Derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol - 2(3h)-she, the method of production thereof, pharmaceutical composition and drug

 

(57) Abstract:

The invention relates to derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(MN)-it General formula I, in which R1is a group (C1-C4)alkyl or the group (C3-C7)cycloalkenyl; X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy or or1and X1together, the group of the formula-och2O-, -O(CH2)2-; -O(CH2)2O - or-O(CH2)3O-; X2is a hydrogen atom or amino group; X3is a hydrogen atom or halogen; R2is a hydrogen atom or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or gruppa General formula -(CH2)nFROM a-Z, in which n = 1 to 6, a Z - group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl. These compounds can be used for the treatment and prevention of disorders involving the receptors 5-HT4and/or H3about sudiste system. The described method of obtaining the above compounds, pharmaceutical composition and a drug. 4 C. and 3 h.p. f-crystals, 2 PL.

The object of the present invention are compounds corresponding to General formula (I)

< / BR>
in which R1is a group (C1-C4)alkyl or (C3-C7)cycloalkenyl,

X1represents a hydrogen atom or halogen or the group (C1-C4)alkoxy, or

OR1and X1together represent a group of the formula-OCH2O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)2O - or-O(CH2)3O-,

X2represents a hydrogen atom or an amino group,

X3represents a hydrogen atom or halogen, and

R2is a or a hydrogen atom, or a possibly substituted group (C1-C4)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl, or a group of cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or a group of General formula -(CH2)nCO-Z, Kotaro-Il.

When R2represents a phenyl group(C1-C3)alkyl, possibly substituted on the phenyl ring, such a group is preferably a group, possibly substituted on the phenyl ring by a halogen atom, triptorelin group or two methoxy groups.

When R2represents a group of General formula -(CH2)nCO-Z, this group is preferably a group 4-oxo-4-(piperidine-1-yl)butyl group, 2-[4-(dimethylamino)piperidine-1-yl] -2-oxoethyl, group 4-[4-(dimethylamino)piperidin-yl]-4-oxobutyl, group 5-[4-(dimethylamino)piperidine-1-yl]-5-oxopent or with a group of 6-[4-(dimethylamino)piperidine-1-yl]-6-oxohexyl.

Compounds according to the invention can exist in the form of free bases or salts of joining acids. In addition, some of the substituents R2contain asymmetric carbon atom; such compounds can therefore exist in the form of pure enantiomers or mixtures of enantiomers.

Connection structure similar to the structures of the compounds according to the invention, and with probably a similar therapeutic effect, but the Central heterocycle which represents a 1,2,4-oxadiazol instead 1,3,4-oxadiazol-2(3H)-she is of the General formula (I) can be obtained by way shown in the following diagram.

< / BR>
< / BR>
< / BR>
< / BR>
Ester of General formula (II) in which R1X1X2and X3such as defined above, and R3represents a methyl group or ethyl, is subjected to the interaction with hydrazinehydrate in the absence of solvent or in a polar proton solvent, for example ethanol, to obtain the hydrazide of General formula (III), which cyclist with getting oxadiazole General formula (IV) or with phosgene in an aprotic solvent, for example dioxane, or using phenylcarbamate in an aprotic solvent, for example toluene. When in the General formula (III) X2represents an amino group, this latter is subjected to interaction with phosgene, and the resulting product atrificial benzyl alcohol, thus protecting the amino group benzyloxycarbonyloxy group. Then oxidiazol General formula (IV) is subjected to interaction with piperidine-4-I of General formula (V) in which R2the same as defined for General formula (I), but other than a hydrogen atom or represents a protective group (1,1-dimethylmethoxy)carbonyl, in the presence of triphenylphosphine and ethyl ester of azodicarboxylic acid in aprotic Rastas through triperoxonane acid, and when R2represents a hydrogen atom, and if desired, the compound obtained is subjected to interaction with a derivative of General formula R2-X, in which X represents a leaving or functionalitywith group, for example halogen atom, methanesulfonate or 4-methylbenzenesulfonate group or carbonyl functional group, a R2the same as defined for General formula (I), but other than a hydrogen atom, in the presence of triethylamine in an aprotic solvent, for example acetonitrile. In the particular case where R2is a group of 2,3-dihydro-1H-indenyl, conduct rehabilitation amination of compound of General formula (I) in which R2represents a hydrogen atom, and the corresponding indanone.

Source esters of General formula (II) or the corresponding acids are known and described in particular in patent applications EP-0231139, EP-0234872, WO-8403281 and WO-9419344.

Piperidine-4-Ola General formula (V) are known and/or can be obtained according to methods similar to those described in J. Mol.Phamacol., (1992) 41(4), 718-726 and in the patent applications WO-9303725 and ER-0309043.

Getting some compounds according to the invention is illustrated in detail in the following PR is dinani, given in parentheses in the header correspond to the numbers in the following table 1. The title compounds dash "-" forms part of the word, and the dash "_" is used only to break at the end of the line; it should be omitted if there is no break and should not replace normal dash or space.

Example 1 (Compound No. 1)

5-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidine-4-yl)-1,3,4 - oxadiazol-2(3H)-she hydrobromide

1.1. The hydrazide of 4-amino-5-chloro-2-methoxybenzoic acid

51,5 g (0,239 mol) of methyl ester of 4-amino-5-chloro-2-methoxybenzoic acid in suspension in 460 ml of ethanol are placed in a reactor of 1 liter Added 119 g (2,39 mol) over 15 min, and the mixture is refluxed for 15 hours the Mixture is cooled in an ice bath and the precipitate is collected by filtration, washed with ethanol and dried under reduced pressure at 80oC for 2.5 hours Receive and 47.5 g of the product.

Melting point: 211oC.

1.2. Fenilmetilovy ether [2-chloro-5-methoxy-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl] carbamino acid

461 ml (0,875 mol) of 1.93 M solution of phosgene in toluene is added dropwise within 1 h at room temperature and with magnetic stirring to a suspension of 37.7 g (0,175 mol) hydrazide is more at room temperature over night, and then heated at 80oC for 1 h, the Excess phosgene is removed, passing a stream of argon at this temperature for 2 hours 3 Quiroga add 72 ml (0.7 mol) of benzyl alcohol and continue heating for 1 h at 100oC. the Mixture is cooled and concentrated under reduced pressure and the residue is triturated in isopropyl ether. The obtained solid is collected by filtration and dried. So get 60,3 g of the product.

Melting point: 214oC.

