Novel method of producing tiotropium salts

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing tiotropium salts of formula 1 , in which X- can denote a monovalent anion, preferably an anion selected from a group which includes chloride, bromide, iodide, methane sulphonate and trifluoromethane sulphonate, distinguished by that compounds of formula 2 , in which X-can assume values given above, are reacted in a single stage in an acceptable solvent while adding an acceptable base to form a compound of formula 3 in situ, where R is a residue selected from a group which includes N-imidazolyl, N-triazolyl, -O- C(=NR')-NHR", -O-SO2-phenyl, -O-SO2-phenylmethyl, -O-SO2-R', -O-CO-C(methyl)3, -O-CO-phenyl-NO2, chlorine, bromine, -N3 and -O-(P=O)R'" where R' denotes C1-C4alkyl or C3-C6cycloalkyl, R" denotes C1-C4alkyl, C3-C6cycloalkyl or C1-C4alkylene- N(C1-C4alkyl)2, and R'" denotes C1-C4alkyl, -O-C1-C4alkyl, phenyl or -O-phenyl, and R1 and R2 have identical or different values and can be methyl, ethyl, propyl, butyl or phenyl which can optionally be substituted with one or more C1-C4alkyl residues to obtain a compound of formula 4 , in which groups X-, R1 and R2 can assume values given above, and then without its extraction, the compound of formula 4 is reacted with an acceptable acid or with an acceptable desilylation agent with removal of the silyl group in the compound of formula 1. The invention also relates to compounds of formulae 3 and 4.

EFFECT: obtaining tiotropium salts of formula 1 using a simpler and more efficient method which increases output of the product.

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The present invention relates to a new method of receiving Tiotropium salts of General formula 1

in which X-may be specified in the claims and in the following description of the values.

Background of invention

Anticholinergics can be used effectively in the treatment of many diseases. Especially it should be noted that they can be used, for example, for the treatment of asthma or chronic obstructive pulmonary disease (COPD). For the treatment of these diseases are available, for example, described in the publication WO 02/03289 anticholinergics with skupinovym, tropaeolum or tropinone skeleton. In addition, the prior art the possibility of using primarily tetrapyrrolic as a highly anticholinergic agents. Tetrapyrrolic known, for example, from EP 418716 A1.

Along with described in the aforementioned prior art methods of synthesis skupinovych esters can be called primarily a method of producing esters Skopina proposed in the publication WO 03/057694.

The present invention was used, the goal is to develop advanced technical method of synthesis of compounds of General formula 1, which would get them more simple and effective than the level of the technology by eating.

Detailed description of the invention

In the present invention proposes a method of receiving Tiotropium salts of formula 1.

in which X-can refer to a singly charged anion, preferably an anion selected from the group comprising chloride, bromide, iodide, methanesulfonate and triftorbyenzola, characterized in that the compound of formula 2

in which X-can have the values indicated above, in one stage, put in an acceptable solvent, adding an acceptable cause for the interaction with the formed in situ with the compound of formula 3.

in which

R represents a residue selected from the group comprising N-imidazolyl, N-triazolyl, -O-C(=NR')-other", -O-SO2-phenyl, -O-SO2-phenylmethyl, -O-SO2-R', -O-CO-(methyl)3, -O-CO-phenyl-NO2, chlorine, bromine, -N3and-O-(P=O)R"', where

R' denotes a1-C4alkyl or C3-C6cycloalkyl,

R" denotes a1-C4alkyl, C3-C6cycloalkyl or1-C4alkylene-N(C1-C4alkyl)2and

R"' denotes a1-C4alkyl, -O-C1-C4alkyl, phenyl or-O-phenyl, and R1and R2have identical or different meanings and can denote methyl, ethyl, propyl, butyl or phenyl, which is first optionally may be substituted by one or more 1-C4alkyl residues with obtaining the compounds of formula 4

in which the groups X-, R1and R2can have the values indicated above, and then the compound of formula 4 without highlighting it translate interaction with acceptable acid or with an acceptable desilicious agent at the time of removal of the silyl group in the compound of formula 1.

In the preferred embodiment proposed in the invention method are the salt of Tiotropium of formula 1 in which X-can refer to a singly charged anion selected from the group comprising chloride, bromide, iodide, methanesulfonate and triftorbyenzola, preferably chloride, bromide, and methanesulfonate, especially preferably may designate bromide.

In a particularly preferred variant of the invention, its proposed method differs in that the interaction is carried out with a educated in situ a compound of formula 3, in which

R represents a residue selected from the group comprising N-imidazolyl, N-triazolyl, -O-C(=NR')-other", " OH-SO2-phenylmethyl, -O-CO-(methyl)3and chlorine, where

R' denotes methyl, ethyl or cyclohexyl, and

R ' denotes methyl, ethyl, cyclohexyl,2-C3alkylene-N(methyl)2or2-C3alkylene-N(ethyl)2and

R1and R2have identical Il the different values and represent methyl,

ethyl, propyl or butyl.

