Method of producing salts of tetrazole methanesulphonic acid and novel compound used therein

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing a salt of tetrazole methanesulphonic acid of formula (I) , which involves acylating a compound (II) with a compound (III) and then adding methanesulphonic acid. The invention also relates to an intermediate compound of formula (II) and a method for production thereof.

EFFECT: method according to the present invention can cut reaction time, improve safety and enables to obtain salts of tetrazole methanesulphonic acid of high purity with high output without using a column chromatography technique.

22 cl, 2 tbl, 3 ex

 

The scope to which the invention relates

The present invention relates to a method for producing salts tetraselenafulvalene acid and to a new connection that is used in it.

Background of the invention

Pharmaceutically acceptable salts of 4-oxo-4H-chromen-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)ethyl]phenyl}-2H-tetrazol-5-yl)-4,5-acid]amine as an inhibitor of P-glycoprotein can be used as inhibitor in resistance to many drugs. In PCT publication no WO 2005/033097 described the way they are received.

In accordance with the above publication, as shown in reaction schemes 1 and 2, nitro compounds (1 and 3) are subjected to hydrogenation in a solvent such as methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran, simple ethyl ether and hexane toluene, in the presence of a metal catalyst, such as palladium, platinum and zinc, to obtain the amino-compounds (2 and 4). Then, the compound obtained is subjected to acylation using a condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, Ν,Ν-dicyclohexylamine, Ν,Ν-diisopropylcarbodiimide and methyl-p-toluensulfonate 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, in the presence of a catalyst such as 4-(dimethylamino)pyridine, dissolve the e, such as dichloromethane, chloroform, Ν,Ν-dimethylformamide, tetrahydrofuran and 1,4-dioxane, to obtain the compounds of tetrazole (5) as the target product.

The reaction scheme 1

The reaction scheme 2

However, the conventional method may cause the risk of dangers such as explosion and fire, in connection with the use of hydrogen and a metal catalyst for large-scale production. It also requires a process of purification using column chromatography on silica gel for separation of clean tetrazole connection, which is unrealistic for large-scale production, since there are restrictions on the size of columns and the number of downloaded material by column chromatography. In addition, the process chromatography requires a high operating cost because of the expensive material gaskets column of silica gel and a large amount of eluent used for the process.

Summary of the invention

Accordingly, the present invention is a method of obtaining salts tetraselenafulvalene acid.

Another objective of the present invention to provide new compounds which can be used to obtain salt tetraselenafulvalene acid, and method of its receipt.

acylation of compounds of formula (II) compound of formula (III) with a compound of the formula (IV); and

add methanesulfonic acid to the compound of formula (IV).

In accordance with another aspect of the present invention relates to the compound of formula (II), which can be used to obtain salt tetraselenafulvalene acid.

In accordance with another aspect of the present invention relates to a method for obtaining compounds of formula formula (II), including the stage of interaction of the compounds of formula (V) with the compound of the formula (VI) in the presence of triphenylphosphine and a base.

Detailed description of the invention

Hereinafter the present invention will be described in more detail.

In the method of obtaining, in accordance with the present invention uses the process of acylation using a new connection, complicated S-benzothiazol-2-silt ether 4-oxo-4H-chromen-2-karbaminovoi acid instead of using a condensing agent, as in conventional methods, to obtain salts tetraselenafulvalene acid with a high purity at a high yield, without updat the enforcement process of cleaning, such as column chromatography.

As shown below in reaction scheme 3, the method of obtaining salts tetraselenafulvalene acid in accordance with the present invention includes: (Stage 1) acylation of compounds of formula (II) compound of formula (III) with a compound of the formula (IV); and (Stage 2) adding methanesulfonic acid to the compound of formula (IV)obtained in the previous phase.

The reaction scheme 3

where Me represents a methyl group.

Firstly, the compounds of formulas (II) and (III) are subjected to acylation in a polar aprotic solvent to obtain compounds of formula (IV).

In particular, the ester compound of the formula (II) and the compound of formula (III) are subjected to acylation in a polar aprotic solvent selected from the group consisting of dichloromethane, tetrahydrofuran, complex ethyl ether, acetone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide and mixtures thereof, preferably dichloromethane. After completion of the acylation, it is added to methanol to deactivate the remaining compounds of formula (II). Then to it add acetone to clean so that you can naturally and efficiently to ensure that the compounds of formula (IV) with a purity of 98% or more.

When the acylation of sedimentary (II) is preferably used in an amount of from 1 to 5 equivalents, per 1 equivalent of the compound of formula (III).

To deactivate the remaining compounds of formula (II) after acylation of the methanol is preferably used in the ratio of volume to mass (about./mass.) from 1 to 2, in an amount in the range from 1 to 2 ml per 1 g of compound of formula (II).

