Derivatives of 2-aminopyrazine-5-carboxamide, the method of receiving and containing drug and pharmaceutical composition

 

(57) Abstract:

The invention solves the problem of creating new compounds with antagonistic activity against1- adrenergic receptors in the lower urinary apparatus. Derivatives of 2-aminopyrazine-5-carboxamide of General formula I, where n = 0 or 1, R1denotes a methyl group, and R2indicates phenoxy(C1-C4)-alkyl group, in which fenoxaprop substituted methoxy - and ethoxypropane, or R1and R2together with the nitrogen atom to which they are attached, form a 4-(phenoxymethyl)piperid-1-idgruppo in which fenoxaprop substituted by one or two (C1-C4)-alkyl groups, or 4-phenylpiperazin-1-idgruppo, in which the phenyl group substituted by one or two substituents, such as halogen, methoxy, ethoxy and (C1-C4)-alkyl group; R3denotes a hydrogen atom or methyl group; R4is a hydrogen atom, R5is a hydrogen atom or a group of the General formula

< / BR>
where R6denotes a hydrogen atom, a tert-butyloxycarbonyl group, 4-carbamoylation-2-idgruppo or 5-carbamoylmethyl-2-idgruppo, in the form of base or of acid-edit the position, containing the compounds of formula I having the above activity. 5 C. p. F.-ly, 1 Il., table 2.

The object of the present invention are derivatives of 2-aminopyrazine-5-carboxamide, processes for their preparation and use in therapy.

Known [Mashkovsky M. C., Medicines, Kharkov, Torching", 1998, S. 259-261] piperazine derivatives, prazosin and doxazosin with selective antagonistic activity against1- adrenergic receptors. They are used for hypertension, congestive heart failure, and prostate adenoma. However, their use may develop tolerance to the drug and have side effects.

The present invention solves the problem of creating new compounds with antagonistic activity against1- adrenergic receptors in the lower urinary system.

Derivatives of 2-aminopyrazine-5-carboxamide according to the invention correspond to the General formula (I)

< / BR>
where n = 0 or 1;

R1denotes a methyl group and R2indicates phenoxy(C1-C4)alkyl group in which fenoxaprop samewithout 4-(phenoxymethyl) piperid-1-yl group, in which fenoxaprop substituted by one or two (C1-C4) alkyl groups, or 4-phenylpiperazin-1-yl group in which the phenyl group substituted by one or two substituents, such as halogen, methoxy, ethoxy and (C1-C4) alkyl group;

R3denotes a hydrogen atom or methyl group;

R4is a hydrogen atom;

R5is a hydrogen atom or a group of General formula

< / BR>
where R6denotes a hydrogen atom, a tert-butyloxycarbonyl group, 4-carbamoylbiphenyl-2-yl group or a 5-carbamoylmethyl-2-yl group.

Compounds according to the invention can exist in the form of bases or acid additive salts.

According to the invention, compounds of General formula (I) can be obtained according to the method presented in the diagram presented at the end of

The amine of General formula (II), where R1and R2as described earlier, usually in the form of a salt, interacts with halogenosilanes reagent of General formula (III), where Y denotes a halogen atom, n is as defined above, or R3is as defined above, a R7denotes a protective group of the amine, for example, triphenylmethyl, or R3and R7together form, in sovokupnostei in an aprotic solvent, for example dimethylformamide, in the presence of an inorganic base, e.g. potassium carbonate, at 40 - 80oC.

The result is a product of General formula (IV), from the end of the alkylamine which otscheplaut protective group, then in the case when R is triphenylmethyl group, spend processing of gaseous hydrochloric acid in an aliphatic alcohol, for example methanol, at 0 - 60oC, when R3and R7form together phthalimido group, carry out processing similar to that described in the above literature, for example, hydrazine.

The result amine of General formula (V), which interacts with 2-chloropyrazine-5-carboxamido with formula (VI) in an aprotic solvent, such as N,N-dimethylformamide, in the presence of a base, for example potassium carbonate, at a temperature of from 20 to 40oC, with the formation of a derivative of 2-aminopyridin-6-carboxamide with the General formula (Ia), which corresponds to General formula (I), where R4and R5each represent a hydrogen atom.

