Amine salts of crth2 antagonist

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining said salts, to pharmaceutical composition, containing said salts, and to application of salt for preparation of medication for treatment, prevention or relief of one or several symptoms of disease, mediated by CRTH2, associated with eosinophils, basophils, where disease is selected from asthma, allergic asthma, asthma of physical effort, allergic rhinitis, atopic dermatitis, contact hypersensitivity and hyper IgE syndrome.

EFFECT: invention relates to novel pharmaceutically acceptable salts, containing pharmaceutically acceptable amine, selected from ethylenediamine, piperazine, benzathine or choline and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidin-5yl}acetic acid.

43 cl, 21 dwg, 4 tbl, 6 ex

 

The SCOPE of the INVENTION

In the present description is provided of amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, processes for their preparation and pharmaceutical compositions. Also provided methods of their use for treating, preventing or alleviating one or more symptoms of diseases or disorders mediated by CRTH2.

BACKGROUND of the INVENTION

CRTH2 is a receptor chemoattractant associated with a G protein, which is 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), a major mediator of inflammation, formed by fat cells, is a natural ligand for CRTH2. It was recently shown that activation of CRTH2 using PGD2induces the migration and activation of Th2 cells and eosinophils, which indicates 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 increased the number of 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 Dermatology, 2002, 119, 609-616). The role of PGD2in launching and sustaining allergic in which palenia additionally has been shown in murine models of asthma, demonstrating that the increased synthesis of PGD2in vivousing PGD2-synthase exacerbates airway inflammation (Fujitani et al., J. Immunol. 2002, 168, 443-449). Therefore, the CRTH2 antagonists are potentially useful for the treatment of CRTH2-mediated diseases and disorders, such as allergic rhinitis, allergic asthma, bronchoconstriction, atopic dermatitis or systemic inflammatory diseases.

BRIEF description of the INVENTION

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

or their pharmaceutically acceptable hydrate and solvate. The compound of formula I has been identified as a CRTH2 antagonist (WO 2004/0022218).

In one embodiment, the implementation of the amine salts containing acid of the formula I and pharmaceutically acceptable amine, are crystalline.

In another embodiment, amine salts are salts of acids of formula I and pharmaceutically acceptable amine, except ethanolamine, triethylamine and Tris(hydroxymethyl)aminomethane.

In yet another embodiment, amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are diamino salt, each of which contains approximately two who olyarnik equivalent acid of formula I and about one molar equivalent of a diamine.

In yet another embodiment, diamino salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are crystalline.

In yet another embodiment, amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are monoamine salts, each of which contains approximately one molar equivalent of the acid of formula I and about one molar equivalent of monoamine.

In another embodiment, the monoamine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid are crystalline.

Also provided is a method of obtaining amine salt of 4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid or its pharmaceutically acceptable hydrate or MES.

In one of the embodiments the method includes the interaction of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with the amine in the solvent at the first predetermined temperature.

In another embodiment, the method further includes the precipitation of the amine salt at a second predetermined temperature.

In yet another embodiment, the method comprises the stage of: (a) obtaining amine salutem interaction of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with the amine in a solvent at a first predetermined temperature; and (b) the precipitation of the amine salt at a second predetermined temperature.

Moreover, provided a pharmaceutical composition comprising amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid or its pharmaceutically acceptable hydrate or MES, and one or more pharmaceutically acceptable carriers or excipients.

Additionally provided is a method of treating, preventing or alleviating one or more symptoms of a CRTH2-mediated diseases or disorders, which includes an introduction to the mammal a therapeutically effective amount of amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid or its pharmaceutically acceptable hydrate or MES.

BRIEF DESCRIPTION of DRAWINGS

In Fig. 1 depicts a fragment of the spectrum of nuclear magnetic resonance (1H NMR) of the crystalline ethylendiamine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of formula I.

In Fig. 2 depicts x-ray powder (XRP) the diffraction pattern of the crystal ethylendiamine salt of the acid of formula I.

In Fig. 3 shows differential scanning calorimetric (DSC) thermogram of the crystalline ethylendiamine salt of the acid form of the s I.

In Fig. 4 shows thermogravimetric (TG) thermogram of the crystalline ethylendiamine salt of the acid of formula I.

In Fig. 5 shows the scanning electron microscope (SEM) pictures of the crystal ethylendiamine salt of the acid of formula I.

In Fig. 6 shows1H NMR spectrum of the crystalline piperazinone salt of the acid of formula I.

In Fig. 7 depicts the XRP diffraction pattern of the crystal piperazinone salt of the acid of formula I.

In Fig. 8 shows a DSC thermogram of the crystalline piperazinone salt of the acid of formula I.

In Fig. 9 shows the TG thermogram of the crystalline piperazinone salt of the acid of formula I.

In Fig. 10 shows SEM pictures of the crystal piperazinone salt of the acid of formula I.

In Fig. 11 shows1H NMR spectrum of the crystalline sensational salt of the acid of formula I.

In Fig. 12 depicts the XRP diffraction pattern of crystalline sensational salt of the acid of formula I.

In Fig. 13 depicts a DSC thermogram of crystalline sensational salt of the acid of formula I.

In Fig. 14 shows the SEM pictures of crystal sensational salt of the acid of formula I.

In Fig. 15 shows1H NMR spectrum of the crystalline Kalinovo salt of the acid of formula I.

In Fig. 16 depicts the XRP diffraction pattern of crystalline Kalinovo salt of the acid of formula I.

On Fig depicts a DSC thermogram of crystalline Kalinovo salt of the acid of formula I.

In Fig. 18 depicts the TG thermogram of crystalline Kalinovo salt of the acid of formula I.

In Fig. 19 shows SEM pictures of crystal Kalinovo salt of the acid of formula I.

In Fig. 20 shows the curve "dose-response" of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of the formula I obtained by the analysis of the competing radioligand binding using CRTH2-transfected cells.

In Fig. 21 depicts a curve "dose-response" of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of formula I (▲), along with DP1-selective antagonist BWA 868C (■) for comparison obtained by the analysis of the competing radioligand binding using DP1-transfected cells.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure, are given in the present description, below defines many of the terms.

As a rule, used in the present description nomenclature and laboratory procedures in organic chemistry, medicinal chemistry and pharmacology, described in the present description, are procedures that are well known and are commonly used in this field. While not defined to the contrary, all technical and scientific terms used in the present description, basically, have the same value is observed in which they are commonly understood by the expert in the field, belongs to this disclosure. If this description has a number of definitions for the term, the definitions in this section have priority until then, unless established otherwise.

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

The term "subject" refers to an animal, including as non-limiting examples of a Primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat or mouse. Typically, in the present description, the terms "subject" and "patient" are used interchangeably in relation to, for example, to a mammalian subject, particularly a human subject.

The meaning of the terms "treat", "treating" and "treatment" includes alleviation or elimination of the disease or disorder or one or more symptoms associated with the disease or disorder; or the reduction or elimination of the causes (reasons) of the disease or disorder.

The terms "prevent", "preventing" refer to the way a delay or prevention of a disease outbreak and/or accompanying symptoms, and separates the subject from acquiring a disease sludge is reducing the risk for the entity to acquire the disease.

The term "therapeutically effective amount" refers to the number of connections that, when introduced is sufficient to prevent development of, or alleviate to some extent one or more symptoms of the disease, condition or disorder to be treated. The term "therapeutically effective amount" also refers to the amount of compound that will elicit the biological or medical response in a tissue, system, animal or person sought by the researcher, veterinarian, medical doctor or Clinician.

The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense that it must be compatible with other ingredients of the pharmaceutical composition. It should also be suitable for use in contact with the tissue or organ of the human animal without increased toxicity, irritation, allergic response, immunogenicity, or other problems or complications, in accordance with the mind of the output ratio of benefit/risk.

The term "naturally occurring" or "native" when used in connection with biological materials such as nucleic acid molecules, polypeptides, cells-owners and the like, refers to materials that are found in nature and are not exposed to humans. Similarly, "not found in nature" or "negativly" refer to material that has not been found in nature or that has been structurally modified or synthesized by man.

The term "CRTH2" refers to the receptor CRTH2 protein or its variant, which is able to mediate cellular response to PGD2in vitroorin vivo. Options CRTH2 include proteins substantially homologous to native CRTH2, i.e. proteins having one or more naturally or not naturally occurring amino acid deletions, insertions or substitutions (e.g., derivatives, homologues and fragments of CRTH2) compared to the amino acid sequence of native CRTH2. Amino acid sequence variants of CRTH2, 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 the receptor protein of prostanoids, other than CRTH2 or its variant, which is capable of incidental is the substance of the cellular response to PGD 2in vivoorin vitro. "Another receptor PGD2" may be selective for PGD2for example DP, or to one another or more other prostanoids. Variants of the "other receptor PGD2" include proteins substantially homologous to the corresponding native receptor of prostanoids, other than CRTH2, i.e. proteins that have one or more natural or not naturally occurring amino acid deletions, insertions or substitutions (e.g., derivatives, homologues and fragments of the native receptor prostanoids, other than CRTH2). Amino acid sequence variants of the native "other receptor PGD2"at least about 80% identical, at least about 90% identical or at least about 95% identical to the corresponding native "another PGD2receptor".

The term "CRTH2 antagonist" refers to a connection that, for example, partially or fully blocks, reduces, prevents, inhibits or reduces the activity of CRTH2 and/or activity of one or more of the other receptors PGD2. The term "antagonist of CRTH2" also refers to a compound that binds, deferreth activation, inactivates or reduces the sensitivity of 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 terms "CRTH2-mediated disorder or disease" and "condition, disorder or disease mediated through CRTH2" refers to the condition, disorder or disease characterized inappropriate, for example, above or below normal, the 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 some intracellular activation, leading, for example, inflammatory and associated with immune disorders or diseases; or decreased expression of CRTH2. CRTH2-mediated condition, disorder or disease may be completely or partially mediated by inappropriate activity of CRTH2. In particular, CRTH2-mediated condition, disorder, or disease is a condition, disorder or disease in which modulation of CRTH2 or one or more other PGD2 receptors results in some effect on the initial condition or disorder, for example, the CRTH2 antagonist or agonist lead to some improvement in at least some of the treated patients is now.

