4-methyl-n-[3-4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide salts

FIELD: chemistry.

SUBSTANCE: invention relates to a novel sulphate of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide, which can be used in treating diseases which respond to protein kinase inhibition. The sulphate is obtained by reacting 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide in form of a free base with sulphuric acid in a solvent medium.

EFFECT: salt has low hygroscopicity and high solubility.

2 cl, 8 dwg, 17 tbl, 11 ex

 

This application claims priority in accordance with the application No. 60/701,406, filed in the U.S. Patent office on July 20, 2005, the text of this application is incorporated into the present application in full by reference.

The scope to which the invention relates.

The present invention relates to salts of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)-benzamide, as well as to methods for their preparation, to pharmaceutical compositions containing these compounds, and to methods of producing such compositions.

Prior art

The compound 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide formula

described in published international application WO 2004/005281 A1. This compound possesses valuable pharmacological properties, due to which it can be used, for example, as an inhibitor of protein kinase, which is used for the treatment of diseases that respond to inhibition of protein kinase activity. In published international application WO 2004/005281 A1 does not describe the specific salts or hydrates of the salts or solvate of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The invention

The present invention relates to the NML 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)-benzamide. Preferred embodiments of the present invention relate to such salts as the hydrochloride, monophosphate, diphosphate, sulfate, methanesulfonate, aconsultant, bansilalpet and p-toluensulfonate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

In addition, the present invention relates to a method of obtaining different crystalline salts of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide, the method includes the following stages: the interaction of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of the free base with an acid of the formula HB in the solvent environment.

The present invention additionally relates to pharmaceutical compositions, including:

(a) a therapeutically effective amount of the salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide; and

(b) at least one pharmaceutically acceptable carrier, diluent, excipient or filler.

The present invention also relates to a method of treatment of a disease that is affected by the inhibition of protein kinase activity, the method includes a step of introducing to a patient in need of such treatment, Ter is piticescu effective amount of the salt of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

Brief description of drawings

The figure 1 shows the spectra of powder x-ray diffraction (XRPD) modifications and salt is hydrochloride of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The figure 2 shows the spectrum of the powder x-ray diffraction (XRPD) salt - monophosphate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The figure 3 shows the spectrum of the powder x-ray diffraction salt - diphosphate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The figure 4 shows the spectra of powder x-ray diffraction modifications and salt - sulfate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The figure 5 shows the spectrum of the powder x-ray diffraction salt - methansulfonate (nelfinavir) 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The figure 6 shows the spectrum of the powder x-ray diffraction salt - econsultant 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The figure 7 shows the spectrum of the powder x-ray diffraction salt - benzosulfimide 4-methyl-N-[3-(4-Mei-1-yl)--triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

The figure 8 shows the spectrum of the powder x-ray diffraction salt - n-toluensulfonate 4-methyl-N-[3-(4-Mei-1-yl)-5-Cryptor-were]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

Detailed description of the invention

The present invention relates to salts of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)-benzamide; the preferred implementation of such salts are described below. In General terms, when used in the text of this application, the term “salt” refers to a compound obtained by the interaction of the drug in the form of acid or base with a pharmaceutically acceptable inorganic or organic acid or base; when used in the text of this application, the term “salt” includes hydrate and solvate salts obtained in accordance with the present invention. Examples of pharmaceutically acceptable inorganic or organic acids or bases are listed in tables 1-8 in: Handbook of Pharmaceutical Salts, P.H. Stahl, C.G. Wermuth (eds.), VHCA, Zurich, pp.334-345 (2002). When used in the text of this application, the term “polymorphs” refers to certain “crystalline modifications” or “polymorphs” or “crystalline forms which differ from each other in their spectra, powder x-ray diffraction, fizi what about the chemical and/or pharmacokinetic properties and thermodynamic stability. In the application for U.S. patent No. 60/701,405 (Attorney Docket No.4-34384), filed concurrently with the present application, describes the different polymorphic modifications of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide and its salts; included in the text of this application in full by reference.

The first variant of implementation of the present invention refers to a salt, the hydrochloride of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. Salt is a hydrochloride (modification, monohydrate) with good reproducibility can be obtained from methanol, in the case when using one equivalent chloroethanol acid. This modification is hygroscopic (at the first testing water absorption amounted to 2% at 60% relative humidity and up to 2.7% at 95% relative humidity, although subsequent testing showed even higher moisture absorption). It is poorly soluble in water and poorly soluble in HCl 0.1 N., ethanol and 2-propanol. In the study by the method of thermogravimetric analysis (TGA) observed two stages of weight loss. The first stage (at approximately 80°C) relates to the dehydration, and the second stage of mass loss (at approximately 173°C) refers to the loss of HCl (decomposition). The crystal structure of this compound varies from well is to great, the connection becomes amorphous when grinding and can withstand the load. Salt is a hydrochloride is stable at room temperature in the conventional estimates of the equilibrium state. Also highlighted other polymorphic modifications of salt is hydrochloride, i.e. modifications of a, a', A", A', SB, SB', S', SC, D, and SE. Range of powder x-ray diffraction modifications and salt is hydrochloride of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 1.

The second variant implementation of the present invention refers to a salt - monophosphate 4-methyl-N-[3-(4-Mei-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. Monosol acid (H3PO4reproducibly obtained from methanol, in the case when using one equivalent of phosphoric acid. The mass loss from room temperature to 200°C) is approximately 0,29%, the sample melts at approximately 208°C and decomposes at about 212°C. the Crystal structure is excellent. Range of powder x-ray diffraction salt-monophosphate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 2.

The third option of implementing the present invention relates to salt - bisphosphate 4-methyl-N-[-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. Dial acid (H3PO4can be obtained from methanol, in the case when using two equivalents of phosphoric acid. The mass loss from room temperature to 200°C) is about 0.2%, the sample decomposes at approximately 210°C. Range of powder x-ray diffraction salt - diphosphate 4-methyl-T-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 3.

The fourth option of implementing the present invention relates to salt - sulfate, 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. Salt of sulfuric acid (H2SO4)(modification) reproducibly obtained from methanol, in the case when using one equivalent of sulfuric acid. The mass loss from room temperature to 200°C) is about 0.15%, and the sample melts with decomposition at about 206°C. the Crystal structure varies from poor to good. Highlighted another form (option A)and the amorphous modification. Spectra, powder x-ray diffraction modifications and salt - sulfate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 4.

The fifth implementation of the present invention refers to a salt - meta is the sulfonate (mesilate) 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. This salt reproducibly obtained from ethyl acetate, in the case when using one equivalent methanesulfonic acid. The mass loss from room temperature to 150°C) is approximately 0.44 per cent, and the sample melts at about 160°C and decomposes at approximately 260°C. the Crystal structure is bad. Range of powder x-ray diffraction salt - methansulfonate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 5.

