Nanosize weakly crystalline modification of 4-methyl-n-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benazamide hydrochloride monohydrate, method for production thereof and pharmaceutical composition based thereon

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt nanosize weakly crystalline modification 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide (nilotinib) hydrochloride monohydrate. Nilotinib is used as an anti leucaemia cytostatic drug during therapy of cancerous diseases. The nanosize weakly crystalline modification is characterised by the following set of interplanar distances (d, E) and respective intensities (Iot, %) 14.70-27.8%; 12.94-19.4%; 11.43-22.2%; 7.474-26.4; 6.480-25.0%; 6.217-26.4%; 6.040-52.8%; 5.134-19.4%; 4.824-16.7%; 4.489-25.0%; 4.367-25.0%; 4.156-30.6%; 4.092-30.6%; 3.738-30.6%; 3.656-34.7%; 3.528-41.7%; 3.468-44.4%; 3.165-52.8%; 3.053-36.1%; 2.999-100%; 2.869-22.2%; 2.823-69.4%; 2.653-33.3%; 2.524-22.2%; 2.383-22.2%; 2.348-22.2%; 2.203-20.8%; 2.151-22.2%; 2.020-19.4%; 1.932-22.2%; 1.849-26.4%; 1.841-25.0%; 1.763-22.2%, three endothermic effects equal to (97.3±0.4) J/g at temperature of (92.6±0.5)°C, (54.5±0.4) J/g at temperature of (173.7±0.5)°C, (215.6±0.4) J/g at temperature of (273.4±0.5)°C, particle size of less than 150 nm, specific surface area of more than 30 m2/g and powder density in free filling of less than 0.024 g/cm3. A method of producing the modification includes preparing an aqueous solution of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide hydrochloride monohydrate at 25-100°C, which is then frozen at a rate of not less than 60 degrees/minute, followed by removing the solvent by freeze-drying for 22-27 hours. The invention also relates to a pharmaceutical composition.

EFFECT: disclosed modification is 15-20 times more soluble than the existing modification A, which means it can be absorbed into the body over a shorter period and has high activity.

3 cl, 8 dwg, 1 tbl, 5 ex

 

The invention relates to organic chemistry and relates to new nanoscale poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative (nilotinib) hydrochloride monohydrate, process for its preparation and pharmaceutical compositions based on it, which can be used in pharmaceutical industry and medicine as anti-leukemic cytotoxic drug in the treatment of cancer.

Known substituted pyrimidinediamine and their pharmaceutical acceptable salt - tyrosine kinase inhibitors, methods for their preparation and compositions containing them for the treatment of neoplastic diseases and, in particular, leukemia (Patent RU №2348627 C2 from 04.07.2003).

However, this patent does not describe a specific salts or hydrates of the salts or their solvates. In addition, the synthesized substances are not characterized for their membership of a particular polymorph and not defined the parameters of the resulting powders. These properties ultimately determine the biological activity of the resulting substances.

Known crystalline salts of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative and their modifications, such as nilotinib monophosphate, nilotinib difof�t, nilotinib sulfate, nilotinib methanesulfonate, nilotinib aconsultant, nilotinib of benzolsulfonat, nilotinib n-toluensulfonate, nilotinib citrate, nilotinib gentisate, nilotinib malonate, nilotinib tartrate and others (WO 2004/005281 A1 dated 15.01.2004, EN 2434864 C2 from 18.07.2006), nilotinib dihydrochloride (WO 2011/033307 from 24.03.2011), nilotinib trihydrochloride (WO 2010/009402 A9 from 21.01.2010), as well as their solvates, hydrates and anhydrous forms (WO 2007/015870 from 8.02.2007 and WO 2007/015871 from 18.07.2006). Known crystalline forms of imatinib free base (US No. 60/701405 on 20/06/2005 and EPO Patent 013464 B1 dated 30.04.2010).

However, all these modifications differ from 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate chemical composition.

Known crystalline modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride, such as: A (dehydrate), AI(monohydrate), AII(anhydrous), B (monohydrate), BI(anhydrous), SB(desolat methanol), SBI(monsalvat methanol), C (monohydrate), CI(anhydrous), SC(monsalvat methanol), SE(solvate with DMF), a mixture of form D (anhydrous) and B (EPO Patent 013464 B1 dated 30.04.2010, Application EPO 201000145 A1 dated 30.06.2010), T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15, T16, T17, " T18, T19 (WO 2010/054056 A2 from 14.5.2010), as well as additional crystalline modification of (WO 2011/086541 A1 dated 21.07.2011).

Known crystal modifications of nilotinib hydrochloride monohydrate characterized by chemical and physicochemical methods such as: the definition of water by the method of K. Fischer, NMR, HPLC, method of x-ray phase analysis (xrpa) - sets of angles 2θ, ° and the intensity (Ifrom,=Ii/Imax×100, %) or directly by radiographs (obtaining diffraction patterns of the authors of the above patents was conducted on a CuKα-radiation); IR-, RAMAN - spectrometric methods of analysis, thermoanalytical studies - defined values of exothermic effects of melting temperature and dependencies of the mass loss from temperature and others.

However, the known crystalline modifications of nilotinib hydrochloride is well crystallized, as evidenced by their x-rays.

Most similar in appearance to the diffraction pattern of x-ray phase analysis (XPA) is x-ray amorphous modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride, which is characterized by x-ray amorphous halo (Patent EPO 013464 B1 dated 30.04.2010, application EPO 201000145 A1 dated 30.06.2010).

However, the x-ray amorphous modification of nilotinib hydrochloride monohydrate no �difraktsionnye highs. In addition, none of the considered modifications not get in pure form with a crystallite size of less than 150 nm (nanoscale). Therefore, we obtained a modification was called the nanoscale. The term "poorly crystallized" was presented in the name of the new modifications in connection with the fact that physico-chemical studies of the obtained salts showed that the broadening of the diffraction maxima 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate linked to the reduction of the size of the crystallites to the level of nanorazmernoi. If the obtained powder was Amalfitan, thermoanalytical curves of clear peaks. It would be the offset of the baseline of the DSC - curves associated with the glass transition [http://wvm.pslc.ws/russian/dsc.htm].

The above modification nilotinib get one of the other "wet methods", by varying the type of solvent, the conditions of preparation of solutions and emulsions: isothermal exposures, cooling, heating, and conditions for the allocation of organic solvents or their mixtures by various methods, such as crystallization from solution, replacing the solvent by vacuum drying, spray drying and other.

The closest in technical essence is a method of producing the modified�tions by spray drying, namely, that prepare a solution in methanol 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride and subjected to spray drying at 65°C (Patent EPO 013464 B1 dated 30.04.2010, Patent EA 016856 B1 dated 30.08.2012, WO 2010/054056 A2 from 14.05.2010).

