Method of obtaining high-purity meloxicam and meloxicam potassium salt

FIELD: medicine.

SUBSTANCE: invention refers to methods for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzotiazin-3-carboxamides-1,1-dioxide (meloxicam) of formula of a high degree purity. In one of the ways potassium salt monohydrate of meloxicam of formula is dissolved, which is produced by interaction of meloxicam formula (II) with potassium hydroxide or potassium carbonate dissolved in water or in a mixture of water and organic solvent and, if desired, crystallisation of this monohydrate potassium salt of meloxicam of formula (I) in water or in a mixture of water and organic solvent, insoluble impurities are removed and the resulting solution is processed with organic or inorganic acid and crystallise meloxicam. The invention also refers to potassium salt monohydrate of meloxicam of formula (I) and method of its production, as well as to anti-inflammatory pharmaceutical composition based on it.

EFFECT: improvement of composition efficacy.

18 cl, 4 ex

 

The scope of the invention

The present invention relates to a method for producing 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide of the formula (II)

also known by the International nonproprietary name (INN) meloxicam, and its high-purity potassium salt monohydrate of the formula (I)

Prior art

Meloxicam belongs to the group of nonsteroidal anti-inflammatory drugs. He manifests its pharmacological effects by inhibiting the enzyme systems of cyclooxygenase (SOH), which plays a significant role in the development of inflammatory processes. The medical value of meloxicam is that meloxicam is selectively inhibits the enzyme SOH-2. This phenomenon results in fewer side effects during drug therapy. It was found that the likelihood of harmful effects associated with the kidneys or the gastrointestinal tract, significantly lower during treatment with the use of meloxicam than when introduced other non-selective inhibitors of SOKH.

How to get meloxicam disclosed in European patent No. 2482. In accordance with the first method, the activated form of 4-hydroxy-2-methyl-2H-1,2-benzothia the h-3-carboxylic acid of formula (III),

such as its methyl, ethyl or isopropyl ester (where the value of the group R in the formula (III) is methyl, ethyl or isopropyl, respectively) are subjected to interaction with 2-amino-6-methyl-thiazole of the formula (IV)

at high temperature. During this interaction also produces by-products with chemical structures similar to meloxicam, and some amount of resin, therefore, required further purification of this crude product. The solvents most commonly used for recrystallization of the crude meloxicam are dichloroethane and dichloromethane. The aforementioned method has the disadvantage that the use of toxic and expensive solvents, which are also harmful to the environment. During the subsequent drying is necessary to ensure that the concentration of residual solvent in the finished active ingredient does not exceed the threshold concentrations established by the health services and pharmacopoeias. When the temperature of the drying takes place thermal decomposition of the active ingredient. The use of halogenated organic solvents requires extensive analytical testing, since the concentration of residual solvent must be defined in costly Ana is eticheskikh measurements.

In the second known method, the nitrogen atom 2H-1,2-benzothiazines ring was identified in using either very expensive methyliodide, or extremely toxic dimethylsulfate. Due to its low yield and high production costs, this method is not applied on an industrial scale.

It was found that when using the above methods, a by-product 4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide of the formula (V)

where the alkyl group corresponds to identical R-group in the initial compound of the formula (III), i.e. the stands, ethyl or isopropyl, is formed in an amount of 1-20% wt./wt. The compounds of formula (V) is a crystalline compound, slightly soluble in organic solvents and having a melting point above 250°C. the Impurity of the formula (V) can be partially removed by filtration of the hot solution of crude product of meloxicam. However, the dissolved portion of the compounds of the formula (V) in an amount of up to several tenths of a percent crystallizes together with meloxicam upon cooling, therefore, the compounds of formula (V) are in the final active pharmaceutical ingredient in an admixture. Observed that the compounds of formula (V) are produced in large quantities (10-20% wt./wt.), if ishodnoj the substance is used as a compound of the formula (III), where R represents methyl. The least amount of compounds of formula (V) is performed in the case where R represents the isopropyl in the initial compound of the formula (III). In accordance with the specifications Pharmacopoeia threshold concentration of compounds of the formula (V) is 0.1% wt./wt., which can only be achieved after recrystallization of the crude product several times from dichloromethane.

In the patent application U.S. No. 20030109701 disclosed methods of obtaining multiple polymorphic forms of meloxicam by dissolving meloxicam in sodium hydroxide solution prepared in water or in a mixture of water and an organic solvent, followed by acidification of a solution of sodium salt of meloxicam, precipitating thereby meloxicam free from its sodium salt. Thus have different crystal modifications of meloxicam depending on the conditions used in the process of dissolution and precipitation. Then the polymorphic form obtained as described above into pharmaceutically acceptable polymorph form I.

Summary of the invention

The objective of the study of the inventors was to develop a method of obtaining high-purity meloxicam suitable as a pharmaceutical active ingredient, and the specified high-purity meloxicam there is TSS is free from impurities 4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide of the formula (V), where the meaning of alkyl is methyl, ethyl or isopropyl.