Amine salts

In the present description is provided of amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid and its solvate; and the way they are received. Also provided pharmaceutical compositions of these amine salts or their solvate and methods of their use for treating, preventing or alleviating one or more symptoms of a CRTH2-mediated disorder or disease.

In accordance with one of the embodiments presented pharmaceutically acceptable amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, which contains an acid of formula I and pharmaceutically acceptable amine. In another embodiment, provided MES pharmaceutically acceptable crystalline amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, which contains an acid of formula I, pharmaceutically acceptable amine and the solvent.

In certain embodiments of the implementation of the molar ratio of the acid of formula I to the amine in the amine salt or the MES is about 0.5 to about 10, from about 0.5 to about 5, from about 0.5 to approximately 3, about 0.5 to about 2, or about 0.8 p is blithedale to 1.2 or approximately 1.

In certain embodiments of the implementation of the molar ratio of the acid of formula I to the solvent in the MES amine salt provided in the present description, is approximately from 0.1 to about 2, from about 0.2 to about 1, or from about 0.3 to about 0.5, or about 0.1, about 0.2, about 0.3, and about 0.4, about 0.5, about 0.6 to, approximately 0.7, about 0.8, about 0.9 to approximately 1.

Suitable amines for use in the amine salt or solvate provided in the present description, include as non-limiting examples of primary amines, including methylamine, ethylamine, ethanolamine, Tris(hydroxymethyl)aminomethan and Ethylenediamine; secondary amines, including dimethylamine, diethylamine, Diisopropylamine, dibutylamine, di-sec-butylamine, dicyclohexylamine, diethanolamine, meglumine, pyrrolidine, piperidine, piperazine and benzathine; tertiary amines including trimethylamine, triethylamine, triethanolamine and 1-(2-hydroxyethyl)pyrrolidin; Quaternary ammonium compounds, including choline, Tetramethylammonium, tetraethylammonium. An overview about the additional amines have had, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, 2002.

In one embodiment, the implementation of the pharmaceutically acceptable amine is the Wallpaper diamine. Pharmaceutically acceptable diamine contains the first and the second amino group, each of which independently represents a primary, secondary or tertiary amino group or Quaternary ammonium group. Suitable diamines for use in Daminova salts include as non-limiting examples are Ethylenediamine, piperazine and benzathine. Diamino salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid contains from approximately 1 to approximately 3, from about 1.5 to about 2.5, from about 1.75 of approximately 2.25 or approximately 2 molar equivalents of the acid of formula I for one molar equivalent of a diamine.

In one group djaminovich salts this option, the first amino group of the diamine is a primary amino group and a second amino group independently represents a primary, secondary or tertiary amino group or Quaternary ammonium. In the other group djaminovich salts first amino group independently represents a secondary amino group and a second amino group is a primary, secondary or tertiary amino group or Quaternary ammonium. In another other group djaminovich salts first amino group independently represents a tertiary amino group and a second amino group before the hat is primary, secondary or tertiary amino group or Quaternary ammonium. In another other group djaminovich salts first amino group is a Quaternary ammonium and a second amino group independently represents a primary, secondary or tertiary amino group or Quaternary ammonium.

In one embodiment, pharmaceutically acceptable amine is a diamine with two primary amino groups. Primary diamino acid salt of formula I contains approximately 1 to approximately 3, from about 1.5 to about 2.5, from about 1.75 of approximately 2.25 or approximately 2 molar equivalents of the acid of formula I for one molar equivalent of a primary diamine.

In yet another embodiment, the primary diamine is an Ethylenediamine. Ethylendiamine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid contains approximately two molar equivalents of the acid of formula I and about one molar equivalent of ethylene diamine, as determined on the basis of its1H NMR spectrum (Fig. 1).

In yet another embodiment, ethylendiamine salt of the acid of formula I is crystalline. Crystal ethylendiamine salt is characterized by a spectrum XRP diffraction, a significant step is no matching is shown in Fig. 2. In particular, crystalline ethylendiamine salt has characteristic XRP diffraction peak in the region of approximately 5.9° two-theta angle. In addition, crystalline ethylendiamine salt has the DSC thermogram substantially coincident with shown in Fig. 3. Crystal ethylendiamine salt has endothermal at peak temperature of about 123°C and the onset temperature of decomposition of 114°C or at a peak temperature of approximately 216°C and the onset temperature of decomposition of about 212°C. Alternatively, the crystalline ethylendiamine salt has endothermal at peak temperature of about 123°C and the onset temperature of decomposition of 114°C and a peak temperature of approximately 216°C and the onset temperature of decomposition of about 212°C.

In yet another embodiment, the present description is provided crystalline ethylendiamine salt of the acid of formula I. the MES is characterized by a spectrum XRP diffraction, largely similar to the one shown in Fig. 2. In particular, the MES has characteristic XRP diffraction peak in the region of approximately 5.9° two-theta angle. In addition, the MES has the DSC thermogram substantially similar to that shown in Fig. 3. MES has endothermal at peak temperature of about 123°C and temperature is the beginning of the round decomposition 114°C or at a peak temperature of approximately 216°C and the onset temperature of decomposition of about 212°C. Alternatively, the MES has endothermal at peak temperature of about 123°C and the onset temperature of decomposition of 114°C and a peak temperature of approximately 216°C and the onset temperature of decomposition of about 212°C.

In one embodiment, the implementation of MES shows a weight loss of approximately 1% to approximately 10%, including as non-limiting examples about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% and about 10% between 125°C and 150°C. In another embodiment, the MES shows the mass loss of 2%, about 3%, about 4% or about 5% between 125°C and 150°C.

In one embodiment, the implementation of the MES contains from about 0.1 to about 2, from about 0.2 to about 1, or from about 0.3 to about 0.5; or about 0.1, about 0.2, about 0.3, and about 0.4, about 0.5, about 0.6 to, approximately 0.7, about 0.8, about 0.9 to approximately 1 molar equivalent of solvent for each molar equivalent of the amine salt. In another embodiment, the MES contains from about 0.3 to about 0.5 molar equivalent of a solvent for each of the first molar equivalent of the amine salt. In yet another embodiment, the MES contains approximately 0.3 molar equivalent of solvent for each molar equivalent of the amine salt. In yet another embodiment, the MES contains about 0.4 molar equivalent of solvent for each molar equivalent of the amine salt. In another embodiment, the MES contains about 0.5 molar equivalent of solvent for each molar equivalent of the amine salt.

In one embodiment, the implementation of the solvent in the MES is alcohol, including as non-limiting examples are 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. In another embodiment, the solvent is an ethanol.

In one embodiment, pharmaceutically acceptable amine is a diamine with two secondary amino groups. Secondary diamino acid salt of formula I contains approximately 1 to approximately 3, from about 1.5 to about 2.5, from about 1.75 of approximately 2.25 or approximately 2 molar equivalents of the acid of formula I for one molar equivalent of a secondary diamine.

In yet another embodiment, the secondary diamine is from the Oh piperazine. Pieperazinove salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid contains approximately two molar equivalents of the acid of formula I and about one molar equivalent of piperazine, as determined on the basis of its1H NMR spectrum (Fig. 6).

In yet another embodiment, pieperazinove salt is crystalline. Crystal pieperazinove salt is characterized by a spectrum XRP diffraction, substantially similar to that shown in Fig. 7. In one of the embodiments pieperazinove salt has characteristic XRP diffraction peaks in the area of approximately 10,7, 15,9, 22,3 and 24.0° two-theta angle. In another embodiment, pieperazinove salt has characteristic XRP diffraction peak at approximately 10,7, 15,9, 22,3 or 24.0° two-theta angle. In yet another embodiment, crystalline pieperazinove salt has the DSC thermogram substantially similar to that shown in Fig. 8. In another embodiment, the crystalline pieperazinove salt has endothermal at peak temperature of about 203°C and the onset temperature of decomposition of about 197°C or at a peak temperature of about 223°C and the onset temperature of decomposition of about 219°C. In an alternative embodiment to istoricheskaya pieperazinove salt has endothermal at peak temperature of about 203°C and the onset temperature of decomposition of about 197°C and a peak temperature of about 223°C and the onset temperature of decomposition about 219°C.

In yet another embodiment, the secondary diamine is a benzathine. Pensativa salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid contains approximately two molar equivalents of the acid of formula (I) and about one molar equivalent of benzathine, as determined on the basis of its1H NMR spectrum (Fig. 11).

In yet another embodiment, pensativa salt is crystalline and characterized by a range XRP diffraction, substantially similar to that shown in Fig. 12. In one of the embodiments pensativa salt has characteristic XRP diffraction peaks in the area of approximately 8,0, 11,5, 16,0, 17,5 and 23.4° two-theta angle. In another embodiment, pensativa salt has characteristic XRP diffraction peak at approximately 8,0, 11,5, 16,0, 17,5 or 23.4° two-theta angle. In yet another embodiment, crystalline pensativa salt has the DSC thermogram substantially similar to that shown in Fig. 13. In an alternative embodiment, the crystalline pensativa salt has endothermal at peak temperature of approximately 156°C and the onset temperature of decomposition of approximately 154°C.

In yet another embodiment, the amine is particularly monoamin. Monoamine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid contains from about 0.5 to about 1.5, from about 0.75 to approximately 1.25 or about 1 molar equivalent(s) of the acid of formula I to the molar equivalent of monoamine.

In one group monoamine salts of this variant implementation of monoamine monoamine salts contains a primary amino group. In the other group monoamine salts monoamin contains a secondary amino group. In another other group monoamine salts monoamin contains a tertiary amino group. In another other group monoamine salts monoamin contains a Quaternary ammonium group.

In an alternative embodiment, the amine is a choline. Kalinova salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid contains approximately one molar equivalent of the acid of formula I and about one molar equivalent of choline, as determined on the basis of its1H NMR spectrum (Fig. 15).

In another embodiment, Kalinova salt of the acid of formula I is crystalline and characterized by a range XRP diffraction, substantially similar to that shown in Fig. 16. In one of the embodiments Kalinova salt has characteristice the Kimi XRP diffraction peaks in the area of approximately 6.5, 19,6, 20,0, 21,9 and 26.4° two-theta angle. In another embodiment, Kalinova salt has characteristic XRP diffraction peak in the region of approximately 6.5, 19,6, 20,0, 21,9 or 26,4° two-theta angle. In another embodiment, the crystalline Kalinova salt has the DSC thermogram substantially similar to that shown in Fig. 17. In an alternative embodiment, the crystalline Kalinova salt has endothermal at peak temperature of approximately 195°C and the onset temperature of decomposition of approximately 193°C.

