Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, hydrates and/or solvates (versions) thereof, for which characteristic powder diffraction patterns with radiation CuKα1 are given, with characteristic peaks expressed in values of d (Å). Said modifications can be used to treat neurological disorder. The invention also relates to pharmaceutical compositions (versions) which may additionally contain folate, separately or together with arginine in an effective amount. The folate is folic acid or tetrahydrofolate selected from tetrahydrofolic acid, 5,10-methylene-tetrahydrofolic acid, 10-formyl-tetrahydrofolic acid, 5-formyl-tetrahydrofolic acid or 5-methyl-tetrahydrofolic acid, or polyglutamate thereof or pharmaceutically acceptable salt thereof. The invention also relates to methods of producing (versions) said crystalline modifications. For example, the method of producing crystalline form A of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride involves dissolving (6R)-L-erythro-tetrahydrobiopterin dihydrochloride in water at ambient temperature, and (1) cooling the solution to a low temperature with solidification of the solution, and removing water at pressure ranging from 0.01 to 1 mbar, or (2) removing water from said aqueous solution by filtering and drying with evaporation of water, and extracting said crystalline form.

EFFECT: improved properties of compounds.

42 cl, 18 tbl, 15 dwg, 6 ex

 

The text descriptions are given in facsimile form.

1. The crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å):
for form A, which is a crystalline polymorph:
15,5 (vs), 12,0 (m), 4,89 (m), 3,70 (s)to 3.33 (s), 3,26 (s), and 3,18 (m);
or
for form F, which is a crystalline polymorph: 17,1 (vs), to 4.92 (m), and 4.68 (m), 3,49 (s)of 3.46 (vs), 3,39 (s), 3,21 (m), and 3.19 (m);
or
for the form J, which is a crystalline polymorph:
14,6 (m), 3,29 (vs), and 3.21 (vs);
or
for form K, the cat heaven is a crystalline polymorph:
14,0 (s), and 6.6 (w), to 4.73 (m), with 4.64 (m), 3,54 (m)to 3.49 (vs), 3,39 (m)to 3.33 (vs), 3,13 (s)3,10 (m), 3,05 (m), 3,01 (m), 2,99 (m), and 2,90 (m);
or
for the form, which is a crystalline hydrate:
a 13.9 (vs), and 8.8 (m), 6,8 (m), equal to 6.05 (m), 4,25 (m)4,00 (m), 3,88 (m), 3,80 (m)and 3.59 (s), 3,50 (m), 3,44 (m), 3,26 (s), 3,19 (vs), 3,17 (s), 3,11 (m), 2,97 (m), and 2.93 (vs);
or
to form D, which is a crystalline hydrate:
8,6 (s), 5.56mm (m), 4,99 (m)4,67 (s), 4,32 (m)3,93 (vs), 3,17 (m), 3,05 (s), 2,88 (m), and 2.79 (m);
or
for form E, which is a crystalline hydrate:
15,4 (s), 4,87 (w), 3,69 (m)to 3.33 (s), 3,26 (vs), is 3.08 (m), 2,95 (m), are 2.87 (m);
or
to form H, which is a crystalline hydrate:
to 15.8 (vs), a 3.87 (m), 3,60 (m), with 3.27 (m), 3,21 (m), 2,96 (m), 2,89 (m), and to 2.67 (m);
or
to form Oh, which is a crystalline hydrate:
8,8 (m), and 6.3 (m), the 5.65 (m), is 5.06 (m)4,00 (m), 3,88 (m), 3,69 (s)to 3.64 (s), 3,52 (vs), 3,49 (s)of 3.46 (s), 3,42 (s), 3,32 (m), with 3.27 (m), 3,23 (s)3,18 (s), 3,15 (vs), 3,12 (m), and 3.04 (vs);
or
to form G, which is a crystalline ethanol MES:
14,5 (vs), 7.0mm (w)to 4.41 (w), 3,63 (m), 3,57 (m), 3,49 (w)to 3.41 (m), 3,26 (m), 3,17 (m), of 3.07 (m), 2,97 (m), 2,95 (m), 2,87 (w), and 2,61 (w);
or
for the form I, which is a crystalline MES acetic acid:
14,5 (m)to 3.67 (vs), 3,61 (m), 3,44 (m), 3,11 (s), and 3,00 (m);
or
to form L, which is a crystalline ethanol mixed MES/hydrate:
14,1 (vs), 10,4 (w), 6,9 (w), 6.5 (w)and 6.1 (w), 4,71 (w), 3.46 in (m)to 3.36 (m), and 2.82 (w);
or
for form M, which represents ristalliceski ethanol MES:
18,9 (s)of 6.4 (m), and 3.22 (vs);
or
to form N, which is a crystalline polymorph:
19.5cm (m), 6,7 (w), of 3.56 (m), and 3.33 (vs), 3,15 (w).