Sixth variant of implementation of the present invention refers to a salt - econsultancy 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. This salt reproducibly obtained from the ethyl acetate in the case when using one equivalent econsultancy acid. The mass loss from room temperature to 150°C) is approximately 0,74%, and the sample melts at about 259°C and decomposes at approximately 220°C. the Crystal structure is bad. Range of powder x-ray diffraction salt - econsultant 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 6.

Seventh variant of implementation of the present invention refers to a salt - benzosulfimide 4-methyl-N-[3-(4-Mei-1-yl)5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. This salt reproducibly obtained from ethyl acetate, in the case when using one equivalent of benzosulfimide acid. The mass loss from room temperature to 250°C) is approximately 0.63%, and the sample melts with decomposition at approximately 260°C. the Crystal structure varies from the structure of bad to good. Range of powder x-ray diffraction salt - benzosulfimide 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 7.

Eighth variant of implementation of the present invention relates to salt - n-toluensulfonate 4-methyl-N-[3-(4-Mei-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. This salt reproducibly obtained from the ethyl acetate in the case when using one equivalent of p-toluensulfonate acid. The mass loss from room temperature to 150°C) is approximately 0.26%of the sample melts at approximately 187°C and decomposes at about 256°C. the Crystal structure varies from good to excellent. Range of powder x-ray diffraction salt - n-toluensulfonate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide shown in figure 8.

Another variant of implementation of the present invention relates to sposobu obtaining a number of crystalline salts of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)-benzamide according to the following scheme:

More specifically, salts of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide get through interaction of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of the free base with an acid of the formula NR in the environment of the solvent. Such interaction is usually carried out in two stages, although the scope of the invention also includes a simple join as a free base and acid in the solvent environment at the same time.

In the first stage, 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base is dissolved or suspended in a suitable solvent at suitable temperatures. Solvents suitable for use in accordance with the present invention, include, but are not limited to, methanol, ethanol, 2-propanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, and combinations thereof. The person skilled in the art can easily determine the required number of reasons that you want to use, and suitable temperature regimes.

In the second stage of the method according to the present invention, 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-Ilam is but)benzamide in the form of the free base is treated with a suitable acid of formula HB. Since the pKa value for 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of the free base form of 5.1 and 3.9, soleobrazutaya acid with a pKa of 0.1 are able to form with him a stable crystalline salt. Suitable acids include, but are not limited to, inorganic acids such as chloromethane acid, phosphoric acid, sulfuric acid and sulfonic acid, and organic acids, such as methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, citric acid, fumaric acid, gentisic acid, malonic acid, maleic acid and tartaric acid.

In optional stage of the method according to the present invention the salt of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide allocate by filtration or other suitable means and the selected salt is dried to remove residual solvent. In accordance with a preferred embodiment the salt is a hydrochloride is first obtained as methanol MES, which is then exposed to moisture in order to turn into salt - monohydrate hydrochloride.

In particular, the preferred implementation n the present invention relates to a method of obtaining monohydrate monochloride 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide, the method includes the following stages:

(a) combining 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base and chloroethanol acid in methanol in a nitrogen atmosphere;

(b) heating the reaction mixture to a temperature ranging from about 42-50°C;

(C) stirring the reaction mixture;

(g) filtering the reaction mixture while maintaining the temperature above 40°C with getting this transparent solution;

(d) cooling the clear solution to about 30°C under stirring in nitrogen atmosphere;

(e) introducing the solution of the seed;

(g) cooling the solution containing the seed to approximately 23°C;

(C) stirring the solution with the receipt of the suspension;

(I) cooling the resulting suspension to about -10°C;

(K) mixing the resulting suspension;

(l) filtering off solids;

(m) washing the solids with cold methanol; and

(h) drying the solids at about 50-55°C and 10-20 Torr to obtain this salt monohydrate monochloride 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

In accordance with the preferred embodiment of the present invention the mixing provocativelysomething 15 minutes on stage (in), cooling is carried out for about 30 minutes on stage (d), the cooling is conducted for approximately 45 minutes on stage (g), stirring is carried out for approximately 3 hours at the stage (C), cooling is carried out for about 1.5 hours on stage (and), the stirring is conducted for about 30 minutes on stage (K), cold methanol, used in stage (m) has a temperature, which is approximately -10°C, and/or drying is conducted for about 8-16 hours.

The tenth variant of implementation of the present invention relates to pharmaceutical compositions, including:

(a) a therapeutically effective amount of the salt of 4-methyl-T-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide; and

(b) at least one pharmaceutically acceptable carrier, diluent, excipient or filler.

The term “therapeutically effective amount” is used for such amount of salt according to the present invention that, when administered to a patient in need this, it is enough to treat this painful condition, which is facilitated by inhibition of protein kinase activity. The amount of certain compounds according to the present invention, which is therapeutically effective amounts of the m, will greatly vary depending on such factors as type of disease and the severity of its symptoms, features of a patient in need of treatment, and the like, the specified number may be installed in a conventional manner an ordinary specialist in the field.

The specified at least one pharmaceutically acceptable carrier, diluent, excipient or filler can be easily selected ordinary person skilled in the art and will be determined necessary by way of introduction. Examples of suitable routes of administration include oral, nasal, parenteral, local, transdermal, and rectal administration. The pharmaceutical compositions according to the present invention may be any pharmaceutical form which the person skilled in the art will deem acceptable. Suitable pharmaceutical forms include solid, semi-solid, liquid and lyophilized preparations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.

Eleventh variant of implementation of the present invention relates to a method of treatment of a disease which responds to inhibition of protein kinase activity, the method includes a step of introducing to a patient in need of such treatment, a therapeutically effective amount with the Lee 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide. As noted above example, the possible routes of administration include oral, nasal, parenteral, local, transdermal, and rectal administration. Introduction crystalline modification can be accomplished through the introduction of a pharmaceutical composition, representing the ninth variant of implementation of the present invention or by other effective means.

The following examples illustrate specific embodiments of the present invention. However, it should be noted that the examples given are for illustration only and do not limit the scope of the present invention.

Example 1. Getting salt monohydrate monohydrochloride

In chetyrehosnuju round bottom flask with a capacity of 1 l, equipped with a mechanical stirrer, a thermometer, a unit to perform heating/cooling and funnel, consistently load 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of the free base (10 g), methanol (250 ml) and 37%chloroethanol acid (1.85 g) in a stream of nitrogen. The resulting mixture was heated to 42-50°C and stirred additionally for 15 minutes. The resulting solution was filtered through a layer ("pillow") polypropylene, maintaining the temperature above 40°C. a Clear solution is arenasat in nitrogen atmosphere to another chetyrehosnuju round bottom flask with a capacity of 1 l, equipped with a mechanical stirrer, thermometer and a block for performing heating/cooling. The mass is stirred and cooled to 30°C for 30 minutes. At this temperature, add a seed crystal (20 mg) and the mass is then cooled to 23°C for 45 minutes. The resulting mass is stirred additionally for 3 hours, thus obtaining a thick white suspension. This suspension is cooled to -10°C for 1.5 hours and stirred additionally for 30 minutes. All the solid is collected by filtration and washed with cold (-10°C) methanol (20 ml). The solid is dried at 50-55°f/10-20 Torr within 8-16 hours, while receiving g - monohydrate monochloride 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (9.8 g) as a white solid.