It should be understood that the numerical values of the peaks of x-ray powder diffraction spectra will vary slightly from one device to another or from one sample to another, and thus these values should not be regarded as absolute, but with an allowable variation, such as 0.1°, which is recommended in the United State Pharmacopeia, 2007, 387-389.

The way to obtain

Also provided is a method of obtaining amine salt of the acid of formula (I). In one of the embodiments the method includes the interaction of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with the amine in the solvent at the first predetermined temperature. In another embodiment, the method further includes the precipitation of the amine salt in the second paragraph is adapelene temperature.

In an alternative embodiment, the process includes the stages of: (a) obtaining the amine salt by interaction of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with the amine in a solvent at a first predetermined temperature; and (b) the precipitation of the amine salt at a second predetermined temperature.

Suitable solvents for use in obtaining the amine salts of the acids of formula I include as non-limiting examples of hydrocarbons, including petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin and cumene; chlorinated hydrocarbons, including dichloromethane (DCM), 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, methyltert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane and anisole; ketones, including acetone, butanone, methyl ethyl ketone (MEK), methylisobutylketone, methylethylketone and METI isobutylketone (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 as sulfolan; 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; carbosulfan; water; and mixtures thereof.

In certain embodiments of the implementation of the reaction of formation of amine salts (i.e. stage a) is carried out at a temperature of approximately -10 to approximately 150°C, from about 10 to approximately 110°C, or from about 20 to about 100°C. In one embodiment, the implementation of the solvent is acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, dimethylsulfoxide, lower alkanol (for example, methanol, ethanol,n-propanol, isopropanol, sec-butanol or 2-methoxyethanol), methyl acetate, ethyl acetate, ethyl formate, isopropylacetate, isobutyl acetate, chloroform, dichloromethane, methyl tert-is Hotelowy ether, tetrahydrofuran, 1,4-dioxane, petroleum ether, hexane, heptane, toluene, water or a mixture. In another embodiment, the solvent is low alkanol from 1 to 5 carbon atoms, such as methanol, ethanol, propanol, isopropanol, sec-butanol, 2-methoxyethanol or their mixture.

In certain embodiments of the implementation of the reaction of formation of amine salts were carried out in the presence of excess amine, to maximize the yield of the reaction. The molar ratio of the amino group in Amina to the acid of formula I is approximately not less than 1,01, approximately not less than 1,05, approximately not less than 1.1, approximately not less than 1.2, approximately from 1.05 to about 10, from about 1.1 to about 5, or from about 1.2 to about 2.5.

In certain embodiments of the implementation of the reaction of formation of salts was carried out in solution, that is, as the acid of formula I and the amine was dissolved in the solvent. In certain embodiments of the implementation of the reaction of formation of salts was carried out in the form of a suspension of a mixture of acids of formula I and an amine in a solvent. In this case, the acid of formula I dissolved completely, whereas the amine is dissolved completely.

In a specific embodiment, the amine salt formed at the stage of formation of the amine, may be precipitated from p is a promotional solution or suspension of the mixture using conventional methods, including as non-limiting examples of cooling, freezing, evaporating the solvent, adding antibacterial or, on the contrary, adding to antibacterial. Stage deposition can be performed at a temperature of from about -50 to about 100°C, from about -30 to about 50°C or from about -10 to about 30°C. To accelerate the stage precipitation (crystallization) process may further comprise the stage of the persecution of the reaction solution or mixture. The process may also include the extraction, in which the precipitate can be isolated by conventional means, such as filtration and centrifugation, followed by washing with a solvent and then drying.

In one embodiment, the implementation of the amine salt is obtained by (a) interaction of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with the amine in the lower alkanol, such as ethanol, at elevated temperature, to obtain a clear reaction solution. When the amine is a diamine, the molar ratio of diamine molecules to the acid of formula I in the reaction solution is approximately not less than worn : 0.505, approximately not less than 0,525, approximately not less than 0.55, which is approximately not less than 0,60; but about the part not more than 10 or about 100. When Amin is monoamin, the molar ratio of the molecules monoamine to the acid of formula I in the reaction solution is approximately not less than 1,01, approximately not less than 1,05, approximately not less than 1.1; but approximately not more than 10 or about 100.

Amine salt can be precipitated by cooling the reaction solution to or below room temperature or by evaporation of the solvent. The precipitate amine salts can also be obtained by adding antibacterial to the reaction solution or by adding the reaction solution to antibacterial.

Suitable antibacterial include as non-limiting examples of hydrocarbons, including petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin and cumene; chlorinated hydrocarbons, including dichloromethane, 1,2-dichloroethane, 1,1-dichlorethene, 1,2-dichloride, chloroform, trichloroethane, trichlorethane, carbon tetrachloride, chlorobenzene and cryptomaterial; alcohols including isopropanol, 1-propanol, 1-butanol, 2-butanol,tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-ethoxyethanol and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyltert-butyl ether, diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimatix is methane, 2.2-dimethoxypropane and anisole; ketones, including butanone, methylisobutylketone, methylethylketone and methyl isobutyl ketone; 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; carbosulfan; water and mixtures thereof.

When the pair of the solvent/antibacterial use two of the solvent, the amine salt of the acid of formula I has a higher solubility in the solvent than in antibacterial. Optionally, the solvent and antibacterial a couple of solvent/antibacterial at least partially mixed.

In another embodiment, amine salt were obtained using (a) reaction of a suspension of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with the amine in a solvent such as ethanol, at room temperature or at elevated temperature. After the reaction of amine salt can be isolated in the form of solids by cooling, solvent evaporation or add antibacterial to the suspension of the reaction mixture.

In order to accelerate phase precipitation (crystallization), the process may further comprise a stage persecution of reactio the aqueous solution or mixture, before or during the early stage of precipitation. The number of added seed crystals exceeds saturating amount of the used solvent to the reaction solution was present undissolved seed crystals.

Other methods of obtaining salt can also be used in the present invention. For example, the amine salt of the acid of formula I can be produced by conversion of the salt of the acid, such as sodium salt or potassium salt, amine salt by casinoonline using cation-exchange column. Amine salt of the acid of formula I can also be obtained by physical grinding solid {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid and amine together in the absence of solvent.

In addition, precipitation and crystallization, solid amine salts provided in the present description, can also be manufactured using conventional methods known to experts in this field, including spray drying, roller drying, lyophilization and crystallization from the melt.

The pharmaceutical composition

Also provided is a pharmaceutical composition, which contains amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}vinegar is Oh acid or its pharmaceutically acceptable hydrate or MES as the active pharmaceutical ingredient in combination with one or more pharmaceutically acceptable carriers or excipients. The choice of excipient largely depends on factors such as the particular mode of administration, the effect of excipient on the solubility and stability of the active ingredient and the nature of the dosage form.

Pharmaceutical compositions provided in the present description, may be provided in the form of dosage forms for single or multiple administration. Dosage forms for a single dose, as used in the present description, refers to physically separate units, suitable for introduction human and animal subject and packaged individually as is known in this field. Each single dose contains a predetermined quantity of active ingredient(s)sufficient to produce the desired therapeutic effect, together with appropriate pharmaceutical carriers or excipients. Examples of dosage forms for a single admission include ampoules, syringes and individually Packed tablets and capsules. Dosage forms for a single admission can be entered separately or in a multiple number. Dosage form for multiple reception is a set of identical dosage forms with a single dosage, Packed in one container, subject to the introduction of a separate dosage form with a single dozirovka is. Examples of dosage forms for repeated administration include vials, bottles of tablets or capsules or bottles in pints or gallons.

Provided in the present description amine salts of the acids of formula I can be introduced separately or in combination with one or more other compounds provided in the present description, one or more other active ingredients. Pharmaceutical compositions that contain amine salt is provided in the present description, may be included in various dosage forms for oral, parenteral or local administration. Pharmaceutical compositions can also be included in the dosage forms with modified release, including dosage forms with delayed, prolonged, sustained, pulsed, controlled, accelerated and rapid, directed, programmed release and retention in the stomach. These dosage forms can be manufactured in accordance with conventional methods and techniques known to experts in this field (see, Remington: 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).

Provided in the present description, the pharmaceutical composition can be administered once or many times cerebroside time. It is clear that the precise dosage and duration of therapy may vary depending on the age, weight and condition of the patient to be treated and can be determined experimentally using known testing protocols or by extrapolating test or diagnostic datain vivoorin vitro. It is also clear that for each individual a special regimen of the drug should be adjusted over time according to individual needs and professional person, misleading or overseeing the introduction of structures.

A. Oral administration

Provided in the present description, the pharmaceutical compositions can be provided in solid, semi-solid or liquid dosage form for oral administration. As used in the present description, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include as non-limiting examples of tablets, capsules, pills, tablets, lozenges, pellets, starch capsules, pellets, chewing gum, containing the drug, granules, no powders, effervescent or nishiuchi powders or granules, solutions, emulsions, suspensions, dissolve the s, plates, sprays, elixirs and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including as non-limiting examples of binders, fillers, diluents, disintegrant, moisturizing agents, sliding agents, substance promoting sliding, dyes, inhibitors mobility colors, sweeteners and flavorings.

Binders or granulators attach the integrity of the tablet to ensure that the tablet will remain unchanged after crushing. Suitable binders or granulators include as non-limiting examples of starches, such as corn starch, potato starch, and pregelatinized starch (such as STARCH 1500); gelatin, sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic resins, such as the Arabian gum, alginic acid, alginates, extracts of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), wigum, erbogachan larch powder tragakant and guar gum; cellulose, such as ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methylcellulose, hydroxyethylcellulose (SCE), hydroxypropylcellulose (GOC), 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 as non-limiting examples of talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrine, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in amounts of from approximately 50 to approximately 99% by weight in the pharmaceutical compositions provided in the present description.

Suitable lubricants include as non-limiting examples, 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 they are present in sufficient quantities, can give some compressed tablets properties that allow for the disintegration in the mouth when chewed. Such compressed tablets can be used as chewable tablets.

