Compound, certain novel forms thereof, pharmaceutical compositions based thereon and methods of production and use

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulphonamide of formula A and/or a pharmaceutically acceptable salt thereof, having KDR and/or FGFR1 inhibitor properties. The compounds can be used to treat disorders associated with KDR mediated angiogenesis, such as cancer and age-related macular degeneration, or various cancerous diseases which respond to FGFR1 inhibition. Compound (A) corresponds to the structural formula (A) given below.

EFFECT: invention relates to crystalline forms I and II of said compound A and methods for production thereof, pharmaceutical compositions and a method of treatment.

38 cl, 8 dwg, 14 ex

 

[001] Angiogenesis is a process in which new blood vessels grow from the existing vascular network. Such a process may occur in the body in the healing of wounds, for example, the restoration of blood flow in the damaged tissue, for example, when the hand trauma. However, excessive angiogenesis can be initiated when specific pathological conditions such as tumor, age-related macular degeneration (AMD), rheumatoid arthritis, psoriasis, etc. In such circumstances there may be a tendency to undesirable formation of new blood vessels with pathological tissues that feed on and damage normal tissue. For example, cancer cells can enter the bloodstream through new blood vessels and invade normal tissue.

[002] VEGF (vascular endothelial growth factor) and its receptor VEGFR-2 (also known as KDR, receptor domain containing kinase insert) can form the main route for the formation of new blood vessels. It was shown that inhibition of KDR may cause apoptosis of endothelial cells, which subsequently blocks the process of angiogenesis (Rubin M. Tuder, Chest, 2000; 117:281). Thus, KDR inhibitors can be used to treat associated with angiogenesis disorders.

[003] FGF (growth factor fibroblast is) is proangiogenic molecule, as well as VEGF. During angiogenesis, it is believed that VEGF is critical for the process of neovascularization, and the axis of the FGF (fibroblast growth factor)/FGFR (receptor fibroblast growth factor) plays a role in the functional maturation of new blood vessels. In addition, aberrant activation of members of the FGF family and their cognate receptors have been found in many cancers, such as breast cancer, bladder and prostate. Levels of FGFR1 and their partners bind FGF1, FGF2, FGF8b and FGF17 also increased. In tumors of other types of FGFR1 participates as an oncogene whose expression is increased compared to normal tissue. Thus, blockade of conduction signal FGF/FGFR may have a beneficial effect in the treatment of cancer, accompanied by activation of the FGF/FGFR.

[004] In this description are disclosed, the compound of Formula A, for example, N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide and/or its pharmaceutically acceptable salt.

N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide

[005] in the present description of the disclosed pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of formula a and/or at least one pharmaceutically pickup is acceptable salt.

[006] in this description, disclosed is a method of treatment of a subject that has the need for treating at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders, which includes the introduction of a specified subject in need an effective amount of the compounds of Formula a and/or its pharmaceutically acceptable salt.

[007] Solid-phase crystalline forms I and II And compounds of Formula discovered and disclosed in this description. The ability of the compound to exist in more than one crystal structure or form is known as polymorphism. Many connection unexpectedly can exist in the form of polymorphic crystals, and the same compounds can also exist in solid amorphous state. Before the opening of the polymorphism was completely unpredictable (1) whether a particular connection to show polymorphism, (2) how to get any of these unknown polymorphs and (3) what properties, such as stability, will be inherent in any of these unknown polymorphs. See, for example, J. Bernstein "Polymorphism in Molecular Crystals", Oxford University Press, (2002).

[008] Due to the fact that the properties of any solid material depend on the structure, as well as the t nature of the connection, different solid forms of the compounds can and often exhibit excellent physical and chemical properties. Differences in chemical properties can be determined by a variety of analytical method (s), which are used for characterization, analysis and comparison. And such differences in chemical properties can eventually be used to distinguish between solid forms, which can be detected. In addition, differences in the physical properties, such as solubility or bioavailability of solid forms of a substance can be important with the introduction of pharmaceutical compounds in drugs. Thus, the new crystalline and amorphous solid forms of matter in the case of pharmaceutically useful compounds, such as compound of the Formula And may be important in the development of such suitable compounds.

[009] in this description disclosed a new form of compounds of Formula A, designated as Form I //-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide.

[010] in the present description discloses methods of obtaining Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[011] in the present description of the disclosed pharmaceutical composition comprising at least one pharmaceutically when memy media and Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide.

[012] in this description, disclosed is a method of treatment of a subject that has the need for treating at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders, which includes the introduction of a specified subject in need an effective amount of Form I of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[013] in this description is disclosed another form of the compounds of Formula A, designated as Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[014] in the present description discloses how to obtain Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[015] in the present description of the disclosed pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide.

[016] in this description, disclosed is a method of treatment of a subject that has the need for treating at least one disease answering in euromania FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders, which includes the introduction of a specified subject in need an effective amount of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

BRIEF DESCRIPTION of FIGURES

[017] figure 1 shows the x-ray powder Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted the diffraction angle 2 theta, and the vertical axis (y axis) plotted the intensity (number of pulses).

[018] figure 2 shows obtained using a differential scanning calorimeter (DSC) thermogram of Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2 - yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted temperature (°C), and the vertical axis (y axis) applied heat flux (mW).

[019] figure 3 shows the spectrum in the infrared region with the Fourier-transform (FT-IR) Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted wavelength (cm-1), and the vertical axis (y axis) plotted the intensity of transmission.

[020] figure 4 shows a thermogravimetric (TG) curve of Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted temperature (°C), and the vertical axis (y axis) plotted the percent mass (%).

[021] figure 5 shows the x-ray powder Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted the diffraction angle 2 theta, and the vertical axis (y axis) plotted the intensity (number of pulses).

[022] figure 6 shows the obtained using a differential scanning calorimeter (DSC) thermogram of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted temperature (°C), and the vertical axis (y axis) applied heat flux (mW).

[023] figure 7 shows the spectrum in the infrared region with the Fourier-transform (FT-IR) Form II N-2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted wavelength (cm-1), and the vertical axis (y axis) plotted the intensity of transmission.

[024] In Fig shows thermogravimetric (TG) curve of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-shall ndol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, where on the horizontal axis (x axis) plotted temperature (°C), and the vertical axis (y axis) plotted the percent mass (%).

[025] the Following abbreviations and terms have these meanings in this description:

[026] the Term "new form" in this description refers to a crystalline form (Form I and Form II) compounds of the Formula And amorphous forms of the compounds of Formula a, as well As mixtures thereof. "Crystalline form" and "polymorph" may be used herein interchangeably.

[027] the Term "compound of Formula a or N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide" is equivalent to a compound with a chemical structure of Formula A (also referred to as "Compound A"):

[028] the Term "solution" means suitable for the purposes of the invention disclosed herein, a mixture of one or more dissolved substances in one or more solvents. The solution is designed to enable a homogeneous mixture and a heterogeneous mixture such as a slurry or other mixture containing a suspension of insoluble (not dissolved) material. [029] the Term "organic solvent" in the broad sense, is intended to designate any suitable organic solvent for the purposes disclosed in this specification.

[030] the Term "organic solvent is, in which the dissolved substance"means any organic solvent which is suitable due to its ability to dissolve the substrate, in whole or in part, in suitable conditions, such as the right number and suitable temperature, for example, room temperature or elevated temperature.

[031] the Term "organic solvent which is not soluble substance" refers to any suitable organic solvent in which the solubility of the substrate is smaller than in an organic solvent in which is dissolved substance.

[032] "Pharmaceutical acceptable salts" include, but are not limited to, salts with inorganic acids, such as hydrochlorate, Hydrobromic, phosphate, diphosphate, sulfate, sulfinate, nitrate and other salts; and salts with organic acid such as malate, maleate, mandelate, fumarate, tartrate, succinate, citrate, aspartate, glutamate, acrolectal, gluconate, propionate, lactate, camphorsulfonate, methanesulfonate, aconsultant, naphthalenesulfonate, n-toluensulfonate, 2-hydroxyethylsulphonic, hydroxybutyrate, benzoate, salicylate, stearate and alkanoate, for example acetate , HOOC-(CH2)n-COOH where n is 0-4, and the like salts. Similarly pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[033 in Addition, if this connection is obtained as an acid additive salt, the free base can be obtained by alkalizing solution of an acid additive salt. Conversely, if the product is in the form of a basic additive salts, in particular pharmaceutically acceptable additive salt can be obtained by dissolving the free base in a suitable organic solvent with the processing solution of the acid in accordance with conventional methods of obtaining the acid additive salts of the basic compounds. Specialists in this field will be familiar with the different methodologies of synthesis that can be used within a template experimentation to obtain non-toxic pharmaceutically acceptable additive salts.

[034] the Term "effective amount" of the compounds of Formula A, including the new form described here, refers to the amount, when administered to a subject with an established need, such as the patient-the person or negumanoidnyh the patient, is effective to relieve symptoms or stop the progression of at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders.

[035], An N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-what ethyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide Formula (Compound A)

and/or its pharmaceutically acceptable salt.

[036] Also proposed a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of Formula a and/or its pharmaceutically acceptable salt. [037] the Compound of Formula a can be synthesized in accordance with the following schema.

Stage 1: Synthesis of 5-((2-chloropyrimidine-4-yl)oxy)-2-methyl-1H-indole (compound 3)

[038] Named in the title compound 3 can be obtained by the reaction of 5-hydroxyl-2-methyl-indole (compound 1) with 2,4-dichloropyrimidine (compound 2) in the presence of a base such as, but not limited NaHCO3, KOH, NaOH, K2CO2Knso3diisopropylethylamine (DIPEA), pyridine, triethylamine (tea) or trimethylamine, in a solvent such as, but not limited to, acetonitrile, N,N-dimethylformamide (DMF), dioxane, tetrahydrofuran (THF). The reaction can be conducted at a suitable temperature, for example at a temperature in the range from 0 to 60°C.

