Derivatives of 5-aryl-3-(8-azabicyclo[3.2.1]oct-3-yl)-1,3,4 - oxadiazol-2(3h)-she, the retrieval method, the drug and pharmaceutical composition

 

(57) Abstract:

The present invention relates to derivatives of 5-aryl-3-(8-azabicyclo[3.2.1] Oct-3-yl)-1,3,4-oxadiazol-2(3H)-it General formula I, in which R1represents an alkyl or cycloalkenyl group, X1represents a hydrogen atom or halogen, or CNS group, or an alternative OR1and X1together represent-co2O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)2O - or-O(CH2)3O - group, X2represents a hydrogen atom or amino group, X3represents a hydrogen atom or halogen, R2represents a hydrogen atom, possibly substituted alkyl group, possibly substituted phenylalkyl group or a group -(CH2)nCO-Z, in which n equals the number of 1 to 6, Z is a 1-piperidino group. There is also described a method of production thereof, pharmaceutical composition and a drug. The connection can be used for treatment and prevention of disorders of the Central nervous system, gastro-intestinal tract. 4 C. and 3 h.p. f-crystals, 2 tab.

The present invention relates to compounds corresponding to General formula (I)
X1represents a hydrogen atom or halogen, or (C1-C4)CNS group, or an alternative

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

R2represents a hydrogen atom, (C1-C6)alkyl group, phenyl(C1-C4)alkyl group or a group of General formula -(CH2)nFROM a-Z, in which n is a number from 1 to 6, and Z is a 1-piperidino or 4-(dimethylamino)-1-piperidino group.

When R2represents an alkyl group, such a group is preferably bucilina group.

When R2represents phenyl(C1-C3)alkyl group, such a group is preferably 2-phenylethylene group.

When R2represents a group of General formula -(CH2)nFROM a-Z, this group is preferably 4-[4-(dimethylamino)-1-piperidyl]-4-oxobutyl group, 5-[4-(dimethylamino)-1-piperidin the invention can exist in the form of free bases or pharmaceutically acceptable salts accession acid. Because tropenbos rings they may also be in the form of endo - or Exo-isomers. Moreover, some of the substituents R2may contain asymmetric carbon atom; therefore, these compounds may exist in the form of various pure or mixed geometric and/or optical isomeric forms.

Known (patent application EP-0554794) N-(8-azabicyclo[3.2.1]Oct-3-yl)benzamide, which have a structure almost the same as that of the compounds according to the invention, and which have affinity to the receptors 5-HT3and 5-HT4.

According to the invention compounds of General formula (I) can be obtained, as shown in the following diagram:

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Ester of General formula (II) in which R1X1, X2and X3are as defined above, and R3represents a methyl or ethyl group, 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 is subjected to cyclization in oxadiazol General formula (IV) or with phosgene in an aprotic solvent, for example dioxane, or using phenylcarbamate in Aprovel with tropaeolum General formula (V), in which R2is the same as defined with respect to General formula (I), but other than a hydrogen atom, or an alternative is a (1,1-dimethylmethoxy)carbonyl protective group, in the presence of triphenylphosphine or utilization.bacteria in an aprotic solvent, for example tetrahydrofuran, and then, if necessary, with the nitrogen atom tropenbos of the ring using triperoxonane acid removes the protection of obtaining compounds of General formula (I) in which 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 group such as halogen atom or methanesulfonate or para-toluensulfonate group, and R2is the same as defined with respect to General formula (I), but other than a hydrogen atom, in the presence of triethylamine in an aprotic solvent, for example acetonitrile. Source esters of General formula (II) and/or the corresponding acids are described in particular in patent applications EP-0231139, EP-0234872, WO-84/03281, WO-93/16072 and WO-94/19344.

Tropanol General formula (V) are known or can be obtained by any known means. 8-[(1,1-Dimethylmethoxy carb is 2">

The following examples illustrate in detail the production of several compounds according to the invention. Elemental microanalysis and IR and NMR spectra confirm the structures of the obtained compounds. Rooms specified in the headers of the compounds given in parentheses correspond to the numbers in the table. 1, shown later.