Suitable disintegrant include as non-limiting examples agar; b is tonic; cellulose, such as methylcellulose and carboxymethylcellulose; forest 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 sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch and pregelatinized starch; clays; aligns and mixtures thereof. The number of disintegrant in the pharmaceutical compositions provided in the present description, varies depending on the type of structure and can easily be determined by experts in the field. Pharmaceutical compositions provided in the present description can include disintegrant in the amount of about 0.5 to about 15% or from about 1 to about 5% by weight.

Suitable lubricants include as non-limiting examples of calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerinated and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogensource vegetable oil, including peanut oil, cottonseed Mac is on, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; etiloleat; ailleret; agar; starch; Likopodija; silicon dioxide or gels of silica, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. Pharmaceutical compositions provided in the present description may contain the lubricant in the amount of approximately 0.1 to approximately 5% by mass.

Suitable substance promoting sliding, includes colloidal silica, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Dyes include any of the approved certified water soluble dyes for food and chemical industries and water-insoluble dyes for food and chemical industries, suspended in the hydrate of aluminum and colored varnishes and their mixtures. Colored nail Polish is a combination obtained by the adsorption of water-soluble dye in water heavy metal oxide, which leads to the formation of insoluble forms of the dye. Flavors include natural flavouring substances extracted from plants, such as fruits, and synthetic blends of compounds which give a pleasant sensation of taste, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin and the artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying substances include gelatin, Arabic gum, tragakant, bentonite, and surfactants, such as polyoxyethylenesorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80) and the triethanolamine oleate. Suspendresume and dispersing substances include carboxymethylcellulose sodium, pectin, tragakant, Wigan, Arabian gum, carbometalation sodium, hypromellose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Moisturizing agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauric ether. 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.

It should be understood that many carriers and excipients can perform several functions, even in the same composition.

Provided in the present description, the pharmaceutical composition can be provided as compressed tablets, tablet powders, javate the performance communications lozenges, bystrorastvorimaya tablets, repeatedly pressed tablets or tablets with intersolubility coated sugar or film tablet. Tablets with intersolubility coating are compressed tablets coated with substances that resist the action of gastric acid, but is dissolved or broken down in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Intersolubility coatings include as non-limiting examples of fatty acids, fats, fenilsalitsilat, waxes, shellac, ammonium shellac and phthalates acetylcellulose. Covered sugar tablets are compressed tablets, surrounded by the sugar-coated, which can be useful for masking unpleasant tastes and odors, and when the protection of tablets from oxidation. Film-coated tablets are compressed tablets coated with a thin layer or film of water-soluble material. Film coating include as non-limiting examples of hydroxyethyl cellulose, carboxymethyl cellulose sodium, polyethylene glycol 4000 and phthalate of acetylcellulose. Film coating provides the same basic properties as sugar shell. Repeatedly compressed tablets are compressed tablets made the village what edstam more than one cycle of crushing, including multi-layer tablets and coated by extrusion or covered during drying of the tablets.

Tablet dosage forms can be made from the active ingredient in powdered, crystalline or granular forms, individually or in combination with one or more carriers or excipients described in the present description, including binders, disintegrant, polymers, controlled release, lubricants, diluents and/or dyes. Flavors and sweeteners are especially useful when creating chewable tablets and tablets for sucking.

Provided in the present description, the pharmaceutical compositions can be provided in the form of soft or hard capsules made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsule, also known as the capsule with the dry filler (DFC), consists of two parts, one is put on the other, thus completely protecting the active ingredient. Soft elastic capsule (SEC) is a soft, globular shell, for example, gelatin shell which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. Soft gelatin shell may contain a preservative to prevent the growth of microorganisms. PR is suitable preservatives are preservatives, described in the present description, including methyl - and propylparaben and sorbic acid. Provided in the present description liquid, semi-solid and solid dosage forms 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 made as described in U.S. patent No. 4328245; 4409239 and 4410545. Capsules can also be coated by methods known to experts in this field in order to modify or maintain the dissolution of the active ingredient.

Provided in the present description, the pharmaceutical compositions can be provided in liquid or 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 balls throughout the other liquid and which can be an oil-in-water and water-in-oil. The emulsion may contain a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent and a preservative. Suspensions can contain pharmaceutically acceptable suspendisse agent and a preservative. Aqueous alcoholic solutions can content the th pharmaceutically acceptable acetal, such as di(lower alkyl)acetal aldehyde lower alkyl (the term "lower" denotes alkyl which has 1 to 6 carbon atoms), such as acetaldehyde diethyl acetal; and miscible with water, the solvent having one or more hydroxyl groups such as propylene glycol and ethanol. Elixirs are clear, sweetened, and water-alcohol 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 acceptable liquid carrier such as water, for easy measurement in the introduction.

Other suitable liquid and semi-solid dosage forms include as non-limiting examples of dosage forms containing the active ingredient(s)provided in the present description, and dialkylamines mono - or polyalkyleneglycol, including, 1,2-dimethoxymethane, simple, dimethyl ether of diethylene glycol, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550 and 750 indicate the approximate average molecular weight of the polyethylene glycol. These compounds can dopolnitelnost one or more antioxidants, such as bottled hydroxytoluene (OSH), bottled hydroxyanisol (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, metabisulfite sodium, thiodipropionic acid and their esters and dithiocarbamate.

Provided in the present description pharmaceutical compositions for oral administration can also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be manufactured as described in U.S. patent No. 6350458.

Provided in the present description, the pharmaceutical compositions can be provided in the form nishiuchi or effervescent granules and powders, recoverable in liquid dosage form. Pharmaceutically acceptable carriers and excipients used in nishiuchi granules or powders, may contain diluents, sweeteners and moisturizing agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders, may contain organic acids and a source of carbon dioxide.

The tinting and flavors can be used in all of the above dosage forms.

Provided in the present description, the pharmaceutical company which positions can be included in the dosage forms for immediate or modified release, including deferred, delayed, pulsed, controlled, targeted and programmed release.

Provided in the present description, the pharmaceutical compositions can be included in conjunction with other active ingredients which do not bring the desired therapeutic action, or with substances that add the desired action, such as antacids, proton pump inhibitors and antagonists of H2-receptor.

B. Injecting

Provided in the present description, the pharmaceutical compositions may be introduced parenterally by injection, infusion or implantation for local or systemic administration. Parenteral as used in this description, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, be, epigastric, intracranial, intramuscular, intra-articular and subcutaneous administration.

Provided in the present description, the pharmaceutical compositions can be included in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for the preparation of solutions or suspensions in liquid prior to injection. Such Lek is stennie forms can be produced in accordance with traditional methods, well-known specialists in the field of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may contain one or more pharmaceutically acceptable carriers and excipients, including as non-limiting examples of aqueous media, water-soluble carriers, non-aqueous media, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, substances that increase solubility, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing hydrating agents or emulsifying agents, complexing agents, stabilizing or chelating agents, cryoprotectants, bioprotector, thickeners, pH regulators and inert gases.

Suitable aqueous media include as non-limiting examples of water, salt solution, saline or phosphate-saline buffer (PBS), sodium chloride injection, ringer's solution for injection, isotonic dextrose injection, sterile water for injection, dextrose and ringer-Lactate for injection. Non-aqueous carriers include as non-limiting examples of non-volatile vegetable oils, castor oil, cook the Uzen 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 seed. Water-soluble carriers include as non-limiting examples of 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 antimicrobial agents or preservatives include as non-limiting examples of phenols, Cresols, drugs, mercury-containing, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoate, thimerosal, benzalkonium chloride, benzethonium chloride, methyl - and propylparaben and sorbic acid. Suitable isotonic substances include as non-limiting examples, the sodium chloride, glycerin and dextrose. Suitable buffering agents include as non-limiting examples of phosphate and citrate. Suitable antioxidants are antioxidants described in the present description, including bisulfite and sodium metabisulfite. Suitable local anesthetics include as non-limiting examples of procaine hydrochloride. Fit suspendiruemye and dispersing substances are suspendresume and dispersing substances, described in the present description, including carboxymethylcellulose sodium, hypromellose and polyvinylpyrrolidone. Suitable emulsifying substances include emulsifying agents, described in the present description, including polyoxyethylenesorbitan monolaurate, polyoxyethylenesorbitan monooleate 80 and the triethanolamine oleate. Suitable stabilizing or chelating substances include as non-limiting examples of EDTA. Suitable pH regulators include as non-limiting examples, the sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complex-forming substances include as non-limiting examples of cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulphobutylether-beta-cyclodextrin, and sulphobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

Provided in the present description, the pharmaceutical compositions can be included in the dosage form for single or multiple administration. Dosage forms for receiving a single Packed in ampoules, tubes or syringes. Dosage forms for multiple admission for parenteral administration should contain an antimicrobial agent in bacteriostatic or fungistatic concentrations. All of parenteral the e formulations must be sterile, what is known and practiced in the field.

In one of the embodiments of the pharmaceutical compositions provided in the form of ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions provided in the form of a sterile dry soluble products, including freeze-dried powders and hypodermic tablets that can be recovered in the medium before use. In yet another embodiment, the pharmaceutical compositions provided in the form of ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions provided in the form of a sterile dry insoluble products that are subject to recovery in the medium before use. In another embodiment, the pharmaceutical compositions provided in the form of ready-to-use sterile emulsions.

Provided in the present description, the pharmaceutical compositions can be included in the dosage forms for immediate or modified release, delayed, sustained, pulsed, controlled, targeted and programmed release.

The pharmaceutical compositions can be included in the suspensions, solid, semi-solid forms, or thixotropic liquid for introduction into the VI is e implanted depot. In one of the embodiments provided in the present description pharmaceutical composition dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids, but allows the active ingredient in pharmaceutical compositions to diffuse outward.

Suitable internal matrix include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, 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, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ion meter, polite interefted, butyl rubber, epichlorohydrine rubber, copolymer of ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl alcohol and ethylene/vinyloxyethoxy copolymer.

C. Local introduction

Provided in the present description, the pharmaceutical compositions can be entered locally on the skin, in the hole or on the mucous. Local injection, as used in this description, includes (via)skin, conjunctival, vnutrirodovoe, intraocular, ocular, ear, percutaneous, nasal, vaginal, urethral, respiratory and rectal administration.

