Tetomilast polymorphs

FIELD: medicine, pharmaceutics.

SUBSTANCE: present inventions refers to a new crystalline form of tetomilast hydrate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 20=10.6°, 12.9°, 21.1°, 22.3° and 25.0°, to a new crystalline form of anhydrous tetomilast type C of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=4.2°, 8.2°, 12.0°, 16.4°, 24.7° and 25.9°, to a new crystalline form of acetonitrile tetomilast solvate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=3.6°, 7.1°, 10.6°, 14.2° and 24.8°, to based pharmaceutical compositions and to methods for preparing.

EFFECT: new crystalline forms shows useful processing characteristics with relation to preparing pharmaceutical drugs of them.

13 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, S. 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, because the crystal 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 DOS is iunie the above objectives. As a result, 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 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 with the spectrum of the x-ray diffraction the fir 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, etc. or funds is m for preventing and/or treating disease 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 the diffraction of x who's 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 to istoricheskoi 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); and

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 will bring the flax 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% is the volume), 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, 10-50 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, approximately 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.

While adding satr the adjustment of the 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.

Thus, the 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 so the 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. However, this new crystalline form tetomilast can be used alone or as a mixture of the two is whether 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 under 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 can be ohla the den to a temperature of 10°C and 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, and preferably, approximately what about 1-1 .5 EQ. per 1 EQ. processed new crystalline 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 and, preferably, approximately 1-1 .5 EQ. per the above used the primary 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 lower 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 is etomidate.

In addition, these methods are used to crystalline forms of the type In anhydrous tetomilast in order 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 with the -1according to its IR-spectrum (KBr).

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

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 in this 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, with 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 form is anhydrous tetomilast. In the case of a mixture of acetone-water (the content of acetone is 40-80%, by volume), it is preferably 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, in particular, is not limited. Usually it is approximately 40-85°C and, preferably, approximately 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 infusion is he to the 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 maintained at a temperature 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 the cross is stilizovala from the solution, obtained by dissolving the above-mentioned new crystalline forms tetomilast in a suitable solvent.

In particular, crystalline form type And 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 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 the 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 selected 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 selection, the selected crystalline form can be processed by drying a known manner. Moreover, the crystalline form can be cleaned by known purification method.

Thus, the obtained Crist is licenca form 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 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.

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. Specifically, 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-1according to 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 vikrita Litvinets crystalline form type With anhydrous tetomilast. The speed of lowering 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, this 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 either the specified cooling, the suspension is cooled to a temperature of 10°C or below and, preferably, to a temperature of about 0-10°C., for from 30 minutes to 3 hours so as to obtain the crystalline form 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.

Thus, the 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 and, more preferably, is 70-100 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 the Colo 30 minutes to 8 hours. After that, the suspension obtained by the above-mentioned cooling, cooled to a temperature of 10°C or lower and, preferably, to a temperature of about 0-10°C. for a time from 30 minutes to 3 hours so as 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 the conditions of 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. Further, 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 crystal f is my 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, deviation ±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 and, 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, the 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 the crystalline form of the 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 lower and, preferably, to a temperature of about 0-10°C. for a time from 30 minutes to 3 hours so as 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 lower and, 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 (mass ratio.

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

In addition, the above solution 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 crystal is army type In anhydrous tetomilast, you can select it using separation methods such as filtration, concentration or extraction. In addition, after selection, the 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 forms of anhydrous tatami the ASTA 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 such a pharmaceutical composition includes a mixture of crystalline forms And anhydrous 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 is t, 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 gastrointestinal tract, 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 preventing and/or treating 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, and in particular, the abnormal production of TNF-α, IL-β, IL-6, IFN-γ, etc. or various types is of deseases, associated with acceleration of adhesive process. In particular, a new crystalline form tetomilast according to the present invention can preferably be used: as a tool for prevention and/or treatment of 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 the prevention and/or treatment 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 sableman the th, 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 transplantation, 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 of the components is tov, selected from the group consisting of:

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

2) receptor antagonists leukotriene LTB4, LTC4, LTD4 or LTE4;

