Crth2 antagonist particles

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel crystalline forms I, II and amorphous form of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidin-5-yl}acetic acid.

EFFECT: invention relates to pharmaceutical composition, containing crystalline form I of compound and to application of crystalline form I for treatment, prevention or relief of one or more symptoms of disease, mediated by CRTH2, associated with eosinophils, basophils, where disease is selected from asthma, allergic asthma, asthma, induced by physical effort, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity.

16 cl, 11 dwg, 8 tbl,11 ex

 

The technical FIELD

In the present invention are considering particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in amorphous and crystalline forms, methods of preparation and their pharmaceutical compositions. Also provided methods of their use for treating, preventing or alleviating one or more symptoms of a disorder or disease mediated by CRTH2.

PRIOR art

CRTH2 is chemoattractant receptor that is associated with G proteins, expressed on Th2 cells, eosinophils and basophils (Nagata et al.,J. Immunol.1999, 162, 1278-1286; Hirai et al.,J. Exp. Med.2001, 193, 255-261). Prostaglandin D2(PGD2), the main mediator of inflammation produced by fat cells, is a natural ligand CRTH2. Recently it was shown that activation of CRTH2 PGD2causes the migration and activation of Th2 cells and eosinophils, suggesting that CRTH2 can play a proinflammatory role in allergic diseases (Hirai et al.,J. Exp. Med.2001, 193, 255-261; Gervais et al.,J. Allergy Clin. Immunol.2001, 108, 982-988). It was also shown that patients with atopic dermatitis, there is an increase in circulating T cells expressing CRTH2, which correlates with disease severity (Cosmi et al.,Eur. J. Immunol.2000, 30, 2972-2979; Iwazaki et al.,J. Investigative Dermatoogy 2002, 119, 609-616). The role of PGD2in the development and maintenance of allergic inflammation has been demonstrated in a model of asthma in mice, showing that excessive production of PGD2PGD2-synthase in vivo enhances airway inflammation (Fujitani et al.,J. Immunol.2002, 168, 443-449). Therefore, antagonists of CRTH2 are potentially applicable for the treatment of disorders or diseases mediated by CRTH2, such as allergic rhinitis, allergic asthma, bronchoconstriction, atopic dermatitis or systemic inflammatory diseases.

DISCLOSURE of INVENTION

Granted particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, which has the formula I:

in amorphous form or crystalline form I or II. The compound of formula I has been identified as a CRTH2 antagonist (WO 2004/0022218).

In one embodiment of the invention the particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are of the form I, which has an x-ray diffraction pattern for the powder, essentially as shown in figure 1, or a thermogram of differential scanning calorimetry, essentially as shown in figure 2.

In another embodiment of the invention the particles of {4,6-bis(l is methylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are of the form II, which has the x-ray diffraction pattern for the powder, essentially as shown in Fig.6.

In yet another embodiment of the invention the particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are amorphous.

Also provided is a pharmaceutical composition containing particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form, crystalline form I or II or mixtures thereof, and one or more pharmaceutically acceptable carriers or excipients.

Additionally provides a method for treating, preventing or alleviating one or more symptoms of a disorder or disease mediated by CRTH2, which includes the introduction of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form, crystalline form I or II or mixtures thereof.

In addition, provides a method for obtaining particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the x-ray diffraction pattern for the powder particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}UKS the red acid in crystalline form I.

Figure 2 shows a thermogram of differential scanning calorimetry (DSC) of the particles of the acid of formula I in form I.

Figure 3 shows thermogravimetric (TG) thermogram of the particles of the acid of formula I in form I.

Figure 4 shows photographs of scanning electron microscopy (SEM) of the particles of the acid of formula I in the form I with increasing 2500 (A)5000 (b) 10000 (C).

Figure 5 shows a distribution graph of the particle size of the acid of formula I in form I.

Figure 6 depicts the XRP diffraction pattern of the particles of the acid of formula I in form II.

Figure 7 shows SEM pictures of particles of the acid of formula I in form II with increasing 370 (A), 2000 (V), 5500 (C) 10000 (D).

On Fig depicts the XRP diffraction pattern of the particles of the acid of formula I obtained by the phase equilibrium between particles in the form I and form II.

Figure 9 shows the XRP diffraction pattern of the acid of formula I in amorphous form.

Figure 10 shows the curve of the dose-response {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of formula I in the analysis of competitive binding of radioligand using cells transfected with the CRTH2.

Figure 11 shows the curve of the dose-response {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of formula I (▲), together with the selective antagonist DP1 BWA 868C (■), in the analysis to the competitive binding of radioligand using cells transfected DP1.

DETAILED DESCRIPTION

In order to facilitate understanding of the description below, a number of terms are defined below.

As used in the present description, the singular number may include the plural forms, if not specifically stated otherwise. Generally, the nomenclature used in this description and laboratory techniques in organic chemistry, medicinal chemistry and pharmacology, described in the present description, is such a well known and commonly used in engineering. If not stated otherwise, all technical and scientific terms used in the present description, typically have the same values, which, as a rule, understand ordinary specialist in the field of technology, belongs to this description. When there are many definitions for the term, prevailing definitions presented in this section, unless otherwise specified.

The term "antibacterial" refers to liquid, which is added to the solvent to reduce the solubility of the compounds in this solvent, leading to the deposition of the connection.

The term "patient" refers to an animal, including, but not limited to the above, a Primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat or mouse. Usually the terms "subject is" and "patient" are used in this description are interchangeable in relation to, for example, the subject is a mammal, particularly patient person.

The terms "treat", "treating" and "treatment" are meant to include alleviating or eliminating the disorder or disease or one or more symptoms associated with the disorder or disease; or alleviating or eliminating the causes(s) of the disorder or the disease itself.

The terms "prevent", "preventing" and "prevention" refer to a method of slowing or preventing the development of disease and/or its attendant symptoms, preventing the patient from developing the disease or reduce the risk of development of disease in a patient.

The term "therapeutically effective amount" refers to the number of connections that, when introduced is sufficient to prevent development of or to some extent alleviate one or more symptoms of the condition or disorder being treated. The term "therapeutically effective amount" also refers to the amount of compound that increases the biological or medical response of a tissue, system, animal or human that is looking for a researcher, veterinarian, medical doctor or Clinician.

The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "natural is logically acceptable excipient" refers to a pharmaceutically acceptable material, the composition or carrier, such as a liquid or solid filler, diluent, solvent or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of compatibility with other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, corresponding to an acceptable value benefit/risk.

The term "naturally occurring" or "native" when used in connection with biological materials such as nucleic acid molecules, polypeptides, cells, media and the like, refers to materials which are found in nature and not man-made. Similarly, "non-natural" or "non-native" refers to a material that is not found in nature or that has been structurally modified or synthesized by man.

The term "CRTH2" refers to a protein receptor CRTH2, or its variant, which is able to mediate cellular response to PGD2in vitroorin vivo. Options CRTH2 include proteins, essentially homologous native CRTH2, i.e. proteins having one or more natural or unnatural deletions, stavo is or substitutions of amino acids (for example, derivatives, homologues and fragments of CRTH2) compared to the amino acid sequence of natural CRTH2. The amino acid sequence of the variant CRTH2 is at least about 80% identical, at least about 90% identical or at least about 95% identical to the native CRTH2.

The term "other receptor PGD2" refers to a protein prostanoid receptor, distinct from the CRTH2, or its variant, which is able to mediate cellular response to PGD2in vivoorin vitro. "Another receptor PGD2" may be selective for PGD2for example, DP, or any one or more other prostanoid. "another receptor PGD2include proteins, essentially homologous to the corresponding native prostanoid receptors other than CRTH2, i.e. proteins having one or more natural or unnatural a deletion, insertion or substitution of amino acids (e.g., derivatives, homologues and fragments of native prostanoid receptor, distinct from the CRTH2). The amino acid sequence of native option"another receptor PGD2" is at least about 80% identical, at least about 90% identical or at least about 95% identical to the corresponding"another receptor PGD2".

The term "CRTH2 antagonist" refers to a compound that, nab is emer, partially or fully blocks, reduces, prevents, inhibits or suppresses the activity of CRTH2 and/or activity of one or more other receptors PGD2. The term "antagonist of CRTH2" also refers to a connection that is associated with, slows activation, inactivates or desensibilisation CRTH2 or one or more other receptors PGD2. The CRTH2 antagonist can act by interfering in the interaction PGD2with CRTH2 or one or more other receptors PGD2.

The term "a disorder or disease mediated by CRTH2 and condition, disorder or disease mediated by CRTH2" refers to the condition, disorder or disease characterized by inappropriate, e.g., less than or greater than normal activity of CRTH2. Inadequate functional activity of CRTH2 may occur as a result of CRTH2 expression in cells which normally do not Express CRTH2, increased expression of CRTH2, or the degree of intracellular activation, leading to, for example, inflammatory or immune-related disorders or diseases; or reduced expression of CRTH2. The condition, disorder or disease mediated by CRTH2 can be completely or partially mediated by inappropriate activity of CRTH2. In particular, condition, disorder or disease mediated by CRTH2, t is aetsa such in which modulation of CRTH2 or one or more receptors PGD2leads to some extent to the background condition or disorder, for example, the antagonist or agonist CRTH2 lead to some improvement in at least some patients receiving treatment.

The term "bulk density after compaction" refers to the bulk density in a closely full with the tap of a fluid, such as discharge from the container filled with the sample a predetermined height again to produce a small pressure on the bottom of the container. Bulk density after compaction can be determined using, for example, Powder Tester PT-D (Hosokawa Micron Corporation, Osaka, Japan).

The term "uniformity coefficient" refers to the parameter that indicates the degree of homogeneity of the distribution of particle size and it is defined as the value obtained by dividing the particle size of 60 percentile on the particle size 10 percentile, which is obtained from the distribution curve of the particles. When the distribution of particle size is more uniform, uniformity coefficient is close to 1.

Particles

In the present description is provided of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II. Particles of the acid of formula I can in order to be characterized using a variety of methods, well-known specialist in the field of technology, including single-crystal x-ray diffraction, x-ray diffraction on the powder (XRPD), microscopy (e.g., scanning electron microscopy (SEM), thermal analysis (e.g., differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and microscopy with a heating table) and spectroscopy (e.g., infrared, Raman, nuclear magnetic resonance of the solid phase). The particle size and size distribution can be determined by conventional methods, such as methods of laser scattering. The purity of the acid particles of the formula I can be determined by standard analytical methods such as thin layer chromatography (TGH), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC) and mass spectrometry (MS).

In one embodiment of the invention the particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in crystalline form I. In one embodiment of the invention, the particles form I have the x-ray diffraction pattern for the powder, essentially as shown in figure 1. In another embodiment of the invention, the particles form I have characteristic peaks XRP diffraction at double-fired sbli is placed approximately 9,8, 13,1, 22,0, and 26,4º. In yet another embodiment of the invention, the particles form I have a typical peak XRP diffraction at a double angle of convergence of approximately 9,8, 13,1, 22,0, and 26,4º. In yet another embodiment of the invention, the particles form I have a typical peak XRP diffraction at a double angle of convergence of approximately 22,0º. In yet another embodiment of the invention, the particles form I have a thermogram of differential scanning calorimetry, essentially as shown in figure 2. In yet another embodiment of the invention, the particles form I have the DSC thermogram with endothermy at peak temperature of about 224º and the onset temperature of decomposition of about 220º. In yet another embodiment of the invention the shape of the crystal particles of form I is essentially a needle (figure 4). In yet another embodiment of the invention, the particles form I have a solubility in water of about 3 mcg/ml at room temperature.

In one embodiment of the invention, the particles form I can have an average particle size ranging from about 0.1 to about 150 microns, from about 0.5 to about 100 microns, from about 1 to about 50 μm, from about 1 to about 25 microns, from about 1 to about 20 microns, from about 1 to about 10 microns, from about 2 to about 10 microns, or from about 2 to about 7.5 microns. In another embodiment of the invention, the particles form I can have a homogeneous distribution is the particle size, that estimate on the coefficient of uniformity, ranging from about 1 to about 20, from about 1 to about 10, from about 2 to about 5, or from about 3 to about 4. In yet another embodiment of the invention the solid particles form I can have a bulk mass after compaction ranging from about 0.1 to about 1.0, from about 0.15 to about 0.8, from about 0.2 to about 0.6, from about 0.25 to about 0.5, or from about 0.3 to about 0.4 g/ml

Particles with these properties of the particles can be directly obtained by the production method, described in the present description. Alternatively, particles of such sizes may also be obtained using any conventional method of producing particles, such as grinding, micronizing or granulation. Particles form I presented in the present description, are suitable for direct receipt of the acid of formula I as therapeutic products, thus simplifying the manufacturing process and eliminating the risks associated with conventional methods for producing particles, such as unwanted conversion substance, crystallizing in different forms.

