Method for preparing substituted imidazopyridine

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

 

The technical FIELD

The present invention relates to a new method of obtaining substituted compounds imidazopyridine more specifically to a new method of obtaining 2,3-dimethylimidazo[1.2-a]pyridine, substituted at the 6th position carboxamides or carboxialkilnuyu group. According to other aspects of the present invention also relates to new intermediates used in the method.

The LEVEL of TECHNOLOGY

The present invention relates to a new method suitable for large-scale production of substituted imidazopyridine formula (1),

in which R1is C1-C6CNS or NH2the group, comprising the step of the reaction of compounds of General formula (2)

in which R1is C1-C6CNS or NH2group, 3-halogen-2-butanone in cyclohexanone.

A similar reaction is described in EP 33094, EP 204285, ER 228 006, EP 308917 and WO 99/55706, in which the substituted connection aminopyridine of General formula (X)

reacts with the compound of the formula

in which X is, for example, N, CH3or ester group, such as SOOSN3or SOOS2H5,

Y - for example, CH3CH2CH3and

Z - this is the leaving group, such as halogen, mesyl or Casilina, to obtain compounds of General structure

in which X and Y such as described above.

The reaction is carried out in an inert solvent, such as acetone, alcohols, benzene, N,N-dimethylformamide, tetrahydrofuran, chloroform or diethyl ether, preferably at elevated temperature, and possibly in the presence of inorganic or organic bases.

The reaction is characterized by a prolonged reaction time, for example from 16 to 84 hours, high reaction temperatures and relatively low output, for example from 22% to 55%. Therefore, the reaction is not suitable for large-scale production of substituted compounds imidazopyridine.

The authors found that when carrying out the process according to the present invention as described in the present description, the reaction time can be shortened, the reaction temperature can be reduced and output increased.

The INVENTION

In this invention a new method is proposed intermodal get substituted imidazopyridine General formula (1)

in which R1means C1-C6alkoxy or NH2by interaction of compounds of General formula (2)

3-halogen-2-butanone in the midst of an inert organic solvent at a temperature of 80-100° Since, at the same time as the inert organic solvent used cyclohexanone.

When the reaction temperature from 80°to 100°With complete metamorphosis occurs within a few hours, for example from 1 to 4 hours. Conversion is usually above 95%, and the output of the selected product is usually above 70%.

The specified 3-halogen-2-butanone can be a 3-bromo-2-butanone or 3-chloro-2-butanone, the latter of which is preferred. The number of 3-halogen-2-butanone can be from 1.1 to 5 molar equivalents. The number of 3-halogen-2-butanone is not critical for the implementation of the present invention. From a practical and economic point of view it is preferable to add from 1.1 to 5 molar equivalents, preferably from 1.1 to 2 equivalents.

Cyclohexanone may be diluted with an inert solvent. The amount of cyclohexanone is not important for the implementation of the present invention and therefore, in practical terms it can be adjusted depending on the need and the equipment used. You can also mix cyclohexanone with inert solvents such as ethers. An example of a suitable inert solvent is not limited to, tetrahydrofuran (THF). The amount of inert solvent may comprise up to about 50%by volume, without reducing output.

In the first embodiment of the present invention the compound of formula (2)

in which R1is C1-C6CNS group, lead reacts with 3-halogen-2-butanone in cyclohexanone, to obtain the compounds of formula (1),

in which R1is C1-C6CNS group.

In the second embodiment of the present invention the compound of formula (2),

in which R1is the NH2the group, lead reacts with 3-halogen-2-butanone in cyclohexanone to obtain the compounds of formula (1),

in which R1is the NH2group.

The method according to the present invention is carried out by dissolving or suspendirovanie the compounds of formula (2),

in which R1is C1-C6CNS or NH2the group, in cyclohexanone, and the addition of 3-halogen-2-butanone, by heating the reaction mixture for several hours and then allocating the compounds of formula (1),

in which R1is1-C6CNS or NH2the group with high output.

Source the material for use in the present invention can be prepared so that as described in WO 99/55706, or alternatively, as described below in Scheme 1.