The above problem is solved according to the present invention.

Unexpectedly, we discovered that the potassium salt monohydrate of meloxicam formula (I) can crystallize from aqueous solution with high purity, which, therefore, enables the purification of a crude meloxicam.

According to the aspect of the present invention, a method for producing high-purity 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (meloxicam) of the formula (II)in which:

a) dissolve the potassium salt monohydrate of meloxicam formula (I) in water or in a mixture of water and an organic solvent, to remove insoluble impurities and process the resulting solution of an organic or inorganic acid and crystallized meloxicam; or

b) transform the crude product meloxicam in crystalline monohydrate potassium salt of meloxicam formula (I), dissolved specified monohydrate potassium salt of meloxicam formula (I) in water or in a mixture of water and an organic solvent, to remove insoluble impurities and process dissolved potassium salt of meloxicam organic or inorganic acid followed by crystallization of meloxicam formula (II); or

C) subjecting the interaction of the compound of General form is s (III), where R represents methyl, ethyl or isopropyl, 2-amino-6-methyl-thiazole of the formula (IV)transform the resulting meloxicam formula (II) in its potassium salt, separating insoluble impurities from water or aqueous-organic solution of the specified potassium salt of meloxicam, process the specified solution of an organic or inorganic acid and crystallized meloxicam.

According to further aspect of the present invention, a method of obtaining potassium salt of meloxicam formula (I) by treatment with meloxicam formula (II) with potassium hydroxide or potassium carbonate, dissolved in water or in a mixture of water and an organic solvent and, if desired, crystallized monohydrate potassium salt of meloxicam compounds of formula (I)generated in this way.

When the above-mentioned method, aimed at obtaining potassium salt of meloxicam formula (I) or its monohydrate, the molar amount of potassium hydroxide or potassium carbonate is 1 to 10 molar equivalents, preferably 4-5 molar equivalents molar amount of meloxicam.

If desired, any of these methods can be performed in water or in a mixture of water and an organic solvent. As the organic solvent can be used an alcohol containing 1-4 carbon atoms, for example methanol, ethanol or isopr is panel, preferably ethanol.

In variants of the above-mentioned method (a)-C) meloxicam formula (II) precipitated free from its potassium salt, dissolved in water or in a mixture of water and an organic solvent, by treatment with an inorganic or organic acid. Such acid treatment is carried out by mixing a solution of the potassium salt of meloxicam formula (I) with concentrated acid or its aqueous solution. Suitable acids include any mineral or organic acids, for example sulfuric acid, hydrochloric acid, phosphoric acid, tartaric acid, acetic acid.

The acid treatment can preferably be under the control of acidity (pH) of a solution of potassium salt of meloxicam formula (I). Acid processing continues until the pH from 3 to 6, preferably pH 6.

According to further aspect of the present invention proposed 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (meloxicam) of the formula (II), essentially free from 4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide of the formula (V), where the alkyl group R of the formula (V) is a methyl, ethyl or isopropyl.

The invention also relates to the monohydrate potassium salt of meloxicam formula (I) preferably in a purified condition, where asana salt is essentially free from 4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide of the formula (V), where the alkyl (group R of the formula (V)is a methyl, ethyl or isopropyl.

According to another further aspect of the present invention proposed pharmaceutical preparations containing the potassium salt monohydrate of meloxicam formula (I) as active ingredient and one or more than one pharmaceutically acceptable carrier or auxiliary agent is preferably in a purified state, where this salt is essentially free from 4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide of the formula (V), where alkyl (group R of the formula (V)is a methyl, ethyl or isopropyl.

The invention also relates to pharmaceutical preparations containing high-purity meloxicam formula (II) as the active ingredient and one or more than one pharmaceutically acceptable carrier or auxiliary agent is preferably in a purified state, where the active ingredient meloxicam is essentially free from 4-hydroxy-2-methyl-N-alkyl-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide of the formula (V), where alkyl (group R of the formula (V)is a methyl, ethyl or isopropyl.

Detailed description of the invention

Organic acids and phenols form a salt with a metal, which is usually soluble in water. This phenomenon is s often used for the purification of these compounds by dissolving the product in alkaline aqueous medium and removing insoluble in alkali and water, the organic impurities by filtration or extraction with a suitable immiscible the solvent.

In the prior art it is known that potassium salts crystallize harder and have a higher solubility in water and in organic solvents than the sodium salt. Potassium salts may be hygroscopic, therefore, these salts are preferably separated from their solution in organic solvents.

Obtaining the sodium salt of meloxicam was disclosed in example 2 of European patent No. 2482. A methanol solution of meloxicam is mixed with approximately an equimolar amount of sodium methylate, the reaction mixture is evaporated to dryness, sodium salt are suspended in a mixture of acetone-ether and filtered.

In the patent application U.S. No. 20030109701 disclosed receipt of the sodium salt of meloxicam by dissolving meloxicam in aqueous-organic solution of sodium hydroxide.