In certain embodiments of the invention the particles of the acid of formula I in the form I can contain at least about 95%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5 per cent by weight of the acid of formula I. the Particles can also is to contain at least about 90%, not less than about 95%, at least about 98%, at least about 99% or at least about 99.5% of the mass of solid particles in the form I.

In certain embodiments of the invention the particles of the acid of formula I in the form I can have a residual content of organic solvent is not more than about 5%, no more than about 2%, no more than about 1%, no more than about 0.9%, not more than about 0.8%, no more than about 0.7%, no more than about 0.6%, not more than 0.5 not more than about 0.4%, not more than about 0.3%, no more than about 0.2%, no more than about 0.1%, not more than about 0.05% or not more than about 0.01% mass.

In certain embodiments of the invention the particles of the acid of formula I in the form I can have a residual methanol content of not more than about 100000 hours/mn, of not more than about 10,000 hours/mn, of not more than about 5000 h/mn, of not more than about 4000 hours/mn, of not more than about 3000 hours/mn, of not more than about 2000 hours/mn, of not more than about 1000 hours/mn, of not more than about 500 h/m or no more than about 100 hours/million

In another embodiment of the invention the particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in crystalline form II. Particles form II have the x-ray diffraction pattern for the powder, essentially as shown in Fig.6. Particles form I have a typical peak XRP diffraction at a double angle of convergence of approximately 31,7th.

In one embodiment, the image is etenia particles form II can have an average particle size, ranging from about 0.1 to about 150 microns, from about 0.5 to about 100 microns, from about 1 to about 50 μm, from about 1 to about 25 microns, from about 1 to about 20 microns, from about 1 to about 10 microns, from about 1 to about 5 microns, or from about 2 to about 5 microns. In another embodiment of the invention, the particles form II may have a homogeneous distribution of particle size as assessed by the coefficient of uniformity, ranging from about 1 to about 20, from about 1 to about 10, from about 2 to about 5, or from about 3 to about 4. In yet another embodiment of the invention, the particles form II may have a bulk weight of the compaction ranging from about 0.1 to about 1.0, from about 0.15 to about 0.8, from about 0.2 to about 0.6, from about 0.25 to about 0.5, or from about 0.3 to about 0.4 g/ml

Particles with these properties of the particles can be directly obtained by the production method, described in the present description. Alternatively, particles of such sizes can also be obtained using any conventional methods, such as grinding, micronizing or granulation.

In certain embodiments of the invention the particles of the acid of formula I in form II can contain at least about 95%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5 per cent by weight of the acid of formula I. the Particles can contain at least about 90%, at least about 95, not less than about 98%, at least about 99% or at least about 99.5% of the mass of particles in the form II.

In certain embodiments of the invention the particles of the acid of formula I in form II may have a residual content of organic solvent is not more than about 5%, no more than about 2%, no more than about 1%, no more than about 0.9%, not more than about 0.8%, no more than about 0.7%, no more than about 0.6%, not more than about 0.5%, not more than about 0.4%, not more than about 0.3%, no more than about 0.2%, no more than about 0.1%, not more than about 0.05% or not more than about 0.01 mass%.

In yet another embodiment of the invention the particles of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are amorphous. Amorphous particles have an x-ray diffraction pattern for the powder, essentially as shown in Fig.9, which has no characteristic peaks XRP diffraction particle form I and/or form II. In one embodiment of the invention, the amorphous particles may contain at least about 95%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5 per cent by weight of the acid of formula I. In another embodiment of the invention, the particles may also contain at least about 90%, at least about 95%, at least about 98%, at least about 99% or at least about 99.5 per cent by weight of amorphous solids.

In certain embodiments of the implementation of the invented what I amorphous particles of the acid of formula I can have a residual content of organic solvent is not more than about 5%, not more than about 2%, no more than about 1%, no more than about 0.9%, not more than about 0.8%, no more than about 0.7%, no more than about 0.6%, not more than about 0.5%, not more than about 0.4%, not more than about 0.3%, no more than about 0.2%, no more than about 0.1%, not more than about 0.05% or not more than about 0.01% by weight.

You must understand that the numerical values of the peaks of the diffraction patterns of x-ray radiation on the powder may slightly vary from one device to another or from one sample to another, and therefore these values should not be regarded as absolute, but with the available variability, such as 0,1º, which is recommended in the United States Pharmacopeia (pages 387-389, 2007).

The way to obtain

Also provided is a method for obtaining particles of the acid of formula I in amorphous form or crystalline form I or II. The methods include the stage of contact of the acid of formula I with a solvent in which the particles of the acid of formula I in amorphous form or crystalline form I or II can be formed from a solution or converted from one solid form to another. The method may additionally include the extraction, in which the particles can be selected in the usual way, such as filtration and centrifugation, followed by washing with a solvent and then drying (for example, drying in a vacuum oven, air drying or drying with desiccant).

On the walking solvents for use in the preparation of solid particles in amorphous form or crystalline form I or II include, but not limited to the mentioned above, hydrocarbons, including petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin and cumin; chlorinated hydrocarbons, including dichloromethane (DHM), 1,2-dichloroethane, 1,1-dichlorethene, 1,2-dichloride, chloroform, trichloroethane, trichlorethane, carbon tetrachloride, chlorobenzene and cryptomaterial; alcohols, including methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethoxy)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane and anisole; ketones, including acetone, butanone, methyl ethyl ketone (MEK), methylisobutylketone, methylethylketone and methyl isobutyl ketone (MIBK); esters including methyl acetate, ethyl formate, ethyl acetate, propyl isopropylacetate, isobutyl acetate and butyl acetate; carbonate including ethylene carbonate resulting and propylene carbonate; amides, including formamide, N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; NITRILES including acetonitrile (ACN); sulfoxidov, such as dimethylsulfoxide (DMSO); sulfones, such as sulfolane; nitro compounds such as nitromethane and nitrobenzene; heterocycles such as N-organic, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane and pyridine; carboxylic acids such as acetic acid, trichloroacetic acid and triperoxonane acid; phosphoramide, such as hexamethylphosphoramide; sulphide of carbon; water; and mixtures thereof.

Solid particles of the acid of formula I in crystalline form I can be obtained from a solution or a dense suspension of the acid of formula I in the solvent using conventional methods, including, but not limited to the above, cooling, freezing, evaporating the solvent or adding antibacterial.

In one embodiment of the invention a method for particulate form stage I includes (a) a solution of the acid of formula I in a solvent at a first temperature and (b) the creation of particle I at the second temperature. To accelerate the formation of particles form I the method may also include the stage of sowing by the persecution of the solution with crystals of form I before or during stage (b). The method may additionally include the extraction, as described in the present description.

The solution can be obtained from any form of the acid of formula I, including, but not limited to the above, oils, semi-solid substances, solids (such as amorphous shape or form I or II) or mixtures thereof. The solution in stage (a) can be obtained as saturated and is almost saturated solution at the first temperature. Saturated or nearly saturated solution can be obtained by dissolving a sufficient amount of acid of the formula I in the solvent at a temperature that is higher than the first temperature, so that when the solution allow to cool to a first temperature, get saturated or nearly saturated solution. Enough acid of formula I may be evaluated on the basis of the solubility of the particle I in the solvent at a first temperature, which can be determined using a method known to the expert in the field of technology.

The first temperature may vary from room temperature to a temperature of about the boiling point of the solvent, for example, from about 20 to about 200ºC, from about 20 to about 150 º C or from about 20 to about 100ºC. The second temperature may range from -100 to 100 º C, from about -50 to about 50 º C, from about -10 to about 30 º C, from about 20 to about 200ºC, from about 20 to about 150 º C or from about 20 to about 100ºC. The first temperature may be higher or lower or the same as the second temperature. To maximize the output and efficiency of the way the second temperature is usually set lower than the first temperature.

In one embodiment of the invention, the particles form I are formed by evaporation of the solvent from the solution at the second temperature. Evaporation of the solvent can be the ü facilitated by the application to the solution of heat and/or vacuum. In one embodiment of the invention the solvent is acetonitrile, dichloromethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, acetone, 1-butanol, MTBE, DMSO, ethanol, ethyl acetate, isobutyl acetate, isopropylacetate, 1-propanol, IPA, MEK, THF or a mixture.

In another embodiment of the invention, the particles form I are formed by cooling the solution to a second temperature. In this case, the second temperature is set lower than the first temperature. In one embodiment of the invention the solvent is DMF, 1,4-dioxane, methanol, 2-methoxyethanol, 1-butanol, 1-propanol, IPA, MEK, THF or a mixture.

In yet another embodiment of the invention, the particles form I is formed by adding antibacterial to the solvent at the second temperature.

Suitable antibacterial include, but are not limited to the mentioned above, hydrocarbons, including petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin and cumin; chlorinated hydrocarbons, including dichloromethane (DHM), 1,2-dichloroethane, 1,1-dichlorethene, 1,2-dichloride, chloroform, trichloroethane, trichlorethane, carbon tetrachloride, chlorobenzene and cryptomaterial; alcohols including isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-e is axiatonal and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane and anisole; ketones, including butanone, methylisobutylketone, methylethylketone and methyl isobutyl ketone (MIBK); esters including methyl acetate, ethyl formate, ethyl acetate, propyl, isopropylacetate, isobutyl acetate and butyl acetate; carbonate including ethylene carbonate resulting and propylene carbonate; nitro compounds, including nitromethane and nitrobenzene; heterocycles; sulphide of carbon; water; and mixtures thereof.

When the pair of the solvent/antibacterial use two of the solvent, the acid of formula I has a higher solubility in the solvent than in antibacterial. Optionally, the solvent and antibacterial paired solvent/antibacterial are at least partially miscible. In one embodiment of the invention the solvent is THF, methoxyethanol, DMSO, DMF or a mixture thereof; and Antibacterials is hexane(s), MTBE, toluene, water or a mixture. In another embodiment of the invention a pair of solvent/antibacterial is THF/hexane, THF/water, DMF/MTBE or DMF/water.

In yet another embodiment of the invention, the particles form I is obtained by adding a solvent to anti is actuarialy at the second temperature. In one embodiment of the invention the solvent is THF, methoxyethanol, DMSO, DMF or a mixture thereof; and Antibacterials is hexane(s), MTBE, toluene, isopropylacetate, water or their mixture. In another embodiment of the invention a pair of solvent/antibacterial are THF/hexane, THF/water, 2-methoxyethanol/hexane, DMSO/water or DMF/water.

In another embodiment of the invention a method for particulate form stage I includes (a) a thick suspension of the acid of formula I in a solvent at a first temperature and (b) obtaining particles of form I by the influence of a heavy suspension of the second temperature. Thick suspension can be obtained from any form of the acid of formula I, including, but not limited to the above, oils, semi-solid substances, solids (such as amorphous shape or form I or II) or mixtures thereof. The method may optionally include the stage of sowing and/or phase separation, as described in the present description.

The first and the second temperature and the solvent are as defined in the present description. In one embodiment of the invention the solvent is acetonitrile, chloroform, dichloromethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, toluene, hexane(s), acetone, 1-butanol, MTBE, DMSO, ethanol, ethyl acetate, ethyl formate, heptane, isobutylated is, isopropylacetate, 1-propanol, IPA, MEK, THF or a mixture.

In yet another embodiment of the invention a method for particulate form stage I includes (a) a solution of the acid of formula I in a solvent at a first temperature (b) the formation of thick slurry by cooling the solution to a second temperature; and (C) creating a solid particle form I by the influence of a heavy suspension of one or more cycles of heating and cooling. The method may optionally include the stage of sowing and/or phase separation, as described in the present description.

The first and the second temperature and the solvent are as defined in the present description. In one embodiment of the invention the solvent is acetonitrile, 1,4-dioxane, 2-methoxyethanol, MIBK, acetone, 1-butanol, ethanol, 1-propanol, IPA, MEK, THF, water/THF (3:7, V/V) or their mixture. Cycles of heating and cooling can be carried out in the temperature range from about -50 to about 120 ºC, from about -50 to about 100ºC, from about -20 to about 80 ° C, from about 0 to about 80, from about 10 to about 80, from about 20 to about 80, from about 20 to about 60 ° C or from about 20 to about 50'C.

Particles of the acid of formula I in crystalline form II can be obtained from a solution or a dense suspension of the acid of formula I in the solvent using conventional methods, including, but not ogranichivayushchei, cooling, freezing, evaporating the solvent or adding antibacterial.

In one embodiment of the invention a method for particulate form II stage includes (a) a solution of the acid of formula I in a solvent at a first temperature and (b) obtaining particles form II at a second temperature. To accelerate the formation of particles form II method may also include the stage of sowing by the persecution of the solution with crystals of form II before or during stage (b). The method may additionally include the extraction, as described in the present description.

