Tetomilast polymorphs

FIELD: chemistry.

SUBSTANCE: invention relates to a novel anhydrous tetomilast type A crystalline form, having powder X-ray diffraction spectrum essentially the same as the powder X-ray diffraction spectrum having characteristic peaks at 2θ = 10.5°, 13.1°, 18.4°, 21.9° and 25.8°, pharmaceutical compositions based thereon and synthesis methods thereof.

EFFECT: considerable advantages in terms of industrial production owing to significantly better filterability.

8 cl, 14 dwg, 8 ex

 

The technical field to which the invention relates

The present invention relates to new crystalline forms tetomilast.

The level of technology

2-(3,4-Dioxyphenyl)-4-(2-carboxy-6-pyridyl)thiazole (or 6-[2-(3,4-dioxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid) is a known compound. This connection is called "tetomilast". Tetomilast has inhibiting active oxygen effect, inhibiting the production of cytokines effect, inhibiting the adhesion effect and so on, and it is suitable for the treatment of ulcerative colitis, Crohn's disease, asthma and the like (JP-A-5-51318 (paragraph [0015], example 371) and JP-A-10-152437 (paragraphs [0024] and [0029]). In addition, tetomilast also suitable as a therapeutic agent for chronic obstructive pulmonary disease (JP-A-2003-104890). In addition, this crystal form tetomilast is stable when heated and under the action of moisture and has excellent properties from the point of view of the ability of tablets to deinterlace and dissolution.

In accordance with example 371 JP-A-5-51318 crystalline form of anhydrous tetomilast (hereinafter, referred to as "crystalline form type In anhydrous tetomilast") are obtained by reacting 3,4-deoxyribozyme with 2-(2-chloroacetyl)-6-pyridineboronic acid and then by precrystallizer the resulting crude tetomilast, for example, from ethanol.

In addition, according to Journal of Medicinal Chemistry, 1995, 38, SS. 353-358, such crystalline form type In anhydrous tetomilast produced by the interaction of 3,4-deoxyribozyme with 2-(2-bromoacetyl)-6-pyridineboronic acid followed by hydrolysis of the obtained methyl ester methyl-6-[2-(3,4-dioxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid and recrystallization of the obtained crude tetomilast of ethyl acetate.

However, since the crystalline form of type In tetomilast tends to form clumps, if such crystalline form type In anhydrous tetomilast receive by way of ordinary recrystallization, the process performance is significantly deteriorated during the filtration. Thus, it is difficult to obtain in industrial scale crystalline form type In anhydrous tetomilast. It is therefore very desirable is getting a new crystalline form tetomilast, which is advantageous from the point of view of production on an industrial scale.

Disclosure of invention

The main purpose of the present invention to provide a new crystalline form tetomilast that can be obtained in large volumes on an industrial scale.

The authors of the present invention conducted intensive research aimed at to the achieving the above goals. The authors of this invention have found that a new crystalline form tetomilast, which can be obtained in large volumes on an industrial scale, can be obtained by mixing the crystalline forms of the type In anhydrous tetomilast in an aqueous solvent, and that the above crystalline form tetomilast then recrystallized using a suitable solvent, or further heated under suspendirovanie in the specific solvent to obtain crystalline form tetomilast having different physical properties. The present invention is made on the basis of these received data.

That is, the present invention relates to the following crystalline form tetomilast and pharmaceutical compositions:

1. Crystalline form, hydrate, tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, presented in figure 2.

2. Crystalline form of type And anhydrous tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, presented in figure 4.

3. Crystalline form type With anhydrous tetomilast having diffraction spectrum of inthenews is their rays powder, which, essentially, is the same as the spectrum of x-ray diffraction powder presented on Fig.

4. Crystalline form of the combined acetonitrile MES tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, presented in Figure 10.

5. The mixture of crystalline form type And anhydrous tetomilast described in claim 2, and crystalline forms of the type In anhydrous tetomilast.

6. Pharmaceutical composition comprising at least one type of crystalline form tetomilast selected from the group consisting of kristallicheskoi form hydrate tetomilast, crystalline form type And anhydrous tetomilast, crystalline form type With anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast.

7. The pharmaceutical composition according to claim 6, which is a tool for the prevention and/or treatment of ulcers of the gastrointestinal tract, the means for the prevention and/or treatment of ischemic heart disease, an agent for preventing and/or treating a cerebrovascular disease, a means to improve the function of liver and kidneys, the tool used in the case of damage caused by transplantation, failure of microcirculation and so on, or the proceeds of the m for the prevention and/or treatment of diseases behceta, cutaneous vasculitis, ulcerative colitis, malignant rheumatoid arthritis, arthritis, atherosclerosis, or diabetes.

8. The pharmaceutical composition according to claim 6, which is a tool for the prevention and/or treatment of chronic rheumatoid arthritis, endotoxic shock, respiratory distress syndrome in adults (ARDS), thermal burn, asthma, chronic heart failure, myocardial infarction, viral myocarditis, or a means for preventing and/or treating ischemic reperfusion disorders, transition state from SIRS (systemic inflammatory syndrome response to damage to the body, multiple lesions of organs, inflammatory intestinal diseases, autoimmune diseases, metastasis, immune rejection that occur during transplantation, monoclonal b-cell abnormalities, polyclonal B-cellular anomalies, trialno Mikami, syndrome Castleman, primary glomerulonephritis, mesangial proliferative nephritis, cachexia in cancer, lymphoma, Lennert, psoriasis, atopic dermatitis, Kaposi's sarcoma, which develops as a result of AIDS, postmenopausal osteoporosis, sepsis, inflammatory diseases or chronic obstructive pulmonary disease.

9. The pharmaceutical composition of claim 8, where inflammation is an intestinal disease is ulcerative colitis or Crohn's disease.

10. The pharmaceutical composition of claim 8, the means for preventing and/or treating a chronic obstructive lung disease.

11. A method of obtaining a hydrate tetomilast, characterized in that it comprises mixing a crystalline form type In anhydrous tetomilast in aqueous solvent.

12. A method of obtaining a crystalline form of the type a waterless tetomilast, characterized in that it comprises recrystallization from a solution obtained by dissolving crystalline form type In anhydrous tetomilast in the solvent.

13. The method according to item 12, where the solvent is ethanol, acetone or a mixture of acetone-water (where the acetone is 40% or more).

14. A method of obtaining a crystalline form of the type a waterless tetomilast, characterized in that it comprises recrystallization from a solution obtained by dissolving in a solvent, at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type With anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast.

15. The method according to 14, where the solvent is a mixed solvent consisting of water and at least one organic solvent selected from the group, with the standing of methanol, ethanol, acetone and tetrahydrofuran.

16. A method of obtaining a crystalline form of the type With anhydrous tetomilast, characterized in that it comprises recrystallization from a solution obtained by dissolving crystalline form type In anhydrous tetomilast in the solvent.

17. The method according to clause 16, where the solvent is methanol or ethanol.

18. A method of obtaining a crystalline form of the type With anhydrous tetomilast, characterized in that it comprises recrystallization from a solution obtained by dissolving in a solvent, at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast.

19. The way of getting p, where the solvent is methanol or ethanol.

20. A method of obtaining a crystalline form of the combined acetonitrile MES tetomilast, characterized in that it comprises recrystallization from a solution obtained by dissolving crystalline form type In anhydrous tetomilast in acetonitrile.

21. A method of obtaining a crystalline form of the combined acetonitrile MES tetomilast, characterized in that it comprises recrystallization from a solution obtained by restorani is in the solvent, at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast and crystalline forms of the type With anhydrous tetomilast.

22. The method of obtaining a mixture comprising the crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, characterized in that it comprises recrystallization from a solution obtained by dissolving crystalline form type In anhydrous tetomilast in the solvent.

23. The method according to item 22, where the solvent is a mixture of acetone-water (where the acetone is 40-95% by volume).

24. The method of obtaining a mixture comprising the crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, characterized in that it comprises recrystallization from a solution obtained by dissolving in a solvent, at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast, crystalline form of the combined acetonitrile MES tetomilast and crystalline forms of the type With anhydrous tetomilast.

25. The method according to paragraph 24, where the two solvent which is a mixture of acetone-water (where the acetone is 40-95% by volume).

According to the present invention, the term "new crystalline form tetomilast" is used to denote a crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast, crystalline form type With anhydrous tetomilast, crystalline form of the combined acetonitrile MES tetomilast and a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast.

In addition, according to the present invention, the term "crystalline form tetomilast" used for the simple designation of common names in the case of such new crystalline forms tetomilast and crystalline forms of the type In anhydrous tetomilast, which is known crystalline form tetomilast.

Brief description of drawings

Figure 1 shows thermogravimetric/differential thermal analysis of crystalline form, hydrate, tetomilast obtained in example 5 (1).

Figure 2 presents the x-ray diffraction powder crystalline form, hydrate, tetomilast obtained in example 5 (1).

3 shows thermogravimetric/differential thermal analysis of crystalline form of the type a waterless tetomilast obtained in example 1 (1).

4 shows x-ray diffraction is led ray powder crystal form type And anhydrous tetomilast, obtained in example 1 (1);

Figure 5 presents thermogravimetric/differential thermal analysis of crystalline form of the type In anhydrous tetomilast obtained in reference example 1 (2)

Figure 6 presents the x-ray diffraction powder crystalline form type In anhydrous tetomilast obtained in reference example 1 (2)

Figure 7 presents thermogravimetric/differential thermal analysis of crystalline form of the type With anhydrous tetomilast obtained in example 2

On Fig presents the x-ray diffraction powder crystalline form type With anhydrous tetomilast obtained in example 2

Figure 9 presents thermogravimetric/differential thermal analysis of crystalline form of the combined acetonitrile MES tetomilast obtained in example 3;

Figure 10 presents the x-ray diffraction powder crystalline form of the combined acetonitrile MES tetomilast obtained in example 3.

Figure 11 presents thermogravimetric/differential thermal analysis of a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast obtained in example 4 (1);

On Fig presents the x-ray diffraction powder mixture consisting of KRI is a metallic form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, obtained in example 4 (1).

On Fig presents thermogravimetric/differential thermal analysis of a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast obtained in example 4 (2).

On Fig presents the x-ray diffraction powder mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast obtained in example 4 (2).

The best option is the implementation of the present invention

Crystalline form, hydrate, tetomilast

Crystalline form, hydrate, tetomilast according to the present invention includes crystalline with the number of water molecules from 0.5 to 3. The crystalline tetomilast according to the present invention, crystalline form of the monohydrate has physico-chemical properties that are described in paras. (1)to(3)below:

(1) the Crystalline form of the monohydrate has an endothermic curve which essentially is the same as the endothermic curve of thermogravimetric/differential thermal analysis (rate of temperature rise/min), presented in figure 1. In particular, this crystalline form of the monohydrate is characterized by the fact that it has an endothermic peak priblizitel is but at a temperature of 189°C and broadened peak approximately at a temperature of 102°C.

(2) the Crystalline form of the monohydrate has a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, presented in figure 2. In particular, it has characteristic peaks at an angle 2θ= 10,6°, 12,9°, 21,1°, 22,3° and 25.0°.

(3) the Crystalline form of the monohydrate has stripes significant absorption in the infrared region at a wavelength of 3516, 3433, 1742, 1709, 1587, 1472, 1267, 1143, 1040, 758 and 716 cm-1according to its IR-spectrum (KBr).

A method of obtaining a crystalline form of a hydrate tetomilast

Crystalline form, hydrate, tetomilast according to the present invention can be obtained by mixing in an aqueous solvent known crystalline form of the type In anhydrous tetomilast or crystalline form of the type In anhydrous tetomilast obtained by the method described below.

Such aqueous solvent is a mixed solvent obtained by mixing an organic solvent, such as methanol, ethanol, isopropanol, acetone or ethylmethylketone, with water. Examples of such mixed solvent may include a mixture of methanol-water (methanol content is 10-80% by volume), a mixture of ethanol-water (ethanol content is 10-70% by volume), a mixture of isopropanol-water (the content of isopropanol is 10-60% on on the jemu), a mixture of acetone-water (the content of acetone is 10-80% by volume) and the mixture ethylmethylketone-water (the content of ethylmethylketone is 10-80% by volume). Of them a mixture of acetone-water (the content of acetone is 10-60% by volume) and the mixture ethylmethylketone-water (the content of ethylmethylketone is 10-60% by volume) are particularly preferred. A mixture of acetone-water (the content of acetone is 35-55% by volume is preferred.