Example 1 (Compound 1)

5-(4-Amino-5-chloro-2-methoxyphenyl)-3-(8-methyl-8-azabicyclo[3.2.1] Oct-3-yl)-1,3,4-oxadiazol-2(ZN)-he

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, suspended in 460 ml of ethanol, loaded into the reactor with a capacity of 1 liter Over a period of time of 15 minutes add 119 g (2,39 mol) of hydrazine hydrate is added and the mixture heated under reflux for 15 hours.

The mixture is cooled using an ice bath, the precipitate is filtered off, washed with ethanol and dried under reduced pressure at 80oC for 2 hours and 30 minutes.

Thus 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 for add to the suspension of 37.7 g (0,175 mole) of the hydrazide of 4-amino-5-chloro-2-methoxybenzoic acid in 1200 ml of dioxane in a reactor with a capacity of 3 liters

This mixture was stirred at room temperature overnight, and then heated at 80oC for 1 hour. The excess phosgene is removed by passing a stream of argon at this temperature for 2 hours. Then 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, the residue is ground to powder with isopropyl ether. The obtained solid is filtered off and dried. So get 60,3 g of the product. The melting point of 214oC.

1.3. Hydrochloride phenylmethylene ether [2-chloro-4-[4-(8-methyl-8-azabicyclo[3.2.1] Oct-3-yl)-5-oxo-4,5-dihydro - 1,3,4-oxadiazol-2-yl] -5-methoxyphenyl]carbamino acid

1 g (2,66 mmol) phenylmethanol ether [2-chloro-5-methoxy-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl] carbamino acid, of 0.47 g of 3.33 mmol) of endo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol and 1.05 g (4 mmol) of triphenylphosphine dissolved in 15 ml of tetrahydrofuran, loaded into a three-neck round bottom flask with a capacity of 50 ml, the mixture is cooled to 0oTo add 0.63 ml, i.e. 0,70 g (4 mmol) of utilization.bacteria and the mixture is stirred at 40oC for 3 hours and 30 minutes.

The solvent is evaporated the e substance is collected by filtration. After washing and drying obtain 1.6 g of a solid substance. The hydrochloride of this solid get in the traditional way and pounded into powder with acetone and recrystallized from ethanol. Get 2,22 g of salt.

1.4. 5-(4-Amino-5-chloro-2-methoxyphenyl)-3-(8-methyl-8-azabicyclo[3.2.1] Oct-3-yl)-1,3,4-oxadiazol-2(3H)-he

0,94 g (1,76 mmol) of the hydrochloride phenylmethylene ether [2-chloro-4-[4-(8-methyl-8-azabicyclo[3.2.1] Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -5-methoxyphenyl] carbamino acid load in a three-neck round bottom flask containing 17 ml of acetic acid, add 3,12 ml of 33% Hydrobromic acid in acetic acid (i.e., 7 equivalents of Hydrobromic acid) and this medium is stirred for 24 hours.

Add 20 ml of diethyl ether, the solid is collected by filtration, washed with diethyl ether and transferred to the water. Add aqueous ammonia until alkaline pH and get a very fine precipitate, which is collected by filtration. After drying allocate 0.45 g connection. Melting point 208oC.

Example 2 (Compound 3)

Hydrochloride 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(8-azabicyclo[3.2.1]Oct-3-yl)-1,3,4-oxadiazol-2(3H)-it

2.1. Penile the l] -2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid

7,1 g (0,030 mol) phenylmethanol ester of endo-8-[(1,1-dimethylmethoxy)carbonyl]-8-azabicyclo[3.2.1]Octan-3-ol, 10 g (0,025 mol)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 (obtained from the corresponding methylbenzoate according to the method described in stages 1.1 and 1.2), 8.44 grams (to 0.032 mol) of triphenylphosphine, 5.6 g (to 0.032 mol) of utilization.bacteria and 400 ml of dry tetrahydrofuran is loaded into a round bottom flask and the mixture was stirred at room temperature overnight. The solvent is evaporated under reduced pressure, the residue is purified by chromatography on silica gel, elwira a mixture of ethyl acetate and heptane (50/50), and get 13,0 g connection. Melting point 210oC.

