Method for preparing pyrimidinone compound and its pharmaceutically acceptable salts

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing pyrimidinone compound of the formula (1) and its salts. Method involves thioamidation reaction of compound of the formula (7) with using Lavesson's reagent followed by treatment of the reaction product with alcoholic reagent as shown in the following reaction scheme 2: (7) → (1) wherein R1 represents (C1-C4)-alkyl with linear or branched chain; R2 represents (C1-C4)-alkyl with linear or branched chain; R3 and R4 represent (C1-C4)-alkyl with linear or branched chain; n is a whole number taken among 1, 2, 3, 4, 5 and 6. Invention provides preparing pyrimidinone compound of the formula (1) by relatively simple and high-effective method. Also, invention relates to pyrimidinone trihydrate compound of the formula 91).

EFFECT: improved preparing method.

10 cl, 2 tbl, 5 ex

 

This invention relates to a method for pyrimidinone compound and its pharmaceutically acceptable salts. More specifically, this invention relates to a convenient and highly productive method for producing pyrimidinone compounds of the following formula 1 and its pharmaceutically acceptable salts, which are suitable for the treatment of cardiovascular diseases, due to the binding of angiotensin II to its receptors, due to the antagonistic activity against angiotensin II receptor.

Formula 1

where R1is1-C4alkyl linear or branched chain, cycloalkyl,1-C4alkylalkoxy or1-C4allylmercaptan;

R2represents H, halogen, C1-C4alkyl linear or branched chain or arylalkyl;

R3, R4that are the same or different, represent H, C1-C4alkyl linear or branched chain, cycloalkyl, carbocyclic aryl, arylalkyl, arylcarbamoyl,1-With4alkoxycarbonyl or aminocarbonyl, are not substituted by H, halogen, hydroxy, C1-C4alkoxy, amino, alkylamino or dialkylamino (where each alkyl residue has From1-C5)1-C4alcox is carbonyl or carboxyla;

R3and R4together with the N atom form a 4-8-membered heterocyclic ring, which may optionally be substituted by one or two substituents selected from the group consisting of cycloalkyl, carbocyclic aryl or arylalkyl, halogen, hydroxyl, C1-C4alkoxy, amino, alkylamino or dialkylamino (where each alkyl residue has From1-C5)1-C4alkoxycarbonyl, carboxy or aminocarbonyl and C1-C4the alkyl linear or branched chain, where the aforementioned heterocyclic ring may optionally include-O-, -S-, -SO-, -SO2or >N-R5; R5represents H, C1-C4alkyl, carbocyclic aryl, arylalkyl, replaced alkenyl, pyridyl, pyrimidyl,1-C4alkyl or arylcarbamoyl,1-C4alkoxycarbonyl, aminocarbonyl, CN or SO2NR3R4;

n is an integer selected from 1, 2, 3, 4, 5 and 6.

Recently there have been numerous studies on the ones antagonist of angiotensin II (US patents 4207324; 4340598; 4576958; 4582847 and 4880804; European open patent publication No. (European Laid-Open Patent Publication Nos) 028834; 245637; 253310; 291969; 323841 and 324377 etc). Among the above European open publications patents No. 028834 and 253310 described imidazole derivatives, substituted biphenyls the th group (for example, losartan), and in European published patent No. 245637 described imidazopyridine derivatives (for example, L158809). These compounds, as stated, have a strong antagonistic effect against angiotensin II. In addition, the European open publications patents No. 407342, 419048 and 445811 described pyrimidinone connection, which represents a 6-membered heterocyclic compound containing an additional nitrogen atom, compared to the 5-membered imidazole derivative mentioned above. However, these pyrimidinone compounds exhibit less activity than imidazole derivatives.

As a result of intensive study pyrimidinone connections created a new pyrimidinone connection with the basis of a different structure in comparison with the above pyrimidinone compounds possessing at the same time, the superior activity, that is 50 times higher than the activity of the above imidazole derivatives [in vitro (rabbit aorta) degree of suppression is equal to 60-70% at a concentration of 10-8˜ 10-9mol], and therefore registered a patent application (international patent application no PCT/KR95/00121, filed September 15, 1995 and PCT/KR 9900198 filed April 26, 1999). Developed pyrimidinone the compounds of formula 1 were obtained, as shown in the following diagram is of aacci 1, described in both of the above applications.