The amount of aqueous solvent is not limited. It is used in the amount of at least 10 ml and preferably 10 to 50 ml per 1 g of the crystalline forms of the type In anhydrous tetomilast.

The temperature of mixing is not particularly limited. Preferably it is in the range of about 10-35°C. and more preferably in the range of about 20-30°C. the mixing Time is preferably approximately from 5 minutes to 3 hours and more preferably about 30-90 minutes.

In addition, when a crystalline form of a hydrate tetomilast obtained from crystalline form type In anhydrous tetomilast, preferably, crystalline form, hydrate, tetomilast, separately obtained in the above manner, was present as the seed crystals in suspension.

Add zadravec what's crystals is not particularly limited. Preferably the addition of the seed crystals before mixing or during mixing.

The obtained crystalline form, hydrate, tetomilast can be distinguished by the methods of separation, such as filtration, concentration or extraction. In addition, after highlighting the selected crystalline form can be processed by drying a known manner. Moreover, the crystalline form can be cleaned by known purification method.

The thus obtained crystalline form, hydrate, tetomilast has purity equal to 95% or more, and it can be cut using conventional crusher (for example, a mill for fine grinding). Thus, it is possible to get crushed tetomilast having an average particle size equal to 10-50 μm, and 90% of all particles which have a size equal to 80 μm or less, suitable for the preparation of medicines.

Crystalline form of type In anhydrous tetomilast

Crystalline form of type In anhydrous tetomilast has physico-chemical properties that are described in paras. (4)to(6)below:

(4) the Crystalline form of type In anhydrous tetomilast has an endothermic curve which essentially is the same as the endothermic curve of thermogravimetric/differential thermal analysis (speed increase rate is the atmospheric temperature/min), presented in Figure 5. In particular, such a crystalline form of type In anhydrous tetomilast characterized by the fact that she has endothermic peaks approximately at a temperature of 177°C and approximately at a temperature of 188°C.

(5) the Crystalline form of type In anhydrous tetomilast has a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder presented on Fig.6. In particular, it has characteristic peaks at an angle 2θ= 4,1°, 8,1°, 11,9°, 16,1° and 24.2°.

(6) the Crystalline form of type In anhydrous tetomilast has stripes significant absorption in the infrared region at a wavelength of 3298, 3090, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 762 and 706 cm-1according to its IR-spectrum (KBr).

Crystalline form type In anhydrous tetomilast can be obtained by the method described in JP-A-5-51318 or in the Journal of Medicinal Chemistry, 1995, 38, pp. 353-358.

In addition, the crystal form of type In anhydrous tetomilast can be obtained by complete dissolution of the new crystalline form tetomilast in the solvent with stirring and heated to boiling point with the return of phlegmy followed by cooling the resulting solution. While this new crystalline form tetomilast can be used alone or as a mixture of two and more types.

Examples of the solvent may include isopropanol, ethyl acetate and obtained from them a mixed solvent.

The amount used of the solvent is not particularly limited as long until it is able to completely dissolve the new crystalline form tetomilast, with stirring and heated to boiling point with the return of phlegmy. If isopropanol is used, the amount is preferably 70-600 ml per 1 g of the new crystalline form tetomilast. In the case of ethyl acetate, it is preferably 30-300 ml per 1 g of the new crystalline form tetomilast. When using a mixed solvent consisting of isopropanol and ethyl acetate, isopropanol is mixed with ethyl acetate in any given ratio and the number of used mixed solvent can be adjusted in order to completely dissolve the new crystalline form tetomilast, with stirring and heated to boiling point with the return of phlegmy.

The resulting solution was cooled to a temperature of approximately 30°C for from about 5 minutes to 1 hour or cooled naturally in order to obtain the crystalline form type In anhydrous tetomilast. Then after the suspension was left to cool, it may be a cooling gap is s to a temperature of 10°C or below and preferably to a temperature of about 0-10°C. By this operation, the crystal form of type In anhydrous tetomilast get high output.

Moreover, such a crystal form of type In anhydrous tetomilast also produced by the impact of primary connections on the new crystalline form tetomilast to form salts by dissolving salts in a suitable aqueous solvent, and then by adding a suitable acid to obtain a solution.

Examples of the basic compound may include a carbonate, a hydroxide of alkali metal and alkali earth metal hydroxide. Of these, the alkali metal hydroxide is especially preferred. Examples of the carbonate may include sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. Examples of the hydroxide of the alkali metal may include sodium hydroxide and potassium hydroxide. Examples of the hydroxide of the alkali earth metal may include calcium hydroxide, barium hydroxide and magnesium hydroxide. These compounds are used individually or as a mixture of two or more types. Of them are potassium hydroxide and sodium hydroxide are particularly preferred.

Add the amount of basic compound is not particularly limited. It is usually 1 EQ. or more, preferably about 1-1,5 EQ., per 1 EQ. processed new Krista is symbolic forms tetomilast.

Examples of the above acid may include inorganic acids such as hydrochloric acid, sulfuric acid and Hydrobromic acid.

The added amount of acid is usually 1 EQ. (the number for neutralization) or more, preferably about 1-1,5 EQ., in the calculation described above is used osnovnoe connection.

Examples of the aqueous solvent used in this context may include, as described above in the case of the method of obtaining crystalline form, hydrate, tetomilast. Amongst a mixture of acetone-water (the content of acetone is 30-70% by volume is particularly preferred.

The amount of aqueous solvent is not limited. It is 5 ml or more, preferably 5 are 300 ml, and more preferably 30-70 ml, per 1 g of the new crystalline form tetomilast.

The temperature of the solution is preferably 10 to 30°C during the addition of acid.

The solution turned into a slurry by adding acid. Thus, such a suspension is cooled typically to a temperature of 10°C or below and preferably to a temperature in the range from 0°C to 10°C, in order to effectively extract the crystalline form type In anhydrous tetomilast.

In addition, these methods are used to crystalline forms of ti is In anhydrous tetomilast with the to obtain the crystalline form of the type In anhydrous tetomilast with high purity.

Crystalline form of type And anhydrous tetomilast

Crystalline form of type And anhydrous tetomilast has physico-chemical properties that are described in paras. (7)-(9)below:

(7) the Crystalline form of type And anhydrous tetomilast has an endothermic curve which essentially is the same as the endothermic curve of thermogravimetric/differential thermal analysis (rate of temperature rise/min)shown in Figure 3. In particular, such a crystalline form of type And anhydrous tetomilast characterized by the fact that it has an endothermic peak approximately at a temperature of 188°C.

(8) the Crystalline form of type And anhydrous tetomilast has a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, presented in figure 4. In particular, it has characteristic peaks at an angle 2θ= 10,5°, 13,1°, 18,4°, 21,9° and 25.8°.

(9) Crystal form of type And anhydrous tetomilast has stripes significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 cm-1according to its IR-spectrum (KBr).

A method of obtaining a crystalline form of the type a waterless etomidate

Crystalline form type And anhydrous tetomilast can be obtained by recrystallization from a solution obtained by dissolving a known crystalline form of the type In anhydrous tetomilast or crystalline form of the type In anhydrous tetomilast obtained in the above manner, when using a suitable solvent.

Examples of the above solvent, which can be used according to the context, may include ethanol, acetone and a mixture of acetone-water (the content of acetone is 40% or more by volume). Of them a mixture of acetone-water (the content of acetone is 40% or more by volume) is particularly preferred.

The amount used of the solvent is not particularly limited as long until it is able to completely dissolve the crystalline form of type In anhydrous tetomilast under stirring and heated to boiling point with the return of phlegmy. In the case of ethanol, the amount used is preferably 70-400 ml per 1 g of the crystalline forms of the type In anhydrous tetomilast. In the case of acetone, it is preferably 30-120 ml per 1 g of the above crystalline forms of the type In anhydrous tetomilast. In the case of a mixture of acetone-water (the content of acetone is 40-80% by volume) it predpochtite the flax is 30-500 ml per 1 g of the above crystalline forms of the type In anhydrous tetomilast.

This crystalline form type In anhydrous tetomilast preferably dissolved in the solvent with stirring and heated to boiling point with the return of phlegmy. The temperature of heating is not limited. Usually it is approximately 40-85°C and preferably about 55-80°C.

After such dissolution temperature of the resulting solution is lowered, so that could yet to crystallize the crystalline form of type And anhydrous tetomilast according to the present invention.

The speed of lowering the temperature is not particularly limited. When ethanol is used as solvent, for example, the rate of temperature drop is preferably of 0.8°C/min or less. In addition, when a mixture of acetone-water (the content of acetone is 40% or more by volume) is used as solvent, the rate of temperature drop is preferably of 0.4°C/min or less. By regulating the speed of lowering the temperature within such a range, the crystal form of type And anhydrous tetomilast according to the present invention can be obtained with greater efficiency.

When a mixture of acetone-water (the content of acetone is 40% or more by volume) is used as a solvent, the above solution can withstand pritemperature in the range from 40°C to 50°C for 60 minutes or more, and then it is cooled so that could yet to crystallize the crystalline form of type And anhydrous tetomilast. The rate of temperature decrease during the above cooling should not particularly influence the crystallization of the crystalline forms of the type And anhydrous tetomilast.

In addition, during such lowering of the temperature, while the temperature is maintained within specific temperature ranges, such as from 40°C to 50°C from 30°C to 40°C from 15°C to 25°C or 0°C to 10°C, the solution is stirred for from about 30 minutes to 5 hours so that the temperature can be lowered stepwise. This step-by-step method of lowering the temperature at a temperature from 40°C to 50°C, as the seed crystals can be added crystalline form type And anhydrous tetomilast, which is obtained separately.

In addition, such a crystal form of type And tetomilast receive using a new crystalline form tetomilast (excluding crystalline form type And anhydrous tetomilast) instead of the known crystalline form of the type In anhydrous tetomilast and precrystallization from a solution obtained by dissolving the above-mentioned new crystalline forms tetomilast in a suitable solvent.

In particular, crystalline form type And anhydrous tetomilast get the by recrystallization from a solution, obtained by dissolving in a solvent, at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type With anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast.

Under this context, a new crystalline form tetomilast used individually or as mixtures comprising two or more types.

This crystalline form type And tetomilast also can be obtained by suspension of the known crystalline form of the type In anhydrous tetomilast or new crystalline forms tetomilast (excluding crystalline form type And anhydrous tetomilast) in an aqueous solvent (water content is 90% or less by volume) and then stirring the suspension.

Examples of the aqueous solvent, which can be used according to the context, may include mixed solvents obtained by mixing an organic solvent having high compatibility with water, such as methanol, ethanol, acetone or tetrahydrofuran with water.

In particular, an aqueous solvent, which can be used as a mixed solvent composed of water and at least one organic solvent, wybir the constituent from the group consisting of methanol, ethanol, acetone and tetrahydrofuran. In particular, a mixture of acetone-water (the content of acetone is 30-60% by volume) is preferred as the aqueous solvent.

The temperature of the suspension is not particularly limited during mixing. It is usually from 0°C to 65°C and preferably from 10°C. to 60°C.

Mixing time is usually from 10 minutes to 48 hours and preferably from 10 minutes to 3 hours.

In addition, these methods are used in the case of crystalline forms such As anhydrous tetomilast in order to obtain the crystalline form of the type a waterless tetomilast with high purity.

The obtained crystalline form type And anhydrous tetomilast you can select it using separation methods such as filtration, concentration or extraction. In addition, after highlighting the selected crystalline form can be processed by drying a known manner. Moreover, the crystalline form can be cleaned by known purification method.

The thus obtained crystalline form of type And anhydrous tetomilast has purity equal to 95% or more, and it can be cut using conventional crusher (for example, a mill for fine grinding). Thus, it is possible to get crushed tetomilast with the size of h is CI, equal to 10-50 μm, and 90% of all particles which have a size equal to 80 μm or less, suitable for the preparation of medicines.