3) PDE4 inhibitors, including 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) 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) of methylxanthines;

14) cromoglicate sodium;

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

16) NSAID (non-steroidal anti-inflammatory lekarstvennye funds), 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) glucocortico the species for inhalation (in case of reduced side effects);

20) tryptase inhibitors;

21) antagonists thrombocytapheresis factor;

22) monoclonal antibodies active against endogenous inflammatory organisms;

23) IPL576;

24) agents tumor necrosis factor (TNF-α);

25) DMARDs (including Leflunomide);

26) TCR peptides;

27) inhibitors internacionalvecinoseu enzyme (ICE);

28) IMPDH inhibitors;

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

30) 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) 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) elastase inhibitors;

<> 49) 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 that increase the level of 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 the us various types of media, 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, kaolin, 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, bicarbonate sodium, 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 base or sodium lauryl sulfate; a humectant, such as glycerin or starch; adsorbents such as starch, lactose, kaolin, bentonite or colloidal silica; lubricants such as purified talc, stearate, boric acid powder or polyethylene glycol. This tablet can then be treated with obtaining tablets with the usual t is blacki 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 crystalline 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; 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 then fill the 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 is in a form that can be used all types of diluents, which are usually used in this field. Examples of such diluents which 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 pre is Arata, is not particularly limited and, therefore, choose from a wide range. Usually in 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, 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 / kg masiela in the 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 forms of the type And anhydrous tetomilast 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 of 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) Termag asymetrically/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 is heated 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 crystallic the Russian 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 liquid 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; vypuskaetsya firm Microtrac).

(7) Determination of moisture content

The amount of moisture contained in the sample is determined according to the methods of the Carl 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, manufactured by Keyence Corporation.

Reference example 1

Obtaining crystalline form type In anhydrous tetomilast

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

(1) Crystalline form type In 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. Afterthis 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 type In anhydrous tetomilast.

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 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 metadisciplinary 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, in order 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 cu is stolichna 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 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).

(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 (razloga the s) 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 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).

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, kristallicheskaja form 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 in the form of columnar crystals (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 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, 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) received kristallicheskimi 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 400 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 p. the Rosca 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).

(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 is 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).

(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 Chris who allow (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 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).

(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 within about 30 minutes, under stirring. Setepolotna the 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, under 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 those the temperature about 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 crystalline form, 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 paramesh what happens when the temperature 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 it is stirred at a temperature of 4-5°C for 2 hours to obtain a 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 melted (decomposes) at a temperature of 187°C to 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 represented is as 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).

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 in t the value of 2 hours. After that, the solution is cooled to a temperature of 5°C for about 2 hours and then stirred at a temperature in the range from -1°C to 5°C for 2 hours, in order 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 ti is a waterless 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 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 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. In the find that the above is the first 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 band has 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 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 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 forms of the 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, at a temperature of about 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 a type of betwedn the th 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 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 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 thermal 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 displaced is Ivanyi and when 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. The above precipitated crystalline form is dried at 50°C for 3 hours, getting to 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, when angle is 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). In the find 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 there is 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 the characteristics of the systematic 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 cm-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 this crystalline form highlight by filtration and then washed with 80 ml of a mixture of acetone-water (the content of acetone 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 the 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 for 1 hour. 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.

Removed And the 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 the crystalline form of the 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. As a result, it is 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 p is obtained samples subjected to investigation in respect of x-ray diffraction powder to establish a crystalline form. As a 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. As a 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 Faure is the 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 of crystals tetomilast 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, hydrate, tetomilast, with a range of x-ray diffraction powder, which has characteristic peaks at an angle 2θ=10,6°, 12,9°, 21,1°, 22,3° and 25.0°.

2. Crystalline form type With anhydrous tetomilast, with a range of x-ray diffraction powder, which has characteristic peaks at an angle 2θ=4,2°, 8,2°, 12,0°, 16,4°, 24,7° and 25.9°.