The scheme of reactions 1

where R1, R2, R3, R4, R5and n have the meanings specified above.

However, the above method, consisting of many stages, partly very complicated and very difficult to isolate the compound of formula 5 due to non-selective reactions of N, O-alkyl compounds, which inevitably causes inconveniences associated with column purification, and the loss associated with a very low output (1,28%).

This invention solves the problems of previous prototypes by providing a new method of obtaining pyrimidinone the compounds of formula 1, where the method comprises the stages: induction of selective reactions of N-alkylation by adding a base to compounds of the formula 3 and formula 4 in a mixed organic solvent, so get the above compound of formula 5; simultaneous hydrolysis and amidation of the compounds of formula 5 to obtain the compounds of formula 7; the reaction of diamidine the compounds of formula 7 using reagent Lawesson without acid handling and processing of the resulting product is an alcohol reagent.

Therefore, the object of this invention is to provide a method of producing pyrimidinone compound and its salts on the relatively simple and highly productive way.

In addition, another object of this invention to provide a hydrate pyrimidinone compounds obtained by the above method, and its pharmaceutically acceptable salts.

Other objects of this invention will be clearly understood from the presented with this purpose the following detailed description.

This invention relates to a method of preparing compounds of formula 1 and their salts, as illustrated in the following reaction scheme 2, which includes stages of diamidine the compounds of formula 7 using reagent Lawesson with subsequent treatment of the product with the alcohol reactant.

The scheme of reactions 2

where R1is1-C4alkyl linear or branched chain, cycloalkyl,1-C4alkylalkoxy or1-C4allylmercaptan;

R2represents H, halogen, C1-C4alkyl linear or branched chain or arylalkyl;

R3, R4that are the same or different, represent H, C1-C4alkyl linear or branched chain, cycloalkyl, carbocyclic aryl, arylalkyl, arylcarbamoyl,1-With4alkoxycarbonyl or aminocarbonyl, are not substituted by H, halogen, hydroxy, C1-C4alkoxy, amino, alkyl is Mino or dialkylamino (where each alkyl residue has From 1-C5)1-C4alkoxycarbonyl or carboxyla;

R3and R4together with the N atom form a 4-8-membered heterocyclic ring, which may optionally be substituted by one or two substituents selected from the group consisting of cycloalkyl, carbocyclic aryl or arylalkyl, halogen, hydroxyl, C1-C4alkoxy, amino, alkylamino or dialkylamino (where each alkyl residue has From1-C5)1-C4alkoxycarbonyl, carboxy or aminocarbonyl and C1-C4the alkyl linear or branched chain, where the aforementioned heterocyclic ring may optionally include-O-, -S-, -SO-, -SO2or >N-R5; R5represents H, C1-C4alkyl, carbocyclic aryl, arylalkyl, replaced alkenyl, pyridyl, pyrimidyl,1-C4alkyl or arylcarbamoyl,1-C4alkoxycarbonyl, aminocarbonyl, CN or SO2NR3R4;

n is an integer selected from 1, 2, 3, 4, 5 and 6.

Next, the method of receiving according to this invention is explained in more detail.

This invention is a method of obtaining pyrimidinone the compounds of formula 1 and its salts, including the stage of diamidine the compounds of formula 7 by use of the reagent of Lawesson and then processing of the product alcohol is the second reagent. In accordance with this method pyrimidinone compound of formula 1 can be conveniently obtained in a single phase with high yield by conducting the reaction tiaanidine. Its pharmaceutically acceptable salt is produced by adding salt to the resulting pyrimidinedione connection in accordance with conventional methods. The reagent Lawesson during tiaanidine used in quantities of 0.5 to 2.0 EQ., preferably in a quantity of 1.0 EQ. Then the protective group is treated with an alcohol reagent, preferably selected from methanol, ethanol, propanol and mixtures thereof. As salt is preferably used salt is potassium or sodium.

The compound of formula 7 receive simultaneous hydrolysis and amidation of the compounds of formula 5 as shown in General terms in the following reaction scheme 3, where the hydrolysis is carried out using sodium hydroxide, and the amidation is conducted using amine and N-hydroxybenzotriazole, N-methylmorpholine and dicyclohexylcarbodiimide in quantities of 1 EQ. in chloroform.