2. The crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å)
for the form:
15,5 (vs), 12,0 (m), 6,7 (m), 6,5 (m), and 6.3 (w)and 6.1 (w), 5,96 (w)5,49 (m), 4,89 (m), 3,79 (m), 3,70 (s), 3,48 (m), of 3.45 (m), 3,33 (s), 3,26 (s), 3,22 (m)3,18 (m), is 3.08 (m), to 3.02 (w), 2,95 (w), 2,87 (m), and 2.79 (w), 2,70 (w);
or
for F:
17,1 (vs), 12,1 (w), or 8.6 (w), 7.0mm (w), 6.5 (w), 6,4 (w), of 5.92 (w)5,72 (w), 5,11 (w)to 4.92 (m), a 4.86 (w), and 4.68 (m), to 4.41 (w), 4,12 (w), 3,88 (w), 3,83 (w), 3,70 (m), 3,64 (w), 3,55 (m), 3,49 (s), 3.46 in (vs), 3,39 (s)to 3.33 (m), and 3.31 (m), with 3.27 (m), 3,21 (m), 3,19 (m)to 3.09 (m), to 3.02 (m), and 2,96 (m);
or
for the form J:
14,6 (m), and 6.6 (w), 6,4 (w), vs. 5.47 (w), 4,84 (w), 3,29 (vs), and 3.21 (vs);
or for the form K:
14,0 (s), and 9.4 (w), and 6.6 (w), 6,4 (w), and 6.3 (w)and 6.1 (w), 6,0 (w), 5,66 (w)5,33 (w), 5,13 (vw), to 4.73 (m), with 4.64 (m), 4,48 (w), 4,32 (vw), 4,22 (w)4,08 (w), 3,88 (w), 3,79 (w), 3,54 (m)to 3.49 (vs), 3,39 (m)to 3.33 (vs), 3,13 (s)3,10 (m), 3,05 (m), 3,01 (m), 2,99 (m), and 2,90 (m);
or
for the form With:
18,2 (m)to 15.4 (w), a 13.9 (vs), 10,4 (w), and 9.6 (w), and 9.1 (w), and 8.8 (m), and 8.2 (w), and 8.0 (w), 6,8 (m), 6.5 (w), equal to 6.05 (m), 5,77 (w), 5,64 (w), 5,44 (w), 5,19 (w), 4,89 (w)4,76 (w), 4,70 (w)to 4.41 (w), 4,25 (m)4,00 (m), 3,88 (m), 3,80 (m)and 3.59 (s), 3,50 (m), 3,44 (m), 3,37 (m), 3,26 (s), 3,19 (vs), 3,17 (s), 3,11 (m), 3,06 (m), to 3.02 (m), 2,97 (vs), 2,93 (m), 2,89 (m), and 2.83 (m), and 2.43 (m);
or
for form D:
8,6 (s), 6,8 (w), 5.56mm (m), 4,99 (m)4,67 (s), 4,32 (m)3,93 (vs), 3,88 (w), 3,64 (w), 3,41 (w), 3,25 (w), 3,17 (m), 3,05 (s)2,94 (w)2,92 (w), 2,88 (m), 2,85 (w), 2,80 w), and 2.79 (m), 2,68 (w), 2,65 (w), 2,52 (vw), 2,35 (w), 2,34 (w), 2,30 (w), and to 2.29 (w);
or
for the form:
15,4 (s), and 6.6 (w), 6.5 (w), 5,95 (vw), 5,61 (vw), 5,48 (w), 5,24 (w), 4,87 (w), 4,50 (vw), 4,27 (w)3,94 (w), of 3.78 (w), 3,69 (m), 3,60 (w)to 3.33 (s), 3,26 (vs), and 3.16 (w), is 3.08 (m), 2,98 (w), 2,95 (m), 2.91 in (w), 2,87 (m), and 2.79 (w), 2,74 (w), 2,69 (w), and 2,62 (w);
or to form H:
to 15.8 (vs), 10,3 (w), and 8.0 (w), and 6.6 (w), 6,07 (w), 4,81 (w), 4,30 (w), a 3.87 (m), 3,60 (m), with 3.27 (m), 3,21 (m), 3,13 (w), 3,05 (w), 2,96 (m), 2,89 (m), 2,82 (w), and to 2.67 (m);
or for the form Of:
15,9 (w)14,0 (w), 12,0 (w), and 8.8 (m), 7.0mm (w), 6.5 (w), and 6.3 (m)6,00 (w), of 5.75 (w), the 5.65 (m), is 5.06 (m), to 4.98 (m), to 4.92 (m), 4,84 (w), 4,77 (w), 4,42 (w), 4,33 (w)4,00 (m), 3,88 (m), of 3.78 (w), 3,69 (s)to 3.64 (s), 3,52 (vs), 3,49 (s)of 3.46 (s), 3,42 (s), 3,32 (m), with 3.27 (m), 3,23 (s)3,18 (s), 3,15 (vs), 3,12 (m), 3.04 from (vs), 2,95 (m)2,81 (s)2,72 (m)to 2.67 (m), and 2,61 (m);
or
for form G:
14,5 (vs), or 10.9 (w), and 9.8 (w), 7.0mm (w), and 6.3 (w), 5,74 (w), 5,24 (vw), 5,04 (vw), 4,79 (w)to 4.41 (w), was 4.02 (w), 3,86 (w), of 3.77 (w), 3,69 (w), 3,63 (m), 3,57 (m), 3,49 (m)to 3.41 (m), 3,26 (m), 3,17 (m), of 3.07 (m), 2,97 (m), 2,95 (m), 2,87 (w), and 2,61 (w);
or
for the form I:
14,5 (m)14,0 (w), and 11.0 (w), 7,0 (vw), 6,9 (vw), 6,2 (vw), and 5.30 (w), 4,79 (w), of 4.44 (w), 4,29 (w), 4,20 (vw), was 4.02 (w), 3,84 (w), 3,80 (w)to 3.67 (vs), 3,61 (m)3,56 (w), 3,44 (m), 3.27 to (w), 3,19 (w), 3,11 (s)of 3.00 (m), 2,94 (w), 2,87 (w), and 2,80 (w);
or
for the form L:
14,1 (vs), 10,4 (w), and 9.5 (w)9,0 (vw), 6,9 (w), 6.5 (w)and 6.1 (w), of 5.75 (w), 5,61 (w)5,08 (w), 4,71 (w), 3,86 (w), of 3.78 (w), 3.46 in (m)to 3.36 (m), 3,06 (w), 2,90 (w), and 2.82 (w);
or
for the form M:
18,9 (s)of 6.4 (m), 6,06 (w), 5,66 (w), 5,28 (w), 4,50 (w), 4,23 (w), and 3.22 (vs);
or
to form N:
19.5cm (m), 9,9 (w), 6,7 (w), 5,15 (w)of 4.83 (w), 3,91 (w), of 3.56 (m), to 3.33 (vs), 3,15 (w), 2,89 (w)2,81 (w)2,56 (w), and a 2.36 (w).