1.3. Fenilmetilovy ether [2-chloro-4-[4-[1-[(1,1-dimethylmethoxy)carbonyl] -piperidine-4-yl]- 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]-5-methoxyphenyl]- carbamino acid

15,03 g (40 mmol) phenylmethanol ether [2-chloro-5-methoxy-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2 - yl)phenyl] carbamino acid in solution in 200 ml of tetrahydrofuran, 13,64 g (52 mmol) of triphenylphosphine and to 9.66 g of 1-[(1,1-dimethylmethoxy)carbonyl] piperidine-4-ol is introduced into the three-neck round bottom flask of 500 ml, at the same time stirring the mixture at 0oC. Enter 9,76 g (56 mmol) of ethyl ester of azodicarboxylic acid and stirring is continued at 0oC for 1 h and at room temperature for 2.5 hours

The mixture is concentrated under reduced pressure, the residue races the pressure. The residue is purified chromatographically on a column of silica gel, and elution is carried 30/70 mixture of ethyl acetate and hexane.

Receive 15 g of compound as a white solid.

Melting point: 140oC.

1.4. Fenilmetilovy ether [2-chloro-4- (5-oxo-4-(piperidine-4-yl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5 - methoxyphenyl]carbamino acid

of 6.52 g (12 mmol) phenylmethanol ether [2-chloro-4-[4-[1-[(1,1- dimethylmethoxy)carbonyl] piperidine-4-yl]-5-oxo-4,5-dihydro-1,3,4 - oxadiazol-2-yl] -5-methoxyphenyl]carbamino acid in the form of a solution in 140 ml of dichloromethane and 13,64 g (120 mmol) triperoxonane acid are placed in a three-neck round bottom flask of 500 ml, and the mixture is stirred at room temperature over night.

Add ice, then chloroform, and then 25% aqueous ammonia solution; the organic phase is separated, and the aqueous phase is extracted 4 times with chloroform. The organic phase is washed with saturated aqueous sodium chloride, dried and the solvent is distilled off under reduced pressure.

Get of 6.26 g of crude product, which is used as it is.

Melting point: 180oC.

1.5. 5-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidine-4-yl)-1,3,4-oxa is-1,3,4-oxadiazol-2-yl)-5 - methoxyphenyl] carbamino acid, dissolved in 5.8 ml of 33% solution of Hydrobromic acid in acetic acid are placed in a round bottom flask of 25 ml, and the mixture is stirred at room temperature for 1 h

Add diethyl ether, and the precipitate was separated by filtration. Get to 0.67 g of the hydrobromide.

Melting point: 278-280oC.

Treatment of aqueous ammonia allocate 0.52 g of free base.

Example 2 (Compound No. 5)

5-(4-Amino-5-chloro-2-methoxyphenyl)-3-[1-(cyclohexylmethyl)piperidine-4 - yl]-1,3,4-oxadiazol-2(3H)-he

a 2.01 ml (13,92 mmol) of triethylamine, and then 0,92 g (5.2 mmol) of cyclohexylethylamine in 5 ml of acetonitrile successively added at room temperature in an argon atmosphere and with magnetic stirring to a solution of 1.13 g (3,48 mmol) 5-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidine-4-yl)-1,3,4 - oxadiazol-2(3H)-she's in 40 ml of acetonitrile, and the mixture was stirred at 70oC for 2 days. The solvent is distilled off under reduced pressure, the residue is transferred into chloroform, the solution washed repeatedly with water and dried, the solvent is distilled off under reduced pressure, and the residue is recrystallized from acetone.

Obtain 0.7 g of a white solid.

Temperature plavini the DIN-4-yl] -1,3,4 - oxadiazol-2(3H)-he

3.1. Fenilmetilovy ether [2-chloro-5-methoxy-4-[5-oxo-4-[1-(2-phenylethyl)- piperidine-4-yl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]phenyl]carbamino acid

1.84 g (4 mmol) phenylmethanol ether [2-chloro-4-(5-oxo-4-(piperidine-4-yl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5 - methoxyphenyl]carbamino acid and 1.67 ml (12 mmol) of triethylamine in suspension in 40 ml of acetonitrile are placed in a round bottom flask of 100 ml, added 0.96 g (5.2 mmol) (2-bromacil)benzene in 1 ml of acetonitrile, the mixture is heated at 60oC for 3 h, add 0.3 ml of (2-bromacil)benzene, and the mixture is heated at 80oC during the night. Distilled off under reduced pressure, the solvent, the residue is extracted three times with chloroform, the organic phase is repeatedly washed with water and dried over sodium sulfate, the solvent is evaporated under reduced pressure and the residue is purified chromatographically on a column of silica gel, and elution carried out with a mixture of ethyl acetate and hexane 80/20.

Get to 2.18 g of pure compound as white solid.

Melting point: 150oC.

3.2. 5-(4-Amino-5-chloro-2-methoxyphenyl)-3-[1-(2-phenylethyl)piperidine-4-yl] -1,3,4 - oxadiazol-2(3H)-he

2,18 g (a 3.87 mmol) phenylmethanol ether [2-chloro-5-methoxy-4-[5-AML 33% solution pomodorini acid in acetic acid, placed in a round bottom flask of 100 ml, and the mixture is stirred at room temperature for 3 hours

Add diethyl ether and the precipitate is separated by filtration. Obtain 1.73 g of the hydrobromide.

This last transfer in water and chloroform, and the mixture is neutralized by adding sodium hydroxide. After separation of the organic phase, extraction of the aqueous phase and the normal processing obtain 1.44 g of the compound in free base form.

Melting point: 184,5oC.

Example 4 (Compound No. 2)

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

4.1. Fenilmetilovy ether [2-chloro-4-[4-(1-methylpiperidin-4-yl)-5-oxo - 4,5 - dihydro-1,3,4-oxadiazol-2-yl]-5-methoxyphenyl]carbamino acid

7.5 g phenylmethylene ether [2-chloro-5-methoxy-4-(5-oxo - 4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl] carbamino acid in suspension in 150 ml of tetrahydrofuran, 6,82 g (26 mmol) of triphenylphosphine and 2.3 g (20 mmol) 1-methylpiperidin-4-ol was placed in a round bottom flask at 2.5 l add at 0oC and magnetic stirring 4,39 g (28 mmol) of ethyl ester of azodicarboxylic acid and stirring is continued for 20 hours the Mixture is concentrated under reduced pressure, the form of a white solid.

Melting point: 142oC.

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

2 g (to 4.23 mmol) phenylmethanol ether [2-chloro-4-[4-(1-methylpiperidin-4-yl)-5-oxo - 4,5-dihydro-1,3,4-oxadiazol-2-yl]-5-methoxyphenyl]carbamino acid, dissolved in 20 ml of acetic acid are placed in a round bottom flask of 100 ml, slowly add 20 ml of 33% solution pomodorini acid in acetic acid, and the mixture is stirred at room temperature for 18 hours, Add diethyl ether and filtered secrete solid.