Provided in the present description, the pharmaceutical compositions can be included in any dosage forms that are suitable for local injection to achieve local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, sprays, rinses, sprays, suppositories, bandages, dermal patches. Local dosage form of the pharmaceutical compositions provided in the present description, may also contain liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Provided in the present description pharmaceutically acceptable carriers and excipients suitable for use in karstenii forms for local administration, include as non-limiting examples of aqueous media, water-soluble carriers, non-aqueous media, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, substances that increase solubility, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing hydrating agents or emulsifying agents, complexing agents, stabilizing or chelating substances, substances that promote penetration, cryoprotectants, bioprotector, thickeners and inert gases.

Pharmaceutical compositions can also be entered locally via electroporation, iontophoresis, phonophoresis, sonophoresis and microholes or needleless injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).

Provided in the present description, the pharmaceutical compositions can be provided in the form of ointments, creams and gels. Suitable carriers for ointments include oily or hydrocarbon bases, including lard, benzoinated lard, olive oil, cottonseed oil, medical vaseline and Plastibase; mulgirigala or absorbent bases such as hydrophilic petrolatum, hydroxystearic sulfate, and anhydrous lanolin; water washable bases such as hydrophilic ointment; vocarstvo what are the bases for ointments, including glycols with different molecular weight; emulsion bases, or emulsions of 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, supra). These carriers are softening, but usually require the addition of antioxidants and preservatives.

A suitable basis for the cream may be a suspension of water-in-oil or oil-in-water. Creamy media can be washed off with water and contain an oil phase, an emulsifier and the aqueous phase. The oil phase is also called the "inner" phase, which typically contains petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, though not necessarily, predominates over the oil phase in volume and, as a rule, contains a humidifier. The emulsifier in a cream dosage form may be a nonionic, anionic, cationic or amphoteric surface-active substance.

Gels are semisolid systems similar to the suspension. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable geleobrazovanie include crosslinked polymers of acrylic acid, such as carbomer, carboxypolymethylene, Carbopol®; hydrophilinae polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose and methylcellulose; gums, such as tragakant and xanthan gum; sodium alginate; and gelatin. In order to produce a homogeneous gel can be added dispersing agents such as alcohol or glycerin, or the gel can be dispersed by using a homogenizer, mechanical stirring and/or shaking.

Provided in the present description, the pharmaceutical composition can be introduced rectal, urethral, vaginal or okoloolgiline in the form of suppositories, pessaries, sticks, compresses or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes, as described in Remington: The Science and Practice of Pharmacy, above.

Rectal, urethral and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperature but which melt or soften at body temperature to release the active is the first ingredient(s) inside the holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include media, such as thickeners, which makes the melting temperature is close to body temperature, when included in the pharmaceutical compositions provided in the present description; and antioxidants, as described in the present description, including bisulfite and sodium metabisulfite. Suitable carriers include as non-limiting examples coconut oil (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, hydroxyethyl methacrylate, polyacrylic acid; glitserinovoye gelatin. You can use a combination of various media. Rectal and vaginal suppositories can be manufactured by a pressing process or molding. Normal weight rectal and vaginal suppository is approximately 2 to 3 g

Provided in the present description, the pharmaceutical composition can be introduced ophthalmicus in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for dilution, gels, eye inlays and implants.

Provided in the present description pharmaceutical HDMI is tion can be introduced into the respiratory tract intranasally or via inhalation. The pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery of the aerosol container, pump, spray, aerosol inhaler, such as aerosol inhaler using electrohydrodynamics for the formation of a fine mist, 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 provided in the form of a dry powder for insufflation, alone or in combination with an inert carrier such as lactose, or a phospholipid; and nasal drops. For intranasal use, the powder may contain bioadhesive substance, including chitosan, or a cyclodextrin.

Solutions or suspensions for use in an aerosol container, pump, spray, aerosol inhaler or nebulizer may enter into the composition containing ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, increasing the solubility or prolonged release of the active ingredient provided in the present description, the propellant as the solvent; and/or surfactant, such as sorbitan trioleate, oleic acid or oligobrachia acid.

Provided in the present description pharmaceutical HDMI is tion can be mikronizirovanny to the size suitable for delivery via inhalation, for example, 50 micrometers or less, or 10 micrometers or less. Particles of such sizes can be manufactured using a grinding method, well-known experts in this field, such as spiral jet milling, grinding fluidized bed on the jet mill, processing supercritical fluid for the formation of nanoparticles, homogenization under high pressure or spray drying.

Capsules, blisters and cartridges for use in an inhaler or insufflator can enter into the composition containing the powder blend pharmaceutical compositions provided in the present description; suitable powder base such as lactose or starch; and the modifier efficiency, such asl-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. Provided in the present description pharmaceutical composition for inhalation/intranasal may optionally contain suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

Provided in the present description of pharmaceutical compositions for the local in which edenia can enter into compounds with immediate release or modified release, including deferred, delayed, pulsed, controlled, targeted and programmed release.

D. Modified release

Provided in the present description, the pharmaceutical compositions can be included in the dosage forms with 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) differ from the speed and location of release dosage form with immediate release in the introduction through the same path. Dosage forms with modified release include dosage forms with delayed, extended, prolonged, sustained, pulsed or pulsed, controlled, accelerated and rapid, directed, programmed-release, and not disintegrating in the stomach. Pharmaceutical compositions in dosage forms with modified release can be manufactured using a variety of techniques and methods modified release, known to specialists in this area, including as non-limiting examples of techniques with a matrix controlled release techniques with osmotic controlled release, reception is with many controlled-release, ion-exchange resin, intersolubility coating, multilayer coatings, microspheres, liposomes, and combinations thereof. The rate of release of active ingredient(s) may also be modified by changing the particle size and polymorphism of active ingredient(s).

Examples of modified release as non-limiting examples include the examples 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. Device with a matrix controlled release

Provided in the present description of the pharmaceutical composition in dosage form with modified release can be produced using the device with a matrix controlled release, known to specialists in this field (see, Takada et al. in "Encyclopedia of Controlled Drug Delivery", Vol. 2, Mathiowitz ed., Wiley, 1999).

In one of the embodiments provided in the present description of the pharmaceutical composition in dosage form with modified release formulate using devices containing measurable erosion of the matrix, which is vodosnabzhenie, erodium or soluble polymers, including synthetic polim the market, and naturally occurring polymers and their derivatives, such as polysaccharides and proteins.

Materials suitable for the formation of measurable erosion of the matrix, include as non-limiting examples of chitin, chitosan, dextran & pullulan; gum agar, Arabic gum, gum karaya, resin plodotvornogo tree, tragacanth gum, 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; cellulose polymers, such as ethylcellulose (EC), metilcellulose (YEC), carboxymethylcellulose (CMC), KMAC, hydroxyethylcellulose (SCE), hydroxypropylcellulose (GOC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), acetobutyrate cellulose (tsab), CAP, Central, hypromellose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetosella (HPMCAT) and metilgidroxiatilzelllozu (AGEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; esters of glycerol and fatty acids; polyacrylamid; polyacrylic acid; copolymers metacrilato acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethylmethacrylate); polylactide; copolymers of L-glutamic acid and et is l-L-glutamate; degradiruete copolymers of lactic acid and glycolic acid; poly-D-(-)-3-hydroxybutiric acid; and other derivatives of acrylic acid, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

In another embodiment, the pharmaceutical compositions are formulated with the device representing resistant to erosion matrix. Active ingredient(s) dissolved or dispersed in an inert matrix and is released primarily by diffusion through an inert matrix in the introduction. Materials suitable for use as anti-erosion of the matrix include, without limitation, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, copolymers of vinyl chloride with vinyl acetate, vinylidenechloride, ethylene and propylene, ion meter polyethylene terephthalate, butyl rubber, epichlorohydrine rubber, copolymer of ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl is the first alcohol, and ethylene/vinyloxyethoxy copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers and hydrophilic polymers, such as ethylcellulose, cellulose acetate, crosspovidone, and cross-linked partially hydrolyzed polyvinyl acetate; fatty compounds, such as Carnauba wax, microcrystalline wax, and triglycerides.

In the system with a 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 relationship of the active ingredient(s) to the polymer and other excipients in the composition.

Provided in the present description of the pharmaceutical composition in dosage form with modified release can be made using methods known to experts in this field, including direct compression, dry or wet granulation followed by pressing, granulation of the melt, followed by pressing.

2. Devices with osmotic controlled release

Provided in the present description of the pharmaceutical composition in dosage form with modified high what opozdaniem can be made using the device with osmotic controlled release, including single-chamber system, two-chamber system, technology asymmetric membrane (AMT) and extrusion of the nucleus (ECS). Basically, these techniques contain at least two components: (a) the core which contains the active ingredient(s); and (b) a semi-permeable membrane, at least one output hole, which encapsulates the core. Semipermeable membrane controls the flow of water to the core from the water environment in order to cause the release of a medicinal product by extrusion through an outlet opening(I).

In addition to the active ingredient(s), the core of the osmotic device optionally contains an osmotic agent, which creates a driving force for transfer of water from the used environment in the core of the device. One class of osmotic substances is vodosnabzhenie polymers, which are also referred to as osmopolitan" and "hydrogels", including as non-limiting examples of hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropyleneglycol (BCP), poly(2-hydroxyethylmethacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copoly is a career with a hydrophobic monomers, such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (SCE), hydroxypropylcellulose (GOC), hypromellose (HPMC), carboxymethylcellulose (CMC) and carboximetilzellulozu (kets), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

Other classes of osmotic substances are cosmogeny, which are able to absorb water in order to influence the osmotic pressure gradient across the barrier of the surrounding shell. Suitable omogeni include as non-limiting examples of inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, Inositol, lactose, maltose, mannitol, 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, glutamic acid,p-toluensulfonate acid, succinic acid and tartaric acid; urea; and mixtures thereof.

Emotions the e substances with different rates of dissolution can be used, to affect the initial rate of delivery of the active ingredient(s) 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 couple of hours to quickly create the desired therapeutic effect, and gradually and continually release of the remaining amount 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 with such speed, to replace the amount of metabolisable and secreted active ingredient.

The core may also include a wide range of excipients and carriers, as described in the present description, to increase the efficiency of the dosage form or to maintain the stability or handling.