Stage 2: Synthesis of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide (compound of Formula (A)

[039] Named in the title compound Formulas And can be synthesized as a crude product compound of the Formula And the reaction of the Compound 3 -(3-AMINOPHENYL)-N-(2-(dimethylamino)ethyl)methanesulfonamide (Compound 4) in the presence of acid, such as, not limited to, acetic acid, formic acid, HCl, H2SO4, toluensulfonate acid, triperoxonane acid or acidic econsultancy acid, in a solvent such as, without limitation, N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethanol, isopropanol or toluene. The reaction can be conducted at a suitable temperature, for example at a temperature in the range from 40 to 100°C.

[040] the Crude product of the compound of the Formula And may be further purified by chromatography on silica gel, high performance liquid chromatography, crystallization, or other suitable methods.

[041] the Crude product of the compound of the Formula And can also be purified by recrystallization using a solvent, such as, without limitation, N-organic, dichloromethane, toluene, N,N-dimethylformamide or a mixture of N,N-dimethylformamide/toluene.

[042] Also suggested that new forms of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[043] In some embodiments, the embodiment described here, new forms can be identified using one or more solid-phase methods of analysis. For example, Form I and/or Form II can be characterized, for example, in accordance with one or more of the following ways: d thestructural analysis of the powder, cell constants were obtained for the single crystal spectroscopy in the infrared region with Fourier-transformation curve data of differential scanning calorimetry (DSC) and thermogravimetric curve. And if the characteristic using any of these methods is consistent with the existence of Form I and/or Form II, this does not mean that the data any other way will not agree with this existence.

[044] In some embodiments, the embodiment described here, a new form may be characterized in accordance with the x-ray powder. However, in this area it is known that the intensity and/or the measured peaks on the x-ray of various parties of the new form may vary, for example due to differences in experimental conditions and/or preferred orientations. And, in accordance with the accuracy of the instrument, the measurement error of the 2θ values is ±0.2 2θ. But, by adjusting the experimental and calculated errors and principles such as preferred orientation, the person skilled in the art can obtain sufficient information about the data x given in this description, to identify the Form I and Form II without having to rely on all the data of x-rays.

Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-in the ol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide

[045] the Proposed Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[046] In some embodiments, embodiments of the x-ray powder Form I described here may contain peaks (2θ), some of which have approximately the following values: to 7.0, and 8.0 and 8.6, each of the angles of diffraction ±0,2° (2θ). In some embodiments, embodiments of the x-ray powder Form I described here may contain peaks (2θ), some of which have approximately the following values: 7,0, 8,0, 8,6, 11,0, 11,8, each of the angles of diffraction ±0,2° (2θ). In some embodiments, embodiments of the diffraction pattern of Form I, described herein, may be substantially similar to that shown in figure 1.

[047] In some embodiments, embodiments Form I of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide can be characterized by means of IR spectrum with the Fourier-transform (FT-IR). For example, a variant Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide, where the spectrum FT-IR shows peaks at approximately 2781,4, 1218,2, 1163,1, 1124,5, 1114,8, 1085,7, 984,9, 705,0, 500,7 and 434,8 cm-1. In some embodiments the embodiment of the FT-IR spectrum of Form I described here, may be substantially similar to th is shown in figure 3.

[048] In some embodiments, embodiments Form I of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide may be characterized in accordance with the DSC thermogram. For example, a version of the Form I described here, where the DSC thermogram substantially similar to that shown in figure 2. For example, a variant embodiment of the Form I described here, where the DSC thermogram contains endothermic peaks at approximately 167-169°C.

[049] In some embodiments, embodiments Form I of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide can be characterized by thermogravimetric analysis (TGA). For example, the variant of embodiment I described here, where the TGA shows a Form I described here in the form of anhydrous or undiluted form. Cm. figure 4.

[050] In some embodiments, embodiments Form I substantially free of Form II and amorphous forms of the compounds of Formula A. for Example, Form I is at least 99 wt.%, at least 95 wt.%, at least 90 wt.% or at least 80%, mass., free of Form II and amorphous forms of the compounds of Formula A. as another example, Form I of at least 70 wt.% or at least 60 wt.% free of Form II and amorphous forms of the compounds is of Formula A. As another example, Form I at least more than 50 wt.%, free of Form II and amorphous forms of the compounds of Formula A.

Methods of obtaining Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide

Method And

[051] Also proposed a method of obtaining Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, which includes:

(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1 I-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide Formula And at least one organic solvent in which the substance is dissolved, and then boiling the mixture under reflux to obtain a solution;

(2) cooling the solution to room temperature, for example, slow cooling; and

(3) the selection of the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[052] In some embodiments of the incarnation at least one suitable organic solvent in which is dissolved substance selected from the proton solvents and aprotic solvents. In some embodiments, embodiments of the proton solvents are alcohols, such as methanol, ethanol, isopropanol, n-butanol, and alcohols containing less than 6 atoms angle of the ode, additionally, including methanol, ethanol and isopropanol. In some embodiments embodiment aprotic solvents selected from acetone, acetonitrile, N,N-dimethylformamide, toluene, dichloromethane and ethyl acetate.

[053] In some embodiments embodiment the solution is cooled to room temperature, for example, is slowly cooled while mixing, such as stirring with an average speed of, for example, with stirring speed from 50 to 200 rpm

[054] In some embodiments, the incarnation number of the at least one solvent in which is dissolved substance, is from 10 to 60 volume (ml) 1 unit mass (g) compounds of the Formula And used in stage (1).

Method B

[055] Also proposed an alternative method of obtaining the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl), which includes:

(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide at least one organic solvent, which dissolves the substance, and then boiling the mixture under reflux to obtain a first solution;

(2) adding at least one organic solvent in which the substance does not dissolve, to the first solution at the boiling point with reverse holo is rinicom to obtain a second solution;

(3) cooling the second solution, for example, slow cooling to room temperature; and

(4) the selection of the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[056] In some embodiments of the incarnation at least one solvent which dissolves the substance is the same as described above. In some embodiments embodiment at least one solvent in which is dissolved substance selected from methanol, ethanol, acetone, acetonitrile and N,N-dimethylformamide.

[057] In some embodiments, embodiments of a suitable solvent which does not dissolve the substance, depending on the conditions selected from water, heptanol, hexanol and other saturated hydrocarbon solvents containing less than 9 carbon atoms; ethyl acetate and other esters of organic acids containing less than 8 carbon atoms; tert-butyl methyl ether and other ethers containing less than 6 carbon atoms; and toluene. In some embodiments embodiment at least one solvent which is not soluble substance selected from water, heptanol, hexanol and ethyl acetate.

[058] In some embodiments the embodiment of the volumetric ratio of at least one solvent in which is dissolved substance, and at least one solvent, in which RA is Dvoretsa substance, varies from 1:3 to 5:1.

[059] In some embodiments, the incarnation number of the at least one solvent which dissolves the substance used in this alternative method, also is from 10 to 60 volume (ml) 1 unit mass (g) compounds of the Formula And used in stage (1).

Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[060] Also proposed Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[061] In some embodiments the embodiment of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide may be characterized in accordance with the x-ray powder. In some embodiments, embodiments of the x-ray powder Form II described herein, may contain peaks (2θ), some of which have approximately the following values: 6,8, 9,8, to 10.5 and 10.7, where each of the angles of diffraction is ±0.2° (2θ). In some embodiments, embodiments of the x-ray powder Form II described in this document may contain peaks (2θ), some of which have approximately the following values: 6,8, 9,8, 10,5, 10,7, 13,6, 15,0, where each of the angles of diffraction is ±0.2°(2θ). In some embodiments, embodiments of the x-ray powder f is RMI II, described here, may be substantially similar to that shown in figure 5. But, by adjusting the experimental and calculated errors, and principles such as preferred orientation, the person skilled in the art can obtain sufficient information about the data x-ray powder shown here for identification Form II, without having to rely on all the data of x-rays.

[062] In some embodiments the embodiment of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide can be characterized according to the IR spectrum with the Fourier-transform (FT-IR). For example, a variant of the embodiment of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide for which spectrum FT-IR shows peaks at wavelengths of approximately 2770,3, 1216,3, 1166,3, 1115,8, 1089,8, 986,5, 872,5, 695,5, 520,5, 456,0 cm-1. In some embodiments, embodiments of the spectrum FT-IR Form II described herein may be substantially similar to that shown in Fig.7.

[063] In some embodiments the embodiment of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide may be characterized in accordance with the DSC thermogram. For example, it is proposed options, the ant embodiment Form II, described here, where the DSC thermogram substantially similar to that shown in Fig.6. For example, a variant of the embodiment of Form II described in this document, where DSK contains endothermic peaks at temperatures of approximately 160-162°C. Cm. 6.

[064] In some embodiments the embodiment of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide can be characterized by thermogravimetric analysis (TGA). For example, a version of the embodiment of Form II described in this document, where TGA indicates the Form II described here as anhydrous or undiluted form. Cm. Fig.

[065] In some embodiments the embodiment of Form II substantially free of Form I and amorphous forms of the compounds of Formula A. for Example, Form II of at least 99 wt.%, at least 95 wt.%, at least 90 wt.% or at least 80 wt.%, free of Form I and amorphous forms of the compounds of Formula A. Then, for example, Form II at least 70 wt.% or at least 60 wt.%, free of Form I and amorphous forms of the compounds of Formula A. then, for example, Form II at least more than 50 wt.%, free of Form I and amorphous forms of the compounds of Formula A.

A method of producing Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-ylamino)phenyl)-methanesulfonamide

Method B

[066] Also proposed a method of producing Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, which includes

(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide at least one solvent in which is dissolved substance, and the mixture heated to boiling under reflux to obtain a first solution;

(2) adding at least one solvent which does not dissolve the substance to the first solution at the boiling point under reflux to obtain a second solution;

(3) cooling the second solution, for example, to 0-5°C, for example, when the cooling rate 1-40°C/min; and

(4) the selection of the Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[067] In some embodiments embodiment the solution is cooled to 0-5°C with a cooling rate of 1-40°C/min under stirring.