The solution can be obtained from any form of the acid of formula I, including, but not limited to the above, oils, semi-solid substances, solids (such as amorphous shape or form I or II) or mixtures thereof. The solution in stage (a) can be obtained as saturated or nearly saturated solution at the first temperature. Saturated or nearly saturated solution can be obtained by dissolving a sufficient amount of acid of the formula I in the solvent at a temperature that is higher than the first temperature, so that when the solution allow to cool to a first temperature, get saturated or nearly saturated solution. Enough acid of formula I may be evaluated on the basis of the solubility of the particles form II to dissolve is hardly the first temperature, which can be determined using the method known to the expert in the field of technology.

In one embodiment of the invention, the particles form II are formed by evaporation of the solvent from the solution at the second temperature. Evaporation of the solvent can be facilitated by application to the solution of heat and/or vacuum. In one embodiment of the invention the solvent is DMF, 1,4-dioxane, methanol, 2-methoxyethanol, 1-butanol, 1-propanol, IPA, MEK, THF or a mixture.

In another embodiment of the invention, the particles form II are formed by cooling the solution to a second temperature.

In yet another embodiment of the invention, the particles form II are formed by adding antibacterial to the solvent at the second temperature. In one embodiment of the invention the solvent is THF, methoxyethanol, DMSO, DMF or a mixture thereof and antibacterial is hexane(s), MTBE, toluene, water or a mixture.

In yet another embodiment of the invention, the particles form II are formed by adding the solution to antibacterial at the second temperature. In one embodiment of the invention the solvent is THF, methoxyethanol, DMSO, DMF and mixtures thereof and antibacterial is hexane(s), MTBE, toluene, water and their mixtures. In another embodiment, osushestvlyaetsya pair solvent/antibacterial is DMF/MTBE.

In another embodiment of the invention a method for particulate form II stage includes (a) a thick suspension of the acid of formula I in a solvent at a first temperature and (b) creating a solid particle form II by acting on the suspension of the second temperature. Thick suspension can be obtained from any form of the acid of formula I, including, but not limited to the above, oils, semi-solid substances, solids (such as amorphous shape, or form I or II), or mixtures thereof. The method may optionally include the stage of sowing and/or phase separation, as described in the present description.

The first and the second temperature and the solvent are as described in the present description. In one embodiment of the invention the solvent is acetonitrile, chloroform, dichloromethane, DMF, 1,4-dioxane, methanol, 2-methoxyethanol, MIBK, toluene, hexane(s), acetone, 1-butanol, MTBE, DMSO, ethanol, ethyl acetate, ethyl formate, heptane, isobutyl acetate, isopropylacetate, 1-propanol, IPA, MEK, THF, water or their mixture.

Amorphous particles of the acid of formula I can be obtained from a solution or a dense suspension of the acid of formula I in the solvent using conventional methods, including, but not limited to the above, cooling, freezing, evaporating the solvent or adding antibacterial.

In one the embodiment of the invention, the method for obtaining amorphous particles of the acid of formula I involves the following stages (a) obtaining a solution of the acid of formula I in a solvent at a first temperature and (b) the creation of amorphous particles at the second temperature. The method may also include the extraction, as described in the present description.

The solution can be obtained from any form of the acid of formula I, including, but not limited to the above, oils, semi-solid substances, solids (such as amorphous shape or form I or II) or mixtures thereof. The solution in stage (a) can be obtained in the form of saturated or nearly saturated solution at the first temperature. Saturated or nearly saturated solution can be obtained by dissolving a sufficient amount of acid of the formula I in the solvent at a temperature that is higher than the first temperature, so that when the solution allow to cool to a first temperature, get saturated or nearly saturated solution. Enough acid of formula I may be evaluated on the basis of the solubility of amorphous particles in a solvent at a first temperature, which can be determined using the method known to the expert in the field of technology.

In one embodiment of the invention, the amorphous particles are formed upon evaporation of the solvent from the solution at the second temperature. Evaporation of the solvent can be facilitated by applying to the solution of heat and/or vacuum. In one embodiment of the invention the solvent is ethyl formate, isobutyl the Etat, MTBE, or their mixture.

In another embodiment of the invention, the amorphous particles are formed by cooling the solution to a second temperature. In one embodiment of the invention the solvent is MEK.

In yet another embodiment of the invention, the amorphous particles are formed by adding antibacterial to the solution at the second temperature. In one embodiment of the invention the solvent is THF, methoxyethanol, DMSO, DMF or a mixture thereof and antibacterial is hexane(s), MTBE, toluene, water or a mixture. In another embodiment of the invention a pair of solvent/antibacterial is THF/hexane or DMSO/water.

In yet another embodiment of the invention, the amorphous particles are formed by adding the solution to antibacterial at the second temperature. In one embodiment of the invention the solvent is THF, methoxyethanol, DMSO, DMF or a mixture thereof and intersterile is hexane(s), MTBE, toluene, water or a mixture. In another embodiment of the invention a pair of solvent/antibacterial is THF/hexane or DMSO/water.

In yet another embodiment of the invention, the method for obtaining amorphous particles of the acid of formula I involves the following stages (a) a thick suspension of the acid of formula I in the solvent at the first t is mperature and (b) the creation of amorphous particles through the conversion phase at the second temperature. Thick suspension can be obtained from any form of the acid of formula I, including, but not limited to the above, oils, semi-solid substances, solids (such as amorphous shape or form I or II) or mixtures thereof. The first and the second temperature and the solvent are as defined in the present description. In one embodiment of the invention the solvent is chloroform, hexane(s), MTBE, ethyl formate, heptane, IPA, water, or their mixture.

Other ways of obtaining particles can also be used to obtain particles of the acid of formula I in amorphous form or crystalline form I or II, including spray drying, roller drying, lyophilization and crystallization from the melt.

The pharmaceutical composition

Also provided is a pharmaceutical composition, which comprises as an active pharmaceutical ingredient particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II or its acceptable hydrate or MES in combination with one or more pharmaceutically acceptable carriers or excipients. The choice of excipients, to a greater extent, depends on factors such as a certain way of introduction, the effect of excipients on the solubility and ailnoth active ingredient and the nature of the dosage form.

Pharmaceutical compositions presented in the present description, may be provided in dosage forms containing a single dose, or dosage forms containing multiple doses. Dosage forms containing a single dose, as used in the present description, refers to a physically separate units, suitable for administration to patients for people and animals and packaged individually as is known in the art. Each single dose contains a predetermined quantity of active ingredient(s)sufficient to provide the desired therapeutic effect, in combination with the required pharmaceutical carriers or excipients. Examples of dosage forms containing a single dose, include ampoules, syringes and individually Packed tablets and capsules. Dosage forms containing a single dose may be administered separately or together. Dosage forms containing multiple doses represent many of the same dosage forms containing a single dose, Packed in a separate container for maintaining in separate dosage forms, containing a single dose. Examples of dosage forms containing multiple doses, include vials, bottles of tablets or capsules or bottles of pints or gallons.

Particles of the acid of formula I presented in this op is sanija, can be introduced separately or in combination with one or more compounds represented in the present description, one or more other active ingredients. Pharmaceutical compositions presented in the present description, can be receptionby in various pharmaceutical forms for oral, parenteral or local administration. Pharmaceutical compositions can also be receptionby in the form of dosage forms with modified release, including dosage forms with delayed, prolonged, prolonged, continuous, pulse, controlled, accelerated and fast, focused, programmable release and dosage forms, held in the stomach. Such dosage forms can be obtained in accordance with conventional methods and techniques known to the expert in the technical field (seeRemington: The Science and Practice of Pharmacy,above;Modified-Release Drug Deliver Technology,Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).

Pharmaceutical compositions presented in the present description, can be administered once or several times with time intervals. Understand that the exact dosage and duration of treatment can vary depending on age, weight and condition of the patient receiving treatment, and can be determined empirically using the-W well-known research protocols or by extrapolation from in vivo or in vitro or diagnostic data. Also understand that for any particular patient specific schemes should over time be korrigirovanija in accordance with the needs of the individual and the professional opinion of the person typing or watching the introduction of the compositions.

A. Oral administration

Pharmaceutical compositions presented in the present description may be presented in solid, semisolid, or liquid dosage forms for oral administration. As used in the present description, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to the mentioned above, tablets, capsules, pills, pellets, tablets, pharmaceutical tablets, starch capsules, balloons, medical chewing gum granules, bulk powder, effervescent or nishiuchi powders or granules, solutions, emulsions, suspensions, solutions, pellets, sprays, elixirs and syrups. In addition to the active ingredient(s) of the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to the above, binders, fillers, diluents, dezintegriruetsja substances, moisturizing agents, lubricants, glidant, paint and, inhibitors migration of dyes, sweeteners and flavorings.

Binders or granulators give the tablet adhesion to ensure that the tablet remained intact after pressing. Suitable binders or granulators include, but are not limited to the mentioned above, starch, potato starch and reptitiously starch (such as STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, extract of Irish moss, Panferova gum, ghatti-gum, mucilage film isabgol, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), wigum, erbogachan larch powder tragakant and guar gum; cellulose, such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hypromellose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to the mentioned above, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrans, kaolin, mannitol, silicic acid, sorbitol, krahm is l, reptitiously starch and mixtures thereof. Binder or filler may be present in the pharmaceutical compositions presented in the present description, in the amount of from about 50 to about 99% by weight.

Suitable diluents include, but are not limited to the mentioned above, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, Inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Certain solvents, such as mannitol, lactose, sorbitol, sucrose and Inositol, when present in sufficient numbers, can give some properties of the compression tablets, which contribute to degradation in the oral cavity during chewing. Such molded tablets can be used as chewable tablets.

Suitable dezintegriruetsja substances include, but are not limited to the mentioned above, agar, bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resin; alginic acid; gums, such as guar gum and veegum HV; citrus pulp; cross-linked cellulose, such as croscarmellose; a cross-linked polymer such as crosspovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as glycolate, starch sodium; polacrilin potassium; starches such as corn starch,potato starch, tapioca starch and reptitiously starch; clays; algina; and mixtures thereof. The number dezintegriruetsja substances in pharmaceutical compositions presented in the present description, ranging from the type of composition and easily obvious to the ordinary specialist in the field of technology. Pharmaceutical compositions presented in the present description may contain from about 0.5 to about 15% or from about 1 to about 5% by weight dezintegriruetsja substances.

Suitable lubricants include, but are not limited to the mentioned above, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as Behinat of glycerol and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; etiloleat; tillaart; agar; starch; Likopodija; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimor, MD) and CAB-O-SIL® (Cabot Co. Of Boston, MA); and mixtures thereof. Pharmaceutical compositions presented in the present description may contain from about 0.1 to about 5% by weight of the lubricant.

Suitable glidant include colloidal silica, CAB-O-SIL® (Cabot Co. Of Boston, MA) and without talc asbestos is. Dyes include any of the approved certified water-soluble dyes, FD&C and water-insoluble dyes, FD&C, suspended on the hydrate of aluminum and coloring varnishes and their mixtures. Coloring lacquer is a combination of absorption of water-soluble paints on water heavy metal oxide, giving an insoluble form of the dye. Flavors include natural flavors extracted from plants such as fruits, and synthetic blends of compounds which give a feeling of pleasant flavor, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragakant, bentonite, and surfactants, such as monooleate of polyoxyethylenesorbitan (TWEEN® 20), monooleate 80 polyoxyethylenesorbitan (TWEEN®80), and triethanolamine oleate. Suspendresume and dispersing agents include carboxymethylcellulose sodium, pectin, tragakant, Wigan, acacia, carboxymethylcellulose sodium, hypromellose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Moisturizing agents include propylene glycol monostearate, monooleate sorbitol, monolaurate dietinglose lauric ester of polyoxyethylene. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in emulsions, include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

You must understand that many carriers and auxiliary substances can have multiple functions, even in the same composition.

Pharmaceutical compositions presented in the present description, can be represented in the form of compressed tablets, powders, tablets, chewable lozenges, rapidly dissolving tablets, repeatedly pressed pellets or tablets coated with enteric-soluble shell, coated tablets sugar or film. Tablets coated with enteric-soluble shell are pressed tablets, coated substance, which is resistant to gastric acid, but is dissolved or decomposed in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric shell include, but are not limited to the mentioned above, fatty acids, fats, fenilsalitsilat, waxes, shellac, ammonioalkyl shellac and acetate-phthalate cellulose. Tablets coated with sugar, p is establet a pressed tablet, surrounded by the sugar-coated, which may be useful in the guise of unacceptable taste or odor and protect tablets from oxidation. Tablets, film-coated, are extruded tablets, which are covered with a thin layer or film of water-soluble material. Film membranes include, but are not limited to the mentioned above, hydroxyethyl cellulose, carboxymethyl cellulose sodium, polyethylene glycol 4000 and acetated cellulose. Film shell give the same General characteristics as sugar shell. Repeatedly pressed tablets are compressed tablets obtained through more than one cycle of pressing, including layered tablets and tablets covered with prints or coated by the dry method.

Dosage forms of tablets can be derived from the active ingredient in powdered, crystalline or granular forms, alone or in combination with one or more carriers or excipients described in the present description, including binders, dezintegriruetsja substances, polymers, controlled release, lubricants, diluents and/or dyes. Flavouring and sweeteners are especially applicable to the formation of chewable tablets and lozenges.