Materials suitable for creating a semi-permeable membrane, include various kinds of acrylic polymers, vinyl polymers, ethers, polyamides, polyesters and cellulose derivatives polymers that are water-permeable and water-insoluble at physiologically relevant pH or able to become water-insoluble by chemical modification, such as stitching. Examples of polymers suitable for the formation of p the closure, include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, acetobutyrate cellulose (tsab), CA ethylcarbamate, CAP, CA methylcarbamate, CA succinate, acetosella cellulose (Central), CA diethylaminoacetate, CA ethylcarbonate, CA CHLOROACETATE, CA ethylacetat, CA methylsulfonate, CA butylsulfonyl, CAp-toluensulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethylacetal, triacetate resin plodotvornogo tree, gidroksilirovanii ethylene-vinyl acetate, EC, PEG, BCPs, PEG/BCP copolymers, PVP, SCE, GOC, CMC, CMAC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkene, polyethers, polysulfones, simple polyethersulfones, polystyrenes, polyvinylchoride, simple and complex polyvinyl ethers, natural waxes and synthetic waxes.

A semi-permeable membrane may also be a hydrophobic microporous membrane, where the pores are substantially filled with gas and not hydrated water, but permeable to water vapor, as disclosed in U.S. patent No. 5798119. Such hydrophobic, but permeable to water vapour membrane is usual consists of a hydrophobic polymer, such as polyalkene, polyethylene, polypropylene, polytetrafluoroethylene, derivatives of polyacrylic acid, polyethers, polysulfones, simple polyethersulfones, polystyrenes, polyvinylchoride, polyvinylidene fluoride, simple and complex polyvinyl ethers, natural waxes and synthetic waxes.

The hole(I) in a semi-permeable membrane can be formed after coating using mechanical or laser drilling. Outlet(I) can also be formedin situthrough erosion of the tubes of the water-soluble material or through a break in the thin part of the membrane above the indentation in the kernel. In addition, the outlet openings can be formed during the coating process, as in the case of coating an asymmetric membrane of this type is that disclosed in U.S. patent No. 5612059 and 5698220.

The total amount of the released active ingredient(s) and the rate of release of a significant degree can be modulated due to the thickness and porosity of the semipermeable membrane, the composition of the nucleus and the number, size and location of the vents.

Pharmaceutical compositions in dosage form osmotic controlled release may additionally contain further conventional excipients, as described in the present description, spadarinia efficiency or processing of the composition.

Dosage form osmotic controlled release can be manufactured in accordance with conventional methods and techniques known to experts in this field (see, Remington: The Science and Practice of Pharmacy, above; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In certain embodiments of the implementation provided in the present description, the pharmaceutical compositions comprise dosage forms with AMT controlled-release, which contains 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. Dosage forms with AMT controlled-release can be manufactured in accordance with conventional methods and techniques known to experts in this field, including direct compression, dry granulation, wet granulation and method of coating by dipping.

In a specific embodiment, provided in the present description, the pharmaceutical compositions comprise dosage forms with ESC controlled-release, which contains an osmotic membrane that coats a core containing the active ingredient(s), hydroxyethylcellulose, etc is further pharmaceutically acceptable excipients.

3. Devices controlled release of individual particles

Provided in the present description of the pharmaceutical composition in dosage form with modified release may be made in the form of a device controlled release of individual particles, which contains many particles, granules or pellets, in the range from approximately 10 μm to approximately 3 mm, from about 50 μm to approximately 2.5 mm, or from about 100 μm to 1 mm in diameter. So many particles can be created using processes known to specialists in this area, including wet and dry granulation, extrusion/spheronization, crushing roller, melting-freezing and coating seed cores. See, for example, Multiparticulate Oral Drug Delivery, Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology, Marcel Dekker: 1989.

Other excipients described in the present description, can be mixed with pharmaceutical compositions to facilitate the processing and formation of many particles. The obtained particles themselves can be many-particle device or can be covered with various film-forming materials such as intersolubility polymers, vodosnabzhenie and water-soluble polymers. Many particles can be further processed in the form of capsules or is tabletky.

4. Targeted delivery

Provided in the present description, the pharmaceutical compositions can also enter in part, directed to a particular tissue, receptor, or other area in the body of the subject to be treated, including delivery systems based on liposomes, resealed erythrocytes and antibodies. Examples include as non-limiting examples of U.S. patents№ 6316652; 6274552; 6271359; 6253872; 6139865; 6131570; 6120751; 6071495; 6060082; 6048736; 6039975; 6004534; 5985307; 5972366; 5900252; 5840674; 5759542 and 5709874.

Applications

In one of the embodiments provides a method of treating, preventing or alleviating one or more symptoms of disorders or diseases associated with CRTH2 and/or one or more other PGD2 receptors, by introducing the subject, which has such a condition or disease or suspected their existence, a therapeutically effective amount of amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, or its pharmaceutically acceptable hydrate or MES, or their pharmaceutical compositions.

In other embodiments, the exercise provided 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 od of the CSO or more other receptors PGD 2includes introduction to the subject, which has such a condition or disease or suspected their existence, a therapeutically effective amount of one or more amine salts or compositions provided in the present description.

In yet another embodiment, provided is 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 PGD2includes introduction to the subject, which has such a condition or disease or suspected their existence, a therapeutically effective amount of one or more amine salts or compositions provided in the present description.

In yet another embodiment, provided is a method of treating, preventing or alleviating one or more symptoms associated with eosinophils, comprising introducing to a subject a therapeutically effective amount of amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, or its pharmaceutically acceptable hydrate or MES, or their pharmaceutical compositions.

In yet another embodiment, provided is a method of treating, preventing or alleviating one or more symptoms of ill the tion, associated with basophils, comprising introducing to a subject a therapeutically effective amount of amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, or its pharmaceutically acceptable hydrate or MES, or their pharmaceutical compositions.

In another embodiment, provided is a method of treating, preventing or alleviating one or more symptoms of an inflammatory disease, comprising administration to the subject a therapeutically effective amount of amine salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid, or its pharmaceutically acceptable hydrate or MES, or their pharmaceutical compositions.

Disorders and diseases amenable to treatment by one or more aminovymi salts provided in the present description, include as non-limiting examples of (1) inflammatory or allergic diseases, including systemic anaphylactic and hypersensitive disorders, atopic dermatitis, urticaria, allergies to medications, allergies to insect bites, allergies to food (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 B is chcete; (4) psoriasis and inflammatory dermatoses, including dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, viral cutaneous pathologies including pathology, developing the infection by the human papillomavirus, HIV or VLR, bacterial, fungal and other parasitic cutaneous pathologies, and cutaneous form of lupus erythematosus; (5) asthma and respiratory allergic diseases, including allergic asthma, allergic rhinitis, otitis media, middle ear infections, asthma, stress, 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, graves ' disease and glomerulonephritis; (7) graft rejection (including allograft rejection and graft-versus-host), for example, graft rejection of the skin graft rejection in solid organ transplant rejection, bone marrow; (8) fever; (9) cardiovascular disorders, including acute heart failure, hypotension, hypertension, angina, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, and vascular stenosis; (10) C rubromaculatus disorders, including traumatic brain injury, stroke, ischemic reperfusion injury and aneurysm; (11) cancers of the breast, skin, prostate, cervix, uterus, ovary, testis, bladder, lung, liver, pharynx, 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) gastrointestinal disorders, including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15) neurological disorders, including Alzheimer's disease; (16) sleep disorders, including insomnia, narcolepsy syndrome sleep apnea syndrome and picwik; (17) pain; (18) renal disorders; (19) ocular disorders, including glaucoma; and (20) infectious diseases, including HIV.

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

In certain embodiments implement disease is a asthma, asthma, stress, allergic rhinitis, atopic dermatitis, chronic obstructive pulmonary disease or allergic conjunctivitis.

In certain embodiments implement disease is a syndrome charge-Strauss or sinusitis.

Depending on the disease to be treated, and the condition of the subject, amine salts or compositions provided in the present description, can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, inside the cavity, intracisternally introduction or infusion, subcutaneous injection, or implant), inhalation, nazalnam, vaginal, rectal, sublingual, or local (the example percutaneous or local) by introducing and can join individually or together, in suitable dosing unit with pharmaceutically acceptable carriers, adjuvants and carriers suitable for each route of administration. Also given the introduction of amine salts, provided in the present description, in depositing the composition in which the active ingredient is released over 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, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer or other conditions, disorders or diseases associated with CRTH2 and/or one or more other receptors PGD2corresponding to the level of dosing is usually from about 0.001 to 100 mg per kg of body weight of the patient per day (mg/kg / day), approximately 0.01 to approximately 75 mg/kg / day, from about 0.1 to about 50 mg/kg / day, about 0.5 to about 25 mg/kg / day or approximately 1 to approximately 20 mg/kg / day, which can be entered in single or multiple doses. P is adelah 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 / day. In certain embodiments of the implementation level of dosage is about 0.001 to 100 mg/kg / day. In certain embodiments of the implementation level of dosage is from about 0.01 to about 75 mg/kg / day. In certain embodiments of the implementation level of dosage is about 0.1 to about 50 mg/kg / day. In certain embodiments of the implementation level of dosage is about 0.5 to about 25 mg/kg / day. In certain embodiments of the implementation level of dosing ranged from approximately 1 to approximately 20 mg/kg / day.

For oral administration the pharmaceutical compositions may be provided in the form of tablets containing 1.0 to 1000 mg of active ingredient, in particular 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 selection of the dosage to the patient to be treated Composition can be used to mode 1 up to 4 times a day including one, two, three times and four times a day.

however, it should be understood that the specific dose level and frequency of dosage for a particular patient may vary and will depend on many factors, including the activity of the specific compound, the metabolic stability and length of action of that compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the particular condition and the owner, subject to therapy.

Also provided is a method of modulating CRTH2 and/or one or more other receptors PGD2that includes the contact of the receptor(s) with one or more aminovymi salts or compositions provided in the present description. In one embodiment, the implementation of the receptor(s) expressed by the cell.

Provided in the present description amine salts can also be combined or used in combination with other agents useful in treating, preventing or alleviating one or more symptoms of diseases or conditions for which are provided in the present description amine salts are useful, including asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic red in the chunks, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, and the above-mentioned pathology.

