Method of producing thiazole through aminomethylation

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a thiazole compound with formula

by reacting a compound with formula with ammonia and formaldehyde, obtaining a hexahydrotriazine compound with formula , with subsequent hydrolysis of compound with formula (2), as well as compounds with general formula (2) and a method of producing said compounds. In general formulae (1), (2) and (3) X1 is a hydrogen atom or a halogen atom, X2 is a halogen atom.

EFFECT: method is described for producing thiazole through aminomethylation.

13 cl, 11 ex

 

The technical field to which the invention relates

The present invention relates to a method for obtaining compounds of thiazole.

Prior art

Connection thiazole, usually, 2-chloro-5-(aminomethyl)thiazole of the formula (3):

in which X1represents a hydrogen atom or a halogen atom, is a useful compound as an intermediate for pharmaceuticals and agricultural chemical means (see, for example, Japanese application JP 7-14916). For the preparation of compounds of thiazole there are several ways. For example, (a) compound of formula (1):

in which X1is the same as defined above, X2represents a halogen atom, is subjected to reaction with hexamethylenetetramine followed by hydrolysis (see, for example, Japanese application JP 4-234864 a and JP 4-21674 A); (b) a compound of formula (1) is subjected to reaction with phthalimide potassium subsequent hydrazinolysis (see, for example, Japanese application JP 4-234864 A); (C) a compound of formula (1) is subjected to reaction with formamide, followed by hydrolysis (see, for example, Japanese patent application, JP 5-286936 A); and (d) compound of formula (1) is subjected to reaction with ammonia (see, for example, Japanese application JP 4-234864 a and JP No. 2000-143648 A).

However, the above processes (a) - (C) are not always satisfied immoritality from the industrial point of view because the yields of the target compounds - thiazole of the formula (3) in these processes are low. Although the above process (d) has the advantage over the processes (a) to (C) due to the use of inexpensive ammonia, a significant number of side compounds of formula (4):

in which X1is such as defined above can be formed even when using ammonia in 20-fold (molar ratio) or more relative to the compound of formula (1), resulting in low yield of the target compounds thiazole of the formula (3). Therefore, it is desirable for more improvement.

The invention

In such circumstances, the authors of the present invention intensively worked on the development of pre-emption from the industrial point of view, method of producing the thiazole compounds of the formula (3) using inexpensive ammonia at suppressing the formation of by-product, i.e. the compounds of formula (4), and found that the target connection thiazole of the formula (3) can be obtained by suppressing the formation of by-product, i.e. the compounds of formula (4), by reacting the compounds of formula (1) with ammonia and formaldehyde, which is also inexpensive and readily available, obtaining connection hexahydrotriazine, which is new is th compound of the formula (2):

in which X1is the same as defined above, and then by hydrolysis of compounds hexahydrotriazine formula (2). Thus the present invention has been accomplished.

That is, the present invention provides a method for obtaining compounds of the thiazole of the formula (3):

in which X1is the same as defined above, which includes stages:

interaction of the compounds of formula (1):

in which X1represents a hydrogen atom or halogen atom, X2represents a halogen atom, with ammonia and formaldehyde to obtain compounds hexahydrotriazine formula (2):

in which X1is the same as defined above,

and hydrolysis of the resulting compound hexahydrotriazine formula (2).

The best option of carrying out the invention

First will be explained the stage of interaction of the compounds of formula (1):

in which X1represents a hydrogen atom or halogen atom, X2represents a halogen atom (hereafter in this document referred to as "compound (1)"), with ammonia and formaldehyde to obtain compounds hexahydrotriazine f is rmula (2):

in which X1is as defined above (hereinafter in this document referred to as "connection hexahydrotriazine (2)").

In the compound (1) X1represents a hydrogen atom or halogen atom, X2represents a halogen atom. Examples of the halogen atom include chlorine atom, bromine atom, iodine atom and the like.

Examples of the compound (1) include, for example, 5-(chloromethyl)thiazole, 2-chloro-5-(chloromethyl)thiazole, 2-chloro-5-(methyl bromide)thiazole, 2-bromo-5-(methyl bromide)thiazole, 2-chloro-5-(iodomethyl)thiazole, 2-bromo-5-(iodomethyl)thiazole, 2-iodine-5-(iodomethyl)thiazole and the like.

The compound (1) can be obtained in accordance with the known method, for example by the method described in Japanese patent application JP 4-234864 A.

The compound (1) may be in free form or may be in salt form, formed by the joining of the acid. Examples of the acid necessary for the formation of a salt by adding this acid include inorganic acids such as muriatic (hydrochloric) acid, Hydrobromic acid, sulfuric acid, perchloric acid and the like; and organic acids such as acetic acid, methanesulfonate, triftoratsetata,p-toluensulfonate and the like.

As ammonia can be the used gaseous ammonia or may be used in liquid ammonia. In addition, there may be used ammonia water (aqueous ammonia) or can be used a solution of ammonia in an organic solvent, which can dissolve the ammonia, such as methanol. From the viewpoint of ease of handling and output preferably use a solution of ammonia in an organic solvent.

