Derivatives of 2-amino-n-[[[4-(aminocarbonyl)-pyrimidine-2-yl]- amino]alkyl]pyrimidine-4-carboxamide or its acid salt additive, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

Compounds of the invention corresponding to General formula I listed in the description, where m = 0 or 1, R1is a methyl group, R2- phenoxy (C1-C4)alkyl group, or R1and R2form together, and with the associated nitrogen atom, a 4-phenoxypyridine-1-ilen group, phenoxymethylpenicillin-1-ilen group or 4-phenylpiperazin-1-ilen group, and R3is a hydrogen atom or, and only if n = 1, the hydroxy-group or a methoxy group. 3 S. and 3 C.p. f-crystals, 2 tab.

The present invention relates to derivatives of 2-amino-N-[[[4 - aminocarbonyl) pyrimidine-2-yl] amino] alkyl] pyrimidine-carboxamide, to the way they are received and to farmkompanijam based on them. Compounds of the invention correspond to General formula (I):

,

where

n = 0 or 1;

m = 0 or 1;

R1is a methyl group;

R2- phenoxy(C1-C2)alkyl group, where the phenyl ring may be substituted by a methoxy group; or R1R2N-4-phenylpiperazin-1-yl, where the phenyl group is substituted by 1 or 2 substituents selected from halogen or metoxygroup; or R1R2N - 4 - phenoxypyridine-1-yl, where the phenyl ring substituted with halogen or the groups lower alkyl;

R3is hydrogen, and when n = 1, R3- hydroxy - or methoxy - group.

Compounds of the invention can exist in the form of bases or addition salts with acids. In addition, if the molecule contains an asymmetric carbon atom, the compound can exist in optically pure form or in the form of mixtures of optical isomers.

Known derivatives of 2-aminopyrimidine-4-carboxamide [1], having pharmaceutical activity.

Also known pharmaceutically active derivatives of 2-aminopyrimidine-4-carboxamide [2], which is closest in structure to the compounds according to the invention and correspond to the General formula:

,

where

m = 2 or 3;

n = 2 or 3;

R1is a hydrogen atom or methyl;

X is a halogen atom, hydrogen, lower alkoxy, methyl and 1-methylethyl.

The applicant has developed a new group of derivatives of 2-aminopyrimidine-4-carboxamide, the above formula I, which has antagonistic activity against 1-adrenergic receptors at the level of the lower part of the urinary organs.

The most interesting from the point of view of activity are derivatives of General formula I, where R1R2N-4-phenylpiperazin-1-yl, where fenil is respectful compounds of this group are derivatives of General formula I, where R1R2N - 4-(5-chloro-2-methoxyphenyl)piperazine-1-yl, in particular, the derivative of General formula I, represents N-[2-[[4- (aminocarbonyl)pyrimidine-2-yl] amino] ethyl] -2-[[3-[4- (5-chloro-2-methoxyphenyl)piperazine-1-yl]propyl]amino] pyrimidine-4-carboxamide.

The invention relates also to a method for producing derivatives of 2 - amino-N-[[[4-(aminocarbonyl)pyrimidine-2-yl] amino] alkyl]pyrimidine - 4-carboxamide of General formula I:

,

where

n = 0 or 1;

m = 0 or 1;

R1= methyl;

R2= phenoxy (C1-C2) alkyl, where the phenyl ring may be substituted by a methoxy group, or R1R2N - 4-phenylpiperazin-1-yl, where the phenyl group is substituted by 1 or 2 substituents selected from halogen or metoxygroup; or R1R2N - 4-phenoxypyridine-1-yl, where the phenyl ring substituted with halogen or methoxy group; or R1R2N - 4-phenoxymethylpenicillin-1-yl, where the phenyl ring is substituted by two groups lower alkyl;

R3is hydrogen, and when n = 1, R3is hydroxy or methoxy group;

or kislotoupornyh salts,

it lies in the fact that the amide of General formula II:

,

where

R1, R2, R3and n are defined above,

way is UP>C is converted into an ester of the General formula III:

,

where

R' is alkyl (C1-C4)

last condense with amines of General formula IV :

,

where

R4is a hydrogen atom or a protective group of the amine, m = 0 or 1,

the process is conducted in an aliphatic alcohol at a temperature from 0 to 60oC and obtained from the amine of General formula V:

if necessary, otscheplaut protective group of the amine and the amine of General formula V, where R4= a hydrogen atom, is subjected to the interaction with 2-chloropyrimidine-4-carboxamide in an aprotic solvent in the presence of a base at a temperature of 20-40oC.

