Novel crystalline forms of n-[-2[[(2,3-difluorophenyl)methyl]thio]-6-{[(1r,2s)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azatidine-sulphonamide

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of N-[-2[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azatidine-sulphonamide, which has an X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1.5418 E and containing, at least, one crystalline peak with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 2 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 3 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1. The said crystalline form can contain additional crystalline peaks with a value 2-theta (in degrees), selected from 12.9 and 18.0, obtained under the said conditions.

EFFECT: crystalline form has the X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1,5418 E, with the crystalline peaks with a value 2-theta (in degrees) 12,9, 13,1, 18,0, 21,0, 22,5, 25,1, 25,3, 28,8, 29,1 and 30,4, and has melting point (beginning) 152,7°C.

6 cl, 3 dwg, 2 tbl, 5 ex

 

The present invention relates to new solid forms of the drug, to pharmaceutical compositions containing them and to methods for their preparation.

It is desirable that the composition of the medicinal compositions of the medicinal substance was in the form in which it will be convenient to treat him and his process. This is important not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical compositions containing the active connection.

Chemical stability, solid state stability, and "shelf life" of the active ingredients are also very important factors. Drug substance, and compositions containing it, should be effectively stored without significant changes in physico-chemical characteristics of the active component (e.g. its chemical composition, density, hygroscopicity and solubility).

In addition, it is also desirable to be able to offer the drug in the form in which it is as chemically pure as possible.

Amorphous or polyamorie substances can create significant problems in this regard. For example, such substances are usually difficult to handle and prepare in the form of a pharmaceutical preparation, provide �nadegnuy solubility and often find them unstable and chemically contaminated.

Specialist it is obvious that if a drug can be easily obtained in a stable crystalline form, the above problems can be solved.

In addition, it was found that crystalline drug compounds provide a more reliable and reproducible concentration profiles in plasma after administration to the patient.

Thus, for the manufacture of commercially viable and pharmaceutically acceptable compositions of drugs is desirable, where possible, to offer the drug essentially in crystalline and stable form.

It should be noted, however, this goal is not always achievable. Indeed, it is usually not possible to predict only on the molecular structure, what will be the nature of the crystallization of compounds. Usually this can only be determined empirically.

In international patent application WO 2006/024823 revealed a number of derivatives of pyrimidinediamine as modulators of chemokine receptors, including the specific compound N-[2-[[(2,3-differenl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl"] oxy}-4-pyrimidinyl]-1-azetidinone (Example 47):

also mentioned in this description of the invention as Compound I.

In WO 2006/024823 disclosed a method for producing Compound I, but not disclosed any con�specific information relative to crystalline forms of this compound.

The inventors found that it is possible to obtain a stable crystalline form of Compound I or its pharmaceutically acceptable salts such crystalline forms may be referred to in this description as "compounds of the invention".

According to one aspect of the invention proposes essentially crystalline form of Compound I or its pharmaceutically acceptable salt (for the avoidance of doubt, these are compounds of the invention").

In another aspect of the invention, it is proposed crystalline form of Compound I or its pharmaceutically acceptable salt.

According to another aspect of the invention proposes essentially crystalline AnyDATA form of Compound I (for the avoidance of doubt, these are compounds of the invention"). In one aspect, Compound I is not in salt form. In addition, it is preferable that it is not in the form of a solvate, i.e. it is a "unsolved". Therefore, the term "anhydrate" covers "unsolved".

The inventors have found that Compound I can be obtained in forms which by their nature are essentially crystalline. Although it is possible to obtain Compound 1 in forms that are more crystalline than about 90%, for example more than approx�RNO 95% (e.g. more than about 98% crystalline and, especially at 100% or about 100% crystalline), "substantially crystalline," the authors of the invention comprise more than about 60%, in another aspect more than about 75%, and in another aspect more than about 80% (e.g. about 90%) crystalline. The degree (%) of crystallinity can be determined by the technician using x-ray diffraction on the powder (XRPD). You can also use other methods, such as NMR solids, FT-IR (infrared spectroscopy with Fourier transform), Raman spectroscopy, differential scanning calorimetry (DSC) microcalorimetry and calculate the true density.