Ammonia is usually used in an amount of from 1 to 30 moles, preferably from 2 to 15 moles, and more preferably from 2 to 10 moles per mole of the compound (1). In the case of the use of the compound (1) in the form of salt accession acid, the amount of ammonia that can be used may be determined taking into account the acid salt accession acid.

As formaldehyde can be used with gaseous formaldehyde, but from the viewpoint of ease of handling, preferably using paraformaldehyde or formalin and more preferably paraformaldehyde. Formaldehyde is usually used in an amount of from 1 to 10 moles, preferably from 1 to 8 moles, and more preferably from 1 to 5 moles per mole of the compound (1). In addition, preferably the amount of formaldehyde that can be used per mole of the compound (1)is less than the amount of ammonia.

The reaction temperature is usually from 15 to 100°C., preferably from 20 to 90°C. the Reaction is usually carried out at atmospheric pressure ilipi pressure of not higher than 0.5 MPa (R, gauge (gauge pressure).

The reaction can be carried out without solvent, but preferably it is carried out in an inert solvent. Examples of the solvent include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene and the like; aliphatic hydrocarbons such as hexane, heptane, cyclohexane and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; aprotic polar solvents such as acetonitrile, propionitrile, dimethylsulfoxide, N,N-dimethylacetamide and the like; and water. They can be used as such or as a mixture of solvents. Alcohols and water are preferred, and alcohols are more preferred. The amount of solvent that can be used is usually from 1 to 10 parts by mass on the mass of the connection part (1).

The reaction is usually carried out by mixing and casting compounds (1) into contact with ammonia and formaldehyde, and the order of mixing is not particularly limited. For example, for the reaction at this temperature the compound (1) may be mixed with ammonia and formaldehyde, or for carrying out the reactions the compound (1), pre-mixed with the formaldehyde may be added to the ammonia. Alternatively, for the reaction of ammonia and formaldehyde can be mixed and to this mixture is added the compound (1). In addition, for the reaction to formaldehyde may be added simultaneously, the compound (1) and ammonia. In addition, for the reaction to ammonia may be added simultaneously, the compound (1) and formaldehyde.

If necessary, the reaction can be carried out in the presence of Quaternary ammonium salts, such as chloride of triethylenediamine, chloride, tri-n-octylacrylamide, chloride of triethyltetramine, bromide of Tetramethylammonium, bromide, Tetra-n-butylamine or the like; or the catalyst phase transfer, such as a crown ether, or the like.

I believe that as a result of this reaction is a compound methylaniline, which is an unstable intermediate compound has the formula (5):

in which X1is the same as defined above, followed by his trimerization with the formation of compound hexahydrotriazine (2).

After completion of the reaction obtain the reaction mixture containing the compound hexahydrotriazine (2)and the connection hexahydrotriazine (2) can be selected by, for example, concentration (thickening) Rea the operating mixture. Alternatively, the connection hexahydrotriazine (2) can be allocated in the form of crystals by cooling the reaction mixture as it is or after partial concentration. In addition, the connection hexahydrotriazine (2) can be isolated by adding water and a hydrophobic organic solvent to the reaction mixture as it is or after concentration, so as to subject the mixture of the extraction processing, and by concentrating the resulting organic layer. In addition, the connection hexahydrotriazine (2) can be isolated as a salt accession acid, such as its hydrochloride, sulfate, or the like.

Examples of the hydrophobic organic solvent include halogenated hydrocarbons such as chlorobenzene, dichlorobenzene and the like; ethers, such as ethyl acetate, butyl acetate and the like; ketones such as methyl ethyl ketone, methyl isobutyl ketone and the like; and aromatic hydrocarbons such as toluene, xylene and the like. They can be used as such or as a mixture of solvents. The amount of the hydrophobic organic solvent that can be used is not specifically limited.

Alternatively, the reaction mixture or the organic layer containing the compound hexahydrotriazine (2), can is to be used in the subsequent hydrolysis step, described further in this document, without releasing connection hexahydrotriazine (2) from the reaction mixture.

Examples of compounds hexahydrotriazine (2)thus obtained include, for example, 1,3,5-Tris{(thiazol-5-yl)methyl}-1,3,5-hexahydrotriazine, 1,3,5-Tris{(2-chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, 1,3,5-Tris{(2-bromothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine and the like.

Next stage will be disclosed receipt of the thiazole compounds of the formula (3):

in which X1is as defined above (hereinafter in this document referred to as "connection thiazole (3)"), by hydrolysis of the compounds obtained hexahydrotriazine (2).

This stage is the hydrolysis of compounds hexahydrotriazine (2)obtained in the previous phase into a connection thiazole (3), and is usually conducted by mixing the compound hexahydrotriazine (2) and the aqueous acid solution, in order to give the opportunity to come into contact with one another. Examples of aqueous acids include, for example, an aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or the like. An aqueous solution of hydrochloric acid or sulfuric acid is preferred. The concentration of acid in water races the thief is not specifically limited. The acid is usually used in an amount of from 1 to 30 moles, preferably from 3 to 15 moles per mole of the compound hexahydrotriazine (2).