Although according to the prior art among the alkali metal salts of meloxicam potassium salt is also mentioned, there is no description available for obtain the potassium salt of meloxicam in solid form, and it is impossible to find data regarding its stability, solubility and purity. In accordance with the prior art salts obtained from meloxicam and organic or inorganic bases, get the sole purpose of increasing the solubility of meloxicam.

In accordance with the prior art does not describe what Holocene meloxicam in high-purity form or purification through his salt, formed with an inorganic or organic base.

Quite unexpectedly discovered that the potassium salt of meloxicam formula (I) can be easily isolated in highly pure form of the monohydrate from the solution of the crude product obtained with water or, if desired, with water and organic solvents, even in the case when the impurity of the formula (V) is present in an amount of about 20% wt./wt.

The advantage of the potassium salt of the formula (I) lies in the fact that in this way the impurities of the formula (V), as well as other insoluble in alkali contamination can be completely and very easy to remove from the crude product.

Despite the fact that the compounds of formula (V) include aromatic hydroxy-group, they do not form a salt with alkali metals, therefore, they are insoluble in aqueous alkaline solution and can be removed from a solution of the potassium salt of meloxicam by filtration. A small amount of impurities present on the surface of a solid crystalline monohydrate potassium salt of meloxicam formula (II), including traces of compounds of the formula (V)can be removed by simply washing with appropriate solvent, as the monohydrate potassium salt of meloxicam formula (I) is practically insoluble in organic solvents, such as ethyl acetate.

According to the next aspect of altoadige of the invention, a method for producing high-purity crystalline monohydrate potassium salt of meloxicam formula (I). In the first stage meloxicam receive, starting from the compounds of formula (III), where the value R is methyl, which is subjected to interaction with the compound of the formula (IV). With this method a by-product of the formula (V), where the value R is methyl, is obtained in the amount of 10-15% wt./wt. The crude product is dissolved in an aqueous solution of potassium hydroxide or potassium carbonate at a temperature of from 50 to 60°C., impurities, insoluble in alkaline-aqueous solvent is removed by filtration or centrifugation, the clear solution is cooled, and high-purity crystalline monohydrate potassium salt of meloxicam formula (I) is recovered by filtration or centrifugation.

According to further aspect of the present invention, a method for conversion of monohydrate potassium salt of meloxicam formula (I) in high purity meloxicam. Monohydrate potassium salt of meloxicam formula (I) is dissolved in water or in a mixture of water and an organic solvent, the solution is filtered, the filtrate acidified with aqueous solution of acid and cooled. Then crystal meloxicam collected, washed and dried.

According to another aspect of the present invention, a method for producing high-purity meloxicam polymorphic form I. the Potassium salt of the formula (I) is dissolved in water at a temperature between 50 and 60°C. this aqueous solution is altroot, and the yellow solution is acidified to pH 6 using concentrated acid solution, the solution is cooled, and precipitated precipitated crystalline polymorphic form I of meloxicam allocate by centrifugation or filtering.

The advantage of the method according to the present invention lies in the fact that the only solvent used in the cleaning process, water is, therefore, not necessary to remove the organic solvent from the product. When the acidity (pH value), above, the product is almost insoluble in water, so the yield is almost quantitative. During the above process, the heat load on the product and its thermal decomposition is minimal, which allows to obtain high-purity product. In the above way are not involved the harmful chemicals, therefore, it has an advantage from the point of view of environmental protection. The use of the method described above also results in significant cost savings.

The aforementioned inventive concept according to the invention can be applied more generally. Among the esters of the formula (III) methyl ether is the cheapest and is in the broadest scale. However, this methyl ester (III), where R represents methyl, and eat common but of limited value in the production process of meloxicam in connection with the fact that a by-product of the formula (V), where R represents methyl, formed during the amidation reaction in a significant number, approximately 10-15% wt./wt., which cannot be removed by crystallization. When using the method according to the present invention of contaminated raw products containing the above-mentioned high amount of compounds of formula (V), where R represents methyl, can be cleaned. Thus, it is possible to use cheaper methyl ester of formula (III), where R represents methyl, instead of the isopropyl ester of the formula (III), where R represents isopropyl.

Raw meloxicam formula (II) is carried out according to the prior art by reacting an ether of formula (III), where R represents methyl, ethyl or isopropyl, and 2-amino-5-methyl-thiazole of the formula (IV) in solvents having a high boiling point, for example in chlorobenzene, decaline or xylene, preferably xylene. The reaction takes place at the boiling point of the reaction mixture at a temperature between about 130 and about 170°C. the reaction Time is usually 12-24 hours. In addition to the product of meloxicam, the reaction mixture contains a significant amount of the compounds of formula (V)corresponding to the original soy is inniu formula (III) in respect of the group R, and a substance such as resin. If desired, the reaction can be carried out in the presence of activated carbon to reduce the amount of resin. In the reaction meloxicam and side product of the formula (V) crystallize and precipitate from the reaction mixture and can be removed by filtration with activated carbon, if present.