Pharmaceutical is e song presented in the present description, can be represented in the form of soft or hard capsules, which can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsule, also known as shaunaolney capsule (DFC), consists of two departments, one mounted on the other, thus completely covering the active ingredient. Soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin capsule, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. Soft gelatin capsules may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are, as described in the present description, including methyl - and propylparaben and sorbic acid. Liquid, semi-solid and solid dosage forms provided in the present description, can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions or suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be obtained as described in U.S. patent No. 4328245, 4409239 and 4410545. Capsules can also be coated, as is well-known specialist in the field of technology, in order to modify or long dissolution actively what about the ingredient.

Pharmaceutical compositions presented in the present description, may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout the other liquid, which may be oil-in-water or water-in-oil. The emulsion can include pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent and preservative. Suspension may include pharmaceutically acceptable suspiciouse agent and preservative. Water-alcohol solutions may include pharmaceutically acceptable acetals, such as di(lower alkyl)acetal lower alkylenediamine (the term "lower" denotes alkyl having from 1 to 6 carbon atoms), for example, diethylacetal acetaldehyde; and miscible with water, the solvent having one or more hydroxyl groups such as propylene glycol and ethanol. Elixirs are transparent, sweet and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugar, for example sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of pharmaceutically priemel the constituent of a liquid medium, for example, water in a degree suitable for injection.

Other applicable liquid and semi-solid dosage forms include, but are not limited to the mentioned above, those containing the active ingredient(s) presented in the present description, and dialkylamines mono - or polyalkyleneglycol, including 1,2-dimethoxymethane, diglyme, trislim, tetralin, dimethyl ether of polyethylene glycol-350, dimethyl ether of polyethylene glycol-550, dimethyl ether of polyethylene glycol-750, where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. Such compositions can optionally include one or more antioxidants, such as bottled hydroxytoluene (EIT), bottled hydroxyanisol (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamate.

Pharmaceutical compositions presented in this description for oral administration, can also be represented in the form of liposomes, micelles, microspheres or nanosystems. Micellar pharmaceutical form can be obtained as described in U.S. patent No. 6350458.

Pharmaceutical compositions presented in the present description, can be is provided in the form of nishiuchi or effervescent granules and powders for recovery in liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in nishiuchi granules or powders may include diluents, sweeteners and moisturizer. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include an organic acid and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosage forms.

Pharmaceutical compositions presented in the present description, can be receptionby in the form of dosage forms for immediate or modified release, including delayed, continuous, pulse, controlled -, targeted and programmed release.

Pharmaceutical compositions presented in the present description, can be jointly receptionby with other active ingredients which do not affect the desired therapeutic action, or with substances that Supplement the desired action, such as antacids, proton pump inhibitors and receptor antagonists H2.

C. Injecting

Pharmaceutical compositions presented in the present description, can be administered parenterally by injection, infusion or implantation, local or systemic administration. Parenteral the first introduction, as used in this description, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

Pharmaceutical compositions presented in the present description, can be receptionby in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be obtained in accordance with customary methods known to the expert in the technical field of pharmaceutical Sciences (seeRemington: The Science and Practice of Pharmacyabove).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to the above, water carriers, carriers, miscible with water, non-aqueous media, antibacterial agents or preservatives against the growth of microorganisms, stabilizers, enhancers solubility, isotonic means, the buffer means, antioxidants, local anesthetics, suspendresume and dispersing funds, SWL is nausia or emulsifying means, complexing tools, complexing or chelating means, cryoprotectants, bioprotector, thickeners, means regulating the pH, and inert gases.

Suitable aqueous media include, but are not limited to the mentioned above, water, saline, physiological saline or phosphate buffer solution (PBS), injectable solution of sodium chloride, injection ringer's solution, isotonic dextrose injection, sterile water for injection, dextrose and lactate ringer's solution for injection. Non-aqueous carriers include, but are not limited to the above, non-volatile vegetable oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and medium chain triglycerides of coconut oil and palm oil seeds. Mixed water media include, but are not limited to the mentioned above, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g. polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide and dimethylsulfoxide.

Suitable antibacterial agents or preservatives include, but are not limited to outline the military, phenols, Cresols, mercury drugs, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride, chloride benzene, methyl - and propylparaben and sorbic acid. Suitable isotonic tools include, but are not limited to the above, sodium chloride, glycerin and dextrose. Suitable buffer means include, but are not limited to the mentioned above, phosphate and citrate. Suitable antioxidants are those described in the present description, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to the mentioned above, hydrochloride, procaine. Suitable suspendresume and dispersing means are such as described in the present description, including carboxymethylcellulose sodium, hypromellose and polyvinylpyrrolidone. Suitable emulsifying means comprise described in the present description, including monolaurate of polyoxyethylenesorbitan, monooleate of polyoxyethylenesorbitan 80 and triethanolamine oleate. Suitable complexing or chelating tools include, but are not limited to the above, EDTA. Suitable means, regulating the pH include, but are not limited to the mentioned above, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Coming up is their complex-forming means include, but not limited to the mentioned above, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and sulphobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

Pharmaceutical compositions presented in the present description, can be receptionby for a single administration or administration of multiple doses. Pharmaceutical compositions containing a single dose, Packed in ampoules, vials or syringes. Parenteral compositions containing multiple doses, should contain the antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral compositions should be sterile, as is known and used in the field of technology.

In one embodiment of the invention the pharmaceutical composition is presented in the form of ready-to-use sterile solutions. In another embodiment of the invention the pharmaceutical composition is presented in the form of a sterile dry soluble products, including freeze-dried powders and hypodermal tablets for recovery media before use. In yet another embodiment, the invention presents a pharmaceutical composition in the form of sterile suspensions ready to use. In yet another variant domestic the invention, pharmaceutical compositions are represented in the form of a sterile dry insoluble products for recovery media before use. In yet another embodiment of the invention the pharmaceutical composition is presented in the form of ready-to-use sterile emulsions.

Pharmaceutical compositions provided in the present description, can be receptionby in the form of dosage forms for immediate or modified release, including delayed, continuous, pulse, controlled -, targeted and programmed release.

The pharmaceutical compositions can be receptionby in suspension, solids, semi-solid substances, or thixotropic liquid for administration in the form of implantable depot. In one embodiment of the invention the pharmaceutical composition provided in the present description, dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane, which is insoluble in the fluids of the body, but allows the active ingredient in pharmaceutical compositions to diffuse through them.

Suitable internal matrix include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylenterephthalat, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, copolymers of ethylene and vinyl acetate, silicone the new rubbers, polydimethylsiloxane, copolymers of carbonate, silica, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene, copolymers of ethylene/propylene, copolymers of ethylene/ethyl acrylate, copolymers of ethylene/vinyl acetate, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, chloride vinylidene, ethylene and propylene, ion meter of terephtalate polyethylene, butyl rubber, epichlorohydrine rubber, copolymer of ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl alcohol and a copolymer of ethylene/vinyloxyethyl.

C. Local introduction

Pharmaceutical compositions presented in the present description, can be administered topically to the skin, holes or mucous membranes. Local injection, as used in this description, includes (intra)dermal, conjunctival, intracorneal, intraocular, ocular, ear, percutaneous, nasal, vaginal, urethral, respiratory and rectal administration.

Pharmaceutical compositions presented in the present description, can be receptionby in l is any dosage forms, suitable for local introduction for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal patches. Local compositions pharmaceutical compositions presented in this description can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the local compositions, presented in the present description, include, but are not limited to the mentioned above, water media, mixed water media, non-aqueous media, antibacterial agents or preservatives against the growth of microorganisms, stabilizers, enhancers solubility, isotonic means, the buffer means, antioxidants, local anesthetics, suspendresume and dispersing funds, moisturizing or emulsifying means, complexing tools, chelating agents or chelating tools, penetration enhancers, cryoprotectant, neoprotestant, condensing means and inert gases.

Pharmaceutical compositions can also be administered topically by elektroborudovaniya, iontophoresis, phonophoresis, sonophoresis and micropolitical beshalach injection, such as POWDERJECTTM(Chiron Corp., Emeryville, CA), and BIOJECTTM(Bioject Medical Technologist Inc., Tualatin, OR).

Pharmaceutical compositions presented in the present description, can be represented in the form of ointments, creams and gels. Suitable topical carriers include oil or hydrocarbon bases, such as fat, betonirovannoy fat, olive oil, cottonseed oil and other oils, white petrolatum; emulsifiable or absorbent bases such as hydrophilic vaseline, the sulfate hydroxystyrene and anhydrous lanolin; bases removed by water, such as hydrophilic ointment; water-soluble ointment bases, including polyethylene glycols of various molecular weights, principles of emulsions or emulsion water-in-oil (W/O) or emulsion oil-in-water (O/W), including cetyl alcohol, glycerylmonostearate, lanolin and stearic acid (see Remington: The Science and Practice of Pharmacy above). Such carriers are softening substances, but usually require the addition of antioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream the media can be water washable and contain an oil phase, an emulsifier and the aqueous phase. The oil phase is also called the "inner" phase, which usually includes petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not party shall, exceeds the oil phase in volume, and typically contains a humidifier. The emulsifier in the composition of the cream can be nonionic, anionic, cationic or amphoteric surface-active substance.

Gels are semisolid systems suspension. Monophasic gels contain organic macromolecules distributed essentially homogeneous throughout a liquid medium. Suitable gel-forming means comprise crosslinked polymers of acrylic acid, such as carbomer, carboxypolymethylene, Carbopol®; hydrophilic polymers such as polyethylene oxides, copolymers of polyoxyethylene-polyoxypropylene and polyvinyl alcohol; cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose and methyl cellulose; gums such as tragakant and xanthan gum; sodium alginate and gelatin. Order to obtain a homogeneous gel can be added dispersing agents such as alcohol or glycerin, or gel-forming means can be dispersed by grinding, mechanical mixing and/or stirring.

Pharmaceutical compositions presented in the present description, can be entered rectal, urethral, vaginal or perivaginal in the form of suppositories, pessaries, Buja, compresses or prepare is, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays or douches. Such dosage forms can be produced using conventional methods, as described inRemington: The Science and Practice of Pharmacyabove.

Rectal, urethral and vaginal suppositories are solid bodies for insertion into the holes of the body, which are solid at ordinary temperature, but melts or softens at body temperature to release the active ingredient(s) inside the holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include media, such as substances that enhance rigidity, which give a melting temperature around body temperature, when receptioni with the pharmaceutical compositions provided in the present description; and antioxidants, as described in the present description, including bisulfite and sodium metabisulfite. Suitable carrier materials include, but are not limited to the mentioned above, cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethyleneglycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di - and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid, gelatin with glice the other. Can be used a combination of different media. Rectal and vaginal suppositories can be obtained by pressing or casting. Normal weight rectal and vaginal suppository is from about 2 to 3 g

Pharmaceutical compositions presented in the present description, can be entered ophthalmologist in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, eye inserts and implants.

Pharmaceutical compositions presented in the present description, can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions can be presented in the form of an aerosol or solution for administration by using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to obtain ultra-fine spray or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-Heptafluoropropane. Pharmaceutical compositions can also be presented as a dry powder for inhalation, alone or in combination with an inert carrier such as lactose, or a phospholipid; and nasal drops. For intranasal use, the powder may include bioadhesive means including the chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be receptionby and contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, dissolving, or extending release of the active ingredient, represented in the present description, the propellant as the solvent; and/or surfactants, such as trioleate sorbitan oleic acid or oligobrachia acid.

Pharmaceutical compositions presented in the present description, can be mikronizirovanny to a size suitable for delivery by inhalation, for example, 50 micrometers or less, or 10 micrometers or less. Particles of such sizes can be obtained using a chopping method, well-known specialist in the field of technology, such as grinding spiral jet grinding in a mill, fluidized bed processing supercritical fluid to obtain nanoparticles, homogenization at high pressure or spray drying.

Capsules, blisters and cartridges for use in an inhaler or insufflator can be receptionby as containing a powder mix of the pharmaceutical compositions provided in the present description; a suitable powder base such as lactose Il the starch; and modifier characteristics, such as l-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. Pharmaceutical compositions presented in this description for inhaled/intranasal may additionally include suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical composition presented in this description for local injection, can be receptiona for immediate release or modified release, including delayed, continuous, pulse, controlled, targeted and programmed release.