As described above, the connection hexahydrotriazine (2)formed in the previous phase can be isolated from the reaction mixture and then hydrolyzed, or the reaction mixture, or an organic layer containing the compound hexahydrotriazine (2), can be subjected to hydrolysis directly without isolating the compounds hexahydrotriazine (2).

The temperature of the hydrolysis is usually from 10 to 100°C., preferably from 25 to 70°C.

As is the hydrolysis of compounds hexahydrotriazine (2), as a by-product is formed formaldehyde. To facilitate removal of by - product formaldehyde, hydrolysis connection hexahydrotriazine (2) is preferably carried out in the presence of compounds of a number of lower alcohols for the conversion of formaldehyde formed as a by-product, in acetal. Examples of compounds of a number of lower alcohols include, for example, compounds of a number of lower alcohols having from 1 to 4 carbon atoms, such as methanol, ethanol and the like. The connection of a number of lower alcohols usually used in an amount of not less than 1.5 mol, preferably not less than 2 mol, more preferably not less than 2.5 mole per mole of the compounds the Oia hexahydrotriazine (2), and the upper limit is not specifically limited. When the reaction mixture containing the compound hexahydrotriazine (2), is used as it is, and when the reaction mixture is present in the connection of a number of lower alcohols, the number of connections number of lower alcohols which may be used may be determined taking into account the amount present in the reaction mixture. In addition, sometimes the formaldehyde remains in the reaction mixture. In this case, the connection of a number of lower alcohols can be used in a quantity sufficient to convert the acetal is not only formaldehyde formed as a by-product, but also formaldehyde remaining in the reaction mixture. Of course, after hydrolysis of the compounds hexahydrotriazine (2) formaldehyde can be converted into the acetal.

After completion of the hydrolysis, the compound of thiazole (3) or its salt formed by the addition of acid may be selected, for example, by concentration. Alternatively, the connection thiazole (3) can be isolated by concentrating the reaction mixture, adding to the concentrated mixture of an aqueous alkali solution and a hydrophobic organic solvent, so as to subject the mixture of the extraction processing, and by concentrating the resulting organic layer. Examples of the aqueous alkali solution VK is ucaut in itself aqueous solution of alkali metal hydroxide, such as aqueous solution of sodium hydroxide or the like. The amount of aqueous alkali solution, which can be used is such that the pH of the aqueous layer by extraction was in the range of usually 8 to 14, preferably 10 to 14.

Furthermore, the acid additive salt of the thiazole compounds (3) can be isolated by mixing the organic layer obtained by the above extraction with aqueous acid solution by layering with obtaining an aqueous solution containing an acid additive salt of the thiazole compounds (3), and, optionally, by partial concentration of the aqueous solution. In addition, the crystals of the acid additive salts of the compounds of thiazole (3) can be precipitated by adding a poor solvent, almost dissolving an acid additive salt of the thiazole compounds (3) to the above-mentioned aqueous solution. Examples of the aqueous acid solution include an aqueous solution of acid such as hydrochloric acid, sulfuric acid, acetic acid, methanesulfonate or the like. The amount of aqueous solution, which can be used is such that the pH of the aqueous layer by extraction was in the range of usually 2.5 to 5.5, preferably 3-5. If the thus obtained aqueous solution containing the salt of the thiazole compounds (3), education is consistent with the accession acid, is painted, the solution may be subjected to treatment with bleaching, for example, by adding an aqueous solution of decolorizing agents, such as activated charcoal.

Examples of compounds thiazole (3)thus obtained include 5-(aminomethyl)thiazole, 2-chloro-5-(aminomethyl)thiazole, 2-bromo-5-(aminomethyl)thiazole and the like.

The present invention will be further illustrated in detail by the following Examples, but the present invention is not limited to these Examples. For the analysis in the Examples was used high-performance liquid chromatography (HPLC=HPLC); and the output and extract were calculated from 2-chloro-5-(chloromethyl)thiazole. In the following Examples, all proportions and percentages are taken by weight, unless otherwise specified.

Example 1

In a glass autoclave was loaded to 95.3 parts of 2-chloro-5-(chloromethyl)thiazole (content: 96,5%), 51.9 parts of paraformaldehyde (content: 95%) and 311 parts of a 12% solution of ammonia in methanol and the mixture was allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.09 MPa. Thus obtained reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing ABT the keyboard 150 parts of methanol, was barbotirovany nitrogen for 15 minutes to remove the ammonia remaining in the reaction mixture, and then concentrated under reduced pressure, driving 60 parts of methanol. To the resulting concentrated residue was added 60 parts of methanol and 188 parts of 35% hydrochloric acid and the mixture is boiled under reflux at an internal temperature of 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 246 parts of the concentrated residue. To the concentrated residue was added 57.5 parts of water, 282 parts of isobutyl ketone and 367 parts of aqueous 27% sodium hydroxide solution to bring the pH to 13, thereby exposing the mixture of the extraction processing, and receiving the organic layer and water layer. The aqueous layer was then extracted three times with isobutyl ketone and received methylisobutylketone layers were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazole was $ 91.2%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 2.8%.