2.2. Fenilmetilovy ether [6-chloro-8-[4-(8-azabicyclo[3.2.1]Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamino acid

of 13.75 g (0,022 mol) phenylmethanol ether [6-chloro-8-[4-[8-[(1,1-dimethylmethoxy)carbonyl] -8-azabicyclo[3.2.1]Oct-3-yl]-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamino acid dissolved in 150 ml of chloroform, loaded into a three-neck round bottom flask with a capacity of 500 ml, slowly for 20 minutes, add the number triperoxonane acid (17,05 ml; 0,221 mol) and the mixture is stirred for 5 hours.

The mixture is concentrated, and the residue is crystallized from 300 ml of diethyl ether. The solid is transferred into 100 ml of water, add 3 ml of 30% sodium hydroxide solution. This mixture is extracted with chloroform and evaporated. The residue is ground to powder with diisopropyl ether. Get 7,88 g connection. Melting point 140oC.

2.3. Hydrochloride 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(8-azabicyclo[3.2.1]Oct-3-yl)-1,3,4-oxadiazol-2(3H)-it

Receive a suspension of 0.88 g (1,72 mmol) phenylmethanol ether [6-chloro-8-[4-(8-azabicyclo[3.2.1]Oct-3-yl]-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamino acid in 10 ml of acetic acid, add 2.2 ml of 33% Hydrobromic acid in acetic acid and the mixture is stirred over night. To the mixture is added diethyl ether, the precipitate is collected by filtration, washed with diethyl ether and placed in water, the solution washed with ethyl acetate, add 0.5 ml of 30% aqueous sodium hydroxide solution, the mixture is extracted four times with chloroform, the organic phase is washed with water, dried over sodium sulfate, filtered and the solvent evaporated. The residue is ground to powder the t solution of hydrogen chloride in ethanol. Finally get to 0.61 g of the hydrochloride. Melting point 210oC.

Example 3 (Compound 5)

The hydrobromide 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(8-butyl-8-azabicyclo[3.2.1]Oct-3-yl)-1,3,4-oxadiazol-2(3H)-it

3.1. Fenilmetilovy ether [6-chloro-8-[4-(8-butyl-8-azabicyclo[3.2.1]Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl-2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid

1.54 g (3 mmol) phenylmethanol ether [6-chloro-8-[4-(8-azabicyclo[3.2.1] Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid and 1.2 g (12 mmol) of triethylamine dissolved in 20 ml of acetonitrile, are loaded into a 100-ml three-neck round bottom flask, add 0,82 g (6 mmol) 1-bromobutane and the mixture is heated at 60oC for 20 hours.

The solvent is evaporated, the residue is transferred into water and extracted with ethyl acetate, the organic phase is washed with water and dried, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on silica gel, elwira mixture of chloroform, methanol and aqueous ammonia (95/5/0,5). Earn 1.25 g of compound. Melting point 142oC.

3.2. The hydrobromide 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(8-BC-8-azabicyclo[3.2.1] Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid, 12 ml of acetic acid and 3 ml of 33% solution of Hydrobromic acid in acetic acid are loaded into a round bottom flask of 50 ml and the resulting solution was stirred at room temperature for 18 hours.

Add diethyl ether and the solid is collected by filtration, washing with diethyl ether, and crystallized from 2-propanol. Get to 0.92 g of the hydrobromide, which is pounded into powder with ethanol and finally get 0,79 g of pure compound. Melting point >260oC.