To obtain the compounds of General formula (I), where R5denotes a group of General formula

< / BR>
amide of General formula (Ia) in which n, R1, R2and R3defined reaction with1-C4-aliphatic alcohol, e.g. methanol, in the presence of acid, for example, gaseous hydrochloric acid, at 0 - 60oC, then the resulting ether interacts with the diamine of General formula (VIII), where R6denotes a protective group of the amine, for example, tert-butyloxycarbonyl group, aliphatic alcohol, for example methanol or n-butanol, at a temperature of from 0 to 100oC, with the formation of compounds of General formula (IB) in which R represents tert-butyloxycarbonyl group.

To obtain compounds with the General formula (I6), in which R6denotes 4-carbamoylbiphenyl-2-yl or 5-carbamoylmethyl-2-yl group, have previously received connection carry out the cleavage of the radical by a known method, for example, with triperoxonane acid in dichloromethane, which leads to the formation of compounds of General formula (IB), where R6denotes hydrogen, the latter interacts with the 2-chloropyrimidine-4-carboxamide or 2-chloropyrazine-5-carboxamido, in an aprotic solvent, such as N,N-dimethylformamide, in the presence of a base, for example potassium carbonate, at 20 - 40oC.

Amines of General formula (II) can be obtained by methods similar to those described in [eagent General formula (III) are either commercially available product in the case when R3and R7together form phthalimido group, or, in the case when R3is H or CH3can be obtained by a method similar to that described in [5].

2-Chloropyrazine-5-carboxamid with formula (VI) can be obtained by a method similar to that described in [6,7,8,9].

2-Chloropyrimidine-4-carboxamide can be obtained in the manner similar to that described in [5].

The diamines with one protective group of the General formula (VII) can be obtained by methods similar to those described in [10].

The following examples illustrate in detail the specific compounds according to the invention. Elemental microanalysis and NMR and CALVES spectra confirm the structures of the obtained compounds.

The numbers indicated in the parentheses in the headings correspond to the numbers in the first column in the table below.

Example 1 (compound No. 1).

2-[[3-[[2-(Methoxyphenoxy)ethyl] methylamino] propyl] -amino] parein-5-carboxamid (E)-but-2-entiat (1:1).

1.1 N-[2-(2-Methoxyphenoxy)ethyl] -N-methyl-N'-(triphenylmethyl-1, C-propandiamine.

with 8.05 g (0,0370 mol) N-methyl-2-(2-methoxyphenoxy)ethylamine hydrochloride, 15.5 g (0,0407 mol) N-triphenylmethyl-3-bromopropylamine (0,0925 mol) ka stirred for a 15.5 hours at 90oC. the Reaction mixture is treated with a mixture of ice water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrate under reduced pressure.

The result of 18.2 g of an orange oil, which was purified by chromatography on silica gel, as the eluent used 98/2 mixture of dichloromethane/methanol. Gain of 13.7 g of oil used in the next stage.

1.2. N-[2-(2-Methoxyphenoxy)ethyl]-N-methyl-1,3-propandiamine.

12.9 g (0.0268 mol) of N-[2-(2-methoxyphenoxy)ethyl]-N-methyl-N'-(triphenylmethyl) -1,3-propandiamine and 250 ml of methanol are mixed in a round bottom flask of 1 liter Pass a stream of gaseous hydrochloric acid for 15 minutes while cooling the mixture of water and ice. The mixture is then warmed to room temperature, adjusted to the temperature of reflux distilled and incubated for 7.5 hours. The mixture is concentrated to dryness, the residue is transferred into ethanol and again concentrated. The residue is transferred into water, the mixture is alkalinized, the top layer of oil transferred into diluted hydrochloric acid and extracted with diethyl ether. An acidic aqueous phase is then treated with sodium hydroxide until alkaline pH and the extraction is carried out with dichloromethane. Organic is up 5.6 g of a yellow oil, used in the next stage.

1.3. 2-[[3-[[2-(2-Methoxyphenoxy)ethyl] -methylamino]-propyl]amino]-pyrazin - 5-carboxamid (E)-but-2-entiat.

5.0 g (0,021 mol) of N-[2-(2-methoxyphenoxy)-ethyl]-N-methyl-1,3-propandiamine, 3.3 grams (0,021 mol) 2-chloropyrazine-5-carboxamide, 100 ml of acetonitrile and a few crystals of sodium iodide is injected under argon in a round bottom flask of 250 ml Add 2.9 g ( 0,021 mol ) of potassium carbonate and again incubated the mixture at the temperature of reflux distilled for 30 hours.