3. The crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-rays diffraction what's streaks powder
for forms And, as shown in figure 1; or
for F, as shown in Fig.6; or
for the form J, as shown in figure 10; or
for form K, as shown in figure 11; or
to form, as shown in figure 3; or
for form D, as shown in figure 4; or
for form E, as shown in figure 5; or
to form H, as shown in Fig; or
for forms, as shown in Fig; or
to form G, as shown in Fig.7; or
for the form I, as shown in Fig.9; or
to form L, as shown in Fig; or
for form M, as shown in Fig; or
to form N, as shown in Fig.

4. The method of obtaining crystalline form And dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dissolving the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin at ambient temperature in water, and (1) cooling the solution to a low temperature curing solution, and removing water at a pressure in the range from 0.01 to 1 mbar, or (2) removing water from the above-mentioned aqueous solution by filtration and drying by evaporation of water, and the allocation of the aforementioned crystalline form.

5. The method of obtaining crystalline form F dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dispersing particles of a solid form And dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in non-aqueous rest retele, which almost does not dissolve the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, below room temperature, stirring the suspension for a time sufficient for the formation of polymorph form F, and the allocation of the aforementioned crystalline form.

6. The method of obtaining crystalline form J dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which includes the form E and the removal of water from a form E by vacuum drying of the form E at an average temperature in the range of from about 25 to 70°C, and the allocation of the aforementioned crystalline form.

7. The method of obtaining crystalline form K dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dissolving the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in a mixture of acetic acid and alcohol containing a small amount of water and a small amount of ascorbic acid at an elevated temperature, reducing the temperature for crystallization dihydrochloride, separating the precipitate and drying the selected sludge at an elevated temperature, optionally in vacuo, and the allocation of the aforementioned crystalline form.

8. A method of obtaining a crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which includes the suspension of the dihydrochloride (6R)-L-ericr the-tetrahydrobiopterin in herstorical, adding sufficient for the formation of monohydrate amount of water and stirring the suspension at ambient temperature or below ambient temperature for time sufficient for the formation of the monohydrate, and the allocation of the aforementioned crystalline form.

9. The method of obtaining crystalline form D dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which includes the addition of approximately at room temperature, concentrated aqueous solutions dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin to excess herstories and stirring the suspension at ambient temperature, and the allocation of the aforementioned crystalline form.

10. The method of obtaining crystalline form E dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which includes the addition of a concentrated aqueous solution of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin to excess herstories cooled to a temperature of from about 10 to -10°C, and stirring the suspension at the said temperature, and the allocation of the aforementioned crystalline form.

11. A method of obtaining a crystalline form of N dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dissolving at ambient temperature dihydrochloride 6R)-L-Erythro-tetrahydrobiopterin in a mixture of acetic acid and water, where the amount of water slightly less than the amount of acetic acid, the addition of herstories, cooling the resulting suspension to a temperature of from -10 to 10°C. and stirring the suspension at the said temperature for some time, and the allocation of the aforementioned crystalline form.

12. A method of obtaining a crystalline form Of dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which includes maintaining polymorphic form F in a nitrogen atmosphere containing water vapor with a relative humidity of approximately 52% for approximately 24 h, and the allocation of the aforementioned crystalline form.

13. The method of obtaining crystalline form G of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dissolving at a temperature of from about room temperature up to 75°From dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in water, optional addition of ethanol required for the complete precipitation, or in a mixture of water and ethanol, cooling the heated solution to room temperature and then to 5-10°C., stirring the resulting suspension at a temperature from 20 to 5°C., filtering off white crystalline solid and drying the solids in air or in the atmosphere of inert gas or nitrogen at approximately room is based temperature and the selection mentioned crystalline form.

14. The method of obtaining crystalline form I dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dissolving the dihydrochloride of L-Erythro-tetrahydrobiopterin in a mixture of acetic acid and water at an elevated temperature, adding to the solution an additional amount of acetic acid, cooled to a temperature of approximately 10°C and heating the resulting suspension to about 15°C., followed by stirring the resulting suspension for a time sufficient to establish the phase equilibrium, the allocation of the aforementioned crystalline form.

15. A method of obtaining a crystalline form of L dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which includes a suspension of hydrated forms of E at room temperature in ethanol and stirring the suspension at a temperature of from 0 to 10°C for a time sufficient to establish the phase equilibrium, the allocation of the aforementioned crystalline form.

16. The method of obtaining crystalline form M dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dissolving the dihydrochloride of L-Erythro-tetrahydrobiopterin in ethanol and evaporation of the solution in a nitrogen atmosphere at a temperature surrounding the it environment or drying form G in a stream of dry nitrogen at a rate from approximately 20 to 100 ml/min, and the selection mentioned crystalline form.

17. A method of obtaining a crystalline form of N dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, which comprises dissolving the dihydrochloride of L-Erythro-tetrahydrobiopterin in a mixture of isopropanol and water, the addition of isopropanol, cooling the resulting suspension to about 0°C, stirring for several hours at this temperature, filtering the suspension, washing the solid residue with isopropanol at room temperature and drying the obtained crystalline material at ambient temperature and reduced pressure, and the allocation of the aforementioned crystalline form.