Scheme 1

Stage i

The compound (3) in Scheme 1 is treated with thionyl chloride or any equivalent reagent at elevated temperature in an appropriate solvent for several hours to get the corresponding chlorine compound. The reaction is carried out using about 1 to 5 equivalents of thionyl chloride, preferably from 1 to 2.5 equivalents, in toluene at a temperature of about 100°over time from 2 to 8 hours. The corresponding chlorine compound is then treated 2-25 equivalents of ammonia, preferably from 3 to 12 equivalents, in the same solvent as described above, at about room temperature, to obtain the compound (4).

Stage ii

The compound (4) according to the Scheme 1 hydronaut in water-ethanol solution using a catalyst, to obtain the compound (5). Examples of suitable catalyst include, but are not limited to, palladium, ruthenium or mixtures thereof. Pasta Pd-Ru/C is the preferred catalyst. Examples of alcohols include, but are not limited to, methanol, ethanol and propanol, among them preferred is methanol.

Substituted compound imidazopyridine formula (1),

in which R1JW is aetsa C 1-C6CNS or NH2the group prepared in accordance with the present invention, may then be used in the preparation of some substituted derivatives of imidazopyridine, which are particularly effective as inhibitors of gastrointestinal N+To+-ATP-ases (adenosinetriphosphatase) and, therefore, as inhibitors of gastric juice.

The compounds of formula (1) you can enter into reaction with the compound of the formula (6),

in which R3- H, C1-C6alkyl, gidroksilirovanii1-C6alkyl or halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; and Y is a leaving group such as halide, Casilina or mesyl group, to obtain a compound of the formula (7),

in which R1, R3, R4and R5defined above. Convenient to carry out this reaction in an inert solvent, for example acetone, acetonitrile, dimethoxyethane, methanol, ethanol or dimethylformamide in the presence of a base or without. The base is a hydroxide of an alkali metal such as sodium hydroxide and potassium hydroxide, a carbonate of an alkali metal such as potassium carbonate and sodium carbonate, or the content of inorganic fillers Amin, such as triethylamine.

The compounds of formula (7), in which R1is C1-C6CNS group, you can further lead in the interaction with the aminecontaining compound of General formula (8),

in which R6and R7are the same or different and they are selected from the group consisting of H, C1-C6of alkyl, C1-C6alkoxy-substituted C1-C6of alkyl, gidrauxilirovannogo C1-C6alkoxy-substituted C1-C6of alkyl, aryl, to obtain a corresponding amide compound.

R6and R7can together with the nitrogen atom to which they are attached, form a saturated or unsaturated ring, possibly containing one or more heteroatom, forming, thus, for example, morpholine, piperazine, pyrrolidine or piperidine.

The reaction can be carried out by heating the reagents in undiluted aminosidine or diluted in an inert solvent under standard conditions.

Alternatively, the compounds of formula (7)

in which R3, R4and R5defined above, and R1is the NH2group can be hydrolyzed under standard conditions to the corresponding compounds of carboxylic acids of formula (9)

in which R3, R4and R5defined above.

The compounds of formula (9) then you can enter into reaction with amino compounds of the formula (8),

in which R6and R7defined above, in the presence of the agent combinations, to obtain a corresponding amide compound. The reaction can be carried out in an inert solvent under standard conditions.

EXAMPLES

Example 1.1

Preparation of 3-bromo-2-butanone

In the reactor suspended sodium bromide (84 kg) in dimethylformamide (125 l). Add 3-chloro-2-butanone (85 kg) at a temperature of 15°S-30°C. Stirring is continued for 4 hours, and then filtered; the filter cake is washed with cyclohexanone (38 l). Thus prepared 3-bromo-2-butanone is ready for use in the cyclization stage.

Example 1.2

Synthesis of methyl 8-amino-2,3-dimethylimidazo [1,2-a]pyridine-6-carboxylate

To a suspension of methyl ester of 5,6-diaminotoluene acid (1 equivalent, of 5.1 g) in cyclohexanone (50 ml) was added 3-bromo-2-butanone (1.2 equivalent of 3.9 g) for 10 minutes. The mixture was heated to 100°C (internal temperature) and stirred for 2.5 hours at this temperature. The mixture was cooled to room temperature, and pale colored solid was filtered and washed TV is E (3× 10 ml). Drying was carried out at reduced pressure at 45°C. the Output was 6,53 g (75%).