Crystalline form type With anhydrous tetomilast

Crystalline form type With anhydrous tetomilast has physico-chemical properties that are described in paras. (10)-(12)below:

(10) Crystal form type With anhydrous tetomilast has an endothermic curve which essentially is the same as the endothermic curve of thermogravimetric/differential thermal analysis (rate of temperature rise/min)presented on Fig.7. In particular, this crystalline form type With anhydrous tetomilast characterized by the fact that she has endothermic peaks approximately at a temperature of 184°C and approximately at a temperature of 189°C.

(11) Crystal form type With anhydrous tetomilast has a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder presented on Fig. In particular, it has characteristic peaks at an angle 2θ= 4,2°, 8,2°, 12,0°, 16,4°, 24,7° and 25.9°.

(12) Crystal form type With anhydrous tetomilast has stripes significant absorption in the infrared region at a wavelength of 3300, 3088, 1744, 1593, 1476, 1346, 1267, 1132, 1045, 754 and 704 cm-1coz the ACLs of its IR-spectrum (KBr).

A method of obtaining a crystalline form of the type With anhydrous tetomilast

Crystalline form type With anhydrous tetomilast can be obtained by recrystallization from a solution obtained by dissolving a known crystalline form of the type In anhydrous tetomilast or crystalline form of the type In anhydrous tetomilast obtained in the above manner, when using a suitable solvent.

Examples of such a solvent, which can be used according to the context, may include methanol and ethanol. Of these, methanol is particularly preferred.

The amount used of the solvent is not particularly limited as long until it is able to completely dissolve the above crystalline form of type In anhydrous tetomilast, with constant stirring and heated to boiling point with the return of phlegmy. The amount used of the solvent is preferably 70-200 ml and more preferably is about 80-120 ml per 1 g of the above crystalline forms of the type In anhydrous tetomilast.

After such dissolution temperature of the resulting solution is reduced to a temperature in the range from 10°C to 30°C, so that could yet to crystallize the crystalline form type With anhydrous tetomilast. RMSE is the General lowering of the temperature is not particularly limited, when the solvent is methanol. It can be about 0.4°C/min 0.6°C/min, When ethanol is used as solvent, the resulting solution can be easily cooled with the rate of temperature decrease, component 5°C/min or more and preferably 10°C./min or more. By regulating the speed of lowering the temperature within such a range, the crystal form of type With anhydrous tetomilast according to the present invention can be obtained with greater efficiency.

In addition such crystalline form type With anhydrous tetomilast obtained by recrystallization from a solution obtained by dissolving in a suitable solvent of a new crystalline form tetomilast (excluding crystalline form type With anhydrous tetomilast), which is used instead of the known crystalline form of the type In anhydrous tetomilast.

In particular, the known crystalline form type In anhydrous tetomilast first added to methanol and then dissolved therein with stirring and heated to boiling point with the return of phlegmy. The resulting solution was allowed to cool to a temperature of approximately 30°C for from about 40 minutes to 1 hour. After that obtained by the above-mentioned cooling, the suspension is cooled to a temperature of 10°C iliniza, preferably to a temperature of about 0-10°C., for from 30 minutes to 3 hours, so you get a crystal form of type With anhydrous tetomilast according to the present invention.

In particular, crystalline form type With anhydrous tetomilast obtained by recrystallization from a solution obtained by dissolving in a solvent, at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast. Under this context, a new crystalline form tetomilast used individually or as mixtures comprising two or more types. The solvent and recrystallization, used in this context, equivalent to those in the case of using the above-mentioned known crystalline form of the type In anhydrous tetomilast as the original substance.

In addition, the above method is used in the case of crystalline form type With anhydrous tetomilast in order to obtain the crystalline form type With anhydrous tetomilast with high purity.

The obtained crystalline form type With anhydrous tetomilast you can select the ri using the methods of selection, such as filtration, concentration or extraction. In addition, after highlighting the selected crystalline form can be processed by drying a known manner. Moreover, the crystalline form can be cleaned by known purification method.

The thus obtained crystalline form type With anhydrous tetomilast has purity equal to 95% or more, and it can be cut using conventional crusher (for example, a mill for fine grinding). Thus, it is possible to get crushed tetomilast having a particle size equal to 10-50 μm, and 90% of all particles which have a size equal to 80 μm or less, suitable for the preparation of medicines.

The crystalline form of the combined acetonitrile MES tetomilast

The crystalline form of the combined acetonitrile MES tetomilast has physico-chemical properties that are described in paras. (13)-(15)below:

(13) the Crystalline form of the combined acetonitrile MES tetomilast has an endothermic curve which essentially is the same as the endothermic curve of thermogravimetric/differential thermal analysis (rate of temperature rise/min)presented on Fig.9. In particular, this crystalline form of the combined acetonitrile MES tetomilast characterized by the fact that it has an endothermic PI and approximately at a temperature of 91°C, approximately at the temperature of 176°C and approximately at a temperature of 189°C.

(14) the Crystalline form of the combined acetonitrile MES tetomilast has a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, presented in Figure 10. In particular, it has characteristic peaks at an angle 2θ= 3,6°, 7,1°, 10,6°, 14,2° and 24.8°.

(15) the Crystalline form of the combined acetonitrile MES tetomilast has stripes significant absorption in the infrared region at a wavelength of 3300, 3090, 2249 (nitrile group), 1744, 1593, 1476, 1346, 1269, 1132, 1045, 752 and 704 cm-1according to its IR-spectrum (KBr).

A method of obtaining a crystalline form of the combined acetonitrile MES tetomilast

Crystalline form combined acetonitrile MES tetomilast can be obtained by recrystallization from a solution obtained by dissolving in acetonitrile known crystalline form of the type In anhydrous tetomilast or crystalline form of the type In anhydrous tetomilast obtained by the above method.

The amount of acetonitrile is not particularly limited as long until it is able to completely dissolve the above crystalline form of type In anhydrous tetomilast, with stirring and heating until the temperature is boiling with the return of phlegmy. The amount of acetonitrile is preferably 70-150 ml, more preferably is 70 to 100 ml, per 1 g of the above crystalline forms of the type In anhydrous tetomilast.

The above crystalline form type In anhydrous tetomilast can be dissolved in acetonitrile, for example, under stirring and heated to boiling point with the return of phlegmy. After such dissolution temperature of the solution in which the dissolved crystalline form type In anhydrous tetomilast, is lowered, so that could yet to crystallize the crystalline form of the combined acetonitrile MES tetomilast according to the present invention. The speed of lowering the temperature is not particularly limited, and it may be from approximately 0.1°C/min up to 1.5°C/min To a crystal form of the combined acetonitrile MES tetomilast according to the present invention, in particular, does not affect this rate of temperature decrease, and this form may preferably be obtained.

In particular, the known crystalline form type In anhydrous tetomilast added to the acetonitrile and then it is dissolved therein with stirring and heated to boiling point with the return of phlegmy. The resulting solution was allowed to cool to a temperature of approximately 30°C for from about the olo 30 minutes to 8 hours. After that, the suspension obtained by the above-mentioned cooling, cooled to a temperature of 10°C or below, preferably to a temperature of about 0-10°C. for a time from 30 minutes to 3 hours, to obtain a crystalline form of the combined acetonitrile MES tetomilast according to the present invention.

In addition, such a crystalline form of the combined acetonitrile MES tetomilast obtained by recrystallization from a solution obtained by dissolving in acetonitrile a new crystalline form tetomilast (excluding crystalline form combined acetonitrile MES tetomilast), which is used instead of the known crystalline form of the type In anhydrous tetomilast.

In particular, the crystalline form of the combined acetonitrile MES tetomilast obtained by recrystallization from a solution obtained by dissolving in acetonitrile at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast and crystalline forms of the type With anhydrous tetomilast. Under this context, a new crystalline form tetomilast used individually or as mixtures comprising two or more types. The solvent and conditions the Oia recrystallization, used in this context, equivalent to those in the case of using the above-mentioned known crystalline form of the type In anhydrous tetomilast as the original substance.

In addition, the above method is used in the case of crystals combined acetonitrile MES tetomilast in order to obtain crystals combined acetonitrile MES tetomilast with high purity.

The obtained crystalline form combined acetonitrile MES tetomilast can be identified in the use of separation methods such as filtration, concentration or extraction. In addition, after highlighting the selected crystalline form can be processed by drying a known manner. Next, the crystalline form can be cleaned by known purification method.

Thus, the obtained crystalline form of the combined acetonitrile MES tetomilast has purity equal to 95% or more, and it can be cut using conventional crusher (for example, a mill for fine grinding). Thus, it is possible to get crushed tetomilast having a particle size equal to 10-50 μm, and 90% of all particles which have a size equal to 80 μm or less, suitable for the preparation of medicines.

The mixture of crystalline form type And anhydrous tetomilast and crystalline fo what we type In anhydrous tetomilast

As a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast receive a mixture of different types of relationships depending on the conditions of reception. As an example, can be obtained mixture having physico-chemical properties that are described in paras. (16)-(18)below:

(16) Level endothermic peak depends on the ratio in the mixture of crystalline form a and crystalline form of type C. figure 11 presents the endothermic peak of the sample with the ratio of components in the mixture a:B = 40:60. The mixture of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast has an endothermic curve which essentially is the same as the endothermic curve of thermogravimetric/differential thermal analysis (rate of temperature rise/min), presented at the 11. In particular, this mixture is characterized by the fact that she has endothermic peaks approximately at a temperature of 175°C and approximately at a temperature of 189°C.

(17) the Spectrum of x-ray diffraction powder mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, represents the sum of the diffraction spectrum of the rent is anowski ray powder pure crystalline form type And anhydrous tetomilast spectrum and x-ray diffraction powder pure crystalline form type In anhydrous tetomilast. The peak intensity derived from each crystal form, is affected by the ratio in the mixture of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast. On Fig presents a range of x-ray diffraction powder pattern having a mixing ratio of the crystalline form of type And anhydrous tetomilast: crystalline form of type In anhydrous tetomilast = 40:60.

(18) a Sample having a ratio in the mixture of crystalline form type And anhydrous tetomilast: crystalline form of type In anhydrous tetomilast = 40:60, has stripes significant absorption in the infrared region at a wavelength of 3298, 3088, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 760 and 704 cm-1according to its IR-spectrum (KBr). In addition, the deviation of ±5 cm-1can be obtained in the case of a peak absorption due to differences in the ratio in the mixture of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast.

In addition, the sample with the ratio of components in the mixture a:B = 10:90, has physico-chemical properties that are described in paras. (19)-(21)below:

(19) the Sample has an endothermic curve which essentially is the same as the endothermic curve of thermogravimetric/differential thermal analysis (rate of decrease of temperature the/min), presented at Fig. In particular, this sample is characterized by the fact that he has endothermic peaks approximately at a temperature of 176°C and approximately at a temperature of 189°C.

(20) the Sample has a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder presented on Fig. In particular, it has characteristic peaks at an angle 2θ= 4,1°, 11,9°, 16,1°, 17,2°, 19,3°, 24,2°, 25,1°, 25,9° and 27.3°.

(21) the Sample has stripes significant absorption in the infrared region at a wavelength of 3298, 3090, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 756 and 706 cm-1according to its IR-spectrum (KBr).

The method of obtaining a mixture comprising the crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast

The mixture of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, can be obtained by recrystallization from a solution obtained by dissolving in a suitable solvent known crystalline form of the type In anhydrous tetomilast or crystalline form of the type In anhydrous tetomilast obtained by the above method.

Type the above solvent is not particularly limited. A mixture of acetone-water (the content of acetone SOS is to place 40-95%, by volume) is preferred.

The amount of the above solvent is not particularly limited as long until it is able to completely dissolve the above crystalline form tetomilast, with stirring and heated to boiling point with the return of phlegmy. The amount used of the solvent is preferably 30-160 ml, more preferably 30-50 ml per 1 g of the above crystalline forms of the type In anhydrous tetomilast.

The above crystalline form tetomilast can be dissolved in the above solvent, for example, under stirring and heated to boiling point with the return of phlegmy. After such dissolution temperature of the solution in which the dissolved crystalline form type In anhydrous tetomilast, is lowered, so that it was possible to obtain a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast according to the present invention. The speed of lowering the temperature may be from about 0.4°C/min up to 1.9°C/min, In particular, the speed of lowering the temperature is adjusted to control the ratio of components in a mixture consisting of crystalline form type And anhydrous tetomilast and to istoricheskoi form type In anhydrous tetomilast according to the present invention.