Receive 2 g of the hydrobromide.

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

Gain of 1.05 g of compound in free base form.

Melting point: 162oC.

The hydrochloride is obtained by processing chloroethanol acid in ethanol.

Melting point: 212-218oC.

Example 5 (Compound No. 19)

5-[4-Amino-5-chloro-2-(cyclopropylmethoxy)phenyl] -3-(1-butylpiperazine-4-yl)-1,3,4 - oxadiazol-2(3H)-she hydrochloride

5.1. Methyl ester of 4-amino-5-chloro-2-(qi and 340 ml of methanol are placed in a three-neck round bottom flask with a volume of 1 l, the solution is cooled to -40oC, is added dropwise 44 ml (0,602 mol) of thionyl chloride, and the mixture is refluxed for 1.5 hours the Mixture is cooled, the solvent is distilled off, the residue is transferred into the water and an aqueous solution of sodium carbonate, the extraction is carried out with dichloromethane, and the crude product is purified chromatographically on a column of silica gel, elwira a mixture of from 90/10 to 80/20 n-heptane and ethyl acetate.

Gain of 8.3 g of compound as a pale yellow solid.

Melting point: 115oC.

5.2. The hydrazide of 4-amino-5-chloro-2-(cyclopropylmethoxy)antinoi acid

6.0 g (23.5 mmol) of methyl ester of 4-amino-5-chloro-2- (cyclopropylmethoxy)benzoic acid and 54 ml of ethanol are placed in a round bottom flask of 250 ml, add in the 40oC 118 g (235 mmol) of hydrazine hydrate is added, and the mixture is refluxed for 18 hours the Mixture is cooled in an ice bath and filtered secrete precipitate, rinse it with ethanol and dried at 70oC under reduced pressure for 4 hours

Get 4.7g connection.

Melting point: 172oC.

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

2.0 g (7.8 mmol) of the hydrazide of 4-amino-5-CHL is bottom flask of 100 ml and the mixture is refluxed for 4 hours

The mixture is cooled to room temperature. Add 2.5 ml (16.4 mmol) of triethylamine, the mixture is refluxed for 3 h and cooled to room temperature, add water and extracted with chloroform. After conventional treatment and chromatographic purification on a column of silica gel, elwira mixture of chloroform, methanol and aqueous ammonia (98/2/0,2), get 0,80 g white solid.

Melting point: 153-154oC.

5.4. 5-[4-Amino-5-chloro-2-(cyclopropylmethoxy)phenyl] -3-(1 - butylpiperazine-4-yl)-1,3,4-oxadiazol-2(3H)-she hydrochloride

The target compound is obtained in the form of a base of 5-[4-amino-5 - chloro-2-(cyclopropylmethoxy)phenyl] -1,3,4-oxadiazol-2(3H)-it and 1-butyl-piperidine-4-ol, and the production is carried out in accordance with the method described in example 4.1, and, after processing solution chlorotalonil acid in ethanol and recrystallization from ethanol, receive hydrochloride.

Melting point: 237-238oC.

Example 6 (Compound No. 28)

5-(8-Amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(piperidine-4-yl)- 1,3,4-oxadiazol-2(3H)-she hydrobromide

6.1. Ethyl ester of 8-amino-2,3-dihydro-1,4-benzodioxin-5 - carboxylic acid

23,5 g (0,198 mol) SUP>oC, with stirring, and the stirring maintain at this temperature for 1 h, added slowly over 15 min and 38.6 g (0,198 mol) of 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid in the form of a solution in 100 ml of ethanol, and the mixture is left to warm to room temperature over night.

This mixture is refluxed for 4 h, the solvent is distilled off under reduced pressure, the residue is transferred into the water and sodium carbonate and the extraction is carried out with chloroform. After washing, drying and evaporating the organic phase, get to 34.06 g of ester in the form of a white solid.

Melting point: 112oC.

6.2. Ethyl ester of 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid

37 g (0,165 mol) of ethyl ester of 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid in the form of a solution in 370 ml of dioxane is introduced into a round bottom flask of 1 l, add at room temperature and magnetic stirring of 23.2 g (0,174 mol) N-chlorosuccinimide and magnetic stirring is maintained for the night.

The mixture is diluted with water, the extraction is carried out with ethyl acetate and, after the customary treatment of the organic phase, obtain 42 g of compound, the cat is the exercise: 105-106oC.

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

of 38.4 g (0,149 mol) of ethyl ester of 8-amino-7-chloro-2,3 - dihydro-1,4-benzodioxin-5-carboxylic acid in suspension in 150 ml of ethanol is introduced into the reactor with a volume of 1 l was added dropwise within 15 min 149 g (2,98 mol) of hydrazine hydrate is added and the mixture refluxed for 1 h

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

Get 33 g connection.

Melting point: 227-231oC.

6.4. Fenilmetilovy ether [6-chloro-8-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1,4 - benzodioxin-5-yl]carbamino acid

of 32.6 g of hydrazide 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5 - carboxylic acid and 330 ml of dioxane is introduced into a reactor of 1 l at room temperature and with magnetic stirring, to the suspension dropwise over 1.5 h add 310 ml (0.4 mol) 0,193 M solution of phosgene in toluene, the mixture is stirred at room temperature overnight and refluxed for 5 hours

The excess phosgene is removed at this temperature passing through the mixture stream of argon for 2 h, is up at 100oWith over night, the mixture is cooled and concentrated under reduced pressure and the residue is triturated in diisopropyl ether. After filtration and drying receive 52,6 g connection.

Melting point: 230oC.

6.5. Fenilmetilovy ether [6-chloro-8-[4-[1-[(1,1-dimethylmethoxy)carbonyl]- piperidine-4-yl] -5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] - 2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid

8.7 g (20 mmol) phenylmethanol ether [6-chloro-8-(5-oxo-4,5-dihydro-1,3,4 - oxadiazol-2-yl)-2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid, 160 ml of tetrahydrofuran, 6,83 g (26 mmol) of triphenylphosphine, 4.83 g (24 mmol) of 1-[(1,1 - dimethylmethoxy)carbonyl]piperidine-4-ol, and then to 4.52 g (26 mmol) ethyl ester of azodicarboxylic acid injected at 0oC with magnetic stirring in a three-neck round bottom flask 250 ml After stirring for 1 h at 0oC and 2.5 h at room temperature the mixture is concentrated under reduced pressure and the residue is recrystallized first from diethyl ether and the second time from ethyl acetate. Obtain 5.5 g of the compound in the form of a white solid.

Melting point: 206oC.