Crude meloxicam, which may also contain activated carbon, dissolved in 20-50 times the mass number of an aqueous solution of potassium hydroxide at a temperature between 50 and 80°C with stirring. If desirable, the dissolution rate of meloxicam can be improved by adding about 3-5%.about. low molecular weight alcohol, for example methanol, ethanol or isopropanol. The volume of solution of potassium hydroxide determine, given the quantity and quality of low molecular weight alcohol.

Water-base solvent dissolves only meloxicam. The compound of formula (V), which is insoluble in the alkaline medium is filtered with activated carbon, if present. Clear yellow filtrate is cooled, and when this occurs the precipitation of the crystalline monohydrate potassium salt of meloxicam formula (I).

Crystallization of the monohydrate potassium salt of meloxicam can be enhanced by vysalivaniya. To achieve the effect Uysal is of the amount of potassium hydroxide or potassium carbonate are added to a solution of the potassium salt of meloxicam in the form of solids or in the form of a concentrated aqueous solution in excess to equimolar quantity, necessary for the formation of salts. The total number of potassium ions present in the solution according to the present invention may be between 1-10 molar equivalents, preferably 4-5 molar equivalents relative to the molar amount of meloxicam.

Solid crystalline monohydrate potassium salt of meloxicam formula (I) allocate, impurities present on the surface of the crystals, wash it off using cold water or an organic solvent or their mixture, for example, using ethyl acetate, ethanol, methanol, isopropanol as the organic solvent.

According to the observations of the invention, using the method according to the present invention, it is possible to obtain the potassium salt monohydrate of meloxicam at high purity even in the worst case, when the reaction mixture contains 15-20% of the compound of formula (V) wt./wt.

According to the present invention, a method for receiving meloxicam polymorphic form I of the formula (II) with high purity, which dissolve the potassium salt monohydrate of meloxicam formula (I) in water or in a mixture of water and 1-20% vol./about. low molecular weight alcohol at a temperature between 50 and 100°C., preferably at temperatures between 60 and 70°C. the Solvent preferably contains 2-5%.about. ethanol in water.

The solution is filtered, and a transparent yellow film the rat is acidified to pH 6, using a mineral or organic acid. For acidification, you can use any mineral or organic acid, for example hydrochloric acid, sulfuric acid or phosphoric acid, acetic acid, tartaric acid. Crystal meloxicam filtered and washed with water and ethanol.

According to further aspect of the present invention proposed pharmaceutical preparations containing the potassium salt monohydrate of meloxicam formula (I) in a mixture with one or more than one common carrier or auxiliary agent essentially free from impurities of formula (V).

Another another aspect of the present invention relates to pharmaceutical preparations containing meloxicam formula (II) in a mixture with one or more than one common carrier or auxiliary agent essentially free from impurities of formula (V).

The pharmaceutical compositions according to the present invention contain as a rule 0.1 to 95% wt./wt., preferably 1-50% wt./wt., in particular 5-30% wt./wt. the active ingredient.

The pharmaceutical compositions of the present invention may be suitable for peroral (for example, powders, tablets, coated tablets, capsules, micro-capsules, pills, solutions, suspensions or emulsions), parenteral (e.g., injection solutions for nutrivene, intramuscular, subcutaneous or intraperitoneal application), rectal (e.g., suppositories), percutaneous (e.g., patches) or local (e.g., ointments or patches) the introduction of or for use in the form of implants. Hard, soft or liquid pharmaceutical compositions according to the invention can be obtained by methods common used in the pharmaceutical industry.

Solid pharmaceutical compositions for oral administration containing a compound of the formula (I)may contain diluents, excipients or carriers such as lactose, glucose, starch, potassium phosphate, microcrystalline cellulose), a binding agent such as gelatin, sorbitol, polyvinylpyrrolidone), disintegrating agents (such as crosscarmellose, Na-carboxymethyl cellulose, crosspovidone), auxiliary agents for tablets (such as magnesium stearate, talc, polyethylene glycol, silica, silicon dioxide) and surface-active agents (e.g. sodium lauryl sulphate).

Liquid compositions containing the potassium salt of meloxicam formula (I) in the dissolved form, known according to the prior art. Liquid pharmaceutical preparations suitable for oral administration according to the present invention, can be a suspension or emulsion. Such compositions may contain suspendresume agents (in the example, gelatin, carboxymethyl cellulose), emulsifiers (for example, servicemanual), solvents (e.g. water, oil, glycerine, propylene glycol, ethanol), buffering agents (e.g., acetate, phosphate, citrate buffers) or preservatives (e.g. methyl-4-hydroxybenzoate).

Soft pharmaceutical compositions containing as active ingredient a compound of General formula (I) or its pharmaceutically acceptable salt accession acid, such as suppositories contain the active ingredient uniformly dispersed in the material basis of suppositories (e.g., polyethylene glycol or cocoa butter).