The similarity of the inventive nanoscale poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)Fe-Neil]-3-[(4-pyridin-3-Yeremey-2-yl)amino] benzamide derivative hydrochloride monohydrate, with the known x-ray amorphous and crystalline modifications of nilotinib hydrochloride is the identity of their chemical composition.

The difference between the claimed nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)Fe-Neil]-3-[(4-pyridin-3-ileri-midin-2-yl)amino]benzamide derivative hydrochloride monohydrate known from x-ray amorphous and crystalline modifications lies in the differences in their physico-chemical properties: specific set of interplanar distances (d, Å) (angles 2θ, °) and intensity (Ifrom,=Ii/Imax×100, %), 3 defined valuesxendothermic effects and their temperature, particle size less than 150 nm, a specific surface area of less than 30 m2/g and a density of the powder in loose backfill is less than 0.024 g/cm3.

Difference method for the preparation�ia claimed nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, from the known x-ray amorphous and crystalline forms is that the solution nilotinib hydrochloride at a temperature from 25°C to 100°C, frozen at a cooling rate of not lower than 60 deg/min and subjected to freeze-drying for 22-27 hours.

The difference between the claimed pharmaceutical composition having activity of an inhibitor of protein kinase, which can be used as anti-leukemic cytotoxic drug for the treatment of cancer, containing 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-illerimi-DIN-2-yl)amino]benzamide derivative hydrochloride monohydrate, from the known composition (Patent RU №2434864 C2 from 27.11.2011) is that as the active substance is used therapeutically effective amount of nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate.

The aim of the invention is to obtain previously unknown nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, development of a method for its preparation and pharmaceutical compositions based on it having the activity of an inhibitor of protein kinase, which can be used as anti-leukemic cytotoxic prep�rata for the treatment of cancer.

The goal is achieved by the present invention, namely obtaining nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, characterized by the following set of interplanar distances (d, Å) and corresponding intensities (Ifrom,=Ii/Imax×100, %): 14,70-27,8%; 12,94-19,4%; 11,43-22,2%; 7,474-26,4; 6,480-25,0%; 6,217-26,4%; 6,040-52,8%; 5,134-19,4%; 4,824-16,7%; 4,489-25,0%; 4,367-25,0%; 4,156-30,6%; 4,092-30,6%; 3,738-30,6%; 3,656-34,7%; 3,528-41,7%; 3,468-44,4%; 3,165-52,8%; 3,053-36,1%; 2,999-100%; 2,869-22,2%; 2,823-69,4%; 2,653-33,3%; 2,524-22,2%; 2,383-22,2%; 2,348-22,2%; 2,203-20,8%; 2,151-22,2%; 2,020-19,4%; 1,932-22,2%; 1,849-26,4%; 1,841-25,0%; 1,763-22,2%, and three endothermic effects, is equal to: (97,3±0,4) j/g at a temperature of (92,6±0,5)°C, (54,5±0,4) j/g at a temperature of (173,7±0,5)°C, (215,6±0,4) j/g at a temperature of (273,4±0,5)°C, a particle size of less than 150 nm, a specific surface area of more than 30 m2/g and a density of the powder in loose backfill is less than 0.024 g/cm3.

The objective is also achieved by the development of a method for producing the inventive nanoscale poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, which is that the aqueous solution of nilotinib hydrochloride at a temperature from 25°C to 100°C, freeze when the velocity is�and not cooling below 60 deg/min, followed by sublimation drying for 22-27 hours.

In addition, the goal is achieved also proposed pharmaceutical composition, where the active substance used is not previously known nanosized poorly crystallized modified 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative (nilotinib) hydrochloride monohydrate having the activity of an inhibitor of protein kinase, which can be used as anti-leukemic cytotoxic drug for cancer therapy.

From patent and scientific literature is not known nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative (nilotinib) hydrochloride monohydrate, process for its preparation and pharmaceutical composition based on it having the activity of an inhibitor of protein kinase, which can be used as anti-leukemic cytotoxic drug for cancer therapy.

We discovered a new, previously unknown, nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, characterized by individual peculiar �Abram interplanar spacings (d, Å) and corresponding intensities (IRel.=(I/Imax×100, %) (tab.1, Fig. 4); the values of three endothermic effects and their temperature (Fig. 5), a particle size of less than 150 nm, a specific surface area of more than 30 m2/g and a density of the powder in loose backfill is less than 0.024 g/cm3proposed method for its preparation and pharmaceutical composition based on it having the activity of an inhibitor of protein kinase, which can be used as anti-leukemic cytotoxic drug for cancer therapy.

Declare a new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate is a light, fluffy powder from yellow to white.

To clarify the essence of the claimed technical solution applied to the description the following tables and figures:

Table 1. Angles 2Θ, the interplanar distances (d, Å) and their intensity (IRel., %) of new nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate.

Fig. 1. NMR13C (1) and NMR1H (2) - spectra of the initial substance of nilotinib hydrochloride monohydrate (Chris�allicesia A - modification).

Fig. 2. NMR13C (1) and NMR1H (2) spectra of nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate.

Fig. 3. The diffraction pattern of the original substance of nilotinib hydrochloride - A - modification.

Fig.4. A typical diffraction pattern of nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate - A) and after elimination of "noise" using the program "Origin" - B).

Fig. 5. thermogram of the original substance of nilotinib hydrochloride - A - modification.

Fig. 6. A typical thermogram of nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate.

Fig. 7. Micrograph of nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate, obtained using scanning electron microscopy.

Fig. 8. Micrograph of nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate obtained by transmission electron microscopy.

To identify the obtained substances was conducted a complex of physicochemical methods of analysis.

Original methods of nuclear magnetic resonance (NMR spectroscopy), determine the water content by Karl Fischer method and high performance liquid chromatography (HPLC) was established �identichnosti chemical formula of the original substance forms And nilotinib hydrochloride and received from her new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate.

Determination of the chemical shifts of the initial substance (modification And nilotinib hydrochloride) and received from him the substance was held in their saturated solution in deuterated dimethylsulfoxide (DMSO-D6) on the NMR spectrometer high resolution VXR-400 "VARIAN" (USA). The data obtained is shown in Fig. 1 (1) - NMR13C range, 1 (2) - NMR1H - spectrum and 2 (1) - NMR13C range, 2 (2) - NMR1H - spectrum, respectively. The comparison of the results presented Fig. 1 (1), Fig. 1 (2) (the initial substance of nilotinib hydrochloride - And - modification), with the data presented in Fig. 2 (1), Fig. 2 (2) (nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate), shows that NMR13C and NMR1H - spectra of the initial and the obtained substance is almost identical [except for the chemical shifts, responsible for the presence of water molecules in the formula, form A, namely: 5,7 2,8...ppm Fig. 1 (2)], i.e., the resulting material is 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide hydrochloride monohydrate.