The mixture is cooled to room temperature, the precipitate is collected by filtration and purified chromatographically on a column of silica gel, eluate using a mixture of dichloromethane/methanol from 100/0 to 90/10.

The obtained solid phase is recrystallized from acetonitrile and get 2,82 g (0,00785 mol) of the Foundation.

Fumarate is obtained from 2,82 g base, dissolved in 50 ml of methanol by the addition of 0.91 g (0,00785 mol) of fumaric acid in solution. The solution is concentrated under reduced pressure and conduct recrystallization from ethanol. Gain of 3.32 g of a white compound.

So pl. 161-163oC.

Example 2 (compound 3).

2-[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy] methyl] -piperid-1-the l] piperid-1-yl] propyl] -1H-isoindole-1,3(2H)-dione.

11,35 g (0.04 mol) of 4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperidine hydrochloride, of 10.72 r (0.04 mol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione and 13.8 g (0.1 mol) of potassium carbonate interact in 113 ml of N,N-dimethylformamide. The mixture is stirred for 3 hours at 100oC. It poured into ice water. The solution is extracted with ethyl acetate and washed with water. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting product is used in the next stage.

2.2 4-[[5-Methyl-2-(1-methylethyl)phenoxy] methyl] -piperidine-1-Propylamine. of 17.35 g (0.04 mol) 2-[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperid-1-yl]propyl]- 1H-isoindole-1,3(2H)-dione interact in 340 ml of ethanol with 3.9 ml (0.08 mol) of hydrazine hydrate. The mixture is heated at the temperature of reflux distilled for 3 hours. The mixture is filtered, the solid washed with a small amount of ethanol, the filtrate is concentrated and transferred to diethyl ether. Insoluble phase is again separated by filtration and the filtrate is again concentrated. Insoluble phase is transferred into a round bottom flask and add 25 ml of concentrated hydrochloric acid and 75 ml of water. The mixture is refluxed for 2 hours under stirring. Its cooling gap is the major water ammonia and exercise three-fold extraction with diethyl ether. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The compound obtained is used in the next stage.

2.3. 2-[[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy] -methyl] piperid-1-yl] propyl]amino]pyrazin-5-carboxamide hydrochloride (1:1).

7,45 g (0,0245 mol) 4-[[5-methyl-2-(1-methylethyl)phenoxy]methyl]piperidine-1-Propylamine, 3,86 g (0,0246 mol) of potassium carbonate interact in 100 ml of acetonitrile. The mixture is heated for 28 hours at the temperature of reflux distilled and the solvent is evaporated under reduced pressure.

The obtained solid phase purified by chromatography on a column of silica gel, as eluent, a mixture of from 100/0 to 80/20 dichloromethane/methanol. The obtained solid phase is recrystallized from ethyl acetate and obtain 1.07 g (0,0025 mol) of the Foundation.

The hydrochloride is obtained from 1.07 g of the base, dissolved in 20 ml of 2-propanol by adding 25 ml of 0.1 N hydrochloric acid in 2-propanol, and then the solvent is evaporated under reduced pressure. The residue is recrystallized from 2-propanol and obtain 0.7 g of the white matter.

So pl. 218-220oC.

Example 3 (compound N5).

2-[[2-[4-(2-Methoxyphenyl)piperazine-1-yl] ethyl] aminoaniline.

10 g (0,273 mol) of 2-bromo-N-(triphenylmethyl)ethanamine, 200 ml of acetonitrile, 5,15 g (0,0273 mol) of 1-(2-methoxyphenyl)piperazine, 5.6 g of anhydrous potassium carbonate, a few crystals of sodium iodide and 1 ml of dimethylformamide are mixed in a round bottom flask with a capacity of 500 ml equipped with a reflux condenser, and placed in a nitrogen atmosphere. The mixture was kept at the temperature of reflux distilled for 15 hours, the solvent is evaporated, add water and dichloromethane, dried over sodium sulfate and the solvent is evaporated under reduced pressure. The result is a viscous oil, purified through chromatography on a column of silica gel, as eluent a mixture of ethyl acetate and dichloromethane. Get 9,24 g of the product used in the next stage.

3.2. 2-[4-(-Methoxyphenyl)piperazine-1-yl)-N-(triphenylmethyl)ethanamine trihydrochloride.