6.6 Fenilmetilovy ether [6-chloro-8-(5-oxo-4-(piperidine-4-yl)-4,gross ether [6-chloro-8-[4-[1-[(1,1-dimethylmethoxy)carbonyl] piperidine-4-yl]-5-oxo - 4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-yl] carbamino acid, 100 ml of dichloromethane and 10.3 g (90 mmol) triperoxonane acid is introduced into the three-neck round bottom flask of 250 ml, and the mixture is stirred at room temperature over night.

The mixture is concentrated under reduced pressure, and the residue is triturated in acetone, collected by filtration, washed with diethyl ether, is treated by slow addition of 17 ml of 25% aqueous ammonia and extracted 4 times with chloroform. After washing with water and then a saturated solution of sodium chloride, drying and evaporating the solvent, obtain 4.4 g of the compound that is used as is in the next stage.

Melting point: 128-130oC.

6.7. 5-(8-Amino-7-chloro-2.3-dihydro-1.4-benzodioxin-5-yl)-3-(piperidine - 4-yl)-1,3,4-oxadiazol-2(3H)-he

3,68 g (27.5 mmol) phenylmethanol ether [6-chloro-8-(5-oxo-4-(piperidine-4-yl)-4,5 - dihydro-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1,4 - benzodioxin-5-yl] carbamino acid and 35 ml of acetic acid are placed in a round bottom flask of 50 ml, add 11 ml of 33% solution pomodorini acid in acetic acid, and the mixture is stirred at room temperature for 22 hours To the formed precipitate add diethyl ether, and the precipitate collected by filtration. Get 4 g of the hydrobromide.

Melting point: 213-215oC.

Example 7 (Compound N 37)

5-(8-Amino-7 - chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-[[4- (trifluoromethyl)phenyl]methyl]piperidine-4-yl]-1,3,4-oxadiazol-2(3H)-he

1,58 g (11,38 mmol) of triethylamine and 0.88 g (of 5.68 mmol) of 4-(trifluoromethyl)benzylbromide in the form of a solution in 5 ml of acetonitrile successively added at room temperature under magnetic stirring and argon atmosphere to a solution of 1 g (2,84 mmol) 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(piperidine - 4-yl)-1,3,4-oxadiazol - 2(3H)"she's in 60 ml of acetonitrile and the mixture is stirred for 2 hours

The solvent is evaporated under reduced pressure, the residue is transferred into chloroform, the solution washed repeatedly with water and dried, and the solvent is evaporated under reduced pressure.

The residue is crystallized from acetone and get to 1.14 g of white solid.

Melting point: 198oC.

Example 8 (Compound N 32)

5-(8-Amino-7-chloro-2,3-dihydro-1,4-benzodioxin - 5-yl)-3-[1-(4,4,4-trifloromethyl)-piperidine-4-yl]-1,3,4-oxadiazol - 2(3H)-he

8.1. Fenilmetilovy ether [6-chloro-8-[5-oxo-4-[1-(4,4,4 - trifloromethyl)piperidine-4-yl] -4,5-dihydro-1,3,4-oxadiazol-2-yl] - 2,3-dihydro-1,4-benzodioxin-5-yl]-carbamino K2,3-dihydro-1,4-benzodioxin-5 - yl] - carbamino acid, 40 ml of acetonitrile and 2.3 ml (16 mmol) of triethylamine is introduced into a round bottom flask of 100 ml, add 1.5 g in (6.67 mmol) of 4,4,4-triphosphorylated in 1 ml of acetonitrile and the mixture is heated at 80oC during the night.

The solvent is evaporated under reduced pressure, the residue is extracted three times with chloroform and the organic phase is washed, dried and evaporated. After purification of the residue by chromatography on a column of silica gel, elwira a mixture of dichloromethane, methanol and aqueous ammonia at a ratio 97/3/0,3, obtain 2.4 g of the compound in the form of a white solid.

Melting point: 158oC.

8.2. 5-(8-Amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(4,4,4-trifloromethyl)piperidine-4-yl]-1,3,4-oxadiazol-2(3H)he

1,72 g (2,88 mmol) phenylmethanol ether [6-chloro-8-[5-oxo-4-[1-(4,4,4 - trifloromethyl)piperidine-4-yl]-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro - 1,4-benzodioxin-5-yl]carbamino acid and 17 ml of acetic acid are introduced into a round bottom flask of 100 ml, add 5 ml of 33% solution of Hydrobromic acid in acetic acid and the mixture is stirred at room temperature for 7 hours To the precipitate, which formed, add diethyl ether and collected by filtration 1.8 g of the hydrobromide.

Melting point: 188oC.

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-oxadiazol-2(3H)-he hydrobromide

9.1. Fenilmetilovy ether [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]carbamino acid

6,27 g (15,53 mmol) phenylmethanol ether [6-chloro-8-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2,3-dihydro - 1,4-benzodioxin-5-yl]carbamino acid in suspension in 80 ml of tetrahydrofuran, 6,12 g (23,3 mmol) of triphenylphosphine and 2.24 g (to 19.4 mmol) 1-methylpiperidin-4-ol is introduced into a round bottom flask of 250 ml and slowly at 0oC and stirring 4,06 ml (with 23.3 mmol) of the ethyl ester of azodicarboxylic acid and the mixture is stirred for 48 hours

The mixture is concentrated under reduced pressure, the residue is dissolved in water, add 1.6 ml of 37% solution chloroethanol acid, and then 60 ml of ethyl acetate, and the mixture is stirred for 1 h and then extracted 4 times with ethyl acetate. The solvent is evaporated under reduced pressure, the residue is treated with an aqueous ammonia to pH 10 and the precipitate collected by filtration.

Receive and 3.16 g of compound in the form of the ro-1,4-benzodioxin-5-yl)-3-(1-methylpiperidin - 4-yl)-1,3,4-oxadiazol-2(3H)-he hydrobromide

1,71 g (3,41 mmol) phenylmethanol ether [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] carbamino acid in solution in 30 ml of acetic acid are placed in a round bottom flask of 100 ml, slowly add 3 ml of 33% Hydrobromic acid and the mixture is stirred for 5 hours To the precipitate, which formed, add diethyl ether, and the precipitate collected by filtration.

Get 1,72 g of the hydrobromide.

Melting point: 248oC.

Example 10 (Compound No. 31)

5-(8-Amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(1 - butylpiperazine-4-yl)-1,3,4-oxadiazol-2(3H)-he hydrochloride

10.1. Fenilmetilovy ether [8-[4-(1-butylpiperazine-4-yl)-5-oxo-4,5 - dihydro-1,3,4-oxadiazol-2-yl] -6-chloro-2,3-dihydro-1,4 - benzodioxin-5-yl] carbamino acid

Obtaining carried out as described in example 9.1, phenylmethanol ether [6-chloro-8-(5-oxo - 4,5-dihydro-1,3,4-oxadiazol-2-yl)-2,3-dihydro-1,4-benzodioxin-5 - yl]carbamino acid and 1-butylpiperazine-4-ol.