Example 1.3

Synthesis of ethyl-8-amino-2,3-dimethylimidazo [1,2-a]pyridine-6-carboxylate

To a suspension of ethyl ester of 5,6-diaminotoluene acid (1 equivalent, of 5.1 g) in cyclohexanone (50 ml) was added 3-bromo-2-butanone (1.4 equivalent, 5,95 g) for 15 minutes. The dark brown mixture was heated to 100°C (internal temperature) and stirred for 1.5 hours at this temperature. The mixture was cooled to room temperature, and the light brown solid was filtered and washed TWO (20 ml). Drying was carried out at reduced pressure at 45°C. the Output was of 5.06 g (65%).

Example 1.4

Synthesis of isopropyl-8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate

To a suspension of isopropyl ether 5,6-diaminotoluene acid (1 equivalent, of 5.1 g) in cyclohexanone (50 ml) was added 3-bromo-2-butanone (1.2 equivalent, 3.4 ml) for 10 minutes. The dark brown mixture was heated to 100°C (internal temperature) and stirred for 1.5 hours at this temperature. The mixture was cooled to room temperature and the pale yellow solid phase was filtered and washed TWO (3×10 ml). Drying was carried out at reduced pressure at 45°C. the Yield was 6.0 g (74%).

the example 1.5

Synthesis of 8-amino-2,3-dimethylimidazo [1,2-a]pyridine-6-carboxamide

5,6-Diaminononane (50 g, 0,313 moles (analytically: 95,4%), 1.0 equivalent) suspended in cyclohexanone (250 ml). The suspension was heated to 100°C. the Filtrate (3-bromo-2-butanone in cyclohexanone) was added at 100°C for 1 hour 10 minutes. Heating was continued for 3 hours, and then the heating source was removed. The reaction mixture was cooled to 20°C and stirred at this temperature for a further 2 hours. The solid phase was filtered off, carefully washed TWO (2×330 ml) and dried to obtain 70,3 g specified in the connection header. The yield was 70%.

Example 1.6

Synthesis of 8-amino-2,3-dimethylimidazo [1,2-a]pyridine-6-carboxamide

NaBr (27,0 g; 0,259 mole; 1.33 equivalents) is suspended in cyclohexanone (220 ml) and added 3-chloro-2-butanone (25.7 mm; 0,242 mole; 1.24 equivalent) at one time. The mixture was heated up to 80°and was stirred for 3 hours. The mixture was cooled to 50°C, white solid was filtered and washed with cyclohexanone (60 ml). To the filtrate was added 5,6-diaminononane (30 g; 0,1946 moles; 1.0 equivalent), and the mixture was heated to 100°C for 4 hours, after which 98%conversion was determined using HPLC (liquid chromatography high pressure). The reaction mixture was cooled to 2° With the stirring was continued for 2 hours at 20°C. the Solid was filtered, washed, TWO (220 ml) and dried to obtain 46.6 g is specified in the header of the substance. Yield: 73%.

Example 1.7

Synthesis of 8-amino-2,3-dimethylimidazo [1,2-a]pyridine-6-carboxamide

5,6-Diaminononane (30.0 g; 0,183 mol; 1.0 equivalent) suspended in cyclohexanone (280 ml). Added 3-chloro-2-butanone (24,ml; 0,22 mol; 1.2 equivalents), and the mixture was heated to 100°C for 4 hours. The reaction mixture was cooled to 20°C and stirred at this temperature for a further 2 hours. The solid phase was filtered, carefully washed TWO (200 ml) and dried to obtain 48,4 g specified in the connection header. The yield was 78%.

Example 1.8

Synthesis of methyl 8-amino-2,3-dimethyl-8-(2,6-dimethylbenzylamine)-imidazo [1,2-a]pyridine-6-carboxylate

Methyl-8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (0.8 g, 3.6 mmole), 2,6-dimethylbenzylamine (0,57 g, 3.7 mmole), sodium carbonate (1.0 g, 9.4 mmole) and a catalytic amount of potassium iodide were added to acetonitrile (10 ml) and subjected to reflux for 20 hours. After filtration of the salt was washed with methylene chloride, and the solvent was boiled away under reduced pressure. The residue was purified column chromatography on silica gel with application as elution solvent a mixture of methylene chloride:ethyl acetate (75:25). The yellow residue was treated with hexane to obtain 0,23 g (19%) specified in the header of the product.