Thus obtained solution containing 2-chloro-5-(aminomethyl)thiazole, washed 33,6 parts of aqueous 14% solution of sodium hydroxide with subsequent addition of 100 parts of water and 55.7 cha the TEI 35% hydrochloric acid to bring the pH to 3.3. Then the layers were separated and 230 parts of the resulting aqueous layer was concentrated under reduced pressure to obtain 194 parts of concentrated residue. To the concentrated residue was added 1 part of activated charcoal and the mixture was kept under stirring at room temperature for 1 hour. Activated charcoal was filtered and washed with approximately 10 parts water with getting 204 parts of an aqueous solution containing the hydrochloride of 2-chloro-5-(aminomethyl)thiazole. The content of the hydrochloride of 2-chloro-5-(aminomethyl)thiazole was 42.4 per cent and the yield amounted to 85.2 %.

Example 2

In a glass autoclave was loaded 16.7 parts of 2-chloro-5-(chloromethyl)thiazole (content: 95,7%), 9.04 parts of paraformaldehyde (content: 95%) and 16.7 parts of methanol, and brought the internal temperature of 70°C. To this for 1 hour and added dropwise 57.9 parts by weight 14% solution of ammonia in methanol. After complete addition, the mixture allowed to react at the same temperature for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.15 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 50 parts of methanol and concentrated under reduced pressure to obtain 42,Casta concentrated residue. To the concentrated residue were added and 73.2 parts of methanol and 32.8 parts of 35% hydrochloric acid and the mixture is boiled under reflux at an internal temperature of 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 42.2 parts of the concentrated residue. To the concentrated residue were added 49 parts of isobutyl ketone and 69 parts of aqueous 27% sodium hydroxide solution to bring the pH up to 13 by subjecting the mixture of the extraction processing, and receiving the organic layer and water layer. The aqueous layer was then extracted three times with isobutyl ketone and received methylisobutylketone layers was combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol amounted to 87.1%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 1.2%.

Example 3

In a glass autoclave was loaded 16.8 parts of 2-chloro-5-(chloromethyl)thiazole (content: 95,6%), 9,05 parts of paraformaldehyde (content: 95%) and 135 parts of 24% ammonia solution in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) during the reaction was 0.37 MPa. Received Rea the operating mixture, containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 20 parts of methanol and concentrated under reduced pressure to obtain 40 parts of concentrated residue. To the concentrated residue were added and 73.2 parts of methanol and 32.8 parts of 35% hydrochloric acid and boiled under reflux at an internal temperature of approximately 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 41.7 parts of the concentrated residue. To the concentrated residue were added 49 parts of toluene and 51.8 parts of aqueous 30% sodium hydroxide solution to bring the pH up to 13 by subjecting the mixture of the extraction processing, and receiving the organic layer and water layer. The aqueous layer was then extracted three times with toluene and the resulting toluene layers were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol amounted to 93.3%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 2.6%.

The resulting solution containing 2-chloro-5-(aminomethyl)thiazole, washed 5.8 parts of aqueous 14% solution of sodium hydroxide with subsequent addition of 17.5 parts of water and 9 parts of 35% of chlorine is stevedorage acid to bring the pH to 4.9 with the to get 38,9 parts of an aqueous solution containing the hydrochloride of 2-chloro-5-(aminomethyl)thiazole. The content of the hydrochloride of 2-chloro-5-(aminomethyl)thiazole was 38.6%, and the yield was 85.1%.

Example 4

In a glass autoclave was loaded 16.6 parts of 2-chloro-5-(chloromethyl)thiazole (content: 96,5%), 9.04 parts of paraformaldehyde (content: 95%) and 54.1 part of a 10.5% solution of ammonia in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.08 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 60 parts of methanol and then concentrated under reduced pressure to obtain 40 parts of concentrated residue. To the concentrated residue were added and 73.2 parts of methanol and 32.8 parts of 35% hydrochloric acid and the mixture is boiled under reflux at an internal temperature of 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 42.8 parts of the concentrated residue. To the concentrated residue was added to 11.4 parts of water, 49 parts of isobutyl ketone and 60.9 parts of water 27% solution of the sodium hydroxide to bring the pH to 13, by exposing this mixture is processed by extraction and obtaining an organic layer and an aqueous layer. The aqueous layer was then extracted three times with isobutyl ketone and received methylisobutylketone layers was combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol amounted to 91.2%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 2.0%.