Suitable crystalline modification of the compound according to the invention essentially does not contain other crystalline modifications of the compound. Accordingly, the crystal modification of the compound of formula I includes, for example, less than 20%, 15%, 10%, 5%, 3% or especially less than 1% of the mass. other crystalline forms of this compound.

Earlier in this description of the invention indicates that the Compound I can be obtained in crystalline form, which is an anhydrate. Under this term, the inventors mean that the crystalline form contains less than 10% (a), hydrate(s) of the form(m) (e.g. monohydrate) of Compound I.

Two preferred�Uo anhydrate crystalline form of Compound I is characterized by x-ray powder diffraction pattern using a wavelength of x-rays 1,5418 Å, contains the following characteristic crystalline peaks with approximate values of 2-theta (in degrees), as well as specifying the relative intensities of these peaks are in parentheses, where the percentage of relative intensity of approximately 25-100% designated as "vs", approximately 10-25% is designated as "s", approximately 3-10% is designated as "m" and about 1-3% is designated as "w":

Form a: characteristic crystalline peaks with at least one value of 2-theta (in degrees) of around (i.e., about or approximately) of 14.8, 17.8 and/or 24.1. In one aspect of the characteristic crystalline peaks with at least one value of 2-theta (in degrees) of 14.8, 17.8 and/or 24.1. In another aspect, the present all these peaks. In another aspect also contains at least one additional crystalline peak with a value of 2-theta (in degrees) of around (i.e., about or approximately) 16,3, 15,5, 11,4, 9,9, 13,1 and/or 4.4. In another aspect there are all of the aforementioned peaks. In another aspect also contains at least one additional crystalline peak with a value of 2-theta (in degrees) 16,3, 15,5, 11,4, 9,9, 13,1 and/or 4.4. In another aspect, the present all of the aforementioned peaks.

In another aspect, form A has characteristic crystalline peaks with at least one of the values 2-theta (in degrees) of around (i.e. at�Erno or approximately) 14,8 (s), 17,8 (vs) and/or 24.1 (vs). In one aspect, all these peaks are present. In another aspect, also contains at least one additional crystalline peak with a value of 2-theta (in degrees) of around (i.e., about or approximately) 16,3 (s), 15.5 cm (s), or 11.4 (vs), 9,9 (vs), 13,1 (vs) and/or 4.4 (vs). In another aspect, the present all these peaks. In one aspect, the form contains all of the characteristic peaks (for instance with the specified relative intensity), as shown in Example 1 below in this description of the invention and, therefore, the shape can be characterized by x-ray powder diffraction pattern which is essentially the same as shown in Fig.1.

Form D: characteristic crystalline peaks with at least one of the values 2-theta (in degrees) of around (i.e., about or approximately) of 12.9, 18.0% and/or 21,0. In one aspect, all these peaks are present. In another aspect, also contains at least one additional crystalline peak with a value of 2-theta (in degrees) of around (i.e., about or approximately) 25,1, 25,3, of 27.0 and/or 29.1. In another aspect there are all these peaks.

In another aspect form D is the characteristic crystalline peaks with at least one of the values 2-theta (in degrees) of around (i.e., about or approximately) 12,9 (vs), 18,0 (vs) and/or 21,0 (s). In one aspect, there are all these PI�I. In another aspect, also contains at least one additional crystalline peak with a value of 2-theta (in degrees) of around (i.e., about or approximately) 25,1 (s), 25,3 (s), 27,0 (s) and/or 29.1 (s). In one aspect, the present all these peaks listed for form D. In another aspect, the form contains all of the characteristic peaks (for instance with the specified relative intensity), as shown in Example 2 below in this description of the invention, and therefore, the shape can be characterized by x-ray powder diffraction pattern which is essentially the same as shown in Fig.2.

In another aspect form D is characterized by x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å and contain at least 1 crystal peak value of 2-theta (degrees) 21,0, is 28.8 and/or 29.1.