The results of the determination of the water content by the method of K. Fischer in the obtained substance at the "Mettler Toledo With 20 coulometric KF titrator" showed that the obtained nanosized poorly crystallized modification n�of latinia hydrochloride monohydrate contains (4,2±0,2) masses. % H2O. This value corresponds to the presence of one water molecule in the chemical formula of the substance. The presence of a slight excess amount of water is due, in our opinion, the high specific surface of the obtained substances and as a consequence, the presence in the powder adsorbed water.

The chromatographic mobility of the source substance (a form of nilotinib hydrochloride) and obtained from nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate was determined by HPLC on a chromatograph Agilent Tech 1200 with column length 150 mm, diameter 4.5 mm, sorbent Pronto SIL-120-5-C18 with simultaneous detection at wavelengths 210,8 and 267,4 nm. As eluent used a mixture (40% -50%) acetonitrile - buffer solution with pH=3 at 42°C and a speed of 1 ml/min. Volume of the tested sample was 2 μl with a concentration of 1.0 mg/ml. it Turned out that the chromatograms of the original substance (form nilotinib hydrochloride) and obtained from nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate contain one peak of the main component with a characteristic retention times 6,380 6,417 minutes and minutes, respectively. These values of the retention times of the form of nilotinib hydrochloride and a new nanosized poorly crystallized modification of nilotinib hydrochlor�Yes monohydrate within the errors of determination - 0.3% of the same. The content of the basic substance in the original substance still of 99.86%, and obtained from her the substance - 99,77%. These experiments, carried out by HPLC method, indicate that in modifying the original nilotinib hydrochloride the decomposition of the substance occurs.

Thus, as obtained by NMR spectroscopy and HPLC chromatography experimental results clearly indicate that the obtained substance is 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide hydrochloride monohydrate.

To confirm that the resulting material is a new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide hydrochloride monohydrate were carried out x-ray phase analysis (XPA), thermoanalytical studies, determination of particle size using scanning and transmission microscopy, determination of the specific surface and bulk of the mass in the free filling density of the powder).

The results of x-ray phase analysis (XPA), conducted on a Rigaku diffractometer (D/MAX-2500 (Rigaku, Japan) with CuKα radiation (λ=1,54056 Å), is presented in Fig. 3. Ibid., for greater clarity, shows edited (removed the "noise" t�using the program "Origin" of the diffraction pattern. The numerical values of the results of the XRF are given in table. 1. In Fig. 4 shows the results of x-ray phase analysis of the raw substance of nilotinib hydrochloride form A. the Comparison of results is shown in Fig. 3 and in table. 1, with the data presented in Fig. 4, and with the literary sources [EPO Patent 013464 B1 dated 30.04.2010. Patent EA 016464 B1 dated 30.08.2012, WO 2010/054056 A2 from 14.05.2010, WO 2011/086541 A1 dated 21.07.2011] shows that the resulting material is not known before the new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifter-methyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide hydrochloride monohydrate, which is characterized by its individual set of diffraction peaks (2θ,° or d Å) and their intensity (IRel, %) (tab. 1) and differs from other known crystal modifications A, AI, AIIIn, BI, SB, SBIC, CI, SC, SEmixtures of forms D and b, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15, T16, T17, " T18, T19, additional crystalline modification, which are characterized by their specific sets of diffraction peaks (d, Å) (and/or angles 2θ,°) and intensity (Ifrom,=Ii/Imax×100, %) or angles 2θ,°, and x-ray amorphous modification of nilotinib hydrochloride, which features�characterized by its x-ray amorphous halo in the diffraction pattern.

Thermoanalytical studies obtained by us previously unknown new nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifter-methyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide hydrochloride monohydrate source and substance of nilotinib hydrochloride (A - form) was performed on thermoanalyzer STA 449 With Jupiter (NETZSCH) in flowing argon at a speed of temperature increase of 10 ° C/min as the sample holders used an aluminum tray. Sample samples was 3.2 and 4.7 mg. the results are shown in Fig. 5 and Fig. 6, respectively. The comparison of results is shown in Fig. 5, with the data presented in Fig. 6, and with the literary sources [EPO Patent 013464 B1 dated 30.04.2010. Patent EA 015856 B1 dated 30.08.2012, WO 2010/054056 A2 from 14.05.2010, WO 2011/086541 A1 dated 21.07.2011] suggests that we obtained a new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ileri-midin-2-yl)amino]benzamide derivative hydrochloride monohydrate is characterized by pronounced their individual 3maxendothermic effects, is equal to: (97,3±0,4) j/g at a temperature of (92,6±0,5)°C, (54,5±0,4) j/g at a temperature of (173,7±0,5)°C, (215,6±0,4) j/g at a temperature of (273,4±0,5)°C. The known modifications, namely: A, AI, AIIIn, BI, SB, S BIC, CI, SC, SEmixtures of forms D and b, T1, T2, T3, T4, T5, T6, T7, T8, T9, T10, T11, T12, T13, T14, T15, T16, T17, " T18, T19, additional crystalline forms and amorphous forms of such set endothermic effects.

Specific surface area was determined by the method of low-temperature adsorption of argon and was calculated by BETH when measuring the amount of adsorbed argon at one point (P/Ps~0,3) (Single Point). Measurements were performed in the gas-chromatographic method using as a carrier gas of helium. It turned out that the specific surface area obtained by us new nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate is (34±3) m2/g. the average particle diameter of the obtained value of specific surface area showed that the crystallite size of the powder is ~122±12 nm.

Determination of the size of powder particles of a new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate was carried out by scanning electron microscope high resolution LEO Supra 50 VP ( Germany) with an accelerating voltage of 100 - 300 kV with magnification from ×to 12 ×900000 times and ultra-high resolution up to 1 nm (20 kV) and transmission electron m�croscope LEO 912 AB (Zeiss, Germany) with the cathode on the basis of LaB6with an accelerating voltage of 120 kV, a magnification of ×80 ×500000 times and a resolution of 0.34 nm. The data obtained is shown in Fig. 7 and Fig. 8, respectively. The data obtained show that the resulting material is an agglomerated powder with a particle size of less than 150 nm.

Determination of the density of the powder of a new, previously unknown nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate was performed by addition of crystallites in a calibrated volume of the vessel, followed by weighing. The results was calculated by the following formula: ρthen.=(mΣ-mTara)/Vcontainers. It turned out that the density of the powder of a new, previously unknown nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate less than 0.024 g/cm3.

Thus, the experimental results x-ray diffraction, thermoanalytical studies, determination of specific surface area, particle size and density of the powder filling in the free clearly indicate that the obtained substance was not previously known, a new nanoscale poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide hydrochloride monohyd�atom. It is characterized by distinct: a certain set of angles 2θ°, interplanar distances (d, Å) and their intensity (Ifrom,=Ii/Imax×100, %) - Fig. 3, tab.1, individual, unique, three endothermic effects: (97,3±0,4) j/g at a temperature of (92,6±0,5)°C; (54,5±0,4) j/g at a temperature of (173,7±0,5)°C: (215,6±0,4) j/g at a temperature of (273,4±0,5)°C - Fig. 5, a specific surface area of more than 30 m2/g, a particle size of less than 150 nm (Fig. 7 and 8) and the density of the powder in loose backfill is less than 0.024 g/cm3.