For cleaning when the acylation can also be used acetone, where the preferred form of acetone is an aqueous solution, preferably 95% aqueous acetone. Acetone is preferably used in an amount in the range from 35 to 45 ml per 1 g of compound of formula (III).

At the next stage methansulfonate acid is added to the compound of formula (IV)obtained in the previous phase, to yield the salt tetraselenafulvalene acid of the formula (I).

In particular, tetrazole compound of formula (IV)obtained in the preceding stage, are dissolved in an organic solvent such as chloroform and methanol, followed by adding thereto methanesulfonic acid. Then it successively added ethyl acetate and acetone for cleaning, so that safe and effective way could be obtained Sol tetraselenafulvalene acid of the formula (I).

In the above-described method methansulfonate acid, which acts as a conjugate base of the acid of formula (IV), preferably used in an amount of from 1 to 1.5 equivalents per 1 equivalent of the compound of formula (IV).

D is more, for purification can be used ethyl acetate and acetone. The ethyl acetate is preferably used in an amount in the range from 1 to 5 ml per 1 g of compound of formula (IV). Acetone can be used in aqueous solution, preferably 95% aqueous acetone, in an amount in the range from 15 to 25 ml per 1 g of compound of formula (IV).

As described above, in the method according to the invention using the compounds of formula (II) to obtain salt tetraselenafulvalene acid can be used only methanol and acetone without the use of column chromatography to obtain compounds of formula (IV) with high purity and high yield. Therefore, compared with conventional methods, including acylation using a condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Ν,Ν-dicyclohexylamine, Ν,Ν-diisopropylcarbodiimide and methyl-p-toluensulfonate 1-cyclohexyl-3-(2-(morpholinoethyl)carbodiimide, the method according to the invention can be obtained a product of high purity by simple filtration, and thus, it provides a very cost-effective and convenient method, suitable for large-scale production.

Meanwhile, the compound of formula (II)used in the above acylation (stage 1)may be obtained by the coupling of compounds of formula (V) with the compound of the formula (VI) in the presence of the tvii of triphenylphosphine and a base, as shown below in reaction scheme 4.

The reaction scheme 4

In particular, the complex S-benzothiazol-2-silt ether 4-oxo-4H-chromen-2-carboxylic acid of formula (II) can be obtained by the interaction between romanovas acid of formula (V) with 2,2'-dithiobisbenzothiazole formula (VI) in an organic solvent in the presence of a base and triphenylphosphine (PPH3) at a temperature in the range from 20 to 25°C for 1-3 hours, where the organic solvent is selected from the group consisting of dichloromethane (CH2Cl2), easy-diethyl ether complex ethyl ether, tetrahydrofuran and mixtures thereof, preferably dichloromethane, and base selected from the group consisting of triethylamine (NEt3), pyridine, imidazole, diisopropylethylamine (DIPEA), 4-dimethylaminopyridine (DMAP) and their mixtures, preferably triethylamine. If the reaction time exceeds 3 hours, it may be formed of an impurity in the form of by-products.

The reaction of the used amount of the compounds of formula (VI) is preferably from 1 to 2 equivalents per 1 equivalent of the compound of formula (V).

The triphenylphosphine is preferably used in an amount of from 1 to 2 equivalents per 1 equivalent of the compound of formula (V).

The base is preferably used in an amount of from 1 to 2 equivalents per 1 equivalent of the HRO is about acid of formula (V).

In addition, the compound of formula (III), which is used as starting material in the method according to the invention for obtaining salt tetraselenafulvalene acid, can be obtained in the following way, as shown in reaction scheme 5, including: (Stage 1) the cyclization of the compounds of formula (VII) with the compound of the formula (VIII) with a compound of formula (IX); and (Stage 2) recovery of the compounds of formula (IX)obtained in the previous phase by the use of metal and acid.

The reaction scheme 5

where Me represents a methyl group.

Firstly, the compounds of formulas (VII) and (VIII) is subjected to cyclization with obtaining compounds nitrophenylhydrazone formula (IX).

In particular, the compound of formula (VII) are allowed to react in the presence of sodium nitrite and hydrochloric acid in aqueous solution, for example 50% ethanol, to obtain the diazonium salts. To it add the compound of formula (VIII) and pyridine and stirred while maintaining the reaction temperature below 10°C or below. The reaction mixture is heated to room temperature and then stirred, washed with 2,5h. a solution of hydrochloric acid, sodium bicarbonate and water and then extracted with dichloromethane. After removal of the organic layer add methanol on what I crystallization to obtain the compounds of formula (IX) as the target product [see Suketaka Ito et al., Bulletin of Chemical Society of Japan, Vol.49(7), 1920-1923 (1976)].

In this case, the compound of formula (VII) can be obtained as shown below in reaction scheme 6, by reacting the compounds of formula (X) with the compound of the formula (XI) with a compound of formula (XII), followed by reduction of compounds of formula (XII)using a metal and an acid.