1H NMR 300 MHz, DMSO-d6), δ 10,9 (s, 1H), 9,58 (s, 1H), 9,29 (s, 1H), 9,20 (s, 1H), to 8.70 (d, 1H), 8,63 (s, 1H), 8,55 (d, 1H), 8,49 (d, 1H), 8,32 (d, 2H), 8,00 (s, 1H), to $ 7.91 (s, 1H), to 7.84 (d, 1H), 7,56-7,44 (m, 3H), 2.50 each (s, 3H), of 2.35 (s, 3H); in the spectrum of the powder x-ray diffraction observed maxima at 2θ=7,4°, 9,4°, 11,6°, 12,1°, 15,8°, 19,3°, 19,6°, 22,1°, 24,1°, 25,7°.

Example 2. Obtaining salt - monophosphate

In a round bottom flask with a capacity of 1 l, equipped with a mechanical stirrer, thermometer and reflux condenser are placed 4 g of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Lai is rimidine-2-ylamino)benzamide in the form of a free base and 500 ml of methanol. The resulting suspension is stirred and heated to 64°C, and then maintained at this temperature for ~30 minutes. To the resulting clear solution was added 7.5 ml of 1 M solution of phosphoric acid (in methanol). The resulting mixture was stirred at 64°C for one hour, cooled to room temperature naturally (cooling rate ~0.5°C/min) and incubated at room temperature for 3-4 hours. The solid is collected by filtration and dried at 50-55°f/10-20 Torr within 8-16 hours, while receiving salt - monophosphate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (3.25 g) as a white solid. Melting point = ~208°C (with decomp.); in the spectrum of the powder x-ray diffraction observed maxima at 2θ=6,1°, 7,5°, 9,1°, 15,8°, 17,5°, 18,3°, 21,8°, 23,1°, 24,9°, 26,6°.

Example 3. Obtaining salt - methansulfonate

In a reactor with a capacity of 75 ml equipped with a thermometer and reflux condenser, are placed 307 mg of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base and 30 ml of ethyl acetate. The resulting suspension is stirred and heated to 76°C. To the solution was added 580 μl of 1 M solution methanesulfonic acid (ethyl acetate). The resulting mixture is stirred is at 76°C for six hours, cooled to 25°C at a rate of 0.5°C/min and maintained at 25°C during the night. The solid is collected by filtration and dried at 50-55°f/10-20 Torr within 8-16 hours, while receiving salt - mesilate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (~250 mg) as a yellowish solid. In the spectrum of the powder x-ray diffraction observed maxima at 2θ=7,7°, 10,1°, 20,3°, 26,2°.

Example 4. Obtaining salt - benzylmalonate

In a round bottom flask with a capacity of 1 l, equipped with a mechanical stirrer, thermometer and reflux condenser, a load of 4 g of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base and 500 ml of ethyl acetate. The resulting suspension is stirred and heated to 76°C (reflux) and maintained at this temperature for 40 minutes. To the resulting clear solution was added 7.5 ml of 1 M solution of benzosulfimide acid (ethyl acetate). The resulting mixture was stirred at 76°C for 5 hours, cooled to room temperature by natural cooling (cooling rate ~0.5°C/min) and incubated at room temperature for ~1 hour. The solid is collected by filtration and dried at 50-55°f/10-20 Torr in those who tell 8-16 hours while receiving salt - monopersulfate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a yellowish solid. Melting point = ~260°C; in the spectrum of the powder x-ray diffraction observed maxima at 2θ=6,5°, 7,8°, 9,4°, 10,4°, 13,7°, 17,0°, 17,5°, 17,9°, 18,8°, 21,2°.

Example 5. Getting salt p-toluensulfonate

In a reactor with a capacity of 75 ml equipped with a thermometer and reflux condenser, are placed 305,6 mg of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base and 30 ml of ethyl acetate. The resulting suspension is stirred and heated to 76°C. To the resulting solution was added 580 μl of 1 M solution of p-toluensulfonate acid (ethyl acetate). The resulting mixture was stirred at 76°C for six hours, cooled to 25°C at a rate of 0.5°C/min and maintained at 25°C during the night. The solid is collected by filtration and dried at 50-55°f/10-20 Torr within 8-16 hours, while receiving salt - n-toluensulfonate 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (~250 mg) as a white solid. Melting point = ~187°C; in the spectrum of the powder x-ray diffraction observed maxima at 2θ=7,3°, 15,4°, 16,1°,17,5°, 18,3°, 19,0°, 19,7°, 22,5°.

Example 6. Salt is a hydrochloride

4-Methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base and approximately 400 ml of methanol are placed in a flask. With stirring, add dropwise 744,4 mg 37%HCl solution. The suspension becomes transparent. The resulting solution was stirred for 30 minutes. Then the solution is concentrated to 100 ml. of the resulting solution was then stirred for 2 hours; receive a suspension. This suspension is filtered and dried under vacuum overnight at 50°C. Polymorphic modification To get to the exit, constituting approximately 72.6 per cent.

Example 7

Approximately 50-60 mg modification And 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base is suspended in 0.75 ml of the indicated solvent. Then the suspension is added a stoichiometric amount of the appropriate acid. In the case of inorganic acids resulting mixture was stirred at ambient temperature for about 5 hours, and in the case of sulfonic acids obtained mixture was stirred at 50°C during the night. The solid is collected by filtration and analyzed by powder x-ray diffraction and NMR.

Table 1
Getting the salt is hydrochloride
SolventCommentsResults
The crystallinity*1H-NMR
MethanolAfter adding HCl suspension becomes more liquid.Good; modificationThe peak of the solvent is missing
EthanolAfter adding HCl suspension becomes more liquid.Good; modification And&InThe peak of the solvent is missing
2-PropanolAfter adding HCl suspension becomes more liquid.Good; modification AndThe peak of the solvent is missing
AcetoneAfter adding HCl suspension becomes more liquid.Excellent; modification And---
The ethyl acetateIn the Le add HCl suspension becomes more liquid. Good; modification And&In---
TetrahydrofuranAfter adding HCl suspension becomes more liquid.Excellent; modification And---
AcetonitrileAfter adding HCl suspension becomes more liquid.Excellent; modification And & In---
* excellent = when main peaks sharp and their intensity more than 70 times,
good = when main peaks sharp and their intensity in the range of 30-70 times.