In the most preferred embodiment of the invention its proposed method differs in that the interaction is carried out with a educated in situ a compound of formula 3, in which

R represents a residue selected from the group comprising N-imidazolyl, N-triazolyl, -O-C(=N-cyclohexyl)-N, -O-C(=N-ethyl)-NH-CH2-CH2-CH2-NME2and-O-CO-(methyl)3preferably represents N-imidazolyl or N-triazolyl, particularly preferably N-imidazolyl,

R1and R2have identical or different meanings and represent methyl, ethyl, propyl or butyl, preferably methyl or ethyl, particularly preferably methyl, and

R2represents methyl or ethyl, preferably methyl.

Under alkyl groups and alkyl groups, forming a part of the other residues are meant branched and unbranched alkyl groups with 1-4 carbon atoms. As examples of such groups can be called methyl, ethyl, propyl and butyl. Unless otherwise stated, the above notion of "drunk" and "butyl" includes all possible isomeric forms of each of these residues. For example, in the concept of "propyl" includes both isomeric balance - n-propyl and isopropyl, and the concept of "butyl" includes n-butyl, isobutyl, sec-butyl is tert-butyl.

Under alkilinity bridge or alkilinity group refers, unless otherwise specified, branched and unbranched alkyl groups with 1-4 carbon atoms, for example, methylene, ethylene, propylene and butylene bridges. Especially preferred methylene, ethylene, propylene and butylene bridges. Unless otherwise stated, the above term "ethylene", "propylene and butylene" includes all possible isomeric forms of each of these residues.

The concepts of "phenylmethyl" and "phenyl-NO2denotes phenyl ring, substituted stands, respectively, by a group of NO2. In such notions also includes all possible isomers (ortho, meta, or para), with special emphasis substitution in the para - or meta-position.

Under cycloalkenyl groups refers cycloalkyl remains with 3-6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Proposed in the invention, the method can be carried out in the following way. First, in an acceptable solvent in situ to form a compound of formula 3. The concept of "in situ" in this case means obtaining the compounds of formula 3 without further selection. The compound of formula 3 is obtained by interaction ditienilglikoleva acid, preferably salts with alkali metals, especially before occhialino of detailslist sodium, agent combinations selected from the group comprising carbonyldiimidazole, carbonelli-1,2,4-triazole, dicyclohexylcarbodiimide, ethyldimethylammonium, toluensulfonate, pivaloyloxy, anhydride nitrobenzoic acid, oxalicacid, phosgene, sulphonylchloride and chlorides of phosphorus, preferably carbonyldiimidazole, carbonelli-1,2,4-triazole, dicyclohexylcarbodiimide and ethyldiethanolamine, particularly preferably carbonyl diimidazol, in an acceptable solvent, preferably a polar aprotic organic solvent, particularly preferably in a solvent selected from the group comprising acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, dioxane and sulfolan, preferably tetrahydrofuran, dimethylformamide and N-organic, at a temperature in the range from -20 to -60°C., preferably from -10 to -45°C., particularly preferably from -10 to -25°C, followed by addition of silyl compounds of formula 5

in which the residues R1and R2can have the above values, a, L denotes a leaving group, preferably selected from the group comprising halide, methanesulfonate, triftorbyenzola and para-toluensulfonate, especially a preference for the equipment methanesulfonate, triftorbyenzola, bromine or chlorine, preferably bromine or chlorine, which are of particular importance according to the invention is given to chlorine.

Silyl compound of formula 5 can either be added to a mixture of ditienilglikoleva acid, respectively, its salts and agent combinations in the above solvent, optionally in the presence of a base, such as pyridine, imidazole or N-alkylamino, or first load into the reactor together with ditienilglikoleva acid, respectively its salt in the above solvent, optionally in the presence of a base, such as pyridine, imidazole or N-alkylamine, and then mix with the above agent combinations.

For the formation of compounds of formula 3 the above three component preferably be added in stoichiometric quantities, however, the reaction can be carried out in the presence of one of the three components in excess (e.g., in the amount of from 1.1 to 1.5 equivalent).

On mol formed in situ compounds of formula 3, these solvents preferably used in quantities of from 0.2 to 1.5 l, particularly preferably from 0.3 to 1 L.

For the formation of compounds of General formula 3 obtained after adding all three components of the solution at the above temperature is stirred, for example, the mixer during the period of time and, approximately from 5 min to 2 h, preferably from 10 min to 1 h, particularly preferably from 20 to 40 minutes

Then, to the thus obtained solution was added the compound of formula 2. When this compound of formula 2 or can be added in the form of a solution or suspension in one or more solvents of the above, or can be added, preferably portions, as such. Adding the compounds of formula 2 in dissolved or suspended in one or more solvents as it is advisable to use the same solvents that are used to obtain the compounds of formula 3 in situ.