D. Modified release

Pharmaceutical compositions presented in the present description, can be receptionby in the form of dosage forms of the modified release. As used in the present description, the term "modified release" refers to the dosage form, in which the rate or place of release of the active ingredient(s) different from those of the dosage form immediate release with the introduction in the same way. The dosage form is modificirovannogo release include dosage form delayed a long, prolonged, continuous, shock or pulse controlled, accelerated and fast, focused, programmable release and dosage forms that are retained in the stomach. Pharmaceutical compositions in dosage forms of the modified release can be obtained using a variety of devices and methods for modified release, well-known specialist in the field of technology, including, but not limited to the above, the device controlled release based on the matrix, the device with the osmotic controlled-release device controlled release of many particles, ion exchange resin, casings, multilayer membranes, microspheres, liposomes, and combinations thereof. The rate of release of active ingredient(s) may also be modified by varying the particle size and polymorphism of the active ingredient(s).

Examples of modified release include, but are not limited to the mentioned above, are described in U.S. patents№ 3845770, 3916899, 3536809, 3598123, 4008719, 5674533, 5059595, 5591767, 5120548, 5073543, 5639476, 5354556, 5639480, 5733566, 5739108, 5891474, 5922356, 5972891, 5980945, 5993855, 6045830, 6087324, 6113943, 6197350, 6248363, 6264970, 6267981, 6376461, 6419961, 6589548, 6613358 and 6699500.

1. Devices controlled release based on the matrix

Pharmaceutical compositions, presented the military into a real description, in the pharmaceutical form modified-release can be obtained using devices controlled release based on the matrix, well-known specialist in the field of machinery (see Takada et al. In “Encyclopedia of Controlled Drug Delivery”, Vol. 2, Mathiowitz ed., Wiley, 1999).

In one embodiment of the invention the pharmaceutical compositions presented in the present description, in the pharmaceutical form modified-release receptorow using device erodible matrix, which is a polymer that is swellable in water, degradable or soluble polymers, including synthetic polymers and natural polymers and derivatives, such as polysaccharides and proteins.

Materials applicable in obtaining biodegradable matrices include, but are not limited to the mentioned above, chitin, chitosan, dextran and pullulan; agar gum, gum Arabic, gum karaya, gum plodotvornogo tree, tragakant, carragenan, ghatti-gum, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulose, as ethylcellulose (EU), metilcellulose (MONTHS), carboxymethylcellulose (CMC), COMPOUNDS, hydroxyethylcellulose (NES), hydro is dipropylacetate (LDCs), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), butyrate cellulose acetate (CAB), cap, CAT, hypromellose (receiver array), WRMSR, HPMCAS, trimellitic acetate hydroxypropylmethylcellulose (NRSET) and metilgidroxiatilzelllozu (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; esters of glycerol and fatty acids; polyacrylamide; polyacrylic acid; copolymers metacrilato acid or methacrylic acid (EURAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethylmethacrylate); polylactide; copolymers of L-glutamato acid and ethyl L-glutamate; degradable copolymers of lactic acid-glycolic acid; poly-D-(-)-3 - hydroxipropionic acid; and other derivatives of acrylic acid, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, acrylate, (2-dimethylaminoethyl)methacrylate and chloride (trimethylaminoethyl)methacrylate.

In another embodiment of the invention the pharmaceutical composition receptorow with non-biodegradable matrix. Active ingredient(s) dissolved or dispersed in an inert matrix and is released when the introduction is mainly by diffusion of the inert matrix. Materials suitable for use as non-biodegradable matrices include, but are not limited to the mentioned above, insoluble place is IKI, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, copolymers of methyl acrylate-methyl methacrylate, copolymers of ethylene and vinyl acetate, copolymers of ethylene/propylene, copolymers of ethylene/ethyl acrylate, copolymers of vinyl chloride with vinyl acetate, chloride vinylidene, ethylene and propylene, ion meter of terephtalate polyethylene, butyl rubber, epichlorhydrin rubber, copolymer of ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl alcohol and a copolymer of ethylene/vinyloxyethyl, polyvinylchloride, plasticized nylon, plasticized polyethylenterephthalat, natural rubber, silicone rubbers, polydimethylsiloxane, copolymers of carbonate silicon and; hydrophilic polymers such as ethylcellulose, cellulose acetate, crosspovidone and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as Carnauba wax, microcrystalline wax, and triglycerides.

In the system matrix controlled release of the desired release kinetics can be controlled, for example, by the type of polymer, the viscosity of the polymer, the particle size of the polymer and/or active ingredient(s), the ratio of active ingredient(s) and polymer and other VSP the service of the substances in the composition.

Pharmaceutical compositions presented in the present description, in the pharmaceutical form modified-release can be obtained by methods known to the expert in the field of technology, including direct compression, dry or wet granulation followed by pressing, granulation of the melt, followed by pressing.

2. Osmotic device controlled release

Pharmaceutical compositions presented in the present description, the dosage form with modified release can be obtained with the use of the osmotic device with controlled-release, including the single-chamber system, two-chamber system, an asymmetric membrane technique (AMT) and extruders core system (ECS). In General, such devices have at least two components: (a) the core which contains the active ingredient(s), and (b) a semipermeable membrane with at least one aperture for delivery, in which the encapsulated core. Semipermeable membrane controls the flow of water to the core from an aqueous environment of use so as to cause the release of a medicinal product by squeezing through the hole(I) for delivery.

In addition to the active ingredient(s) the core of the osmotic device optionally includes checks the ical means, which creates the driving force for water transfer from the environment into the core of the device. One class of osmotic means are swellable in water, hydrophilic polymers, which are also called "osmopolitan" and "hydrogels", including, but not limited to the above, hydrophilic vinyl polymers and acrylic, polysaccharides such as calcium alginate, polyethylene oxide (REO), polyethylene glycol (PEG), polypropyleneglycol (PPG), poly(2-hydroxyethylmethacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), copolymers of PVA/PVP copolymers of PVA/PVP with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large blocks REO, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (NES), hydroxypropylcellulose (LDCs), hypromellose (receiver array), carboxymethylcellulose (CMC) and carboximetilzellulozu (SES), sodium alginate, polycarbophil, gelatin, xanthan gum and starch glycolate sodium.

Another class of osmotic means are cosmogeny, which are able to absorb water for influencing the osmotic pressure gradient across the barrier surrounding membranes. Suitable omogeni include, but are not limited to the mentioned above, inorganic salts such as magnesium sulfate, chlorine is d magnesium, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, carbonate into three, sodium sulfite, sodium sulfate, potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, Inositol, lactose, maltose, lures, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sabotinova acid, sorbic acid, adipic acid, adetola acid, glutamina acid, p-toluensulfonate acid, succinic acid and tartaric acid; urea; and mixtures thereof.

Osmotic means with different rates of dissolution can be used to influence how quickly the active ingredient(s) of the source is released from the dosage form. For example, amorphous sugars, such as Mannogeme EZ (SPI Pharma, Lewes, DE)can be used to provide faster delivery during the first few hours appropriate for obtaining the desired therapeutic effect, and gradually and continually release other amounts to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released so fast to replace metabolisable and excr is together with the amount of the active ingredient.

The core may also include a wide variety of other auxiliary substances and carriers, as described in the present description to enhance the introduction of the dosage form or to provide stability or processing.

Materials applicable in obtaining a semi-permeable membrane, include varying degrees of derivatives of acrylic, vinyl ethers, polyamides, polyesters and cellulose, which are permeable to water and insoluble in water at physiologically important pH or capable of becoming insoluble in water by chemical changes, such as knitting. Examples of suitable polymers used in obtaining the shell will include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, butyrate cellulose acetate (CAB), ethylcarbamate SA, SAR, methylcarbamate SA, succinate SA, trimetallic cellulose acetate (CAT), dimethylaminoacetyl SA, ethylcarbonate SA, CHLOROACETATE, SA, ethylacetat SA, methylsulfonate SA, butylsulfonyl SA, p-toluensulfonate SA, acetate agar, amylose triacetate, acetate, beta-glucan, triacetate, beta-glucan, dimethylacetal acetaldehyde, triacetate resin plodotvornogo tree, gidroksilirovanii the ethylene vinyl acetate, EU, PEG, PPG, copolymers of PEG/PPG, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic)sour the s and esters and poly(methacrylic acid and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkene, polyesters, polysulfones, polyethersulfones, polystyrenes, polivinilhlori, polyvinyl complex and ethers, natural waxes and synthetic waxes.

Semi-permeable membranes can also be a hydrophobic microporous membrane, where the pores are essentially filled with gas and not hydrated water, but permeable to water vapor, as described in U.S. patent No. 5798119. Such hydrophobic, but permeable to water vapour membrane usually consists of hydrophobic polymers, such as polyalkene, polyethylene, polypropylene, polytetrafluoroethylene, derivatives of polyacrylic acid, polyethers, polysulfones, polyethersulfone, polysterol, polivinilhlori, fluoride of polyvinylidene, polyvinyl complex and ethers, natural waxes and synthetic waxes.

Inlet(I) a semi-permeable membrane can be formed after coating the shell by mechanical or laser drilling. Inlet(I) can also be formed in place by destroying the tube of water-soluble material or by breaking the thin part of the membrane over the depressions in the kernel. In addition, the inlet can be formed during the process of coating the shell, as in the case of asymmetric membrane membranes of the type described in U.S. patent No. 5612059 and 5698220.

The total amount of the released active ingredient(s) and the rate of release can essentially be modulated using the thickness and porosity of the semipermeable membrane, the composition of the nucleus and the number, size and location of the inlet ports.

Pharmaceutical compositions in osmotic dosage forms with controlled release may also include additional conventional excipients, as described in the present description, to ensure performance or processing of the composition.

Osmotic dosage forms with controlled release can be obtained in accordance with conventional methods and techniques known to the expert in the technical field (seeRemington: The Science and Practice of Pharmacyabove; Santus and Baker,J. Controlled Release1995, 35, 1-21; Verma et al.,Drug Development and Industrial Pharmacy2000, 26, 695-708; Verma et al.,J. Controlled Release2002, 79, 7-27).

In certain embodiments of the invention the pharmaceutical compositions presented in the present description, receptioni as AMT dosage forms with controlled release, which include asymmetric osmotic membrane that coats a core containing the active ingredient(s) and other pharmaceutically acceptable excipients. Cm. U.S. patent No. 5612059 and WO 2002/17918. AMT dosage forms with controlled the dummy release can be obtained in accordance with conventional methods and techniques, well-known specialist in the field of technology, including direct compression, dry granulation, wet granulation and method of coating by dipping.

In a particular embodiment of the invention the pharmaceutical compositions presented in the present description, receptioni as ESC dosage forms with controlled release, which includes an osmotic membrane that coats a core containing the active ingredient(s), hydroxyethylcellulose and other pharmaceutically acceptable excipients.

3. Devices controlled release of many particles

Pharmaceutical compositions presented in the present description, in the pharmaceutical form modified-release can be submitted in devices for the controlled release of many particles, which include a multitude of particles, granules or pellets, ranging from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to 1 mm in diameter. So many particles can be obtained by methods known to the expert in the field of technology, including wet and dry granulation, extrusion/spheronization, roller seal, freezing of the melt and coated surface sown cores by spraying. See, for example,Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and<> Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients, as described in the present description, can be mixed with pharmaceutical compositions to improve the treatment and education of many particles. The obtained particles may themselves be a device with many particles, or may be coated from a variety of film-forming materials, such as enteric-soluble polymers, polymers, swelling in water and soluble in water. Many particles can be further presented in the form of capsules or tablets.

4. Directed the introduction

Pharmaceutical compositions presented in the present description, can also be receptionby to target a particular tissue, receptor, or other area of the body of the patient receiving treatment, including delivery systems based on liposomes released erythrocytes and antibodies. Examples include, but are not limited to the mentioned above, U.S. patent№6316652, 6274552, 6271359, 6253872, 6139865, 6131570, 6120751, 6071495, 6060082, 6048736, 6039975, 6004534, 5985307, 5972366, 5900252, 5840674, 5759542 and 5709874.

Applications

In one embodiment, the invention presents a method of treating, preventing or alleviating one or more symptoms of disorders or diseases associated with CRTH2 and/or one or more other receptors PGD2, PU is eating the introduction of the patient, having or suspected of having such a condition or disease, a therapeutically effective amount of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II.

In other embodiments, the invention presents a method of treating, preventing or alleviating one or more symptoms of diseases or disorders that are responsible for the modulation of CRTH2 and/or one or more other receptors PGD2involving the introduction of a patient having or suspected of having such a condition or disease, a therapeutically effective amount of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II.

In yet another embodiment, the invention presents a method of treating, preventing or alleviating one or more symptoms of diseases or disorders mediated by CRTH2 and/or one or more other receptors PGD2involving the introduction of a patient having or suspected of having such a condition or disease a therapeutically effective amount of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or a crystal is a political form I or II.

In yet another embodiment, the invention presents a method for treating, preventing or alleviating one or more symptoms associated with eosinophils, comprising the administration to a patient having or suspected of having such a condition or disease, a therapeutically effective amount of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II.

In yet another embodiment, the invention presents a method for treating, preventing or alleviating one or more symptoms associated with basophils, comprising the administration to a patient having or suspected of having such a condition or disease, a therapeutically effective amount of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II.