The reaction scheme 3

The compound of formula 5 can be easily obtained by selective formation of N-alkylated compounds by adding a base to compounds of formulas 3 and 4 in a mixed organic solvent.

The reaction scheme 4

Kacha is the firmness of the mixed organic solvent, a mixture of dimethylformamide and ethyl acetate, preferably when blending 1˜50:50˜1, and more preferably 1˜10:10˜1. In addition, as the base may be provided hydrides of alkali metals or organic salts of alkali metals and hydrides of alkali metals is most preferable to use lithium hydride.

As a result, in accordance with the method of the present invention may receive the N-alkylated compounds of formula 5 with a high selectivity, which further makes possible a convenient mode of operation during isolation and purification. In addition, you may receive pyrimidinone the compounds of formula 1 with a significantly high yield (28,2%).

This invention also provides hydrates pyrimidinone compounds obtained by the above method, and its pharmaceutically acceptable salts. As described above, pyrimidinone compound of formula 1 is described in international application number PCT/KR95/00121, filed September 15, 1995, and PCT/KR 9900198 filed April 26, 1999. However, when the above connection is in anhydrous form, it has a tendency to absorb moisture from the air. Thus, if the drug is produced from the above anhydrous pyrimidinone connection, it becomes unstable due to the moisture present in the air.

This izobreteny is additionally illustrated by the following examples. Specialists in this field will be obvious that these examples are given only to more fully illustrate this invention, and the invention is not limited to the examples presented.

Example of getting a 1: Getting 2-n-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine

1,41 kg of valeramide and 1.41 kg Diethylenetriamine was dissolved in 4.5 l of methanol and added to 1.16 kg of potassium hydroxide. The mixture was stirred for 15 hours at room temperature and then under stirring was added in 14 liters of water. The obtained solid was filtered, dried and dissolved in 6 l of ethanol. Then was added dropwise 840 g of thionyl chloride for 2 hours and was stirred for 12 hours at 60°C. To the mixture was added a solution of 1.22 kg of sodium bicarbonate in 15 l of water, the obtained solid was filtered and dried to obtain 1.35 kg (47,8% yield) specified in the connection header.

IR (KBr) cm-1: 1740, 1665, 1620.

1H NMR (DMSO-d6): δ to 0.89 (t, 3H), of 1.12 (t, 3H), 1,20˜of 1.40 (m, 2H), 1,52 is 1.70 (m, 2H), 2,18 (s, 3H), of 2.50 (t, 2H), 3.45 points (s, 2H), 4,08 (kV, 2H), 12,38 (Sirs, 1H).

Example 1: Obtain 2-n-butyl-5-ethoxycarbonylmethyl-6-methyl-3-[[2'-(N-triphenylmethanol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-it

1.35 kg of the compound of example obtaining 1 was dissolved in 18 l of a mixed solution of dimethylformamide and ethyl acetate (mixing ratio 1:8 and cooled to 0° C. To the mixture was added 47 g of lithium hydride and stirred for 30 minutes. Then to the resulting mixed solution was added 4.26 kg 4-[2'-(N-triphenylmethanol-5-yl)phenyl]benzylbromide and was stirred for 90 hours at 55°C. the Product was filtered and dried to obtain 3,54 kg (90% yield) selectively N-alkylated specified in the connection header.

IR (pure) cm-1: 1740, 1665, 1600.

1H NMR (CDCl3): δ 0,86 (t, 3H), 1,25(t, 3H), 1,52 is 1.70 (m, 4H), of 2.30 (s, 3H), 2,52 (t, 2H), 3,63 (s, 2H), 4,18 (kV, 2H), 5,19 (s, 2H), 6,85˜6,98 (m, 7H), 7,05˜for 7.12 (m, 3H), 7,20˜7,40 (m, 9H), 7,40˜to 7.50 (m, 3H), of 7.90˜to 7.95 (DD, 1H).

Example 2: Obtain 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(N-triphenylmethanol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-it

2,75 kg of the compound of example 1 was dissolved in 8 liters of a mixed solution of methanol and tetrahydrofuran (ratio of 1:3) and was cooled to 0°C. To the mixture was added 2 l of 10% sodium hydroxide solution for two hours and then was stirred for 4 hours. Added to 1.2 l of 4 N hydrochloric acid to neutralize the solution, and then concentrated in vacuo, then extracted 10 l of chloroform.