9,24 g of 2-[4-(2-methoxyphenyl)piperazine-1-yl)-N-(triphenylmethyl)ethanamine dissolved in 400 ml of methanol and, after homogenization, through the solution for 10 minutes let in a stream of gaseous hydrochloric acid. The precipitate is collected, washed with methanol and dried under vacuum. The result 5,33 g white matter.

3.3. 2-[[2-[4-(2-methoxyphenyl)piperazine-1-yl] ethyl] -amino] parein-5-RH) 2-chloropyrazine-5-carboxamide, 200 ml of acetonitrile and 3.75 g (0,0242 mol) of sodium carbonate are mixed in a round bottom flask with a capacity of 500 ml equipped with a reflux condenser, and placed in a nitrogen atmosphere. The mixture is heated at the temperature of reflux distilled for 22 hours, cooled and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, as eluent, a mixture of from 100/0 to 85/15 dichloromethane/methanol, the obtained solid phase is recrystallized from ethyl acetate. The result is 0.97 g of a white solid.

So pl.: 220-222oC.

Example 4 (compound N12).

2-[[3-[4-(2-Cyclopropylmethyl)piperazine-1-yl] propyl] -methylamino] pyrazin-5-carboxamid (E)-but-2-entiat (1:1).

4.1. 3-[4-(2-Cyclopropylmethyl)piperazine-1-yl)-N-methylpropanamide trihydrochloride.

9.0 g (0,0444 mol) of 1-(2-cyclopropylethyl)piperazine, 200 ml of dimethylformamide, and 17.5 g (0,0444 mol) 3-bromo-N-(triphenylmethyl)propanamine and 9 g of potassium carbonate are mixed in a round bottom flask with a capacity of 500 ml equipped with a reflux condenser, placed in a nitrogen atmosphere, the mixture three times for 6 hours, heated at a temperature of 96oC. the Solvent is evaporated under reduced pressure, the residue is extracted with water and dichlor the reduced pressure. The result of 4.17 g of 3-[4-(2-cyclopropylmethyl)piperazine-1-yl] -N-methyl-N-(triphenylmethyl) propanamine in the form of oil, dissolve it in 200 ml of methanol was passed through it for 10 minutes a stream of gaseous hydrochloric acid, the mixture is concentrated and incubated for 2 days and separate the precipitate by filtration. The result 2,94 g connection.

4.2. 2-[[3-[4-(2-Cyclopropylamino] pyrazin-5-carboxamid (E)-but-2-entiat (1:1).

of 3.77 g (0,0138 mol) of 3-[4-(2-cyclopropylmethyl)piperazine-1-yl]-N-methylpropanamide, 2.17 g (0,0138 mol) 2-chloropyrazine-5-carboxamide, 1.9 grams (0,0138 mol) of potassium carbonate and 100 ml of acetonitrile is introduced into a round bottom flask with a capacity of 500 ml equipped with a reflux condenser, and placed in a nitrogen atmosphere. The mixture is heated at the temperature of reflux distilled for 18 hours, cooled, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, as eluent, a mixture of from 100/0 to 90/10 dichloromethane/methanol. The resulting material is recrystallized from ethyl acetate and get 2,37 g (0,006 mol) of the Foundation.

Fumarate is obtained from 2.37 g of the base, dissolved in 50 ml of methanol, and 0.7 g (0.06 mol) of fumaric acid dissolved in 50 ml of methanol. The NVA.

So pl.: 184-186oC.

Example 5 (compound N10).

2-[[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl] propyl] amino] pyrazin-5-carboxamid (E)-but-2-entiat (1:1).

5.1. 2-[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl]-propyl]-1H-isoindole - 1,3(2H)-dione.

17,16 g (0,05236 mol) of 1-(5-chloro-2-methoxyphenyl)piperazine (E)-but-2-indioate (1: 1), 14,04 g (0,05236 mol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione and of 7.24 g (0,05236 mol) of potassium carbonate in suspension in 150 ml of dimethylformamide make in a round bottom flask with a capacity of 500 ml and heated the mixture for 4 hours at 90oC. the Reaction mixture is poured into 300 ml of water and the extraction is carried out with ethyl acetate (2150 ml). The organic phase is washed with water (3150 ml), then dried over sodium sulfate, filtered and evaporated the solvent under reduced pressure. The crude residue is recrystallized from diethyl ether and the result of 14.7 g of solid substance.

So pl. 130-131oC.

5.2. 3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl]-propanamine.