Example 1.9

Synthesis of ethyl-2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo [1,2-a]pyridine-6-carboxylate

Ethyl-8-amino-2,3-dimethylimidazo [1,2-a]pyridine-6-carboxylate (0.7 g, 3.0 mmole), 2-ethyl-6-methylbenzylamine (0.5 g, 3.0 mmole), sodium carbonate (0.64 g, 6.0 mmole) and a catalytic amount of potassium iodide was added to an acetone (50 ml) and subjected to reflux for 20 hours. After filtration of the acetone boiled away under reduced pressure to obtain oil. The oily product was purified column chromatography on silica gel using as eluent a mixture of diethyl ether:petroleum ether (1:1), to obtain 0.12 g (9%) specified in the header of the product.1H-NMR (500 MHz, CDCl3): δ 1.25 (t, 3H), 1.5 a (t, 3H), of 2.35 (s, 3H), 2,42 (s, 3H), of 2.44 (s, 3H), of 2.75 (q, 2H), 4,45 to 4.5 (m, 4H), 4,9 (bs, 1H), 6,8 (s, 1H), 7,05 to 7.2 (m, 3H), and 8.1 (s, 1H).

Example 1.10

Synthesis of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-N-propyl-imidazo [1,2-a]pyridine-6-carboxamide

Ethyl-2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (0.12 g, of 0.33 mmole), Propylamine (1.0 g, 17 mmole) and a catalytic amount of sodium cyanide was subjected to reflux in methanol (20 ml) for 24 hours. objavili more Propylamine (1.0 g, 17 mmol)and the reaction mixture was subjected to reflux for 24 hours. The solvent is boiled away under reduced pressure, and the residue was purified column chromatography on silica gel using diethyl ether as eluent. Crystallization from diethyl ether gave 0,053 g (42%) specified in the header of the product.1H-NMR (300 MHz, CDCl3): δ 1,0 (t, 3H), 1,2 (t, 3H), of 1.65 and 1.75 (m, 3H), 2,3 (s, 3H), of 2.35 (s, 3H), of 2.38 (s, 3H), and 2.7 (q, 2H), 3,4-3,5 (m, 2H), 4,35 (d, 2H), 4,9 (bs, 1H), 6,2 (bs, 1H), 6,357 (s, 1H), 7,0-7,2 (m, 4H), the 7.85 (s, 1H).

Example 1.11

Synthesis of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo [1,2-a]pyridine-6-carboxamide

8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide (3,3 g, 16.2 mmole), 2-ethyl-6-methylbenzylamine (2,73 g, 16.2 mmole), potassium carbonate (8.0 g, 58 mmol) and potassium iodide (1.1 g, 6.6 mmole) was added to an acetone (150 ml) and subjected to reflux for 20 hours. Added additional amount of 2-ethyl-6-methylbenzylamine (1.0 g, 5.9 mmole)and the reaction mixture was subjected to reflux for 7 hours. Added methylene chloride (60 ml) and methanol (30 ml). The reaction mixture was filtered, and the solvent was boiled away under reduced pressure. The residue was purified column chromatography on silica gel using as eluent a mixture of methylene chloride:methanol (100:7). retalitate from ethyl acetate gave 2.8 g (50%) specified in the header of the product. 1H-NMR (300 MHz, CDCl3): δ 1,2 (t, 3H), of 2.34 (s, 3H), of 2.36 (s, 3H), of 2.38 (s, 3H), and 2.7 (q, 2H), 4,4 (d, 2H), 4,9 (bs, 1H), 6,0 (bs, 2H), 6,45 (s, 1H), 7,0-7,2 (m, 3H), and 7.9 (s, 1H).

Example 1.12

Synthesis of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo [1,2-a]pyridine-6-carboxylic acid

Mesilate (methylsulfonate) 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide (11,0 g of 0.025 mmole) and sodium hydroxide (7.0 g, 0.17 mmol) was dissolved in 120 ml of ethanol (95%) and subjected to reflux for 20 hours. The solvent is boiled away under reduced pressure and to the residue was added water (150 ml). Brought the pH to 5 by addition of concentrated HCl and acetic acid, and precipitated precipitated solid substance was separated by filtration, washed with water and acetone and dried, to obtain 7.6 g (88%) specified in the header of the substance.1H-NMR (500 MHz, DMSO-d6): δ to 1.15 (t, 3H), and 2.26 (s, 3H), of 2.34 (s, 3H), 2,39 (s, 3H), 2,69 (q, 2H), to 4.38 (d, 2H), 5,2 (bs, 1H), 6.73 x (s, 1H), 7,07 to 7.2 (m, 3H), 8,12 (s, 1H).