Determination of the activity of new nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate was performed by dissolution in distilled water, acidified to pH=40,1 n hydrochloric acid. The experiments were carried out in comparison with the original substance of nilotinib hydrochloride (crystalline form). This kind of experiments it is essential to further predict the behavior of the drug in biological environment and assimilation in the body.

Determination of time of dissolution of the original substance of nilotinib hydrochloride (form A) and obtained from her new nanosized poorly crystallized modification in acidified distilled water was performed by the following method a Weighed sample of the drug 2 mg was placed under stirring with a magnetic stirrer at 50 rpm in 5 ml of acidified distilled water and a stopwatch measured time of dissolution. It turned out that the original substance of nilotinib hydrochloride time of dissolution in water amounted to 40-50 C, and for a new nanosized poorly crystallized modifications - with 2-3, i.e., the dissolution rate of a new modification 15-20 times higher than for the known modifications A.

Experiments on determination of time of dissolution in acidified to pH=4 with distilled water showed that the new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate more active compared to the original substance, which should affect the reduction of absorption in the body, to increase its biological activity.

Differences of the proposed method of obtaining the claimed nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate are: temperature of the aqueous solution of nilotinib hydrochloride from 25°C to 100°C, the freezing rate is not below 60 deg/min and the time of freeze-drying for 22-27 hours.

Preparation of solution of nilotinib hydrochloride at elevated temperatures were used to accelerate the dissolution process of nilotinib hydrochloride.

Reducing the temperature of the aqueous solution of nilotinib hydrochloride below room temp�available - 25°C is not advisable, since it requires additional energy consumption for the cooling system.

The increase in the temperature of the aqueous solution of nilotinib hydrochloride above 100°C is also not advisable because of the need for special equipment.

The decrease in the rate of freezing below 60 deg/min speed cryocrystals solution nilotinib hydrochloride decreases and approaches an equilibrium process. This yields the already known variants. New nanosized poorly crystallized modified 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate in its purest form cannot be obtained.

Reducing the time of freeze-drying is less than 22 h results in uncured product: "powder nilotinib hydrochloride monohydrate his frozen solution". System at room temperature is melted, the powder is partially dissolved, precrystallization, forming the known modifications. New nanosized poorly crystallized modified 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate in its purest form cannot be obtained.

Increasing the time of freeze-drying is impractical because it does not bring� to increase the yield of the target product - new nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate and only increases the cost of production.

The possibility of implementation of the present invention is illustrated by the following examples, but is not limited thereto.

Example 1. 100 ml of an aqueous solution containing a source of the substance 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride 42 mg (in terms of nilotinib hydrochloride monohydrate) at room temperature (25°C) poured into a stainless steel container and freeze at a speed of 60 deg/min dip bottom of pan in a mixture of acetone - dry ice (T=-78°C). The obtained frozen product on the pallet is transferred to a sublimation chamber and subjected to freeze-drying at temperatures: on the capacitor -50...-55°C; the product -78 to+30°C and a residual pressure in the chamber (8-6)·10-2Torr for 22 h. the Yield was 41.5 mg (98.8 per mass. %). According to the XRD of the obtained substance is characterized by typical diffraction pattern presented in Fig. 3, and a set of interplanar spacings and intensities coinciding with the corresponding values for a new nanosized poorly crystallized modification of nilotinib HYDR�chloride monohydrate, presented in table. 1. The results of thermoanalytical studies show that the values of the three endothermic effects equal to: (97,1±0,4) j/g at a temperature of (92,3±0,5)°C; (54,3±0,4) j/g at a temperature of (173,5±0,5)°C; (216,0±0,4) j/g at a temperature of (273,8±0,5)°C, which coincides with the values of endothermic effects and their temperatures typical of new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate. Determination of the specific surface (SUD.) the resulting powder showed that SUD=30.5 m2/g. According to scanning and transmission electron microscopy the resulting material is an agglomerated powder with a particle size of less than 150 nm. Determination of the density of the loose powder in the powder showed that it is equal to 0,020 g/cm. Results physico-chemical analysis indicate that the resulting material is a new nanosized poorly crystallized modification of 4-methyl-T-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate.

Example 2. 350 g of an aqueous solution containing a source of the substance 4-methyl-N-[3 -(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-Piri-DIN-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride 0,1485 g (in terms of nilotinib hydrochloride monohydrate) in 100�C freeze at a speed of 3×10 2deg/min infusion solution into pre-cooled and filled with liquid nitrogen (TKip=-196°C) stainless steel tray. The obtained frozen product on the pallet is transferred to a sublimation chamber and subjected to freeze-drying at temperatures: on the capacitor -50...-55°C; the product 78...+30°C and a residual pressure in the chamber (5-6)·10-2Torr for 27 h. the Yield was 0,1472 g (99.1 masses. %). According to the XRD of the obtained substance is characterized by typical diffraction pattern presented in Fig. 3, and a set of interplanar spacings and intensities coinciding with the corresponding values for a new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate, is presented in table. 1. The results of thermoanalytical studies show that the values of the three endothermic effects are equal (97,3±0,4) j/g at a temperature of (92,6±0,5)°C; (54,5±0,4) j/g at a temperature of (173,7±0,5)°C; (215,6±0,4) j/g at a temperature of (273,4±0,5)°C, which coincides with the values of endothermic effects and their temperatures typical of new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate. Determination of the specific surface (Sbeats) the resulting powder showed that Sbeats=32 m2/G. According to the scanning and transmission of microsc�FDI the resulting material is an agglomerated powder with a particle size of less than 150 nm. Determination of the density of the loose powder in the powder showed that it is equal to 0.024 g/cm3. Results physico-chemical analysis indicate that the resulting material is a new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-illerimi-DIN-2-yl)amino]benzamide derivative hydrochloride monohydrate.

Example 3. 200 g of an aqueous solution containing a source of the substance 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-Piri-DIN-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride of 60.0 mg (in terms of nilotinib hydrochloride monohydrate) at 60°C freeze at a speed of about 105deg/min sharp pouring a thin layer of solution in pre-cooled to -196°C stainless steel tray. Received on the pallet frozen product is transferred into a sublimation chamber and subjected to freeze-drying at temperatures: on the capacitor -75...-80°C; the product -78 to+30°C and a residual pressure in the chamber 8-10-3Torr for 24 h. the Yield was $ 59.3 mg (98.8 per mass. %). According to the XRD of the obtained substance is characterized by typical diffraction pattern presented in Fig. 3, and a set of interplanar spacings and intensities coinciding with the corresponding values for a new nanosized poorly sacris�ilizovano modification nilotinib hydrochloride monohydrate, presented in table. 1. The results of thermoanalytical studies show that the values of the three endothermic effects are equal (97,5±0,4) j/g at a temperature of (92,7±0,5)°C; (54,6±0,4) j/g at a temperature of (173,8±0,5)°C: (to 215, 4±0,4) j/g at a temperature of (273,2±0,5)°C, which coincides with the values of endothermic effects and their temperatures typical of new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate. Determination of the specific surface (Sbeats) the resulting powder showed that Sbeats=36 m2/g. According to scanning and transmission microscopy the resulting material is an agglomerated powder with a particle size of less than 150 nm. Determination of the density of the loose powder in the powder showed that it is equal 0,018 g/cm. Results physico-chemical analysis indicate that the resulting material is a new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-illerimi-DIN-2-yl)amino]benzamide derivative hydrochloride monohydrate.