Example 4 (Compound 4)

5-(8-Amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[8-(2-phenylethyl)-8-azabicyclo[3.2.1]Oct-3-yl]-1,3,4-oxadiazol-2(3H)-he

4.1. Fenilmetilovy ether [6-chloro-8-[4-[8-(2-phenylethyl)-8-azabicyclo[3.2.1] Oct-3-yl] -5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid

1,33 g (2.6 mmol) phenylmethanol ether [6-chloro-8-[4-(8-azabicyclo[3.2.1] Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl]carbamino acid, of 1.05 g (10.4 mmol) of triethylamine and 0.96 g (5.2 mmol) (2-bromacil)benzene dissolved in 20 macedoniella, loaded into a three-neck round bottom flask with a capacity of 100 ml, and this mixture is heated at 60oC for 18 hours.

To the.

The solvent is evaporated under reduced pressure, the residue is transferred into water and extracted with chloroform, the organic phase is washed with water and dried, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elwira mixture of chloroform, methanol and aqueous ammonia (99/1/0,1), Obtain 1.28 g of product, crystallization from diisopropyl ether leads to obtain 1.18 g of the pure compound. Melting point 118oC.

4.2. 5-(8-Amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[8-(2-phenylethyl)-8-azabicyclo[3.2.1]Oct-3-yl]-1,3,4-oxadiazol-2(3H)-he

1.18 g (1,91 mmol) phenylmethanol ether [6-chloro-8-[4-[8-(2-phenylethyl)-8-azabicyclo[3.2.1] Oct-3-yl]-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl] -2,3-dihydro-1,4-benzodioxin-5-yl] carbamino acid, 12 ml of acetic acid and 2.95 ml of Hydrobromic acid dissolved in acetic acid are loaded into a round bottom flask with a capacity of 50 ml, and the solution is stirred at room temperature for 18 hours.

Add diethyl ether, the precipitate is collected by filtration, washing with diethyl ether. Thus obtained crude hydrobromide transferred to a 13 ml of water and 20 ml of chloroform, add 0.5 ml of 30% , and the residue is ground to powder with diisopropyl ether. Get 0,703 g of pure compound in free base form. Melting point 227oC.

Example 5 (Compound 7)

Hydrochloride 3-(8-azabicyclo[3.2.1] Oct-3-yl)-5-(6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl)-1,3,4-oxadiazol-2(3H)-it

2.83 g in (11.2 mmol) of 5-(6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl)-1,3,4-oxadiazol-2(3H)-she (obtained from the corresponding methylbenzoate according to the method described in stages 1.1 and 1.2), 2,54 g in (11.2 mmol) of endo-8-(1,1-dimethylethoxysilane)-8-azabicyclo[3.2.1]Octan-3-ol and 4.11 g (15,68 mmol) of triphenylphosphine load in 100 ml of tetrahydrofuran, the mixture is cooled to 0oIn argon atmosphere, add 3.0 ml of utilization.bacteria and the mixture was stirred at room temperature over night.

The solvent is evaporated under reduced pressure, the residue is transferred in 100 ml of dichloromethane, add a 17.3 ml triperoxonane acid and the mixture is stirred for 12 hours.

The mixture is concentrated until dry, the residue is transferred in 1 N. hydrochloric acid, the mixture was washed with diethyl ether and then with ethyl acetate, the aqueous phase add the potassium carbonate and the mixture extracted with chloroform. The aqueous phase is washed and dried, the solvent is evaporated under reduced giving the status and the residue is recrystallized from a mixture of water and 2-propanol (9/1). After filtration and drying obtain 1.8 g of the connection. Melting point 254oC.

Example 6 (Compound 9)

Hydrochloride 3-(8-butyl-8-azabicyclo[3.2.1] Oct-3-yl)-5-(6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl)-1,3,4-oxadiazol-2(3H)-it

A mixture of 0.96 g (of 2.38 mmol) of the hydrochloride of 3-(8-azabicyclo[3.2.1]Oct-3-yl)-5-(6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl)-1,3,4-oxadiazol-2(3H)-she, of 0.28 ml, i.e., 0.36 g (2,62 mmol), bromobutane, 0,72 g (5,24 mmol) of potassium carbonate and 40 ml of acetonitrile is heated at 60oWith in 24 hours.