19.7 g (mol 0,05105) 2-[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl]propyl] -1H-isoindole - 1,3(2H)-dione, dissolved in 300 ml of ethanol, making a round bottom flask with a capacity of 1 l, then there is added of 5.11 g (0,1021 mol) of hydrazine hydrate Genii, then to the crude residue was added 100 ml of water and 17 ml of concentrated hydrochloric acid and again carry out the heating for 3 hours at the temperature of reflux distilled solvent.

The insoluble fraction is separated by filtration, the filtrate is alkalinized 30% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulfate, filtered, and the solvents are then evaporated under reduced pressure and the result is 13,76 g of oil used in the next stage.

5.3. 2-[[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl] propyl]amino]pyrazin - 5-carboxamid (E)-but-2-entiat (1:1).

13,67 g ( 0,04817 mol) of 3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl] propanamine, 8.65 g (0,062 mol) of potassium carbonate and to 7.59 g (0,04817 mol) 2-chloropyrazine-5-carboxamide in the form of a suspension in 200 ml of dimethylformamide make in a round bottom flask with a capacity of 500 ml, the mixture was kept at room temperature for 48 hours with continuous stirring.

The solvent is evaporated under reduced pressure, the residue is purified by recrystallization from ethyl acetate, and the result of 12.6 g of the base.

Fumarate is obtained from 1,58 g (0,039 mol) of the Foundation, Rast the product is recrystallized from methanol/methanol. The result of 1.08 g (0,00207 mol) of white powder.

So pl.: 219-223oC (decomposition).

Example 6 ( Compound 13).

1 1,1-Dimethylethyl 2-[[[2-[[3-[4-(5-Chloro-2-methoxyphenyl) piperazine-1-yl] propyl]amino]pyrazin-5-carboxylate.

6.1 Methyl 2-[[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl]propyl]amino] pyrazin-5-carboxylate.

9.7 g (0,024 mol) 2-[[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl] propyl]amino]pyrazin-5-carboxamide dissolved in 400 ml of methanol, bring in a round bottom flask with a capacity of 1 liter, in a few minutes miss a stream of gaseous hydrochloric acid, and then conducting heating for 5 hours at the temperature of reflux distilled methanol.

The solvent is evaporated under reduced pressure, to the residue is added 200 ml of dichloromethane and cooled the mixture to 0oC. Then the mixture is alkalinized with a saturated aqueous solution of sodium bicarbonate, conduct its separation by settling, the organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated under reduced pressure.

After chromatography on a column of silica gel (eluent: 100/0 to 90/10 mixture of dichloromethane/methanol) followed by recrystallization from cyclo is 4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl]propyl] amino]-pyrazin-5-yl] carbonyl]amino]ethylcarbamate.

4 g (0,0095 mol) of methyl 2-[[3-[4-(5-Chloro-2-methoxyphenyl) piperazine-1-yl] propyl] amino] -pyrazin-5-carboxylate and 3.05 g (0.02 mol) of 1,1-dimethylethyl 2-aminoethylamino dissolved in 10 ml of 2-propanol in a round bottom flask with a capacity of 500 ml and the mixture is heated at the temperature of reflux distilled for 2 days.

The solvent is evaporated under reduced pressure purification using chromatography on a column of silica gel (eluent: from l 100/0 to 90/10 dichloromethane/methanol) receives a yellow oil, which crystallized by rubbing the powder in diethyl ether. The result is 1.5 g (0,00274 mol) of the compound.

So pl.: 159-161oC.

Example 7 (compound 14).

N-(2-amino-ethyl)-2-[[3-[4-(5-Chloro-2-methoxyphenyl)-piperazine-1-yl] propyl] amino]pyrazin-5-carboxamide.

2 g (0,00365 mol) 1,1-dimethylethyl 2-[[2-[[3-[4-(5-chloro-2 - methoxyphenyl)piperazine-1-yl] propyl] amino]pyrazin-5-yl]carbonyl] amino]ethylcarbamate dissolved in 10 ml of water in a round bottom flask with a capacity of 0.25 l, and then added dropwise 10 ml of concentrated hydrochloric acid. The mixture is cooled to 0oC with a mixture of ice/salt/water and added in several portions 30% sodium hydroxide solution, as long as the pH does not become alkaline value. Spend extra is igenom pressure and the result of 1.32 g (0,00295 mol) of amorphous substances.

So pl.: 45-55oC.

Example 8 (compound No. 15 ).