3. The crystalline form of the combined acetonitrile MES tetomilast, with a range of x-ray diffraction powder is, which has characteristic peaks at an angle 2θ=3,6°, 7,1°, 10,6°, 14,2° and 24.8°.

4. Pharmaceutical composition comprising at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast according to claim 1, crystalline form type With anhydrous tetomilast according to claim 2 and crystalline form of the combined acetonitrile MES tetomilast according to claim 3 as an active ingredient for the prevention and/or treatment of ulcers of the gastrointestinal tract, for the prevention and/or treatment of ischemic heart disease, for the prevention and/or treatment of cerebrovascular diseases, disorders of the liver and kidney caused by transplantation, failure of microcirculation or for preventing and/or treating disease behceta, cutaneous vasculitis, ulcerative colitis, malignant rheumatoid arthritis, arthritis, atherosclerosis, or diabetes.

5. Pharmaceutical composition comprising at least one type of crystalline form tetomilast selected from the group consisting of crystalline form, hydrate, tetomilast according to claim 1, crystalline form type With anhydrous tetomilast according to claim 2 and crystalline form of the combined acetonitrile MES tetomilast according to claim 3 as an active ingredient for the prevention and/or treatment of chronic rheumatoid arthritis is one endotoxic shock, respiratory distress syndrome in adults (ARDS), thermal burn, asthma, chronic heart failure, myocardial infarction, viral myocarditis, or for the prevention and/or treatment of 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-cell abnormalities, trialno Mikami, syndrome Castleman, primary glomerulonephritis, mesangial proliferative nephritis, cachexia if your 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.

6. The pharmaceutical composition according to claim 5, where the inflammatory intestinal disease is ulcerative colitis or Crohn's disease.

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

8. A method of obtaining a hydrate tetomilast according to claim 1, the best of the decomposing those that includes mixing a crystalline form type In anhydrous tetomilast, with a range of x-ray diffraction powder, which has characteristic peaks at an angle 2θ=4,1°, 8,1°, 11,9°, 16,1° and 24.2°, in a mixed solvent obtained by mixing methanol, ethanol, isopropanol, acetone or ethylmethylketone with water.

9. A method of obtaining a crystalline form of the type With anhydrous tetomilast according to claim 2, 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 has characteristic peaks at an angle 2θ=4,1°, 8,1°, 11,9°, 16,1° and 24.2°in methanol.

10. A method of obtaining a crystalline form of the type With anhydrous tetomilast according to claim 2, comprising dissolving crystalline form type In anhydrous tetomilast, with a range of x-ray diffraction powder, which has characteristic peaks at an angle 2θ=4,1°, 8,1°, 11,9°, 16,1° and 24.2°, in ethanol, followed by lowering the temperature of the resulting solution at a speed of 5°C./min or more.

11. A method of obtaining a crystalline form of the type With anhydrous tetomilast according to claim 2 comprises recrystallization from a solution obtained by dissolving in methanol or ethanol, at least one type of crystal is the political form tetomilast, selected from the group consisting of crystalline form, hydrate, tetomilast according to claim 1, crystalline form type And anhydrous tetomilast and crystalline form of the combined acetonitrile MES tetomilast according to claim 3 where the specified crystal form of type And anhydrous tetomilast has a range of x-ray diffraction powder, which has characteristic peaks at an angle 2θ=10,5°, 13,1°, 18,4°, 21,9° and 25.8°.

12. A method of obtaining a crystalline form of the combined acetonitrile MES tetomilast according to claim 3, 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 has characteristic peaks at an angle 2θ=4,1°, 8,1°, 11,9°, 16,1° and 24.2°, in acetonitrile.

13. A method of obtaining a crystalline form of the combined acetonitrile MES anhydrous tetomilast according to claim 3, characterized in that it comprises 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 according to claim 1, crystalline form type And anhydrous tetomilast and crystalline forms of the type With anhydrous tetomilast according to claim 2, where the specified crystal form type is anhydrous tetomilast has a range of x-ray diffraction powder, which has characteristic peaks at an angle 2θ=10,5°, 13,1°, 18,4°, 21,9° and 25.8°.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R1 is a 3-7-member carbocyclic ring and n is a number ranging from 1 to 8, and the rest of the radicals are described in the claim.