In particular, crystalline form type In anhydrous tetomilast first added to a mixture of acetone-water (the content of acetone is 40-95% by volume) and then dissolved therein with stirring and heated to boiling point with the return of phlegmy (approximately 60°). The resulting solution was allowed to cool to a temperature of approximately 30°C for a time from about 15 minutes to 1 hour. After that, the suspension obtained by the above-mentioned cooling, cooled to a temperature of 10°C or below, and preferably to a temperature of about 0-10°C. for a time from 30 minutes to 3 hours, to obtain a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast according to the present invention. When the solution obtained after stirring under heating to boiling point with the return of phlegmy, cooled rapidly (for example, the solution is cooled to a temperature of 10°C or below, preferably to a temperature of about 0-10°C. for a time from about 5 minutes to 1 hour), can be obtained mixture having a ratio of the crystalline form of type And anhydrous tetomilast: crystalline form of type In anhydrous tetomilast = ~ 10:90 (weight ratio).

The ratio of components in the mixture, ostoja crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, is not particularly limited.

In addition to the above, the mixture can also be obtained using a new crystalline form tetomilast (excluding a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast) instead of the known crystalline form of the type In anhydrous tetomilast. In particular, the above mixture is obtained by recrystallization from a solution obtained by dissolving in a solvent, at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast, crystalline form type With anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast.

The solvent and recrystallization applied in this context, equivalent to those in the case of using the above-mentioned known crystalline form of the type In anhydrous tetomilast as the original substance.

The resulting mixture, consisting of a crystalline form of the type a waterless tetomilast and crystalline forms of the type In anhydrous tetomilast, you can select it using separation methods such as filtration, concentration or extraction. In addition, after the shock the texts selected crystalline form can be processed by drying a known manner. In addition, the crystalline form can be cleaned by known purification method.

The thus obtained mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast has a purity (ratio of the content of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast to the General content), equal to 95% or more, and it can be cut using conventional crusher (for example, a mill for fine grinding). Thus, it is possible to get crushed tetomilast having a particle size equal to 10-50 μm, and 90% of all particles which have a size equal to 80 μm or less, suitable for the preparation of medicines.

The pharmaceutical composition

The pharmaceutical composition according to the present invention includes at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast, crystalline form type With anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast.

The pharmaceutical composition according to the present invention further includes a crystalline form type In anhydrous tetomilast. An example of this FA the pharmaceutical composition includes a mixture, consisting of a crystalline form of the type a waterless tetomilast and crystalline forms of the type In anhydrous tetomilast.

New crystal form tetomilast according to the present invention has activity against the suppression of the release of active oxygen species from neutrophils or eliminate particles of chemically active oxygen. Thus, the above new crystalline form tetomilast has the effect of preventing the formation of lipid peroxides in vivo or decrease the level of their education. Therefore, a new crystalline form tetomilast according to the present invention is suitable as a means for the prevention and/or treatment of various types of disorders or diseases that arise due to the above-mentioned excess formation of particles of reactive oxygen species, accumulation of lipid peroxides in vivo or violation of a protective mechanism due to these phenomena. More specifically, the tool comprising a pharmaceutical composition according to the present invention, usable in the pharmaceutical field as a means to protect various cell types of the tissue from ischemia and disorders associated with revascularization, such as means for the prevention and/or treatment of ulcers of the gastro-kiseon the th path, including stress ulcer; means for the prevention and/or treatment of ischemic heart diseases such as myocardial infarction or arrhythmia; means for the prevention and/or treatment of cerebrovascular diseases such as cerebral hemorrhage, cerebral infarction or transient ischemic attack; a means for improving the function of the liver and kidneys, the tool used in the event of irregularities caused by transplantation, failure of microcirculation and so on; or a means to suppress various types of cellular damage that can be caused by abnormal production of active oxygen due to causes other than myocardial ischemia, such as means for the prevention and/or treatment disease behceta, cutaneous vasculitis, ulcerative colitis, malignant rheumatoid arthritis, arthritis, atherosclerosis, or diabetes.

In addition, a new crystalline form tetomilast according to the present invention is effective against various types of diseases associated with abnormal production of cytokines, particularly abnormal production of TNF-α, IL-β, IL-6, IFN-γ, etc. or various types of diseases associated with acceleration of adhesive process. In particular, a new crystalline form tetomilast according to the present invention can preferably be used: as a means is to prevent and/or treat various diseases, such as chronic rheumatoid arthritis, endotoxic shock, ARDS caused by accidental ingestion of gastric juice, toxic gas; or sepsis, thermal burn, or asthma, or myocardial infarction, which is an ischemic condition of the infarction, viral myocarditis, such as the acute phase of viral myocarditis, chronic heart failure, such as ischemic micardis, spontaneous dilated cardiomyopathy and so on; and as a means for preventing and/or treating ischemic reperfusion disorders that occur during surgical intervention in case of coronary artery bypass (CABG) or during the use of heart-lung; transition state from SIRS (systemic inflammatory syndrome response to damage to the body (heavy stage of acute pancreatitis, DIC, etc) or multiple organ damage caused by the severe stage of acute pancreatitis; liver failure that occurs after hepatectomy with liver cancer, etc.; inflammatory intestinal diseases such as Crohn's disease, ulcerative colitis, etc.; number of autoimmune diseases, such as hypergammaglobulinemia, systemic lupus erythematosus (SLE) or multiple sclerosis; metastasis, immunological rejection occurring during the trance is santali, monoclonal b-cell abnormalities (myeloma etc), polyclonal b-cell abnormalities, trialno Mikami, syndrome Castleman, primary glomerulonephritis, mesangial proliferative nephritis, cachexia in cancer, lymphoma, Lennert, psoriasis, atopic dermatitis, Kaposi's sarcoma, which develops as a result of AIDS, postmenopausal osteoporosis, diabetes, sepsis, atherosclerosis, or inflammatory diseases such as vasculitis or hepatitis; or means for preventing and/or treating a chronic obstructive lung disease.

In particular, a new crystalline form tetomilast according to the present invention has effect in relation to mitigate symptoms associated with lung function, such as obstruction of the air flow, and it shows an extremely high therapeutic effect in chronic obstructive pulmonary disease.

Crystalline forms tetomilast according to the present invention can be used, at least with one component selected from the group consisting of:

1. inhibitors of leukotriene biosynthesis (an inhibitor of 5-lipoxygenase or antagonists activates 5-lipoxygenase protein (FLAP));

2. the receptor antagonists of leukotrienes LTB4, LTC4, LTD4 or LTE4;

3. the PDE4 inhibitors, including the Aya inhibitors of the isoform PDE4D;

4. inhibitors of 5-lipoxygenase and antagonists activates 5-lipoxygenase protein (FLAP);

5. dual inhibitors of 5-lipoxygenase and antagonists of platelet activating factor (PAF);

6. the leukotriene antagonists (LTRA), including those for LTB4, LTC4, LTD4, and LTE4;

7. antagonists antihistaminico H1-receptor;

8. antagonists H2-receptor;

9. agonists α1 - and α2-adrenergic receptors vasoconstrictor sympathomimetic agents, administered orally or topically for use as protivozastojnye funds;

10. agonists α1 - and α2-adrenergic receptors in combination with inhibitors of 5-lipoxygenase;

11. anticholinergic agents;

12. agonists β1 - β4-adrenergic receptors;

13. the methylxanthines;

14. cromoglicate sodium;

15. antagonists of muscarinic receptor (M1, M2 and M3);

16. NSAID (non-steroidal anti-inflammatory drugs), including inhibitors of MOR-1 selective inhibitors SOH-2 and nitric monoxide;

17. insulin-like growth factor-1 (IGF-1) and its mimetics;

18. ciclesonide;

19. glucocorticoids for inhalation (in case of reduced side effects);

20. inhibitors of tryptase;

21. antagonists thrombocytapheresis factor;

22. monoclonal antibodies active against endogenous inflammatory organisms;

23. IPL576;

24. agents necrosis factor SDA is Oli (TNF-α);

25. DMARDs (including Leflunomide);

26. TCR peptides;

27. inhibitors internacionalvecinoseu enzyme (ICE);

28. inhibitors of IMPDH;

29. inhibitors of adhesion molecules, including antagonists of VLA-4;

30. of cathepsins;

31. inhibitors MAR-kinase;

32. inhibitors of glucose-6-phosphate dehydrogenase;

33. antagonists of kinin-B1 - or kinin-B2-receptor;

34. gold in the form of eurotorp in combination with hydrophilic groups;

35. immunosuppressive agents;

36. anti-gout;

37. inhibitors of xanthine oxidase;

38. tools that promote uric acid excretion;

39. anticancer agents;

40. accelerators of growth hormone secretion;

41. inhibitors of MMP (matrix metalloprotease);

42. TGF-β (transforming growth factor);

43. PDGF (a growth factor derived from platelets);

44. the fibroblast growth factor (e.g., basic fibroblast growth factor: b-FGF);

45. factor, colony stimulating granulocytes and macrophages (GM-CSF);

46. capsaicinoid cream;

47. antagonists tachykinin NK1 and NK3 receptors;

48. inhibitors of elastase;

49. the PDE3 inhibitors;

50. antagonist H4-receptor or inverse agonists;

51. antioxidants;

52. catching radicals agents;

53. combinations of agonists β2-adrenergic receptors and glucocorticoids;

54. agents, increases the operating level of the protein in the case of hypoxia-induced factor-1α (HIF-1α);

55. antioxidant proteins controlled by HIF-1α;

56. amplifiers secretion of vascular endothelial growth factor (VEGF); and

57. agonist VEGF-receptor.

A new crystalline form tetomilast according to the present invention is usually used in the form of conventional pharmaceutical preparation. Such pharmaceutical drug get using commonly used diluents or excipients such as filler, extender, binder, wetting agent, disintegrity agent, surfactant or grease. In the event of such a pharmaceutical preparation of various types of forms can be selected depending on therapeutic purpose. A typical form of such a pharmaceutical preparation can include tablet, pill, powder, solution, suspension, emulsion, granule, capsule, suppository and injection (solution, suspension etc). When crystalline form tetomilast according to the present invention is compressed in a tablet form, it can be widely used in a variety of media types, which are previously known in this field. Examples of such media that can be used in this context may include: excipients such as lactose, sucrose, sodium chloride, grape sugar (glucose, urea, starch, calcium carbonate, kao is in, crystalline cellulose or silica; binders such as water, ethanol, propanol, regular syrup, dextrose in water, the starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, or polyvinylpyrrolidone; dezintegriruetsja agents, such as dry starch, sodium alginate, agar powder, laminarinases powder, sodium bicarbonate, calcium carbonate, polyoxyethylenesorbitan esters of fatty acids, sodium lauryl sulfate, monoglyceride, starch or lactose; disintegration inhibitors such as sucrose, stearin, cacao butter, or hydrogenated oil; causing absorption agents, such as Quaternary ammonium or sodium lauryl sulfate; a humectant, such as glycerin or starch; adsorbents such as starch, lactose, kaolin, bentonite or colloidal silica; and lubricants such as purified talc, stearate, boric acid powder or polyethylene glycol. This tablet can then be treated with obtaining tablets with normal for tablet coating, such as a tablet coated with a coating of sugar-coated gelatin tablet, tablet with intersolubility coated tablet film-coated tablet with a double coating and multi-layer tablet, if necessary. When crystallizes the second form tetomilast according to the present invention compressed into pill form can be widely used media that previously known in this field. Examples of such media that can be used in this context may include: excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin or talc; binders such as gum Arabic, powdered tragakant, gelatin or ethanol; and dezintegriruetsja agents, such as laminaran or agar. When crystalline form tetomilast according to the present invention is compressed in the form of a suppository, can be widely used media that previously known in this field. Examples of such media may include polyethylene glycol, cacao butter, higher alcohol esters of higher alcohols, gelatin and semi-synthetic glycerides. In the case of capsules which is the active ingredient compound is usually mixed with various types of media, as described above, in accordance with the General method, and the resulting mixture is then filled hard gelatin capsule, soft capsule, etc. When crystalline form tetomilast according to the present invention is in the form of injection, it is preferable that the liquid agent, emulsion and suspension were sterilized and were isotonic with blood. When the crystalline form according to the present invention finds the I in such form, you can use all types of diluents, which are usually used in this field. Examples of such diluents that can be used according to the context, include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polyethoxysiloxane isostearoyl alcohol and ethers of polyoxyethylenesorbitan and fatty acids. In this case, it is possible that common salt, glucose or glycerin can be mixed with a pharmaceutical preparation in a quantity sufficient to obtain isotonic. It is also possible that conventional solubilizer, buffer, soothing agent, or the like is added to the pharmaceutical preparation. Further, it is also possible that the dye, preservative, flavoring agent, agent for flavor, sweetener or other pharmaceutical agents is mixed with a pharmaceutical preparation, if necessary.