The solvent is evaporated under reduced pressure, the residue is transferred into water and extracted with chloroform, the aqueous phase is washed and dried, the solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica, elwira dichloromethane. Base transferred to 1 equivalent of a solution of hydrogen chloride in ethanol, the solution is concentrated and the salt is recrystallized from 2-propanol, filtered and dried. Get 0,38 g connection. Melting point 242oC.

Example 7 (Compound 10)

Hydrochloride 3-(8-azabicyclo[3.2.1] Oct-3-yl)-5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,3,4-oxadiazol-2(3H)-it

3.58 g (15 mmol) of 5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,3,4-oxadiazol-2(3H)-she (Pol-(1,1-dimethylethoxysilane)-8-azabicyclo[3.2.1] Octan-3-ol and the 5.51 g (21 mmol) of triphenylphosphine load in 120 ml of tetrahydrofuran, the mixture is cooled to 0oIn argon atmosphere, add 4.0 ml, i.e., of 4.44 g (25.5 mmol), utilization.bacteria and the mixture was stirred at room temperature over night.

The solvent is evaporated under reduced pressure, the residue is transferred into 150 ml of dichloromethane, add 23,1 ml triperoxonane acid and the mixture is stirred for 12 hours. The mixture is concentrated until dry, the residue is transferred in 1 N. hydrochloric acid, the mixture was washed with diethyl ether and then with ethyl acetate, the aqueous phase add potassium carbonate to pH 10 and the mixture is extracted with chloroform. The organic phase is washed and dried, the solvent is evaporated under reduced pressure, the residue is transferred to 1 equivalent of a solution of hydrogen chloride in ethanol, the mixture is concentrated until dry and the residue is recrystallized from a mixture of 2-propanol and water (49/1). After filtration and drying obtain 1.7 g of the compound. Melting point >260oC.

Example 8 (Compound 11)

Hydrochloride 3-[8-(2-phenylethyl)-8-azabicyclo[3.2.1]Oct-3-yl]-5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,3,4-oxadiazol-2(3H)-it

A mixture of 0.80 g (of 2.08 mmol) of the hydrochloride of 3-(8-azabicyclo[3.2.1]Oct-3-yl)-5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,3,4-oxadiazol-2(3H)-she 0,31 P>oWith in 24 hours.

The solvent is evaporated under reduced pressure, the residue is transferred into water and extracted with chloroform, the organic phase is washed and dried, the solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica gel, elwira a mixture of dichloromethane and ethanol (98/2) Base transferred to 1 equivalent of a solution of hydrogen chloride in ethanol, the solution is concentrated and the salt is recrystallized from ethanol, filtered and dried. Obtain 0.84 g connection. Melting point 266oC.

Example 9 (Compound 15)

The hydrobromide 5-(4-amino-5-chloro-2-methoxyphenyl)-3-(8-azabicyclo[3.2.1]Oct-3-yl)-1,3,4-oxadiazol-2(3H)-it

9.1 Fenilmetilovy ether [2-chloro-4-[4-(8-azabicyclo[3.2.1]Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]-5-methoxyphenyl]carbamino acid

5,78 g (15 mmol) phenylmethanol ether [2-chloro-5-methoxy-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl] carbamino acid, 6.0 g (23 mmol) of triphenylphosphine and 3.5 g (15 mmol) of 8-[(1,1-dimethylmethoxy)carbonyl]-8-azabicyclo[3.2.1] Octan-3-ol dissolved in 50 ml of tetrahydrofuran, loaded into a three-neck round bottom flask with a capacity of 100 ml, the solution is cooled to 0oC and added dropwise to 3.64 ml of ethyl ether Azadirachta under reduced pressure, the residue is transferred in 50 ml of dichloromethane, at 0oWith add 25 ml triperoxonane acid and the resulting solution was stirred at room temperature for 4 hours.

The solvent is evaporated under reduced pressure, add 50 ml of water and 100 ml diethyl ether and the precipitate collected by filtration, washed with diethyl ether and dried. Obtain 5.0 g of a white solid. Melting point 156-157oC.