[068] In some embodiments of the incarnation at least one suitable organic solvent in which is dissolved substance selected from the proton solvents and aprotic solvents. In some embodiments, embodiments of the proton solvents are alcohols, such as methanol, ethanol, isopropanol, n-butane is l, and alcohols containing less than 6 carbon atoms, such as methanol, ethanol and isopropanol. In some embodiments embodiment aprotic solvents selected from acetone, acetonitrile, N,N-dimethylformamide, toluene, dichloromethane and ethyl acetate.

[069] In some embodiments, embodiments of suitable alcohols selected from methanol and ethanol. In some embodiments embodiment aprotic solvents selected from acetone, acetonitrile, ethyl acetate and N,N-dimethylformamide.

[070] In some embodiments embodiment, the ratio by weight of the compounds of Formula But with a volume of at least one solvent which dissolves the substance varies from 0.03:1 to 0.08:1 (g/ml).

Method D

[071] Also proposed an alternative method of producing Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, which includes:

(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide at least one solvent in which is dissolved substance, and boiling the mixture under reflux to obtain a solution;

(2) cooling the solution with the subsequent introduction of the seed Form II described here, the cooled solution;

(3) cooling the solution with the seed crystal to room temperature; and

(4) the selection of the Form II N-(2-(dimethyl what Mino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

[072] In some embodiments, embodiments of the solution in stage (2) slowly cooled to 45-55°C prior to depositing the seed.

[073] In some embodiments, embodiments of a seed crystal Form II is added to the solution with stirring.

[074] In some embodiments, embodiments of the solution with a seed crystal is cooled to room temperature, allowing it to stand at room temperature.

[075] In some embodiments of the incarnation at least one suitable organic solvent in which is dissolved a substance selected from a proton solvents and aprotic solvents. In some embodiments, embodiments of the proton solvents are alcohols, such as methanol, ethanol, isopropanol, n-butanol, and alcohols containing less than 6 carbon atoms, such as methanol, ethanol and isopropanol.

In some embodiments embodiment aprotic solvents selected from acetone, acetonitrile, N,N-dimethylformamide, toluene, dichloromethane and ethyl acetate.

[076] In some embodiments, embodiments of suitable alcohols selected from methanol and ethanol. In some embodiments embodiment aprotic solvents selected from acetone, acetonitrile, ethyl acetate and N,N-dimethylformamide

[077] In some embodiments, embodiments of a seed crystal Form II is added to the solution with stirring.

[078] In some embodiments embodiment the ratio of the masses of the compounds of the Formula And the amount of at least one solvent, which dissolves the substance varies from 0.03:1 to 0.08:1 (g/ml).

[079] In some embodiments, the incarnation number of the seed Form II varies from 0.01 to 0.5 wt.%, relative to the weight of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide used in stage (1). In some embodiments, the incarnation number of the seed Form II is 0.5 wt.%, relative to the weight LC-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide used in stage (1).

[080] All described in this description of the methods of obtaining Form I or Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide optionally may additionally include another stage between stage 1 and stage (2)where obtained in stage (1) the solution is filtered while hot to remove insoluble particles. In order to avoid precipitation during any stage of the hot filtration funnel for filtering can be heated during or before filtration. Formed during the hot filtration sediment can be re-dissolved by heating of the leachate before performing the next operation.

Pharmaceutical composition and methods of treatment

[081] In some embodiments, embodiments at least one of the active phased array is aseptically ingredient, selected from the compounds of Formula (Compound a) and/or its pharmaceutically acceptable salts, and Forms I and II compounds of the Formula And may be suitable for treating at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorder. In some embodiments, embodiment associated with angiogenesis disorder selected from age-related macular degeneration and various types of cancer. Various kinds of cancer, as described herein, include, but are not limited to, liver cancer, lung cancer, head and neck cancer, breast cancer, bladder cancer, cancer of the colon, rectum, stomach cancer, pancreatic cancer, ovarian cancer, prostate cancer, kidney cancer and sarcoma.

[082] In some embodiments, embodiments of the method of treatment of a subject suffering from at least one cancer and/or at least one associated with angiogenesis disease, with an established need in the treatment of such diseases includes the introduction of the specified entity with the established need of treatment an effective amount of at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II connection is of Formula A, to ensure the specified at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders.

[083] In some embodiments, embodiments of the method of treatment of a subject suffering from at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorder, with an established need for treatment, includes an introduction to the specified entity with the established need of treatment an effective amount of Form I of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide for treatment of the specified at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders.

[084] In some embodiments, embodiments of the method of treatment of a subject suffering from at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders, installed need to change is the institutional capacity in the treatment, thus, it includes an introduction to the specified entity with the established need of treatment an effective amount of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide for treatment of the specified at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorder.

[085] In some embodiments, embodiments of the method of treatment of a subject suffering from at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorder, with an established need for treatment, thus, includes the introduction of the specified entity with the established need of treatment an effective amount of a pharmaceutical composition comprising: at least one pharmaceutically acceptable carrier and a compound of Formula a and/or its pharmaceutically acceptable salt to ensure such treatment.

[086] In some embodiments, embodiments of the method of treatment of a subject suffering from at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease from ecause on the inhibition of KDR, such as associated with angiogenesis disorder, with an established need for treatment, thus, includes the introduction of the specified entity with the established need of treatment an effective amount of a pharmaceutical composition comprising: at least one pharmaceutically acceptable carrier and Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl) to ensure such treatment.

[087] In some embodiments, embodiments of the method of treatment of a subject suffering from at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorder, with an established need for treatment, thus, includes the introduction of the specified entity with the established need of treatment an effective amount of a pharmaceutical composition comprising: at least one pharmaceutically acceptable carrier and Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide to ensure such treatment.

[088] the Amount of at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II compounds Faure the uly And, effective to achieve the target biological effect may depend on many factors, for example, provided for use, route of administration and the clinical condition of the patient. Daily dose of, for example, can vary from 0.1 mg to 3 g/day (for example, from 0.5 mg to 2 g /day, for another, for example from 100 mg to 1 g/day). Dose medications that can be administered orally include, for example, tablets or capsules.

[089] For the treatment of the aforementioned conditions, at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II compounds of the Formula And may be used as the actual connection, but typically each of them will be applied in the form of a pharmaceutical composition with one or more acceptable carriers/excipients. Typical examples of carriers/excipients must be compatible with other ingredients of the composition and must not be hazardous to the health of the patient. Carrier/excipient may be a solid or a liquid, or both, and may be entered in the product with the compound of the Formula A, such as Form I and/or Form And described in this description, dose form such as a tablet, which may contain from 0.05 wt.% to 95 wt.%, soedineniya is ormula And, described in this description. The pharmaceutical compositions described herein, can be obtained well-known in the field of pharmacy ways, for example, includes mixing the ingredients with pharmacologically acceptable carriers and/or excipients and/or diluents.

[090] In some embodiments, the embodiments are typical examples of carriers/excipients can include, but are not limited to: microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, glycine, disintegrant, such as starch, sodium cross-linked carboxymethylcellulose, composite silicate and polyethylene glycol of high molecular weight binders for granulation (such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum) and lubricants (such as magnesium stearate, glycerin and talc).

[091] In some embodiments of the incarnation at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II compounds of the Formula And may be combined with at least one component, such as a carrier and/or excipient and/or diluent selected from sweeteners, flavorings and unobtrusive smell, painted materials, dyes and emolga the Directors.

[092] In some embodiments the embodiment of Form I or Form II, described in this description may not be entered in the drug with one or more pharmaceutically acceptable diluents. In other embodiments, the embodiment of Form I or Form II, described in this description, may be converted, in whole or in part, in one or more other forms, including neverovatnih, with the introduction of the drug with one or more pharmaceutically acceptable carriers/solvents/auxiliaries. Examples of carriers/diluents/excipients include, but are not limited to, water, ethanol, propylene glycol, glycerin and mixtures thereof. In some embodiments the embodiment of Form I or Form II, described in this description may be dissolved with the introduction of the pharmaceutical composition. Accordingly, in a case of this "dissolution" of the Form I or Form II no longer exists in the corresponding crystalline form of pharmaceutical compositions.

[093] In some embodiments of the incarnation at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, may be introduced into a suitable dosage form.

[094] the Pharmaceutical compositions described herein, may be suitable for oral and PE is oral administration (for example, sublingual), although suitable route of administration may depend in each case on the nature and severity of the condition to be treated and on the nature of at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II And compounds of Formula used in each case to obtain the pharmaceutical composition. Also available preparations of coating and drugs slow release coating. It is possible to obtain preparations that are resistant to the action of acid and gastric juice. Suitable resistant to gastric juice coatings include cellulose acetate phthalate, polyvinylacetate, hydroxypropylmethylcellulose phthalate, anionic polymers of methacrylic acid and methyl methacrylate.

[095] Suitable pharmaceutical compositions for oral administration prepared from at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula a can be in the form of separate units such as, for example, capsules, sachets and tablets, including lozenges, each of which can be obtained with a certain amount of at least one active pharmaceutical the ski ingredient, described here, and in the form selected from powders, granules, solutions, suspensions in aqueous or non-aqueous liquids and emulsions oil-in-water and water-in-oil. Such compositions, as described above, can be obtained by any suitable method of obtaining pharmaceutical drugs, such as methods, including the stage, where a is at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, and the carrier (which may consist of one or more additional ingredients, including diluents and excipients). The whole composition can be obtained by uniform and homogeneous mixing at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula a with a liquid and/or finely powdered solid carrier, after which the product may be attached to the form. Thus, for example, a tablet may be obtained by compressing or molding a powder or granules of at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, the ri needed with one or more additional ingredients. Molded tablets can be obtained by tabletting at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, in the form of loose structures of substances such as powder or granules, optionally mixed with a binder agent for improving the sliding means, inert diluent and/or one or more surface-active/dispersing agent in a suitable apparatus. Molded tablets can be obtained by forming at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, in the form of powder, moistening the inert liquid diluent in a suitable apparatus. The composition can also be obtained by wet granulation. Thus, for example, the composition can be obtained by wet granulation while mixing at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, with one or more optional ingredients, suitably the m solvent and a binder agent to obtain a wet granulate, drying the wet granulate and grinding the dry granulate. The method may further include adding at least one lubricant to dry molotow the granules and compressing the dried ground granulate with reception of tablets. Optional additional ingredients may include, for example, at least one diluent and/or at least one disintegrant. A suitable solvent may be water. In some embodiments embodiment the diluent is selected from calcium carbonate, calcium phosphate (dibasic and/or trehosnovnogo), calcium sulfate, powdered cellulose, dextrates, dextrin, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, microcrystalline cellulose, sorbitol, sucrose and starch. In some embodiments embodiment, the diluent may be present in amount from about 35% to about 90% by weight of the tablet. In some embodiments, embodiments of the binder agent may be selected from acacia gum, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methyl cellulose, polyethylene oxide and povidone. In some exemplary embodiments, the embodiment of the binding agent is present in amount from about 0.5% to PR is approximately 5% by weight of the tablet. In other exemplary embodiments, the above-mentioned embodiment, the preparations contain about 0.05-5 g, at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula a, the ml or gram of the drug.