Derivatives of 2-aminopyrimidine-4-carboxamide of General formula (II) can be obtained by methods similar to those described in patent applications FR-2678271 and EP-0480794.

Mannosamine the diamines of General formula (IV) can be obtained by methods similar to those described in Synthesis (1984) 1032-1033 and Synthesis (1990) 366-368.

The following examples illustrate the obtaining of some compounds in accordance with the invention. Elemental microanalysis spectra and infrared and nuclear magnetic resonance confirmed the structures of the obtained compounds. The numbers of the compounds given in parentheses in the title is at N-[2-[[4-(aminocarbonyl) pyrimidine-2-yl] amino] ethyl]-2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazine-1-yl] propyl] amino] pyrimidine-4-carboxamide

1.1 2-[[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl]propyl] amino]pyrimidine-4-carboxylate bromide

In a flask with a capacity of 0.5 l enter 7,8 g (19.2 mmol) 2-[[3-[4-(5- chloro-2-methoxyphenyl)piperazine-1-yl] propyl]amino]pyrimidine-4 - carboxamide in 300 ml of methanol, and then let the gas flow of hydrochloric acid for several minutes and heat the mixture under reflux for 1 hours 45 minutes

The solvent is evaporated under reduced pressure, to the residue is added 200 ml of dichloromethane and then cooled to 0oC. the Mixture is alkalinized with a saturated aqueous solution of sodium bicarbonate. The organic phase is dried on sodium sulfate, filtered, and then the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluant: a mixture of dichloromethane/methanol from 100/0 to 90/10), then recrystallized in cyclohexane. Get of 5.84 g (13.9 mmol) of ester. Melting point: 118,5-119oC.

1.2. [2-[[[2-[[3-[4-(5-Chloro-2-methoxyphenyl)piperazine - 1-yl]propyl]amino] pyrimidine-4-yl]carbonyl]amino]ethyl] 1,1 - dimethylthiocarbamate

In a flask with a capacity of 500 ml is injected 5,07 g (31,65 mmol) (2 - amino-ethyl) 1,1-dimethylthiocarbamate, 10 g (23.8 mmol) 2-[[3-[4-(5- chloro-2-methoxyphenyl)piperazine-1-yl] propyl] am the Solvent is evaporated under reduced pressure, the residue is purified by chromatography on a column of silica gel (eluant: dichloromethane/methanol from 100/0 to 90/10) to obtain 10,77 g (19,65 mmol) of target compound in the form of oil, which is used in this form in the next step.

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

In a flask with a capacity of 0.5 l enter 10,77 g (19,65 mmol) of the compound[2-[[[2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazine-1-yl] propyl]amino] pyrimidine-4-yl] carbonyl] amino] ethyl] 1,1-dimethyl - ethylcarbamate in 50 ml of water then was added dropwise 25 ml of concentrated hydrochloric acid. The mixture is cooled to 0oC with a mixture of ice/salt/water, then add portions 30% sodium hydroxide until alkaline pH. Extracted with dichloromethane, the organic phase is dried on sodium sulfate, filtered and evaporated the solvent under reduced pressure and obtain 8.8 g (19,65 mmol) of target compound in the form of oils, which are used in this form in the next step.

1.4. The hydrochloride of N-[2[[4-(aminocarbonyl)pyrimidine-2-yl] amino]ethyl]-2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazine-1-yl] propyl] amino] pyrimidine-4-carboxamide

In a flask with a capacity of 0.5 l in the atmosphere of argon injected 8.8 g (19,65 mmol) of N-(2-amino-ethyl)-2-[[3-[4-(5-chloro-2-methoxyphenol) of potassium carbonate in 250 ml of acetonitrile is heated under reflux for 18 hours The mixture is cooled to room temperature, the insoluble residue is filtered off, then washed with water. Dissolve the product in a mixture of dichloromethane/methanol, then purified it by chromatography on a column of silica gel (eluant: dichloromethane/methanol from 100/0 to 85/15). After recrystallization in a mixture of acetonitrile and dichloromethane get 7,03 g (12,35 mmol) of target compound in the form of a Foundation. Melting point: 196 to 199oC.