The chloroform was concentrated to 6 l, then sequentially added 330 g of dimethylamine hydrochloride, 550 g of N-hydroxybenzotriazole, 900 ml of N-methylmorpholine and 920 g of decollage is silbermedaille at 0° C and was stirred for 15 hours at room temperature. The obtained solid was filtered, then the filtrate was washed with 2 l of water and 2 l of saturated sodium bicarbonate solution and concentrated in vacuum. The residue was dissolved in 5 l of ethyl acetate and was added dropwise to 10 l of hexane to obtain a solid product, which was filtered and dried to obtain 1.97 kg (82%) specified in the connection header.

IR (KBr) cm-1: 1660, 1620, 1555.

1H NMR (CDCl3): δ of 0.87 (t, 3H), 1,25-1,40 (m, 2H), 1,55-1,75 (m, 2H), measuring 2.20 (s, 3H), 2,58 (t, 2H), 2,87 (s, 3H), 3,11 (s, 3H), of 3.56 (s, 2H), 5,10 (s, 2H), 6,85˜6,98 (m, 8H), 7,11 (DD, 2H), 7,22˜7,38 (m, 10H), of 7.48 (m, 2H), 7,98 (DD, 1H).

Example 3: Getting 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-it

1.97 kg of the compound of example 2 was dissolved in 8 l of toluene and the resulting mixture was added a reagent Lawesson (1.1 kg) at room temperature. In the resulting turbid solution was performed interaction for 6 hours at 80°and then cooled to room temperature, to filter out solid. Then there was concentration in vacuo, to the residue was added to 6 liters of methanol was heated under reflux for 3 hours and concentrated. The obtained concentrate was dissolved in 4.5 l of ethyl acetate. To the resulting solution was added to 4.5 l of water, t is to to obtain a solid product. The obtained solid product was filtered and washed with 1 l water, 1 l of ethyl acetate and 3 l of isopropyl ether, separated, and dried for 24 hours at 60°obtaining 1.1 kg (80%) specified in the connection header.

Melting point: 96,8-101,8°

TLC Rf: 0,28 (5% Meon in CHCl3)

1H NMR (CDCl3): δ to 0.89 (t, 3H), 1,28˜to 1.45 (m, 2H), 1,58˜of 1.74 (m, 2H), and 2.26 (s, 3H), 2.63 in (t, 2H), 3,44 (s, 3H), 3.46 in (s, 3H), of 3.77 (s, 2H). with 5.22 (s, 2H), 7,07 (s, 5H), 7,33˜of 7.60 (m, 3H), 7,94 (DD, 1H).

Example 4: Stability of 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-4(3H)-it

Table 1


Time (hours)
Conditions
Room temperature and room humidity

60% Q


75% Q
13,4%6,2%9,05%
25,6%9,1%9,1%
39,1%9,15%9,1%
49,2%9,1%9,15%
59,1%9,2%9,2%
69,1%9,1%9,1%

To whom it can be seen from table 1, the moisture content of the compound of example 3 was measured every hour. As a result, the moisture content increased over time. However, after a certain period of time the content is no longer increased. The result revealed that the hydrate pyrimidinone compounds in the air is more stable than the anhydride. Elemental analysis data in respect of the above hydrates is illustrated in the following table 2.

Table 2
theoretical content (%) (molecular formula: C27H36N7OSK)The practical content (%)
54,6154,82±0,70
N6,115,96±0,20
N16,5117,47±0,26
About10,788,44±0,14
Sof 5.405,46±0,39

As confirmed in the above table, pyrimidinone connection absorbs moisture, becomes trihydrate type and is considered stable.

As described above, this invention is a method of obtaining pyrimidinone the compounds of formula 1 and its salts, including the stage of diamidine the compounds of formula 7 with COI is whether the agent Lawesson and subsequent processing of the product alcohol reagent. As shown in the above example 1, the compound of formula 5 can be obtained by the method of only one reaction selective N-alkylation, which in turn does not require a cleanup procedure using the column in a continuous way. Therefore, in accordance with the method of the present invention pyrimidinone connection and its salts get with a significantly higher yield compared to conventional method.