[096] the Compositions disclosed herein, can be applied topically or administered systemically.

[097] Pharmaceutical compositions suitable for peroral (sublingual) administration may include lozenges, which can be prepared from at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, with the use of flavoring, which is usually chosen from sucrose, Arabian gum, tragacanth gum and lozenges.

[098] the Pharmaceutical compositions described herein may also be suitable for parenteral, by inhalation spray, or via an implantable reservoir. Solid carriers, for example, starch, lactose, microcrystalline cellulose, aluminum silicate, liquid carriers, for example, water for injection, polyvinyl alcohol, nonionic surfactants and corn oil, and any other ingredients suitable to the d the I the intended method of administration. Other excipients commonly used in pharmaceutical formulation, include dyes, preservatives, means for correction of flavor and antioxidants, such as vitamin E, vitamin a, equivalent and bottled hydroxyanisol.

[099] the Compound of Formula A, such as Form I or Form II, as described herein also may be administered intraperitoneally. Also a solution and a suspension of the compound can be obtained by dissolving or suspendirovanie compounds in water containing a suitable surfactant. Dispersed suspensions can be obtained by using glycerol, polyethylene glycol (PEG), or a mixture thereof with suitable oils. Preservatives can be added to these preparations to prevent growth of microorganisms in the application.

[0100] Injectable comprises a solution or suspension of sterile powder in sterile water. In all cases, such drugs must be sterilized and easily removed from the syringe, and should be stable under conditions of manufacture and storage and, to the extent possible, free from pollution and the impact of microorganisms. The media can be a solvent or dispersing agents include water, alcohol and some suitable oil.

[0101] At least one active pharmace the critical ingredient, selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, can also be administered in combination with one or more other active ingredients. With the introduction of combinations of active ingredients can be introduced into the drugs as separate compositions that are administered simultaneously or sequentially at different points in time, or the active ingredients can be entered in single dose form, i.e. as a single composition, provided that the active ingredients in such single dose form will not be incompatible with other active ingredients or components of the dosage form or when merging will not occur other unwanted effects.

[0102] In some embodiments of the incarnation at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, can be entered with one or more other known means for treating at least one disease that responds to inhibition of FGFR1, such as cancer, and/or at least one disease that responds to inhibition of KDR, such as associated with angiogenesis disorders.

[0103] the Expression "concomitant therapy" (or "combination therapy") or "in combination with" in this description the AI controls the at least one active pharmaceutical ingredient, selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II, the compounds of Formula A, as described herein, and one or more other active ingredients, such as, for example, antineoplastics funds. In this description, the term "antineoplastics tool" means any tool that is administered to a patient with cancer to a subject for treatment of cancer. Non-limiting examples antineoplastics funds include radiotherapy, immunotherapy, damaging DNA chemotherapeutic agents and chemotherapeutic agents that disrupt cell replication.

[0104] non-limiting examples of damaging DNA chemotherapeutic agents include inhibitors of topoisomerase I (e.g., irinotecan, topotecan, camptothecin and their analogues or metabolites, and doxorubicin; topoisomerase II inhibitors (e.g. etoposide, teniposide and daunorubicin); alkylating agents (such as melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustin, lomustin, semustine, streptozocin, dacarbazine, meteksan, mitomycin C and cyclophosphamide); intercalatory DNA (e.g., cisplatin, oxaliplatin and carboplatin; intercalatory DNA and generators of free radicals, such as bleomycin; and nucleoside mimetics (for example, 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, mercapto is Rin, tioguanin, pentostatin and hydroxyurea).

[0105] Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047); inhibitors proteincontaining (e.g., imatinib mesilate and gefitinib); proteasome inhibitors (e.g. bortezomib); inhibitors of NF-Kappa b, including the inhibitor I Kappa b kinase; antibodies that bind with over-expressed in cancer protein, which, thus, down regulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes that are proven, up regulated, overly expressed or activated in various cancers, the inhibition of which down regulates cell replication.

[0106] During concomitant therapy introduction each of the active ingredients may occur sequentially in the scheme of obtaining a favorable effect of the combination of drugs; and/or concomitant introduction of the above-mentioned compounds can be substantially simultaneously (e.g., in the form of a single dosage form such as capsule, containing a fixed ratio of active ingredients or in the form of NESCO is gcih separate capsules for each active ingredient and so on).

[0107] Thus, described herein is not limited to the sequence of administration; at least one active pharmaceutical ingredient selected from the compounds of Formula a and/or its pharmaceutically acceptable salts, and Forms I and II compounds of the Formula As described herein, may be introduced prior to, concurrently or after administration of one or more other active ingredients. [0108] the following non-limiting examples.

Experiments

[0109] All reagents, except intermediate compounds used in this description are commercially available. All the names of the compounds, with the exception of the reagents formed using ChemBioDraw Ultra 12,0.

[0110] Unless otherwise stated, x-ray powder obtained using x-ray diffractometer Bruker D8 ADVANCE, with the generation of radio waves by the source sica at 40 mA and 40 kV, and the device can operate in the range of 2θ 3-45° with a step scan of 0.02°and a scanning speed of 4°/min

[0111] thermal analysis DSC was performed on the instrument PerkinElmer DSC 7, where ventilation was used with nitrogen flow rate of 50 ml/min, the Specimens were examined in corrugated aluminum cups. The instrument was calibrated for temperature using India. The samples for DSC experiments were carried out in the usual way with the speed of nahrawan what I 5-10°C/min in the temperature interval from 25 to 200°C.

[0112] the IR spectra were recorded using a spectrometer MagnaTI-IR750 (NICOLET), from each specimen by compacting received KBr disks.

[0113] Thermogravimetric (TG) curves, which can be used to determine changes in the weight of materials as a function of temperature, obtained using a Perkin-Elmer Thermal TGA and N2for blowing a flow rate of 50 ml/min, the heating rate was 10°C/min

Example 1

Synthesis of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide

Stage 1: Synthesis of 5-((2-chloropyrimidine-4-yl)oxy)-2-methyl-1H-indole (Compound 3):

[0114] a 3-necked round bottom flask with a capacity of 50 liters, equipped with a mechanical stirrer, funnel for adding and thermometer, was placed 2-methyl-1H-indol-5-ol (compound 1, 3 kg), anhydrous acetonitrile (9 l) and potassium carbonate (4.2 kg). The reaction mixture is cooled to 0-5°C under stirring in nitrogen atmosphere N2. A solution of 2,4-dichloropyrimidine (Compound 2, 3,05 kg in 9 ml of acetonitrile) is added to the reaction mixture dropwise, maintaining the internal temperature of the reaction mixture in the range from 0 to 5°C. After complete addition, the reaction mixture is allowed to warm to a temperature in the range from 5 to 10°C during a period of 4-8 hours. After completion of the reaction, the reaction mixture is poured with stirring at 54 l distiller the bath water in the reactor with a capacity of 100 l and stirred for 1 hour at room temperature. The precipitate was separated by filtration, and the filter residue is washed with pure water to obtain Compound 3 (5.7 kg).

Stage 2: Synthesis of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide (Compound of the Formula:

[0115] a 3-necked round bottom flask with a capacity of 10 l, equipped with a mechanical stirrer and thermometer, was placed a Connection 3 (1.05 kg), 1-(3-AMINOPHENYL)-N-(2-(dimethylamino)ethyl)methanesulfonamide (Compound 4, 1.06 kg), n-toluensulfonate acid (0,86 kg) and N,N-dimethylformamide (5,25 l). The reaction mixture is carefully heated to a temperature in the range from 55 to 65°C and stirred at the specified temperature for 16-20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and transferring portions of 5% aqueous solution of potassium carbonate. After complete addition, the resulting suspension is stirred for 1-2 hours. The crude product is separated by filtration, and the wet residue on the filter is transferred into the reactor with a capacity of 200 liters

[0116] In a reactor add toluene (104 kg) and the suspension is refluxed to remove water using traps Dean-stark. After removal of water, the solution is evaporated to a final volume of 30-40 l under reduced pressure, cooled to 15-20°C. the Product is collected and dried to obtain specified in the connection header (Conn the General Formula A, 1,07 kg). Next, the resulting material can be used to produce new forms of compounds of Formula A, such as Form I and/or Form II.

Example 2

In vitro activity of inhibition of KDR kinase

[0117] Investigated the connection:

- N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide (Compound of Formula A1

- N-methyl-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide (Combination Formula)

- N4-(4-fluoro-2-methyl-1H-indol-5-yl)-N2-(3-(2-

morpholinoethoxy)phenyl)pyrimidine-2,4-diamine (Compound of Formula (C)

[0118] the Ability of the above 3 compounds to inhibit KDR kinase was investigated using the test kit Z-Lyte.

Materials and methods:

[0119] the Peptide Z'-LYTE™ Tyrl (Invitrogen, cat. No. PV3190) was used to analyze the activity of the above compounds as inhibitors of KDR kinase. System analysis contained 300 ng/ml of recombinant catalytic domain of human KDR, 10 μm ATP, 1 μm substrate peptide, and analyzed the connection in series of concentrations in 384-well the tablet (Thermo Labsystems, cat. No. 7805); the total volume was 10 µl. Inhibition of the enzyme was carried out at room temperature (25°C) for the of 1 hour with shaking, then add 5 ál of the amplifier, and incubated for 1 hour at room temperature and shaking. 5 µl of stopping solution was added to stop the reaction. The activity of the compounds, inhibitory KDR kinase, was calculated based on the method recommended by the manufacturer. The values of the IC50activity inhibition of KDR kinase was calculated using the software XLfit.