A reaction scheme 6

where Me represents a methyl group.

In particular, the compound of formula (X) is subjected to interaction with the compound of the formula (XI) in a solvent such as Ν,Ν-dimethylformamide, in the presence of anhydrous potassium bicarbonate (K2CO3) and sodium iodide (NaI) at a temperature in the range from 70 to 100°C under stirring to obtain compounds nitrobenzophenone formula (XII). Then dried the compound of formula (XII) is subjected to a restoring metal and acid in aqueous solution, for example 50% ethanol, to obtain the compounds of aminobenzophenone formula (VII), where the metal is selected from the group consisting of iron, tin, zinc and Nickel, preferably iron, and acid selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, acetic acid and mixtures thereof.

Recovery can be carried out for 3 hours at 80°C. After recovery to reactio the Noah mixture may be added a 10% aqueous solution of sodium chloride to neutralize and filtered through a pad of cellite. After removal of the organic layer, the residue utverjdayut simple with ethyl ether to obtain the compounds of formula (VII). When recovering the metal may be used in amounts of from 2 to 10 equivalents per 1 equivalent of the compound of formula (XII), and the acid may be used in quantities of from 0.1 to 0.5 equivalents per 1 equivalent of the compound of formula (XII).

In addition, the compound of formula (VIII) can be obtained as shown in reaction scheme 7, by reacting the compounds of formula (XIII) with the compound of the formula (XIV).

A reaction scheme 7

where Me represents a methyl group.

In particular, the compound of formula (XIII) is subjected to interaction with the compound of the formula (XIV) in ethanol at a temperature in the range from 70 to 80°C followed by filtration and drying to obtain the compounds of formula (VIII) [see Suketaka Ito et al., Bulletin of Chemical Society of Japan, Vol.49(7), 1920-1923 (1976)].

In reaction scheme 5, the compound of formula (IX)obtained in stage 1, then subjected to recovery using a metal and an acid, to obtain the compounds of formula (III) (stage 2).

In particular, the compound of formula (IX) is subjected to recovery of the metal in the acid to obtain the compounds of formula (III), where the metal is selected from the group consisting of iron, tin, zinc and Nickel, metal, preferably iron, and acid SEL is on of the group, consisting of hydrochloric acid, nitric acid, sulfuric acid, acetic acid and mixtures thereof, preferably acetic acid, such as 50% aqueous solution of acetic acid.

Recovery is preferably carried out at 80°C for 3 hours. After recovery, the mixture was filtered through a pad of cellite and then neutralized. After removal of the organic solvent the residue is stirred in methanol to obtain the compounds of formula (III).

When recovering the metal may be used in quantities of from 5 to 15 equivalents per 1 equivalent of the compound of formula (IX), and the acid may be used in an amount in the range from 2 to 5 ml per 1 g of compound of formula (IX).

As described above, in the present invention in the recovery process when obtaining the compounds of formula (III) and (VII) use the metal and the acid, instead of palladium and hydrogen gas used in traditional ways, so that he could shorten the reaction time, as well as the risk of explosion due to the increased security recovery.

In accordance with another aspect of the present invention relates to the compound of formula (II), which can be used to obtain salt tetraselenafulvalene acid of the formula (I):

In addition, the present invention relates to the person obtaining the compounds of formula (II), including the stage of interaction of the compounds of formula (V) with the compound of the formula (VI) in the presence of a base:

Hereinafter the present invention will be described more specifically by the following examples, but they are presented only for purposes of illustration, and the present invention is not limited to them.

Example: obtain the salt of N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-acid)-4-oxo-4H-chromen-2-carboxamid methanesulfonic acid

Stage 1-1) of 6,7-dimethoxy-2-(4-nitrophenacyl)-1,2,3,4-tetrahydroisoquinoline

5 l Ν,Ν-dimethylformamide, 2-(4-nitrophenyl)ethylbromide (1.0 kg, 4.35 mol) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (DTIH, 1.0 kg, 4.35 mol) was added to the reactor and stirred. To the reaction mixture were added potassium carbonate (1.80 kg, 13 mol) and sodium iodide (780 g, 5,20 mol), the reactor was heated to 100°C and then stirred for 12 hours. After checking the completion of the reaction by thin-layer chromatography (eluent: chloroform/methanol = 15/1) the reaction mixture was cooled to room temperature.

In a separate reactor was added 20 l of cold water and then the reaction mixture obtained in the previous phase was slowly added thereto, followed by stirring for 4 hours. The resulting mixture was filtered, washed with 3 l of water and then dried hot the air at 40°C in a furnace with obtaining specified in the title compound (1.34 kg, 90%).

1H-NMR (CDCl3d: 8,17 (d, 2H), 7,43 (d, 2H), 6,62 (c, 1H), 6,54 (c, 1H), a 3.87 (c, 3H), 3,85 (c, 3H), 3,66 (c, 2H), 3,03 (t, 2H), 2,82-2,78 (m, 6H).