To obtain the hydrochloride is dissolved it in a number of 3.03 g (5.32 mmol) in a mixture of 50 ml of dichloromethane and 50 ml of methanol, add a 53.2 ml of 0.1 N hydrochloric acid in propan-2-OLE.

Evaporated the solvent under reduced pressure and the residue will recrystallized in a mixture of methanol and ethyl acetate. The result 2,63 g of the hydrochloride. Melting point: 197,5-200,5oC.

Example 2 (Compound 11)

N-[2[[4-(aminocarbonyl)pyrimidine-2-yl] amino] ethyl]-2-[[2- [4-(2,5-acid)piperazine-1-yl]ethyl]amino]pyrimidine-4 - carboxamide

2.1. 2-[[2-[4-(2,5-Acid)piperazine-1-yl] ethyl] amino]pyrimidine-4-methylcarbonate.

In a flask with a capacity of 1 l enter 8,76 g (cushion 22.66 mmol) 2-[[2-[4-(2,5- acid)piperazine-1-yl]ethyl]amino]pyrimidine-4-carboxamide in 650 ml of methanol, then prophetie 5 o'clock The solvent is evaporated under reduced pressure, to the residue add 300 ml of dichloromethane, then alkalinized a mixture of saturated aqueous sodium bicarbonate. The organic phase is dried on sodium sulfate, filtered, then the solvent is evaporated under reduced pressure. After purification by chromatography on a column of silica gel (eluant: a mixture of dichloromethane/methanol from 100/0 to 90/10), then recrystallized in cyclohexane, get 6,93 g (17,26 mmol) of ester. Melting point: to 85.5-87oC.

2.2 N-(2-amino-ethyl)-2-[[2-[4-(2,5-acid)piperazine-1-yl] ethyl] amino]pyrimidine-4-carboxamide

In a flask with a capacity of 0.25 l injected 1.5 g (3,74 mmole) 2-[[2-[4-(2,5 acid)piperazine-1-yl] ethyl] amino] pyrimidine - 4-methylcarbonate in 20 ml of dichloromethane and 150 ml of methanol, then 3 ml of Ethylenediamine (2.7 g, 44,9 mmole). The mixture is stirred for 4 hours at room temperature, then evaporated the solvent under reduced pressure. The crude residue is dissolved in 150 ml of dichloromethane, the organic phase is washed five times with water. Dried on sodium sulfate, filtered and the solvent is evaporated under reduced pressure and obtain 1.6 g (3,74 mmole) of the desired product in the form of oils, which are used in this f is piperazin-1-yl]ethyl]amino] pyrimidine-4-carboxamide

In a flask with a capacity of 0.5 l injected 1.6 g (3,74 mmole) of N-(2-amino-ethyl) -2-[[2-[4-(2,5-acid)piperazine-1-yl] ethyl] amino] pyrimidine-4-carboxyla, 0,59 g (3,74 mmole) 2-chloropyrimidine-4 - carboxamide and 0.8 g (5.8 mmol) of potassium carbonate in 200 ml of acetonitrile, the mixture is heated under reflux for 16 hours the solvent is Evaporated under reduced pressure and the crude residue add 200 ml of water and 500 ml of dichloromethane. The organic phase is dried on sodium sulfate, then the solvent is evaporated under reduced pressure and purify the residue by chromatography on a column of silica gel (eluant: a mixture of dichloromethane/methanol from 100/0 to 90/10), then recrystallization in a mixture of acetonitrile/dichloromethane. Obtain 1.1 g (2 mmole) of target compound. Melting point: 158-160oC.

Example 3 (Compound 12)

N-[2-[[4-(aminocarbonyl)pyrimidine-2-yl] amino] ethyl] -2- [[3-[[2-(2-methoxyphenoxy)ethyl]methylamino]propyl]amino] pyrimidine-4-carboxamide.