Method of analysis:

[0120] (1) the Breeding of the studied compounds: each of these 3 compounds are dissolved in DMSO to obtain a 10 μm backup solution and stored at -20°C in a freezer. Alternate solution before use dilute with 8% DMSO to a concentration of 4 times the target concentration for analysis.

[0121] (2) to 1.33× buffer analysis: Dilute 5× buffer analysis ddH2O up to 1.33× buffer analysis.

[0122] (3) the Breeding of the catalytic domain of KDR kinase (KDR CD): dilute the original backup solution KDR CD of 1.33× buffer analysis 10 times. Selected aliquots of 5 µl/vial and stored at a temperature of -80°C. avoid repeated freezing and thawing.

[0123] (4) a Mixture of kinase/substrate: add alternate solution KDR CD and peptide Tyrl to 1.33× buffer analysis with obtaining a mixture containing 0.6 ng/ál KDR CD, and diluted 250-fold peptide Tyrl. Stand the mixture on ice until use is litvania.

[0124] (5) the Mixture for control wells NW: diluted phospho-peptide substrate of 1.33× buffer analysis 250 times. Gently mixed and incubated on ice.

[0125] (6) the ATP Solution: dilute 10 mm spare ATP solution ddH2O 250 times. Get 40 μm ATP solution and selected aliquots of 100 µl/vial, and stored at -20°C.

[0126] (7) Inhibition of kinases: add the following components in turn 384-well plate. Holes in the double repetition examined for each concentration of each tested compound, and the average value used for the calculation.

[0127] a) Added to 2.5 μl of the diluted solution of the compound obtained in stage (1) to all wells, except the control wells C1, C2 and C3. Add a 2.5 ál of 8% DMSO instead of the solution of the compounds in the control wells C1, C2, C3.

[0128] b) Add 5 ál of the mixture kinase-substrate obtained in stage (4) to all wells, including the control wells C1 and C2, but not in the hole C3. 5 μl of a mixture of C3 obtained in stage (5)add the control hole C3.

[0129] in) is Added to 2.5 μl of 40 μm ATP solution obtained in stage (6) to all wells, including the control hole C2, but not in wells C1 and C3. a 2.5 μl of 1.33× buffer analysis add in the control wells C1 and C3 instead of a solution of ATP.

[0130] g) the Tablet briefly centrifuged at a speed of 1000 Rev/min closedeye all components of the reaction in the hole. Sealed tablet with aluminum foil and allow the reaction to proceed at room temperature (25°C) for 1 hour with shaking (250 rpm).

[0131] d) Breeding amplifier solution (immediately before use): in accordance with the manufacturer's recommendations diluted alternate solution of the amplifier showing the dilution buffer to 128 times.

[0132] e) Strengthening fluorescence: add 5 μl/well of the diluted solution of the amplifier to all wells, briefly centrifuged at a speed of 1000 rpm./minutes, again sealed the tablet and allow the reaction to proceed at room temperature for another 1 hour with shaking.

[0133] f) Add 5 μl/well stop solution to all wells, briefly centrifuged at a speed of 1000 rpm was Stirred at room temperature for 2 minutes with shaking and read the fluorescence signal on the device Victor3 (Perkin Elmer) at a wavelength of excitation 400 nm, emission - 445 nm/530 nm.

[0134] the Calculation of the activity of inhibition of KDR kinase:

(1) the Calculation of the ER (emission ratio):

With aaboutabouttnaboutWenandeemandwith awith aandand=Emandwith awith aandIKymand pandnand(445nm)Emandwith awith aandIflyaboutpewith aCeandnand(520nm)

(2) calculation of the rate of phosphorylation (%)

%faboutwith afaboutpandlandpaboutinandnandI=1-(With aaboutabouttnaboutWenandeemandwith awith aandand×F100%)-With a100%(C0%-C100%)+[With aaboutabouttnaboutWenandeemandwith awith aandand×(F100%-F0% )

where

The emission ratio=ratio of coumarin/fluorescein in the wells with sample

With100%=average signal level of emission of coumarin from 100% FOS. control (C3, 445 nm).

With0%=average signal level of emission of coumarin from 0% FOS. control (C1, 445 nm).

F100%=average signal emission of fluorescein from 100% FOS. control (C3, 520 nm).

F0%=average signal emission of fluorescein from 0% FOS. control (C1, 520 nm).

[0135] based On the above conditions analysis determined the activity of inhibition of KDR kinase compounds of Formulas a, b and C.

[0136] Results: the values of 1C5about activity of inhibition of KDR kinase for compounds of Formulas a, b, C are 0,021 μm, of 0.038 μm and 0,111 μm, respectively.

Example 3

The in vitro activity of inhibition of FGFR1 kinase

[0137] In the analysis of the activity of FGFR1 kinase used technology Transcreener FP (Bellbrook Labs). The kinase reaction was performed in 96-well half black plates (Greiner, cat. No. 675076). To each well was added 5 µl of the tested compound in 5% DMSO, 10 μl of 0.3 ng/ál FGFR1 kinase (Invitrogen, PV3146), diluted with buffer analysis. The reaction was initiated by adding 10 μl of 62.5 ng/ml poly (Glu:Tyr, 4:1) substrate (Sigma, R) and 25 µmol/l of a mixture of ATP and then incubated for 60 minutes at room tempera is ur. The final terms of the analysis of the kinase were as follows: 10 μm ATP, 0.12 ng/ál FGFR1 kinase, 25 ng/ál substrate, 53.6 mmol/l HEPES (pH 7.5), 21.6 mmol/l MgCl2, 0,536 mmol/l MnCl2, 1 mmol/l dithiothreitol (DTT) and 0.01% Triton X-100, 1% DMSO.

[0138] At the same time received a standard curve of ATP. A standard curve was simulated response of the kinase in the absence of the tested compound, kinases and lipid substrate. The standard curve consisted of 12 point concentrations and in General [ATP+ADP] stretched from 10 μm to 0.01 μm. 5 μl of 5% DMSO and 10 μl of buffer analysis was added instead of the compounds and FGFR1 kinase, respectively. Other conditions were the same as described above.

[0139] After reaction for 60 minutes at room temperature was added 25 μl of reagent from a set of Transcreener Kinase Kit - Mixture for the detection of ADP (Bellbrook Labs), and the reaction proceeded for 1.0 hour. Then the tablets were read on the device Tecan Infinite F500 at a wavelength of 610 nm excitation and emission at 670 nm. A standard curve was obtained using the software Origin 8.0 in. The inhibitory effect of the compounds on the production of ADP was calculated based on the concentration of ADP, calculated using the standard curve. The values of the IC50was obtained with the use of the software XLfit of 2.0. Results

ConnectionIC50(µm)
The connection Formulas And0,053

Example 4: Analysis of hERG

4.1 cell Culture

[0140] For this study used a cell line of Cho, stable transtitional hERG cDNA and expressing hERG channels. Cells were cultured in a medium containing:

Modified Dulbecco-Wednesday Needle (DMEM/F12)

10% (V/V) V / V heat inactivated calf serum embryo (traction)

1% (V/V) penicillin/streptomycin

500 μg/ml of the reagent Geneticin® (G418)

[0141] Before analysis, cells were collected using Accumax (Innovative Cell Technologies).

[0142] To register electrophysiological data used the following solutions.

4.2 Solution

[0143]
Table
The composition of internal and external solutions used in studies of hERG by way of fixing capacity
ReagentThe external solution was (mm)The internal solution (mm)
CaCl21,8-
MgCl21,01
KCl4130
NaCl137-
Glucose10-
HEPES1010
EGTA-5
ATP-5
pH7,4 (correction7,25 (correction
by using NaOH),by using KOH),

osmolaritythe osmolarity of ~280 mOsm
~280 mOsm

4.3 registration System

[0144] the Registration of whole cells was performed using device 700 In (Axon Instruments). For cells installed plated clip with the potential retention -80 mV. The hERG current activated by depolarization to +20 mV for 2 s, the donkey which the current is turned in the opposite direction to -50 mV for 2 s to eliminate inactivation and watched the deactivation of residual current. The first stage at -50 mV was used as background values for measuring the peak amplitude of the residual current.

4.4 Handling and breeding of connections

[0145] Prepared spare a solution of the compound in 10 mm DMSO in a glass vial. Alternate solution was vigorously stirred for 10 minutes at room temperature. Alternate solution was diluted in a glass vial using an External solution; dilution was prepared not earlier than 30 minutes before use. Equal amounts of DMSO (0.1 per cent) were present in the final dilution.

4.5 Electrophysiological methods

[0146] After achieving the whole cell configuration of the cells was controlled within 90 to assess the stability and washed the External solution for 66 C. Next, the above-described voltage Protocol was applied to the cells every 20 s during the entire method. Only stable cells with the registered settings above the threshold used in the methods of the study of the connection.

[0147] the External solution containing 0.1% DMSO (solvent), were applied to the cells to obtain background values. After stabilization current for 3 minutes inflicted investigated the connection. The solution of tested compound was added in stage 4, and the cells were kept in the studied solution up until the influence of soedineniya reached the plateau phase, or no more than 6 minutes It was further added to the positive control (10 nm cisapride). Spent washing the external solution as long as the recovery current does not reach the plateau phase.

4.6 data Analysis

[0148] the Data were analyzed using Clampfit (both from Axon Instruments) and Origin 7 (Originlab Corporation).

[0149] the Compound of Formula inhibited hERG current value IC500,547 μm, whereas the connection Formulas And inhibited hERG with the value of the IC506.8 microns.