Table 2
Obtaining salt - sulfate
SolventCommentsResults
The crystallinity*1H-NMR
MethanolAfter adding H2SO4the suspension is ranovitsa more liquid. Good; modification And&InThe peak of the solvent is missing
EthanolAfter adding H2SO4the suspension becomes more liquid.Good; modificationThe peak of the solvent is missing
2-PropanolAfter adding H2SO4the suspension becomes more liquid.Poor---
AcetoneAfter adding H2SO4the suspension becomes more liquid.Poor---
The ethyl acetateAfter adding H2SO4the suspension becomes more liquid.Poor---
TetrahydrofuranAfter adding H2SO4the suspension becomes more liquid.Poor---
AcetonitrileAfter adding H2SO4the suspension becomes more liquid.Loja ---
* good = when main peaks sharp and their intensity is in the range of 30-70 times
bad = when main peaks are broad and their intensity is lower than 30 times; may refer to an amorphous salt and the free base in the form of modifications And

Table 3
Obtaining salt - methansulfonate
SolventCommentsResults
The crystallinity*1H-NMR
AcetoneThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Poor1) 1,3% (wt.) acetone 2) acid: base = 1,2:1,0
TetrahydrofuranThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Amorphous substances is about ---
* bad = when main peaks are broad and their intensity is lower than 30 times

Table 4
Obtaining salt - econsultant
SolventCommentsResults
The crystallinity*1H-NMR
AcetoneThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Good1) in 0.9% (wt.) acetone 2) acid : base = 1,4:1,0
TetrahydrofuranThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Poor

* good = when main peaks sharp and their intensity in the range of 30-70 times
bad = when main peaks are broad and their intensity is lower than 30 times

In the case of salt - econsultant obtained from acetone, in the spectrum of the powder x-ray diffraction observed maxima at 2θ=6,6°, 7,9°, 9,5°, 14,2°, 17,8°.

Table 5
Obtaining salt - benzosulfimide
SolventCommentsResults
The crystallinity*1H-NMR
TetrahydrofuranThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Poor1) 1,2% (wt.) THF 2) acid : base = 1,4:1,0
AcetoneThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Poor
* bad = in the case when cos the main peaks are broad and their intensity is lower than 30 times

Table 6
Obtaining salt - n-toluensulfonate
SolventCommentsResults
The crystallinity*1H-NMR
TetrahydrofuranThe suspension becomes more liquid after adding acid. Does not become clear at 50°C. the White solid is obtained by filtration.Good1)4,6% (wt.) THF 2) acid: base = 1,2:1,0
AcetoneThe suspension becomes more liquid after adding acid. Does not become clear at 50°C. the White solid is obtained by filtration.Good
* good = when main peaks sharp and their intensity in the range of 30-70 times.

Example 8

Approximately 300 to 310 mg of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)is ansamed in the form of a free base, modification In, suspended in 9 ml of 2-propanol in the case of HCl and 15 ml of acetone in the case of sulfonic acids. To the suspension is then added a stoichiometric amount of the specified acid. In the case of HCl the resulting mixture was stirred at ambient temperature for 5 hours, and in the case of sulfonic acids obtained suspension is stirred at 50°C during the night. Then the mixture is cooled to ambient temperature, carry out the filtering and the resulting product analyzed by the methods of powder x-ray diffraction and NMR.

Table 7
Results
AcidCommentsThe crystallinity1H-NMR
HClAfter adding HCl1) Good1) the Values of the shifts changed
the suspension becomes yellow, then not quite white. After incubation for 4 hours, the suspension becomes pasty, bad flows is poorly filtered. 2) Modification And
2) the Peak of the solvent is missing
Methane-sulfonic acidThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Poor1) the Values of the shifts changed
2) of 0.67% (wt.) acetone
Econsultancy acidThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C.Poor1) the Values of the shifts changed
2) the peak of the solvent
p-Tawassul-background acidThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C. the White solid is obtained by filtration.Good1) the Values of the shifts changed
2) the peak of the solvent is missing

Example 9

Washed with 100 mg of 4-methyl-N-[3-(4-Mei-1-yl)-5-t is iformatter]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base, modification In, suspended in 15 ml of methanol in the case of inorganic acids Yves 15 ml of THF in the case of the sulfonic acids listed below. Then add a stoichiometric amount of these acids to the suspension, except for H3PO4for which use two equivalent. The resulting solution was stirred at 50°C for about 5 hours and then cooled to ambient temperature. The solid is collected by filtration of the resulting suspension; in addition, use of a weak current of the N2for evaporation of a certain amount of the solvent, while receiving more dense suspension for filtering. The solid is analyzed by powder x-ray diffraction and NMR.

Table 8
AcidCommentsResults
The crystallinity1H-NMR
HClAfter heating the suspension becomes transparent and remains so. Use a weak current of the N2for evaporation of a certain amount of solvent.1) Good 1) the Values of the shifts changed
2) Modification
2) the peak of the solvent is missing
H2SO4After heating the suspension becomes transparent. When cooled thickens.1) Good1) the Values of the shifts changed
2) modification of a+b
2) <2% methanol
H3PO4The suspension becomes1) Excellent1)
(diphosphate)more liquid after addition of acid.2) Differs from the free base and monosolshifts are not changed 2) the peak of the solvent is missing
Methane-sulfonic acidThe suspension becomes more liquid and turns yellow after addingPoor1) the Values of the shifts changed
the acid. Does not become clear at 50°C. 2) the peak of the solvent is missing
Benzene-sulfonic acidThe suspension becomes more liquid and turns yellow after addingGood1) the Values of the shifts changed
the acid. Does not become clear at 50°C.2) the peak of the solvent is missing
p-Toluene sulfonic acidThe suspension becomes more liquid and turns yellow after adding acid. Does not become clear at 50°C. the White solid is obtained by filtration.Excellent1) the Values of the shifts changed
2) the peak of the solvent is missing

To test the possibility of salt - diphosphate using elemental analysis. The following results are obtained:

Table 9
NNP
In theory the second 45,913,8313,39of 8.47
H3PO4above45,863,8113,329,01

Example 10

Approximately 100 mg of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base, modified, suspended in 15 ml of methanol in the case of HCl and H2SO4Yves 15 ml of ethyl acetate in the case methanesulfonic acid. Then the suspension is added the specified number corresponding to the specified acid. The resulting solution was stirred at ambient temperature (HCl) or 50°C (H2SO4and methansulfonate acid). The solid obtained when the process of evaporation of the solvent using a low current N2and analyzed by powder x-ray diffraction and NMR.