Stage 1-2) 4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)benzolamide

Iron (1.27 kg, 23,48 mol), hydrochloric acid (127 ml, 1.54 mol) and 6.7 l of 50% aqueous ethanol was added to the reactor and stirred for 1 hour at 80°C. To this mixture slowly over 1 hour was added obtained in stage 1-1 6,7-dimethoxy-2-(4-nitrophenacyl)-1,2,3,4-tetrahydroisoquinoline (1.3 kg, 3,91 mol) followed by stirring for 3 hours at 80°C. After checking the completion of the reaction by thin-layer chromatography (eluent: chloroform/methanol = 15/1) the reaction mixture was cooled to room temperature. To it was added 5.3 l of dichloromethane and 5.3 liters of water, the reaction mixture was neutralized by adding 804 ml of 10% aqueous sodium hydroxide solution. The resulting mixture was filtered through a pad of cellite and washed with 3 l of methylene chloride. The organic layer was collected, dried over magnesium sulfate and then filtered. The solvent was removed under reduced pressure and dried with hot air at 40°C in a drying Cabinet with obtaining specified in the title compound (1.05 kg, 90%).

1H-NMR (CDCl3d: 7,02 (d, 2H), 6,65-6,53 (m,4H), of 3.84 (s, 3H), 3,83 (s, 3H), 3,63 (s, 2H), only 3.57 (s, 2H), 2,84-of 2.86 (m, 8H).

Stage 2) 4,5-dimethoxy-2-nitro-p-toluensulfonate

12.5 l this is Ola, p-toluensulfonate (1 kg, 5.37 mol) and 6-nitrosalicylaldehyde (1.2 kg, 5,907 mol) was added to the reactor and then heated up to 80°C with subsequent stirring for 6 hours. After checking the completion of the reaction by thin-layer chromatography (eluent: chloroform/methanol = 15/1) the reaction mixture was cooled to room temperature. The resulting mixture was filtered, washed with 12.5 liters of ethanol and dried with hot air at 40°C in a drying Cabinet with obtaining specified in the connection header (1,47 kg, 99,6%).

1H-NMR (CDCl3d: 8,48 (c, 1H), 8,08 (c, 1H), 7,89 (d, 2H), to 7.59 (c, 1H), 7,42 (c, 1H), 7,33 (d, 2H), was 4.02 (c, 3H), 3,98 (c, 3H), 2,44 (c, 3H).

Stage 3) Complex S-benzothiazol-2-silt ether 4-oxo-4H-chromen-2-karbaminovoi acid

Chroman-2-carboxylic acid (700 g, 3,68 mol), 2,2'-bitious-benzothiazole (1,47 kg, was 4.42 mol), triphenylphosphine (1.16 kilograms, was 4.42 mol) and 14.7 l of dichloromethane was added to the reactor and stirred. To the reaction mixture was slowly added triethylamine (616 ml, was 4.42 mol) in 2 l of dichloromethane and stirred for 6 hours. After completion of the reaction the mixture was filtered, washed with 4 l of acetone and then dried with hot air at 40°C in a drying Cabinet with obtaining specified in the connection header (0,99 kg, 80%).

1H-NMR (CDCl3d: 8,30 (d, 1H), 8,16 (d, 1H), 8,01 (d, 1H), 7,88 (t, 1H), of 7.70 (d, 1H), to 7.61-7,31 (m, 3H), 7,15 (c, 1H).

Stage 4) 2-(4-(5-(4,5-dimethoxy-2-nitrophenyl)-2H-tetrazol-2-yl)fenet the l)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)benzolamide (1.0 kg, 3.2 mol), obtained in stage 1-2, 3 l of 50% aqueous ethanol and hydrochloric acid (850 ml, 12.5 mol) was added into A reactor and stirred at 0°C. To the reaction mixture was slowly added sodium nitrite (227 g, 3.3 mol) in 330 ml of water and was stirred for 3 hours.

A 20-liter reactor B was added 4,5-dimethoxy-2-nitro-p-toluensulfonate (1.2 kg, 3.2 mol), obtained in stage 2, and 12 l of pyridine and cooled to 0°C. To it was slowly added to the mixture from A reactor, followed by stirring for 6 hours at room temperature. After checking the completion of the reaction by thin-layer chromatography (eluent: chloroform/methanol = 15/1) the reaction mixture was subjected to extraction with 12 l of dichloromethane and 12 l of water. The organic layer was collected, washed three times 18 l 2,5h. hydrochloric acid and washed with sodium bicarbonate solution. The organic layer was dried and person to distil under reduced pressure. The residue was mixed with 10 l of methanol and was stirred for 4 hours. The resulting mixture was filtered and was dried with hot air at 40°C in a drying Cabinet with obtaining specified in the connection header (1,08 kg, 62%).