Example 5: a Study of the pharmacokinetics (PK)

[0150] the Method of the experiment: the Pharmacokinetics of the compounds was studied on male ICR mice (n=6 for each group, weight 20-30 g) after a single intravenous (IV) and oral (p/o) in a dose of 2.5 and 10 mg/kg, respectively. For the/in the compound was dissolved in a mixture of DMSO (0.25 per cent)-solutol (10%)-ethanol (10%)physiological salt solution (79,75%) at a concentration of 0.25 mg/ml oral introduction preparing the drug (1 mg/ml) in 0.5% CMC-Na. After the on/in or n/o injection blood samples were collected from the eye vein at time points 0 (before administration of the dose), 5, 15, 30 min and 1, 1,5, 2, 4, 8, 24 hours spent anticoagulant treatment with heparin-Na. After centrifugation of the samples plasma was separated, and the protein precipitated with acetonitrile (containing internal standard). Next, the concentration of the compounds in the obtained plasma samples was determined by the method of W IS/MS/MS.

[0151] Results: After oral administration at a dose of 10 mg/kg, the values of AUC and Cmax Connection was 26 ng/ml hour and 20 ng/ml, respectively. By oral administration of the same dose (10 mg/kg), the values of AUC and Cmax Connection And was 397 ng/ml hour and 138 ng/ml, respectively. As you can see, after oral administration to mice, the compound of the Formula And demonstrated a much higher degree of contact with the plasma, i.e. higher values of AUC and Cmax than the Connection Century.

[0152] In the following examples 6-10 shows the different ways to get the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

The Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide

Example 6

[0153] the Compound of Formula (151 mg) was dissolved in 3 ml of ethanol under heating and stirring. The solution is filtered while hot to remove insoluble particles. The filtrate is heated for 5 minutes to obtain a clear solution and then cooled slowly to room temperature with stirring. At room temperature the mixture is stirred for 4 hours at an average speed of stirring (100 rpm). The precipitate was separated by filtration and dried at 60°C, soaking at this temperature for 2 hours under vacuum, the floor is in white crystalline powder Form I, 136 mg), MP (DSC): 166,6-168,2°C.

[0154] the Obtained x-ray powder Form I is shown in figure 1. It contains peaks (2θ)selected from those that have the following values: 7,1, 8,0, 8,7, 11,1, 11,8, where each of the angles of diffraction is ±0.2° (2θ) and where the characteristic peaks (2θ) identified as of 7.1, and 8.0 and 8.7.

[0155] the Study of the way the DSC showed that the melting temperature obtained Form I was 166,6-168,2°C.

Example 7

[0156] the Compound of Formula (152 mg) was dissolved in 3 ml of acetonitrile under heating and stirring. The stirring and heating continued until complete dissolution. Insoluble particles are removed by filtration while hot. The filtrate is refluxed for 5 minutes to obtain a clear solution and then allowed to cool to room temperature under stirring with an average speed (100 rpm).

[0157] Then, the suspension is stirred for 2 hours, the precipitate was separated by filtration and dried at 60°C in a vacuum oven for 4 hours to obtain a product of the Form I (113 mg, yield of 74.3%).

[0158] the x-ray powder is substantially similar to the x-ray Form I obtained in Example 5.

Example 8

[0159] the Compound of Formula (141,8 mg) is dissolved in 8 ml of toluene under heating and stirring. The stirring and heating continued until a complete solution is Oia. The mixture is allowed to cool to room temperature under stirring with an average speed (100 rpm). After that, the suspension is stirred for 2 hours, the precipitate was separated by filtration and dried at 60°C in a vacuum oven for 4 hours to obtain a product of the Form I (86 mg).

[0160] the x-ray powder substantially similar to the x-ray product Form I obtained in Example 5.

Example 9

[0161] the Compound (150 mg) is dissolved in 2.5 ml of acetone while heating and stirring. Insoluble particles are removed by hot filtration. The filtrate is refluxed for 5 minutes to obtain a transparent solution. Then to the solution was added 2.5 ml of water. At the end of the addition the solution is allowed to cool to room temperature under stirring with an average speed (100 rpm).

[0162] the Suspension is stirred for 4 hours. The precipitate was separated by filtration and dried at 60°C in a vacuum oven to obtain a product of the Form I (123 mg). Melting point (according to DSC): 165,6-167,5°C.

[0163] the x-ray powder of the resulting product is substantially similar to the x-ray product Form I obtained in Example 5.

Example 10

[0164] the Compound a (180,3 mg) was dissolved in 6.0 ml of methanol under heating and stirring. The stirring and heating continued until the full process is possible. Insoluble particles are removed by filtration while hot. The filtrate is refluxed for 5 minutes to obtain a transparent solution. To the resulting solution was slowly added heptane (6,0 ml). At the end of the addition the mixture is evaporated to a final volume of 10 ml and then allowed to cool to room temperature.

[0165] the Precipitate was separated by filtration and dried at 60°C in a vacuum oven to obtain a product of the Form I (118 mg).

[0166] the x-ray powder is substantially similar to the x-ray Form I obtained in Example 6.

[0167] In the following examples 11-12 shows the different ways to obtain Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

The Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide

Example 11

[0168] Compound (2.4 g) is dissolved in 35 ml of acetone while heating and stirring. The stirring and heating continued until complete dissolution. Insoluble particles are removed by filtration while hot. The filtrate is refluxed for 5 minutes to obtain a transparent solution. Then to the solution was added heptane (20 ml) under stirring. After the addition the mixture is quickly cooled to 0-5°C with peremeci the years. At the same temperature, the mixture is stirred for another 4 hours.

[0169] the Precipitate was separated by filtration and dried at 60°C, soaking at this temperature for 2 hours in a vacuum oven, to obtain the product Form II (2.0 g, yield 83,3%), MP (DSC): 160,3-161,6°C.

[0170] the x-ray powder obtained Form II is shown in figure 5. It contains peaks (29), some of which have approximately the following values: 6,8, 9,8, 10,5, 10,7, 13,6, 15,0, where each of the angles of diffraction is ±0.2° (2θ) and where the characteristic peaks (29) identified as 6,8, 9,8, to 10.5 and 10.7.

Example 12

[0171] the Compound (17 g) was dissolved in 425 ml of ethanol under heating and stirring. The stirring and heating continued until complete dissolution. Insoluble particles are removed by filtration while hot. The filtrate is refluxed for 5 minutes to obtain a transparent solution. The solution is cooled to 50°C and added 0.34 g (2% weight/weight) of seed crystal Form II. At the end of the addition the solution is allowed to cool to room temperature. The mixture is stirred for 4 hours at room temperature, the precipitate was separated by filtration and dried at 60°C in a vacuum oven to obtain 15 g of the product of crystalline Form II, the output 88,0%.

[0172] the x-ray powder is substantially similar to the x-ray product Form II, the floor of the military in Example 11.

[0173] the DSC Measurements showed that the temperature of the emergence of Form II was to 160.3°C with a peak at 161,6°C.

Example 13

Research hygroscopicity of Form I and Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide

[0174] the Hygroscopicity of Form I and Form II were investigated by the method of saturated salt solution.

[0175] Approximately 1 g samples of Form I and Form II, respectively, were carefully weighed, and samples were placed in a desiccator containing a saturated solution of NaCl. The desiccator was closed and left for 10 days at 25°C. Then the samples were removed and again weighed, and then calculated the increase in mass.

Material0-day10th day
FormFormThe increase in mass (%mass/mass)
Form I sampleII<0,1%
Form II sampleIIII<1%

[0176] Found that a sample of Form I is not hygroscopic, and for the increase of the weight of 92.5% relative humidity was less than 0.1%. Found that a sample of Form II is slightly hygroscopic with increasing mass of less than 1%. Samples of Form I and Form II after the study was analyzed using x-ray diffractometer, found that the obtained diffraction pattern comparable to the diffraction patterns presented in figures 1 and 5, respectively.

[0177] the results of the analysis of hygroscopicity show that both Form I and Form II are stable in the studied conditions, humidity, and light surface absorption of moisture does not change the crystalline form. Thus, Form I and Form II can be used in a pharmaceutical product for the application described here.

Example 14

Comparison of thermodynamic stability

[0178] a suspension of a mixture of Form I and Form II in methanol was stirred at 60°C, soaking at this temperature for 20 hours. Next, the suspension was filtered through a Buechner funnel with a paper disk and dried in a vacuum oven. The dried sample was then analyzed by the method of x-ray analysis of the powder, and it was found that the diffraction pattern is comparable to that presented in figure 1.

[0179] the Characteristic diffraction peaks of Form II were not detected on the obtained x-ray diffraction the diffraction pattern, which is evidence of the transformation of Form II in suspension in the Form I during the suspension, when the eat Form I is with physical and/or thermodynamic point of view, more stable, than Form II in the transforming of conditions.

[0180] Thus, Form I can be obtained by transformation of Form II in a suitable solvent.

[0181] the Results:

- Form I is stable under conditions of high humidity and solvents for recrystallization, and can be obtained on an industrial scale,

Form II can be used as intermediate compounds for receipt of Form I, which can be used as a suitable solid-phase crystalline form in pharmaceutical dosage form. The Form II can also be used in the dosage form due to its high stability.

1. N-(2-(Dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide

and/or its pharmaceutically acceptable salt.

2. Pharmaceutical composition having the properties of KDR inhibitor and/or FGFRI kinase containing at least one pharmaceutically acceptable carrier and an effective amount of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide
,
and/or its pharmaceutically acceptable salt.

3. Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide is a, which is characterized by a powder x-ray diffraction containing the peak, which has an angle 2θ equal to 8.0±0,2.

4. Form I according to claim 3, characterized in that Form I is essentially free of amorphous form of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, and essentially free of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

5. The method of obtaining the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide described in claim 3, including:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide at least one organic solvent, which dissolves the substance, and subsequent heating of the mixture to the boiling point under reflux to obtain a solution;
(2) cooling the solution to room temperature; and
(3) the selection of the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

6. The method according to claim 5, characterized in that at least one organic solvent in which is dissolved substance selected from alcohols and aprotic solvents.

7. The method according to claim 5, characterized in, Thu the alcohols are selected from methanol, ethanol and isopropanol.