1. The method of obtaining pyrimidinone the compounds of formula 1 and its salts, including the stage of diamidine the compounds of formula 7 using reagent Lawesson and subsequent processing of the product alcohol reagent, as illustrated in the following reaction scheme 2:

The reaction scheme 2

where R1is1-C4alkyl linear or branched chain;

R2is1-C4alkyl linear or branched chain;

R3, R4are1-C4alkyl linear or branched chain;

n is an integer selected from 1, 2, 3, 4, 5 and 6.

2. The method according to claim 1, wherein said reagent Lawesson used in quantities of 0.5 to 2.0 equivalents.

3. The method according to claim 1, wherein said alcohol reactant selected from the group consisting of methanol, ethanol, propanol and mixtures thereof.

4. The method according to claim 1, in which the indicated compound of formula 7 receive simultaneous hydrolysis and amidation of the compounds of formula 5, as shown in the following reaction scheme 3:

The reaction scheme 3

where R1, R2, R3, R4, R5and n have the meanings indicated in claim 1.

5. The method according to claim 4, in which the compound of formula 5 is obtained by adding the base to the compound of formula 3 and the compound of formula 4 in a mixed organic solvent, as illustrated in the following reaction scheme 4:

The reaction scheme 4

where R1, R2and n have the meanings indicated in claim 1.

6. The method according to claim 5, in which the specified mixed organic solvent is a mixed solvent of dimethylformamide and ethyl acetate.

7. The method according to claim 5, in which the specified base is a hydride of an alkali metal or organic salt of an alkali metal.

8. The method according to claim 7, in which the specified alkali metal hydride is lithium hydride.

9. The method according to any one of claims 1 to 8, in which the specified salt is a salt of sodium or potassium.

10. Trihydrate pyrimidinone the compounds of formula (1)

where R1is1-C4and the keel with a linear or branched chain;

R2is1-C4alkyl linear or branched chain;

R3, R4are1-C4alkyl linear or branched chain;

n is an integer selected from 1, 2, 3, 4, 5 and 6.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to organic chemistry and can find application in medicine

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

FIELD: inorganic synthesis and explosives.

SUBSTANCE: invention relates to methods for preparing explosives, in particular to a method of preparing (5-nitroterazolato)pentaammino cobalt(III) perchlorate, which can be used in production of initiators of elevated safety in handling. Synthesis is accomplished via interaction of aquapentaammino cobalt(III) perchlorate with 50nitroterazole sodium salt tetrahydrate in 1.0-4,0% chloric acid aqueous solution at 89-96°C and molar ration of reactants between 1:1.2 and 1:1.5, respectively, followed by double recrystallization of product from o.1-0.3% chloric acid solution under simplified conditions. In order to reduce sensitivity of product to mechanic effects and to enable transportation thereof to long distances, product is moistened to 30-40% moisture with water/ethanol mixture. Yield of (5-nitroterazolato)pentaammino cobalt(III) perchlorate is increased by 12%.

EFFECT: increased preparation safety due to less sensitive starting material and reduced sensitivity of product to friction.

3 cl, 2 tbl, 10 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to medicine and relates to means for inhibiting endothelialised enzymes, which is a product of the formula (I), method of its production and pharmaceutical compositions containing the product of formula (I) as active principle

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to new amide derivatives of General formula (I) or their salts, where a means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole; X is a bond, -NR5-, -NR5CO-, -NR5CONH-, NR5SO2-, -NR5C(= NH)NH-; R1means H, lower alkyl, aryl, pyridyl, thienyl, furyl, thiazolyl, benzimidazolyl, imidazopyridine, triazolyl, thiadiazolyl, imidazolyl, imidazothiazoles, benzothiazolyl, cyclohexyl, which may be optionally substituted with halogen, lower alkyl, -OH, -CN, -NO2, -CF3, -NH2, -O-lower alkyl, and the Deputy of the lower alkyl may be substituted by phenyl, naphthyl, fullam, tanila or pyridium;2a, R2bmean H or lower alkyl; R3means hydrogen or lower alkyl; R4a, R4bmean H or HE, or taken together form a group =O or =N-O-lower alkyl; R5means H or lower alkyl

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

Up!