Table 10
AcidCommentsResults
The crystallinity1H-NMR
1 equivalent HClWhen heating the suspension becomes transparent and remains the same.1) Good1) the Values of the shifts changed
2) modification2) the peak of the solvent is missing
2 equivalent HClWhen heating the suspension becomes transparent and remains the same.Amorphous substance
0.5 equivalent of H2SO4When heating the suspension becomes transparent and remains the same.1) Good1) the Values of the shifts changed
2) modification of the a & free base modification In2) a small peak of solvent
1 equivalent of H2SO4The suspension becomes transparent after adding the acid remains the same.1) Good1) the Values of the shifts changed
2) modification And2) the peak of the solvent does not is t
1 equivalent of methane-sulfonic acidThe suspension becomes transparent after adding acid and remains after conditioning for at least 4 hours.Poor1) Acid: base = 1,3:1,0
2) the peak of the solvent is missing
2 equivalent methane-sulfonic acidThe suspension becomes transparent after adding acid and remains after conditioning for at least 4 hours.Poor1) Acid: base = 1,9:1,0
2) the peak of the solvent is missing

Example 11

Approximately 300 mg of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of a free base, modified, suspended in 30 ml of methanol in the case of inorganic acid and 30 ml of ethyl acetate in the case of sulfonic acids. The resulting suspension is heated under reflux to a temperature of flavobacteria -64°C in the case of methanol and 76°C in the case of ethyl acetate. Then add a stoichiometric amount of the specified acid dissolved in a match who eat solvent. The resulting solution was stirred at the boil under reflux for 5 hours and then cooled to ambient temperature. The solid is collected by filtration and analyzed by powder x-ray diffraction.

Table 11
AcidCommentsForm
H2SO4The suspension becomes transparent while boiling under reflux. The solid precipitate upon standing.1) Sulfate
2) Modification
H3PO4The suspension becomes transparent while boiling under reflux. The solid precipitate upon standing.Monophosphate
Methane-sulfonic acidThe mixture boiling under reflux remains in suspension. It becomes less dense and turns yellow after addition of acid.Methanesulfonate
Benzene-sulfonic acid The mixture boiling under reflux remains in suspension. It becomes less dense and turns yellow after addition of acid.Bansilalpet
p-Toluene-sulfonic acidThe mixture boiling under reflux remains in suspension. Becomes transparent after adding acid.p-Toluene-sulfonate

Thermal behavior

Losses during drying (LOD) and the decomposition temperature of the salts according to the present invention is determined by the method of thermogravimetric analysis (TGA), the melting temperature is determined by the method of differential scanning calorimetry (DSC).

Table 12
SolLosses during dryingDecomposition temperature (°C)*Melting point (°C)
Hydrochloride (option)2,60% (room temperature - 150°C) 4,87% 150-250°C)
Monophosphate0,29% (room temperature - 200°C)212 -208
Sulfate0,15% (room2011) 126.5
(option)temperature - 200°C)2) 206,2
Methanesulfonate0,44% (room temperature - 150°C)260160,1
Econsultant0,74% (room2201) 259,2
temperature - 150°C)2) 261,3
Bansilalpet0,63% (room temperature - 250°C)260>258,7
p-Toluene0,26% (room2561) 187
sulfonatetemperature - 150°C)2) 232
* Decomposition temperature determined by the first derivative of the La TGA curve temperature (based on the mass loss temperature)

Hygroscopicity

The hygroscopicity of the salts according to the present invention, are determined by thermogravimetric analysis after one day of finding at ambient temperature and at 93% relative humidity.

Table 13
SolIncrease humidity, %
Hydrochloride (option)0,20
Monophosphate1,33
Sulfate (option)0,22
Methanesulfonate0,22
Econsultant1,11
Bansilalpet0,11
p-Toluensulfonate1,02
Control - in the form of a free base modification In0,08

It should be noted that in further tests, the data concerning the hygroscopicity change, at least in relation to salt is the hydrochloride, when testing the moisture can be lost too quickly is, that distorts the true value; this can also occur with other salts.

Solubility

The solubility of the salts according to the present invention determines, using buffers with a pH of 6.8, pH 3.0 and pH of 1.0 by suspension 1-5 mg of each salt in 10 ml of the appropriate aqueous solution. Samples left to reach equilibrium at ambient temperature for at least 20 hours at a pH of 6.8 and 3.0, or for approximately 5 hours pH of 1.0. The supernatant was filtered and used for determining the solubility by UV spectroscopy in the visible region (UV-VIS). The solid residue is analyzed by powder x-ray diffraction.

Table 14
The dissolved substanceSolubility at pH of 6.8(µg/ml)Solubility at pH 3.0 (µg/ml)Solubility at pH of 1.0 (g/ml)
Salt is a hydrochloride (option)0,30,91040
Sol - monophosphate--------1160
Salt - sulfate (modify the tion In) 0,16,51380
Sol-methanesulfonate0,45,21330
Sol-econsultant0,42,8----
Sol-bansilalpet<3,0----1420
Sol - p-toluene-sulfonate<8,0<10,01340
Control - in the form of a free base-modification0,22,8839

Comparative testing

Stability as 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of the free base (option b), or salt monohydrate hydrochloride of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (modification In) investigated thus, as described below.