The quantity added of the compound of formula 2, is determined by the number formed in situ compounds of formula 3. When used for the formation of compounds of formula 3, all three components, which are ditienilglikoleva acid, respectively its salt, agent combination and the compound of formula 5, in the stoichiometric quantities of the compound of formula 3 is formed in a molar amount selected for these three components, which are ditienilglikoleva acid, respectively its salt, agent combination and the compound of formula 5. When using for the formation of compounds of formula 3 above three components, which are ditienilglikoleva acid, with therefore, its its salt, agent combination and the compound of formula 5, not stoichiometric amounts of the compound of formula 3 is formed in a molar quantity equal to the molar quantity of the component on which share among the three parent compounds, which are ditienilglikoleva acid, respectively its salt, agent combination and the compound of formula 5, had the lowest number.

The molar ratio between the compound of formula 2 and formed in situ with the compound of formula 3 should preferably be from 2:1 to 1:5, more preferably from 1.5:1 to 1:3, particularly preferably from 1:1 to 1:2, most preferably from 1:1 to 1:1,5.

Obtained after adding the compounds of formula 3, the reaction mixture is mixed with, dissolved in an acceptable solvent base. As such a solvent according to the invention it is possible to use the above-mentioned solvents. It is preferable to use the same solvent used for formation of the compounds of formula 3. As a basis you can apply organic or inorganic bases. As organic bases, it is preferable to use imidazolidin alkali metals, which can be obtained, for example, in situ from alkali metals and imidazole or hydrides of alkali metals and imidazole. As imidazolides alkaline m is the metal, it is preferable to use imidazolidin lithium sodium or potassium, the preferred of which according to the invention imidazole sodium or lithium. Especially preferable to use the alkali metal alcoholate derived from sterically obstructed alcohols (for example, tert-butlt potassium). The preferred bases according to the invention also include base selected from the group comprising diisopropylamide lithium (DAL), hexamethyldisilazane lithium (GMDSS), hexamethyldisilazane sodium (GMDSS). As inorganic bases, it is preferable to use the hydrides of lithium, sodium or potassium. However, the most preferably used as inorganic bases sodium hydride.

Per mole of the used compounds of formula 2, the base is preferably added in an amount of from 0.5 to 2 moles, especially preferably from 1 to 1.5 moles. However, the implementation proposed in the invention method in most cases is sufficient to add used per mole of compound of formula 2 only from 1 to 1.1 mole of base.

For preparation of a solution or suspension of the grounds specified solvent is preferably used in an amount of from 0.2 to 1.5 l, particularly preferably from 0.3 to 1 l, based on one mole of the base.

The base is preferably added at a temperature in the range from -20 to +60°C, over predpochtitelno from 0 to 45°C, particularly preferably from 0 to 25°C. For the formation of compounds of formula 4 obtained after the addition of substrate the mixture is stirred at constant temperature for period of time of about from 10 min to 6 h, preferably from 30 minutes to 3 hours, particularly preferably from 45 min to 1.5 hours

To highlight the compounds of formula 1 of the formed in situ compounds of formula 4 to the reaction mixture, preferably at temperatures below 10°C, particularly preferably at a temperature of about 0°C, add the appropriate acid N-H. the choice of the particular acid is determined by the anion X-in the desired end product of General formula 1. According to the present invention along with the acid H-X if necessary, you can add an acceptable desilicious agent, in which it is preferable to use a compound from the group of ammonium fluoride, particularly preferably tetrabutylammonium fluoride, fluoride of tetraethylammonium, fluoride designed, fluoride of tetradecylammonium or fluoride of tetraoctylammonium, or hydrogen fluoride in free form or in the form of complex compounds, for example, in the form of fluoride, pyridinium or complex of triethylamine with HF.

Instead of applying one of the above acid compound of formula 1 can also be allocated exclusively through at azannyh above desilicious agents.

As proposed in the invention method, it is preferable to synthesize the compounds of General formula 1 in which X-indicates the bromide, the following explanations are to receive preferred according to the invention of tetrapyrrolic. However, for the person skilled in the art it is obvious that the same by an appropriate reagent N-X, respectively Y-F, where Y may denote a cation such as a proton or a metal cation, ammonium, alkylammonium, tetraalkylammonium or pyridine or complex, such as a complex of aluminum TRIFLUORIDE with HF or other donor fluoride, such as diethylaminoacetate, you can get also those compounds in which X-is different from bromide value.

To obtain compounds of formula 1 in which X-denotes bromide (i.e. to obtain tetrapyrrole), in terms of the connection formula 2 at a constant temperature type preferably from 0.2 to 20 moles, more preferably from 0.5 to 15 moles, especially preferably from 1 to 14 moles, HBR. Used hydrogen bromide can be added either in gaseous form or in the form of solutions, preferably saturated. According to the invention hydrogen bromide, it is advisable to add in the dissolved ice is kusnoy acid or in water. Particularly preferable to use at the same time 33%solution of hydrogen bromide in glacial acetic acid or 62%aqueous Hydrobromic acid. Such acid preferably be added slowly so that the temperature of the reaction mixture did not rise above 20°C. On completion of addition the mixture at a constant temperature, optionally under ice cooling, stirred (for 0.5-6 h).