18. Pharmaceutical composition for the treatment of neurological disorders, which contains an effective amount of purified crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in accordance with claim 1, with a purity of at least about 98% according to high performance liquid chromatography, or a combination of more than one purified crystalline form, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

19. The pharmaceutical composition in accordance with p, which additionally contains folate, separately or together with arginine in an effective amount.

20. The pharmacy is practical composition in accordance with claim 19, in which folate is folic acid or tetrahydrofolate selected from tetrahydrofolic acid, 5,10-methylenetetrahydrofolic acid, 10-formyltetrahydrofolate acid, 5-formyltetrahydrofolate acid or 5-methyltetrahydrofolate acid, or its polyglutamate or its pharmaceutically acceptable salt.

21. The pharmaceutical composition in accordance with claim 19, in which folate is present as optically pure diastereoisomer, a mixture of diastereomers, or a racemic mixture, and/or the pharmaceutically acceptable salt is a salt of sodium, potassium, calcium or ammonium.

22. Pharmaceutical composition for the treatment of neurological disorders, which contains an effective amount of a stable, above about 20°C, purified crystalline polymorph dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, form B, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with the following characteristic peaks expressed in d values (Å): 8,7 (vs), 5,63 (m), was 4.76 (m), and 4.40 (m)4,00 (s), 3,23 (s), 3,11 (vs); or
which has a characteristic x-ray diffraction lines on the powder, as shown in figure 2;
and pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

23. Pharmaceutical composition for treating neurological Rastro the STV, which contains an effective amount of a stable, above about 20°C, purified crystalline polymorph dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, form B, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with the following characteristic peaks expressed in d values (Å): 8,7 (vs), 6,9 (w), 5,90 (vw), 5,63 (m), 5,07 (m), was 4.76 (m), and 4.40 (m), 4,15 (w)4,00 (s), 3,95 (m), 3,52 (m), 3,44 (w), 3,32 (m), 3,23 (s), 3,17 (w), 3,11 (vs), 3,06 (w), 2,99 (w), 2,96 (w)to 2.94 (m), 2,87 (w)2,84 (s), 2,82 (m), 2,69 (w), 2,59 (w), and 2,44 (w);
and pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

24. Pharmaceutical composition for the treatment of neurological disorders, which contains an effective amount of a stable, above about 20°C, purified crystalline polymorph dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, form B, which has a characteristic x-ray diffraction lines on the powder, as shown in figure 2;
and pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

25. Pharmaceutical composition for the treatment of neurological disorders, which contains an effective amount of the active ingredient where the above-mentioned active ingredient consists essentially of a stable, above about 20°C, purified crystalline polymorph dihydro who lorida (6R)-L-Erythro-tetrahydrobiopterin, form, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with the following characteristic peaks expressed in d values (Å): 8,7 (vs), 5,63 (m), was 4.76 (m), and 4.40 (m)4,00 (s), 3,23 (s), 3,11 (vs); or
which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with the following characteristic peaks expressed in d values (Å): 8,7 (vs), 6,9 (w), 5,90 (vw), 5,63 (m), 5,07 (m), was 4.76 (m), and 4.40 (m), 4,15 (w)4,00 (s), 3,95 (m), 3,52 (m), 3,44 (w), 3,32 (m), 3,23 (s), 3,17 (w), 3,11 (vs), 3,06 (w), 2,99 (w), 2,96 (w)to 2.94 (m), 2,87 (w)2,84 (s), 2,82 (m), 2,69 (w), 2,59 (w), and 2,44 (w);
or
which has a characteristic x-ray diffraction lines on the powder, as shown in figure 2;
and pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

26. The pharmaceutical composition in accordance with A.25, in which purified crystalline polymorph dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin has a purity of at least about 98% according to high performance liquid chromatography.

27. The method of obtaining crystalline polymorph dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å): 8,7 (vs), 5,63 (m), was 4.76 (m), and 4.40 (m)4,00 (s), 3,23 (s), 3,11 (s); or which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å): 8,7 (vs), 6,9 (w), 5,90 (vw), 5,63 (m), 5,07 (m), was 4.76 (m), and 4.40 (m), 4,15 (w)4,00 (s), 3,95 (m), 3,52 (m), 3,44 (w), 3,32 (m), 3,23 (s), 3,17 (w), 3,11 (vs), 3,06 (w), 2,99 (w), 2,96 (w)to 2.94 (m), 2,87 (w)2,84 (s), 2,82 (m), 2,69 (w), 2,59 (w), 2,44 (w); or which has a characteristic x-ray diffraction lines on the powder, as shown in figure 2;
then the next form,
where the method includes dispersing the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in a suitable solvent, which almost does not dissolve the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, at room temperature or above, and mixing the resulting suspension.