Example 5

In a glass autoclave was loaded with 29 parts of 2-chloro-5-(chloromethyl)thiazole (content: 96,5%), 10.5 parts of paraformaldehyde (content: 95%) and 94.6 parts of a 9% solution of ammonia in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.09 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 60 parts of methanol and then concentrated under reduced pressure to obtain 57.8 parts of the concentrated residue. To the concentrated residue were added 128 parts of methanol and 57.4 parts of 35% hydrochloric acid and the mixture is boiled under reflux at an internal temperature of 60°C for one and a half hours. The mixture was cooled to an internal temp is atory not higher than 40°C and then concentrated under reduced pressure to obtain 75,1 part of the concentrated residue. To the concentrated residue were added 20 parts of water, 85.7 parts of isobutyl ketone and 113,5 parts of aqueous 27% sodium hydroxide solution to bring the pH up to 13 by subjecting the mixture of the extraction processing, and receiving the organic layer and water layer. The aqueous layer was then extracted with isobutyl ketone and received methylisobutylketone layers was combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol made 86.2%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 4.3%.

Example 6

In a glass autoclave was loaded 10.6 parts of 2-chloro-5-(chloromethyl)thiazole (content: 95%), and 2.3 parts of paraformaldehyde (content: 95%) and 30.5 parts of 10% solution of ammonia in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was of 0.10 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 30 parts of methanol and then concentrated under reduced pressure to obtain 27,1 parts by weight of the concentrated residue. To the concentrated residue were added 45.8 parts of methanol and 11.8 parts of 35% chloris vodorodnoi acid and the mixture is boiled under reflux at an internal temperature of 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 35.8 parts of the concentrated residue. To the concentrated residue was added 30.6 parts of isobutyl ketone and 24.5 parts of aqueous 30% sodium hydroxide solution to bring the pH up to 13 by subjecting the mixture of the extraction processing, and receiving the organic layer and water layer. The aqueous layer was then extracted three times with isobutyl ketone and received methylisobutylketone layers was combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol amounted to 80.1%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 8.9%.

Example 7

In a glass autoclave was loaded 16.7 parts of 2-chloro-5-(chloromethyl)thiazole (content: 95,7%), 23,2 parts of formalin (content: 37%) and 30.9 parts of a 21% solution of ammonia in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.05 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 60 parts of methanol, and then concentrated under reduced Yes is the process to obtain 50,9 parts of the concentrated residue. To the concentrated residue were added and 73.2 parts of methanol and 32.8 parts of 35% hydrochloric acid and the mixture is boiled under reflux at an internal temperature of 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 52.5 parts of the concentrated residue. To the concentrated residue were added 49 parts of isobutyl ketone and 67,3 parts of aqueous 27% sodium hydroxide solution to bring the pH up to 13 by subjecting the mixture of the extraction processing, and receiving the organic layer and water layer. The aqueous layer was then extracted three times with isobutyl ketone and received methylisobutylketone layers was combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol amounted to 87.5%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 2.2%.

Example 8

In a glass autoclave was loaded 29,3 part 2-chloro-5-(chloromethyl)thiazole (content: 95,7%), 15.8 parts of paraformaldehyde (content: 95%) and 87.3 part of a 13% solution of ammonia in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.08 MPa. After SeverEnergia, the reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, was cooled to an internal temperature of 5°C in order to precipitate a solid, and this solid is collected by filtration. The collected solid was dried under reduced pressure to obtain 21.9 parts of 1,3,5-Tris{(2-chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine.

Mass spectroscopy (ionization method field desorption): m/z 480 at monoisotopic peak (isotopic distribution of Cl×3)

1H-NMR (CDCl3), 270 MHz, δ/ppm)

3,50 (Sh.S., 2H), 3,82 (s, 2H), 7,33 (s, 1H)

13C-NMR (CDCl3, 68 MHz, δ/ppm)

48,85, 72,34, 138,73, 139,29, 151,71

Thus obtained 1,3,5-Tris{(2-chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine hydrolyzed in hydrochloric acid in methanol to obtain 2-chloro-5-(aminomethyl)thiazole. Output: 65,9%. The yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 0.5%.

Example 9

In a stainless steel autoclave was loaded 15.5 parts of 2-chloro-5-(chloromethyl)thiazole (content: 96,5%), 8.7 parts of paraformaldehyde (content: 92%) and 24.4 parts of 24% ammonia solution in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.02 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-the l)methyl}-1,3,5-hexahydrotriazine, moved to another flask by washing autoclave approximately 15 parts of methanol and then concentrated under reduced pressure to obtain 45.2 parts by weight of the concentrated residue. To the concentrated residue were added methanol in order to fill the volume of the solution up to 228 parts, then added 32.5 parts of 35% hydrochloric acid and the mixture under stirring was maintained at an internal temperature of 50°C for 30 minutes. The mixture is then cooled to room temperature and to this was added water to obtain of 260.2 parts of an aqueous solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol amounted to 93.3%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 2.0%.