The number which is the active ingredient compounds contained in the above-mentioned pharmaceutical preparation is not particularly limited, and, therefore, choose from a wide range. Typically, the pharmaceutical preparation may contain about 1-70 wt.% such compounds as the active ingredient.

The method of introducing the above-mentioned pharmaceutical preparation is not particularly limited is echenim, and pharmaceutical drug is administered in a way that depends on different types of pharmaceutical forms, age, sex and other conditions of the patient, severity of disease, etc. for Example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, these pharmaceutical preparations are administered orally. In the case of injection, the drug is injected separately or as a mixture with conventional replacement environment, such as glucose or amino acid. Further, if necessary, such an injection is administered in the form of disposable, intramuscularly, intradermally, subcutaneously or administered intraperitoneally. The suppository is administered intrarectally.

The dosage of the above pharmaceutical drug is appropriately selected depending on the use, age, sex and other conditions of the patient, severity of disease, etc. Usually the number used as the active ingredient compounds may be defined as approximately 0.2 to 200 mg per kg of body weight per day.

As for the crystalline form, hydrate, tetomilast, crystalline form type And anhydrous tetomilast, crystalline form type With anhydrous tetomilast, crystalline form of the combined acetonitrile MES tetomilast and mixtures of the above crystalline form of the type a of anhydrous detail the one hundred and crystalline forms of the type In anhydrous tetomilast according to the present invention, these crystalline forms are easy to control by recrystallization, and these crystalline forms are excellent in terms of filterability. Thus, these crystalline forms suitable for industrial mass production.

In addition, these crystalline forms tetomilast possess a characteristic that is equivalent to or better than that, the crystalline forms of the type In anhydrous tetomilast in respect of stability under heating and under the influence of moisture and from the point of view of the ability of tablets to disintegration and dissolution. Accordingly, these crystalline forms tetomilast preferably can be used as pharmaceutical compositions.

EXAMPLES

The present invention is described in more detail in the following reference examples, examples and sample the finished dosage form.

Analytical method

(1) Thermogravimetric/differential thermal analysis

Thermogravimetric/differential thermal analysis carried out using a measuring instrument that includes both the controller TA60WS and device for thermogravimetric/differential thermal analysis DTG-60A manufactured by Shimadzu Corporation. In particular, using the above apparatus, 5-10 mg of sample heating is jut from 20°C (room temperature) up to 250°C with a rate of temperature rise of 5°C/min in an atmosphere of dried nitrogen. As the standard substance used α-alumina.

(2) the x-ray Diffraction powder

Range of x-ray diffraction powder obtained when the angle of diffraction, changing in the range from 3° to 40°, in accordance with the General method of testing according to the Pharmacopoeia of Japan, using diffractometer RAD-2B (radiation source: CuKα)manufactured by Rigaku Denki. During the measurement, the magnitude of the voltage/current is 35 kV/20 mA and the scanning speed is set to 5°C/min

The ratio of components in a mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, obtained by comparison of the spectrum of x-ray diffraction powder to the above mixture with the spectrum of x-ray diffraction powder mixture formed by mixing pure crystalline form type And anhydrous tetomilast and pure crystalline form type In anhydrous tetomilast in different ratios.

(3) Analysis by IR spectroscopy

The IR spectrum is removed by the method using KBr.

(4) Analysis by1H-NMR spectrometry

1H-NMR-spectrum shoot in DMSO-d6using tetramethylsilane was (TMS) as standard.

(5) Determination of purity

The purity determined using high-performance liquids is strong chromatography (HPLC). Terms definitions are as follows:

Sample: 0.03 g of sample is dissolved in 80 ml of acetonitrile and then to the solution was added 20 ml of water to obtain a sample solution. Determination carried out using 10 μl of the sample solution.

Detector: ultraviolet photometric detector (wavelength equal UV 254 nm).

Column: Wakosil 5C18 HG.

Mobile phase: acetonitrile/10 nm aqueous solution of Na2SO4/phosphoric acid(500:500:1).

(6) Determination of particle size

To determine particle size of 0.1 g of the measured particles are suspended in 20 ml n-hexane solution, which contains 0.2 g of 0.1 wt.%/about. polyoxyethylene(10)octylphenols simple ether, and then the resulting suspension is treated with ultrasound.

Then carry out the measurement using the apparatus to determine the distribution of particle sizes (Microtrac HRA; manufactured by a company Microtrac).

(7) Determination of moisture content

The amount of moisture contained in the sample, determined by Karl Fisher.

(8) Determination of the melting temperature (restated)

To determine the melting temperature, the sample is heated using the heating device (name: LK6000PM manufactured by Japan High Tech Co., Ltd.) assuming the speed of temperature increase of 5°C/min, and then the phase of melting observed using a microscope VH-7000C you usemy company Keyence Corporation.

Reference example 1

Obtaining crystalline form type In anhydrous tetomilast

Crystalline form B anhydrous tetomilast get the techniques described in paras.(1)to(3), below.

(1) Crystalline form B anhydrous tetomilast receive according to the method described in Journal of Medicinal Chemistry, 1995, 38, pp.353-358. That is, the crystal form of type In anhydrous tetomilast obtained as follows.

First methyl-6-[2-(3,4-dioxyphenyl)thiazol-4-yl]pyridine-2-carboxylate (49 g, 127 mmol) and 10%sodium hydroxide solution (100 ml) are added to ethanol (1.4 l) and the resulting mixture is then stirred for 4 hours at boiling under reflux. From the resulting solution remove most of the solvent and then to the residue to separate add water and ethyl acetate. The aqueous layer obtained by separation, acidified by adding 10%hydrochloric acid followed by extraction with ethyl acetate. Then quickly extract was washed with saturated aqueous sodium chloride and then dried over a large number of magnesium sulfate. The resulting mixture was recrystallized from ethyl acetate, obtaining the crystalline form B anhydrous tetomilast.

Part of the obtained crystalline form B anhydrous tetomilast is melted at a temperature of approx the flax 175°C and turns into a needle-like crystalline form. After that, the above crystalline form completely melted (decomposition) at a temperature in the range from 187°C to 189°C.

The obtained crystalline form B anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peaks, as shown in Figure 5.

Receive a range of x-ray diffraction powder obtained crystalline form type In anhydrous tetomilast. In the detect that they see the same spectrum as shown in Fig.6.

Remove the IR-spectrum (KBr) of the obtained crystalline form type In anhydrous tetomilast. The results reveal that the obtained crystalline form type In anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3298, 3090, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 762 and 706 cm-1according to its IR-spectrum (KBr).

(2) 5 g of crystalline form type And anhydrous tetomilast obtained by the method of example 1, as described later, is dissolved in 400 ml of isopropanol under stirring and boiling under reflux. The resulting solution was cooled to a temperature of approximately 30°C for about 1 hour and then further cooled to a temperature of 10°C or below within 1 hour is so, to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, obtaining 4.6 g of crystalline form type In anhydrous tetomilast in the form of needle crystals (yield: 92%).

Part of the obtained crystalline form type In anhydrous tetomilast is melted at a temperature of approximately 175°C and turns into a needle-like crystalline form. After that, the above crystalline form completely melted (decomposition) at a temperature in the range from 187°C to 190°C.

The obtained crystalline form type In anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. The results reveal that the observed endothermic peaks, as shown in Figure 5, at a temperature of about 177°C and 188°C.

Receive a range of x-ray diffraction powder obtained crystalline form type In anhydrous tetomilast. The results reveal that the above crystalline form has characteristic peaks, as shown in Fig.6, when the angle 2θ= 4,1°, 8,1°, 11,9°, 16,1° and 24.2°.

Remove the IR-spectrum (KBr) of the obtained crystalline form type In anhydrous tetomilast. The results reveal that the obtained crystalline form type In anhydrous tetomilast and eat stripes significant absorption in the infrared region at a wavelength of 3298, 3090, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 762 and 706 cm-1according to its IR-spectrum (KBr).

(3) 10 g of crystalline form type And anhydrous tetomilast obtained by the method of example 1, as described later, is dissolved in 400 ml of ethyl acetate under stirring at the boiling temperature under reflux. The resulting solution was cooled to a temperature of approximately 30°C for about 1 hour and then further cooled to a temperature of 10°C or below within 1 hour in order to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, getting 9.3 g of crystalline form type In anhydrous tetomilast in the form of needle crystals (yield: 93%).

Part of the obtained crystalline form type In anhydrous tetomilast is melted at a temperature of approximately 175°C and turns into a needle-like crystalline form. After that, the above crystalline form completely melted (decomposition) at a temperature in the range from 187°C to 190°C.

The obtained crystalline form type In anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peaks, as shown in Figure 5.

Receive a range of diffracts and x-ray powder obtained crystalline form type In anhydrous tetomilast. In the detect that they see the same spectrum as shown in Fig.6.

Remove the IR-spectrum (KBr) of the obtained crystalline form type In anhydrous tetomilast. The results reveal that the obtained crystalline form type In anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3298, 3090, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 762 and 706 cm-1according to its IR-spectrum (KBr).

Example 1

Obtaining crystalline form type And anhydrous tetomilast

Crystalline form type And anhydrous tetomilast get the techniques described in paras. (1)to(7), below.

(1) 5 g of crystalline form type In anhydrous tetomilast obtained in reference example 1 (3), is dissolved in a solution consisting of 140 ml of acetone and 35 ml of water, under stirring and boiling under reflux. The resulting solution was cooled to a temperature of 40°C for 100 minutes at this temperature, the crystal form of type And anhydrous tetomilast precipitates) and then further cooled to a temperature of 10°C or below in order to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 60°C for 18 hours, obtaining 4.0 g of crystalline form type And anhydrous tetomilast as starchitecture (yield: 80%).

The obtained crystal form of type And anhydrous tetomilast melted (decomposition) at a temperature in the range from 187°C to 189°C.

The obtained crystalline form type And anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. The results reveal that the observed endothermic peak at a temperature of about 188°C, as shown in Figure 3.

Receive a range of x-ray diffraction powder obtained crystalline form type And anhydrous tetomilast. The results reveal that the above crystalline form has characteristic peaks as shown in figure 4, at an angle 2θ= 10,5°, 13,1°, 18,4°, 21,9° and 25.8°.

Remove the IR-spectrum (KBr) of the obtained crystalline form type And anhydrous tetomilast. The results reveal that the obtained crystalline form of type And anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 cm-1according to its IR-spectrum (KBr).

(2) 5 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), as described later, is dissolved in 400 ml of ethanol under stirring and boiling under reflux. The resulting solution was cooled to a temperature of approximately 30°C for the ome 1 hour and then further cooled to a temperature of 10°C or below within 1 hour with the to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, obtaining 4.3 g of crystalline form type And anhydrous tetomilast in the form of columnar crystals (yield: 86%).

The melting point of the obtained crystalline form type And anhydrous tetomilast is 188-190°C (decomposition).

The obtained crystalline form type And anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peak, as shown in Figure 3.

Shooting range x-ray diffraction powder obtained crystalline form type And anhydrous tetomilast. In the detect that they see the same spectrum as shown in Figure 4.

Remove the IR-spectrum (KBr) of the obtained crystalline form type And anhydrous tetomilast. The results reveal that the obtained crystalline form of type And anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 cm-1according to its IR-spectrum (KBr).