9.2. The hydrobromide 5-(4-amino-5-chloro-2-methoxyphenyl)-3-(8-azabicyclo[3.2.1]Oct-3-yl)-1,3,4-oxadiazol-2(3H)-it

5.0 g (10.6 mmol) phenylmethanol ether [2-chloro-4-[4-(8-azabicyclo[3.2.1]Oct-3-yl)-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]-5-methoxyphenyl] carbamino acid, dissolved in 10 ml of 33% Hydrobromic acid in acetic acid are placed in a round bottom flask with a capacity of 25 ml and the mixture is stirred at room temperature for 24 hours.

Add diethyl ether, the precipitate is collected by filtration and washed several times with ether. Get to 4.2 g of compound. Melting point 235-237oC.

Example 10 (Compound 13)

(-)-Bitartrate 5-{ 4-amino-5-chloro-2-methoxyphenyl)-3-[8-[1-[5-[4-(dimethylamino)piperidine-1-yl] -5-oxobutyl] -8-azabicyclo[3.2.1]Oct-3-yl]-1,3,4-oxadiazole-2(3H)-it, 0,286 g (1,16 mmol) 1-(5-chloro-1-oxobutyl)-N,N-dimethylpiperidin-4-amine and 0,484 ml (3,48 mmol) of triethylamine, dissolved in 10 ml of N,N-dimethylformamide, loaded into a three-neck round bottom flask with a capacity of 25 ml and the mixture is heated under reflux for 18 hours.

The solvent is evaporated under reduced pressure, water is added and the mixture extracted with dichloromethane. The solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica gel, elwira first with a mixture of dichloromethane and methanol (90/10), and then a mixture of dichloromethane, methanol and aqueous ammonia (80/20/2).Receive the oil which is treated with two equivalents of tartaric acid, and finally obtain 0.35 g of a white solid. Melting point 198-201oC.

Table. 1 illustrates the chemical structures and physical properties of some compounds according to the invention.

The tests, which were subjected to the compounds according to the invention, demonstrate the importance of these compounds as therapeutically active substances.

Thus, the compounds according to the invention was investigated in respect to their affinity for the receptors 5-HT4in the striatum Guinea pigs in accordance with known (Grossman , Dalat their brain and striatum excised and frozen at -80oC.

On the day of the experiment, the tissue is thawed to 4oWith 33 volumes of buffer solution HEPES-NaOH (50 mm, pH 7.4 at 20oC) the mixture is homogenized using a homogenizer, the homogenate was centrifuged at 48000 x g for 10 minutes, the precipitate was separated and resuspended, the suspension is again centrifuged in the same way, and the final precipitate resuspended in buffer solution HEPES-NaOH in the ratio of 30 mg of tissue in 1 ml 100 μl of this membrane suspension is incubated at 0oC for 120 minutes in the presence of [3H] GR 113808 (ligand described in the above-mentioned article, the specific activity of 80-85 Curie/mmol) in a final volume of buffer solution HEPES-NaOH (1 ml, 50 mm, pH 7.4) in the presence or in the absence of the test compound. The incubation terminated by filtration through filter Whatman GF/B, pre-treated with 0.1% polyethylenimine, each tube rinsed with 4 ml of buffer solution at 0oWith, perform additional filtering and liquid scintigraphy to measure the radioactivity remaining on the filter.

The nonspecific binding determined in the presence of 30 μm serotonin. Specific binding is the AI of the test compounds to determine the percent inhibition of specific binding of [3H] GR 113808, and later IR50the concentration of the test compound that inhibits binding by 50%.

Value IR50the most active compounds are between 1.3 and 340 nm.

Compounds according to the invention also investigated for their agonistic or antagonistic action on the receptors 5-HT4in the esophagus of rats in accordance with the described method (Baxter et al., Naunyn. Schmied. Arch. Pharmacol., 1991, 343-439).