The pharmaceutical compositions according to the present invention can be prepared by known methods of the pharmaceutical industry. The active ingredient is mixed with a pharmaceutically acceptable solid or liquid carriers and/or auxiliary agents, and this mixture leads to a formulation. Carriers and auxiliary agents together with ways that you can use in the pharmaceutical industry, are disclosed in the literature (Remington''s Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990).

The pharmaceutical compositions according to the present invention contain, as a rule, the standard dose.

Additional details of the present invention are given in the example below the x without limiting the scope of protection of these examples.

Example 1

4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide potassium salt monohydrate (compound of formula (I)

350 ml of xylene is transferred into the apparatus, equipped with a nozzle Markusson and provided with means for blowing inert gas. Start blowing with argon and added to 35.0 g (130 mmol) of 4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxylic acid methyl ester of formula (III), (where the value R is methyl), 15.0 g (132 mmol) of 2-amino-5-methyl-thiazole of the formula (IV) and 6.0 g of activated carbon under continuous stirring and blowing with argon.

The reaction mixture is heated for 24 hours using an oil bath, at a temperature between 170 and 180°C. the Heating is adjusted so that only a minimum amount of distillate (2-5 ml/h) was formed in the nozzle. The distillation of methanol is terminated by the end of the reaction.

The reaction mixture is cooled to 25°C, crude meloxicam containing carbon and about 12% impurity of formula (V), filtered and washed on the filter with xylene and ethanol. The crude product containing carbon, stirred into 1200 ml of 0.5% aqueous solution of potassium hydroxide at 50°C for one hour, the carbon and the impurity of the formula (V), insoluble in alkaline solution, is filtered off and the clear yellow solution at 25°C. is added dropwise to a solution of 3 g of potassium hydroxide in 100 ml of water. Potassium salt of meloxicam is deposited in the form of yellow crystals, which are easily separable by filtration. The suspension of crystals is stirred for two hours at 10°C, filtered and washed with water.

Output: 42,9 g [81,0%, calculated on the amount of the compounds of formula (III)]

Content (based on the content of potassium): 99,5%

Water (Karl Fischer method): 4,6%

Melting point: 170-171°C

Elemental analysis [C14H12KN3O4S2·H2O (of 407.5)]

Calculated: 41,26; N: Of 3.46; N:10,31; S: 15,74

Measured With: 41,20; H: 3,52; N: Of 10.21; S: 15,61

Purity (HPLC): 99,8%.

Tg: the product loses 4,75% water at 175-245°C

Example 2

4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (compound of formula (II), polymorphic form I of meloxicam

to 34.1 g (83.7 mmol) of potassium salt monohydrate of meloxicam dissolved in a mixture of 1500 ml of 0.5% aqueous solution of potassium hydroxide and 25 ml of ethanol at a temperature of 40-45°C by stirring for 30 minutes. To this yellow solution was added 2.0 g of activated carbon, and after stirring for ten minutes, the carbon is filtered off. To this mixture was added 100 ml of an aqueous hydrochloric acid solution prepared by diluting 20 ml (23,6 g) of concentrated hydrochloric acid to a final volume of 100 ml at 30°C for 30 minutes (pH 3-5). The suspension is stirred in t is the treatment of two hours at a temperature of 10°C, filtered, and the product is washed on the filter with water.

Yield: 28.5 g (97.1%of calculated mass monohydrate potassium salt of meloxicam as a source connections)

Melting point: 246-248°C

Elemental analysis (C14H13N3O4S2(351,4)

Calculated: 47,85; N: To 3.73; N: 11,96; S: 18,25

Measured With: 47,80; N: 3,82; N: 11.87 Per; S: 18,20

Example 3

Monohydrate potassium salt of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (compound of formula (I))

Receive in accordance with Example 1 with the difference that instead of the methyl ester of 4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxylic acid [compound of formula (III), where R represents methyl)] use 36,83 g (130 mmol) of ethyl ester of 4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxylic acid [compound of formula (III), where R represents ethyl].

Output: 46,9 g (88.5 percent, calculated based on the weight of starting compound methyl ester 4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxylic acid of formula (III))

Content (based on the content of potassium): 99,6%

Water (Karl Fischer method): 4,7%

Elemental analysis [C14H12KN3O4S2·H2(Of 407.5)]

Calculated: 41,26; N: Of 3.46; N: 10,31; S: 15,74

Measured With: 41,22; N: 3,38; N: Of 10.25; S: 15,69

Purity (HPLC): 99,8%.

Example 4

Polymorphic form I of meloxicam

Receive according to note is ru 2 with the only difference the solution of the potassium salt is treated with 6.0 ml of 96% acetic acid instead of hydrochloric acid.