Example 4. 1500 g of an aqueous solution containing a source of the substance 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Ile-rimidine-2-yl)amino]benzamide derivative hydrochloride of 0.65 g (in terms of nilotinib hydrochloride monohydrate) at 80°C frozen with� a speed of about 10 3deg/min spraying a solution of a pneumatic injector at pressure of 0.7 kg/cm2in the reactor filled with liquid nitrogen (TKip=-196°C). Received cryogeny frozen solution is transferred into a stainless steel container and subjected to freeze-drying at temperatures: on the capacitor -42...-47°C; the product -78 to+30°C and a residual pressure in the chamber (2-3)·10-2Torr for 26 h. the Yield was 0,628 g (96.6 per mass. %). According to the XRD of the obtained substance is characterized by typical diffraction pattern presented in Fig. 3, and a set of interplanar spacings and intensities coinciding with the corresponding values for a new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate, is presented in table. 1. The results of thermoanalytical studies show that the values of the three endothermic effects are equal (96,9±0,4) j/g at a temperature of 92.5±0,5)°C; (54,1±0,4) j/g at a temperature (to 173.3±0,5)°C; (215,2±0,4) j/g at a temperature of (273,5±0,5)°C, which coincides with the values of endothermic effects and their temperatures typical of new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate. Determination of the specific surface (Sbeats) the resulting powder showed that Sbeats=35,5 m2/g. According to scanning�her and transmission electron microscopy the resulting material is an agglomerated powder with a particle size of less than 150 nm. Determination of the density of the loose powder in the powder showed that it is equal 0,022 g/cm3. Results physico-chemical analysis indicate that the resulting material is a new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate.

Example 5. Pharmaceutical composition. To prepare 10.0 g of known composition (instructions for use of tasigna), comprising as an active ingredient of nilotinib hydrochloride monohydrate and excipients in a ratio (mass. %):

Of imatinib mesilate55,15
Lactose monohydrate39,03
PolyplasdoneOf 3.98
Poloxamer 1880,80
Silicon dioxide colloidal0,52
Magnesium stearate0,52

5,515 g powder new nanosized poorly crystallized modification of nilotinib hydrochloride monohydrate is mixed for 5 minutes in the Aga�mortar type with auxiliary substances: 0,080 g of nonionic surface-active substance poloxamer 188 (BASF Corporetion Webssite Retrieved 2008-12-09 "BASF - Product information the chemicals catalog - Pluronics"); 3,903 g of lactose monohydrate (according to the US Pharmacopoeia and European Pharmacopoeia), 0,398 g of polyplasdone (the United States Pharmacopoeia and European Pharmacopoeia), 0.052 g of silicon dioxide colloidal (the United States Pharmacopoeia and European Pharmacopoeia) and 0,052 g of magnesium stearate (TU 6-09-16-1533-90). The resulting mixture was subjected to biological methods of analysis. Experiments were performed on rabbits-males weighing 2.0 to 2.5 kg. To obtain reliable results in a parallel series of experiments used at least 5trabbits. The timing of the appearance of nilotinib hydrochloride in blood was performed in vivo by oral administration of the composition with further sampling of plasma from the ear. In all cases, the amount injected into an animal of the active substance (in terms nilotinib) was 5.0 mg 10.0 mg of the mixture). It was found that for compositions containing nanosized poorly crystallized modified 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifter-methyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, the time of appearance of nilotinib in the blood of rabbits is equal to 15±4 min and the known composition, containing as active substance source nilotinib hydrochloride (form A) - 26±4 min.

Thus, the experimental results of physico-chemical methods of research:x-ray phase analysis, thermoanalytical studies, determination of specific surface area, particle size and density of the powder filling in the free clearly indicate that the obtained substance was not previously known, a new nanoscale poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide hydrochloride monohydrate. It is characterized by distinct: a certain set of angles 2θ°, interplanar distances (d, Å) and their intensity (Ifrom,=Ii/Imax×100, %) - Fig. 3, tab.1, individual, unique, three endothermic effects: (97,3±0,4) j/g at a temperature of (92,6±0,5)°C; (54,5±0,4) j/g at a temperature of (173,7±0,5)°C: (215,6±0,4) j/g at a temperature of (273,4±0,5)°C - Fig. 5, a specific surface area of more than 30 m2/g, a particle size of less than 150 nm (Fig. 7 and 8) and the density of the powder in loose backfill is less than 0.024 g/cm3.

In addition, the proposed pharmaceutical composition using as an active ingredient of a new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate has improved bioavailability.

From the above it can be concluded that the leadership of�may new nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, method for its preparation and pharmaceutical composition based on it are new and meet the criteria of "inventive step" and "industrial applicability".

Table 1.
№ p/p*)2θ, °d, ÅIRel.,%**)№ p/p*)2θ, °d, ÅIRel., %**)№ p/p*)2θ, °d, ÅIRel., %**)
16,0014,7027,81221,344,15630,62333,722,653A 33.3
2About 6,8212,9419,41321,684,0922435,502,52422,2
37,72Of 11.4322,21423,763,73830,62537,682,38322,2
411,827,47426,41524,303,65634,72638,262,34822,2
513,646,48025,01625,203,52841,72740,902,20320,8
614,226,2171725,643,46844,42841,922,15122,2
714,646,04052,81828,143,16552,82944,782,02019,4
817,245,13419,41929,203,053The 36.13046,961,93222,2
918,364,82416,72029,742,9991003149,181,849 26,4
1019,744,48925,02131,122,86922,23249,421,84125,0
1120,304,36725,02231,642,82369,43351,761,76322,2
*)№ p/p - number provided in accordance with Fig. 3.
**)The relative intensity IRel.expected a relatively smooth line.