(3) 10 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), as described later, is dissolved in 40 ml of acetone with stirring and boiling under reflux. The resulting solution was cooled to a temperature of approximately 30°C for about 1 hour and then further cooled to a temperature of 10°C or below within 1 hour in order to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, getting to 8.3 g of crystalline form type And anhydrous tetomilast in the form of columnar crystals (yield: 83%).

The obtained crystal form of type And anhydrous tetomilast melted (decomposition) at a temperature 188-190°C.

The obtained crystalline form type And anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peak, as shown in Figure 3.

Receive a range of x-ray diffraction powder obtained crystalline form type And anhydrous tetomilast. In the detect that they see the same spectrum as shown in Figure 4.

Remove the IR-spectrum (KBr) of the obtained crystalline form type And anhydrous tetomilast. The results reveal that the obtained crystalline form of type And anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 is m -1according to its IR-spectrum (KBr).

(4) 10 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), as described later, is dissolved in a solution consisting of 320 ml of acetone and 80 ml of water with stirring and boiling under reflux. The resulting solution was gradually cooled to a temperature of 30°C for about 3 hours, then cooled to a temperature of 20°C for 1 hour and then further cooled to a temperature of 10°C for 0.5 hour to obtain a precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, getting to 8.3 g of crystalline form type And anhydrous tetomilast in the form of columnar crystals (yield: 83%).

The obtained crystal form of type And anhydrous tetomilast melted (decomposition) at a temperature 187-189°C.

The obtained crystalline form type And anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peak, as shown in Figure 3.

Receive a range of x-ray diffraction powder obtained crystalline form type And anhydrous tetomilast. In the detect that they see the same spectrum, as is expressed in Figure 4.

Remove the IR-spectrum (KBr) of the obtained crystalline form type And anhydrous tetomilast. The results reveal that the obtained crystalline form of type And anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 cm-1according to its IR-spectrum (KBr).

(5) 5 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), as described later, is dissolved in a solution consisting of 450 ml of acetone and 300 ml of water with stirring and boiling under reflux. The resulting solution was cooled to a temperature of approximately 30°C for about 1 hour and then further cooled to a temperature of 10°C or below within 1 hour in order to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, getting to 4.2 g of crystalline form type And anhydrous tetomilast in the form of columnar crystals (yield: 84%).

The obtained crystal form of type And anhydrous tetomilast melted (decomposition) at a temperature 188-190°C.

The obtained crystalline form type And anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the find h is about watching the same endothermic peak, as shown in Figure 3.

Receive a range of x-ray diffraction powder obtained crystalline form type And anhydrous tetomilast. In the detect that they see the same spectrum as shown in Figure 4.

Remove the IR-spectrum (KBr) of the obtained crystalline form type And anhydrous tetomilast. The results reveal that the obtained crystalline form of type And anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 cm-1according to its IR-spectrum (KBr).

(6) to 41.4 g of ethyl-3-oxo-3-(6-methoxycarbonyl-2-pyridyl)propionate dissolved in a solution consisting of 42 ml of water and 414 ml of ethyl acetate, and the resulting solution is then cooled to a temperature of 5-10°C. After this, the solution obtained by dissolution of 35.6 g of sulfurylchloride in 83 ml of ethyl acetate, are added dropwise to the above cooled solution for approximately 30 minutes under stirring. Then the resulting mixture is stirred at a temperature in the range of 10-20°C for 1 hour. After that, the reaction mixture is heated up to a temperature of about 90°C. while removing the solvent from the reaction solution. The reaction solution is continuously heated at a temperature in the range from about 90°C to 100°C for 2 hours PR is stirring. Thereafter, the resulting mixed suspension (containing crystals) is cooled to a temperature of approximately 10°C and then stirred for 1 hour, then filtered, obtaining 27,99 g 2-(2-chloroacetyl)-6-pyridineboronic acid in the form of crystals yellow-brown (melting point: 184-189°C purity: 98-99%).

20 g of 2-(2-chloroacetyl)-6-pyridineboronic acid and 22.6 g of 3,4-deoxyribozyme dissolved in a solution consisting of 100 ml of water and 200 ml of dimethoxyethane. The resulting solution was refluxed for 2 hours under stirring and the reaction solution is then cooled to a temperature of 5°C or below in order to obtain a precipitate of yellow-brown color by filtering.

After that, the above precipitated crystalline form is dissolved in a solution obtained by dissolving 6,18 g of potassium hydroxide in 372 ml of water. The resulting solution was extracted twice with ethyl acetate (2×186 ml). Then to separate the aqueous layer was added 1 g of activated charcoal and the resulting solution was then stirred at a temperature of approximately 30°C for 30 minutes. After that, the activated carbon is removed by filtration and to the filtrate add 372 ml of acetone and 11.2 g of concentrated hydrochloric acid, collecting the slurry (the mixture of the crystalline forms of the hydrate tetomilast and crystalline forms of the type In anhydrous tetomilast). In order to transfer the mixture of crystalline form, hydrate, tetomilast and crystalline forms of the type In anhydrous tetomilast in crystalline form type And anhydrous tetomilast, the above suspension is heated at 60°C for 30 minutes and then cooled to room temperature to obtain crystalline form by filtration, thereby obtaining a crude crystalline form type And anhydrous tetomilast (34,82 g, wet).

8,67 g of crude crystalline form, without drying, was dissolved in a solution consisting of 213 ml of acetone and 53 ml of water, when heated to a temperature of 60°C followed by filtration while hot. The resulting filtrate is again heated and then see the dissolution of the crystalline form. Then, the filtrate is cooled to a temperature of 50°C. 79 mg of crystalline form type And anhydrous tetomilast added as seed crystals to the cooled filtrate and the resulting mixture is then stirred at a temperature of 42-50°C (internal temperature) for 2 hours. The resulting solution is cooled to a temperature of 20°C for approximately 20 minutes and then stirred at a temperature of 19-25°C for 2 hours. Then the solution is cooled to a temperature of 5°C for 35 minutes and then its u who remediat at a temperature of 4-5°C for 2 hours with the to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at a temperature of 80°C during the night, getting to 7.25 g of crystalline form type And anhydrous tetomilast (the output of which is 78,4%when 6-chloroacetyl-2-pyridylcarbonyl acid used as standard). Purity according to HPLC obtained crystalline form type And anhydrous tetomilast is 99.9%.

Part of the obtained crystalline form type And anhydrous tetomilast is melted at a temperature of approximately 175°C, and it turns into a needle-like crystalline form. Then the above crystalline form completely melted (decomposition) at a temperature in the range from 187°C to 190°C.

The obtained crystalline form type And anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peak, as shown in Figure 3.

Receive a range of x-ray diffraction powder obtained crystalline form type And anhydrous tetomilast. In the detect that they see the same spectrum as shown in Figure 4.

Remove the IR-spectrum (KBr) of the obtained crystalline form type And anhydrous tetomilast. In the result of detecting the Ute, the resulting crystalline form of type And anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 cm-1according to its IR-spectrum (KBr).

The obtained crystalline form type And anhydrous tetomilast crushed in the mill for fine grinding in order to obtain a powder having an average particle size equal to a 30.4 μm, and 90% of all particles which have a size equal to 57 microns.

(7) 32,36 g of crude crystalline form, hydrate, tetomilast obtained in example 5 (2), as described later, is dissolved in a solution consisting of 197 ml of purified water and 793 ml of acetone, when heated to a temperature of approximately 60°C followed by filtration while hot. Then the obtained filtrate is again heated and then see the dissolution of the crystalline form. After that, the filtrate is cooled to a temperature of 45°C. To the cooled filtrate is added 290 mg of crystalline form type And anhydrous tetomilast and the resulting mixture is then stirred at 45°C for 2 hours. Then the obtained solution is cooled to a temperature of 20°C for about 1 hour and then stirred at a temperature of 20-24°C for 2 hours. After that, the solution is cooled to a temperature of 5°C for about 2 hours and then stirred at which the temperature in the range from -1°C to 5°C for 2 hours with the to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at a temperature of 80°C for 4 hours, getting 24,11 g of crystalline form type And anhydrous tetomilast.

The obtained crystalline form type And anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peak, as shown in Figure 3.

Receive a range of x-ray diffraction powder obtained crystalline form type And anhydrous tetomilast. In the detect that they see the same spectrum as shown in Figure 4.

Remove the IR-spectrum (KBr) of the obtained crystalline form type And anhydrous tetomilast. The results reveal that the obtained crystalline form of type And anhydrous tetomilast band has significant absorption in the infrared region at a wavelength of 3306, 3084, 1746, 1593, 1474, 1348, 1271, 1132, 1045, 758 and 704 cm-1according to its IR-spectrum (KBr).

Example 2

Obtaining crystalline form type With anhydrous tetomilast

5 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), dissolved in 500 ml of methanol under stirring and heated to the boiling temperature under reflux the resulting solution was cooled to a temperature of approximately 30°C for about 1 hour and then cooled to a temperature of 10°C or below within 1 hour with the to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, obtaining 3.8 g of crystalline form type With anhydrous tetomilast in the form of ribbon crystals (yield: 76%).

Needle crystalline form is received on the crystal surface of the obtained crystalline form type With anhydrous tetomilast at a temperature of 184°C, and the above crystalline form melts (decomposition) at a temperature in the range 187-190°C.

The obtained crystalline form type With anhydrous tetomilast subjected to thermogravimetric/differential thermal analysis. The results reveal that the observed endothermic peaks at temperatures of approximately 184°C and a temperature of about 189°C, as shown in Fig.7.

Receive a range of x-ray diffraction powder obtained crystalline form type With anhydrous tetomilast. The results reveal that the above crystal has characteristic peaks, as shown in Fig at the angle 2θ= 4,2°, 8,2°, 12,0°, 16,4°, 24,7° and 25.9°.

Remove the IR-spectrum (KBr) of the obtained crystalline form of the type A waterless tetomilast. The results reveal that the obtained crystalline form of type And anhydrous tetomilast has bands of mn is significant absorption in the infrared region at a wavelength of 3300, 3088, 1744, 1593, 1476, 1346, 1267, 1132, 1045, 754 and 704 cm-1according to its IR-spectrum (KBr).

Example 3

Obtaining a crystalline form of the combined acetonitrile MES tetomilast

5 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), dissolved in 400 ml of acetonitrile with stirring and heated to the boiling temperature under reflux. The resulting solution was cooled to a temperature of approximately 30°C for about 1 hour and then cooled to a temperature of 10°C or below within 1 hour in order to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, getting to 5.1 g of crystalline form of the combined acetonitrile MES tetomilast in the form of ribbon crystals (yield: quantitative).

The obtained crystalline form of the combined acetonitrile MES tetomilast becomes turbid at a temperature of 90°C, and the above crystalline form melts (decomposition) at a temperature in the range 187-190°C.

The obtained crystalline form combined acetonitrile MES tetomilast subjected to thermogravimetric/differential thermal analysis. The results reveal that the observed endothermic peaks, as shown in Fig.9, when the temperature of the app is siteline 91°C, at a temperature of about 176°C. and a temperature of about 189°C.

Receive a range of x-ray diffraction powder obtained crystalline form of the combined acetonitrile MES tetomilast. The results reveal that the above crystalline form has characteristic peaks as shown in Figure 10, when the angle 2θ= 3,6°, 7,1°, 10,6°, 14,2° and 24.8°.

Remove the IR-spectrum (KBr) of the obtained crystalline form of the combined acetonitrile MES tetomilast. The results reveal that the obtained crystalline form of the combined acetonitrile MES tetomilast band has significant absorption in the infrared region at a wavelength of 3300, 3090, 2249 (nitrile group), 1744, 1593, 1476, 1346, 1269, 1132, 1045, 752 and 704 cm-1according to its IR-spectrum (KBr).