28. Method according to item 27, in which the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin is amorphous.

29. Method according to item 27, in which the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin is a crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å):
for form A, which is a crystalline polymorph:
15,5 (vs), 12,0 (m), 4,89 (m), 370 (s), of 3.33 (s), 3,26 (s), and 3,18 (m);
or
for form F, which is a crystalline polymorph:
17,1 (vs), to 4.92 (m), and 4.68 (m), 3,49 (s)of 3.46 (vs), 3,39 (s), 3,21 (m), and 3.19 (m);
or
for the form J, which is a crystalline polymorph:
14,6 (m), 3,29 (vs), and 3.21 (vs); or
for form K, which is a crystalline polymorph:
14,0 (s), and 6.6 (w), to 4.73 (m), with 4.64 (m), 3,54 (m)to 3.49 (vs), 3,39 (m)to 3.33 (vs), 3,13 (s)3,10 (m), 3,05 (m), 3,01 (m), 2,99 (m), and 2,90 (m);
or
for the form, which is a crystalline hydrate:
a 13.9 (vs), and 8.8 (m), 6,8 (m), equal to 6.05 (m), 4,25 (m)4,00 (m), 3,88 (m), 3,80 (m)and 3.59 (s), 3,50 (m), 3,44 (m), 3,26 (s), 3,19 (vs), 3,17 (s), 3,11 (m), 2,97 (m), and 2.93 (vs);
or
to form D, which is a crystalline hydrate:
8,6 (s), 5.56mm (m), 4,99 (m)4,67 (s), 4,32 (m)3,93 (vs), 3,17 (m), 3,05 (s), 2,88 (m), and 2.79 (m);
or
for form E, which is a crystalline hydrate:
15,4 (s), 4,87 (w), 3,69 (m)to 3.33 (s), 3,26 (vs), is 3.08 (m), 2,95 (m), are 2.87 (m);
or
to form H, which is a crystalline hydrate:
to 15.8 (vs), a 3.87 (m), 3,60 (m), with 3.27 (m), 3,21 (m), 2,96 (m), 2,89 (m), and to 2.67 (m);
or
to form Oh, which is a crystalline hydrate:
8,8 (m), and 6.3 (m), the 5.65 (m), is 5.06 (m)4,00 (m), 3,88 (m), 3,69 (s)to 3.64 (s), 3,52 (vs), 3,49 (s)of 3.46 (s), 3,42 (s), 3,32 (m), with 3.27 (m), 3,23 (s)3,18 (s), 3,15 (vs), 3,12 (m), and 3.04 (vs);
or
to form G, which is a crystalline ethanol MES:
14,5 (vs), 7.0mm (w)to 4.41 (w), 3,63 (m), 3,57 (m), 3,49 (w)to 3.41 (m), 3,26 (m), 3,17 (m), of 3.07 (m), 2,97 (m), 2,95 (m), 2,87 (w), and 2,61 (w);
or
for the form I which is a crystalline MES acetic acid:
14,5 (m)to 3.67 (vs), 3,61 (m), 3,44 (m), 3,11 (s), and 3,00 (m);
or
to form L, which is a crystalline ethanol mixed MES/hydrate:
14,1 (vs), 10,4 (w), 6,9 (w), 6.5 (w)and 6.1 (w), 4,71 (w), 3.46 in (m)to 3.36 (m), and 2.82 (w);
or
for form M, which is a crystalline ethanol MES:
18,9 (s)of 6.4 (m), and 3.22 (vs); or
to form N, which is a crystalline polymorph:
19.5cm (m), 6,7 (w), of 3.56 (m), and 3.33 (vs), 3,15 (w).

30. Method according to item 27, in which the solvent is selected from methanol, ethanol, C3 and C4 alcohols, acetic acid, acetonitrile, tetrahydrofuran, methyl-t-butyl ether, 1,4-dioxane, C3-C6 acetates, methyl ethyl ketone, methyl-C3-C5-alkylthio and their combinations.

31. The method of obtaining crystalline polymorph dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å): 8,7 (vs), 5,63 (m), was 4.76 (m), and 4.40 (m)4,00 (s), 3,23 (s), 3,11 (vs); or which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å): 8,7 (vs), 6,9 (w), 5,90 (vw), 5,63 (m), 5,07 (m), was 4.76 (m), and 4.40 (m), 4,15 (w)4,00 (s), 3,95 (m), 3,52 (m), 3,44 (w), 3,32 (m), 3,23 (s), 3,17 (w), 3,11 (vs), 3,06 (w), 2,99 (w), 2,96 (w)to 2.94 (m), 2,87 (w)2,84 (s), 2,82 (m), 2,69 (w), 2,59 (w), 2,44 (w); or which has characteristics which eticheskuyu x-ray diffraction lines on the powder, as shown in figure 2;
then the next form,
where the method includes dissolving a solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in the solvent, cooling the solution, and, optionally, depositing the seed in a solution.