Comparative Example 1

In a stainless steel autoclave was loaded 15.7 parts of 2-chloro-5-(chloromethyl)thiazole (content: 95,7%) and 25.4 parts of 24% ammonia solution in methanol and the mixture allowed to react under stirring at an internal temperature of 70°C for 3 hours. The maximum internal pressure (gauge pressure) in the reaction time was of 0.28 MPa. The reaction mixture was transferred into another flask by washing autoclave approximately 15 parts of methanol and then concentrated under reduced pressure to obtain 26,1 part of the concentrated residue. To the concentrated residue was added to the methanol with the to obtain 228 parts of a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazole was 41.4%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine amounted to 24.5%.

Example 10

In a glass autoclave was loaded 29,3 part 2-chloro-5-(chloromethyl)thiazole (content: 95,7%), 15.8 parts of paraformaldehyde (content: 95%), 56,9 parts of 20% solution of ammonia in methanol and 43.9 parts of toluene and the mixture allowed to react under stirring at an internal temperature of 70°C for 5 hours. The maximum internal pressure (gauge pressure) in the reaction time was 0.09 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 46 parts of methanol,and then concentrated under reduced pressure to obtain 162,4 parts of the concentrated residue. To the concentrated residue was added 23.6 parts of methanol and 57.4 parts of 35% hydrochloric acid and the mixture is boiled under reflux at an internal temperature of 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 74,3 parts of the concentrated residue. To the concentrated residue were added 20 parts of water, 85.7 parts of isobutyl ketone and to 108.2 parts of water is about 27% solution of sodium hydroxide to bring the pH to 13, by exposing this mixture is processed by extraction and obtaining an organic layer and an aqueous layer. The aqueous layer was then extracted three times with toluene and the resulting toluene layers were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazole was 92.3%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 2.2%.

Because the aqueous layer after extraction with toluene contained 2.5% of 2-chloro-5-(aminomethyl)thiazol that are calculated from the output, the reaction of 2-chloro-5-(aminomethyl)thiazole amounted to 94.8%.

Example 11

In a glass autoclave was loaded 15.8 parts of paraformaldehyde (content: 95%) and 94.6 parts of a 12% solution of ammonia in methanol. To the mixture was added 29 parts of 2-chloro-5-(chloromethyl)thiazole (content: 96,6%) at room temperature and the resulting mixture allowed to react under stirring at an internal temperature of 40°C for 3 hours then when the inner temperature of 50°C for 3 hours, and then, at an internal temperature of 70°C for 1 hour. The maximum internal pressure (gauge pressure) in the reaction time was 0.09 MPa. The resulting reaction mixture containing 1,3,5-Tris{(2-[chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, moved in chetyrehosnuju flask by washing autoclave 60 parts methane is a and then concentrated under reduced pressure to obtain 87,9 parts of the concentrated residue. To the concentrated residue was added 101 of the water and then the mixture was concentrated under reduced pressure to obtain 146,9 parts of the concentrated residue. To the concentrated residue was added 117 parts of toluene in order to subject the mixture of the extraction processing when the internal temperature of 75°C to obtain 149 parts toluene layer and water layer. When the toluene layer was analyzed by HPLC (HPLC), it contained 1,3,5-Tris{(2-chlorothiazole-5-yl)methyl}-1,3,5-hexahydrotriazine, 2-chloro-5-(aminomethyl)thiazole and bis{(2-chlorothiazole-5-yl)methyl}amine with outputs of 91.8%, 2.7% and 2.1 per cent respectively.

To parts of 148.6 obtained toluene layer with stirring was added 21.5 parts of 35% hydrochloric acid and then allowed to stand to separate an oil layer and an aqueous layer. To the oil layer was added to 1.2 parts of water in order to subject the mixture of the extraction processing, and the resulting aqueous layer was combined with the previously obtained aqueous layer. To the combined aqueous layer was added 39.5 parts of methanol and the mixture is boiled under reflux at an internal temperature of approximately 60°C for one and a half hours. The mixture was cooled to an internal temperature not higher than 40°C and then concentrated under reduced pressure to obtain 38,9 parts of the concentrated residue. To the concentrated residue were added 20 castaway, 82.6 parts of toluene and 35 parts of aqueous 27% sodium hydroxide solution to bring the pH up to 13 by subjecting the mixture of the extraction processing, and receiving the organic layer and water layer. The aqueous layer was then extracted three times with toluene and the resulting toluene layers were combined with the previously obtained organic layer to obtain a solution containing 2-chloro-5-(aminomethyl)thiazole. The yield of 2-chloro-5-(aminomethyl)thiazol have reached 87.2%, and the yield of bis{(2-chlorothiazole-5-yl)methyl}amine was 1.9%.

Industrial applicability

In accordance with the present invention, the connection of the thiazole of the formula (3), which is useful as intermediate compounds for the pharmaceutical and agrochemical funds can be obtained industrially mainly for suppressing the formation of by-product of the formula (4).

1. The method for obtaining compounds of the thiazole of the formula (3):

where X1represents a hydrogen atom or halogen atom, which comprises steps:
interaction of the compounds of formula (1):

in which X1is the same as defined above, and X2represents a halogen atom, with ammonia and formaldehyde to obtain compounds hexahydrotriazine formula (2):

where X 1is the same as defined above, and hydrolysis of the resulting compound hexahydrotriazine formula (2).