10.2. 5-(8-Amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(1 - butylpiperazine - 4-yl)-1,3,4-oxadiazol-2(3H)-he hydrochloride

Obtaining carried out as described in example 9.2, phenylmethanol ether [8-[4-(1-butyi and pomodorini acid, and the hydrochloride is obtained by processing chloroethanol acid in ethanol.

Melting point: 280-283oC.

Example 11 (Compound No. 62)

5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-3-(piperidine-4-yl)-1,3,4 - oxadiazol-2(3H)-he hydrochloride

11.1. The hydrazide 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid

57,3 ml (1.18 mol) of hydrazine hydrate is added add to 25,14 g (amount of 0.118 mol) of methyl ester of 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid in suspension in 300 ml of methanol, and the mixture is refluxed for 4 hours

The mixture is cooled using an ice bath and the precipitate is collected by filtration, washed with ethanol and dried under reduced pressure. Get 24,34 g connection.

Melting point: 182oC.

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

24,34 g (0,115 mole) of the hydrazide 5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid and 500 ml of dioxane is injected at room temperature and with magnetic stirring in a reactor of 1 l was added via the dropping funnel 178 ml (0,343 mol) 0,193 M phosgene in toluene, and the mixture is stirred at room temperature for 24 h, and then refluxed for 4 h to remove excess phosgene.t by filtration and dried.

Obtain 27 g of compound.

Melting point: 270oC.

11.3. 5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-3-[1-[(1,1- dimethylmethoxy)carbonyl]-piperidine-4-yl)-1,3,4-oxadiazol-2(3H)-he

20 g (0.08 mol) of 5-(5-chloro-2,3-dihydrobenzofuran-7-yl)- 1,3,4-oxadiazol-2(3H)-it is in the form of a suspension in 250 ml of tetrahydrofuran is introduced into the three-neck round bottom flask of 500 ml, cooled to 0oC and set of magnetic stirring, then add 10,06 g (0.05 mol) of 1-[(1,1-dimethylmethoxy)carbonyl] piperidine-4-ol, 18,36 g of triphenylphosphine and 14,81 g (of 0.085 mol) of ethyl ester of azodicarboxylic acid, and the mixture is stirred at room temperature for 4 h

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

Gain of 14.7 g of beige solid substances.

Melting point: 203oC.

11.4. 5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-3(piperidine-4-yl)-1,3,4 - oxadiazol-2(3H)-she hydrochloride

of 14.7 g (0.035 mol) of 5-(5-chloro-2,3-dihydrobenzofuran-7-yl)3-[1 -[(1,1- dimethylmethoxy)carbonyl]piperidine-4-yl]-1,3,4-oxadiazol-2(3H)-she dissolved in 150 ml of dichloromethane in a round bottom flask of 500 ml, add at 0oC and 26.8 ml triperoxonane the Yes of sodium in 300 ml of water, the mixture is extracted with chloroform, the organic phase is dried, and the solvent is evaporated under reduced pressure.

Obtain 10.8 g of the base in the form of a white solid.

Melting point: 180oC.

3.5 g of the hydrochloride is obtained by treatment of 5 g of the base with a solution of gaseous chloroethanol acid in ethanol.

Melting point: > 260oC.

Example 12 (Compound N 67)

5-(5-Chloro-2,3 - dihydrobenzofuran-7-yl)-3-[1-(2-phenylethyl)piperidine-4-yl] -1,3,4 - oxadiazol-2(3H)-he hydrochloride

2.5 g (to 7.77 mmol) 5-(5-chloro-2,3 - dihydrobenzofuran-7-yl)-3(piperidine-4-yl)-1,3,4-oxadiazol-2(3H)- it is in the form of a solution in 50 ml of butane-2-it is introduced into the three-neck round bottom flask, 250 ml, add 2,87 g (of 15.5 mmol) phenylethylamine, and then of 2.36 g (23,3 mmol) of triethylamine, and the mixture was stirred at education phlegmy for 20 hours the precipitate is collected by filtration, the filtrate is evaporated under reduced pressure, the residue is transferred into water and extracted twice with chloroform, and the organic phase is evaporated under reduced pressure.

The residue is dissolved in a solution of gaseous chloroethanol acid in ethanol, add diethyl ether and the precipitate collected filter is P>oC.

Example 13 (Compound N 65)

5-(5-Chloro-2,3-dihydrobenzofuran-7-yl)- 3-(1-butylpiperazine-4-yl)-1,3,4-oxadiazol-2(3H)-he

of 2.38 g (0.01 mol) of 5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,3,4-oxadiazol-2(3H)-it is in the form of a suspension in 80 ml of tetrahydrofuran is introduced into the three-neck round bottom flask, 250 ml, cooled to 0oC and set of magnetic stirring, add of 1.57 g (0.01 mol) 1-butylpiperazine-4-ol, 3,41 g (0,013 mol) of triphenylphosphine, and then 2,44 g (0.014 mol) of ethyl ester of azodicarboxylic acid, and the mixture is stirred at room temperature for 3 h and then at 40oC for 3 hours the Solvent is evaporated under reduced pressure, and the residue is dissolved in water and extracted five times with diethyl ether.

The organic phase is dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure, and the residue purified by chromatography on a column of silica gel, elwira a mixture of ethyl acetate and heptane 80/20.

Get 3 g connection.

Melting point: 133,8-134oC.

Example 14 (Compound N 71)

5-(6-Chloro-3,4-dihydro-2H-benzopyran-8-yl)-3- (piperidine-4-yl)-1,3,4-oxadiazol-2(3H)-she hydrochloride

14.1. Hydrazide 6-chloro-3,4-dihydro-2H-benzopyran-8-Caro-2H-benzopyran-8-carboxylic acid in the form of a solution in 250 ml of ethanol and the mixture refluxed for 8 hours The mixture is cooled in an ice bath and the precipitate is collected by filtration, washed with ethanol and dried under reduced pressure.

Get 31 g connection.

Melting point: 149oC.

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

31 g (0,137 mole) of the hydrazide 6-chloro-3,4 - dihydro-2H-benzopyran-8-carboxylic acid and 500 ml of dioxane is injected at room temperature and with magnetic stirring in a reactor with a capacity of 1 l was added via the dropping funnel 212,7 ml (0,411 mol) 0,139 M phosgene in toluene and the mixture refluxed for 2 h

The precipitate is collected by filtration and dried.