3.1. 2-[[3-[[2-(Methoxyphenoxy)ethyl] methylamino] propyl] amino]pyrimidine-4-methylcarbamoyl

In a flask with a capacity of 0.5 l enter 12.7 g (35.3 mmol) 2-[[3-[[2-(2- methoxyphenoxy)ethyl]methylamino]propyl]amino]pyrimidine-4 - carboxamide and 300 ml of methanol, and then pass the stream of hydrochloric acid in g is Italy is evaporated under reduced pressure, to the residue was added 100 ml of dichloromethane and cooled to 0oC. the Mixture is alkalinized with saturated aqueous sodium bicarbonate solution, decanted and the organic phase is dried on sodium sulfate, filtered, then the solvent is evaporated under reduced pressure.

After purification by chromatography on a column of silica gel (eluant: a mixture of dichloromethane/methanol from 96/4 to 88/12), obtain 8.7 g of the target compound in the form of oil, which is used in this form in the next step.

3.2. N-(2-amino-ethyl)-2-[[3-[[2-(2-methoxyphenoxy) ethyl]methylamino]propyl]amino]pyrimidine-4-carboxamide

In a three-neck flask with a capacity of 0.25 l injected 3.0 g (8 mmol) 2-[[3-[[2-(2-methoxyphenoxy)ethylmethylamino]propyl]amino]pyrimidine-4 - methylcarbonate and 4.8 g (80 mmol) of Ethylenediamine in 100 ml of a mixture of 1/1 methanol/dichloromethane. The reaction medium is stirred for 48 h at room temperature, then evaporated the solvent under reduced pressure.

Absorb the crude residue with 100 ml of dichloromethane, the organic phase is washed with water (2 100 ml), dried on sodium sulfate, filtered, then the solvent is evaporated under reduced pressure and get 3,05 g of target compound in an oil form) which Inoxi)ethyl]methylamino]propyl]amino] pyrimidine-4-carboxamide

In a three-neck flask with a capacity of 0.25 l lead 3.0 g (7,45 mmol) of N- (2-amino-ethyl)-2-[[3-[[2-(2-methoxyphenoxy)ethyl] methylamino] propyl] amino]pyrimidine-4-carboxamide, of 1.23 g (7.8 mmol) of 2-chloropyrimidine - 4-carboxamide, 1.55 g (11.2 mmol) of potassium carbonate, 0.1 g of sodium iodide in 40 ml of N,N-dimethylformamide, the reaction medium is heated at 60oC for 15 hours Cooled to room temperature, the reaction product was poured into 100 ml of water and extracted with ethyl acetate (3100 ml). The organic phase is washed with water, dried on sodium sulfate, filtered and evaporated the solvent under reduced pressure. After recrystallization in ethyl acetate receive 1,95 g of target compound. The melting point 131-133oC.

Example 4. (Compound 13)

N-[2-[[4-(aminocarbonyl)pyrimidine-2-yl] amino] ethyl] -2- [[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy] methyl]piperidine-1-yl] propyl]amino]pyrimidine-4-carboxamide

4.1. 2-[[3-[4[[5-Methyl-2-(1-methylethyl)phenoxy] methyl] piperidine-1-yl] propyl]amino]pyrimidine-4-methylcarbamoyl

In a flask with a capacity of 1 liter injected 6.3 g (14.8 mmol 2-[[3-[4-[[5-methyl-2- (1-methylethyl)phenoxy] methyl]piperidine-1-yl]propyl]amino] pyrimidine-4-carboxamide and 250 ml of methanol, and then pass the stream of hydrochloric acid in the gas phase within a few Minudobrenia, to the residue, add 150 ml of dichloromethane and cooled to 0oC. the Mixture is alkalinized with saturated aqueous sodium bicarbonate solution, decanted and the organic phase is dried on magnesium sulfate, filtered, then the solvent is evaporated under reduced pressure.

After purification by chromatography on a column of silica gel (eluant: a mixture of dichloromethane/methanol from 100/0 to 90/10), obtain 4.3 g of the target compound in the form of oil, which is used in the next step.

4.2. [2-[[[2-[[3-[4-[[5-Methyl-2-(1-methylethyl)phenoxy]methyl] piperidine-1-yl]propyl]amino]pyrimidine-4-yl]carbonyl] amino]ethyl]1,1-dimethylthiocarbamate

In a flask with a capacity of 0.1 l injected 4.3 g (mmol 9,76) 2-[[3-[4-[[5- methyl-2-(1-methylethyl)phenoxy] methyl] piperidine-1-yl] propyl]amino] pyrimidine-4-methylcarbonate and 1.9 g (11.7 mmol) of (2-amino-ethyl)1,1 - dimethylthiocarbamate in 15 ml of a 2/1 mixture propan-2-ol with methanol, the mixture is heated under reflux for 10 hours, the Solvent is evaporated under reduced pressure and purify the residue on a column of neutral alumina (eluent: cyclohexane/ethyl acetate from 80/20 to 0/100) and obtain 2.8 g of the target compound in the form of oil, which is used in the next step.