Remove NMR spectrum (DMSO-d6) of the obtained crystalline form of the combined acetonitrile MES tetomilast. The results reveal that the peak of the methyl group of acetonitrile observed at δ = 2,1 ppm

Example 4

Obtain a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast

The mixture of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast receive according to the method described in paragraph (1) or p. (2), below:

(1) 10 g Krista is symbolic forms And anhydrous tetomilast, obtained in example 1 (6), is dissolved in a solution consisting of 320 ml of acetone and 80 ml of water with stirring and heated to the boiling temperature under reflux. The resulting solution was cooled to a temperature of approximately 30°C for about 1 hour and then cooled to a temperature of 10°C for about 10 minutes. After that, the solution is further cooled to a temperature of 10°C or below within 1 hour in order to obtain the precipitated crystalline form by filtration. The above precipitated crystalline form is dried at 50°C for 3 hours, obtaining 8.5 g of a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 40:60) in the form of columnar crystals (yield: 85%).

Only a small portion of the mixture comprising the crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast, is melted at a temperature of 178°C, and it crystallizes in the form of needle crystals. The mixture is then melted (decomposition) at a temperature in the range 188-190°C.

The resulting mixture, consisting of a crystalline form of the type a waterless tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 40:60), is subjected to thermogravimetric/differential mention the mini-analysis. The results reveal that the observed endothermic peaks at a temperature of approximately 175°C. and a temperature of about 189°C, as shown in figure 11.

In addition a range of x-ray diffraction powder mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 40:60). In the find that the above mixture has characteristic peaks, as shown in Fig at the angle 2θ= 4,2°, 11,9°, 13,2°, 16,2°, 17,3°, 24,3°, 25,3°, 25,9° and 27.5°.

In addition, remove the IR-spectrum (KBr) of the mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 40:60). In the find that the resulting mixture has a strip of significant absorption in the infrared region at a wavelength of 3298, 3088, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 760 and 704 cm-1according to its IR-spectrum (KBr).

(2) 10 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), is dissolved in a solution consisting of 320 ml of acetone and 80 ml of water with stirring and heated to the boiling temperature under reflux. The resulting solution was cooled rapidly to a temperature of 10°C for 30 minutes in order to obtain the precipitated crystalline form by filtration. Visayas is nnow precipitated crystalline form is dried at 50°C for 3 hours, receiving of 7.8 g of a mixture of crystalline forms And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 10:90), in the form of a powder (yield: 78%). Part of the obtained mixture is melted at a temperature of 176°C, and it crystallizes in the form of needle crystals. The mixture is then melted (decomposition) at a temperature in the range 187-190°C.

The resulting mixture, consisting of a crystalline form of the type a waterless tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 10:90), is subjected to thermogravimetric/differential thermal analysis. The results reveal that the observed endothermic peaks at a temperature of about 176°C. and a temperature of about 189°C, as shown in Fig.

Receive a range of x-ray diffraction powder mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 10:90). In the find that the above mixture has characteristic peaks, as shown in Fig at the angle 2θ= 4,1°, 11,9°, 16,1°, 17,2°, 19,3°, 24,2°, 25,1°, 25,9° and 27.3°.

Remove the IR-spectrum (KBr) of the mixture consisting of crystalline form type And anhydrous tetomilast and crystalline forms of the type In anhydrous tetomilast (A:B = 10:90). The result found is more, that the resulting mixture has a strip of significant absorption in the infrared region at a wavelength of 3298, 3090, 1744, 1593, 1474, 1348, 1269, 1132, 1045, 756 and 706 cm-1according to its IR-spectrum (KBr).

Example 5

Obtaining a crystalline form of the monohydrate tetomilast

Crystalline form of the monohydrate tetomilast get the techniques described in paras. (1)to(3)below:

(1) to 18.7 g of 2-(2-chloroacetyl)-6-pyridineboronic acid and 21.1 g of 3,4-deoxyribozyme dissolved in a solution consisting of 94 ml of water and 187 ml of dimethoxyethane, and the resulting mixture is then stirred at a temperature of approximately 80°C (boiling under reflux) for 2 hours. The resulting solution was cooled to a temperature of 5°C and then stirred for 1 hour to obtain a precipitate of yellow-brown color by filtering. Above is dissolved in a solution obtained by dissolving 5,78 g of potassium hydroxide in 348 ml of water. The resulting solution mixture is washed twice with 174 ml of ethyl acetate. After this, the solution obtained by suspension of 0.9 g of activated charcoal in 1.9 ml of water is added to separate the aqueous layer and the resulting mixture is then stirred at a temperature of 30-31°C for 30 minutes. After that, the activated carbon is removed by filtration and then to the obtained filtrate add 348 ml of acetone. Then the UDA also added 10.4 g of concentrated hydrochloric acid with stirring and the resulting mixture is then stirred for 1 hour. After that, the precipitated crystalline form highlight by filtration. This crystalline form is suspended in 348 ml of water and the resulting mixture is then stirred at a temperature in the range of 27-30°C for 30 minutes. Then, the obtained crystalline form highlight by filtration. The resulting crystalline form is washed with a solution consisting of 35 ml of acetone and 35 ml of water, getting 29,53 g of crystalline form of the monohydrate tetomilast.

The obtained crystalline form of the monohydrate tetomilast subjected to thermogravimetric/differential thermal analysis. The results reveal that the observed endothermic peak at a temperature of about 189°C and then broadened peak observed at a temperature of approximately 102°C, as shown in figure 1.

Receive a range of x-ray diffraction powder obtained crystalline form of the monohydrate tetomilast. The results reveal that the above crystalline form has characteristic peaks as shown in figure 2, when the angle 2θ= 10,6°, 12,9°, 21,1°, 22,3° and 25.0°.

Remove the IR-spectrum (KBr) of the obtained crystalline form of the monohydrate tetomilast. The results reveal that the obtained crystalline form has stripes significant absorption in the infrared region at a wavelength of 3516, 3433, 1742, 1709, 1587, 1472, 1267, 1143, 1040, 758 and 716 is m -1according to its IR-spectrum (KBr).

(2) 50 g of crystalline form type And anhydrous tetomilast obtained in example 1 (6), is dissolved in the solution obtained by dissolution of 8.33 g of potassium hydroxide in 500 ml of water. This solution is filtered and then to the resulting filtrate is added 500 ml of acetone. After that add 13 ml (1.1 EQ.) concentrated hydrochloric acid under stirring (deposited at this time, the product is a crystalline form type In anhydrous tetomilast). The resulting solution was stirred at room temperature for about 10 minutes. After stirring to the solution was added 2.5 g of crystalline form of the monohydrate tetomilast obtained in the above example 5 (1) as the seed crystals, and the resulting mixture was continuously stirred for 2 hours (during such mixing occurs, the progression of the transformation due to the solvent. If the mixing time is short, you get a mixture of crystalline form, hydrate, tetomilast and crystalline forms of the type In anhydrous tetomilast). The precipitated crystalline form highlight by filtration and the obtained crystalline form then suspended in 400 ml of water. The resulting mixture is stirred at a temperature of 20-30°C for 30 minutes. After that, kristallicheskuyu form highlight by filtration and then washed with 80 ml of a mixture of acetone-water (the content of acetone is 50% by volume). The product is dried under reduced pressure over night, getting 51,5 g of crystalline form of the monohydrate tetomilast.

The obtained crystalline form of the monohydrate tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peak, as shown in figure 1.

Receive a range of x-ray diffraction powder obtained crystalline form of the monohydrate tetomilast. In the detect that they see the same spectrum, as shown in figure 2.

Remove the IR-spectrum (KBr) of the obtained crystalline form of the monohydrate tetomilast. The results reveal that the obtained crystalline form has stripes significant absorption in the infrared region at a wavelength of 3516, 3433, 1742, 1709, 1587, 1472, 1267, 1143, 1040, 758 and 716 cm-1according to its IR-spectrum (KBr).

(3) 2.37 g of crystalline form type In anhydrous tetomilast obtained in reference example 1 (3), suspended in a solution consisting of 50 ml acetone and 50 ml of water, and the resulting mixture is then stirred for approximately 5 minutes. After that, crystalline form, hydrate, tetomilast added as seed crystals to the above mixture and the thus obtained mixture is optionally stirred at a temperature of 30°C in techenie hours. Crystalline form highlight by filtration and then dried at 60°C during the night, receiving of 2.34 g of crystalline form, hydrate, tetomilast.

The humidity value obtained crystalline form, hydrate, tetomilast is to 4.68%. This value is almost the same as theoretical value of humidity (with 4.64%) of crystalline form of the monohydrate tetomilast.

The above monohydrate becomes turbid at a temperature of approximately 100°C. and is melted (decomposition) at a temperature in the range 188-189°C.

The obtained crystalline form of the monohydrate tetomilast subjected to thermogravimetric/differential thermal analysis. In the detect that they see the same endothermic peak, as shown in figure 1.

Receive a range of x-ray diffraction powder obtained crystalline form of the monohydrate tetomilast. The result is the same spectrum as shown in Figure 2.

Remove the IR-spectrum (KBr) of the obtained crystalline form of the monohydrate tetomilast. The results reveal that the obtained crystalline form has stripes significant absorption in the infrared region at a wavelength of 3516, 3433, 1742, 1709, 1587, 1472, 1267, 1143, 1040, 758 and 716 cm-1according to its IR-spectrum (KBr).

Example 6

Thermal transformation of crystalline Faure, the s-type In anhydrous tetomilast in crystalline form type And anhydrous tetomilast

Thermal transformation of the crystalline form of the type In anhydrous tetomilast in crystalline form type And anhydrous tetomilast confirmed by the method described in paras. (1)to(3)below:

(1) Crystalline form type In anhydrous tetomilast obtained in reference example 1 (3), maintained at a temperature in the range from 20°C to 30°C for approximately 1 year, and after that this crystalline form are examined using x-ray diffraction powder. The result confirmed that the above crystalline form is stored in the form of a crystalline form of the type In anhydrous tetomilast.

(2) 5 g of crystalline form type In anhydrous tetomilast obtained in reference example 1 (3), suspended in a solution consisting of 40 ml of acetone and 10 ml of water, and the resulting mixture is then stirred at 20°C. At this time, carry out sampling in intervals of 15 minutes, 30 minutes, 60 minutes and 120 minutes, and each of the samples subjected to investigation in respect of x-ray diffraction powder to establish a crystalline form. In the result, it was confirmed that each of the samples taken after stirring for 15 minutes, 30 minutes and 60 minutes, retains its shape in the form of a crystalline form of the type In anhydrous tetomilast.

On the other hand, it was confirmed that the sample selected after stirring for 120 minutes, is a mixture of crystalline forms of the type In anhydrous tetomilast and crystalline forms of the type And anhydrous tetomilast (A:B = 70:30).

(3) 5 g of crystalline form type In anhydrous tetomilast obtained in reference example 1 (3), suspended in a solution consisting of 40 ml of acetone and 10 ml of water, and the resulting mixture is then stirred at 40°C. At this time, carry out sampling in intervals of 15 minutes, 30 minutes, 60 minutes and 120 minutes, and each of the samples subjected to investigation in respect of x-ray diffraction powder to establish a crystalline form. In the result, it was confirmed that the sample selected after stirring for 15 minutes, is a mixture of crystalline forms of the type In anhydrous tetomilast and crystalline forms of the type And anhydrous tetomilast (A:B = 50:50).

On the other hand, it was confirmed that each of the samples, which was stirred for 30 minutes, 60 minutes and 120 minutes, turned into a crystalline form type And anhydrous tetomilast.

While crystals tetomilast with different crystal forms receive depending on the type of the solvent, the obtained crystalline form does not depend on the crystalline forms crystallochemical, used as the starting materials. So, in this context illustrates the use of crystalline form type And anhydrous tetomilast (purity is 99.9%). When using a new crystalline form tetomilast, other than the crystal form of type And anhydrous tetomilast get the same results.

An example of the finished dosage form

Tablets composition per tablet comprising 5 mg of crystalline form type With anhydrous tetomilast, 132 mg of starch, 18 mg of magnesium stearate and 45 mg of lactose, get in the usual way.

1. Crystalline form of type And anhydrous tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, having characteristic peaks at an angle 2θ=10,5°, 13,1°, 18,4°, 21,9° and 25.8°.

2. Pharmaceutical composition comprising as an active ingredient crystalline form type And anhydrous tetomilast according to claim 1, which means for the prevention and/or treatment of ulcers of the gastrointestinal tract, ischemic heart disease, cerebrovascular disease, means to improve the function of liver and kidneys used in the case of damage caused by transplantation, failure of microcirculation, etc. or what edstam for preventing and/or treating disease behceta, cutaneous vasculitis, ulcerative colitis, malignant rheumatoid arthritis, arthritis, atherosclerosis, or diabetes.