8. The method according to claim 5, wherein the aprotic solvent is selected from acetone, acetonitrile, ethyl acetate, toluene, dichloromethane and N,N-dimethylformamide.

9. The method of obtaining the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide described in claim 3, including:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide at least one solvent in which is dissolved substance, and subsequent heating of the mixture to the boiling point under reflux to obtain a first solution;
(2) adding at least one organic solvent in which the substance does not dissolve, to the first solution at the boiling point under reflux to obtain a second solution;
(3) cooling the second solution at room temperature; and
(4) the selection of the Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

10. The method according to claim 9, characterized in that at least one solvent which dissolves a substance selected from methanol, ethanol, acetone, acetonitrile, and N-dimethylformamide.

11. The method according to claim 9, characterized in that at least one solvent in which the e-soluble substance, choose from water, heptane, hexane and ethyl acetate.

12. The method according to claim 9, wherein the volumetric ratio of at least one solvent in which is dissolved substance, and at least one solvent which does not dissolve the substance varies from 1:3 to 5:1.

13. Pharmaceutical composition having the properties of KDR inhibitor and/or FGFRI kinase containing at least one pharmaceutically acceptable carrier and an effective amount of Form I of N-(1-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide.

14. Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, which is characterized by a powder x-ray diffraction containing the peak, which has an angle 29, equal to 9.8±0,2.

15. Form II according to 14, characterized in that the Form II substantially free of amorphous forms of the compounds of Formula a, as well As substantially free of Form I of the compound of Formula A.

16. A method of producing Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, characterized in 14, including:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide at least one will dissolve the LEM, in which the dissolved substance, and heating the mixture under reflux to obtain a first solution;
(2) adding at least one solvent which does not dissolve the substance to the first solution at the boiling point under reflux to obtain a second solution;
(3) cooling the second solution to 0-5°C at a cooling rate of 1-40°C/min; and
(4) the selection of the Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, characterized in 14.

17. The method according to item 16, wherein the at least one solvent which dissolves a substance selected from alcohols and aprotic solvents.

18. The method according to 17, wherein the alcohols are selected from methanol and ethanol.

19. The method according to 17, wherein the aprotic solvent is selected from acetone, acetonitrile, ethyl acetate, toluene, dichloromethane and N,N-dimethylformamide.

20. A method of producing Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, characterized in 14, including:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide at least one solvent in which is dissolved substance, and heating the mixture to a boil with education is essential fridge with obtaining a solution;
(2) cooling the solution, followed by the introduction of the seed crystal Form II in the specified cooled solution;
(3) the specified cooling solution with a seed crystal to room temperature, and
(4) the selection of the Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, characterized in 14.

21. The method according to claim 20, characterized in that the solution is slowly cooled to 45-55°C.

22. The method according to claim 20, characterized in that the solution with the seed crystal is slowly cooled to room temperature.

23. The method according to claim 20, characterized in that at least one solvent which dissolves a substance selected from alcohols and aprotic solvents.

24. The method according to item 23, wherein the alcohols are selected from methanol and ethanol.

25. The method according to item 23, wherein the aprotic solvent is selected from acetone, acetonitrile, ethyl acetate, toluene, dichloromethane and N,N-dimethylformamide.

26. Pharmaceutical composition having the properties of KDR inhibitor and/or FGFRI kinase containing at least one pharmaceutically acceptable carrier and an effective amount of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide, characterized in 14.

27. The method of treatment of a subject in need of treatment at least one tie is spent with angiogenesis disorder, mediated KDR activity, including the introduction of a specified subject in need an effective amount of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide and/or its pharmaceutically acceptable salts.

28. The method according to item 27, wherein the at least one associated with angiogenesis disorder selected from cancer and age-related macular degeneration.

29. The method of treatment of a subject in need of treatment at least one associated angiogenesis disorder mediated KDR activity, including the introduction of a specified subject in need an effective amount of Form I of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide described in item 3.

30. The method according to clause 29, wherein the at least one associated with angiogenesis disorder selected from cancer and age-related macular degeneration.

31. The method of treatment of a subject in need of treatment at least one associated angiogenesis disorder mediated KDR activity, which includes the introduction of a specified subject in need an effective amount of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonyl is Yes, characterized in 14.

32. The method according to p, characterized in that at least one is associated with angiogenesis disorder selected from cancer and age-related macular degeneration.

33. The method of treatment of a subject with an established need for treating at least one disease that responds to inhibition of FGFR1, which includes the introduction of a specified subject in need an effective amount of N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)methanesulfonamide and/or its pharmaceutically acceptable salts.

34. The method according to p, characterized in that at least one disease selected from various types of cancer that respond to inhibition of FGFR1.

35. The method of treatment of a subject with an established need for treating at least one disease that responds to inhibition of FGFR1, which includes the introduction of a specified subject in need an effective amount of the Form 1N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)- methanesulfonamide described in item 3.

36. The method according to p, characterized in that at least one disease selected from various types of cancer that respond to inhibition of FGFR1.

37. The method of treatment of a subject with an established need for treatment is at least real the disease, responsible for inhibition of FGFR1, including the introduction of a specified subject, which needs treatment, an effective amount of Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidine-2-yl)amino)phenyl)-methanesulfonamide, characterized in 14.

38. The method according to clause 37, wherein the at least one disease selected from various types of cancer that respond to inhibition of FGFR1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to substituted pyrrolidine-2-carboxamides of formula I or their pharmaceutically acceptable salts, where values X, Y, R1, R2, R3, R3, R4, R5, R6 and R7 are given in item 1 of the formula. Compounds can be used in pharmaceutical composition, inhibiting interaction of MDM2-p53.

EFFECT: compounds can be used as anti-cancer medications.

46 cl, 4 dwg, 347 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinazoline derivatives of formula , where each of R1, R2 and R5, independently, represents H; one of R3 and R4 represents where n - 1 or 2; each Ra represents H, C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkoxy, C1-10alkansulfonyl carboxy-group, 5-6-membered monocyclic heterocycloalkyl, which has one or several heteroatoms, selected from O and N, where N atom can be substituted with C1-10alkyl, phenyl, optionally substituted with halogen, 5-6-membered monocyclic heteroaryl, which has one or several heteroatoms, selected from N and S, 7-membered bicyclic heterocycloalkyl, which has 2 N atoms; C2-10alkenyl; C2-10alkinyl; cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms; each of Rb and Rc, independently, represents H or C1-10alkyl, optionally substituted C1-10alkoxy, or Rb and Rc, together with atom of nitrogen, with which they are bound, form bicyclic ring of the following formula: , where each of m1, m2, m3, and m4 is 0, 1 or 2; A is CH; B is NR, where R is H or C1-10alkyl; and each of Ri, Rii, Riii, RiV, Rv, Rvi, Rvii and Rviii is H; or 6-7-membered monocyclic heterocycloalkyl, containing 1-2 N atoms, optionally substituted with substituent, selected from group, including hydroxy, C1-10alkyl, optionally substituted C1-10alkoxy, C1-10alkyl, optionally substituted with C3-6cycloalkyl; and each of Rd, Re, independently represents H, C2-10alkenyl; C2-10alkinyl; or C1-10alkyl, optionally substituted with substituent, selected from group, including C1-10alkyloxy, hydroxy, CN, 5-6-membered monocyclic heterocycloalkyl, which has 1 or 2 N atoms, optionally substituted with C1-10alkyl, halogen or 5-6-membered heterocycloalkyl, which has 1 N atom, phenyl, optionally substituted with halogen, cycloalkyl, representing saturated cyclic group, containing 3-6 carbon atoms, 5-6-membered monocyclic heteroaryl, which has one or 2 N atoms; or Rd and Re, together with nitrogen atom, with which they are bound, form 5-6-membered saturated heterocycloalkyl, which has 1-2 heteroatoms, selected from N and O, optionally substituted with substituent, selected from group, including C1-10alkyl (which is optionally substituted with C3-6cicloalkyl, C1-10alkoxy, halogen), 5-membered heterocycloalkyl, which has one N atom, halogen, C1-10alkansulfonyl, C1-10alkylcarbonyl, optionally substituted with halogen, or Rd and Re, together with nitrogen, with which they are bound, form 7-10-membered, saturated, bicyclic heterocycloalkyl, containing 1-2 heteroatoms, selected from N and O, optionally substituted with C1-10alkyl; and the other of R3 and R4 represents H, halogen or C1-10alkoxy; X represents NRf, where Rf represents phenyl, substituted with C2-4 alkinyl; and Z represents N. Invention also relates to particular quinazoline derivatives, based on it pharmaceutical composition, and to method of cancer treatment.

EFFECT: novel quinazoline derivatives, inhibiting EGFR activity are obtained.

11 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 4-aminocyclohexane derivatives of general formula I: where: R1 and R2 independently denote C1-3-alkyl, H or R1 and R2 together with an N tom form a (CH2)3, (CH2)4 ring; R3 optionally denotes a phenyl or thienyl linked through a C1-3-alkyl chain, each unsubstituted; or an unsubstituted C1-6-alkyl; R4 denotes indole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, optionally mono- or multi-substituted with a substitute selected from a group comprising F, CI, Br, CN, CH3, C2H5,' NH2, tert-butyl, Si(ethyl)3, Si(methyl)2(tert-butyl), SO2CH3, SO2-phenyl, C(O)CH3, NO2, SH, CF3, OCF3, OH, OCH3, OC2H5, N(CH3)2; in form of a racemate; enantiomers, diastereomers, mixtures of enantiomers or diastereomers or separately an enantiomer or diastereomers; bases and/or salts of physiologically compatible acids or cations; as well as a drug based on compounds I for treating neuropathic pain.

EFFECT: improved properties.