4.3. N-(2-amino-ethyl)-2-[[3-[4-[[5-methyl-2-(1 - Yat 2.8 g (4,92 mmole) [2-[[[2-[[3-[4- [[5-methyl-2-(1-methylethyl)phenoxy] methyl]piperidine-1-yl]propyl] amino]pyrimidine-4-yl] carbonyl] amino] ethyl] 1,1-dimethylthiocarbamate, dissolved in 20 ml of dichloromethane, then add 20 ml triperoxonane acid and the mixture heated under reflux for 5 hours, the Solvent is evaporated under reduced pressure, the crude residue add 70 ml of water, then 1N sodium hydroxide. Extracted with dichloromethane (3 150 ml), then washed the organic phase with water (100 ml), dried on sodium sulfate, filtered, then the solvent is evaporated under reduced pressure. Get 2,31 g of target compound in the form of oils, which are used in the next step.

4.4. N-[2-[[4-(aminocarbonyl)pyrimidine-2-yl] amino] ethyl] - -2-[[3-[4-[[5-methyl-2-(1-methylethyl)phenoxy] methyl] piperidine-1-yl] propyl]amino]pyrimidine-4-carboxamide

In a flask with a capacity of 0.25 l in an atmosphere of argon injected 2,31 g (4,92 mmole) of N-(2-amino-ethyl)-2-[[3-[4-[[5-methyl-2-(1-methyl-ethyl)phenoxy] methyl] piperidine-1-yl] propyl] amino] pyrimidine-4- -carboxamide, of 0.82 g (5.2 mmol) of 2-chloropyrimidine-4-carboxamide, 0,89 g (6.4 mmol) potassium carbonate and 75 ml of acetonitrile and heated under reflux for 30 hours

The solvent is evaporated, then the crude residue was added 100 ml of water and extracted with dichloromethane (3 100 ml). The organic phase is washed with water (100 ml), dried it on sodium sulfate,a column of silica gel (eluant: dichloromethane/methanol from 100/0 to 90/10) and recrystallizing it in acetonitrile. The result of 1.75 g of the target compound. Melting point: 164-167oC.

Example 5 (Compound 15)

()-N-[2-[[4-(aminocarbonyl)pyrimidine-2-yl]amino]ethyl]- 2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazine-1-yl]-2-hydroxypropyl] amino]pyrimidine-4-carboxamide

5.1. ()-2-[[3-[4-(5-Chloro-2-methoxyphenyl)piperazine-1-yl]- 2-hydroxypropyl]amino]pyrimidine-4-methylcarbazole.

In a flask with a capacity of 1 liter injected 4.7 g (11.6 mmol) ()-2-[[3-[4- (5-chloro-2-methoxyphenyl)piperazine-1-yl] -2-hydroxypropyl] amino] pyrimidine-4-carboxamide and 450 ml of methanol, and then pass the stream of hydrochloric acid in the gas phase in several minutes and heated under reflux for 2 hours the solvent is Evaporated under reduced pressure, to the residue add 300 ml of dichloromethane and cooled to 0oC. the Mixture is alkalinized with a saturated aqueous solution of sodium bicarbonate, decontinued and again extracted with dichloromethane. Dried the organic phase on sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The product was then purified by chromatography on a column of silica gel (eluant: a mixture of dichloromethane/methanol from 100/0 to 90/10) and recrystallized in cyclohexane. The floor is l) piperazine-1-yl]-2-hydroxypropyl] amino] pyrimidine-4-yl]carbonyl] amino]ethyl] 1,1-dimethylthiocarbamate

In a flask with a capacity of 0.25 l enter of 2.21 g (5,07 mmol) ()-2-[[3- [4-(5-chloro-2-methoxyphenyl)piperazine-1-yl]-2-hydroxypropyl]amino] pyrimidine-4-methylcarbonate and 2.6 g (16.2 mmol) of (2-amino-ethyl) 1,1 - dimethylcarbamate in 25 ml of propan-2-ol, the reaction mixture is heated for 16 hours the Solvent is evaporated under reduced pressure and purify the product by chromatography on a column of silica gel (eluant: dichloromethane/methanol from 100/0 to 90/10). Obtain 2.8 g pasty target compound, which is used in the next step.