1H-NMR (CDCl3d: 8,08 (d, 2H), 7,66 (c, 1H), 7,45 (d, 2H), 7,32 (c, 1H), 6,59 (d, 2H), 4,03 (c, 6H), 3,85 (c, 6H), 3,68 (c, 2H), 3,01 (m, 2H), 2,84 (m, 6H).

Stage 5) 2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro chinolin-2 (1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxybenzene

Iron (433 g, 7,76 mol) and 5.4 liters of 50% aqueous acetic acid was added to the reactor and stirred for 1 hour at 80°C. it slowly for two hours was added 2-(4-(5-(4,5-dimethoxy-2-nitrophenyl)-2H-tetrazol-2-yl)phenethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.06 kg, 1.94 mol), obtained in stage 4, followed by stirring for 1 hour. After checking the completion of the reaction by thin-layer chromatography (eluent: chloroform/methanol = 15/1) the reactor was cooled to room temperature slowly. It was added 5.3 l of chloroform and 2.4 l of water, and the resulting mixture was filtered through a pad of cellite. The organic layer was collected, it was slowly added to 6.6 l of saturated sodium bicarbonate solution with stirring. The organic layer was collected and the aqueous layer was further extracted using 1.25 l of chloroform. The obtained organic layer was dried over magnesium sulfate and then person to distil under reduced pressure to remove solvent. The residue was mixed with 10.6 l of methanol, followed by stirring. The resulting mixture was filtered and was dried with hot air at 40°C in a drying Cabinet with obtaining specified in the connection header (0,87 kg, 87%).

1H-NMR (CDCl3d: to 8.14 (d, 2H), 7,75 (c, 1H), 7,49 (d, 2H), 6,63 (d, 2H), 6,40 (c, 1H), 5,34 (d, 2H), 3,97 (d, 6H), 3,89 (c, 6H), 3.72 points (c, 2H), 3,06 (t, 2H), 2.91 in-2,84 (m, 6H).

Stage 6) N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-digidroid the quinoline-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-acid)-4-oxo-4H-chromen-2-carboxamide

2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxybenzene (850 g, 1.6 mol), obtained in stage 5, the complex S-benzothiazol-2-silt ether 4-oxo-4H-chromen-2-karbaminovoi acid (723 g, 2.1 mol), obtained in stage 3, and 17 l of dichloromethane was added to the reactor and stirred at for 6 hours at room temperature. After checking the completion of the reaction by thin-layer chromatography (eluent: chloroform/methanol = 15/1) to the mixture was sequentially added 1.1 l of methanol and 35.7 l 95% aqueous acetone, followed by stirring for 16 hours at room temperature. The resulting mixture was filtered, washed 4.3 liter of acetone, dried with hot air at 40°C in a drying Cabinet with obtaining specified in the connection header (1,10 kg, 97%).

1H-NMR (CDCl3d: 12,53 (c,1H), 8,60 (c, 1H), 8,23 (d, 1H), 8,14 (d, 2H), to 7.77 (d, 2H), 7,74 (c, 1H), 7,50-7,44 (m, 3H), 7,26 (d, 2H), 6,60 (d, 2H), 4,01 (c, 6H), a 3.87 (c, 6H), 3,70 (c, 2H), is 3.08 (t, 2H), 3,02-2,83 (m, 6H).

Stage 7) salt of N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-acid)-4-oxo-4H-chromen-2-carboxamid methanesulfonic acid

N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-acid)-4-oxo-4H-chromen-2-carboxamide (1.06 kg, 1.54 mol), obtained in stage 6, was dissolved in a mixed solution of 18.1 liters of chloroform and 1.06 l of methanol and the resulting mixture f is literaly. It slowly for 30 minutes was added methanesulfonyl acid (102 ml, 1.57 mol) in 300 ml of ethyl acetate. To him for 1 hour was slowly added 3,95 l of ethyl acetate, followed by stirring for 16 hours at room temperature. The resulting mixture was filtered, washed with 1 l of ethyl acetate and dried with dry air at 40°C in a drying Cabinet.

The product was subjected to the first recrystallization, using chloroform and then filtered, washed with ethyl acetate and dried with dry air at 40°C in a drying Cabinet. The dried solid was plunged second recrystallization using a mixed solvent (dichloromethane/methanol/ethyl acetate = 17/1/4) to obtain the crystalline solid. To remove residual solvent, i.e. dichloromethane, the product was mixed with 95% aqueous acetone, followed by stirring for 16 hours. The resulting mixture was filtered and was dried with dry air at 40°C in a drying Cabinet with obtaining specified in the connection header (0,84 kg, 70%).