Output: 29,0 g (98.5 per cent, calculated on the basis of the number monohydrate potassium salt of meloxicam formula (I)used as starting compound)

Melting point: 246-248°C

Elemental analysis (C14H13N3O4S2(351,4)

Calculated: 47,85; N: To 3.73; N: 11,96; S: 18,25

Measured With: 47,89; N: 3,68; N: 11,91; S: 18,29

Purity (HPLC): 99,8%.

Example 5

Preparation of anti-inflammatory pharmaceutical preparation containing meloxicam formula (II) or monohydrate potassium salt of meloxicam formula (I)

Received in accordance with the above examples meloxicam formula (II) or monohydrate potassium salt of meloxicam formula (I) in an amount of 15 mg was mixed with purified water to volume of 100 ml of the resulting preparation is suitable for oral administration and can be used as an anti-inflammatory drug.

1. The way to obtain 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (meloxicam) of the formula (II)

a high degree of purity, in which
dissolve the potassium salt monohydrate of meloxicam formula (I)

which is obtained by interaction meloxicam formula (II) with potassium hydroxide or the carb is the gateway potassium, dissolved in water or in a mixture of water and an organic solvent, and, if desired, crystallization specified monohydrate potassium salt of meloxicam formula (I),
in water or in a mixture of water and an organic solvent to remove insoluble impurities and process the resulting solution of an organic or inorganic acid and crystallized meloxicam.

2. The method according to claim 1, characterized in that the molar amount of potassium hydroxide or potassium carbonate is 1 to 10 molar equivalents, preferably 4-5 molar equivalents molar amount of meloxicam.

3. The method according to claim 1, characterized in that the organic solvent used alcohol containing 1-4 carbon atoms, for example methanol, ethanol or isopropanol, preferably ethanol.

4. The method according to claim 1, characterized in that the acid treatment solution of potassium salt of meloxicam in water or in a mixture of water and an organic solvent is carried out by mixing the specified solution with an organic or inorganic acid, for example sulfuric acid, hydrochloric acid, phosphoric acid, tartaric acid, acetic acid, preferably acetic acid or hydrochloric acid.

5. The method according to claim 4, characterized in that the continue treatment with an acid to a pH of from 3 to 6, preferably to a pH of 6.

6. Way obtained the I 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (meloxicam) of the formula (II)

a high degree of purity, in which
turn the crude product meloxicam in crystalline monohydrate potassium salt of meloxicam formula (I) by the interaction meloxicam formula (II) with potassium hydroxide or potassium carbonate, dissolved in water or in a mixture of water and an organic solvent, and crystallization of the obtained potassium salt monohydrate of meloxicam formula (I), dissolved specified monohydrate potassium salt of meloxicam formula (I) in water or in a mixture of water and an organic solvent, to remove insoluble impurities and process dissolved potassium salt of meloxicam organic or inorganic acid followed by crystallization of meloxicam formula (II).

7. The method according to claim 6, characterized in that the molar amount of potassium hydroxide or potassium carbonate is 1 to 10 molar equivalents, preferably 4-5 molar equivalents molar amount of meloxicam.

8. The method according to claim 6, characterized in that the organic solvent used alcohol containing 1-4 carbon atoms, for example methanol, ethanol or isopropanol, preferably ethanol.

9. The method according to claim 6, characterized in that the acid treatment solution of potassium salt of meloxicam in water or in a mixture of water and an organic solvent is carried out by mixing the decree of the aqueous solution with an organic or inorganic acid, for example sulfuric acid, hydrochloric acid, phosphoric acid, tartaric acid, acetic acid, preferably acetic acid or hydrochloric acid.

10. The method according to claim 9, characterized in that the continue treatment with an acid to a pH of from 3 to 6, preferably to a pH of 6.

11. The way to obtain 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide (meloxicam) of the formula (II)

a high degree of purity, in which
subjected to the interaction of the compound of General formula (III)

where R represents methyl, ethyl or isopropyl, 2-amino-5-methyl-thiazole of the formula (IV)

turn the resulting meloxicam formula (II) in its potassium salt by interaction meloxicam formula (II) with potassium hydroxide or potassium carbonate, dissolved in water or in a mixture of water and an organic solvent, and, if desirable, the crystallization of the obtained potassium salt monohydrate of meloxicam formula (I), separating insoluble impurities from water or aqueous-organic solution of the specified potassium salt of meloxicam, process the specified solution of an organic or inorganic acid and crystallized meloxicam.

12. The method according to claim 11, characterized in that the molar amount of potassium hydroxide sludge is potassium carbonate is 1 to 10 molar equivalents, preferably 4-5 molar equivalents molar amount of meloxicam.

13. The method according to claim 11, characterized in that the organic solvent used alcohol containing 1-4 carbon atoms, for example methanol, ethanol or isopropanol, preferably ethanol.

14. The method according to claim 11, characterized in that the acid treatment solution of potassium salt of meloxicam in water or in a mixture of water and an organic solvent is carried out by mixing the specified solution with an organic or inorganic acid, for example sulfuric acid, hydrochloric acid, phosphoric acid, tartaric acid, acetic acid, preferably acetic acid or hydrochloric acid.