3. Pharmaceutical composition comprising as an active ingredient crystalline form type And anhydrous tetomilast according to claim 1, for the prevention and/or treatment of chronic rheumatoid arthritis, endotoxic shock, respiratory distress syndrome in adults (ARDS), thermal burn, asthma, chronic heart failure, myocardial infarction, viral myocarditis, reperfusion disorders, transition state from SIRS (systemic inflammatory syndrome response to damage to the body, multiple lesions of organs, inflammatory intestinal diseases, autoimmune diseases, metastasis, immune rejection that occur during transplantation, monoclonal b-cell abnormalities, polyclonal B-cell abnormalities, trialno Mikami, syndrome Castleman, primary glomerulonephritis, mesangial proliferative nephritis, cachexia in cancer, lymphoma, Lennert, psoriasis, atopic dermatitis, Kaposi's sarcoma, which develops as a result of AIDS, postmenopausal osteoporosis, sepsis, inflammatory diseases or chronic obstructive pulmonary disease.

4. The pharmaceutical composition according to claim 3, g is e, inflammatory intestinal disease is ulcerative colitis or Crohn's disease.

5. The pharmaceutical composition according to claim 3, for the prevention and/or treatment of chronic obstructive pulmonary disease.

6. A method of obtaining a crystalline form of the type a waterless tetomilast according to claim 1, characterized in that it comprises recrystallization from a solution obtained by dissolving crystalline form type In anhydrous tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, having characteristic peaks at an angle 2θ=4,1°, 8,1°, 11,9°, 16,1° and 24.2°, in ethanol or acetone.

7. A method of obtaining a crystalline form of the type a waterless tetomilast according to claim 1, characterized in that it comprises dissolving crystalline form type In anhydrous tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, having characteristic peaks at an angle 2θ=4,1°, 8,1°, 11,9°, 16,1° and 24.2°, in a mixture of acetone-water (where the acetone is 40% or more by volume) and then maintaining the resulting solution at a temperature of from 40 to 50°C for 60 min or more, and then cooling the solution to obtain crystalline form type And anhydrous tetomilast.

8. The method of obtaining crystalline form is anhydrous tetomilast according to claim 1, characterized in that it comprises mixing a suspension obtained by suspendirovanie in a mixed solvent consisting of water and at least one organic solvent selected from the group consisting of methanol, ethanol, acetone and tetrahydrofuran, at least one crystalline form of tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, having characteristic peaks at an angle 2θ=10,6°, 12,9°, 21,1°, 22,3° and 25.0°, the crystalline forms of the type In anhydrous tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, having characteristic peaks at an angle 2θ=4,1°, 8,1°, 11,9°, 16,1° and 24.2°, the crystalline form type With anhydrous tetomilast, with a range of x-ray diffraction powder, which essentially is the same as the spectrum of x-ray diffraction powder, having characteristic peaks at an angle 2θ=4,2°, 8,2°, 12,9°, 16,4°, 24,7° and 25.9°, and the crystal form of the combined acetonitrile MES tetomilast, with a range of x-ray diffraction powder, which, essentially, is that W is, as the spectrum of x-ray diffraction powder, having characteristic peaks at an angle 2θ=3,6°, 7,1°, 19,6°, 14,2° and 24.8°, and the reaction temperature is from 0 to 65°C, mixing time is from 19 minutes to 48 hours



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic cytoskeleton-active compounds which are from the family of natural latrunculin A or latrunculin B and have structural formulae

and described in the formula of invention. Present invention also relates to a pharmaceutical composition containing said compounds and a pharmaceutically acceptable carrier. The invention also pertains to a method of preventing or treating diseases and conditions associated with actin polymerisation. In one embodiment of the invention, high intraocular pressure, such as during primary open angle glaucoma, is treated using the method. The method involves administering a therapeutically effective amount of the cytoskeleton-active compound of formula I or II to a subject, where the said amount is sufficient for acting on a cytoskeleton, for example through actin polymerisation inhibition.

EFFECT: compounds are highly effective.

16 cl, 75 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula I: and their pharmaceutically acceptable salts, in which R1-R4 have values, given in item 1 of invention formula. Said compounds possess inhibiting activity with respect to 11-beta-hydroxysteroid-dehydrogenase and can be applied for production of medications, intended for treatment and prevention of diabetes, especially, diabetes of II type, obesity, malnutrition and hypertension.

EFFECT: development of efficient method of obtaining formula I compounds and based on them pharmaceutical composition.

25 cl, 1 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula (I), R1 denotes: C1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R1 and R2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C1-6-alkyl; one or another of radicals R4 and R5 is a group Z and one or another of radicals R4 and R5 is a -C(X)R6 group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R6 denotes a C1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

, in which A is a counter ion, a=1-3, b=0-3, X=1-6C alkyl, R1=1-6C alkyl, one or R2 and R3 is 1-6C alkyl and the other is XN+Hb(R1)3-b, or R2 and R3 form a methylenedioxy group, one or R4 and R5 is a halogen and the other is a halogen-substituted 1-6C alkyl, or R4 and R5 are bonded to form a 6-10C aromatic ring or a substituted 6-10C aromatic ring in which the substitute is selected from 1-6C alkoxy, halogen and halogen-substituted 1-6C alkyl. The invention also relates to a method of measuring content of analysed substance capable of ensuring proportional colour change as a result of a reaction in a biological fluid, involving the following steps: ensuring availability of the disclosed tetrazolium salt as an indicator and determination of concentration of the said analysed substance in the biological fluid using the said tetrazolium salt which is used as an indicator.

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing montelukast of formula (I), used as a leukotriene biosynthesis inhibitor for treating asthma. The method involves the following steps: (a) reacting a halogen-phosphate compound of formula (V) with a diol compound of formula (IV) in a solvent in the presence of a base to form a phosphate compound of formula (III); and (b) mixing the phosphate compound of formula (III) with a thio-carboxylic acid of formula (II) in a solvent in the presence of a base: (I) (II) (III) (IV) (V), where R denotes H or Na; R1 denotes H, methyl or ethyl; R2 denotes methyl, ethyl or phenyl; X denotes a halogen; Y denotes sulphur or oxygen.

EFFECT: novel method of producing montelukast or sodium salt thereof with high degree of purity and high output.

11 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: novel compounds have general formula (1), or salts thereof:

, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of

, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.

EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.

20 cl, 147 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and to their pharmaceutically acceptable salts. In formula (I)

, R1 represents hydrogen; each of R2, R3, R4, R5, R4 and R5 independently represents hydrogen or C1-C6alkyl; x equals 0 or 1; Arepresents oxygen, sulphur, S(O) or S(O)2; D represents oxygen or NR6; W represents bond or CR6aR6b; n equals integer number from 0 to 2; R6 represents hydrogen, C1-C6alkyl, C1-C6alkoxycarbonyl; Y represents bond, CR2eR2f; R2a, R2b, R2c, R2d, R2e, R2f, R6a and R6b represent independently hydrogen or C1-C6alkyl; R7a represents hydrogen or NHR7b; R7b represents hydrogen, C1-C6alkyl, C1-C6alkoxycarbonyl; R7 represents 6-12-member aromatic ring system, probably substituted with halogen, trifluoromethyl, C1-C6alkyl. Invention also relates to pharmaceutical composition, containing invention compound, as well as to

compounds ; , where R represents hydrogen or benzyl.

EFFECT: obtaining compounds, which possess properties of β2-adrenoreceptors agonist.

15 cl, 2 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to the development of new drugs for inflammatory diseases, particularly asthma. The pharmaceutical compositions under the invention contain 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-oxy-6-bromoindole in the effective amount or its pharmaceutically acceptable salts and/or hydrates as an active ingredient. The drug can be presented in the form of tablets, capsules, injections or aerosol.

EFFECT: provided anti-inflammatory and antiasthmatic action, as well as practically absolute absence of by-effects proper for the formerly known drugs administered for the same intended purpose.

10 cl, 4 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazopyrazines of formula where Q1 and R1 have the values specified in the patent claim, and to their pharmaceutically acceptable salts showing IGF-1R enzyme inhibiting activity and applicable for treatment and/or prevention of various diseases and conditions which are sensitive to tyrosine kinase inhibition.

EFFECT: preparation of the compounds showing IGF-1R enzyme inhibiting activity.

27 cl, 294 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (III): , in which D is a benzene ring, 2-pyridone ring, pyridine ring, benzoxalone ring, benzoxadinone ring or benzimidazole ring; R1 denotes carboxy or hydroxy; R2 independently denotes a halogen atom; alkyl optionally substituted with a halogen atom, aryl or alkylamine; alkynyl, optionally substituted alkoxy; hydroxy; carboxy; alkoxy optionally substituted with phenyl, aromatic heterocyclic ring which denotes a 5-6-member aromatic monocyclic carbocyclic ring containing one or two heteroatoms, independently selected from oxygen and nitrogen atoms; alkylsulphonyl; aryloxy; amino optionally substituted with alkyl; acyl optionally substituted with alkyl or alkyloxy; alkyloxycarbonyl; alkanesulphonyl; arylsulphonyl or alkylcarbamoyl; carbamoyl optionally substituted with alkyl, phenyl, cycloalkyl, acetyl, alkanesulphonyl, heteroarylalkyl, cycloalkylalkyl, heteroaryl which denotes a 5-6-member aromatic monocyclic ring containing one or three heteroatoms independently selected from oxygen and nitrogen atoms, and which is optionally substituted with alkyl or cycloalkyl; acylcyano; nitro, aryl; heteroaryl which denotes a 5-6-member aromatic ring containing one or more heteroatoms independently selected from oxygen, sulphur and nitrogen atoms, and which is optionally substituted with alkyl; alkylsulphonyl; morpholinylsulphonyl; non-aromatic heterocyclic group which denotes a 5-6-member non-aromatic heterocyclic ring containing one or more nitrogen atoms and optionally an oxygen and/or sulphur atom; R3 denotes C1-C6alkyloxy, C1-C6alkylthio; R4 denotes a halogen atom or alkyloxy; R5 denotes alkyl; M denotes sulphonyl; L3 independently denotes alkylene optionally containing one oxygen or nitrogen atom, alkenylene, or -N(R7)-; R7 independently denotes a hydrogen atom, alkyl; Y denotes a single bond or CO; Z denotes CH or N; n equals 0 or 1; p equals 0, 1, or 2; q equals 0 or 1; provided that R1 does not denote carboxy when ring D is a benzene ring, -L3- denotes -(O-alkylene)- and the substitution position of L3 and Y is an ortho-position in ring D; to pharmaceutically acceptable salts thereof. The invention also relates to compounds of formula (IV), a pharmaceutical composition, a method of treating diseases associated with the DP receptor, use of compounds in any of the claims 1-17, as well as compounds of general formula (V).

EFFECT: obtaining novel biologically active compounds having DP receptor antagonist activity.

30 cl, 8 ex, 62 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicinal agents and combination for treatment of respiratory disease, containing (a) efficient amount of β2-agonist selected from group that consists of formoterol and salmeterol not necessarily in the form of their racemic compounds, their enantiomers, their diastereoisomer and their mixtures and their mixtures and not necessarily their pharmacologically compatible acid-additive salts, and (b) efficient amount of antagonist of muscarinic receptors M3, which represents 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonibicyclo[2.2.2]octane in the form of salt with anion X, which represents pharmaceutically acceptable anion of mono- or polyvalent acid. Also product, set and package are disclosed, which contain (a) β2-agonist and (b) antagonist of muscarinic receptors M3, as well as use of active ingredients (a) and (b) for production of medicinal agent and method for treatment of patient suffering from respiratory disease.

EFFECT: reduced maximum frequency of heart contractions and its duration.

19 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered application of 5-biphenyl-4-yl-5-[4-(4-nitrophenyl)-piperazine-1-yl]pyrimidine-2,4,6-trione for preparation of a drug for treatment or prevention of inflammatory bronchial diseases.

EFFECT: higher clinical effectiveness in asthma, decrease in eosinophilia caused by allergen action.

2 cl, 5 tbl, 3 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

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