N-[2-[[4-(Aminocarbonyl)pyrimidine-2-yl] amino] ethyl]-2-[[3- [4-(5-chloro-2-methoxyphenyl)piperazine-1-yl]-propyl]amino] pyrazin-5-carboxamide.

1,32 g (0,00295 mol) of N-(2-amino-ethyl)-2-[[3-[4-(5-chloro-2 - methoxyphenyl)piperazine-1-yl] -propyl]amino]pyrazin-5-carboxamide, 0.5 g (0,00317 mol) 2-chloropyrimidine-4-carboxamide and 0.6 g (0,00434 mol) of potassium carbonate are dissolved in 50 ml of dimethylformamide in a round bottom flask with a capacity of 0.25 l, the mixture is heated at 40oC for 40 hours.

The solvent is evaporated under reduced pressure and the crude residue purified via chromatography on a column of silica gel, as eluent, a mixture of from 98/2 to 80/20 dichloromethane/methanol. After recrystallization from acetone receive 0,99 g (0,00174 mol) of the compound.

So pl.: 197-199oC.

In table. 1 presents the chemical structure and physical properties of some compounds according to the invention.

Notes to the table. 1:

In the column "Salt", "FUM" means (E)-but-2-entiat (1:1) (fumarate), "HCl" denotes a hydrochloride (1:1) and "-" denotes a compound in the basic form. In column I. pl. (oC)" "p" refers to melting point with decomposition.

With the oseney to1adrenergic receptors in the lower urinary system.

Their activity in vitro was studied on isolated rabbit urethra (IRU).

Urethral ring adult male rabbits were treated according to the method of [11] , and then, after sensitization to norepinephrine, filmed curve of the dependence of the reaction on phenylephrin from its concentration in the absence and in the presence of the compounds.

The value of 1adrenergic antagonism of each compound was determined by calculating RA2, antilogarithm molar concentration of antagonist, in the presence of which the concentration of agonist should be doubled, to cause the same effect, as in his absence.

The values of RA2compounds shown in table. 2 in the column IRU RA2.

The affinity sub1and1b1receptors were investigated on the salivary glands of the rat1a) and rat liver1b).

Studies were performed according to C. Faure et al. European Journal of Pharmacology, Molecular Pharmacological section, 268 (1994), 141-149.

1. Obtaining tissue membrane.

The membrane of the salivary gland of the rat and rat liver were obtained by homogenization and centrifugation twice at 37000 g is of the ligand was carried out in 50 mm Tris-HCI buffer, a pH of 7.4. Preparations of cell membranes (4 g prot) were incubated with [3H]-prazozinom at 25oC for 30 min in a total volume of 2 ml of Tissue membranes were incubated with [3H]-prazozinom for 1 h at 25oC with a total volume of 2 ml Phentolamine (10 μm) was used to determine nonspecific binding. Incubation was graduated from the high-speed filtering, using the header cells of Brendella through glass-fiber filters Whatman GF/b Filters were washed h ml buffer, dried and measured radioactively by liquid scintillation spectrometry. Data saturation and competitive inhibition were analyzed using nonlinear regression analysis. The results were expressed as 1C50) (the concentration of compound at which there is inhibition of the binding of radioligand 50%). The results are shown in table. 2.

In vivo activity of the compounds according to the invention were investigated for their effects on urethral hypertension caused by stimulation of the sympathetic fibers of the hypogastric nerve in cats shot.

Adult males were anestesiologi pentabarbital sodium, processed according to the method of [12] , causing urethral hypertension by stimulating with the main doses from 1 to 1000 μg/kg was detected reduction of the urethra in response to electrical stimulation of the hypogastric nerve.

The value of1- adrenergic antagonism of each compound was evaluated by calculating ID50dose that inhibits urethral hypertension by 50%.

ID values50compounds according to the invention are in the range from 0.001 to 1 mg/kg

The results of the tests show that the compounds according to the invention exhibit in vitro antagonistic activity towards adrenergic receptors of the smooth muscles of the lower urinary apparatus (urethra), stimulated1adrenergic agonist (phenylephrine). They inhibit In vivo urethral hypertension caused by stimulation of the sympathetic nerve.

Compounds according to the invention can be used for symptomatic use in diseases and complaints, which include hyperactivity1adrenergic system at the level of the lower urinary apparatus, and especially for the treatment of urinary disorders associated with benign prostatic hypertrophy, such as dysuria and pollakiuriya.