2. The method according to claim 1, where formaldehyde is a paraformaldehyde or formalin.

3. The method according to claim 1, where formaldehyde is used in an amount of from 1 to 10 moles per mole of the compounds of formula (1).

4. The method according to claim 1, where the ammonia is used in an amount of from 2 to 10 moles per mole of the compounds of formula (1).

5. The method according to claim 1, where the hydrolysis is carried out by bringing into contact connection hexahydrotriazine formula (2) and the aqueous acid solution.

6. The method according to claim 5, where the hydrolysis is carried out in the presence of compounds of a number of lower alcohols.

7. Connection hexahydrotriazine formula (2):

in which X1represents a hydrogen atom or halogen atom, or its salt accession acid.

8. The method of obtaining compounds of hexahydrotriazine formula (2):

in which X1represents a hydrogen atom or halogen atom, which includes the interaction of the compounds of formula (1):

in which X1is the same as defined above, and X2represents a halogen atom, with ammonia and formaldehyde.

9. The method of claim 8, where formaldehyde is used in an amount of from 1 to 10 moles of molinietalia formula (1).

10. The method of claim 8, where the ammonia is used in an amount of from 2 to 10 moles per mole of the compounds of formula (1).

11. The method for obtaining compounds of the thiazole of the formula (3):

in which X1represents a hydrogen atom or halogen atom, which comprises the hydrolysis of compounds hexahydrotriazine formula (2):

in which X1is the same as defined above.

12. The method according to claim 11, where the hydrolysis is carried out by bringing the connection hexahydrotriazine formula (2) into contact with an aqueous acid solution.

13. The method according to item 12, where the hydrolysis is carried out in the presence of compounds of a number of lower alcohols.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula and their pharmaceutically acceptable salts used as inhibiting agent in the relation of fermentative beta-secretase and it also relates to pharmaceutical compositions based on the formula. In general formula one of RN and RN' represents hydrogen, and another represents - C(=O)-(CRR')0-6R100, or where R4 is chosen from the group including H; NH2; -NR50CO2R51; -(C1-C4)-alkyl-NR50CO2R51; where n7 is equal to 0, 1, 2 or 3; R50 represents H or C1-C6alkyl; R51 is chosen from the group including phenyl-(C1-C4)-alkyl and (C1-C6)-alkyl; X is chosen from the group including -(C1-C6)-alkylidenyl optionally substituted with 1, 2 or 3 metal groups; Z is chosen from the group including bond, SO2, SO and S; Y stands for (C1-C10)-alkyl; R1 represents -(C1-C6)-alkylphenyl where phenyl ring is optionally substituted by 1, 2, 3 or 4 halogen atoms; R and R' independently represent hydrogen or (C1-C6)-alkyl; R2 represents hydrogen; R3 represents hydrogen; Rc represents - (CR245R250)0-4-aryl; where aryl is optionally substituted by 1, 2 or 3 R200; R200 is chosen from the group including (C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups R205; halogen; C=N; R205 stands for halogen; R245 and R250 in each case stands for H; either R245 or R250 are taken together with carbon atom whereto attached to form carbocycle from 3, 4, 5, 6 or 7 carbon atoms; R100 represents 5-6-merous heteroaryl with 1-2 heteroatoms chosen from nitrogen and sulphur, -phenyl-W-heteroaryl where heteroaryl is 5-6-merous ring containing 1-2 heteroatoms, chosen from nitrogen and oxygen and where cyclic parts of each group are optionally substituted by 1, 2 or 3 groups independently chosen among C1-C6alkyl, -(CH2)0-4-CO2-NR105R'105, -(CH2)0-4-SO2-NR105R'105, -(CH2)0-4-N(R150)-CO-R105, -(CH2)0-4-N(R150)-SO2-R105; W represents -(CH2)0-4; R105 and R'105 independently represent (C1-C6)-alkyl optionally substituted with -NH2 or halogen; R150 represents hydrogen.

EFFECT: compounds can be applied to prevent and treat diseases mediated by excess activity of beta-secretase such as Alzheimer's disease.

11 cl, 12 tbl, 3 dwg, 1729 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

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

The invention relates to new heterocyclic compounds having therapeutic activity, to processes for their preparation and intermediate compounds used for their production, to pharmaceutical preparations containing these compounds and to the use of these compounds in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new compound, i. e. to 4-[2-(aminomethyl)-1,3-thiazole-4-yl]-2,6-di-(tert.-butyl)phenol and a pharmaceutical composition used for inhibition of lipid peroxidation and/or as a modulating agent of sodium channels and a medicinal agent comprising this compound. Invention provides the enhanced effectiveness of inhibition of lipid peroxidation and modulation of sodium channels activity.

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

22 cl, 349 ex

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new compound, i. e. to 4-[2-(aminomethyl)-1,3-thiazole-4-yl]-2,6-di-(tert.-butyl)phenol and a pharmaceutical composition used for inhibition of lipid peroxidation and/or as a modulating agent of sodium channels and a medicinal agent comprising this compound. Invention provides the enhanced effectiveness of inhibition of lipid peroxidation and modulation of sodium channels activity.