In yet another embodiment, the invention presents a method for treating, preventing or alleviating one or more symptoms of an inflammatory disease, comprising the administration to a patient having or suspected of having such a condition or disease, a therapeutically effective amount of particles {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzo the IDO)benzyl)pyrimidine-5-yl}acetic acid in an amorphous form or crystalline form I or II.

Disorders and diseases, curable particles presented in the present description, include, but are not limited to, (1) inflammatory or allergic diseases, including systemic anaphylaxis and disorders hypersensitivity, atopic dermatitis, urticaria, drug allergies, allergies to insect bites, food allergies (including coeliac disease and the like), and mastocytosis; (2) inflammatory bowel diseases, including Crohn's disease, ulcerative colitis, REIT and enteritis; (3) vasculitis syndrome and behceta; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including resulting from human papillomavirus, HIV or RLV infection, bacterial, fungal and other parasitic skin diseases and cutaneous lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, asthma, caused by physical stress, allergic rhinitis, otitis media, allergic conjunctivitis, hypersensitive lung disease and chronic obstructive pulmonary disease; (6) autoimmune diseases, including arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis disease G is awsa and glomerulonephritis; (7) graft rejection (including allograft rejection and disease graft-versus-host), for example, rejection of the skin graft, graft rejection of solid organs, transplant rejection, bone marrow; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis, and vascular stenosis; (10) diseases of the cerebral vessels, including traumatic brain injury, stroke, ischemia-reperfusion damage and aneurysm; (11) cancer of the breast, skin, prostate, cervix, uterus, ovaries, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system; (12) fibrosis, connective tissue disease and sarcoidosis, (13) genital and reproductive conditions, including erectile dysfunction; (14) diseases of the gastrointestinal tract, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurological disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, sonl the stability, syndrome sleep apnea syndrome and picwik; (17) pain; (18) kidney; (19) diseases of the eye, including glaucoma; and (20) infectious diseases, including HIV.

In certain embodiments of the invention the disease is selected from the group consisting of asthma, allergic asthma, asthma induced by exercise, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, contact dermatitis, conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, Hyper IgE syndrome, systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, transplant rejection, reperfusion injury, chronic obstructive pulmonary disease, syndrome charge-Strauss, sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, COPD (chronic obstructive pulmonary disease), arthritis, rheumatoid arthritis, psoriatic arthritis and osteoarthritis.

In certain embodiments of the invention the disease is asthma, asthma induced by exercise, allergic rhinitis, at the microscopic dermatitis, chronic obstructive pulmonary disease or allergic conjunctivitis.

In certain embodiments of the invention the disease is a syndrome charge-Strauss or sinusitis.

Depending on the disease being treated, and patient with the solid particles or compositions presented in the present description, can be administered orally, parenterally (e.g., intramuscular, intraperitoneally, by intravenous, ICV, by injection or infusion in the tank, subcutaneous injection, or implant), inhalation, nazalnam, vaginal, rectal, sublingual, or local (e.g., transdermal or local) routes of administration and can be receptionby separately or together, in suitable dosage forms with pharmaceutically acceptable carriers, additives and carriers suitable for each route of administration. Also presents the introduction of solids presented in the present description, in the compositions of the depot, in which the active ingredient is released within a predetermined period of time.

In the treatment, prevention or alleviation of one or more symptoms of asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclero is a, transplant rejection, inflammatory bowel disease, cancer or other conditions, diseases or disorders associated with CRTH2 and/or one or more receptors PGD2corresponding to the level of dosage is typically from about 0.001 to 100 mg per kg of body weight of the patient per day (mg/kg / day), from about 0.01 to about 75 mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5 to about 25 mg/kg / day or from about 1 to about 20 mg/kg per day, you can enter single or multiple doses. In this range the dosage may range from 0,005 to 0,05, from 0.05 to 0.5, or from 0.5 to 5.0, from 1 to 15, 1 to 20 or from 1 to 50 mg/kg per day. In certain embodiments of the invention, the dose level is from about 0.001 to 100 mg/kg per day. In certain embodiments of the invention, the dose level is from about 0.01 to about 75 mg/kg per day. In certain embodiments of the invention, the dose level is from about 0.1 to about 50 mg/kg per day. In certain embodiments of the invention, the dose level is from about 0.5 to about 25 mg/kg per day. In certain embodiments of the invention, the dose level is from about 1 to about 20 mg/kg per day.

For oral administration the pharmaceutical composition may be presented in the form that the notches, containing 1.0 to 1000 mg of active ingredient, especially about 1, about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient receiving treatment. Compositions can be administered in the scheme from 1 to 4 times per day, including one, two, three times or four times daily.

However, it is understood that the specific dose level and frequency of introduction for any particular patient may vary and will depend on many factors, including the activity of specific compounds used, the metabolic stability and length of action of this compound, the age, body weight, General health, sex, diet, type and time of administration, excretion rate, combination of drugs, the severity of a particular condition and organism being treated.

Also in the present description presents how the modulation of CRTH2 and/or one or more other receptors PGD2that includes the contact of the receptor(s) with particles in one or more solid forms, as presented in the present description. In one embodiment of the invention, the receptor(s) expressed by the cell.

The particles presented in this description can also be combined or used in combination with other means, applicable in the treatment, prevention or alleviation of one or more symptoms of a disease or condition for which the particles presented in this description are applicable, including asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer and pathological conditions noted above.

Such other means, or drugs, can be administered by and in quantities normally used for them, simultaneously or sequentially with particles presented in this description. When the particles presented in the present description, are used in conjunction with one or more drugs can be used in a pharmaceutical composition containing such other drugs in addition to the particles presented in the present description, but not necessarily. Accordingly, the pharmaceutical compositions presented in the present description, include those that also contain one or more other active ingredients or therapeutic agents in addition to the particles presented in this description.

The mass ratio of the particles, predstavlennyh the present description, the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Commonly used effective dose of each. Therefore, for example, when the particles presented in this description, combined with NSAIDs, the mass ratio of solid particles to NSAIDs may range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. The combination of particles presented in the present description, and other active ingredients are usually found within the aforementioned range, but in each case must be used effective dose of each active ingredient.

EXAMPLES

Particles of the acid of formula I in the following examples were characterized by diffractometry x-ray radiation on the powder (XRPD), differential scanning calorimetry (DSC), thermogravimetric (TGA) and scanning electron microscopy (SEM).

The x-ray diffraction pattern for the powder were recorded using a diffractometer x-ray radiation on the powder Rigaku MiniFlex (Rigaku Americas, The Woodlands, TX). Radiation was CuKa (40 kV, 40 mA). Data were obtained at room temperature from 3 to 45 degree double angle of convergence of 0.02 degrees per step and 0.6 seconds per step. Samples were obtained on a glass specimen holder in the form of a thin layer of powdered material without solvent.

Different the actual scanning calorimetry was performed using a Mettler 850, TA 2920. The samples were placed in sealed aluminum pans for analyses with a blank aluminum pan as a control. The heating rate 10 ° /min was used in the temperature range from 30 º C to 280º.

Thermogravimetric analysis was performed on a Mettler 850, TA 2920. The samples were placed in a ceramic or aluminum tray for samples. The heating rate 20 ° /min was used in the temperature range from -20 ° C up to 600ºC.

Example 1

Determination of the solubility of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid

Saturated solutions of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of formula I in the solvent listed in table 1, were obtained from acid mainly in the form I at 25 and 50'C. The concentration of each of the saturated solution was determined using HPLC, and the results are summarized in table 1.

Example 2

Receive {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid form I

A thick suspension of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in methanol was stirred over night at room temperature. Then the particles were filtered, washed with hexane and dried.

The x-ray diffraction pattern for the powder the ke of the particles is illustrated in figure 1. The particles had characteristic peaks XRP diffraction expressed in double angles of convergence at approximately 9,8, 13,1, 22,0, and 26,4º, assuming that the particles are crystalline. As shown in figure 4, the particles represent long needle crystals ranging in size from about 1 to about 5 microns.

Differential scanning calorimetric thermogram of particles is illustrated in figure 2. Particles have the endotherm with a peak temperature of 223,8 degrees Celsius) and the onset temperature of decomposition 220,2.

thermogravimetric analysis thermogram of particles in the form I is shown in figure 3. Particles are very stable and do not show significant weight loss to decomposition of about 200ºC.

The average particle size and size distribution of particles in the form I was measured using a Microtrac S3000 (Microtrac Inc., Montgomeryville, PA). The results are shown in figure 5 and summarized in table 2. Particles in the form I have an average particle size (MV) 6,495 μm and the coefficient of uniformity 3,24.

TABLE 2
The DISTRIBUTION of PARTICLES BY SIZE
PercentileParticle size (µm)
101,807
202,393
303,004
403,713
504,627
605,852
707,498
809,825
9013,70
9517,57

Example 3

Receive {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in the form II

A solution of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid (50 mg) in DMF (0.5 ml) were obtained from acid mainly in the form of I. Then the solution was added to 8 ml of MTBE at room temperature. After stirring at room temperature for an additional 15 minutes, the mixture became a thick slurry. Then the particles were filtered, washed with hexane and dried.

The x-ray diffraction pattern for the powder particles is illustrated in Fig.6. The particles had characteristic peaks XRP diffraction expressed in double angle of convergence of approximately 31,7th, assuming that h is Itza is located in the crystal form (form II), which differs from form I. the Crystalline characteristics of the particles form II is shown in Fig.7.

Example 4

Balancing phases

On the basis of the solubility of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in various solvents, as defined in example 1 acid particles mainly in the form I was exposed to the solvents listed in table 3, at 25 or 50 º C for a sufficient period of time. The particles were filtered and dried and then analyzed using XRPD. The results are summarized in table 3.

Example 5

Balancing the phases between form I and form II

Particles form II was obtained in the form of dense suspension, as described in example 2. Briefly, a solution of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid (50 mg) in DMF (0.5 mg) was added to 8 ml of MTBE to obtain a dense suspension of particles form II. Particles form I (20 mg) was then added to the suspension and the resulting suspension was stirred over night at room temperature. Then the particles were filtered, washed with hexane and dried. The particles were analyzed using XRPD. The XRP diffraction pattern shown in Fig, indicating that the particles after the equilibration phase was in the form I.

Example 6

Particle formation by in the of pariwana solvent

On the basis of the solubility of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid in various solvents, as defined in example 1, the acid is predominantly in the form I was dissolved in the solvent system, listed in table 4. The solvent was allowed to evaporate from the solution at 25 or 50'C. The obtained particles were obtained by filtration and analyzed using XRPD. The results are summarized in table 4.

TABLE 3
CRYSTALLINE FORM AFTER EQUILIBRATION PHASE
SolventSubstance, crystallizing in different shapes
2550 º C
AcetonitrileForm IForm I
ChloroformForm IForm I
DichloromethaneForm I
DMFNAa
1,4-d is oxan Form IForm I
MethanolForm IForm I
2-methoxyethanolForm IForm I
MIBKForm IForm I
TolueneForm IForm I
HexaneForm IForm I
AcetoneForm IForm I
n-butanolForm IForm I
MTBEForm IForm I
DMSONA
EthanolForm IForm I
The ethyl acetateForm IForm I
Ethyl formateForm Form I
HeptaneForm IForm I
The isobutyl acetateForm IForm I
IsopropylacetateForm IForm I
1-propanolForm IForm I
IsopropanolForm IForm I
WaterForm IForm I
MEKForm IForm I
THFForm IForm I
aNA: not available. The sample does not provide any or sufficient quantities of solids.

Example 7

Particle formation by adding antibacterial

Saturated solutions of acids of formula I in the solvents listed in table 5, were obtained from acid mainly in the form of I. Then to saturated solutions to allali antibacterial to obtain deposition. THF, 2-methoxyethanol, DMSO and DMF was used as solvent for dissolving particles form I, whereas hexane, MTBE, toluene and water were used as Antibacterials. The obtained particles were collected by filtration and analyzed using XRPD. The results are summarized in table 5.

Example 8

Particle formation when adding back antibacterial

Saturated or nearly saturated solution of the acid of formula I in the solvents listed in table 6, were obtained from acid, mainly in the form of I. Then the solvents, each added more mix of antibacterial. THF, 2-methoxyethanol, DMSO and DMF was used as solvent for dissolving solids, whereas hexane, MTBE, toluene and water were used as Antibacterials. The obtained particles were collected by filtration and analyzed using XRPD. The results are summarized in table 6.