Finally, you can use them in all forms, acceptable for enteral and parenteral administration, in combination with pharmaceutical excipients, for example in the form of tablets, coated sharief, moreover, in such amount to provide a daily dose of from 0.1 to 500 mg of active substance. The following are examples of pharmaceutical compositions suitable for compounds of the present invention. To obtain using traditional methods.

Obtaining a granulate for capsules or tablets

Ingredients, %:

The active ingredient is 0.1 - 20

Lactose - 40 - 80

The hypromellose - 5 - 10

Microcrystalline cellulose - 15 - 25

Carboximetilkrahmal, sodium salt of 2 - 4

Colloidal silicon dioxide is 0.1 to 0.3

Magnesium stearate - 2 - 3 - 100%

Injection

Ingredients mg:

The active ingredient is 4 - 6 mg

Glucose - 250

Pyrogen-free water for injection in a quantity sufficient to bring the volume up, ml - 5

Bottle, ml - 5,

1. Derivatives of 2-aminopyrazine-5-carboxamide of General formula I

< / BR>
where n = 0 or 1;

R1denotes a methyl group and R2indicates phenoxy (C1-C4) alkyl group in which fenoxaprop substituted methoxy - and ethoxypropane, or R1and R2together with the nitrogen atom to which they are attached, form a 4-(phenoxymethyl)piperid-1-idgruppo, which is the Rupp, in which the phenyl group substituted by one or two substituents, such as halogen, methoxy, ethoxy and (C1-C4) alkyl group;

R3denotes a hydrogen atom or methyl group;

R4is a hydrogen atom,

R5is a hydrogen atom or a group of General formula

< / BR>
where R6denotes a hydrogen atom, a tert-butyloxycarbonyl group, 4-carbamoylbiphenyl-2-idgruppo or 5-carbamoylmethyl-2-idgruppo,

in the form of a base or an acid additive salt.

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

< / BR>
where R1and R2defined above,

usually in the form of salt, is subjected to the interaction with halogenosilanes reagent of General formula III

< / BR>
where Y is a halogen atom;

n is defined in paragraph 1;

R3or as defined in paragraph 1, and R7means triphenylmethyl group, or R3and R7together form together with the nitrogen atom to which they are attached, phthalimido group

in an aprotic solvent in the presence of an inorganic base at 40 - 80oC with the formation of the diamine of General formula IV

< / BR>
limit alkylamine which is devoid of a protective group, then aznoe hydrochloric acid in an aliphatic alcohol at 0 - 60oC, and when R3and R7together form phthalimido group, spend processing hydrazine, getting amine of General formula V

< / BR>
which is subjected to interaction with 2-chloropyrazine-5-carboxamide in an aprotic solvent in the presence of a base at 20 - 40oC with the formation of a derivative of 2-aminopyrazine-5-carboxamide of General formula Ia

< / BR>
which corresponds to the General formula I,

where R4and R5is a hydrogen atom,

then, if necessary, to obtain the compound of General formula I, where R5denotes a group of General formula

< / BR>
amide of General formula Ia is transferred to the ether of General formula VII

< / BR>
where R8stands WITH1-C4alkyl group,

by conducting reactions with1-C4-aliphatic alcohol in the presence of acid at 0 - 60oC, after which the thus obtained ester is subjected to interaction with the diamine of General formula VIII

< / BR>
where R6denotes tert-butyloxycarbonyl group

in the aliphatic alcohol at 0 - 100oC obtaining compounds of General formula IB

< / BR>
where R6denotes tert-butyloxycarbonyl group

then if you want to get with, the t of the obtained compound otscheplaut protective group using triperoxonane acid in dichloromethane, the resulting compounds of General formula IB, where R6- hydrogen, which is subjected to interaction with 2-chloropyrimidine-4-carboxamide or 2-chloropyrazine-5-carboxamide in an aprotic solvent in the presence of a base at 20 - 40oC.

3. Medication, which has antagonistic activity against1- adrenergic receptors, characterized in that it contains a connection on p. 1.

4. Pharmaceutical composition having antagonistic activity against adrenergic receptors, characterized in that it contains 0.1 to 500.0 mg of the compound under item 1 in combination with an inert filler.

5. The compound of General formula VII

< / BR>
where n, R1, R2and R3defined in paragraph 1;

R8stands WITH1-C4is an alkyl group,

as an important intermediate product of the method according to p. 2.

 

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