Such other substances or drugs can be introduced through the path and number, common to them, simultaneously or sequentially with the amine salt provided in the present description. When provided in the present description amine salt is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to provided in the present description amine salt may be used but is not necessary. Thus, provided in the present description, the pharmaceutical compositions include pharmaceutical compositions that contain one or more other active ingredients or therapeutic agents, in addition to the amine salt provided in the present description.

The mass ratio given in the present description amine salt to the second active ingredient may vary and will depend upon the effective dose of each ingredient. As a rule, each will be used effective dose. Thus, for example, when provided to the traveler in the present description amine salt is combined with an NSAID, the mass ratio given in the present description amine salt to NSAIDs may be in the range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations provided in the present description Amin and other active ingredients, as a rule, will also be within the above limit, but in each case must be used effective dose of each active ingredient.

EXAMPLES

Amine salts of the acids of formula I in the following examples were characterized by nuclear magnetic resonance spectroscopy (NMR), x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetry (TGA) and scanning electron microscopy (SEM).

All1H NMR spectra were recorded at 300 MHz on a Bruker NMR Instruments, unless stated otherwise. Constant interaction (J) are given in Hertz (Hz) and the peaks are listed relative to TMS (δ 0,00 ppm).

Data x-ray powder diffraction was recorded on x-ray powder diffractometer Rigaku MiniFlex (Rigaku Americas, The Woodlands, TX). CuKa radiation was (40 kV, 40 mA). Data were collected at room temperature from 3 to 45 degrees two theta when 0,02 degrees on stage and 0.6 with on stage. The samples were prepared on glass sample holders in the form of a thin layer of parashkevov the material without solvent.

Differential scanning calorimetry was performed using a Mettler 850, TA 2920. The samples were placed in sealed aluminum pans for analysis and used an empty aluminum pan as a reference. The heating rate 10°C/min was used for the temperature range from 30°C to 280°C.

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°C/min was used for the temperature range from 20°C to 600°C.

The average particle size of the solid amine salts was determined using scanning electron microscopy.

Example 1

The choice of basis for the salt of 4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl)acetic acid

Organized the screening of free acid {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with twenty-two pharmaceutically acceptable bases and the results are combined in table 1, along with their solubility in water. Participating in the screening grounds Ethylenediamine, piperazine, benzathine and choline formed crystalline solid, suitable for pharmaceutical compositions and used as described in the present description.

Example 2

Getting atiende mirovoi salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid

A mixture of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid (to 25.2 mg, 0.05 mmol) and Ethylenediamine (1,68 mg, 0.03 mmol) in ethanol (1.1 ml) was heated at a temperature of phlegmy to obtain a clear solution. Then the clear solution was allowed to cool to room temperature and was stirred for additional 2 hours. The precipitate was collected by filtration, washed in 0.5 ml of EtOH/heptane (1:1, vol/about.) and were dried at ambient temperature under vacuum to obtain lamellar crystals (20,1 mg) (Fig. 5).

Stoichiometry ethanolamine salt was determined using1H NMR (Fig. 1). Ethylendiamine salt of the acid of formula I contains approximately two molar equivalents of the acid and one molar equivalent of ethylene diamine. Two molar equivalent of ethanol accounts for about one molar equivalent of ethanol in the salt crystal. Crystal ethylendiamine salt contains approximately 4% ethanol. X-ray powder diffraction pattern ethylendiamine salt, shown in Fig. 2, has characteristic XRP diffraction peak that appears in the field when 5,9° two-theta angle. This confirms that ethylendiamine salt is a crystalline material.

Differential scanning calorimetric thermogram atlantium the new salt is shown in Fig. 3. Ethylendiamine salt gives endothermy at peak temperature 123,1°C and the onset temperature of decomposition 114,1°C and a peak temperature 216,0°C and the onset temperature of decomposition 212,1°C.

TABLE 1
Screening basics
BasisResultSolubility in water at 25°C (mg/ml)
The EthylenediamineCrystalline solid5,8
PiperazineCrystalline solidof 5.4
The benzathineCrystalline solid0,08
CholineCrystalline solid24,0
Sodium hydroxideLow solubility
The potassium hydroxideLow solubility
G is droxia calcium Low solubility
DiethanolaminInstant
EthanolamineInstant
N-methyl-D-glucamineDepleted crystalline salt
1-(2-hydroxyethyl)pyrrolidinInstant
L-lysineFormed very little crystalline salt
L-arginineLow solubility
AmmoniaFormed very little crystalline salt
DeanolFormed very little crystalline salt
DiethylaminBad crystal salt
2-(diethylamino)ethanolAbout azonano very little crystalline salt
PyrrolFormed very little crystalline salt
Magnesium hydroxideFormed very little crystalline salt
4-(2-hydroxyethyl)morpholineBad crystal salt
TriethanolamineFormed very little crystalline salt
TromethamineBad crystal salt

thermogravimetric analysis thermogram shown in Fig. 4. Ethylendiamine salt showed a small weight loss of up to 75°C and the loss 3,951% mass between 125°C and 150°C, which is consistent with observations from1H NMR characteristics (Fig. 1), indicating that the crystalline ethylendiamine salt contains approximately 4% ethanol.

Other systems of solvents are also considered to obtain the crystalline ethylendiamine salt of the acid of formula I. the Results are combined in table 2.

TABLE 2
Screening of solvents for ethylendiamine salt
The solvent systemResults
Methyl ethyl ketone (MEK)Soluble solid
MeOHSoluble solid
EtOHCrystalline solid
AcetoneInsoluble solid
Methyl isobutyl ketone (MIBK)Soluble solid

Example 3

Getting piperazinone salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl)acetic acid

A mixture of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid (25.0 mg, 0.05 mmol) and piperazine (2.38 mg, 0.03 mmol) in ethanol (1.1 ml) was heated at a temperature of phlegmy to obtain a clear solution. Then the clear solution was allowed to cool to room temperature and was stirred for additional 2 hours. The precipitate was collected by filtration, washed in 0.5 ml of tert-butyle the silt ether (TBME) and were dried at ambient temperature under vacuum to obtain acicular crystals (21,7 mg) (Fig. 10).

The stoichiometry of piperazinone salt was determined using1H NMR (Fig. 6). Pieperazinove salt of the acid of formula I contains approximately two molar equivalents of the acid and one molar equivalent of piperazine.

X-ray powder diffraction pattern piperazinone salt, shown in Fig. 7, has characteristic XRP diffraction peaks that appear in the field when 10,7, 15,9, 22,3 and 24.0° two-theta angle. This confirms that pieperazinove salt is a crystalline material.

DSC thermogram of piperazinone salt is shown in Fig. 8. Pieperazinove salt gives a strong endotherm with a peak temperature 223,2°C and the onset temperature of decomposition 219,3°C and a weak endotherm with a peak temperature 202,6°C and the onset temperature of decomposition 198,4°C.

thermogravimetric analysis thermogram of piperazinone salt is shown in Fig. 9. Ethylendiamine salt showed a slight weight loss of up to 75°C and the loss 3,951% mass between 125 and 150°C.

Other systems of solvents were also evaluated to obtain the crystalline piperazinone salt of the acid of formula I. the Results are combined in table 3.

TABLE 3
Screening of solvents for piperazinone salt
The solvent systemResults
EtOhCrystalline solid
AcetoneInsoluble
THFCrystalline solid
EtOH/H2OCrystalline solid
Methyl ethyl ketone (MEK)Insoluble
Isopropanol (IPA)Insoluble
AcetonitrileInsoluble

Example 4

Getting sensational salt of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid

A mixture of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid (250.0 mg, 0.5 mmol) and benzathine (RUR 134.4 mg, 0,56 mmol) in ethanol (3.0 ml) was heated at a temperature of phlegmy with obtaining a clear solution. Then the clear solution was allowed to cool to room temperature and was stirred for additional 2 hours. The precipitate was collected by filtration, washed with 2 mlra/heptane (1:1, about./about.) and dried under vacuum to obtain a solid substance with a rod-shaped crystals (256,8 mg) (Fig. 14).

Stoichiometry sensational salt was determined using1H NMR (Fig. 11). Pensativa salt of the acid of formula I contains approximately two molar equivalents of the acid and one molar equivalent of benzathine.

X-ray powder diffraction pattern sensational salt, shown in Fig. 12, has characteristic XRP diffraction peaks that appear in the field when 8,0, 11,5, 16,0, 17,5 and 23.4° two-theta angle. This confirms that pensativa salt is a crystalline material.

DSC thermogram sensational salt is shown in Fig. 13. Pensativa salt gives a strong endotherm with a peak temperature 155,8°C and the onset temperature of decomposition to 154.2°C.

Example 5

Getting Kalinovo salt (4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid

A mixture of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid (249,5 mg, 0.5 mmol) and choline (69,4 mg of 0.58 mmol) in IPA (3.5 ml) was heated at a temperature of phlegmy with obtaining a clear solution. Then, the resulting transparent solution was allowed to cool to room temperature and was stirred for another 2 hours. The precipitate was collected by filtration, PR is mawali in 2 ml of IPA/heptane (1:1, about./about.) and were dried at ambient temperature under vacuum to obtain a solid substance with rod-shaped and diamond-shaped crystals (232 mg) (Fig. 19).

Stoichiometry Kalinovo salt was determined using the1H NMR (Fig. 15). Kalinova salt of the acid of formula I contains approximately one molar equivalent of the acid and one molar equivalent of choline.

X-ray powder diffraction pattern Kalinovo salt, shown in Fig. 16, has characteristic XRP diffraction peaks that appear in the field when 6,5, 19,6, 20,0, 21,9 and 26.4° two-theta angle. This confirms that Kalinova salt is a crystalline material.

DSC thermogram Kalinovo salt is shown in Fig. 17. Kalinova salt gives a strong endotherm with a peak temperature 194,8°C and the onset temperature of decomposition 192,6°C.

thermogravimetric analysis thermogram Kalinovo salt is shown in Fig. 18. Kalinova salt almost shows no weight loss up to 200°C.

Other systems of solvents were also evaluated to obtain crystalline Kalinovo salt of the acid of formula I. the Results are combined in table 4.