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

22 cl, 349 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 5-amidino-2-hydroxybenzenesulfonamide of the general formula (I): wherein R2 means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (A): wherein (A) means -COORA, -CONRBRC, 3-7-membered monocyclic heterocycloalkyl group comprising one or two heteroatom in ring chosen from atoms N, O, S that can comprise oxo-group and 5-6-membered monocyclic aromatic heterocyclic group comprising one-three heteroatoms in ring chosen from atoms N, O, S that can comprise oxo-group or lower alkyl wherein RA means hydrogen atom (H), 3-7-membered monocyclic aliphatic alkyl group, lower alkyl that can comprises a substitute chosen from the group (i) wherein (i) means -COORA1 wherein RA1 means hydrogen atom (H), -OCORA2 wherein RA2 means lower alkyl group, -OCOORA3 wherein RA3 means lower alkyl, -ORA4 wherein RA4 means hydrogen atom (H), lower alkyl -CONRA5RA6 wherein RA5 and RA6 mean independently hydrogen atom (H), lower alkyl, or -NRA5RA6 forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; wherein RB and RC mean independently hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (ii), or -NRBRC forms 5-6-membered monocyclic amino-group comprising one heteroatom in ring chosen from atoms N, O, S and another one distinct from nitrogen atom (N) instead a bond; (ii) means -COORB1 wherein RB1 means hydrogen atom (H), lower alkyl; T means oxygen atom (O), sulfonyl group; or TR1 means -SO2NRB3RC3 wherein RB3 and RC3 means independently hydrogen atom (H), lower alkyl; R2 means lower alkyl, phenyl that can comprise one-three substitutes chosen from the group (B) wherein (B) means halogen atom, -COORE, sulfamoyl, lower alkylsulfonyl wherein RE means lower alkyl; Q means hydrogen atom (H), lower alkyl that can comprise a substitute chosen from the group (D) wherein (D) means 5-6-membered monocyclic aromatic heterocyclic group that can comprise one-three heteroatom chosen from atoms N, O, S that can comprise a substitute chosen from the group (iv) wherein (iv) means oxo-group, lower alkyl; Z means hydrogen atom (H), hydroxyl group (OH), -COORN wherein RN means lower alkyl that can comprise a substitute chosen from the group (viii) wherein (viii) means -OCOR5 wherein RN5 means lower alkyl that can comprise -OCORN51 wherein RN51 means lower alkyl; or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit activated factor X in blood coagulation system that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and compositions.

12 cl, 5 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a thiazole compound with formula

by reacting a compound with formula with ammonia and formaldehyde, obtaining a hexahydrotriazine compound with formula , with subsequent hydrolysis of compound with formula (2), as well as compounds with general formula (2) and a method of producing said compounds. In general formulae (1), (2) and (3) X1 is a hydrogen atom or a halogen atom, X2 is a halogen atom.

EFFECT: method is described for producing thiazole through aminomethylation.

13 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

where A, B and D each denotes N or CR5, where one of A, B and D denotes N, R1 denotes OR6, R2 denotes halogen, C1-C4alkyl, halogen(C1-C4)alkyl or OR7, R3 denotes a heteroarylalkyl group in which the heteroaryl fragment contains 5-6 atoms in the ring, at least one of which is an N atom, and the alkyl fragment with a branched or straight chain contains 1-5 carbon atoms, R4 denotes C3-C10cyclalkyl, C6-C14aryl, unsubstituted or substituted with one or more substitutes selected from a group comprising halogen, alkoxy, terazol-5-yl, 2-(heterocyclyl)tetrazol-5-yl or a carboxy group; heteroaryl containing 5-6 atoms in the ring; heterocyclic group saturated or partially saturated, containing 5-6 atoms in the ring, at least one of which is an N atom, unsubstituted or substituted with one or more substitutes selected from a group comprising alkoxy, alkoxyalkoxy, oxo, alkoxycarbonyl, alkylsulfanyl, alkylsufonyl or phenylsulfonyl; R5 denotes H; R6 denotes H or C1-C4alkyl with a branched or straight chain, unsubstituted or substituted with one or more halogens, R7 denotes H or C1-C12alkyl with a branched or straight chain, unsubstituted or substituted with one or more substitutes selected from a group which includes halogen; C3-C10cyclalkyl; saturated heterocyclic group containing 5-6 atoms in the ring, at least one of which is an O atom, or a heterocylcylalkyl group in which the heterocyclic fragment is saturated, partially saturated or unsaturated and contains 5-10 atoms in the ring, at least one of which is an O atom; or to a pharmaceutically acceptable salt thereof, as well as to a pharmaceutical composition for inhibiting PDE4 enzyme activity and to use of the said compound to prepare a medicinal agent.

EFFECT: novel compounds which can be used in medicine are obtained and described.

65 cl, 17 ex

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