Example 9

Particle formation by cold damping

Saturated solutions of acids of formula I in the solvents listed in table 7, were obtained from acid mainly in the form I at about 30-50'C. Solutions extinguished by the cold bath acetone/ice. The obtained particles were collected by filtration and analyzed using XRPD. The results are summarized in table the CE 7.

td align="left"> Isopropanol
TABLE 4
CRYSTALLINE FORM UPON evaporation of the SOLVENT
SolventSubstance, crystallizing in different shapes
2550 º C
AcetonitrileForm IForm I
ChloroformNAaNA
DichloromethaneNA
DMFForm IForm I
1,4-dioxaneForm IForm I
MethanolForm IForm I
2-methoxyethanolForm IForm I
MIBKForm IForm I
TolueneNA
HexaneNANA
AcetoneForm IForm I
n-butanolNAForm I
MTBENAForm I
DMSOForm IForm I
EthanolForm IForm I
The ethyl acetateForm IForm I
Ethyl formateAmorphousNA
HeptaneNANA
The isobutyl acetateForm IForm I
IsopropylacetateForm IForm I
1-propanolForm IForm I
Form IForm I
WaterNANA
MEKForm IForm I
THFForm IForm I
aNA: not available. The sample is absolutely not gave or did not give sufficient solids.

TABLE 5
CRYSTALLINE FORM AFTER ADDING ANTIBACTERIAL
SolventAntibacterialSubstance, crystallizing in different shapes
THFHexaneForm I
THFMTBENAa
THFTolueneNA
THFWater
2-methoxyethanolHexaneNA
2-methoxyethanolMTBENA
2-methoxyethanolTolueneNA
2-methoxyethanolWaterNA
DMSOHexaneNA
DMSOMTBENA
DMSOTolueneNA
DMSOWaterPredominantly amorphous
DMFHexaneNA
DMFMTBEA small number (?)
DMFTolueneNA
DMFWaterForm I
aNA: not available. The sample is absolutely not gave or did not give sufficient solids.

Example 10

Particles during crystallization cycles of heating and cooling

Saturated solutions of acids of formula I in the solvents listed in table 8, were obtained from acid, mainly in the form I at about 30-50'C. The solution was slowly cooled using programmable circulating bath to obtain a thick slurry. Then, the resulting thick suspension was first heated to 50 º C for 2 hours followed by cooling to 25 OC for 2 hours. This process of heating and cooling was repeated throughout the night. The obtained particles were then collected by filtration and analyzed using XRPD. The results are summarized in table 8.

TABLE 6
CRYSTALLINE FORM on the REVERSE ADD ANTIBACTERIAL
SolventAntibacterialSubstance, crystallizing in different shapes
THF (1 ml)Hexane (4 ml)Form I
THF (0.5 m the) MTBE (8 ml)NAa
THF (0.5 ml)Toluene (8 ml)NA
THF (0.5 ml)Water (4 ml)Form I
2-methoxyethanol (0.5 ml)Hexane (8 ml)Form I
2-methoxyethanol (0.5 ml)MTBE (8 ml)NA
2-methoxyethanol (0.5 ml)Toluene (8 ml)NA
2-methoxyethanol (0.5 ml)Water (8 ml)NA
DMSO (0.5 ml)Hexane (8 ml)NA
DMSO (0.5 ml)MTBE (8 ml)A small number (?)
DMSO (0.5 ml)Toluene (8 ml)NA
DMSO (1 ml)Water (4 ml)Form I
DMF (0.5 ml) Hexane (8 ml)NA
DMF (0.5 ml)MTBE (8 ml)Form II
DMF (0.5 ml)Toluene (8 ml)NA
DMF (1 ml)Water (4 ml)Form I
aNA: not available. The sample is absolutely not gave or did not give sufficient solids.

TABLE 7
The CRYSTALLINE FORM of RAPID COOLING
SolventSubstance, crystallizing in different shapes
DMFNAa
1,4-dioxaneNA
2-methoxyethanolNA
AcetonitrileForm I
MethanolForm I
n-butanolNA
1-propanolForm I
IsopropanolNA
MEKForm I
THFNA
aNA: not available. The sample is absolutely not gave or did not give sufficient solids.

TABLE 8
CRYSTALLINE FORM FOR EVAPORATION
SolventSubstance, crystallizing in different shapes
AcetonitrileForm I
1,4-dioxaneForm I
2-methoxyethanolForm I
MIBKForm I
AcetoneForm I
n-butanolForm I
EthanolForm I
1-propanol Form I
IsopropanolForm I
Water/THF (3:7, V/V)Form I
MEKForm I
THFForm I

Example 11

Analysis of competitive binding of radioligand

The ability of binding and selectivity of amine salts of 4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid presented in the present description, were evaluated using analysis of competitive binding of radioligand with the stable-transfitsirovannykh cell lines expressing CRTH2 or DP1.

Prostaglandin D2and 13,14-dihydro-15-keto PGD2was obtained from Cayman Chemical (Ann Arbor, MI). Labeled with a radioactive label PGD2(5,6,8,9,12,14,15-3N(N)) with a specific activity of 160 CI/mmol was obtained from PerkinElmer (Boston, MA). The medium for cell culture RPMI 1640, HEPES buffer, phosphate buffer solution (PBS), L-glutamine and solution penicillin-streptomycin were obtained from Mediatech (Herndon, VA). Embryonic serum of calves (FCS) were obtained from Cambrex (Walkersville, MD). Puromycin were obtained from Invitrogen (San Diego, CA). Poly(ethylenimine) (PEI) was obtained from Acros Organics (Morris Plains, NJ). Purified monoclonal rat anti-human anti-Christ. ate to CRTH2 (BM16), Rat IgG2a, κ (clone R35-95) and goat anticrimine Ig-FITC was obtained from Becton Dickinson Biosciences (San Diego, CA). BSA (fraction V) and sodium azide were obtained from Sigma Chemical Company (St. Louis).

Stable cell lines CRTH2 and DP1 were created in accordance with the methodology described by Sugimoto et al. (J. Pharm. Exp. Therap.2003, 305, 347-352). These cell lines were kept in culture medium RPMI 1640 containing HEPES buffer (25 mm), FCS (10%), L-glutamine (2 mm), penicillin (10 IU/ml), streptomycin (100 μg/ml) and puromycin (1 μg/ml).

Surface expression of CRTH2 in transfected cell lines was monitored periodically during cultivation and before each analysis of competitive binding of radioligand. Cells expressing CRTH2, and nitrostilbene cells were incubated on ice or with purified anti-CRTH2 antibody (clone VM) or izotopnymi control antibody (Rat IgG2a,κ) for 15 minutes and Then the cells were washed in 2 ml of FACS buffer (PBS containing 1% BSA (fraction V) and 0.1% sodium azide. Cells were subsequently incubated on ice with FITC-conjugated anticrisisnye antibodies (goat anticrimine Ig-FITC). After washing with cold FACS buffer, the cells were analyzed using FACScan analyzer II and CellQuest software, both from Becton Dickinson (Mountain View, CA).

The functionality of the cells, the transfected receptors was also evaluated by direct measurement of calcium mobilization is in response to PGD 2as described (Sugimoto et al.,J.Pharm.Exp.Therap.2003, 305, 347-352; Sugimoto et al.,Eur.J.Pharmacol.2005, 524, 30-37).

Analyses linking radioligand conducted in accordance with the methods Sugimoto et al. (J.Pharm.Exp.Therap.2003, 305, 347-352;Eur.J.Pharmacol.2005, 524, 30-37). Test compounds were dissolved in DMSO at a concentration of 100 mm as the main solution. Serial dilutions of 10 μm was obtained in binding buffer before analysis. Transfetsirovannyh cells were respendable in binding buffer (50 mm Tris-HCl, 40 mm MgCl2and 0.1% bovine serum albumin at pH 7.4) at a concentration of 4×106/ml at room temperature. Then transfetsirovannyh cells were seeded in U-bottom polypropylene 96-well plates (Fisher) by adding 50 ál of the cell suspension, followed by adding 10 ál of3H-PGD210 μl of a solution of test compound in various concentrations or dilutions of control, 30 ál of binding buffer to bring the final volume to 100 ál. The final concentration of3H-PGD2in each cell was 1 nm. After incubation for 1 hour at room temperature with careful shaking, the cell suspension was transferred into a filter plates (Millipore, MA), which was pre-moistened with 0.5% buffer PEI. Precipitation cells were washed three times with binding buffer, and the plates were allowed to air dry. SP is scillator (50 μl; MicroscintTM20, Perkin Elmer, Boston, MA) was added to each cell and the radioactivity was counted on a TopCount (Packard Bioscience, Meriden, CT). Data analysis was performed using a graphics program PrizmTM(GraphPad Software Inc., San Diego, CA). As shown in figure 10 and 11, {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of formula I had a high affinity and selectivity was associated with CRTH2.

The examples mentioned above are presented in order to give ordinary specialist in the field of technology full description and explanation of how to make and use embodiments of the invention, and are not intended to limit the description. Modifications of the above embodiments of the descriptions, which are obvious to a person skilled in the art are within the following claims. All publications, patents and patent applications mentioned in this specification are incorporated into this description by reference as if each such publication, patent or patent application were specifically and separately presented for inclusion in the present description by reference.

1. {4,6-bis(Dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of the formula I

in the crystalline needle form I; where the crystalline form is characterized difractogram the th x-ray radiation on the powder, obtained using CuKα radiation source, with peaks corresponding to the angles 2θ of approximately 9,8, 13,1, and 22,0 26,4°; and a thermogram of differential scanning calorimetry with endothermy at peak temperature of about 224°C and the onset temperature of decomposition of about 220°C.

2. The crystalline form according to claim 1, characterized by x-ray diffraction pattern for the powder, essentially, as shown in figure 1.

3. The crystalline form according to claim 1, characterized by thermogram of differential scanning calorimetry, essentially, as shown in figure 2.

4. The crystalline form according to claim 1, having a solubility in water of about 3 mcg/ml at room temperature.

5. {4,6-bis(Dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid formula I:

in the crystalline form II; where the crystalline form is characterized by x-ray diffraction pattern for the powder obtained using CuKα radiation source, with a peak corresponding to the angle 2θ of approximately 31,7.

6. The crystalline form according to claim 5, characterized by x-ray diffraction pattern for the powder, essentially, as shown in Fig.6.

7. {4,6-bis(Dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid formula I:
in amorphous form; where the amorphous form is characterized by x-ray diffraction pattern for the powder obtained using CuKα radiation source, essentially, as shown in Fig.9.

8. Pharmaceutical composition with the activity of CRTH2 antagonist containing a crystalline form according to claim 1 in a therapeutically effective amount and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, where the composition is prepared for oral, nasal, bronchial or local injection.

10. The pharmaceutical composition of claim 8 or 9, where the composition is prepared in the form of dosage forms for injection single dose.

11. The use of a crystalline form according to claim 1 in getting medicines for treating, preventing or alleviating one or more symptoms of a disease mediated by CRTH2.

12. The use of a crystalline form according to claim 1 in getting medicines for treating, preventing or alleviating one or more symptoms associated with eosinophils.

13. The use of a crystalline form according to claim 1 in getting medicines for treating, preventing or alleviating one or more symptoms associated with basophils.

14. The application of claim 11, where the disease is mediated by CRTH2 is a will nosplit the aspects of the disease.

15. The use according to any one of § § 11-14, where the disease is selected from the group consisting of asthma, allergic asthma, asthma induced exercise, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity.

16. The application indicated in paragraph 15, where the disease is asthma, asthma induced by exercise, allergic rhinitis and atopic dermatitis.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which have protein kinase inhibiting properties and can be used in treating diseases which are dependent on any one or more protein kinases from FGFR1, FGFR2, FRF3 and/or FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2 and/or Ret Such diseases can be proliferative diseases, for example bladder cancer, breast cancer and multiple myeloma. In formula

the left-side ring , right-side ring , there are the following fragments, denoted "left-side ring" and "right-side ring", respectively: where X denotes C-R5, and Y and Z both denote N. The left-side ring corresponds to fragment (A):

n equals 0, 1, 2, 3, 4 or 5, X1 denotes hydrogen, where R1 denotes a group of formula Rz-NRa-, where Ra denotes hydrogen and Rz is selected from (1) a straight or branched C1-C4alkyl or (2) a group of formula , where ring A denotes phenyl, cyclohexenyl, cyclohexyl or pyridyl, m equals 0, 1 or 2, one or each of Rb is independently selected from a group -L2-NRcRd; -L2-RING, where RING denotes a 5- or 6-member saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen and oxygen, optionally substituted, as indicated below, halogen; hydroxy; amino; cyano, and a straight or branched C1-C4alkyl optionally substituted with one or more halogens and/or one or two hydroxy groups, wherein the hydroxy and amino groups are in turn optionally substituted on at least one heteroatom with one or, if necessary, more C1-C7aliphatic groups, where L2 denotes a direct bond, a link selected from a group comprising -O-, -S-, -C(O)-, -OC(O)-, -NRaC(O)-, -C(O)-NRa -OC(O)-NRa, -NRa-; or denotes a straight C1-C4alkyl which is optionally interrupted and/or ends in one terminal fragment or in two terminal fragments with the said link, and where Rc and Rd are each independently selected from a group comprising hydrogen and straight or branched C1-C4alkyl, or Rc and Rd together with a neighbouring nitrogen atom form a 5- or 6-member heterocyclic ring which optionally contains an additional heteroatom selected from nitrogen and oxygen, and optionally substituted as indicated below, said optionally substituted rings are independently substituted with 0, 1, 2, 3, 4 or 5 C1-C7aliphatic substitutes which are optionally substituted with one or more halogen atoms; R2 denotes hydrogen or C1-C4alkyl; R3 denotes hydrogen or straight or branched C1-C4alkyl or straight C1-C4alkyl substituted with a 5- or 6-member saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms in the ring, selected from nitrogen, oxygen and sulphur; R4 is selected from hydroxy, protected hydroxy group, alkoxy, alkyl, trifluoromethyl and halogen, where the alkyl or alkyl part of the alkoxy is straight or branched and contains 1, 2, 3 or 4 carbon atoms; or R5 denotes hydrogen or C1-C4alkyl; or pharmaceutically acceptable salts, hydrates, solvates, ethers, N-oxides thereof, optionally in form of trans-isomers thereof.