14 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention includes (a) at least one optical bleaching agent of formula (1) , wherein R1 denotes hydrogen or SO3M, R2 denotes hydrogen or SO3M, R3 denotes hydrogen or CH2CO2M, R4 denotes CH2CO2M, CH(CO2M)CH2CO2M or CH(CO2M)CH2CH2CO2M, where M denotes hydrogen, a cation of an alkali metal, ammonia, mono-methyl-di-C2-C3-hydroxyalkylammonium, dimethyl-mono-C2-C3- hydroxyalkylammonium, ammonium, which is mono-, di- or trisubstituted with a C2-C3 hydroxyalkyl radical, or a mixture of said compounds, (b) a magnesium salt or (c) binder, which is selected from a group consisting of natural starch, enzyme-modified starch, and chemically modified starch, wherein there are 0.1-15 parts of component (b) for one part of component (a). The invention also relates to a method of bleaching paper using said composition.

EFFECT: composition is a more efficient means of achieving high paper whiteness.

9 cl, 4 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) where R1 denotes hydrogen or SO3, R2 denotes hydrogen or SO3, R3 denotes hydrogen or CH2CO2, R4 denotes CH2CO2, CH(CO2)CH2CO2 or CH(CO2)CH2CH2CO2, and where M denotes a stoichiometric cation equivalent required to balance the anionic charge in formula (1) and is a combination of Mg2+ with at least 1 additional cation. The additional cations are selected from a group consisting of H+, a cation of an alkali metal, a cation of an alkali-earth metal other than Mg2+, ammonium, mono-C1-C4 alkyl-di-C2-C3-hydroxyalkylammonium, di-C1-C4-alkyl-mono-C2-C3-hydroxyalkylammonium, ammonium, which is mono-, di- or trisubstituted with a C2-C3 hydroxyalkyl radical, and mixtures thereof. The invention also relates to versions of the method of producing said compound and use of said compound in binding compositions for bleaching paper.

EFFECT: compound is a more efficient paper bleaching agent.

8 cl, 4 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new uracil derivatives possessing human dUTPase inhibitory activity. In formula (I) n is equal to an integer 1 to 3; X member a bond, an oxygen atom, a sulphur atom, an alkenyl group containing 2 to 6 carbon atoms, a bivalent aromatic hydrocarbon group containing 6 to 14 carbon atoms, or a bivalent 5-7-merous saturated or unsaturated heterocyclic group containing 1 nitrogen or sulphur atom; Y means a bond or a linear or branched alkylene group containing 1 to 8 carbon atoms optionally having a cycloalkylydene structure containing 3 to 6 carbon atoms on one carbon atom; and Z means -SO2NR1R2 or -NR3SO2-R4, wherein R4 means an aromatic hydrocarbon group containing 6 to 14 carbon atoms which is optionally substituted by 1-2 substitutes, or an unsaturated 5-7-member heterocyclic group containing 1 nitrogen or sulphur atom which is optionally substituted by 1-2 halogen atoms; the radical values R1, R2 and the substitutes of the group R4 are presented in the patent claim.

EFFECT: invention relates to a pharmaceutical compositions comprising said compounds, to a human dUTPase inhibitor and a method of treating a human dUTPase-associated disease.

10 cl, 85 tbl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention relates to methods of producing compounds of formulae: II (a) and , which can be used in producing compounds of formula (I) and salts thereof.

EFFECT: improved properties of compounds.

15 cl, 2 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound, which is N3-1H-indol-5-yl-5-pyridin-4-ylpyrazine-2,3-diamine, or a pharmaceutically acceptable salt thereof, which can act as inhibitors of protein kinase, especially FLT3 tyrosine kinase. The invention also relates to a pharmaceutical composition which contains said compound in combination with another molecularly directed (target) agent, which is a traditional cytotoxic agent or a compound used after chemotherapy, supporting therapy targeted on stem cells and in case of MLL rearrangement acute lymphoblastic leukaemia in children.

EFFECT: obtaining a novel compound which can be used in medicine for preventing or treating haematological malignant growths such as AML, MLL, T-ALL, B-ALL and CMML, myeloproliferative diseases, autoimmune diseases and skin diseases, such as psoriasis and atopic dermatitis.

16 cl, 2 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

Antihypotonic agent // 2506082

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to antihypotonic agents representing 2-amino-5,6-dihydro-4H-1,3 triazine salts that may be used for creating therapeutic agents for treating hypotension caused by a severe blood loss. What is presented is using seven 2-amino-5,6-dihydro-4H-1,3 triazine salts of general formula I wherein HX=HBr; 2-(AcO)C6H4COOH; 2-(OH)C6H4COOH; CH3(CH2)14COOH; 3,4-(OMe)2 C6H3CH2COOH; C6H5CH2COOH; HOOCCH2CH2COOH, as an antihypotonic agent for treating hypotension caused by a severe blood loss, and a based pharmacological composition for the same applications.

EFFECT: what is shown is the manifested hypotensive property of the known chemical substance in the presence of a severe blood loss.

3 cl, 13 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted benzamides, which can be applied as antagonists of sphingonsine-1-phosphate receptors.

EFFECT: compounds are useful in treatment of wide series of disorders, associated with modulation of sphingonsine-1-phosphate receptors.

9 cl, 1 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition exhibiting the property of endothelial dysfunction reduction, containing herbal docosahexaenic acid, vitamin K2, polydatin, nicotinic acid, magnesium stearate in a certain amount.

EFFECT: composition reduces the endothelial dysfunction correction in cardiovascular diseases.

2 cl, 1 dwg, 2 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 organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-aminocyclohexane derivatives, having affinity for the µ- opioid receptor and ORL1 receptor. In formula

Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' denote -H; Q denotes -R0, -C(O)-R0 or -C(=NH)-R0; R0 and R3 in each case independently denote -C1-8-aliphatic, -aryl, -heteroaryl, -C1-8-aliphatic-C5-cycloaliphatic, -C1-8-aliphatic-aryl; R1 and R2 independently denote unsubstituted -C1-8-aliphatic; -C1-8-aliphatic-C5-cycloaliphatic, -C1-8-aliphatic-aryl; n denotes 0; X denotes -NRa-; Ra denotes unsubstituted -C1-8-aliphatic; Rb denotes unsubstituted -C1-8-aliphatic; "aliphatic" represents a straight saturated hydrocarbon residue which is unsubstituted or mono- or multi-substituted with F atoms; "cycloaliphatic" represents a saturated, unsubstituted monocyclic hydrocarbon residue with 5 carbon atoms in the ring; "aryl" represents phenyl, which can be substituted with -F, -R0 and -OR0; "heteroaryl" represents a 5-member cyclic aromatic moiety containing 1 heteroatom. The heteroatom is N or S, and the heterocyclic ring can be substituted with -F, -R0 and -OR0; the heterocyclic ring can be part of a bicyclic system including phenyl.

EFFECT: invention also relates to a drug containing said compounds and use of the compounds to produce a drug for treating pain, stress, epilepsy, learning and memory disorders, drug dependence, cardiovascular diseases, eating disorders and locomotory impairments.

9 cl, 10 tbl, 164 ex

FIELD: biotechnologies.

SUBSTANCE: invention proposes a monoclonal antibody that specifically binds sulphatides and sulphated proteoglycans, as well as a pharmaceutical composition for treatment of atherosclerosis and a set of reagents for diagnostics of atherosclerotic damages, use of an antibody for obtaining a medicinal agent for treatment of atherosclerosis and as a vaccine.

EFFECT: as per the present invention, an antibody has increased reaction capacity in relation to sulphatides and sulphated proteoglycans in comparison to antibody P36.

7 cl, 6 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely therapy, and concerns treating the patients suffering the multiple organ pathology using ozone therapy. That is ensured by the intravenous introducing of ozonised saline 200 ml at 10-15 ml/min for 15-20 min into the patient with the inactive disease. The adult patients require the ozone therapy to be performed daily in the form of 6 sessions with the saline ozone concentration of 0.15 mg/l, while the ozone therapy in the elderly and senile patients is performed every second day in the form of 10 sessions with the saline ozone concentration of 0.10 mg/l.

EFFECT: method provides the effective and safe treatment of the multiple organ pathology ensured by the low saline ozone concentration, providing the absence of hemolysis, and by choosing the mode and ozone concentration optimal for the various age groups.

2 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition with anti-inflammatory, cardio- and chondroprotective activity, action preventing gastropathies caused by non-steroidal anti-inflammatory drugs. The above composition contains sodium diclofenac 5 - 25%, quercetin in the form of dihydrate or an anhydrous substance 10 - 40%, polyvinylpyrrolidone 10 - 50%, sodium lauryl sulphate 0.25 - 10%, microcrystalline cellulose 20 - 40%, croscarmellose sodium salt 1 - 15% and magnesium stearate 0.25 -5.0% at total weight of the composition. The invention also concerns the method for preparing the specified compound.

EFFECT: invention provides preparing the pharmaceutical composition with high anti-inflammatory, cardio- and chondroprotective activities.

2 cl, 2 dwg, 17 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, therapy of patients suffering lung cancer and having contraindications to the surgical management. There are prescribed autohemochemotherapy (AHCT) that is administering chemopreparations incubated with autoblood, and radiation therapy (RT). Pre-therapeutic blood prolactin and progesterone are measured, and before the beginning of the AHCT, the patient starts taking bromocriptine 2.5 mg once a day with food; besides, oxyprogesterone capronate 1 ml is administered intramuscularly twice a week every 3 days. That is followed by the AHCT course consisting of 1-3 administrations of autoblood CP, and if observing a complete tumour resorption, the surgical management to the extent of pneumoectomy is supposed to follow, while a partial resorption observed two weeks after the last auroblood CP administered, implies the RT: at first 2 Gy twice a day every 4-5 hours starting from 5 days a week to achieve a basic dose of 28 Gy. That is followed by a 2-week pause, then 4 Gy daily, 3 radiation fractions a week, 6 fractions in total, up to a total radiation dose of 52 Gy for the whole RT course. Throughout the treatment, the patient keeps taking bromocriptine and oxyprogesterone capronate with controlling the blood prolactin and progesterone values: as compared to the pre-therapeutic values, prolactin is expected to fall to the end of the treatments, while progesterone - to rise.

EFFECT: method provides improving the conservative therapeutic effect in the patients of the given group: downsizing the tumour and lymph nodes until the primary tumour regresses completely by 30%, and the patients change to the resectable state; improving the patient's quality of life.

2 ex, 1 tbl

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