1. Nanosized poorly crystallized modification of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate, characterized by the following set of interplanar distances (d, Å) and corresponding intensities (Ifrom, %) 14,70-27,8%; 12,94-19,4%; 11,43-22,2%; 7,474-26,4; 6,480-25,0%; 6,217-26,4%; 6,040-52,8%; 5,134-19,4%; 4,824-16,7%; 4,489-25,0% 4,367-25,0%; 4,156-30,6%; 4,092-30,6%; 3,738-30,6%; 3,656-34,7%; 3,528-41,7%; 3,468-44,4%; 3,165-52,8%; 3,053-36,1%; 2,999-100%; 2,869-22,2%; 2,823-69,4%; 2,653-33,3%; 2,524-22,2%; 2,383-22,2%; 2,348-22,2%; 2,203-20,8%; 2,151-22,2%; 2,020-19,4%; 1,932-22,2%; 1,849-26,4%; 1,841-25,0%; 1,763-22,2%, and three endothermic effects equal to (97,3±0,4) j/g at a temperature of (92,6±0,5)°C, (54,5±0,4) j/g at a temperature of (173,7±0,5)°C, (215,6±0,4) j/g at a temperature of (273,4±0,5)°C, a particle size of less than 150 nm, a specific surface area of more than 30 m2/g and a density of the powder in loose backfill is less than 0.024 g/cm3.

2. The method of obtaining nanosized poorly crystallized modifications of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate solution preparation of 4-methyl-N-[3-(4-methylimidazole-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate and drying, characterized in that the prepared aqueous solution at 25 to 100°C of the specified compounds, which are frozen at a speed of not freezing below 60 deg/min, followed by removal of the solvent by sublimation drying for 22-27 hours.

3. Pharmaceutical composition having the properties of protein kinases suitable for use as anti-leukemic cytotoxic drug for the treatment of cancer, containing a therapeutically effective amount of 4-methyl-N-[3-(4-me�eliminator-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-Yeremey-2-yl)amino]benzamide derivative hydrochloride monohydrate in the form of nanosized poorly crystallized modification according to claim 1



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of the structural formula (1), which possesses the activity increasing erythropoietin production. In formula

R1 represents a group of the structural formula

,

in which R4 and R5, each independently, represent a hydrogen atom, halogen atom or C1-C6alkyl group, R6 represents a hydrogen atom, halogen atom or C1-C6alkyl group, R7 represents a hydroxyC1-C6alkyl group, hydroxyhalogenC1-C6alkyl group, C1-C6alkoxyC1-C6alkyl group, which can have 1 substituent, independently selected from a group of substituents α, (C1-C6alkoxy)carbonyl group, C1-C6alkoxyC1-C6alkoxyC1-C6alkyl group, hydroxyC1-C6alkoxygroup, C1-C6alkylcarbamoyl group, (C1-C6alkyl)(C1-C6alkyl) carbamoyl group, (C1-C6alkyl)(C1-C6alkyl) carbamoylC1-C6alkyl group or C2-C7alkanoyloxyC1-C6alkyl group, α represents a hydroxygroup, Q1 ring represents a piperidinyl group, rings Q2 and Q3 represent a phenyl or pyridyl group, X represents a simple bond or methylene, R2 represents a C1-C3alkyl group and R3 represents a hydrogen atom.

EFFECT: invention relates to a pharmaceutical composition, containing the said compounds, to the application of a compound for obtaining a medication for the enhancement of erythropoietin production and to a method of treatment or prevention of a disease, caused by reduced erythropoietin production, such as anaemia.

33 cl, 1 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , wherein Y and Z are independently specified in a group of a) or b) so that one of Y or Z is specified in the group a), and another one - in the group b); the group a) represents i) substituted C6-10aryl; ii) C3-8cycloalkyl; iii) trifluoromethyl or iv) heteroaryl specified in a group consisting of thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyridinyl, isoxazolyl, imidazolyl, furasan-3-yl, benzothienyl, thieno[3,2-b]thiophen-2-yl, pyrazolyl, triazolyl, tetrazolyl and [1,2,3]thiadiazolyl; the group b) represents i) C6-10aryl; ii) heteroaryl specified in a group consisting of thiazolyl, pyridinyl, indolyl, pyrrolyl, benzoxazolyl, benzothiazolyl, benzothienyl, benzofuranyl, imidazo[1,2-a]pyridin-2-yl, furo[2,3-b]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, thieno[2,3-b]pyridinyl, quinolinyl, quinazolinyl, thienyl and benzimidazolyl; iii) benzofused heterocyclyl attached through a carbon atom, and when a heterocyclyl component contains a nitrogen atom, the carbon atom is optionally substituted by one substitute specified in a group consisting of C3-7cycloalkylcarbonyl; C3-7cycloalkylsulphonyl; phenyl; phenylcarbonyl; pyrrolylcarbonyl; phenylsulphonyl; phenyl(C1-4)alkyl; C1-6alkylcarbonyl; C1-6alkylsulphonyl; pyrimidinyl and pyridinyl; C3-7cycloalkylcarbonyl, phenyl, phenylcarbonyl, phenyl(C1-4)alkyl and phenylsulphonyl are optionally substituted by trifluoromethyl, or by one or two fluor-substitutes; iv) phenoxatiynyl; vi) fluoren-9-on-2-yl; vii) 9,9-dimethyl-9H-fluorenyl; viii) 1-chlornaphtho[2,1-b]thiophen-2-yl; ix) xanthen-9-on-3-yl; x) 9-methyl-9H-carbazol-3-yl; xi) 6,7,8,9-tetrahydro-5H-carbazol-3-yl; xiii) 3-methyl-2-phenyl-4-oxochromen-8-yl; or xiv) 1,3-dihydrobenzimidazol-2-on-5-yl optionally substituted by 1-phenyl, 1-(2,2,2-trifluoroethyl), 1-(3,3,3-trifluoropropyl) or 1-(4,4-difluorocyclohexyl); 1-phenyl is optionally substituted by one or more fluor-substitutes or trifluoromethyl; or xv) 4-(3-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl; R1 represents C6-10aryl, C1-3alkyl, benzyloxymethyl, hydroxy(C1-3)alkyl, aminocarbonyl, carboxy, trifluoromethyl, spirofused cyclopropyl, 3-oxo or aryl(C1-3)alkyl; or when s is equal to 2 and R1 represents C1-3alkyl, the substitutes C1-3akyl is taken with a piperazine ring to form 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.2]octanyl ring system, and its pharmaceutical compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a method of obtaining a quinolone compound, which includes a stage of interaction of a dechloroquinolone compound, or its pharmaceutically acceptable salt, or ether with a chlorinating agent and acid, in which the molar ratio of the acid to the dechloroquinolone compound constitutes from 0.008 to 0.012 and in which less than 0.40% of a dimeric admixture is obtained in a percentage of the area counted per the obtained quinolone compound, and where the quinolone compound represents 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or its pharmaceutically acceptable salt or ether, the dechloroquinolone compound represents 1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinolin-3-carboxylic acid, or its pharmaceutically acceptable salt, or ether and the dimeric admixture represents 1-amino-3-(azetidin-3-yloxy)propane-2-olbis(H,H'-quinolonecarboxylic acid) or its pharmaceutically acceptable salt or ether.