Use of male rats Sprague-Dawley weighing from 300 to 450, Quickly remove the fragment of the end portion of the esophagus (approximately 1.5 cm), remove the muscle layer and longitudinally to expose the internal muscular mucosa, enclosed in an insulated container containing Krebs-Henseleit solution at 32oWith, oxygenated flow of Carbogen (95% 02and 5% C02), and is associated with an isometric transducer at a basal tension of 0.5, the Reduction in tissue induce the addition of 0.5 μm carbachol, and after stabilization reduction (15 minutes) on the drug affect serotonin (1 μm) for the quantitative determination of maximum relaxation. The fabric is washed,and after 20 minutes, add an additional amount of 0.5 µm carbachol and drug act iSpazio, considered as a 5-HT4agonist.

For compounds that do not induce relaxation, medication affect serotonin, increasing cumulative concentrations from 0.1 nm to the concentration that induces maximum relaxation, and then the curve of the relaxation caused by serotonin, in the presence of the test compound, compared with the standard curve determined in the absence of the specified connection. If its presence induces a shift of the curve to the right, then the test compound is considered as a 5-HT4antagonist.

The results of these two biological tests show that the compounds according to the invention are strong ligands of the serotonin receptors 5-HT4type and that they act on these receptors either as agonists or as antagonists.

In conclusion, the compounds according to the invention were tested in vitro for their affinity to histaminergic receptors N3rat brain, in essence known (A. Korte et al., Biochem. Phys. Res. Commun., 1990, 160, 979-986, and West R. E. et al., Mol. Pharmacol., 1990, 38, 610-613) method.

Rats male Sprague Dawley (OFA, Iffa Credo, France) weighing 250 to 300 g kill and remove their brain. Tissue homogenized with ispol,4 at 22oC). The homogenate was centrifuged at 1000 x g for 10 minutes and then re-centrifuged supernatant liquid at a 45,000 x g for 20 minutes at 4oC. Then the precipitate is washed with resuspendable in buffer solution, homogenization and centrifugation. The final precipitate resuspended in a buffer solution at a ratio of 100 mg original tissue to 1 ml, and then divided into 11 ml aliquot fractions, which are frozen at -80oC. on the day of the experiment the membrane suspension (100 ál, 300 to 400 mg of protein) is incubated at 30oC for 60 minutes in the presence of 0.5 nm [3N] N-methylhistamine (specific activity of from 75 to 80 Curie/mmol, New England Nuclear, DuPont de Nemours, Boston, USA) in a final volume of buffer solution Tris-HCI (500 μl) in the presence or in the absence of the test compound. The incubation terminated by filtration through filters Whatman GF/B, pre-treated polyethylenimine (0.4 percent). Each reaction tube rinsed three times with 4 ml of cold (0o(C) buffer solution Tris-HCI. The filters are dried in an oven at 120oC for 5 minutes. The radioactivity remaining on the filters determined by liquid scintigraphy. The nonspecific binding determined in the presence II test connection count percent inhibition of specific binding of [3N] N-methylhistamine, after which determine the concentration IR50that inhibits binding by 50%.

Compounds according to the invention, which are the most active in this test, a value IR50approximately 35 nm.

The results of the different biological tests carried out on the compounds according to the invention, show that the compounds are ligands of the receptors 5-HT4and/or H3.

These results indicate that the compounds can be used for the treatment and prevention of disorders that involve the receptors 5-HT4and/or H3in particular in relation to the Central nervous system, gastrointestinal system, the lower part of the urinary system or the cardiovascular system.

As for the Central nervous system, these disorders and diseases include, mainly neurological and psychiatric disorders such as cognitive disorders, psychosis, compulsive and obsessive behavior, and depression and anxiety. Cognitive disorders include, for example, deficits of memory and attention state of dementia (senile demen and Parkinson's disease. Psychosis include, for example, paranoia, schizophrenia, mania and autism. Compulsive and obsessive behavior includes, for example, disorders associated with eating, such as bulimia or anorexia. Depression and anxiety include, for example, the anxiety associated with waiting time (before surgery, before dental treatment and so on), and anxiety caused by alcohol or drug dependence or withdrawal. Finally, you can also mention mania, epilepsy, sleep disorders, seasonal affective disorder and migraine.