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

In a flask with a capacity of 0.5 l injected 2.8 g (4,96 mmol) ()-[2-[[[2- [[3-[4-(5-chloro-2-methoxyphenyl)piperazine-1-yl] -2-hydroxypropyl] amino] pyrimidine-4-yl] carbonyl] amino] ethyl-1,1-dimethylthiocarbamate dissolved within a few millimeters of methanol, and then was added dropwise 7 ml of concentrated hydrochloric acid. After 15 min stirring, the mixture is cooled to 0oC with a mixture of ice/salt/water, then add small portions of 1N sodium hydroxide until alkaline pH. Extracted with dichloromethane, the organic phase is dried on sodium sulfate, filtered and evaporated the solvent under reduced pressure. Received the carbonyl)pyrimidine-2-yl] amino] ethyl]-2-[[3-[4-(5-chloro-2-methoxyphenyl)piperazine-1-yl] -2 - hydroxypropyl] amino]pyrimidine-4-carboxamide

In a flask with a capacity of 0.5 l in the atmosphere of argon injected 2,32 g (4,96 mmole) of ()-N-(2-amino-ethyl)-2-[[3-[4-(5-chloro-2-methoxyphenyl) piperazine-1-yl]-2-hydroxypropyl] amino] pyrimidine-4-carboxamide, 0.8 g (5.1 mmol) of 2-chloropyrimidine-4-carboxamide, 1 g (7.2 mmol) potassium carbonate in 150 ml of acetonitrile and heated under reflux for 17 hours

The mixture is cooled to room temperature, separating the insoluble residue by filtration and make an atonement for him by chromatography on a column of silica gel (eluant: dichloromethane/methanol from 100/0 to 85/15). After recrystallization in acetonitrile obtain 0.6 g of the target compound. Melting point: 178-181oC.

In table. 1 illustrates the chemical structures and physical properties of some compounds of the invention.

Compounds of the invention were evaluated for their activity as antagonists1- adrenergic receptors at the level of the lower part of the urinary organs.

Their activity in vitro was investigated on isolated rabbit ureter.

Purchasing rings from the ureter adult male rabbit according to the method of Ueda et al., Eur. J. Pharmacol., (1984), 103, 249-254, then after sensitization by norepinephrine determine the curve of concentration - the result is I as antagonist 1-adrenergicheskih receptors by calculating pA2, antilogarithm molar concentration of antagonist, in which the concentration of agonist should be doubled to produce the same effect as in its absence. The results are shown in the table below.

The activity in vivo of the compounds according to the invention was investigated from the point of view of their influence on hypertension of the ureter caused by stimulation of the sympathetic fibers hypogastric nerve in shot of a cat.

Anaesthetize adult male cats sodium by pentobarbital, prepare them according to the method Theobald, J. Auton. Pharmac, (1983), 3, 235-239, causing hypertension ureter by stimulation of the sympathetic fibers hypogastric nerve. Note contracture responses of the ureter on electrical stimulation of hypogastric nerve before and after the intravenous administration of the compounds under study, at doses of 1-1000 μg/kg Estimate the effect of each compound as an antagonist1- adrenergic receptors, by calculating DI50that inhibits 50% hypertension ureter.

The results are shown in table. 2. The numbers of the compounds correspond to the numbers in the table. 1. In table. 2 bring the UB> -adrenergic receptors (expressed in pA2), and test in vivo (expressed in DI50) on the effect of antagonism 1-adrenergic receptors.

The research results show that the compounds according to the invention have in vitro antagonistic activity towards1/-adrenergic receptors on smooth muscles of the lower section of the urinary organs (urethra) stimulated 1- -adrenergic agonist (phenylephrine) in the test, in vivo they inhibit hypertension of the ureter caused by stimulation of the sympathetic nerve.

Conducted tests regarding the toxicity of the compounds showed the following: after 14 days after treatment with compounds according to the invention rats with doses of 400, 800 and 1200 mg/kg/day and in dogs with doses of 50 mg/kg/day no mortality was found. Therefore, new compounds belong to the category of non-toxic compounds.