Example 1.13

Synthesis of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-6-(morpholinomethyl)-imidazo[1,2-a]pyridine

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, of 0.44 mmole) and o-benzotriazol-1-yl-N,N,N',N'-tetramethylpropylenediamine (TBTU) (0.14 g, of 0.44 mmole) was added to methylene chloride (10 ml). Added morpholine (0,12 is, 1.4 mmole)and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture is added to a column of silica gel, and by purification using chromatography using as eluent a mixture of ethyl acetate:methylene chloride (1:1) was obtained 0.12 g (66%) of the desired product.1H-NMR (300 MHz, CDCl3): δ 1,2 (t, 3H), 2,32 (s, 3H), of 2.35 (s, 3H), is 2.37 (s, 3H), and 2.7 (q, 2H), and 3.7 (s, 8H), 4,35 (d, 2H), 4.95 points (bs, 1H), x 6.15 (s, 1H), 7,07 to 7.2 (m, 3H), and 7.4 (s, 1H).

Example 1.14

Synthesis of (2-ethyl-6-methylbenzylamino)-N(2-(2-hydroxyethoxy)ethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.3 g, from 0.88 mmole) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (0.29 grams, of 0.90 mmole) was added to methylene chloride (10 ml). Added 2-(2-aminoethoxy)ethanol (0.2 g, 1.9 mmole)and the reaction mixture was stirred at room temperature for 2 hours. The solvent is boiled away under reduced pressure, and the residue was purified using column chromatography on silica gel using as eluent a mixture of methylene chloride:methanol (9:1). Crystallization from diethyl ether gave 0.24 g (80%) of the desired product.1H-NMR (500 MHz, CDCl3): δ 1,25 (t, 3H), of 2.25 (s, 3H), 2,3 (s, 3H), of 2.35 (s, 3H), of 2.75 (q, 2H), 3,4-of 3.45 (m, 2H), 3,55-3,7 (m, 6H), 4,35 (d, 2H), of 5.05 (t, 1H), 6,45 (s, 1H), 7,07 to 7.2 (m, 4H), and 7.5 (s, 1H).

Use the 1.15

Synthesis of isopropyl-8-[(2,6-dimethylbenzyl) amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate

Isopropyl-8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (9,85 kg, 1.0 equivalent, 29,71 mole) suspended in isopropanol (59 l); added Nal (0.6 equivalent, 2,68 kg, 17,88 mol) and K2CO3(2.5 equivalent, 10,29 kg, 74,48 mol)and the mixture was heated to about 70°C. 2,6-Dimethylbenzylamine (1.1 equivalent, 5,22 kg, 32,77 mol) was dissolved in isopropanol (about 60 l)and this solution added to the reaction mixture. After the addition the temperature was maintained equal to 60°C for another 1.5 hours. Additionally added K2CO3(9,15 kg), and the resulting suspension was stirred for another 2 hours at 60°C. Advanced slowly added at a temperature of 60°2,6-dimethylbenzylamine (2.76 kg) in isopropanol (22 l); after adding the reaction mixture was stirred for another 4 hours at this temperature. The suspension was diluted with water (124 l), cooled, mixed and filtered. The filter cake was washed with water and then with cold isopropanol, and dried under reduced pressure at 40°With obtaining 11,37 kg of wet material, yield: 90%.

Example 1.16

Synthesis of 8-[(2,6-dimethylbenzyl)amino)]-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide

In reactor C is loaded isopropyl-8-[(2,6-dimethylbenzyl)amino)]-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (11,30 kg, 1 equivalent, 27,02 mol) and THF (45 l)was added ethanolamine (18,97 kg, 11 equivalents, 309,2 mole) at a temperature of about 20°C. the Suspension was heated to about 100°C. a Certain amount of solvent is boiled away, and then added THF (35 l) and continued distillation. The procedure of adding THF and evaporation was repeated until complete conversion. To the suspension was added ethanol (140 l) and the suspension was heated to reflux distilled. To get a clear solution was added an additional amount of ethanol (13 l). The hot solution was filtered and then cooled. White solid was filtered, washed with ethanol and dried to obtain the product as a white powder (8271 g).