In another aspect form D is characterized by x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å and contain at least 2 crystal peak value of 2-theta (degrees) 21,0, is 28.8 and/or 29.1.

In another aspect form D is characterized by x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å and contain at least 3 crystalline peak with the char�rising 2-theta (degrees) 21,0, of 28.8 and/or 29.1.

In another aspect form D is characterized by x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å and containing additional crystalline peak with a value of 2-theta (in degrees) selected from the 12.9 and 18.0.

In another aspect form D is characterized by x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å and containing crystalline peaks with a value of 2-theta (in degrees) 12,9, 13,1, 18,0, 21,0, 22,5, 25,1, 25,3, 28,8, 29,1 and 30.4.

In one aspect, the compounds of the invention are crystallographically essentially pure. The expression "substantially crystallographically pure" the authors of the invention include the crystalline form of anhydrate of Compound I, as far as it can be estimated through measurements of x-ray diffraction on the powder (XRPD), which contains less than about 5%, in another aspect less than about 3%, and in another aspect less than about 1% of other crystalline forms of Compound I (or other anhydrate form or another, and is assessed by the presence of XRPD peaks such other crystalline forms).

The DSC analysis shows that the Form D has an onset of melting at 152,7°C. the DSC Thermogram presented in Fig.3. In one aspect, the invention relates to a crystalline form of compound forms�radio 1 with a melting point of about 152,7°C (the beginning).

The inventors have discovered that for some anhydrate of Compound I drying of solvent during the crystallization process) is not necessary in order to ensure their education. However, to ensure receipt of anhydrate, the solvent from which crystallization takes place, can be dried, either before the crystallization process or during it, to lower the water content below a critical level, which preferably should not be exceeded during crystallization. The solvent can be dried during the crystallisation process, for example by reducing the water content in the mixture of compounds, which will crystallize and a suitable system of organic solvent/water solvent (for example by increasing the amount of organic solvent that is present and/or by the removal of water through the formation of azeotropic mixtures with subsequent distillations).

Consequently, the anhydrate of Compound I can be obtained by crystallization from a solvent system, which essentially does not contain water.

In the expression "essentially does not contain water," the authors of the invention include the fact that the water content in the solvent system is below the level that leads to the formation of not more than 10% of monohydrate for any given solvent system and set the condition�th crystallization.

Crystalline Form D of anhydrate of Compound I can be obtained by suspending the Compound I (e.g., in amorphous form or in another crystalline form, such as a Form) in the system of solvents. Therefore, it is proposed crystalline form obtained in this way transformation (crystallization). Expert it is clear that the method of suspending represents essentially a way of "suspension" or method that includes at least a partial (but not complete) dissolution in the solvent system.

Therefore, in one aspect of the invention proposes the conversion of one crystalline form (for example one anhydrate forms) of Compound I in another. In particular, Form A (also referred to in this description of the invention as A-form) can be transformed into the Form D (also referred to in this description of the invention as D-form). Therefore, again offered the crystalline form obtained in this way transformation (crystallization).

To obtain a D-shape, A-shape can be suspended or to form a suspension (or at least partially dissolve in the solvent system that is not conducive to the formation of solvate forms of Compound I.

The terms "suspended" and "forming a suspension" (or "partially dissolved") is well understandable language.� specialist. For example, to form a suspension or slurry, is added an excess of solids relative to its solubility in the solvent, so that (undissolved) solids present in the system of solvents during the process of "suspend" or "suspension". Therefore it is also called in this description of the invention "partial dissolution".

The preferred solvent system used to obtain the D-form by suspending or sediment re-suspension (i.e., to achieve the transformation, for example, amorphous Compound I or A-form to D-form), include any suitable solvent (also referred to in this description of the invention "solvent for suspension") or the mixture of solvents that does not lead to the formation of a solvate of Compound I. Preferred solvent system can include systems in which Connection I only partially (or at least partially soluble. In one aspect, the solvent system contains (or, in another aspect, essentially consists of a) organic(s) solvent(s), which are polar, for example alcohols such as lower alkyl alcohols, such as C1-6alcohol). In another aspect, the solvent system contains (or, in another aspect, essentially consists of a) ethanol or especially methanol. Therefore, �above polar organic solvents are particularly preferred solvents for suspending, used in the system of solvents (and in another aspect, the solvent system consists primarily or essentially of such solvents to suspend). In one aspect, the solvent for suspending (for example an alcohol, such as methanol) is at least 90% wt./mass. (for example at least 95%, such as about 100%) of the entire system of solvents, which are used to obtain the D-form. That is, the solvent for suspension may contain up to 10 wt%./mass. (for example up to 5% or about 0%) other (undesirable or less desirable) solvents.