32. The method in accordance with p, in which the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin is amorphous.

33. The method in accordance with p, in which the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin is a crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å):
for form A, which is a crystalline polymorph:
15,5 (vs), 12,0 (m), 4,89 (m), 3,70 (s)to 3.33 (s), 3,26 (s), and 3,18 (m);
or
for form F, which is a crystalline polymorph:
17,1 (vs), to 4.92 (m), and 4.68 (m), 3,49 (s)of 3.46 (vs), 3,39 (s), 3,2 (m), and 3.19 (m);
or
for the form J, which is a crystalline polymorph:
14,6 (m), 3,29 (vs), and 3.21 (vs); or
for form K, which is a crystalline polymorph:
14,0 (s), and 6.6 (w), to 4.73 (m), with 4.64 (m), 3,54 (m)to 3.49 (vs), 3,39 (m)to 3.33 (vs), 3,13 (s)3,10 (m), 3,05 (m), 3,01 (m), 2,99 (m), and 2,90 (m);
or
for the form, which is a crystalline hydrate:
a 13.9 (vs), and 8.8 (m), 6,8 (m), equal to 6.05 (m), 4,25 (m)4,00 (m), 3,88 (m)3,0 (m), 3,59 (s), 3,50 (m), 3,44 (m), 3,26 (s), 3,19 (vs), 3,17 (s), 3,11 (m), 2,97 (m), and 2.93 (vs);
or
to form D, which is a crystalline hydrate:
8,6 (s), 5.56mm (m), 4,99 (m)4,67 (s), 4,32 (m)3,93 (vs), 3,17 (m), 3,05 (s), 2,88 (m), and 2.79 (m);
or
for form E, which is a crystalline hydrate:
15,4 (s), 4,87 (w), 3,69 (m)to 3.33 (s), 3,26 (vs), is 3.08 (m), 2,95 (m), are 2.87 (m);
or
to form H, which is a crystalline hydrate:
to 15.8 (vs), a 3.87 (m), 3,60 (m), with 3.27 (m), 3,21 (m), 2,96 (m), 2,89 (m), and to 2.67 (m);
or
to form Oh, which is a crystalline hydrate:
8,8 (m), and 6.3 (m), the 5.65 (m), is 5.06 (m)4,00 (m), 3,88 (m), 3,69 (s)to 3.64 (s), 3,52 (vs), 3,49 (s)of 3.46 (s), 3,42 (s), 3,32 (m), with 3.27 (m), 3,23 (s)3,18 (s), 3,15 (vs), 3,12 (m), and 3.04 (vs);
or
to form G, which is a crystalline ethanol MES:
14,5 (vs), 7.0mm (w)to 4.41 (w), 3,63 (m), 3,57 (m), 3,49 (w)to 3.41 (m), 3,26 (m), 3,17 (m), of 3.07 (m), 2,97 (m), 2,95 (m), 2,87 (w), and 2,61 (w);
or
for the form I, which is a crystalline MES acetic acid:
14,5 (m)to 3.67 (vs), 3,61 (m), 3,44 (m), 3,11 (s), and 3,00 (m);
or
to form L, which is a crystalline ethanol mixed MES/hydrate:
14,1 (vs), 10,4 (w), 6,9 (w), 6.5 (w)and 6.1 (w), 4,71 (w), 3.46 in (m)to 3.36 (m), and 2.82 (w);
or
for form M, which is a crystalline ethanol MES:
18,9 (s)of 6.4 (m), and 3.22 (vs); or
to form N, which is a crystalline polymorph:
19.5cm (m), 6,7 (w), of 3.56 (m), and 3.33 (vs), 3,15 (w).

34. The method in accordance with p, to the which stage of dissolution is carried out at a temperature of approximately 20°to approximately 70°C;
and/or
stage cooling is carried out at a temperature of from about -40°C. to about 0°C.; and/or suspension contains less than about 5 wt.% water, based on the total weight of the suspension;
and/or the solvent is a mixture of water, acetic acid and tetrahydrofuran in a volume ratio of 1:3:2 to 1:9:4.

35. The method in accordance with clause 34, in which the solvent is a mixture of water, acetic acid and tetrahydrofuran in a volume ratio of approximately 1:5:4.

36. The method of obtaining crystalline polymorph dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å): 8,7 (vs), 5,63 (m), was 4.76 (m), and 4.40 (m)4,00 (s), 3,23 (s), 3,11 (vs); or which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å): 8,7 (vs), 6,9 (w), 5,90 (vw), 5,63 (m), 5,07 (m), was 4.76 (m), and 4.40 (m), 4,15 (w)4,00 (s), 3,95 (m), 3,52 (m), 3,44 (w), 3,32 (m), 3,23 (s), 3,17 (w), 3,11 (vs), 3,06 (w), 2,99 (w), 2,96 (w)to 2.94 (m), 2,87 (w)2,84 (s), 2,82 (m), 2,69 (w), 2,59 (w), 2,44 (w); or which has a characteristic x-ray diffraction lines on the powder, as shown in figure 2;
then the next form,
where the method includes dissolving a solid form of the dihydrochloride (6R)-L-e is the Jethro-tetrahydrobiopterin in the solvent, combining the resulting solution with a sufficient quantity of herstories with the formation of the suspension, and, optionally, mixing, and/or cooling, and/or depositing the seed in a mortar;
and the subsequent allocation of the formed crystalline form C.