15. The method according to 14, characterized in that the continue treatment with an acid to a pH of from 3 to 6, preferably to a pH of 6.

16. The way to obtain the potassium salt monohydrate of meloxicam formula (I), which is subjected to interaction meloxicam formula (II) with potassium hydroxide or potassium carbonate, dissolved in water or in a mixture of water and an organic solvent, and, if desirable, crystallized monohydrate potassium salt of meloxicam formula (I)obtained in this way.

17. Monohydrate potassium salt of meloxicam formula (I).

18. Anti-inflammatory pharmaceutical composition comprising a potassium salt monohydrate of meloxicam Fort the uly (I) 17 and one or more pharmaceutically acceptable carrier or auxiliary agent.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: claimed compounds show effect on receptor activated by peroxysome proliferate δ (PPARδ). In formula I: [Formula I] , [Formula VII] , [Formula VI] , A is R1 is C1-4alkyl group; R3 groups are different and denote halogen atom or C1-4alkyl group substituted or unsubstituted by halogen; R4 is R5 is hydrogen atom or hydroxyl group; the other radicals are as defined in the invention claim. Also invention refers to methods of compound I obtainment, to intermediary compounds VI, VII and methods of their obtainment, to medicines of diabetes, obesity, atherosclerosis, hyperlipidemia treatment and prevention, containing thiazole derivative of the formula I as active component.

EFFECT: enhanced activity of derivatives.

21 cl, 10 tbl, 102 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula 1 , where R1, R2, R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, alkylcarboxylate, alkyl, alkenyl, cycloalkyl, nitro, sulfonyl chloride, sufonyl hydrazide, alkyl sulfonyl, heterocycylsulfonyl, heteroarylsufonyl, sulfonamide, alkyl-NH-SO2-, cycloalkyl-NH-SO2-, heterocyclyl-NH-SO2-, heteroalkyl-NH-SO2-, heteroarylalkyl-NH-SO2-, heterocyclyl, heteroaryl, guanidinocarbonyl, guanidine, -NR'R" and N=R'"; R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, halogenalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, aminoalkyl, mono- or dialkyl substituted aminoalkyl, cycloalkylaminoalkyl, aralkylaminoalkyl, alkoxyaralkylaminoalkyl, heterocyclylalkyl, heterocyclylaminoalkyl, heterocyclylalkylaminoalkyl, heterocyclylalkyl-N(alkyl) alkyl, heteroarylalkyl, heteroaralkylaminoalkyl, alkoxyaralkyl-N(alkyl)alkyl, aralkyl-N(alkyl)alkyl, alkoxycarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl alkylcarbonyl; R'" is selected from heterocyclyl, cycloalkyl and alkyl; where the alkyl is unsubstituted or substituted with 1, 2 or 3 identical or different substitutes selected from halogen, halogen alkyl, hydroxy, alkoxy, alkylamino, carbonyl, cycloalkylamino, nitro, cycloalkyl, aryl, heteroaryl and heterocyclyl; aryl is (C6-C10)aryl which is unsubstituted or substituted with 1-2 identical or different substitutes selected from nitro, alkyl, alkoxy, halogen, halogenalkyl, amino and mono or dialkylamino-; heteroaryl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from halogen, nitro, amino, alkylamino, alkyl, alkoxy and cycloalkyl; heterocyclyl is a 5- or 6-member ring system containing 1, 2 or 3 atoms in the ring selected from N, O and S, which is unsubstituted or substituted with 1-2 identical or different groups selected from alkyl, cycloalkyl, hydroxyalkyl, alkylaminoalkyl, cycloalkylalkyl, cycloalkylcarbonyl, heterocyclylalkyl, heteroarylalkyl, heteroarylcarbonyl, arylalkyl and oxo; and guanidino and guanidinocarbonyl are unsubstituted or substituted with 1, 2 or 3 identical or different groups selected from alkyl and alkylcarbonyl; provided that at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is guanidine or guanidine carbonyl; U is C(O), CRaRb, O or NRa; V is CRaRb or NRa; and W is S(O)m; where Ra is H, alkyl, cycloalkyl or alkenyl; Rb is H, alkyl, OH or ORa, and m equals 1 or 2; or to pharmaceutically acceptable salts thereof. The invention also relates to a method of obtaining formula 1 compounds, to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining new biologically active compounds which are sodium/proton exchange (Na+/H+) (NHE) inhibitors.