2. PREPARATION of starting MATERIALS

Example 2.1

Synthesis of 6-amino-5-nitro-nicotinamide

100 g of 6-hydroxy-5-nitro-nicotinic acid (0,54 mol; HPLC>98%) suspended in toluene (750 ml). Added DMF (1 ml of 0.013 mol, 0.024 equivalent), and the mixture was heated to 110°C (internal temperature). Within 120 minutes was added thionyl chloride (99 ml, 2.5 equivalents). Heating was continued for 4 hours at 110°C. the Reaction mixture was concentrated to half volume (drove 400 ml of solvent), and added toluene (400 ml).

This procedure was repeated again (410 ml of toluene was distilled, and I added fresh toluene (410 ml)). Then the solution was cooled to 20°and ment the NGO added to aqueous solution of ammonia (25%, 440 ml, 12 equivalents) for 40 minutes. Immediately began the deposition. During the addition the temperature was maintained below 15°C. After the addition was completed, the reaction mixture was left to warm to room temperature and continued stirring for 16 hours. The solid was filtered, washed with water (500 ml), ethanol (250 ml), TWO (250 ml) and dried (50-10 mbar, bath temperature 40°C, 16 hours), with the receipt of 91.3 g is specified in the header of the substance (0,501 mol, 87%).

Example 2.2

Synthesis of 5,6-diaminononane

of 44.5 g of 6-amino-5-nitronicotinic (0,24 mol; HPLC: 93% of the area) suspended in methanol/water 1:1 (500 ml), was added 5.0 g of the catalyst [Pd(4%)-Ru(1%)/C paste (62% N2Oh, the type 485; Johnson Matthey); type 485; Johnson Matthey)]. The hydrogenation was carried out at a pressure of 5 bar and 30°C for 5 hours. After the catalyst was filtered and washed with a mixture of methanol/water 1/1 (50 ml). Drove 480 ml of solvent. The resulting suspension was cooled to 20°and was filtered. The solid is washed with methanol (20 ml) and TWO (30 ml). After drying (200-10 mbar; bath temperature 40°C, 16 hours) scored 27.3 g is specified in the header of the substance (0,18 mol, 73%).

Example 2.3

Synthesis of 5,6-diaminononane

of 42.3 g of 6-amino-5-nitro-nicotinamide (0,23 mol; HPLC: 93% of the area) suspended in methanol/water 1:1 (500 ml). Added to 5.2 g of the catalyst [Pd5%)/C(57,8% H 2O; type: 39, Johnson Matthey]. Spent hydrogenation at 5 bar and 30°C for 4 hours. After the catalyst was filtered and washed with a mixture of methanol/water 1/1 (100 ml). Drove 550 ml of solvent. The resulting suspension was cooled to 20°and was filtered. The solid phase was washed with methanol (20 ml) and TWO (30 ml). After drying (200-10 mbar; bath temperature 40°C, 16 hours) received 28.5 g is specified in the header of the substance (0,18 mol, 73%).

1. The method of obtaining substituted imidazopyridine General formula (1)

where R1means C1-C6alkoxy or NH2,

by reacting compounds of General formula (2)

where R1has the above values

3-halogen-2-butanone in an inert organic solvent at a temperature of 80-100°C, characterized in that as the inert organic solvent used cyclohexanone.

2. The method according to claim 1, in which the 3-halogen-2-butanone is 3-bromo-2-butanone or 3-chloro-2-butanone.

3. The method according to claim 1 or 2, in which the number of 3-halogen-2-butanone is from 1.1 to 5 molar equivalents.

4. The method according to claim 1, in which cyclohexanone diluted with an inert solvent.

5. The method according to claim 1, in which R1is C1-C6alcox the school group.

6. The method according to claim 1, in which R1is the NH2group.

7. The method according to claim 1, characterized in that the compound of General formula (2), where R1mean NH2produced by hydrogenation of compounds of formula (4)

in water-ethanol solution in the presence of a catalyst.

8. The method according to claim 7, in which the catalyst is Pd-Ru/C paste.

9. The method according to claim 7 or 8, characterized in that the compound (4) are obtained by reacting compounds of the formula (3)

with thionyl chloride followed by treatment with ammonia obtained the corresponding chlorinated.



 

Same patents:

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and drug.

17 cl, 6 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

EFFECT: improved preparing method, valuable properties of compounds and compositions.

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

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

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

Up!