The invention relates also to a pharmaceutical composition having an antagonistic activity against1- -adrenergic receptors containing as active principle a compound of formula I, described above.

Compounds according to the invention can be used for simptomy at the level of the lower part of the urinary system and in particular, for the treatment of disorders of urination in benign hypertrophy of the prostate, such as dysuria and pollakiuriya.

The compositions may be presented in any form suitable for enteral or parenterale introduction and contain in addition to the active principle pharmaceutically acceptable excipient. The composition can be in the form of tablets, pills, gelatin capsules, solutions or suspensions for drinking or injection, suppository, containing a daily dose of 0.1 to 500 mg of active principle.

Below are some examples of formulations of different preparative forms:

Tablets - %

Connection example 3 - 0,1

Lactose - 70,0

The hypromellose - 5,8

Microcrystalline cellulose - 20

Carboxymethyl-starch sodium - 2,0

Colloidal silicon dioxide is 0.1

Magnesium stearate - 2,0

Total - 100%

Gelatin capsules - %

The compound of example 8 - 20,0

Lactose - 50,0

The hypromellose - 9,0

Microcrystalline cellulose - 15,0

Carboxymethyl-starch sodium - 2,7

Colloidally silica - 0,3

Magnesium stearate - 3,0

Total - 100%

Formulations for injection volume 5 ml:

Conn is the gathering of example 14 - 6 mg

Glucose is 250 mg

1 Water to 5 ml

1. Derivatives of 2-amino-N-[[[4-(aminocarbonyl)-pyrimidine-2-yl]amino]alkyl]pyrimidine-4 - carboxamide of General formula I

< / BR>
where n = 0 or 1;

m = 0 or 1;

R1= methyl;

R2= phenoxy (C1- C2)alkyl, where the phenyl ring may be substituted by a methoxy group, or R1R2N - 4-phenylpiperazin-1-yl, where the phenyl group is substituted by 1 or 2 substituents selected from halogen or metoxygroup, or R1R2N - 4-phenoxypyridine-1-yl, where the phenyl ring substituted with halogen or methoxy group, or R1R2N - 4-phenoxymethyl-piperidine-1-yl, where the phenyl ring is substituted by two groups lower alkyl;

R3is hydrogen, and when n = 1, R3is hydroxy or methoxy group,

or their acid additive salt.

2. Derivatives of General formula I on p. 1, where R1R2N - 4-phenylpiperazin-1-yl, where the phenyl group is substituted by 1 or 2 substituents selected from halogen or metoxygroup.

3. Derivatives of General formula I on p. 1. where R1R2N - 4-(5-chloro-2-methoxyphenyl)piperazine-1-yl.

4. Derivative of General formula I on p. 1, representing N-[2-[[4-(aminocarbonyl)pyrimid 5. The method of obtaining derivatives of 2-amino-N-[[[4-(aminocarbonyl)pyrimidine-2-yl] amino] alkyl] pyrimidine-4 - carboxamide of General formula I

< / BR>
where n = 0 or 1;

m = 0 or 1;

R1is methyl;

R2- phenoxy (C1- C2)alkyl, where the phenyl ring may be substituted by a methoxy group, or R1R2N-4-phenylpiperazin-1-yl, where the phenyl group is substituted by 1 or 2 substituents selected from halogen or metoxygroup, or R1R2N - 4-phenoxypyridine-1-yl, where the phenyl ring substituted with halogen or methoxy group, or R1R2N - 4-phenoxymethylpenicillin-1-yl, where the phenyl ring is substituted by two groups lower alkyl;

R3is hydrogen, and when n = 1, R3is hydroxy or methoxy group;

or their acid additive salts, characterized in that the amide of General formula II

< / BR>
where R1- R3and n are defined above,

by interacting with aliphatic alcohol C1- C4in the presence of acid and 0 - 100oC is converted into an ester of General formula III

< / BR>
where R1- C1- C4-alkyl, the latter is condensed with an amine of General formula IV

< / BR>
where R4is hydrogen or a protective group of the amine;

m = 0 or 1,4- hydrogen, is subjected to the interaction with 2-chloropyrimidine-4-carboxamide in an aprotic solvent in the presence of a base at 20 - 40oC.