EFFECT: improved properties of the compound.

38 cl, 1 tbl, 231 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-substituted pyrimidines of general formula (I), their pharmaceutically acceptable additive salts probably in form of their stereochemically isomeric form. In general formula (I), A represents -CH2-CH2-, -CH=CH-; each of R1 independently represents hydrogen; R2 represents cyano; X1 represents -NR1-; R3 represents H, C1-6-alkyl, halogen; R4 represents H, C1-6-alkyl, halogen; R5 represents nitro, amino, mono- and di(C1-4-alkyl)amino, phenyl, probably substituted by halogen, halogen, -CO-H-, -COOR7, -NH-C(=O)H, -NH-C(=O)R6, -CH=N-O-R8; R6 represents C1-4-alkyl, amino, mono- or di(C1-4-alkyl)amino or polyhalogen-C1-6-alkyl; R7represents hydrogen, C1-6-alkyl; R8 represents hydrogen, C1-6-alkyl. Invention also relates to pharmaceutical composition based on novel compounds.

EFFECT: elaborated are compounds which possess antiviral activity with respect to HIV infection.

7 cl, 2 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula I, as well as to their diastereoisomers, enentiomers and/or pharmaceutically acceptable salts, which possess inhibiting action with respect to cyclin-dependent kinases and/or tyrosinekinases of VEGF receptor. In compound of general formula (I) Q stands for group where D, E, G, L, M and T in each case represent carbon, R1 represents hydrogen, halogen or CF3, R2 represents C1-C10-alkyl, which can optionally be disrupted with one group-C(O), C2-C10-alkinyl, C3-C10-cycloalkyl or phenyl, which is optionally substituted in one or more places in similar or different way by hydroxyl, halogen, C1-C6-alkoxy, C1-C6-alkyl, C3-C10-cycloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl or -COR8, X represents oxygen, sulphur or group -NH-, R3 represents hydroxy, halogen, CF3 or C1-C6-alkoxy, m represents 0-4, R4 represents hydrogen or group -COR8, NO2 or -SO2R7, or represents C1-C10-alkyl or C3-C10-cycloalkyl, R5 represents C1-C10-alkyl, which can be optionally substituted in one or more places, in similar or different way, by hydroxyl or C3-C10-cycloalkyl, or C3-C10-cycloalkyl, R7 represents C1-C10-alkyl, which is optionally substituted by group trimethylsilanyl (TMS), R8 represents C1-C6-alkyl, C1-C6-alkoxy. Invention also relates to intermediate compounds.

EFFECT: compounds can be applied for obtaining medication intended for treatment of cancer, selected from Kaposhi's sarcoma, Khodgkin's disease, leukemia or solid tumour, such as carcinoma of mammalian gland, kung, large intestine or prostate gland, autoimmune disease, such as psoriasis, and/or proliferative diseases, such as hemangioma or angiofibroma.

21 cl, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds exhibiting antiproliferative activity of formula (1) where W means N or C-R2; X means -NH-; Y means CH; Z means halogen, -NO2, C2-C3alkynyl-, halogen-C1-C3alkyl- and -C(=O)-C1-C3alkyl, A means a group of formula (i), (ii) or (iii) Q1 means phenyl; B1, B2, B3 and B4 independently mean C-RgRh, N-Ri or O; R1 means hydrogen; R2 means a residue specified from the group including hydrogen, halogen and -OR4; Ra, Rb, Rc, Rd, Re and Rf independently mean hydrogen; Rg and Rh independently mean a residue specified from the group including hydrogen, =O, -OR4 and -NR4C(=O)R5; or mean optionally a residue monosubstituted or twice-substituted with equal or different substitutes and specified from the group including C1-C6alkyl and phenyl, the substitute/substitutes is/are specified from the group including R8/, -OR4, -C(=O)R4, -C(=O)OR4 and -C(=O)NR4R5 where R8/ and other values of radicals are specified in the patent claim, optionally in the form of their pharmacologically noncontaminating acid addition salts. The invention also concerns a pharmaceutical composition.

EFFECT: new compounds have effective biological properties.

8 cl, 6 dwg, 1086 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of 2,4-di(hetero)arylaminopyrimidine of general formula I or its pharmaceutically acceptable salt, possessing properties of ZAP-70 inhibitors. In compounds of formula I: Z stands for =CR2-; each of radicals R0 and R1 represents hydrogen; R2 represents (C1-C4)alkoxy; R3 represents -SO2NH2; or R1 and R2 form together with C-atoms, to which they are bound, 5-7-member non-aromatic carbocyclic or heterocyclic residue, where said heterocyclic residue includes 1 or 2 heteroatoms, selected from N and O, and heterocyclic residue, containing 1-2 atoms of oxygen can be substituted with fluorine atoms; R4 and R6 represent hydrogen, R5 represents hudrogen, halogen, (C1-C4)alkyl or CF3; one of R7, R8 and R9 represents NR10R11, and one or two others represent hydrogen, halogen, COOH, CF3 or (C1-C4)alkyl; R10 and R11 independently represents hydrogen or (C1-C4)alkyl. Invention also relates to methods of obtaining compounds.

EFFECT: compounds can be applied, for instance in case of acute or chronic rejection of organ or tissue, in treatment of atherosclerosis and other diseases, when inhibition of ZAP-70 is of importance.

9 cl, 7 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess properties inhibiting HIV replication, of general formula (I) , in form of E-isomer, in which -a1=a2-a3=a4- represents bivalent radical of formula -CH=CH-CH=CH- (a-1); -b1=b2-b3=b4. Represents bivalent radical of formula -CH=CH-CH=CH- (b-1); n equals 0; m equals 2; each of R1 radicals independently on each other stands for hydrogen atom; C1-6alkyl; R2a stands for cyanogroup; X1 stands for -NR1-; R3 represents C2-6alkenyl, substituted with cyanogroup; R4 stands for C1-6alkyl; R5 represents radical of formula -Y-Alk-L, -Alk'-Y-L or -Alk'-Y-Alk-L; each of radicals Alk or Alk' independently represents bivalent C1-6alkyl or C2-6 alkenyl group; L stands for aryl or Het; Y stands for NR1; -CH=N-O-; Het stands for 5- or 6-member fully saturated ring system, in which one, two or three ring elements represent heteroatoms, each of which is independently selected from group, including nitrogen, oxygen and sulphur, and in which other ring elements represent carbon atoms; and, if possible, any nitrogen ring element can be optionally substituted with C1-6alkyl; and ring system can be optionally bound with benzene ring; and in which any carbon atom of ring, including any carbon atom of optionally bound benzene ring, each independently can be substituted with substituent selected from such groups as halogen atom, C1-6alkyl, hydroxyC1-4alkyl, carboxyC1-4alkyl, C1-4 alkylcarbonyloxyC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, aryloxy, morpholinyl, aryl, Het1; Het1 stands for thienyl, isoxazolyl, thiadiazolyl, each of which can be optionally substituted with one or two C1-4alkyl radicals; Q stands for hydrogen atom; each aryl represents phenyl or phenyl, substituted with one, two substituents, each of which is independently selected from such groups as halogen atom, C1-6alkyl, C2-6alkinyl, cyano, polyhalogen C1-6alkyl or Het1, as well as to its pharmaceutically acceptable additive salts Invention also relates to pharmaceutical composition.

EFFECT: creation of novel compounds, which possess properties inhibiting HIV replication

5 cl, 7 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, particularly to such binding elements specific for IgE as antibody molecules or its antigen-binding fragments.

EFFECT: antibody or its versions specific for IgE are effective for treating IgE-associated disorders, such as allergy and asthma.

17 cl, 17 dwg, 8 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely allergology, and may be used for treating atopic dermatitis. That is ensured by the introduction of a preparation of a complex of cause significant allergens is combined with using antiallergic antimediators and topic steroids. The procedures of allergovaccination are conducted once a day in dose 0.1 ml to be increased by 0.1 ml daily to 0.9 ml in the 10-6 potency of cause significant allergens to 1 ml of the undiluted complex of allergens introduced once every 2 weeks for 3 years. The allergovaccination by cause significant allergens is performed with underlying pharmacological remission (control) of atopic dermatitis by external steroids and systemic therapeutic antimediators.

EFFECT: method provides higher clinical effectiveness in atopic dermatitis ensured by improved pharmacological control of the disease during the staged allergen-specific immune therapy, as well as enables effective arrest of the manifestations of atopic dermatitis with multiple sensibilisation.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly allergology and represents a pharmaceutical preparation for human allergy prevention, inhibition or elimination differing by the fact that an active ingredient is presented by genome DNA of probiotic, gram-positive bacteria and/or Lactobacillus gasseri PA 16/8 and/or Bifidobacterium bifidum MG 20/5 and/or Bifidobacterium longum SP 07/3 bacterial strains as viable and/or inactivated bacteria.

EFFECT: invention provides effective antiallergic action.

6 cl, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amine compound of formula (I), pharmaceutically acceptable addition salts, hydrates or solvates thereof, having immunodepressive effect , where R - H or P(=O)(OH)2; X - O or S; Y denotes -CH2CH2- or -CH=CH-; Z denotes C1-5-alkylene, C2-5-alkenylene or C2-5-alkynylene; R1 denotes CF3, R2 denotes C1-4-alkyl, substituted with OH or halogen; R3 and R4 independently denotes H < or C1-4-alkyl; A denotes optionally substituted C6-10-aryl, heteroaryl containing 5-10 ring atoms, where 1 or 2 atoms are selected from N, O and S, C3-7-cycloalkyl optionally condensed with optionally substituted benzene, or heterocycloalkyl containing 5-7 ring atoms, where 1 or 2 atoms are selected from N and O, where said substitutes are selected from C1-4-alkylthio, C1-4-alkylsulphanyl, C1-4-alkylsulphonyl, C2-5-alkylcarbonyl, halogen, cyano, nitro, C3-7-cycloalkyl, C6-10-aryl, C7-14-aralkyloxy, C6-10-aryloxy, optionally substituted with oxo or halogen, C2-3-alkyleneoxy, C3-4-alkylene or C1-2-alkylenedioxy, optionally substituted with halogen C1-4-alkyl or C1-4-alkoxy.

EFFECT: novel compound which is effective in reducing the level of lymphocytes in peripheral blood, suppresses tissue breakdown and exhibiting less side effects, such as bradycardia, is disclosed.

20 cl, 237 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly the preparation fexofenadine for allergic diseases. The pharmaceutical composition contains an effective amount of fexofenadine as an active ingredient, and excipients - hydroxypropyl cellulose, a filler, desintegrant glidant, a solubiliser and stearic acid salt. The filler represents a combination of lactose and starch. As glidant, the composition contains colloidal silicon dioxide.

EFFECT: pharmaceutical composition is presented in the form of tablets and is characterised by a high degree of release of the active substance and storage stability.

7 cl, 1 tbl, 3 ex

FIELD: food industry.

SUBSTANCE: invention is related to food industry and may be used for food allergy prevention. Hydrolysed by fermentative method egg whites with hydrolysis degree from 15% to 28% are applied in production of food compositions.

EFFECT: invention ensures tolerance to egg whites contained in food products with mammals.

5 cl, 5 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: the invention relates to medicine and pharmaceutics, in particular, to creation of pharmaceutical composition in the form of suspension with anti-shock and anti-allergic action. The pharmaceutical composition with said actions contains dexamethasone sodium phosphate and “Micellate of calcium carbonate and magnesium”. The pharmaceutical compositions also contain sodium hyalurate, alcohol, Nipagin, fructose and water. A variant of the invention is a suspension which additionally contains sodium fluoride and ascorbic acid. Research was carried out and it proved that the offered pharmaceutical compositions have expressed specific pharmacological effect, they express anti-shock action, and have no toxic effect with various doses and various routes for experimental animals. The compositions have no irritant effect, sensibilizing action was not expressed.

EFFECT: the offered pharmaceutical compositions are effective and safe medication and can be used to treat state of shock, suitable for treatment of patients additionally suffering from diabetes mellitus.

2 cl, 2 ex, 1 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

Up!