impairment, psychosis, compulsive and paranoid behavior, and depression and anxiety. Cognitive impairment consists, for example, of memory and attention loss, dementia status (Alzheimer's type senile dementia or age-related dementia), cerebral vascular deletion or Parkinson's disease. Psychosis consists of, for example, paranoia, schizophrenia, manic and autism. Compulsive and editorial behaviors consist of, for example, loss of appetite or anorexia nervosa. Depression and anxiety include, for example, developmental anxiety (before surgery, before dental care, etc.) or anxiety caused by alcohol or drug dependence or withdrawal. Finally, mention may also be made of manic, epilepsy, sleep disorders, seasonal emotional disorders or migraine headaches.

At the level of the gastrointestinal system, these diseases and disorders are particularly direct or indirect diseases of the intrinsic motility of the esophagus, stomach or intestines, dyspepsia, ulcers, gastro-esophageal reflux, flatulence, irritable bowel symptoms, intestinal secretions or diarrhea, eg Nausea or certain complaints, such as caused by, for example, cholera or carcinoid syndrome, or diseases associated with or not associated with air pollution such as asthma, rhinitis and dyspnea.

At the level of the lower urinary tract, these diseases and disorders consist in particular of urinary incontinence, urination disorders or fairy bodies.

At the cardiovascular level, these diseases and disorders are particularly associated with cardiac arrhythmias, hypertension, ischemia, myocardial infarction or pathology or recombination directly or indirectly associated with unstable angina, e.g. fibrolytic or thrombolytic therapy, angioplasty or heart It consists of the problem of postoperative re bite.

Glaucoma is also a disease that can be treated with the compounds of the present invention.

 The compounds of the present invention are enteral or parenteral, such as tablets, sugars, capsules, including hard gelatin capsules, suspensions or solutions that are inhaled or injected, such as syrups or pears, in combination with appropriate excipients at dosages of 0.001 to 20 mg / kg per day. It may be provided in the form of any composition suitable for oral administration.

Claims (3)

A compound according to formula (I) in the form of a free base or in the form of an addition salt with an acid, optionally in the form of a pure optical isomer or a mixture of such isomers. Formula I (In the above formula R ₁ represents a (C ₁ -C ₄ ) alkyl or (C ₃ -C ₇ ) cycloalkylmethyl group, X ₁ represents hydrogen or a halogen atom or a (C ₁ -C ₄ ) alkoxy group, or OR ₁ and X ₁ together represent the formula -OCH ₂ O-, -O (CH ₂ ) _2- , -O (CH ₂ ) _3- , -O (CH ₂ ) ₂ O- or-O (CH ₂ ) ₃ O Represents a group of- X ₂ represents a hydrogen atom or an amino group, X ₃ represents hydrogen or a halogen atom, R ₂ is a hydrogen atom or a (C ₁ -C ₆ ) alkyl group or a phenyl (C ₁ -C ₄ ) alkyl group or a phenyl (C ₂ -C ₃ ) alkenyl group or phenoxy (C ₂ -C ₄ ) alkyl group or cyclo (C ₃ -C ₇ ) alkylmethyl group or 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl group or n represents the numbers 1 to 6 and Z is piperi A group of the general formula-(CH ₂ ) _n CO-Z which represents a din-1-yl or 4- (dimethylamino) piperidin-1-yl group.) A compound according to claim 1, wherein R ₂ is a 4-oxo-4- (piperidin-1-yl) butyl group, a 2- [4- (dimethylamino) piperidin-1-yl] -2-oxoethyl group, 4- [4- (dimethylamino) piperidin-1-yl] -4-oxobutyl group, 5- [4- (dimethylamino) piperidin-1-yl] -5-oxopentyl group or 6- A compound characterized by representing a [4- (dimethylamino) piperidin-1-yl] -6-oxohexyl group.  Formula II Wherein the ester of (wherein R ₁ , X ₁ , X ₂ and X ₃ are as defined in claim 1 and R ₃ represents a methyl or ethyl group) is reacted with hydrazine hydrate to give Formula III Obtain hydrazide of this formula IV (IV) Cyclized with oxadiazole and then the latter in the presence of triphenylphosphine and ethyl azodicarboxylate (Formula Ⅴ) Reacted with piperidin-4-ol (wherein R ₂ is as defined for Formula I but other than a hydrogen atom, or otherwise represents a (1,1-dimethylethoxy) carbonyl protecting group) , If necessary, deprotecting the nitrogen of the piperidine ring and when R ₂ represents a hydrogen atom, the compound obtained if desired represents X leaving group or functional group and R ₂ is as defined for formula (I) but Reacted with a derivative of the general formula R ₂ -X, wherein R ₂ represents a final compound of the 2,3-dihydro-1H-indenyl group, where R ₂ corresponds to the compound of formula (I) Process for the preparation of a compound according to claim 1, characterized in that reductive amination is carried out with indanone.