Mass (ESI)calculated for C38H36N6O7;

m/z 688,26 (M+)+; found, m/z 689,32 (M+H)+

1H-NMR (CDCl3d: 12,43 (c, 1H), 11,66 (c, 1H), 8,49 (c, 1H), 8,17 (d, 1H), of 8.06 (d, 2H), 7,79-to 7.67 (m, 2H), 7,54 (d, 3H), 7,46 (t, 1H), 7,14 (c, 1H), to 6.67 (d, 2H), 4,78 (d, 1H), 4,19-4,12 (m, 1H), 3.96 points-a 3.87 (m, 12H), 3,56-to 3.36 (m, 6H), 3.04 from (d, 1H), 2,78 (c, 3H).

Comparative example

Tetrazolyl what about the acid was obtained in accordance with the procedure disclosed in international patent publication no WO 2005/033097, which includes recovery using palladium and hydrogen gas and acylation using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and the condensing agent 4-dimethylaminopyridine (DMAP)

Experimental example

For comparison of the method according to the invention, including the recovery of metal and acid, with the conventional method using palladium and hydrogen, were evaluated product purity, safety and economic feasibility of recovery processes in the example and comparative example, and the results are summarized in table 1, where the result of the comparative example was checked with the company catalog (Aldrich) 2009-2010

As shown in table 1, both the recovery process gave the target products with the same frequency, but the recovery process in accordance with the present invention could obtain the target product more safe, without risks of explosion and cost-effective manner, as compared with the conventional method.

Table 1
ExampleComparative example
Reducing agentIron/acidPalladium/hydrogen
The purity of the product95%95%
SecurityGoodExplosion hazard (solvent vapours, gases H2)
Economic implementation of the reducing agent- Budget (1 g: 123 KRW)
- used in the amount of 40% of the mass. reagent to obtain a compound of formula (III)
- used in the amount of 40% of the mass. reagent to obtain a compound of formula (VII)
- Expensive (1 g: 37,000 KRW)
- used in the amount of 10% by weight of reagent

To compare the efficiency of the method according to the invention, which uses a compound of the formula II, with the conventional method, which uses 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP) as the condensing agent, the yield percentage, purity and purification method of the compounds of the formula (IV) in example and comparative example are summarized below in table 2.

As shown in table 2, in the method according to the invention can also be obtained compound of the formula (IV) if more you the eye percentage yield and purity, compared with the conventional method. Can also be shown that the method according to the invention can be obtained pure chemical product only through recrystallization without additional process column chromatography.

Table 2
ExampleComparative example
ConnectionThe compound of formula (II)EDCI/DMAP
Output95%65%
Purity>98%94%
Cleaning methodRecrystallizationColumn chromatography

Although the invention has been described in relation to the above specific embodiments, it should be understood that the specialists in this field of technology can make to this invention various modifications and changes are also included in the scope of the invention defined by the attached claims.

1. The method of obtaining salt tetrazole analhooboy acid of the formula (I), which involves the following stages:
acylation of compounds of formula (II) compound of formula (III) with a compound of the formula (IV); and
add methanesulfonic acid to the compound of formula (IV):

2. The method according to claim 1, where the acylation is carried out in a polar aprotic solvent selected from the group consisting of dichloromethane, tetrahydrofuran, complex ethyl ether, acetone, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide and mixtures thereof.

3. The method according to claim 1, where the compound of formula (II) are obtained in the presence of triphenylphosphine and the Foundation of the interaction of the compounds of formula (V) with the compound of the formula (VI):

4. The method according to claim 3, where the base is selected from the group consisting of triethylamine, pyridine, imidazole, diisopropylethylamine, 4-dimethylaminopyridine and mixtures thereof.

5. The method according to claim 3, where the interaction of the compounds of formula (V) and compounds of formula (VI) is carried out in an organic solvent selected from the group consisting of dichloromethane, easy-diethyl ether complex ethyl ether, tetrahydrofuran and mixtures thereof.

6. The method according to claim 3, where the interaction of the compounds of formula (V) and compounds of formula (VI) is carried out at a temperature in di the range from 20 to 25°C under stirring for 1-3 hours.

7. The method according to claim 1, where the compound of formula (III) are obtained by a process comprising the stages:
cyclization of compounds of formula (VII) with the compound of the formula (VIII) with a compound of formula (IX);
and recovery of the compounds of formula (IX) using metal and acid:


8. The method according to claim 7, where the metal is selected from the group consisting of iron, tin, zinc and Nickel.

9. The method according to claim 7, where the metal is used in an amount of 5 to 15 equivalents per 1 equivalent of the compound of formula (IX).

10. The method according to claim 7, where the acid is selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, acetic acid and mixtures thereof.

11. The method according to claim 7, where the acid is used in an amount in the range from 2 to 5 ml per 1 g of compound of formula (IX).