For further processing it is possible to use known methods, especially methods described below in the examples. Thus, in particular, the reaction mixture is mixed with proton solvent, preferably with alcohol, particularly preferably methanol, ethanol or isopropanol. According to the invention is based on the mole of the used compounds of formula 2 add preferably from 0.5 to 20 l, particularly preferably from 0.7 to 13 liters of alcohol and the resulting mixture is stirred at a temperature in the range from 0 to 60°C, preferably from 10 to 45°C., particularly preferably from 15 to 25°C., for about 0.5 to 6 hours, preferably 0.5 to 5 hours, particularly preferably 0.5 to 4 hours At the completion of the resulting solution is mixed with a nonpolar organic solvent, preferably a solvent selected from the group comprising ketone (such as acetone or methyl ethyl ketone), Speer is (such for example, as methanol, ethanol, propanol, isopropanol, butanol or amyl alcohol, toluene, ethyl acetate, n-butyl acetate, dichloromethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane, particularly preferably isopropanol, toluene, and acetone.

After thorough mixing vegascasinoonline the product is separated and washed with the above solvent. For separation of water-soluble impurities, the crude product can be treated with water or aqueous solutions of bromides, for example, a solution of bromide of sodium or potassium.

For a deep cleaning thus obtained compounds of formula 1 can, if necessary, clean chromatography on silica gel or by recrystallization from suitable for this purpose solvents, e.g. lower alcohols, such as methanol, ethanol or isopropanol, optionally with prior treatment with activated charcoal.

Given the Central role that the compound of formula 3 plays as an intermediate product in the formation of compounds of formula 1 proposed in the invention method, the object of the present invention is also the compound of formula 3

in which R, R1and R2can have the values indicated above.

In addition, given the Central role that the connection is ormula 4 plays as an intermediate product in the formation of compounds of formula 1 proposed in the invention method, the object of the present invention is also the compound of formula 4

in which X-, R1and R2can have the values indicated above.

The invention relates further to the use of the above compounds of formula 3 to obtain the compounds of formula 1.

The invention relates also to the use of the above compounds of formula 4 to obtain the compounds of formula 1.

Below we propose the invention of the method for the synthesis of Tiotropium salts are illustrated by examples. In this case, however, the scope of the invention is not considered limited to these examples of possible variants of its implementation.

Example 1

To a mixture of 13.1 g (50 mmol) of detailslist sodium and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of N-methylpyrrolidone (N-MP) at 20°C is added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 30-minute stirring, first add 9,38 g (37.5 mmole) of copymetadata, and then at 20°C is added dropwise a solution of 2,59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of N-MP and stirred for 1 h at 20°C. After cooling to 0°C. are added dropwise 50 ml of a 33%solution of hydrogen bromide in glacial acetic acid, the temperature of the reaction mixture should not exceed 20°C. Then add 50 ml of methanol and the reaction to shift the ü stirred for 1 h at 20°C. The mixture is then extracted twice with toluene portions of 200 ml and after separation of the toluene phase is crystallized using 150 ml of isopropanol at 0°C. the Crude product is filtered off, washed with 30 ml of cold isopropanol and dried in vacuum.

Yield: 15.0 g (85% in terms of ScopeRecord).

Example 2

To a mixture of 13.1 g (50 mmol) of detailslist sodium and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of dimethylacetamide at 20°C is added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 30-minute stirring, first add 9,38 g (37.5 mmole) of copymetadata, and then at 20°C is added dropwise a solution of 2,59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 30 ml of dimethylacetamide and stirred for 1 h at 20°C. After cooling to -4°C and added dropwise 50 ml of a 33%solution of hydrogen bromide in glacial acetic acid, the temperature should not exceed 20°C. Then add 50 ml of methanol and the reaction mixture was stirred for 3 h at 20°C. the mixture is Then extracted with 500 ml of toluene and after separation of the toluene phase is crystallized using 150 ml of isopropanol at 0°C. the Crude product is filtered off, washed with 30 ml of cold isopropanol and dried in vacuum.

Yield: 14.1 g (80% in terms of ScopeRecord).

Example 3

To a solution of 13.1 g (50 mmol) ditioning is the cut sodium and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of dimethylformamide at 20°C. are added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 30-minute stirring, first add 12.5 g (50 mmol) of copymetadata, and then at 20°C is added dropwise a solution of 2,59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of dimethylformamide and stirred for 1 h at 20°C. After cooling to -5°C. are added dropwise 50 ml of a 33%solution of hydrogen bromide in glacial acetic acid, the temperature should not exceed 20°C. Then add 20 ml of methanol and the reaction mixture was stirred for 1 h at 20°C. the mixture is Then extracted twice with toluene portions of 200 ml and after separation of the toluene phase is crystallized using 150 ml of isopropanol at 5°C. the Crude product is filtered off and recrystallized from 120 ml of methanol, adding 5 g of activated charcoal. After cooling to 0°C. the resulting tetrapyrrole filtered off, washed with 5 ml of cold methanol and dried in vacuum.