EFFECT: improved method of obtaining a quinolone derivative, useful as an anti-infective agent, is elaborated.

15 cl, 21 dwg, 2 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to pyrazine derivatives of formula I, as well as to their enanthiomers, diastereomers and pharmaceutically acceptable salts, wherein R1 is specified in a group consisting of ii) pyridinyl optionally having one substitute specified in a group consisting of C1-4alkoxy and cyano; and iii) pyrimidin-5-yl; or R1 optionally represents methoxymethyl, when Y represents ethinyl; Y represents ethinyl or a bond; R2 represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl substituted by methyl, phenyl has one to two substitutes independently specified in a group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, difluoromethyl, trifluoromethyl and hydroxy; or R2 represents phenyl having one C1-4alkylcarbonylamino or 1H-imidazol-1-yl substitute; X represents O or CH2; L is absent, and R3 represents 4-aminocyclohexyl, or L represents methylene, while R3 is specified in a group consisting of i) pyrrolidin-2-yl; ii) 1-aminoeth-1-yl; and iii) 1-aminocyclopent-1-yl; or R3 is combined into one cycle with L nitrogen atom to which L is attached to form piperazinyl. Besides, the invention refers to specific compounds, a pharmaceutical compound based on a compound of formula I, a method of treating pain and some neurodegenerative diseases.

EFFECT: there are produced new pyrazine derivative effective in treating pain and some neurodegenerative diseases.

21 cl, 3 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: present invention refers to compounds having formula III such as below, wherein: Q represents C(Y3) or N; R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl or heterocyclyl each of which is optionally substituted by one or more C1-6alkyls, hydroxyC1-6alkyls, oxogroups or halogenC1-6alkyls; R2 represents -C(=O), -O, -C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2', C(R2')2 N(R2')C(=O), -C(=NH), -C(R2')2NR2' or -S(=O)2; each R2' independently represents H or C1-6alkyl; R3 represents H or R4; R4 represents C1-6alkyl, C1-6alkoxygroup, aminogroup, C1-6alkylaminogroup, di(C1-6alkyl)aminogroup, heterocyclyl, C1-10alkylheterocycloalkyl, heterocycloalkylC1-10alkyl each of which is optionally substituted by one or more C1-6alkyls, C1-6alkylaminogroups, di(C1-6alkyl)aminogroups, hydroxygroups, hydroxyC1-6alkyls, C1-6alkoxygroups, oxogroups or halogenC1-6alkyls; X represents CH; X' represents CH; and the rest symbols have values as specified in the patent claim. The compounds of formula III inhibit Bruton's tyrosine kinase (Btk). There are also described compositions containing the compounds of formula III, and at least one carrier, thinner or excipient, and a method for producing the compound of formula X in accordance with the following procedure.

EFFECT: compositions are effective for modulating Btk activity and treating diseases related to Btk hyperactivity, and can be used for treating inflammatory and autoimmune diseases related to disturbed B-cell proliferation, such as rheumatoid arthritis.

22 cl, 2 tbl, 260 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound of formula or to its pharmaceutically acceptable salt, where Alk represents linear C1-6 alkylene group, branched C1-6 alkylene group or C1-6 alkylene group, which has ring structure, where part of carbon atoms, constituting ring structure can be optionally substituted with oxygen atom, in ring X, X1 represents N or CRX1, X2 represents N or CRX2, X3 represents CRX3, X4 represents N or CRX4, where RX1, RX2, RX3 and RX4 each independently represents hydrogen atom; linear or branched C1-6alkyl group; linear or branched C1-6alcoxygroup; or halogen atom, in ring Y, Y1 represents CRY1, Y2 represents N or CRY2, Y3 represents N or CRY3, Y4 represents N or CRY4, RY1, RY2, RY3 and RY4 each independently represents hydrogen atom; linear or branched C1-6alkyl group, which can be substituted with halogen atom(s); C3-7alkyl group, which has ring structure; linear or branched C1-6alkoxygroup; halogen atom or cyanogroup, in ring Z, RZ represents linear or branched C1-6alkyl group, which can be substituted with halogen atom(s), or C3-7alkyl group, which has ring structure, which can be substituted with halogen atom(s). Invention also relates to particular compounds, DGAT1 inhibitor based on formula (I) compound, application of formula (I) compound, method of prevention or treatment of diseases, mediated by DGAT1 inhibition.

EFFECT: obtained are novel compounds, possessing useful biological activity.

19 cl, 19 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: measurement equipment.

SUBSTANCE: method may be used in scanning probing microscopy for determination of electric voltage, modulus of elasticity, hardness, viscosity, plasticity of piezoelectric materials, components of micro and nanoelectromechanical systems, as well as biomicroelectromechanical devices. Nanoindentation of the material is done with a stiff indentor with continuous speed. Simultaneously they measure change of electric voltage and contact force as the indentor is pressed into the material, for instance, piezoelectric. Measurements are made at least for two temperatures of the material.

EFFECT: expansion of functional capabilities of material properties detection by nanoindentation, possibility to determine load value that results in phase transition.

2 cl, 5 dwg

FIELD: nanotechnology.

SUBSTANCE: distinctive feature of the proposed method is the use of biopag-D and the microcapsule shells of sodium carboxymethyl cellulose, as well as the use of a precipitator - 1,2-dichloroethane in the preparation of nanocapsules by physico-chemical precipitation method by nonsolvent.

EFFECT: simplifying and speeding up the process of obtaining the microcapsules and increase in the yield by weight.

3 ex

FIELD: chemistry.

SUBSTANCE: invention provides a method of encapsulating a medicinal preparation via a nonsolvent deposition method, characterised by that the core of the nanocapsule used is fenbendazole, the envelope used is pectin, which is deposited from a suspension in benzene by adding tetrachloromethane as the nonsolvent at 25°C.

EFFECT: simpler and faster process of producing microcapsules, reduced losses when producing microcapsules.

6 ex

FIELD: nanotechnology.

SUBSTANCE: distinctive feature of the proposed method is the use of 2,4-dichlorophenoxyacetic acid and the shell of carrageenan nanocapsules, as well as the use of a precipitator - acetonitrile in the preparation of nanocapsules by physico-chemical precipitation method with nonsolvent.

EFFECT: simplification and acceleration of the process of preparation of nanocapsules and increase in the yield by weight.

3 ex

FIELD: measurement equipment.

SUBSTANCE: sensor comprises a tight body, inside of which there is a piezoelectric acoustic line, on the working surface of which there is a transceiving interdigital transducer (IDT), loaded to an antenna, which is arranged outside the tight body, a support reflecting IDT and a reflecting IDT loaded to impedance located outside the tight body, the value of which is sensitive to the measured value, and an acoustic absorber applied at the ends of the acoustic line. The impedance is made in the form of a lattice of parallel connected nanorods of zinc oxide.

EFFECT: provision of maximum sensitivity of a sensor to concentration of carbon monoxide due to usage of zinc oxide rods as impedance depending on carbon monoxide concentration, with resistance close to resistance of radiation of a reflecting IDT.