Table 15
Test conditionView salt
Free base (option)Monohydrate hydrochloride (option)
Decomposition productsAppearanceDecomposition productsAppearance
Data analysis [% area]Data analysis [% area]
Without load0,00 100,99 [100,001----0,00 99,10 [100,00]----
0.1% solutions or suspensions, 1 week at 80°C
pH 1 (pH60,61A*62,06A*
measured: 1,26) pH 1; 1 week @ 50°C50,22 [45,31] 6,58 94,01 [93,44]A*46,68 [42,93] 6,86 94,14 [93,21]A*
pH 2 (pH measured: 2,00) 5,20 96,00 [94,86]In↓to 8.41 91,77 [91,61]In↓
pH 3 (pH measured: 2,94)0,00 102,19 [100,00]And↓0,00 98,84 [100,00]In↓
pH 5 (pH measured: 5,01)0,00 100,80 [100,00]A↓0,00 100,02 [100,00]And↓
pH 7 (pH measured: 6,02)0,00 100,14 [100,00]And↓0,00 99,56 [100,00]In↓
pH 9 (pH measured: 8,92)0,00 99,19 [100,00]And↓0,00 101,19 [100,00]In↓
pH 11 (pH measured: 10,86)0,00 100,50 [100,00]And↓0,00 102,19 [100,00]B↓
Water (pH measured: 4,74)(pH measured for HCl salt: 4,22)0,00 101,93 [100,00]And↓0,00 101,43 [100,00]And↓
Ethanol0,04 99,85 [99,96]A*0,06 100,41 [100,00]A*
Acetonitrile0,00 100,16 [100,00]A*0,00 100,33 [100,00]In↓
Methanol1,06 to 98.04 [98,90]A*1,29 99,169 [98,72]A*
2% solution or suspension, 1 day at room temperature
of 0.5% CMC0,00 98,28 [100,00]And↓0,00 103,06 [100,00]And↓
0.5% of a receiver array cellulose 40000,00 98,27 [100,00]And↓0,00 100,44 [100,00]And↓
0.8% tween 800,00 98,78 [100,00]And↓0,00 102,42 [100,00]And↓
5% solutions in DMSO, 1 day at room temperature the
Dilution ratio 1:1000,00 96,98 [100,00]And↓0,00 101,85 [100,00]And↓
Test conditionView salt
Free base (option)Monohydrate hydrochloride (option)
Decomposition productsAppearanceDecomposition productsAppearance
Data analysis [% area]Data analysis [% area]
a buffer with a pH of 6.8
Solid state, 1 week 80°C, tight container
In mass (IHVR)0,00 99,77 [100,00]And0,00 100,77 [100,00]And
In bulk (powder x-ray is led diffraction) No changesNo changes
30% of the mixture 10,00 100,11 [100,00]And0,00 101,23 [100,00]And
30% of the mixture 22,17 94,28 [97,75]And2,08 93,43 [97,82]And
Solid state, 1 week 80°C, 75% relative humidity
In mass (IHVR)0,00 99,97 [100,00]And0,00 100,71 [100,00]And
In mass (x-ray powder diffraction pattern)No changesNo changes
30% of the mixture 10,00 99,38 [100,00]In0,00 100,88 [100,00]In
30% of the mixture 23,71 89,37 [6,02] In1.89 92,17 [97,99]In
Illumination with a xenon lamp (approximately 1200 Klux)
In mass (IHVR)0,00 96,03 [100,00]And0,00 99,73 [100,00]And
In mass (x-ray powder diffraction pattern)No changesNo changes
Corrosivity, mass
2 days,80% relative humidity with a steel sampleN/ONo changes
↓ suspension* a clear solution after testing under load
A - no change of colorIn a slight change of color

A mixture of 1: 30% 4-methyl-N-[3-(4-Mei-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (in the form of a free base of ilicali), a mixture of 63% lactose 100 mesh/lactose 200 mesh (in the ratio 50:50), 5% crosspovidone, 1% Aerosil 200, 1% magnesium stearate

A mixture of 2: 30% 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (in the form of free base or salt), 34% mannitol 60, 34% Avicel PH102, 1% Aerosil 200, 1% of magnesium stearate (% by weight of free base or salt)

Chemical, physico-chemical and morphological features such as 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of the free base (option b), or salt monohydrate hydrochloride of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide (option) assessed thus, as described below.

Determining the approximate solubility: weighed amount (20-50 mg) of sample was placed in 2 ml of solvent. The resulting slurry to achieve equilibrium for 24 hours at room temperature and then filtered. The concentration of the dissolved substance (DS) in a saturated filtrate was measured by UV spectroscopy or by means of an analysis method GHUR.

The dissolution rate (IDR): measuring the rate of dissolution is carried out at 37°C using the method of a rotating disk ("VanKell Instrument"). Use one of skorostrelnye - 200.minutes To determine the rate of dissolution in HCl 0.1 N., use the volume 800 ml, and to determine the rate of dissolution in water, use a volume of 200 ml. of the Solution is continuously pumped through the cell UV spectrometer and then return back to the vessel, where the dissolution occurs.

Hygroscopicity: isotherms sorption/desorption register on the instrument for analysis of dynamic vapor sorption system "Surface Measurements Systems (DVS-1). The measurements were carried out at 25°C.

%h
Table 17
Chemical and physico-chemical characteristics
View salt
Free base modification InMonohydrate hydrochloride (option)
Elemental analysisCalculatedFoundCalculatedFound
%63,4663,5857,5857,66
4,153,974,294,25
%F10,7610,229,779,83
%N18,51a 18.57Ls 16.8016,58
%O3,02of 3.565,48of 5.68
%ClN/a 0N/a 0between 6.086,00
Purity according to data DSC (mol. %) (10°C/min)98,65N/O due to decomposition before melting
Purity according to GHUR ([% area)100,00100,00
Melting point according to DSC (°C) (10°C/min)H/O due to decomposition before melting
The enthalpy of melting(j/g)other 153.9H/O due to decomposition before melting
pH of 1% solution or slurry in water7,992,53
Solubility (approximately 25°C, mg/ml)
HCl 0.1 N.0,600,94
of 0.01 N. HCl0,00140,08
Phosphate buffer, pH 6,8is 0.0002Below detection
WaterBelow detection0,17
Ethanol0,633,69
Isopropanol0,33 1,93
Thermogravimetry (weight loss, %) (10°C/min)0,026 (from room temperature to 200°C)of 0.91 (from room temperature up to 80°C)
Residual solvent (%)0,20,0
The dissolution rate (mg min-1cm-2)
pH 1 (0,1 HCl solution)0,170,17
Water0,00130,0024

Although above in the description of the present invention provides different ways of implementation, it is obvious that other changes and modifications of the embodiment of the present invention, which are within the stated of the invention. All such changes shall be within the scope of the invention defined by the attached claims. All patent applications, patents and other publications cited in the text of this application, incorporated in full by reference.

1. Sulfate Sol-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide.

2. The method of obtaining the sulfate salt of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide, which includes the stage of interaction of 4-methyl-N-[3-(4-Mei-1-yl)-5-triptoreline]-3-(4-pyridine-3-Yeremey-2-ylamino)benzamide in the form of the free base with sulfuric acid in the solvent environment.



 

Same patents:

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula ,

X means N or CH, R1 means hydrogen or cyano, R2 means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C3-C6-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: described are 1,2-disubstituted heterocyclic compounds of formula (I) where HET, X, Y and Z values are presented in description, which are phosphodiesterase 10 inhibitors. Also described are pharmaceutical composition and methods of treating central nervous system (CNS) disorders and other disorders, which can influence CNS function.

EFFECT: among disorders that can be subjected to treatment, there are neurological, neurodegenerative and psychiatric disorders, which include, but are not limited by them, disorders, associated with impairment of cognitive ability or schizophrenic symptoms.