19 cl, 203 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and their pharmaceutically acceptable salts and esters. The disclosed compounds have cdk4 inhibition properties. In formula (I) n equals 0 or 1; R1 and R2 are each independently selected from a group consisting of H, lower alkyl, CO2R5, SO2R6 and COR6; or alternatively, R1 and R2 can form a ring containing 5-6 atoms in the ring, where the said ring contains carbon atoms, where the said carbon atoms are optionally substituted with oxygen, and the said atoms in the ring are optionally substituted with OR6; R3 is selected from a group consisting of H, lower alkyl, O-lower alkyl, halogen, OH, CN, NO2 and COOH; R4 is selected from a group consisting of H, lower alkyl, C3-C6-cycloalkyl, O-lower alkyl, halogen, NO2, S-lower alkyl, NR5R6, CONR7R8, OH and CN; or alternatively R3 and R4, together with two carbon atoms and the bond between them from the benzene ring, to which R3 and R4 are bonded, can form a ring containing 5-7 atoms, where the said 5-7-member ring contains carbon atoms, where the said carbon atoms are optionally substituted with one or two heteroatoms selected from O and N, and the said atoms in the ring are optionally substituted with CO2R6; R4 represents H or halogen; R5 and R6 are each independently selected from a group consisting of H and lower alkyl; R7 and R8 each represents H. The invention also relates to a pharmaceutical composition for treating or controlling diseases progression of which can be enhanced by inhibiting cdk4, containing an effective amount of the disclosed compound as an active ingredient, to use of disclosed compounds for preparing medicinal agents and method of producing said compounds.

EFFECT: more effective treatment.

30 cl, 1 tbl, 142 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compounds, radicals of which are defined in the formula of invention, are described. A pharmaceutical composition containing formula (I) compounds is also described.

EFFECT: obtaining compounds which have inhibitory activity on protein kinase MEK1/2 and are meant for use as a therapeutically active substance which is useful for treating MEK1/2 mediated diseases.

13 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I)

Values of radicals R1-R6 are given in the formula of invention. The compounds inhibit protein kinase MEK1/2. Also described is a pharmaceutical composition for administration in diseases mediated by MEK1/2.

EFFECT: compounds are highly efficient.

16 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and their pharmaceutically acceptable salts and esters. The disclosed compounds have cdk4 inhibition properties. In formula (I) n equals 0 or 1; R1 and R2 are each independently selected from a group consisting of H, lower alkyl, CO2R5, SO2R6 and COR6; or alternatively, R1 and R2 can form a ring containing 5-6 atoms in the ring, where the said ring contains carbon atoms, where the said carbon atoms are optionally substituted with oxygen, and the said atoms in the ring are optionally substituted with OR6; R3 is selected from a group consisting of H, lower alkyl, O-lower alkyl, halogen, OH, CN, NO2 and COOH; R4 is selected from a group consisting of H, lower alkyl, C3-C6-cycloalkyl, O-lower alkyl, halogen, NO2, S-lower alkyl, NR5R6, CONR7R8, OH and CN; or alternatively R3 and R4, together with two carbon atoms and the bond between them from the benzene ring, to which R3 and R4 are bonded, can form a ring containing 5-7 atoms, where the said 5-7-member ring contains carbon atoms, where the said carbon atoms are optionally substituted with one or two heteroatoms selected from O and N, and the said atoms in the ring are optionally substituted with CO2R6; R4 represents H or halogen; R5 and R6 are each independently selected from a group consisting of H and lower alkyl; R7 and R8 each represents H. The invention also relates to a pharmaceutical composition for treating or controlling diseases progression of which can be enhanced by inhibiting cdk4, containing an effective amount of the disclosed compound as an active ingredient, to use of disclosed compounds for preparing medicinal agents and method of producing said compounds.

EFFECT: more effective treatment.

30 cl, 1 tbl, 142 ex

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: medicine.

SUBSTANCE: invention refers to medicine, particularly to treatment of proliferative disease especially that one associated with a solid tumour. That is ensured by introduction of an effective amount of epothilone B of formula I wherein residual A represents O, R stands for hydrogen or methyl, and Z means O. The patient is exposed to ionising radiation additionally, simultaneously or consistently in any order.

EFFECT: choice of a specific epothilone derivative combined with radiation provides synergetic effect on suppression of tumour tissue.

8 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns derivatives of thiazolidine-4-one of general formula (I) and general formula (II), to their isomers and pharmaceutically acceptable salts which can be used as a medical product with immunosuppressive activity. In formulae (I) and (II), R1 and R14 independently represent lower alkyl, lower alkenyl; cycloalkyl; 5,6,7,8-tetrahydronaphth-1-yl; phenyl group or phenyl group independently mono- or disubstituted with lower alkyl, halogen, lower alkoxy or group -CF3; R2 and R15 independently represent lower alkyl; allyl; cyclopropyl; or di- lower alkylamino; R3 represents -NR5R6 or -O-CR7R8-CR9R10-(CR11R12)n-O-R13; R23 represents hydrogen; hydroxycarbonyl-lower alkyl or 1-glyceryl. Values of the other radicals are specified in the patent claim. The invention also concerns application of one or more compounds of general formula (I) or (II) for preparation of a medical product with immunosuppressive activity.

EFFECT: agent exhibits improved efficiency.

24 cl, 1 tbl, 157 ex

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 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

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