Obtain 26 g of compound.

Melting point: 246oC.

14.3. 5-(6-Chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-(piperidine-4 - yl)-1,3,4-oxadiazol-2(3H)-she hydrochloride

20 g (0.08 mol) of 5-(6 - chloro-3,4-dihydro-2H-benzopyran-8-yl)-1,3,4-oxadiazol-2(3H)-she is in suspension in 300 ml of tetrahydrofuran, is introduced into the three-neck round bottom flask of 500 ml, which was cooled to 0oC and placed under magnetic stirrer, add 15,94 g (0.08 mol) of 1-[(1,1-dimethylmethoxy)carbonyl]piperidin-Ola, up RUB 35.36 g (0,134 mol) of triphenylphosphine and 21.1 ml (0,134 mol) of ethyl ether azodicarbon pressure, the residue is dissolved in 250 ml of dichloromethane, the solution is cooled to 0oC, add 100 ml triperoxonane acid, and the mixture is stirred at room temperature for 2 hours Its concentrated under reduced pressure, add 100 ml of 1N. hydrochloric acid and the precipitate collected by filtration and dried.

Obtain 19 g of the hydrochloride.

Melting point: 297oC.

Example 15 (Compound No. 77)

5-(6-Chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-[1-[4-[4- (dimethylamino)piperidine-1-yl] -4-oxobutyl] piperidine-4-yl] - 1,3,4-oxadiazol-2(3H)-she hydrochloride

1 g (2.68 mmol) of 5-(6-chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-(piperidine-4 - yl)-1,3,4 - oxadiazol-2(3H)-she hydrochloride in solution in 50 ml of acetonitrile is introduced into the three-neck round bottom flask, 250 ml, add to 1.24 ml (are 5.36 mmol) of 1-(4-chloro-1-oxobutyl)-N,N - dimethylpiperidin-4-amine and 1.12 ml (8 mmol) of triethylamine, and the mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure, and the residue is dissolved in water and extracted three times with chloroform. The organic phase is dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elwira a mixture of dt with a solution of gaseous chloroethanol acid in ethanol and, after recrystallization from ethanol, and finally allocate 0,22 g of the hydrochloride.

Melting point: 193oC.

Example 16 (Compound N 74)

5-(6-Chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-[1-(1-methylethyl)piperidine-4 - yl]-1,3,4-oxadiazol-2(3H)-she hydrochloride

From 0.5 g (of 1.34 mmol) 5-(6-chloro - 3,4-dihydro-2H-benzopyran-8-yl)-3-(piperidine-4-yl)-1,3,4 - oxadiazol-2(3H)-she hydrochloride and 0,378 g (of 1.34 mmol) 1-bromo-1-metalicana, through interaction, as described in example 15, to obtain 0.33 g of the connection.

Melting point: 241oC.

Example 17 (Compound N 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-oxadiazol - 2(3H)-she hydrochloride

1 g (2.68 mmol) of 5-(6-chloro-3,4-dihydro-2H - benzopyran-8-yl)-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(3H)-she hydrochloride are added to a solution of 1.13 g (8.60 mmol) indan-2-she's in 15 ml of methanol containing 0,169 ml of acetic acid, add at room temperature 0,709 g (1.13 mmol) of laborgerate sodium, and the mixture is stirred for 18 hours

Add 15 ml of hydrochloric acid and, after stirring for 30 min, the mixture is neutralized 2M aqueous solution of sodium hydroxide.

The mixture is extracted with dichloromethane, the organization of operativnoy thin-layer chromatography, moreover, the elution is carried 98/2 mixture of dichloromethane and methanol.

Get a white solid, hydrochloride which receive the usual way. Allocate 0.8 g of salt.

Melting point: 283-284oC.

Example 18 (Compound N 75)

5-(6-Chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-[1-[5-[4- (dimethylamino)piperidine-1-yl]-5-oxobutyl]piperidine-4-yl]-1,3,4 - oxadiazol-2(3H)-she fumarate (1:2)

A suspension of 2.0 g (5.37 mmol) of 5-(6-chloro-3,4-dihydro-2H-benzopyran-8-yl)-3-(piperidine-4-yl)-1,3,4 - oxadiazol-2(3H)-she hydrochloride in 75 ml of acetonitrile containing 2,24 ml (16 mmol) of triethylamine and 1.44 g (5.37 mmol) of 1-(5-chloro-1-oxobutyl)-N, N-dimethylpiperidin-4-amine, refluxed for 2 h

Add additional 2,88 g (a 10.74 mmol) of 1-(5-chloro-oxobutyl)-N, N-dimethylpiperidin-4 - amine and the boiling continued for 18 h

The solvent is evaporated under reduced pressure, and the residue is dissolved in water and extracted with chloroform. After drying the organic phase, the residue is purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane and methanol in a ratio of from 98/2 to 90/10. Obtain 0.4 g of product in the form of the base, the fumarate of which receive the usual way.

the s according to the invention are illustrated in table 1. In columns R1and R2SS3H5means cyclopropyl group, cC6H11means tsiklogeksilnogo group, cC6H5denotes a phenyl group, a C6C4-n-X denotes a phenyl group substituted by X in the n-position, C6H3-m, n-X2denotes a phenyl group substituted by X in m - and n-positions, 1-C9H9represents 2,3-dihydro-1H-inden-1 - yl, 2-C9H9refers to a group of 2,3-dihydro-1H-inden-2-yl, NC5H10denotes the group piperidine-1-yl and NC5H9-4-(CH3)2refers to a group of 4-(dimethylamino)piperidine-1 Il.

In the column of Salt "-" denotes a base, HBr denotes the hydrobromide, HCl denotes a hydrochloride, 2HCl (1:2) denotes a hydrochloride, fum. means fumarate, 2fum. refers to (1:2) fumarate and tar. means tartrate.

In the column MP.(oC (d) denotes the melting point with decomposition.

Compounds according to the invention were subjected to the tests which have demonstrated their usefulness as substances with therapeutic activity.

Thus, the compounds according to the invention were tested for their affinity towards the receptors 5-HT4in the striatum Guinea pigs in choosing the France), weighing 300 to 400 g, the humane omerville, removed the brain and striatum were cut and frozen at -80oC.