12. The method according to claim 7, where the compound of formula (VII) is produced by interaction of the compounds of formula (X) with the compound of the formula (XI) with a compound of formula (XII), followed by reduction of compounds of formula (XII) using metal and acid:


13. The method according to item 12, where the metal used for the recovery of the compounds of formula (XII)is selected from the group consisting of iron, tin, zinc and Nickel.

14. With the persons indicated in paragraph 12, where metal is used for recovering the compound of formula (XII)is used in an amount of from 2 to 10 equivalents per 1 equivalent of the compound of formula (XII).

15. The method according to item 12, where the acid used for the recovery of the compounds of formula (XII)is selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, acetic acid and mixtures thereof.

16. The method according to item 12, where the acid used for the recovery of the compounds of formula (XII)is used in an amount of from 0.1 to 0.5 equivalents per 1 equivalent of the compound of formula (XII).

17. The method according to claim 7, where the compound of formula (VIII) is produced by interaction of the compounds of formula (XIII) with the compound of the formula (XIV):

18. The compound of formula (II)

19. The method of obtaining the compounds of formula (II), which includes the stage of interaction of the compounds of formula (V) with the compound of the formula (VI) in the presence of triphenylphosphine and reasons:


20. The method according to claim 19, where the base is selected from the group consisting of triethylamine, pyridine, imidazole, diisopropylethylamine and 4-dimethylaminopyridine.

21. The method according to claim 19, where the reaction is carried out in an organic solvent, selected from the group sotoyama is of dichloromethane, simple diethyl ether complex ethyl ether, tetrahydrofuran and mixtures thereof.

22. The method according to claim 19, where the reaction is conducted under stirring for 1-3 hours at a temperature in the range from 20 to 25°C.



 

Same patents:

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates organic chemistry and specifically to novel pyridine amide derivatives of general formula I where n equals 1; R1 and R2 together denote a residue selected from a group consisting of -CH=N-NH- and -CH=CH-N=CH-, which is bonded in any desirable direction to the parent structure or R2 and R3 together denote a residue selected from a group consisting of -CH=N-NH-; -CR28=N-NH-; -S-C(=S)-NH-; -S-CR29=N-; -N=CR30-O-; -N=CH-NH-; -N=N-NH-; -O-CH2-O-; -CH2-CH2-CH2-NH, -O-CH2-CH2-O-; -N=CH-CH=N-; -CH=CH-CH=N-, which is bonded in any desirable direction to the parent structure, or R3 and R4 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, or R4 and R5 together denote a -CH=N-NH- residue, which is bonded in any desirable direction to the parent structure, and the rest of the residues R1, R2, R3, R4 and R5, mutually independently, in each case denote H; where R28 denotes F; Cl; Br or I; R29 and R30, mutually independently, in each case denote -NH-C(=O)-R31; -NH2; -NH-S(=O)2-R32; -NH-C(=O)-O-R33; -S-R34; where R31, R32, R33 and R34, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R6 denotes H or denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; R7 denotes hydrogen or -OH; R denotes -CF3; or denotes an unsubstituted tert-butyl residue; T denotes C-R35 and U denotes C-R36, V denotes N and W denotes C-R38; where R35 and R36 denote H; where R38 denotes -NR40R41; -OR42 or -SR43; where R40, R41, R42 and R43, mutually independently, in each case denote a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; or denote a saturated, unsubstituted 3-, 4-, 5-, 6-, 7-, 8- or 9-member cycloaliphatic residue, or where R40 and R41 in each case together with a nitrogen atom as a ring member which binds them together, form a saturated 6-member heterocycloaliphatic residue, optionally substituted with one R57 residue, where R57 denotes a straight or branched, saturated, unsubstituted aliphatic C1-10 residue; in each case in form of corresponding physiologically acceptable salts. The invention also relates to a method of producing a compound of formula I, a medicinal agent based on the compound of formula I and use of the compound of formula I.

EFFECT: obtaining novel amide derivatives of pyridine, useful in treating vanilloid receptor 1 mediated diseases.

25 cl, 1 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method for preparing N-(1,5,3-dithiazocynan-3-yl)amides of formula , wherein R=p-C5H4N (a), (CH3)3CO (b), o-CH3OC6H4 (c), which can find application as biologically active compounds, selective sorbents and precious metal extractants. Substance of the method consists in the reaction of N1,N1,N7,N7 - tetramethyl-2,5-dithiaheptane-1,7-diamine with hydrazides RC(O)NHNH2 in the presence of the catalyst samaric nitrate crystallohydrate Sm(NO3)3·6H2O at temperature 65-75°C for 20-26 h.