EFFECT: possibility of using such compounds and compositions in therapy as metabotropic glutamate receptor modulators.

33 cl, 367 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, in particular to device for transdermal bisoprolol introduction, which includes base and layer of sensitive to pressure adhesive, which contains bisoprolol, which is layered on one base surface, where maximal value of bisoprolol release in time period immediately from application on skin within 24 hours constitutes 30 mcg/cm2/hour or less; and where velocity of bisoprolol release 24 hours after application on skin constitutes 10 mcg/cm2/hour or less.

EFFECT: device for transdermal introduction reduces skin irritation, especially in case of layering, and can constantly introduce into living organism therapeutically or preventively efficient amount of bioprolol.

5 cl, 3 tbl, 3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is a coformulated drug for treating various ischemic pathologies containing succinic acid and 2-ethyl-3-(N,N-dimethylcarbamoyloxy)-6-methylpyridine salts with succinic or hydrochloric acid of general formula I where HX is salt-forming succinic or hydrochloric acid, m + 0.1-3.0; showing antihypoxic, antiamnestic and anticonvulsant activity characterised by the fact the relation in I between 2-ethyl-3-(N,N-dimethylcarbamoyloxy)-6-methylpyridine salts and the second component providing a 'synergistic' (potentiating) pharmacological effect by succinic acid makes 1:>0.3. It is shown that succinic acid potentiates declared action of the compound of formula I. It is a reason to create the coformulated drugs exceeding common preparations of 3-oxypyridine groups in pharmacological activity: emoxypin and mexidol, used for treating ischemic pathologies, particularly in diseases accompanied by cerebral ischemia.

EFFECT: preparation of new pharmaceutical compositions for treating ischemic pathologies.

5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically cardiology and concerns treating ischemic heart disease (IHD). For this purpose, the standard integrated drug treatment involving statin is added with administration of the biologically active additive MARISTIM 4.5 mg/day.

EFFECT: method provides higher clinical effectiveness of statins in the given group of patients due to elimination of their inhibitory effect on enzymes of a mitochondrial respiratory chain.

2 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of treating hypertension, congestive cardiac failure, stenocardia, myocardial infarction, atherosclerosis, stroke. A method of treating involves introduction to a patient requiring such treatment of the solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in which the active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet and produced by methods other than wet granulation with excipients by means of water and/or a water solution of a binding agent.

EFFECT: realisation of the specified purpose.

12 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of binuclear sulphur-nitrosyl complex of anion type iron of formula Na2[Fe2(S2O3)2(NO)4]·4H2O as vasodepressor means for obtaining medication for treatment of ischemic diseases.

EFFECT: invention ensures extension of arsenal of cardiotropic medications with improved activity spectrum based on said iron complex, which is non-toxic water-soluble NO donor.

2 cl, 4 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg in an animal every days for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction ensured by reducing the intensity of an acute inflammatory reaction, providing faster granulation tissue formation.

2 tbl

FIELD: medicine.

SUBSTANCE: modelling a myocardial infraction is followed in a rat is followed by intravenous introduction of the immune corrector tamerite 3 mg/kg. The preparation is injected daily for seven days. The histological results of the myocardial tissue presented after the first, third and seventh days show the sufficiency and efficacy of the therapy.

EFFECT: effective therapy of the acute myocardial infraction with high possibility of cure ensured by reduced manifestations of systemic inflammation response syndrome, faster granulation tissue formation and necrotic zone replacement by cicatricial tissue.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound 4-(1-(4-(4-methoxyphenylthio)-2,5-dioxo-2,5-dihydro-1H-pyrro-3-yl)-1H-indol-3-yl)butyl carbamimidothioate (the compound "ЛХТА-1833") which can be used in therapy of colon cancer, breast cancer, melanoma, leucosis.

EFFECT: preparing the new compounds for treating cancer.

2 cl, 2 tbl, 3 dwg, 1 ex

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