On the day of the experiment, the tissue is thawed at +4oC in 33 volumes of buffer HEPES-NaOH (50 mm, pH 7,4 at 20oC) and homogenized using a mill transmitter stationthe homogenate was centrifuged at 48000 g for 10 min, the precipitate in the centrifuge tube is collected, again suspended and centrifuged in the same conditions, and the final precipitate in the test tube again suspended in buffer HEPES-NaOH in the ratio of 30 mg tissue in ml 100 μl of this membrane suspension is incubated at 0oC for 120 min in the presence of [3H] GR1138808 (ligand described in the cited article, the specific activity of 80 to 85 CI/mmol) in a final volume of 1 ml buffer HEPES-NaOH (50 mm, pH 7,4) in the presence or in the absence of the test compound. The incubation is stopped by filtration through filter Whatman GF/B, pre-treated with 0.1% polyethylenimine, each rinse test tube with 4 ml of buffer at 0oC, again carry out filtering and measure remaining on the filter radioactivity using liquid scintigraphy.

The nonspecific binding determined in the presence of 30 μm serotonin. Specific binding of the studied compounds the percent inhibition of specific binding of [3H]GR1138808, and then determine the IC50the concentration of test compound that inhibits 50% of specific binding.

Nachine IC50the most active compounds are in the range between 0.1 and 10 nm.

Compounds according to the invention were also studied with regard to their effectiveness as agonists or antagonists against the receptors 5-HT4in the esophagus of rats, in accordance with the method described by Baxter and others in Naunyn Schmied. Arch. Pharmacol., (1991) 343, 439. Used male rats Sprague-Dawley, weighing from 300 to 400, Quickly removed from the end of the esophagus fragment of approximately 1.5 cm, remove the muscle layer and reveal the entire length of the inner muscular relating to the mucous membrane, the membrane is placed in a separate vessel containing a solution of Krebs-Henseleit when the 32oC, saturated with oxygen by means of a current of Carbogen (95% O2and 5% CO2), and is associated with an isometric transducer in the basal tension of 0.5, the Reduction of tissue called the addition of 0.5 μm carbachol, there is a waiting period until the compression is stabilized (15 min), and then the product is subjected to the action of serotonin (1 μm) to determine the maximum relaxation. The fabric is washed and after 20 munye concentration from 0.1 to 1 μm. Compounds that cause relaxation, considered as a 5-HT4agonists.

In the case of compounds that do not cause relaxation, the drug is subjected to the action of serotonin with increasing additive concentrations from 0.1 nm to the concentration that causes maximum relaxation, and the relaxation curve caused by serotonin in the presence of the compounds, is then compared to the control curve obtained in the absence of the specified connection. If his presence causes the curve to shift to the right of the studied compound in this case is considered as a 5-HT4antagonist.

The results of these two biological tests show that the compounds according to the invention are strong ligands for serotoninergicheskih receptor type 5-HT4and that they act on these receptors either as agonists or as antagonists.

Finally, the compounds according to the invention have in vitro studies regarding their affinity to H3histaminergic receptors of rat brain, essentially as described by A. Korte and others, Biochem.Phys.Res.Commun., 168, 979-986, and West, R. E., and others, Mol.Pharmacol.,(1990) 38, 610-613.

Male rats Sprague-Dawley (OFA, lffa Credo, France) weighing 250 to 300 g, humane worldsuck) in 20 volumes of buffer Tris-HCl (50 nm, a pH of 7.4 at 22oC). The homogenate was centrifuged at 1000 g for 10 min and then the supernatant is subjected to further centrifugation at 45000 g for 20 min at 4oC. 3 Quiroga precipitate in the centrifuge tube was washed and re-suspended in buffer, homogenized and centrifuged. The final precipitate is again suspended in buffer at a ratio of 100 mg original tissue per ml, and then divided into 11 aliquot fractions, which are frozen at -80oC. on the day of the experiment the membrane suspension (100 ál, 300 to 400 μg protein) are incubated at 30oC for 60 min in the presence of 0.5 nm [3H]N- - methylhistamine (specific activity of from 75 to 80 CI/mmol, New England Nuclear, DuPont de Nemours, Boston, USA) in a final volume of 500 ál of buffer Tris-HCl in the presence or in the absence of the test compound. The incubation is stopped by filtration through filters Whatman GF/BBTpre-treated polyethylenimine (0.4 percent). Each reaction tube rinsed 3 times with 4 ml of cold (0oC) buffer Tris-HCl. The filters are dried in a thermostat at 120oC for 5 minutes Remaining on the filters radioactivity determine liquid scintigraphy. The nonspecific binding determined in the presence of 10 μm tabemasu connection calculate the percent inhibition of specific binding of [3H]N-methylhistamine, and then determine the concentration of the IC50of a compound that inhibits 50% of the binding.

The most active compounds according to the invention in this test have the IC50about 5 nm.

The results of the various biological tests carried out on the compounds according to the invention show that they are ligands for receptors 5-HT4and/or H3receptors (see table. 2).

These results suggest that these compounds can be used for the treatment and prevention of disorders in which the involved receptors 5-HT4and/or H3in particular at the level of the Central nervous system, gastrointestinal tract, lower urinary tract or cardiovascular system.

At the level of Central nervous system disorders and problems include, in particular, neurological and psychiatric disorders such as cognitive disorders, psychosis, obsessive or compulsive behavior and depression and anxiety. Cognitive disorders include, for example, deficits of memory and attention state of dementia (senile dementia type Alzheimer's disease or als in itself, for example, paranoia, schizophrenia, mania and autism. Compulsive neuroses include, for example, eating disorders, losses of appetite or sharply increased feelings of hunger. Depression and anxiety include, for example, anxiety when waiting for something (before surgery, before dental treatment, etc.,) or anxiety caused by dependence or withdrawal from alcohol or drugs. Finally, you can also mention mania, epilepsy, sleep disorders, temporary emotional disorders or migraine.

At the level of the gastro-intestinal system disorders and problems include, in particular, direct or indirect violation of the motility of the esophagus, stomach or intestines, nausea or specific complaints, such as dyspepsia, ulcer, eructation, flatulence, irritable bowel syndrome, disorders of intestinal secretion or diarrhea, such as diarrhea caused by cholera or cancer syndrome, or violations that may or may not be associated with air pollution, such as asthma, rhinitis, and difficulty breathing.

At the system level lower urinary tract these disorders and problems include in particular urinary incontinence, dysuria or zadiristy pathology, related directly or indirectly to cardiac arrhythmia, increased pressure, ischemia, myocardial infarction, unstable or acute pain in the heart, or to the problems of re-blockage after restoring the conductivity of blood vessels, for example, after fibrinolytic or thrombolytic therapy, angioplasty or cardiac surgery.

Glaucoma is a disorder that can be treated with compounds according to the invention.