EFFECT: what is developed is a method for preparing new high-selectivity N-(1,5,3-dithiazocynan-3-yl)amides.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I , in which X1, X2, X3, X4 and X5 independently denote -CH- or N; or X3, X4 and X5 independently denote -CH- or N, and X1 and X2 independently denote C and are part of an additional 6-member aromatic ring; in which R1 denotes methyl or ethyl, or R1 denotes hydrogen; R2 denotes methyl, ethyl, propyl, tert-butoxy carbonylmethyl, allyl, difluoromethyl, ethylbenzene, methylbenzene, butenyl, hydroxyethyl, tolyl, pentenyl, methoxyethyl, butynyl, propynyl, methylcarbonyloxy, cyclopentyl, each of which can be substituted with one or more identical or different substitutes selected from R5; or R2 denotes hydrogen; R3 denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, halogenalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy or alkoxyalkyl, each of which can be substituted with one or more identical or different substitutes selected from R6; or R3 denotes hydrogen, -CH2-C(O)-heterocycloalkyl or -CH2-C(O)NR9-R12; R11 denotes one or more identical or different substitutes selected from hydrogen, halogen, cyano, amino, alkyl, methylthionyl, methylsulphonyl, amino, cyano or alkoxy; where R5, R6, R9, R12 are as indicated in claim 1, under the condition that R1, R2 and R3 cannot be methyl at the same time; under the condition that when R2 and R3 both denote hydrogen, R1 cannot be methyl or hydrogen; under the condition that when R1 denotes methyl or hydrogen, R2 denotes methyl and R3 denotes hydrogen when ring B cannot be phenyl; and pharmaceutically acceptable salts and N oxides thereof. The invention also describes a pharmaceutical composition for use in case of skin diseases, said composition containing a compound of formula I, and use of said compound in preparing a medicinal agent for preventing conditions associated with skin wounds.

EFFECT: novel compounds which can be useful in treating skin diseases are obtained and described.

19 cl, 304 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 2-aminoquinoline derivatives of formula , or to pharmaceutically acceptable salts thereof, wherein R1 represents 6-member heterocycloalkyl (tetrahydropyranyl); R2 is specified in a group consisting of hydrogen and halogen; L1 is specified in a group consisting of -CH2-NRA, -CH2CH2-NRA, -CH2-O- and -CH2-S-; wherein RA means hydrogen; R3 is specified in a group consisting of carboxy substituted C1-4alkyl, aryl(phenyl), -(C1-4alkyl)-aryl(phenyl), -(C1-4alkyl)-heteroaryl(imidazolyl, pyridinyl); wherein aryl analysed either individually, or as a part of a substituting group, carries one to three substitutes independently specified in a group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, -C1-4alkoxygroup- and -C1-4alkyl-CO2H; either RA and R3 together with a nitrogen atom whereto attached form a ring structure representing 6-member heterocycloalkyl (piperazinyl). Further, the invention refers specific compounds and , a pharmaceutical composition of the compounds of formula (I), (II-a) and (II-b), a method for preparing the pharmaceutical composition, a method for treating the above disorders, a method for inhibiting enzyme β-secretase activity and using the compounds of formulas (I), (II-a) and (II-b).

EFFECT: there are prepared new 2-amino-quinoline derivatives effective for treating the β-secretase mediated disorders.

25 cl, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazolone derivatives used as drugs being kinase inhibitors, described by formula (I), wherein; R1 represents a C1-C3 alkyl radical or a hydrogen atom, and/or an aryl radical, Ar1 is specified in or , R represents the group R2-S-, R2 is thereby specified in the radicals like T1-(CH2)n, wherein n=0, 1, 2 or 3, and T1 represents a metal, vinyl, alkyl, alkynyl, nitrile, C3- or C4-cycloalkyl radical, hal, Z-O, Z-CO, wherein Z represents C1-C3 alkyl or hal, hal represents F, Cl, Br or I, or the group CCl3, or the group R3-NH-, R3 is thereby specified in the radicals like T2-(CH2)n, wherein n=0, 1 or 2, and T2 represents a metal, vinyl radical, Z-O, Z-CONH-, -CH-(OZ)2, ZCO, wherein Z represents H or C1-C4 linear or branched alkyl, NH2, C3-cycloalkyl, aryl, substituted aryl, or R3 represents H, or the group R4-CONH-, R4 is thereby specified in C3-C5 branched alkyl, or Ar2- or Ar2-3-, Ar2 is specified in a phenyl radical, substituted phenyl or benzodioxolyl; and have IC50 less than 5 mcM.

EFFECT: invention also refers to pharmaceutical compositions based on the compounds of formula I for treating neurodegenerative disorders and to using these compounds as DYRKIA inhibitors.

11 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 2H-chromen compound or a derivative thereof having action of a S1P1 agonist. The above may be used for preventing and/or treating a disease caused by undesired lymphocyte filtration, or a disease caused by abnormal cell proliferation or accumulation.

EFFECT: preparing the compounds for preventing and/or treating the disease caused by undesired lymphocyte filtration, or the disease caused by abnormal cell proliferation or accumulation.

8 cl, 131 tbl, 156 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

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