Yield: 15.0 g (64% in terms of ScopeRecord).

Example 4

To a solution of 13.1 g (50 mmol) of detailslist sodium and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of dimethylformamide at 20°C. are added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 30-minute stirring, first add 12.5 g (50 mmol) of copymetadata, and then at 20°C is added dropwise a solution of 2,59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of hidri the sodium (60%) in 15 ml of dimethylformamide and stirred for 1 h at 20°C. After cooling to -5°C. are added dropwise 50 ml of a 33%solution of hydrogen bromide in glacial acetic acid, the temperature should not exceed 20°C. Then add 20 ml of methanol and the reaction mixture stirred for 1 h at 20°C. the mixture is Then extracted twice with toluene portions of 200 ml and after separation of the toluene phase is crystallized using 150 ml of isopropanol at 5°C. the Crude product is filtered off and recrystallized from 120 ml of methanol, adding 5 g of activated charcoal. After cooling to 0°C. the resulting tetrapyrrole filtered off, washed with 5 ml of cold methanol and dried in vacuum. Thus obtained crystal was dissolved in 20 ml of water at 90°C and crystallized the monohydrate tetrapyrrolic cooled to 15°C. the Product is filtered, washed with 7 ml of water and 8 ml of acetone, and after drying off by vacuum-filtering.

Yield: 9.8 g (40% in terms of ScopeRecord).

Example 5

To a solution of 13.1 g (50 mmol) of detailslist sodium and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of dimethylformamide at 20°C. are added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 30-minute stirring, first add 12.5 g (50 mmol) of copymetadata, and then at 20°C is added dropwise a solution of 2,59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of d is methylformamide and within 1 h and stirred at 20°C. After cooling to 0°C. added dropwise 5 ml of a 33%solution of hydrogen bromide in glacial acetic acid, the temperature should not exceed 10°C. Next, add 120 ml of 1-molar solution of tetrabutylammonium fluoride in THF (0.12 moles) and the reaction mixture stirred for 1 h at room temperature. The mixture is then mixed with 800 ml of dichloromethane and within 1 h and stirred at room temperature. Vegascasinoonline the crude product is filtered off and recrystallized from 120 ml of methanol, adding 5 g of activated charcoal. After cooling to 0°C. the resulting tetrapyrrole filtered off, washed with cold methanol and dried in vacuum.

Yield: 9.5 g (44% in terms of ScopeRecord).

Example 6

To a solution of 13.1 g (50 mmol) of detailslist of sodium in 25 ml of dimethylformamide at 20°C. are added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 30 minutes stirring at room temperature are added in several portions of 8.1 g (50 mmol) of carbonyldiimidazole and stirred for 10 minutes Then first add 10 g (40 mmol) of copymetadata, and then at 20°C is added dropwise a solution of 2,59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of dimethylformamide and stirred for 1 h at 20°C. After cooling to -5°C. are added dropwise 50 ml of 33%R is the target HBR in glacial acetic acid, the temperature should not exceed 20°C. Then add 20 ml of methanol and the reaction mixture was stirred for 30 min at room temperature. The mixture is extracted twice with toluene portions of 200 ml and cooled to 5°C crystallized in 150 ml of isopropanol. Vegascasinoonline the crude product is filtered off and recrystallized from 120 ml of methanol, adding 5 g of activated charcoal. After cooling to 0°C. the resulting tetrapyrrole filtered off, washed with cold methanol and dried in vacuum. After that, the product is dissolved in 24 ml of water at 90°C and crystallized the monohydrate tetrapyrrolic cooled to 15°C. finally, the product is filtered off, washed with 6.5 ml of water and 10.5 ml of acetone and dried.

Output: 8,1 g (42% in terms of ScopeRecord).

Example 7

To a solution of 13.1 g (50 mmol) of detailslist of sodium in 25 ml of dimethylformamide at 20°C. are added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 30 minutes stirring at room temperature are added in several portions of 8.1 g (50 mmol) of carbonyldiimidazole and stirred for 10 minutes Then first add 10 g (40 mmol) of copymetadata, and then at 20°C is added dropwise a solution of 2,59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of dimethylformamide and stirred for 1 h at 20°C. of Th is cooling to 10°C. are added dropwise 6 ml of a 33%aqueous solution of methyl hydrogen in glacial acetic acid, the temperature should not exceed 20°C. Then add 120 ml of 1-molar solution of tetrabutylammonium fluoride in THF (0.12 moles) and the reaction mixture was stirred for 30 min at room temperature. The mixture is mixed with 800 ml of dichloromethane and stirred for 15 min at room temperature. Vegascasinoonline the crude product is filtered off and recrystallized from 120 ml of methanol, adding 2 g of activated charcoal. After cooling to 0°C. the resulting tetrapyrrole filtered off, washed with cold methanol and dried in vacuum. Then the product is dissolved in 18 ml of water at 90°C and crystallized the monohydrate tetrapyrrolic cooled to 15°C. finally, the product is filtered, washed with 5 ml of water and 8 ml of acetone and dried.