Compounds according to the invention can be presented in all forms of compositions suitable for enteral or parenteral administration, such as tablets, pills, capsules, including hard gelatin capsules, suspensions or solutions, which must be swallowed or injected, such as syrups and the like, in combination with suitable excipients, and in doses that make possible the daily introduction of from 0.001 to 20 mg/kg

Examples of pharmaceutical compositions

Solution for injection, mg:

The active substance is 5

Glucose - 250

Water for injection, ml - Up to 5

one ampoule of 5 ml

Gelatin capsule, mg:

Active substance - 100

Talc - 24

Silica gel - 1

one capsule 125 mg

Tablet, mg:

Activable 475 mg.

Syrup

The active ingredient, g - 5

Methyl ester of 4-hydroxybenzoic acid, mg - 150

Sucrose, d - 50

Distilled water, ml - 100

one vial 100 ml

These compositions are prepared by simple mixing of components in accordance with conventional technologies.

1. Derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(3H)-she may be in the form of a pure optical isomer or mixture of such isomers, corresponding to the General formula I

< / BR>
in which R1group (C1-C4)alkyl or (C3-C7)cycloalkenyl;

X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy, or or1and X1together a group of the formula-OCH2O-, -O(CH2)2-, -O(CH2)3-; -O(CH2)2O - or-O(CH2)3O-;

X2is a hydrogen atom or amino group;

X3the atom of hydrogen or halogen;

R2or a hydrogen atom, or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)Alki the CO-Z, in which n = 1 to 6, and Z is the group piperidine-1-yl or 4-(dimethylamino)piperidine-1-Il,

in free base form or salt accession acid.

2. Connection on p. 1, wherein R2- group 2-ethoxy-2-oxoethyl, group 2-(dimethylamino)-2-oxoethyl, group 2-[(methylsulphonyl)amino] ethyl group, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, butyl group, group, 4,4,4-triptorelin or group 4 trifter-3-hydroxybutyl.

3. Connection on p. 1, wherein R2the phenyl group(C1-C3)alkyl, possibly substituted on the phenyl ring by a halogen atom, a trifluoromethyl group or by one or two methoxy groups.

4. Connection on p. 1, wherein R2- group 4-oxo-4-(piperidine-1-yl)butyl, 2-[4(dimethylamino)-piperidine-1-yl]-2-oxoethyl, group 4-4-dimethylamino)piperidine-1-yl]-4-oxobutyl, group 5-[4-(dimethylamino)piperidine-1-yl] -5-oxopent or group of 6-[4-(dimethylamino)-piperidine-1-yl]-6-oxohexyl.

5. The method of obtaining compounds on p. 1, characterized in that the ester of General formula II

< / BR>
in which R1X1X2and X3such, as defined in paragraph 1,

R3- the group is methyl or ethyl,

subject cooperation is by giving oxadiazole General formula IV

< / BR>
the latter are then subjected to interaction with piperidine-4-I of General formula V

< / BR>
in which R2the same as defined for General formula (I), but other than a hydrogen atom, or it represents a protective group (1,1-dimethylmethoxy)carbonyl,

in the presence of triphenylphosphine and ethyl ester of azodicarboxylic acid, and then, if necessary, remove the protection from the nitrogen atom piperidino ring, and when2is a hydrogen atom, and if desired, the compound obtained is subjected to interaction with a derivative of General formula R2- X, in which X represents a leaving or carbonyl functional group, and R2the same as defined for General formula (I), but other than a hydrogen atom, and when it is necessary to obtain the target compound, in which R2is a group of 2,3-dihydro-1H-indenyl, conduct rehabilitation aminirovanie corresponding indanone compound of General formula (I) in which R2- the hydrogen atom.

6. Drug exhibiting the property of ligands and / or prevention of disorders of the receptors 5-HT4and/or H3, characterized in that it consists of a connection on one of the PP.1 to 4.

7. The pharmaceutical what is the connection site of the PP.1 - 4 in combination with excipients.

Priority signs and items:

09.11.95 on PP.2 and 3; p. 1 except for the features set forth below; in paragraph 4 R2is a group of 4-oxo-4-(piperidine-1-yl)butyl group, 4-[4-(dimethylamino)piperidine-1-yl]-4-oxobutyl.

04.03.96: in paragraph 1 OR1and X1together, the group of the formula-O(CH2)2-, -O(CH2)3-; in paragraph 4 R2- group 5-[4-dimethylamino)piperidine-1-yl]-5-oxopent.

05.11.96 (PCT): p. 1 R2- group phenoxy(C2-C4)alkyl, a group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl or a group of General formula -(CH2)nCO-Z, in which n = 1 to 6, and Z is the group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl; in paragraph 4 R2- group 2-[4-(dimethylamino)piperidine-1-yl]-2-oxoethyl or group of 6-[4(dimethylamino)piperidine-1-yl]-6-oxohexyl.

 

Same patents:

The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular to substituted derivatives of pyrazole and means of having a weed-killing activity

The invention relates to a derivative (azetidin-1-illlil)lactams of the formula (I) and their pharmaceutically acceptable salts, where R - (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, aryl or het1and (C3-C7-cycloalkyl, optionally substituted with 1-2 substituents selected from (C1-C4)-alkyl and fluorine; R1is phenyl, optionally substituted by 1-2 halosubstituted; R2- -CONR3R4, -CONR5((C3-C7-cycloalkyl), -NR3R4that gets3or a group of formula (a), (b), (C); X - (C1-C4-alkylene; X1- directional communication, X2- directional communication or CO; m = 1; used in the treatment of diseases by producing antagonistic action on tachykinin, working in human NK1-, NK2- and NK3the receptor or in their combinations

The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia

The invention relates to new isoxazol derivative of General formula I, where R1denotes optionally substituted C6-C14airgroup or 5-6-membered heterocyclic group containing one heteroatom selected from nitrogen, oxygen, sulfur; R2denotes a hydrogen atom, halogen atom, optionally substituted C1-C6alkyl group, a C2-C6alkenylphenol group2-C6alkylamino group3-C10cycloalkyl group3-C10cycloalkenyl group, cyano, carboxitherapy,1-C7alkanoglu,2-C7alkoxycarbonyl group or optionally substituted carbamoyl; R3denotes optionally substituted by an amino group or a saturated 5-6-membered heterocyclic group containing a nitrogen atom; X represents an oxygen atom or a sulfur atom; n denotes an integer from 2 to 6, and their pharmaceutically acceptable salts

The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to new 4-substituted piperidine derivative that is related to ones antagonists neirokinina 2 (NK), which can be used, for example, in the treatment of diseases such as asthma, and method of production thereof

The invention relates to medicine, in particular it is proposed to use derivatives of the formula I, where R = CH3or6H5and n = 0 or 1, as vasodilator, hypotensive, antispasmodic, anti-means and platelet aggregation inhibitors and pharmaceutical compositions on their basis
Up!