37. The method in accordance with p, in which the solvent at the stage B) is water.

38. The method in accordance with p, in which the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin is amorphous.

39. The method in accordance with p, in which the solid form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin is a crystalline form of the dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin, which has a characteristic x-ray diffraction lines on the powder with radiation CuKα1with characteristic peaks expressed in d values (Å):
for form A, which is a crystalline polymorph:
15,5 (vs), 12,0 (m), 4,89 (m), 3,70 (s)to 3.33 (s), 3,26 (s), and 3,18 (m);
or
for form F, which is a crystalline polymorph:
17,1 (vs), to 4.92 (m), and 4.68 (m), 3,49 (s)of 3.46 (vs), 3,39 (s), 3,21 (m), and 3.19 (m);
or
for the form J, which is a crystalline polymorph:
14,6 (m), 3,29 (vs), and 3.21 (vs); or
for form K, which is a crystalline polymorph:
14,0 (s), and 6.6 (w), to 4.73 (m), with 4.64 (m), 3,54 (m)to 3.49 (vs), 3,39 (m)to 3.33 (vs), 3,13 (s)3,10 (m), 3,05 (m), 3,01 (m), 2,99 (m), and 2,90 m);
or
for the form, which is a crystalline hydrate:
a 13.9 (vs), and 8.8 (m), 6,8 (m), equal to 6.05 (m), 4,25 (m)4,00 (m), 3,88 (m), 3,80 (m)and 3.59 (s), 3,50 (m), 3,44 (m), 3,26 (s), 3,19 (vs), 3,17 (s), 3,11 (m), 2,97 (m), and 2.93 (vs);
or
to form D, which is a crystalline hydrate:
8,6 (s), 5.56mm (m), 4,99 (m)4,67 (s), 4,32 (m)3,93 (vs), 3,17 (m), 3,05 (s), 2,88 (m), and 2.79 (m);
or
for form E, which is a crystalline hydrate:
15,4 (s), 4,87 (w), 3,69 (m)to 3.33 (s), 3,26 (vs), is 3.08 (m), 2,95 (m), are 2.87 (m);
or
to form H, which is a crystalline hydrate:
to 15.8 (vs), a 3.87 (m), 3,60 (m), with 3.27 (m), 3,21 (m), 2,96 (m), 2,89 (m), and to 2.67 (m);
or
to form Oh, which is a crystalline hydrate:
8,8 (m), and 6.3 (m), the 5.65 (m), is 5.06 (m)4,00 (m), 3,88 (m), 3,69 (s)to 3.64 (s), 3,52 (vs), 3,49 (s)of 3.46 (s), 3,42 (s), 3,32 (m), with 3.27 (m), 3,23 (s)3,18 (s), 3,15 (vs), 3,12 (m), and 3.04 (vs);
or
to form G, which is a crystalline ethanol MES:
14,5 (vs), 7.0mm (w)to 4.41 (w), 3,63 (m), 3,57 (m), 3,49 (w)to 3.41 (m), 3,26 (m), 3,17 (m), of 3.07 (m), 2,97 (m), 2,95 (m), 2,87 (w), and 2,61 (w);
or
for the form I, which is a crystalline MES acetic acid:
14,5 (m)to 3.67 (vs), 3,61 (m), 3,44 (m), 3,11 (s), and 3,00 (m);
or
to form L, which is a crystalline ethanol mixed MES/hydrate:
14,1 (vs), 10,4 (w), 6,9 (w), 6.5 (w)and 6.1 (w), 4,71 (w), 3.46 in (m)to 3.36 (m), and 2.82 (w);
or for form M, which is a crystalline ethanol MES:
18,9 (s)of 6.4 (m), and 3.22 (vs); or for form N, which is predstavljaet a crystalline polymorph:
19.5cm (m), 6,7 (w), of 3.56 (m), and 3.33 (vs), 3,15 (w).

40. The method in accordance with p in which stage of cooling is carried out at a temperature of from about -40°C. to about 0°C.; and/or
the stage of dissolution is carried out at a temperature from about 10°to about 40°C.; and/or
herstorical choose from a group that includes methanol, ethanol, acetic acid and combinations thereof; and/or
concentration dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in the solvent is from about 10% to about 80% of the mass.

41. The method in accordance with p in which stage of dissolution is carried out at a temperature of approximately 23°C; and/or
concentration dihydrochloride (6R)-L-Erythro-tetrahydrobiopterin in the solvent is from about 20% to about 60% of the mass.

42. A method of obtaining a pharmaceutical composition having activity in the treatment of neurological disorders, by mixing an effective amount of the crystalline polymorph received on any of PP, 31 or 36 with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: source of radioactive iodine or radioactive bromine is added to an aqueous solution of an alkaline salt of folic acid so that pH of this solution is approximately 7 in order to obtain a solution which contains folic acid or an iodide or bromide ion. PH of this solution is then lowered to 3.5-4.9 by adding an oxidising agent selected from N-chlorosulfamides of acids in a buffer solution to the said solution. The oxidising agent is mainly chloramines T or chloramines B.

EFFECT: possibility of adding isotopic tags to folic acid through radicals.

2 cl, 2 ex

FIELD: vitamins, chemical technology, food industry, pharmacy.

SUBSTANCE: invention relates to crystalline alkaline-earth salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid with the content of at least one equivalent of crystallizing water per equivalent of 5-methyltetrahydrofolic acid, in particular, 5-methyl-(6R)-tetrahydrofolic acid crystalline calcium salt or to different types of 5-methyl(6S)-tetrahydrofolic acid crystalline calcium salts. These salts can be used in preparing medicinal agents or as a nutrition supplement for treatment or prophylaxis of folic acid-mediated diseases. Also, invention relates to a method for preparing crystalline salts of 5-methyl-(6R,S)-, -(6S)- and -(6R)-tetrahydrofolic acid by crystallization of the corresponding salt of 5-methyl-(6R,S)-, -(6S)- or -(6R)-tetrahydrofolic acid from a polar medium by using heat treatment at temperature above 60°C followed, if necessary, by drying the prepared product. Also, invention relates to a composition for pharmaceutical agents or nutrition supplements.

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

13 cl, 5 dwg, 4 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

The invention relates to a method for producing calcium folinata

The invention relates to new stable crystalline calcium or magnesium salts of (6R,S),(6S) - or (6R)-tetrahydrofolate acid, method for their production and pharmaceutical compositions based on them

The invention relates to crystalline forms of 6(R) or 6(S)-tetrahydrofolate acid, method for their production and pharmaceutical compositions

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

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: medicine, pharmaceutics.

SUBSTANCE: invention relates to 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol maleate of formula in form of enantiomer with absolute configuration (1R, 2R), which possesses pain-killing action.

EFFECT: invention relates to methods of obtaining said maleate, including crystalline forms A and B, pharmaceutical composition and application of maleate of formula (i) for preparation of pharmaceutical composition, intended for treatment of pain states.

33 cl, 4 dwg, 4 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to neurosurgery and biotechnology, and can be used for cultivation of nerve stem cells of mammal, excluding embryonic human cells, and for treatment of spasticity, rigidity, spinal cord or amniotrophic state in subject, requiring such treatment. For cultivation of said cells preliminarily incubated in culture vessel is solution, which contains poly-D-lysine in concentration from 0.1 mkg/ml to 1 mg/ml during from 5 minutes to 3 hours. After that, culture vessel is rinsed and dried. Nerve stem cells are inoculated into said culture vessel without serum. After that, solution of fibronectin and, at least, one mitogen is added into culture vessel and nerve stem cells are cultivated without serum. Then, cultivated nerve stem cells are passed until fusion. For treatment of said states nerve stem cells, cultivated be claimed method, are concentrated. Therapeutically efficient amount of said concentrated nerve stem cells is introduced into region of patient's central nervous system tissue with decreased level of GABA-producing or glycin-producing neurons.