Yield: 6.5 g (34% in terms of ScopeRecord).

Example 8

To a solution of 13.1 g (50 mmol) of detailslist of sodium in 25 ml of tetrahydrofuran at 20-30°C and added dropwise 5,43 g (50 mmol) of chlorotrimethylsilane. After 60 minutes of mixing the first type of 8.1 g (50 mmol) of carbonyldiimidazole, and then after 30 minutes add to 10.01 g (40 mmol) of copymetadata and stirred for 30 minutes Then at 20°C is added dropwise a solution of 2,60 g (38 mmol) of imidazole and of 1.65 g (38 mmol) of sodium hydride (55%) in 25 ml of dimethylformamide and stirred for 1 h at 20°is. After cooling to 0°C. added dropwise 20 ml of 62%Hydrobromic acid, the temperature should not exceed 20°C. After 40 minutes of stirring the reaction mixture at 20°mingle With 350 ml of isopropanol and then cooled to 10°C. the Crude product is filtered off, washed with 50 ml of cold isopropanol and dried in vacuum.

Output: 18,9 g of crystals of reddish-brown. Data TLC analysis correspond to the reference data.

The crude product together with 2.2 g of activated carbon are dissolved in 100 ml of methanol at reflux and filtered. Then the solution is concentrated to a volume of 30 ml and cooled to 3°C. the Crystals are filtered, washed with 5 ml of cold methanol and dried.

Yield: 12.1 g of white crystals beige color. Data TLC analysis correspond to the reference data.

Thus obtained crystals together with 1.2 g of activated carbon are dissolved at 80°C in 28 ml of water and filtered. After cooling to 15°C vegascasinoonline the monohydrate tetrapyrrolic filtered and dried.

Yield: 9.4 g (48% in terms of used ScopeRecord).

Example 9

The solution to 39.3 g (150 mmol) of detailslist sodium in 117 ml of tetrahydrofuran at 0°C dropwise added 17.9 g (165 mmol) of chlorotrimethylsilane. After 60 minutes of stirring at 10-20°C. the mixture is cooled to 0°C and p the drops add a solution of 24.3 g (150 mmol) of carbonyldiimidazole in 105 ml of dimethylformamide. After a further 30 minutes of stirring of 30.3 g (121 mmol) of copymetadata and stirred for 60 minutes at a temperature of 10-20°C. the mixture is Then cooled to 10°C, then at 10-20°C. are added dropwise thereto a solution of 16.8 g(150 mmol) of potassium tert-butylate in 90 ml of tetrahydrofuran and stirred for 60 min at 20°C. After cooling to 0°C. added dropwise 60 ml of 62%Hydrobromic acid, the temperature should not exceed 20°C. After 40 minutes of stirring the reaction mixture at 20°mingle With 1150 ml of isopropanol and cooled to 10°C. the Crude product is filtered off, washed with 70 ml of cold isopropanol and dried in vacuum.

Output: 61,5 g of crystals of reddish-brown. Data TLC analysis correspond to the reference data.

The crude product together with x 6.15 g of activated carbon is dissolved in 615 ml of methanol at reflux and filtered. Then distilled 570 ml of methanol and the solution is cooled to 10°C. the Crystals are filtered, washed with 35 ml of cold methanol and dried.

Output: of 40.9 g of white crystals beige color. Data TLC analysis correspond to the reference data.

Thus obtained crystals together with 2.2 g of activated carbon are dissolved at 80°C in 94 ml of water and the solution is filtered, then washed with 24 ml of water. After cooling to 15°With bicrystal isavasya the monohydrate tetrapyrrolic filtered off, washed with 25 ml of water and 35 ml of acetone and dried.

Output: 28.6 g (48% in terms of used ScopeRecord).

1. The method of receiving Tiotropium salts of formula 1
,
in which X-can refer to a singly charged anion, preferably an anion selected from the group comprising chloride, bromide, iodide, methanesulfonate and triftorbyenzola, characterized in that the compound of formula 2
,
in which X-can have the values indicated above, in one stage, put in an acceptable solvent, adding an acceptable cause for the interaction with the formed in situ with the compound of formula 3
,
in which R represents a residue selected from the group comprising N-imidazolyl, N-triazolyl, -O-C(=NR')-other", -O-SO2-phenyl, -O-SO2- phenylmethyl, -O-SO2-R', -O-CO-(methyl)3, -O-CO-phenyl-NO2, chlorine, bromine, -N3and-O-(P=O)R"', where
R' denotes a1-C4alkyl or C3-C6cycloalkyl,
R" denotes a1-C4alkyl, C3-C6cycloalkyl or1-C4alkylene-N(C1-C4alkyl)2and
R"' denotes a1-C4alkyl, -O-C1-C4alkyl, phenyl or-O-phenyl, and
R1and R2have identical or different meanings and may represent a methyl, ethyl, is ropel, butyl or phenyl, which optionally may be substituted by one or more1-C4alkyl residues with obtaining the compounds of formula 4
,
in which the groups X-, R1and R2can have the values indicated above, and then the compound of formula 4 without highlighting it translate interaction with acceptable acid or with an acceptable desilicious agent at the time of removal of the silyl group in the compound of formula 1.