6. Pharmaceutical composition having antagonistic activity against 1- adrenergicheskih receptors containing the active principle and a pharmaceutically acceptable additive, characterized in that the active agent it contains the compounds of formula I on p. 1 in an effective amount.

Priority signs:

03.07.92 - the compounds of formula I, where R1R2N - 4-phenylpiperazin-1-yl, phenyl ring which is substituted by one or two substituents selected from halogen atoms and methoxy groups;

14.12.92 - the compounds of formula I, where R1R2N - 4-phenoxypyridine-1-yl, phenyl group which is substituted with halogen or methoxy group, or R1R2N - 4-phenoxymethyl-piperidine-1-yl, phenyl ring which is substituted by two groups lower alkyl.

 

Same patents:

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to new biologically active chemical compounds, derived pyrazine formula I listed in the description, which is obtained by the interaction of the previously obtained through collaboration pyrazinamide with Amida sodium in liquid ammonia Na-salt pyrazin-2-carboxamide and 6-methyl-5-uracil sulfochloride in liquid ammonia

The invention relates to new derivatives of benzimidazolone, possessing valuable pharmacological properties, in particular derivatives benzimidazolone General formula

< / BR>
where R1and R2the same or different and mean a hydrogen atom, halogen atom, trifluoromethyl, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms, carboxyl, alkoxycarbonyl with 1 to 6 carbon atoms, hydroxy, nitro group or amino group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, acylamino with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, carbarnoyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, cyano, alkylsulfonyl with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aminosulfonyl, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms, or aminosulfonyl group, unsubstituted or N-mono - or disubstituted by alkyl with 1 to 4 carbon atoms;

R3a hydrogen atom, alkyl with 1 to 6 carbon atoms, alkenyl with 2-6 carbon atoms or quinil with 2-6 carbon atoms;

And the group-CO - or-CONH-, or the same As the ode;

m and n independently of one another denote an integer of 1 to 3;

R4phenyl, naphthyl or benzodioxan, unsubstituted or substituted by at least one Deputy from the group comprising halogen atom, trifluoromethyl, cyano, alkoxy with 1 to 3 carbon atoms and alkyl with 1 to 4 carbon atoms,

mixtures of their isomers or individual isomers and their acid additive salts

The invention relates to organic chemistry, in particular to a method of obtaining an individual stereoisomers of 4-diprosone glutamic acid of General formula

< / BR>
< / BR>
ALK is a lower alkyl

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to new biologically active chemical compounds, derived diaminodiphenylsulfone General formula;

< / BR>
which is obtained by the interaction equimolecular amounts of diaminodiphenylsulfone and orotovoy acid in water

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to new derivatives of arylsulfonamides, namely, potassium salt of N-(4,6-dimethylpyrimidin-2-yl)-N'-/2- (methoxycarbonyl)phenylsulfonyl/urea (potassium salt of sulfometuron-methyl), which may find application in forestry planting cedar (Siberian pine, Korean) and non-agricultural land use as a herbicide

The invention relates to a series of substituted 5-arylpyrimidines, to methods for their preparation, to pharmaceutical remedies containing these compounds and to their use in therapy, in particular in the treatment of a range of diseases and disorders of the Central nervous system (CNS)

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

The invention relates to new derivatives of arylalkylamines, as well as containing their farbkomposition, which can find application in pathological conditions involving the system of neurokinin
The invention relates to a method of allocation of 2-alkyl-4-amino-5-alkoxystyrene (aminopyrimidine), which is an intermediate in the synthesis of vitamin b1and other biologically active compounds, and may find application in the medical industry

The invention relates to new derivatives of 2-anilinopyrimidines having biological activity

The invention relates to a method of combating fungi on plants by practicing their new derivatives of 2-aniline-pyrimidine of the General formula I

NNwhere R1hydrogen, halogen; C1-C3-alkyl, C1-C2-halogenated,1-C3-alkoxy;

R2hydrogen, halogen;

R3WITH1-C4-alkyl, C1-C3-halogenated, cyclopropyl;

R4unsubstituted or substituted with halogen, methyl cyclopropyl

The invention relates to chemical-pharmaceutical industry, in particular to a method of obtaining a combined drug analyticheskogo, antipyretic, anti-inflammatory action in hard gelatin capsules
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