As for the gastrointestinal system, these disorders and diseases include direct and indirect disorders gastropodes of the esophagus, stomach or intestines, nausea, specific disorders, such as indigestion, ulcers, gastroesophageal reflux, flatulence, irritable bowel syndrome, putting secretory disorders, diarrhea caused by cholera or carcinoid syndrome, and disorders that can be associated or not associated with atmospheric pollution, such as asthma, rhinitis and breathing difficulties.

As for the lower part of the urinary system, these disorders and boece-vascular system, these disorders and diseases mainly include pathologies associated, directly or indirectly, cardiac arrhythmia, hypertension, ischemia, myocardial infarction or unstable angina, problems reocclusion after vascular permeability, for example, after fibrinolytic or thrombolytic therapy, angioplasty or heart surgery. In addition, a disorder that can be treated using compounds according to the invention is glaucoma.

Compounds according to the invention can be presented in all forms of compositions suitable for enteral or parenteral administration, such as tablets, pills, coated with sugar, gelatin capsules, pills, drinking or injectable suspensions or solutions, such as syrups or capsules and so on , combined with suitable excipients and dosage for daily injections from 0.001 to 20 mg/kg

Data on biological activity are given in table. 2.

1. Derivatives of 5-aryl-3-(8-azabicyclo[3.2.1] Oct-3-yl)-1,3,4-oxadiazol-2(3H)-it is in the form of pure geometric or optical isomer or mixture of isomers corresponding to General formula (I)

< / BR>
in which R1is a (C1is hydrogen or halogen, or (C1-C4) CNS group, or an alternative OR1and X1together represent a group of the formula-och2O-, -O(CH2)2-, -O(CH2)3-, -O(CH2)2Oh or-O(CH2)3O-;

X2represents a hydrogen atom or an amino group;

X3represents a hydrogen atom or halogen;

R2represents a hydrogen atom, (C1-C6) alkyl group, phenyl (C1-C4) alkyl group or a group of General formula -(CH2)nCO-Z, in which n is 1 to 6, Z is a 1-piperidino or 4-(dimethylamino)-1-piperidino group

in free base form or pharmaceutically acceptable salt accession acid.

2. Connection on p. 1, wherein R2represents boutelou group.

3. Connection on p. 1, wherein R2is a 2-phenylethylene group.

4. Connection on p. 1, wherein R2is a 4-[4-(dimethylamino)-1-piperidyl] -4-oxobutyl, 5-[4-(dimethylamino)-1-piperidyl] -5-oxopentanoic or 6-[4-(dimethylamino)-1-piperidyl] -6-oxohexyl group.

5. The way receiv X2and X3are as defined in paragraph 1, and R3represents a methyl or ethyl group, is subjected to the interaction with hydrazinehydrate getting hydrazide of General formula (III)

< / BR>
which is subjected to cyclization in oxadiazol General formula (IV)

< / BR>
either with phosgene or with the help of phenylcarbamate, then oxidiazol General formula (IV) is subjected to interaction with tropaeolum General formula (V)

< / BR>
in which R2is the same as defined with respect to General formula (I), but other than a hydrogen atom, or an alternative is a (1,1-dimethylmethoxy)carbonyl protective group, in the presence of triphenylphosphine or utilization.bacteria, and then, if necessary, with the nitrogen atom tropenbos of the ring using triperoxonane acid removes the protection of obtaining compounds of General formula (I) in which 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 group, and R2is the same as defined with respect to General formula (I), but other than a hydrogen atom.

6. Drug screens from the connection on one of the PP. 1-4.

7. The pharmaceutical composition exhibiting the property of the ligands of the receptors 5-HT4and/or H3, characterized in that it contains a compound according to one of paragraphs. 1-4 in combination with excipients.

 

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