2. The method according to claim 1, characterized in that in formula 1, X-can refer to a singly charged anion selected from the group comprising chloride, bromide, iodide, methanesulfonate and triftorbyenzola, preferably chloride, bromide, and methanesulfonate, especially preferably may designate bromide.

3. The method according to claim 1 or 2, characterized in that conduct interaction with the formed in situ with the compound of formula 3, in which
R represents a residue selected from the group comprising N-imidazolyl, N-triazolyl, -O-C(=NR')-other", -O-SO2-phenylmethyl, -O-CO-(methyl)3and chlorine, where
R' denotes methyl, ethyl or cyclohexyl, and
R ' denotes methyl, ethyl, cyclohexyl,2-C3alkylene-N(methyl)2or3-C3alkylene-N(ethyl)2and
R1and R2have identical or different meanings and represent methyl, ethyl, impregnated is or butyl.

4. The method according to claim 1 or 2, characterized in that conduct interaction with the formed in situ with the compound of formula 3, in which
R represents a residue selected from the group comprising N-imidazolyl, N-triazolyl, -O-C(=N-cyclohexyl)-NH, -O-C(=N-ethyl)-NH-CH2-CH2-CH2-NMe2and-O-CO-(methyl)3preferably represents N-imidazolyl or N-triazolyl, particularly preferably N-imidazolyl,
R1and R2have identical or different meanings and represent methyl, ethyl, propyl or butyl, preferably methyl or ethyl, particularly preferably methyl, and
R2represents methyl or ethyl, preferably methyl.

5. The method according to claim 1 or 2, characterized in that the compound of formula 3 is formed in situ in an appropriate solvent interaction ditienilglikoleva acid or its salts formed with alkali metals, with the agent combinations selected from the group comprising carbonyldiimidazole, carbonelli-1,2,4-triazole, dicyclohexylcarbodiimide, ethyldimethylammonium, toluensulfonate, pivaloyloxy, anhydride nitrobenzoic acid, oxalicacid, phosgene, sulphonylchloride and chlorides of phosphorus, followed by the addition of silyl compounds of formula 5
,
in which the residues R1and R2can they the be the above values, a L denotes a leaving group, preferably selected from the group comprising halide, methanesulfonate, triftorbyenzola and para-toluensulfonate.

6. The method according to claim 5, characterized in that the solvent is chosen from the group comprising acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide, dimethylacetamide, tetrahydrofuran, dioxane and sulfolan.

7. The compound of formula 3
,
in which R, R1and R2can be specified in claims 1 to 5 values.

8. The compound of formula 4
,
in which X-, R1and R2can be specified in claims 1 to 5 values.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound, namely to (1'S,5'S,9'S,10'R)-methyl-5-[2-(3-benzyl-6-carboxy-4-oxo-10-oxa-3-azatricyclo[5.2.1.01.5]deca-8-ene-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphtylene-1-carboxylate of formula (I) .

EFFECT: possesses anti-oxidant, hepatoprotective and hemostimulating activity, has low toxicity, and can be applied in medicine.

1 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

8 cl, 11 tbl, 463 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of diaryl compounds with formulae given below ,

.

, in which M is S(O)2, Rx represents alkyl, R1, R2, R3 and R4 are each independently selected from OH and -NR7S(O)2R8, R5 and R7 each independently represents hydrogen or alkyl, R8 is alkyl; and their pharmaceutically acceptable derivatives, as well as to pharmaceutical compositions containing said compounds and their use in making a medicinal agent with inhibitory activity on Aβ, IAPP amyloid fibrils or synuclein fibrils.

EFFECT: substituted n-arylbenzamide and related compounds for treating amyloid diseases and synucleinopathy are disclosed.

11 cl, 19 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to the method of producing compounds with formula I and to their pharmaceutical salts. In formulae I, II, IV, V: R1 or R2 represent H, -(CH2)t(5-member heterocyclic compound), where t equals 4 and where the heterocyclic compound contains one nitrogen atom as the heteroatom, R3 is -(CH2)t(C6-C10aryl), where t equals 1. The given R3 groups are optionally substituted with 3 R4 groups. Each R4 is independently chosen from halogen. R8 is C1-C10alkyl, R9 is C1-C10alkyl, and n equals 2.