2 dwg

Adjuvant // 2550263

FIELD: biotechnology.

SUBSTANCE: invention can be used in human and veterinary medicine for construction and production of highly efficient vaccines.

EFFECT: invention enables to create vaccines with low toxicity, increased immunogenic activity, and stable in storage.

FIELD: nanotechnologies.

SUBSTANCE: inventions relate to nanotechnology and may be used to manufacture catalysts and sorbents. Graphene pumice contains graphenes arranged in parallel at distances of more than 0.335 nm, and amorphous carbon as a binder at their edges, with the graphene-binder ratio from 1:0.1 to 1:1 by mass. The specific area of the surface is more than 1000 m2/g. The absolute hardness is 1 unit by the Mohs scale and less, specific density is 0.008-0.3 g/cm3 for solids, loose specific density of 0.005-0.25 g/cm3 for granules. The composition is produced by burning of a homogeneous powder mix of graphite oxide, unstable organic material and organic and inorganic metal salts with the moisture of all components of 10-15% in a heat-resistant open or tight mould. The source material for the binder is represented by chemical compounds capable of being in a liquid state up to 180°C, not soaking the graphite/graphene surface and damaged at a temperature of not more than 800°C. Graphene pumice is activated by restoration in hydrogen at 400-450°C and pressure of 0.05-0.11 MPa for 10-30 min or in methane at 800-950°C for at least 1 hour at atmospheric pressure with subsequent cooling.

EFFECT: produced sorbents make it possible to multiply increase the capacity of reservoirs for the storage and transportation of natural gas.

15 cl, 8 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: preoperative patient preparation involves urinary catheterisation and rectal drainage. That is followed by radical surgical d-bridement of a purulonecrotic centre and wide opening of the involved site. The pus pockets are drained, and the necrotic tissues are excised to form a vast wound surface. The radical surgical d-bridement of the purulonecrotic centre leaves a sphincter muscle of anus and a serous-muscular layer of the rectal walls preserved. On the 3rd-4th postoperative day, after multiple necrectomies of the wound surface and intensive infusion, detoxification and antibacterial therapy, the vast wound surface is covered with a porous sponge and/or a gauze bandage as a wound filler. The sponge is made of a hydrophilic polyurethane base impregnated with activated carbon. The gauze bandage is impregnated with a colloidal solution of zerovalent metal silver Ag0 particles having a silver nanoparticle size from 2 to 25 nm. The patient is anaesthetised adequately and placed in a plastic air-tight transparent isolator chamber configured as cut down trousers with the vast wound surface covered with the wound filler. The 3-5 postoperative days involve 3-4 continuous vacuum drainage of inflammation products of the involved soft tissues through the porous sponge and/or gauze bandage coverage. The vacuum drainage does not require the dressings to be changed and uses a negative pressure of 85-130 mmHg. After each procedure of the vacuum drainage of the wound surface and every time the isolator chamber is opened, the wound is visually inspected, examined for bacterial contamination and explored. Necrectomy is performed if needed. After the inflammation is arrested completely and the wound surface is clean, whereas the wound surface is decreased considerably, a bacterial swab test is conducted. That is followed by the stages of skin repair of the wound defect with the use of local tissues. The vacuum drainage of the necrotic putrid inflammation products contaminating the soft tissues uses the porous sponge having 30 to 45 pores 700 to 1,500 mcm in size per 1 cm2 of the surface area. In case the combined use of the porous sponge and gauze bandage covering the vast wound surface during the vacuum drainage of the inflammation products contaminating the soft tissues, the gauze bandage is first to cover the wound, and then it is the porous sponge that is placed. The vacuum drainage of the inflammation products contaminating the soft tissues is combined with rectal drainage implying the controlled faecal diversion and urine diversion through a urinary catheter into an external urine bag.

EFFECT: reduced hyperemia and wound edge oedema, providing accurate visualisation of tissue necrosis, reducing the time of formation of the clean wound with adequate granulation tissue, preventing anaerobic flora growth, reducing the time of pus pockets cleansing and healing in a combination with higher quality of patient's life.

4 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: concentration of pentaerythritol in aqueous solutions is determined using a solution with pentaerythritol content of 1-100 100 mg/dm3. The method includes determining pentaerythritol concentration therein at spectrophotometric detector wavelength of 190 nm. The eluent used is 0.0002 M sulphuric acid solution in deionised water. A column of weakly cross-linked styrene divinylbenzene resins is used.

EFFECT: shorter time for determining a chemical substance in water, simplifying the process while maintaining the quality of determination.

1 tbl

FIELD: instrumentation.

SUBSTANCE: magnetoellipsometer contains a radiation source with a monochromator, a polariser armfitted with a position switch from 0° to 45°, a magnetic system for effecting a sample, an analyser arm of an ellipsometer fitted with the position switch from 0° to 45°, the controller with a detector for synchronous measurement of light fluxes, and also the magnetoresistance measurement unit assembled according to the quadripolar measuring bridge circuit and consisting of three resistors and one replaceable module designed as a substrate onto which the witness sample is sputtered with the composition identical to that of the studied sample, and the magnetic system is designed as a pair of optimised Helmholtz's coils and perpendicularly located solenoid.

EFFECT: expansion of functionality of the ellipsometer verification method, improvement of accuracy of measurements, obtaining the additional information on electric or magnetic properties within a uniform method.

4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of the structural formula (1), which possesses the activity increasing erythropoietin production. In formula

R1 represents a group of the structural formula

,

in which R4 and R5, each independently, represent a hydrogen atom, halogen atom or C1-C6alkyl group, R6 represents a hydrogen atom, halogen atom or C1-C6alkyl group, R7 represents a hydroxyC1-C6alkyl group, hydroxyhalogenC1-C6alkyl group, C1-C6alkoxyC1-C6alkyl group, which can have 1 substituent, independently selected from a group of substituents α, (C1-C6alkoxy)carbonyl group, C1-C6alkoxyC1-C6alkoxyC1-C6alkyl group, hydroxyC1-C6alkoxygroup, C1-C6alkylcarbamoyl group, (C1-C6alkyl)(C1-C6alkyl) carbamoyl group, (C1-C6alkyl)(C1-C6alkyl) carbamoylC1-C6alkyl group or C2-C7alkanoyloxyC1-C6alkyl group, α represents a hydroxygroup, Q1 ring represents a piperidinyl group, rings Q2 and Q3 represent a phenyl or pyridyl group, X represents a simple bond or methylene, R2 represents a C1-C3alkyl group and R3 represents a hydrogen atom.

EFFECT: invention relates to a pharmaceutical composition, containing the said compounds, to the application of a compound for obtaining a medication for the enhancement of erythropoietin production and to a method of treatment or prevention of a disease, caused by reduced erythropoietin production, such as anaemia.

33 cl, 1 tbl, 55 ex

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