TABLE 4
Screening of solvents for Kalinovo salt
The solvent systemResults
IPA/H2OSoluble solid
IPACrystalline solid
EtOHSoluble solid
EtOH/H2OSoluble solid

Example 6

Analysis of the competing radioligand binding

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

Prostaglandin D2and 13,14-dihydro-15-keto PGD2was obtained from Cayman Chemical (Ann Arbor, MI). Radiometry PGD2(5,6,8,9,12,14,15-3H(N)) with a specific activity of 160 CI/mmol was obtained from PerkinElmer (Boston, MA). The cell medium for the cultivation of RPMI 1640, HEPES buffer, phosphate-saline buffer (PBS), L-glutamine and solution penicillin-streptomycin were obtained from Mediatech Inc. (Herndon, VA). Fetal calf serum (FCS) was obtained from Cabrex (Walkersville, MD). Puromycin were obtained from Invitrogen (San Diego, CA). Poly(ethylenimine) (PEI) was obtained from Acros Organics (Morris Plains, NJ). Purified rat monoclonal antibodies against human CRTH2 (BM16), rat IgG2a, κ (clone R35-95), and goat protivokrazhnye 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).

CRTH2 and DP1 stable cell lines were created in accordance with the procedure described by the authors Sugimoto et al. (J. Pharm. Exp. Therap. 2003, 305, 347-352). These cell lines were maintained in the medium for cultivation 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).

Periodically observed the expression of CRTH2 on the surfaces of cells transfected cell lines in the cultivation process and before each analysis the competing radioligand binding. Cells expressing CRTH2, and nitrostilbene cells were incubated on ice or with purified antibodies against CRTH2 (clone BM 16) or isotopically 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% of sodium azide. Cells sequentially incubated on ice with FITC-conjugated with anti-rat antibody (goat protivokrazhnye Ig-FITC). Then washed with cold FACS buffer, cells were analyzed with use of the cation FACScan analyzer II and CellQuest software, which were obtained from Becton Dickinson (Mountain View, CA).

The functionality of the receptor transfectants were also evaluated by direct measurement of calcium activation in response to PGD2as described (Sugimoto et al., J. Pharm. Exp. Therap. 2003, 305, 347-352; Sugimoto et al., Eur. J. Pharmacol. 2005, 524, 30-37).

Assays radioligand binding was performed in accordance with 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 basic solutions. Serial dilutions of 10 μm was performed in binding buffer before analysis. Transfetsirovannyh cells resuspendable in binding buffer (50 mm Tris-HCl, 40 mm MgCl2and 0.1% bovine serum albumin, at pH of 7.4) at a concentration of 4×106/ml at room temperature. Then transfetsirovannyh cells were sown in U-bottom polypropylene 96-well plates (Fisher) by adding 50 ál of cell suspension, followed by adding 10 ál of3H-PGD210 μl of solutions of the test compounds with serial concentrations or controls, 30 ál of binding buffer to bring the final volume to 100 ál. The final concentration of3H-PGD2in each well was 1 nm. After incubation for 1 hour at room temperature and gentle shaking the cell suspension was transferred into a filter PL is nsity (Millipore, MA), which was pre-moistened with 0.5% PEI buffer. The cell precipitates were washed three times in binding buffer and the plates were allowed to air dry. The scintillator (50 μl; Microscint™ 20, Perkin Elmer, Boston, MA) was added to each well and counted for radioactivity on a TopCount (Packard Bioscience, Meriden, CT). Analysis of data was performed using a graphical program Prizm™ (GraphPad Software Inc., San Diego, CA). As shown in Fig. 20 and 21, 4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of formula I and its pharmaceutically acceptable salts possess high affinity and selectivity of binding to CRTH2.

The above examples are provided to give people with ordinary skills in this area a complete disclosure and description of how to make and use embodiments of, and are not intended to limit the scope of the disclosure. It is expected that modifications to the above methods of execution disclosure, which are obvious to the professionals in this field and are within the scope of the following claims. All cited in this description publications, patents and patent applications are incorporated herein by reference as if each such application, patent, or patent application is specifically and individually indicated that it is included in asteady document as a reference.

1. Pharmaceutically acceptable salt in crystalline form containing a pharmaceutically acceptable amine and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of the formula I

where the pharmaceutically acceptable amine represents Ethylenediamine, piperazine, benzathine, or choline.

2. Pharmaceutically acceptable salt, containing pharmaceutically acceptable amine and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid of the formula I

where the pharmaceutically acceptable amine represents Ethylenediamine, piperazine, benzathine, or choline.

3. Salt according to claim 1 or 2, where the pharmaceutically acceptable amine is an Ethylenediamine.

4. Salt according to claim 3, containing approximately two molar equivalents of the acid of formula I and about one molar equivalent of ethylene diamine.

5. Salt according to claim 3, characterized by x-ray powder diffraction pattern shown in figure 2, where the x-ray powder diffraction pattern obtained using CuKα radiation source.

6. Salt according to claim 3, characterized by x-ray powder diffraction pattern containing the peak in the area at approximately 5,9° 2θ angle, where the x-ray powder diffraction pattern obtained using the source is the infrared radiation CuKα.

7. Salt according to claim 3, characterized by the differential scanning calorimetric thermogram shown in figure 3.

8. Salt according to claim 3, characterized DSC-thermogram with endothermy at peak temperature of about 123°C. and the temperature at which decomposition of approximately 114°C.

9. Salt according to claim 3, characterized DSC-thermogram with endothermy at peak temperature of approximately 216°C and the onset temperature of decomposition of about 212°C.

10. Salt according to claim 3, characterized by a solubility in water of approximately 6 mg/ml at 25°C.

11. Salt according to claim 1 or 2, where the pharmaceutically acceptable amine is a piperazine.

12. Salt according to claim 11, containing approximately two molar equivalents of the acid of formula I and about one molar equivalent of piperazine.

13. Salt according to claim 11, characterized by x-ray powder diffraction pattern shown in Fig.7, where the x-ray powder diffraction pattern obtained using CuKα radiation source.

14. Salt PN, characterized by x-ray powder diffraction pattern containing the peak in the area at approximately 10,7, 15,9, 22,3 and 24.0° 2θ angle, where the x-ray powder diffraction pattern obtained using CuKα radiation source.

15. Salt according to claim 11, characterized by a differential scanning calorimetric thermogram shown in Fig.

16. Salt according to claim 11, characterized DSC-thermogram with endothermy at peak temperature of about 203°C and the onset temperature of decomposition of about 198°C.

17. Salt according to claim 11, characterized DSC-thermogram with endothermy at peak temperature of about 223°C and the onset temperature of decomposition of about 219°C.

18. Salt according to claim 11, characterized by a solubility in water of about 5 mg/ml at 25°C.

19. Salt according to claim 1 or 2, where the pharmaceutically acceptable amine is a benzathine.

20. Salt according to claim 19, containing approximately two molar equivalents of the acid of formula I and about one molar equivalent of benzathine.

21. Salt according to claim 19, characterized by x-ray powder diffraction pattern shown in Fig, where the x-ray powder diffraction pattern obtained using CuKα radiation source.

22. Salt according to claim 19 characterized by x-ray powder diffraction pattern containing peaks in the area at approximately 8,0, 11,5, 16,0, 17,5 and 23.4° 2θ angle, where the x-ray powder diffraction pattern obtained using CuKα radiation source.

23. Salt according to claim 19, characterized by the differential scanning calorimetric thermogram shown in Fig.

24. Salt according to claim 19, characterized DSC-thermogram with endothermy at peak temperature when listello 156°C and the onset temperature of decomposition of approximately 154°C.

25. Salt according to claim 19, characterized by a solubility in water of approximately 0.08 mg/ml at 25°C.

26. Salt according to claim 1 or 2, where the pharmaceutically acceptable amine is a choline.

27. Salt p, containing about one molar equivalent of the acid of formula I and about one molar equivalent of choline.

28. Salt p characterized by x-ray powder diffraction pattern shown in Fig, where the x-ray powder diffraction pattern obtained using CuKα radiation source.

29. Salt p characterized by x-ray powder diffraction pattern containing peaks in the range of approximately 6,5, 19,6, 20,0, 21,9 and 26.1° 2θ angle, where the x-ray powder diffraction pattern obtained using CuKα radiation source.

30. Salt p, characterized by a differential scanning calorimetric thermogram shown in Fig.

31. Salt p characterized by DSC-thermogram with endothermy at peak temperature of approximately 195°C and the onset temperature of decomposition of approximately 193°C.

32. Salt p, characterized by a solubility in water of approximately 24 mg/ml at 25°C.

33. Pharmaceutical composition having the properties of a CRTH2 antagonist-receptor containing a therapeutically effective amount of the salt according to claim 1 or 2, and pharmaceutically who Lemley media or excipient.

34. The pharmaceutical composition according p, where the composition is included in the composition for oral, nasal, bronchial or local injection.

35. The pharmaceutical composition according p, where the composition is formulated in a dosage form for a single admission.

36. The use of a salt according to claim 1 or 2 for the preparation of medicines for treating, preventing or alleviating one or more symptoms of a CRTH2-mediated diseases.

37. The use of a salt according to claim 1 or 2 for the preparation of medicines for treating, preventing or alleviating one or more symptoms associated with eosinophils disease.

38. The use of a salt according to claim 1 or 2 for the preparation of medicines for treating, preventing or alleviating one or more symptoms associated with the basophils of the disease.

39. The use of a salt according to claim 1 or 2 for the preparation of medicines for treating, preventing or alleviating one or more symptoms of an inflammatory disease mediated by CRTH2.

40. Use p, where the disease is selected from the group consisting of asthma, allergic asthma, asthma physical effort, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypercholesterol the STI and Hyper IgE syndrome.

41. Use p, where the disease is a asthma, asthma physical effort, allergic rhinitis or atopic dermatitis.

42. The method of obtaining salt according to claim 1 or 2, which includes stages
(a) education amine salt by interaction of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidine-5-yl}acetic acid with the amine in a solvent at a first temperature and
(b) deposition of amine salt at a second temperature,
where the first temperature is from about 20 to about 100°C and
where the second temperature is from about -23°to 35 ° C.

43. The method according to § 42, where the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, tetrahydrofuran, water and mixtures thereof.



 

Same patents:

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

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 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

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: 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

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