EFFECT: treatment of hyper-proliferative diseases using new intermediate compounds with formulae II, IV, V.

15 cl, 2 dwg, 11 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, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of phenoxy-N-[4-(1,1-dioxoisothiazolidin-2-yl)-valeramide and describes compounds of the formula (I): wherein E represents phenyl or isoquinoline each of that is monosubstituted with group R1 wherein R1 represents -CN, amidino-group, halogen atom, -NH2, -CH2NH2 or compound of the formula: W represents -OCHAr', -OCHA, -NHCHAr', -NHCHA, -NHCOOCHAr', -NHCONHCHAr' or piperidine-1,2-diyl; Ar' represents unsubstituted phenyl or mono- or disubstituted phenyl, Hal, A or -CF3; A represents alkyl with 1, 2, 3, 4, 5, 6 or 7 C-atoms; X represents -CONH; Y represents Ar-diyl; T represents group -(CH2)3; Ar represents unsubstituted phenyl or mono- or disubstituted phenyl, Hal, A or -CF3; Hal represents fluorine (F), chlorine (Cl), bromine (Br) or iodine (J) atoms. These compounds are the coagulation factor Xa inhibitors. Also, invention relates to a method for synthesis of compounds of the formula (I), a medicinal agent containing these compounds and using compounds of the formula (I) for preparing a drug used in treatment of thrombosis, myocardium infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, restenosis after plastic surgery in vessels, intermittent lameness, migraine, tumors, tumor diseases and/or tumor metastasis and a kit (set). Also, invention relates to intermediate compounds of the formula (I-1): wherein R1 represents -NO2 or -NH2; R represents methyl, chlorine atom or trifluoromethyl and their salts. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 14 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new derivatives of phenylsulfonylacetate General formula (I), which are herbicide and regulating plant growth properties and can find application in agriculture

The invention relates to new Amida isothiazolinones acid of the formula I, where R is selected from formula (a), (b), (C), (d), (i) and (f), in which R1means cyano, phenyl, cyclopentyl, cyclohexyl, cycloheptyl, R2means- (CH3)3, -CH(C2H5)2, -CH2-S-R3and so on, R3represents alkyl with 1-5 carbon atoms or phenyl, optionally, from mono - to tizamidine the same or different residues selected from the group comprising fluorine, chlorine, bromine and alkyl with 1-4 carbon atoms, R10means fluorine, chlorine, bromine, methyl, etc., n means an integer from 0 to 3 provided that when n represents 2 or 3, R10means the same or different residues

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

Organic compounds // 2382783

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is 1-[2-(2-ethyl-2H-tetrazol-5-yl)ethyl]-3-[5-(3-fluoro-4-methanesulfonylphenyl)-4-methylthiazol-2-yl]urea in free form or in form of a pharmaceutically acceptable salt.

EFFECT: composition has inhibitory activity on phosphatidylinositol-3-kinase, which contains the disclosed compound as an active ingredient, to use of the compound to prepare a pharmaceutical composition for treating diseases mediated by phosphatidylinositol-3-kinase and synthesis method thereof.

6 cl, 9 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds that are lipoxin A4 analogues of general formula (I) and (II) where R1, R2, R3, R4 and R5 have values specified above. The inventions also refers to specific compounds of formula 1 and 11, to pharmaceutical compositions based thereon and to methods of treating inflammatory and autoimmune diseases in a human, and also treating inflammation of pulmonary or respiratory tracts in a human.

EFFECT: higher clinical effectiveness.

40 cl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and can be used for treating cold-related diseases. It is ensured by introduction of herbal potion containing leaves of buck-bean, coltsfoot, herb of yarrow, garden violet, Saint-John's-wort, origanum, nettle, camomile blossom, licorice rhizome. Besides said herbal potion contains the plants with microelements of increased neutron-capture cross-section, including Alexandrian laurel, burdock, alder blossom, fennel seeds, celandine herb and sage. All components are taken in equal portions, mixed, powdered, taken in amount 25-35 g and filled with 300-350 ml of boiling water. Then the prepared mixture is boiled no more than 3 minutes, kept within 3-3.5 hours and filtered. The prepared warm potion is introduced 70-100 ml 3-4 times a day after a meal during disease till recovery, and 2 times a day within 2 months thereafter.

EFFECT: method allows improving clinical effectiveness in cold-related diseases.

1 ex

FIELD: medicine.

SUBSTANCE: present invention refers to application of antiinflammatory and local anaesthetic pharmaceutical compositions containing ambroxol or one of its pharmacologically acceptable salts for local application for skin diseases chosen from the group including anaesthesia, burning, itching, inflammation, mosquito stings and skin redness of allergic, immunologic or idiopathic origin, applied directly on the skin.

EFFECT: invention provides antiinflammatory and local anaesthetic action in skin application, increases duration of application and do not show collateral actions.

6 cl, 15 ex

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