EFFECT: group of inventions ensures efficient method of cultivating mammalian nerve stem cells, excluding embryonic human cells, which makes it possible to achieve in vitro higher degree of neuronal differentiation to the level sufficient for treatment of said states and improvement of survival in vivo of such cells, as well as efficient treatment of spasticity, rigidity or amniotrophic state in subject due to introduction into their central nervous system tissues with lower level of GABA-producing or glycin-producing neurons of cells, able to differentiate into sufficient number of GABA-producing or glycin-producing neurons in said tissue.

10 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to neurosurgery and biotechnology, and can be used for cultivation of nerve stem cells of mammal, excluding embryonic human cells, and for treatment of spasticity, rigidity, spinal cord or amniotrophic state in subject, requiring such treatment. For cultivation of said cells preliminarily incubated in culture vessel is solution, which contains poly-D-lysine in concentration from 0.1 mkg/ml to 1 mg/ml during from 5 minutes to 3 hours. After that, culture vessel is rinsed and dried. Nerve stem cells are inoculated into said culture vessel without serum. After that, solution of fibronectin and, at least, one mitogen is added into culture vessel and nerve stem cells are cultivated without serum. Then, cultivated nerve stem cells are passed until fusion. For treatment of said states nerve stem cells, cultivated be claimed method, are concentrated. Therapeutically efficient amount of said concentrated nerve stem cells is introduced into region of patient's central nervous system tissue with decreased level of GABA-producing or glycin-producing neurons.

EFFECT: group of inventions ensures efficient method of cultivating mammalian nerve stem cells, excluding embryonic human cells, which makes it possible to achieve in vitro higher degree of neuronal differentiation to the level sufficient for treatment of said states and improvement of survival in vivo of such cells, as well as efficient treatment of spasticity, rigidity or amniotrophic state in subject due to introduction into their central nervous system tissues with lower level of GABA-producing or glycin-producing neurons of cells, able to differentiate into sufficient number of GABA-producing or glycin-producing neurons in said tissue.

10 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and deals with medical form and method for delivery of medical substances, in particular, dependence habit-forming medical substances, which are characterised by stability to solvent extraction, compression, crushing and milling.

EFFECT: ensuring initial fast release of medicinal substance with following continuous period of controlled release of medicinal substance.

42 cl, 9 ex, 34 tbl, 22 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neonatology, and can be used for prevention of development of severe forms of bronchopulmonary dysplasia (BPD) in preterm newborn babies. For this purpose, in child of 3-4 days old presence of at least two of five criteria is detected: 1) gestation age <32 weeks, 2) performing artificial lung ventilation (ALV) for not less than 3 days or application of respiratory support with positive pressure in respiratory ways through nasal catheters, 3) dependence on oxygen in concentration more than 21% for not less than 3 days, 4) presence of symptoms of respiratory failure (RF) for more than 3 days, 5) X-ray changes in form of interstitial edema, nodose-reticular network, increased pneumatisation, homogenous shadows without hyperinflation. In case if at least two of said criteria are present, nebuliser treatment with budesonide is administered; if child had symptoms of moderate severe or severe RF, simultaneously inhalations with berodual or atrovent are carried out; in case of impossibility to disconnect child from ALV apparatus, aminofylline is added. On the 14-th day of life repeated examination is performed. From 14 to 28 day of life inhalations with budesonide are continued, in case of RF is absent; in case of RF of I-III degree - inhalations with budesonide with addition of berodual or atrovent, in case of impossibility to disconnect child from ALV apparatus, dexamethasone is applied.

EFFECT: invention contributes to efficient prevention of development of severe BPD in children of risk group due to differentiated administration of drug therapy.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and is intended for treatment of lingering versions of jaundice course in newborn babies. UDCA preparations are administered in dose 20-30 mg/kg per day, therapy is carried out for not less than 3 months. Viferon suppositories are administered rectally. Day dose is 50 thousand units/kg. Scheme of introduction is 10 days-daily, after that every second day from 3 to 9-12 months. Cytomegalovirus is suppressed with application of medication aciclovir-akri and its analogues zovirax, valtrex for 21-30 days. To suppress causing agents of mycoplasmosis, ureaplasmosis and chlamidiosis, preparations from group of macrolids rovamicin and sumamed are administered. Scheme is: rovamicin in dose 100 thousand units/kg for 7 days, after that, sumamed with a single dose 10 mg/kg once, according to discontinuous scheme 1 time per week, for 3 weeks. Additionally applied are medications, enhancing phagocytocis: licopid, polyoxydonium, solution of dimephosphone in age doses.

EFFECT: method makes it possible to reduce treatment terms and avoid complications.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely to infectious diseases, and can be used for treating a influenza virus infection, reduction of severity, intensity or length of the complications related to the influenza virus infection, and also to a composition for prevention of the influenza virus infection. That is ensured by diagnosing of the influenza virus infection is followed by introduction of an effective amount of cystamine or its salts to a subject. What is also offered is a composition for prevention of the influenza virus infection including an effective amount of cystamine or its salts, and an antiviral agent.

EFFECT: inventions provide clinical effectiveness, reduces risk of complications related to the influenza virus infection, and also promote prevention of the influenza virus infection.

16 cl, 2 dwg, 2 tbl, 3 ex

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