14 cl, 824 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 5-phenyl-1 H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one of general formulas I-III: , where: R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl, which stands for monocyclic radical, which contains 5-6 atoms in cycle and one or several heteroatoms N, optionally substituted by one or some lower alkyls; R2 represents -C(=O), -C(=O)NR2'; where R2' represents H or lower alkyl; R3 represents H or R4; where R4 represents lower alkyl or heterocycloalkyl, which stands for monovalent saturated cyclic radical, consisting of one ring, which contains one or two ring-shaped heteroatoms, selected from N and O; X represents CH or N; Y1 represents H, lower alkyl or lower halogenalkyl; each Y2 independently represents lower alkyl, which is optionally substituted by one or several substituents, selected from group, which consists of hydroxygroup, lower alkoxygroup; n has value 0, 1, 2 or 4; Y3 represents Y4a, Y4b, Y4c or Y4d; where Y4a represents H; Y4b represents lower alkyl, optionally substituted by one or sseveral substituents, selected from group, consisting of lower halogenalkyl, halogen; Yc represents lower cycloalkyl, optionally substituted by one or some substituents, selected from group, consisting of lower alkyl, lower halogenalkyl, halogen; and Y4d represents aminogroup, optionally substituted by one or some lower alkyls; or to its pharmaceutically acceptable salt. Also described are: pharmaceutical composition, based on upper said compounds, as well as application of compounds of I-III formulas for treatment of inflammatory or autoimmune condition.

EFFECT: described are novel compounds, which can be useful for modulating Btk activity and treatment of diseases, associated with excess Btk activity.

14 cl, 102 ex, 1 tbl

Jnk inhibitors // 2504545

FIELD: biotechnologies.

SUBSTANCE: in formula

each of R1 and R2 independently represents H or C1-6alkyl; or R1 and R2 together form C3-6cycloalkyl circle, which is optionally replaced with one or more R2'; R2' represents C1-6alkyl, hydroxy group, halogen, amino group, C1-6alkoxy group, C1-6hydroxyalkyl or C1-6haloalkyl; R3 represents H or N(R4)(R5); R4 represents H, C1-6alkyl or C(=O)OR4'; R4' and R5 represents H or C1-6alkyl; represents H or C1-6alkyl; or R2 and R3 together form 5-membered heterocycle containing 1 atom of N in the amount of heteroatom, which is optionally replaced with one or more R2'; Q represents CH or N; Z1 represents (CH2)u; u and v mean 1; Z2 represents (CH2)v; m, n, p, r, q mean 0; Y1 represents CH(Y1'); Y1' represents H or C1-6alkyl; Y2 represents H or represents C1-6alkyl. Invention also refers to compounds of structural formulae (II), (IV) and to pharmaceutical composition containing the above compounds.

EFFECT: improving inhibiting activity in relation to JNK kinase.

10 cl, 4 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphonamide derivatives of general formula:

where m equals 0, 1 or 2; n equals 1 or 2; o equals 0, 1 or 2; p equals 0, 1 or 2; q equals 0, 1, 2 or 3; r equals 0, 1 or 2, under the condition that q+r is not greater than 3; v equals 0 or 1; w equals 0 or 1; under the condition that if v equals 0, then w equals 0; An- denotes a halide anion; Q denotes a single bond, -O- or -CH2-; R1 denotes aryl; R2 and R3 have values given in (i) or (ii): (i) R2 denotes H, C1-6-alkyl, C3-8-cycloalkyl, a bicyclic 8-12-member carbocyclyl, CH(aryl)2 or aryl; or denotes a heteroaryl bonded through a C1-6-alkylene group, the heteroaryl being selected from pyridinyl; R3 denotes H, C1-6-alkyl or aryl; or (ii) R2 and R3, together with the -N-(CH-)- group bonding them, form a heterocycle which can be annelated with an aryl residue, where the heterocycle is 6-membered, saturated or at least monounsaturated but not aromatic, and together with the N heteroatom to which the residue R2 is bonded, can contain at least another O heteroatom; R4 denotes aryl or heteroaryl, selected from pyridinyl; R5 and R6 independently denote H or C1-6-alkyl, wherein R5 and R6 do not simultaneously denote H; or R5 and R6 together denote a substituted or unsubstituted 5- or 6-member heteroaryl which, together with an N atom to which R5 and R6 are bonded, can contain at least another N heteroatom; or R5 and R6 together denote a group selected from -(CH2)d- or -(CH2)e-X-(CH2)f, where d denotes 2, 3, 4, 5 or 6 and e and f are independently equal to 1, 2 or 3, under the condition that e+f is not greater than 5; and X denotes NR12, where R12 denotes H or C1-6-alkyl; R20 denotes C1-6-alkyl; and where said aryl and heteroaryl residues in case can be unsubstituted or monosubustituted or multi-substituted with the same or different residues selected from a group comprising F, Cl, Br, I, O-C1-6-alkyl, CF3 and C1-6-alkyl; and said C1-6-alkyl residues in each case can be branched or straight; in form of a separate enantiomer or separate diastereomer, racemate, enantiomers, diastereomers, mixtures of enantiomers and/or diastereomers, and in each case in form of bases and/or physiologically compatible salts thereof. The invention also relates to a method of producing the described compound, a drug having antagonistic action on B1R, based on compounds of formula I and use of said compound to produce a drug.

EFFECT: novel compounds which can be used in medicine are obtained and described.

15 cl, 131 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 5-fluorouracil derivatives of general formula (I) or pharmaceutically acceptable salts thereof. In general formula (I), R1 denotes a hydrogen atom or a protective hydroxy group which is selected from a C1-C6aliphatic acyl group; C5-C6 alicyclic acyl group; aromatic acyl group which is selected from a benzoyl group or a halogen-benzoyl group, R2 denotes a lower alkoxy-lower alkyl group; X denotes CH or a nitrogen atom and Y denotes a halogen atom.

EFFECT: compounds have anti-tumour activity, balanced with toxicity level, and can be used as an active ingredient for producing a drug for treating malignant diseases.

11 cl, 4 dwg, 4 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and particularly to preparations for a therapy of oncological diseases, treatment of allergy, prevention and health improvement. The invention represents a method for preparing fraction 4 (ADP-f4) and fraction (ADP-f5) adaptogenic Dorogov's preparations, characterised by the fact that a primary product is a fraction 2 antiseptic Dorogov's stimulator (ADP-f2) to be thermally treated.

EFFECT: implementing the given invention provides the more effective prevention and eliciting anti-stress reactions for the purpose of improving the functional state of organism and increasing a resistance in an activation therapy.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns using 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)phenyl]propionitrile or 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazol[4,5-c]quinolin-2-one.

EFFECT: preparing a pharmaceutical formulation for treating a VBGF-stimulated angiogenic disease, a method of treating a VBGF-stimulated angiogenic disease and using the above compounds for the high-efficacy treatment of the above diseases.

5 cl, 4 dwg, 4 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a method for obtaining a compound of formula 682, which is in a crystalline form, where the above method involves the following: (i) treatment of the compound of formula 682-9 with palmitic anhydride mixed with H2O/dioxane so that the compound of formula 682 is formed; (ii) treatment of the product obtained at stage (i) with methanol so that the compound of formula 682 is obtained in the form of solvate with methanol (Form K); (iii) extraction of the compound of formula 682, which has been obtained at stage (ii) in the form of solvate with methanol (Form K); (iv) optional cleaning of the product of stage (iii) by recrystallisation. Besides, the invention proposes a method for obtaining the compound of formula 682-4, where the above method involves the following: (i) conversion of the compound of formula 682-1 to the compound of formula 682-2' by treatment of the above compound of formula 682-1 with 1,3-dichloro-1,1,4,4-tetraisopropyldisiloxane (CIPS) in pyridine; (ii) conversion of the above compound of formula 682-2' to the compound of formula 682-3 by treatment of the above compound of formula 682-2' with acetic anhydride to EtOH; and (iii) conversion of the above compound of formula 682-3 to the compound of formula 682-4 by treatment of the above compound of formula 682-3 with an oxidiser, preferably with free radical 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) and NaOCl. Further aspects of the invention refer to use of the above methods for obtaining 2'-cyano-2'-deoxy-N4-palmitoyl-1-β-D-arabinofuranosylcytosine, pyrimidine nucleoside, and are suitable for treatment and/or prevention of cancer.

EFFECT: improvement of compounds.

22 cl, 1 tbl, 1 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to new purine compounds of formula I and their pharmaceutically acceptable salts that have properties of an inhibitor of lipidic kinases including p110 alpha and other isoforms of PI3K. In formula I , R1 is chosen from H, C1-C12alkyl and -(C1-C12alkene)-(C5-C6 heterocyclyl), where heterocyclyl can contain 1-2 heteroatoms in a cycle, which are chosen from nitrogen, and in which alkyl and heterocyclyl are optionally replaced with one or more groups independently chosen from -NHCOCH3, -NHS(O)2CH3, -OH, -S(O)2N(CH3)2 and -S(O)2CH3; R2 is chosen from C1-C12alkyl, -(C1-C6alkene)-(C5-C6heterocyclyl) or -(C1-C6alkene)-C(=O)-(C5-C6heterocyclyl), in each of which heterocyclyl contains 1-2 heteroatoms chosen from nitrogen and oxygen, -(C1-C6alkene)-(C6aryl), where aryl is chosen from phenyl, and -(C1-C6alkene)-(C5-C6heteroaryl), where heteroaryl contains 1 atom of nitrogen, in which alkyl, heterocyclyl, aryl and heteroaryl are optionally replaced with one or more groups independently chosen from F, Cl, Br, I, CH3, -CF3, -CO2H, -COCH3, -CO2CH3, -CONHCH3, -NHCOCH3, -NH(SO)2CH3, -OH, -OCH3, -S(O)2N(CH3)2 and -S(O)2CH3; and R3 represents monocyclic heteroaryl chosen from derivatives of pyridine and pyrimidine, which are specified in Claim 1 of the invention formula.

EFFECT: applicability of a compound for treatment of proliferative diseases, such as cancer.

7 cl, 2 dwg 1 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, where R1 is H or R1 and R2 together with a nitrogen group can form where A, B, C and D are independently selected from a group consisting of CR1a and N; where at least one of A, B, C and D is CR1a; where R1a is selected from a group consisting of H, -ORi, -SRii, -S(O)Riii, -C(O)NRvRvi and CF3, where Ri is selected from a group consisting of methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, 2-oxo-2-phenylethyl, butyl, acetonitrile and benzyl; Rii, Riii and Riv denote methyl; Rv and Rvi are independently selected from a group consisting of H, methyl, ethyl, hydroxyethyl, hydroxypropyl, diethyalminoethyl, phenyl, pyridinyl, methoxyethyl, hydroxyethoxyethyl, benzyl, phenylethyl, 2-hydroxy-1-hydroxymethyl-2-phenylethyl and carbomoylethyl, or Rv and RVi together form morpholine or ethyl ester of piperazine; R2 is selected from a group consisting of phenyl, naphthyl, pyrazolyl and C1-C8alkylene phenyl; R3 is C1-C8alkylene; R4 is selected from a group consisting of H, C1-C8alkyl and -C=NH(NH2). The invention also relates to compounds of formulae I-A

I-B I-C

I-D I-E

values of radicals of which are given in the claim; a method of treating said pathological conditions, a pharmaceutical composition based on said compounds, a method of identifying a Trp-p8 agonist and specific compounds.

EFFECT: obtaining compounds which are useful as Trp-p8 modulators.

25 cl, 19 dwg, 8 tbl, 17 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to bicyclic heterocycles of formula I and formula II , in which radicals and symbols have values specified in the formula of the invention. These compounds have inhibiting activity in relation to MEK kinase. The invention also refers to a pharmaceutical composition for treatment of hyperproliferation disease or inflammatory disease, to a method for inhibition of abnormal growth of cells or treatment of hyperproliferation disorders and to a treatment method of inflammatory diseases of a mammal. Besides, the invention refers to use of a pharmaceutical composition for preparation of a medicinal agent for treatment of the above diseases of a mammal.

EFFECT: improving compound application efficiency.

19 cl, 29 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: pox virus of variolovaccine is proposed, which includes a defect F2L gene and a suicide gene. Pox virus has oncolytic activity. Besides, a reproduction method of such pox virus and its use for treatment of proliferative diseases or diseases with increased activity of osteoclasts is proposed.

EFFECT: improving compound application efficiency.

31 cl, 12 dwg, 3 tbl

FIELD: biotechnologies.

SUBSTANCE: an in vitro generation method of antigen-specific cytotoxic cells with activity against ovarian carcinoma cells is proposed. Simultaneously, a non-adhesive fraction of mononuclear cells (MNC) and mature dendritic cells (DC) are cultivated in presence of recombinant human interleukine-12 and recombinant human interleukine-18. MNC are extracted from peripheral blood of patients having ovarian carcinoma. Mature DC are obtained from monocytes of adhesive MNC fraction after two-day cultivation, and first, activation by lysate of autologous ovarian carcinoma cells, and then maturation of DC loaded with lysate during one day in presence of recombinant human TMF-α (tumor necrosis factor).

EFFECT: use of the invention provides reduction of a stage for obtaining mature DC, in vitro increases cytotoxicity of antigen-specific cytotoxic cells with antitumor activity and provides an immune response via T-helper to type 1 in respect to ovarian carcinoma, which can be used in ovarian carcinoma therapy.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology. What is disclosed is a vaccine representing four RNAs coding a prostate-specific antigen (PSA), a prostate-specific membrane antigen (PSMA), a prostate stem cell antigen (PSCA) and a six-transmembrane epithelial antigen of the prostate (STEAP). The vaccine is applicable for treating prostate carcinoma, preferentially neo-adjuvant and/or hormone resistant prostate carcinoma, as well as related diseases or disorders. Using the vaccine and a kit are also disclosed. The invention can be used in medicine.

EFFECT: preparing the vaccine for treating prostate carcinoma.

16 cl, 23 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

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