Phase transformation in the system of solvents including a solvent for suspending described above in this description of the invention) to obtain the D-form may take a period of several weeks (e.g. six weeks; see Example later in this description), but the length of time can be reduced depending on the temperature method (or it can be made longer if run at lower temperatures) and so on. However, the expert can easily determine the length of time required for the conversion of D-form. In addition, the D-form can be obtained by using a seed crystal, for example, as described later in this description.

A-shape With�connection I can crystallize from the amorphous form of Compound I in the mixture, containing a specific solvent (for example acetonitrile), an inorganic acid (e.g. phosphoric acid) and water, where the mixture can be heated and then cooled to promote crystallization, as described below in this description of the invention (see, e.g., Example 2).

A-form of Compound I may crystallize from N-[2-[[(2,3-differenl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidin-sulfonamide in a mixture containing a specific solvent (for example acetonitrile), an inorganic acid (e.g. phosphoric acid) and water, where the mixture can be heated and then cooled to promote crystallization, as described below in this description of the invention (see e.g. Example 2).

The crystallization described in this description of the invention, can be stimulated by the addition of seed crystals (if available).

For example, the D-form may also be obtained by using priming using the following procedure: dissolving Compound I (e.g. one mass %) in a solvent (such as alcohol, for example isopropanol; for example 30 relative volumes); stirring at elevated temperature (e.g. 70°C) for some period of time (which can amount to several hours) to achieve complete dissolution; continuation of stirring at an elevated those�ture (for example 55°C; that is, at a temperature below that required to achieve dissolution) during the time period, such as several hours (e.g. over night); the use of priming with Form D of Compound I (e.g. 0.1 wt.%); cooling to a lower temperature (e.g. 20°C) and filtration with obtaining a D-shaped.

Alternatively, the D-form can also be obtained using priming using the following procedure: dissolving Compound I (e.g. one relative mass %) in a solvent (such as alcohol, for example ethanol; for example 15 relative volumes); stirring at elevated temperature (e.g. 65°C), for example within a time period (which can amount to several hours) to achieve complete dissolution; continuation of stirring at an elevated temperature (e.g. 55°C; i.e. at a temperature below that required to achieve dissolution) for some period of time, such as several hours (e.g. over night); the use of priming with Form D of Compound I (e.g. 0.1 wt.%); cooling to a lower temperature (e.g. 20°C) and filtration with obtaining a D-shaped.

To confirm that the crystalline forms as described in this description of the invention receive in the absence of other crystalline forms, crystallization can a ful�measured using priming with nucleation sites and/or seed crystals of the target crystalline form in the absence of nucleation sites and/or seed crystals of other crystalline forms.

Specialist it is obvious that the concentration in the solution of the connection, which should be kristallizirovany, and the solvent system used can influence the crystallization temperature and the duration of crystallization.

Different crystalline forms may have different solubility in different organic solvents at any given temperature. In this respect, the above-mentioned or other solvents can be used as a "Antibacterials" (i.e. a solvent in which compounds of the invention are poorly soluble, but which is miscible with another solvent in which compounds of the invention are more soluble), and can thus facilitate the crystallization method.

Specialist it is obvious that the obtained crystalline form depends on both the kinetics and thermodynamics of the solidification process. In certain thermodynamic conditions (solvents, temperature, pressure and concentration of the compounds according to the invention) one crystalline form may be more stable than the other (or any other). However, other crystalline forms, which may have a relatively relatively low thermodynamic stability, can be kinetically preferred. Thus, optionally, kinetics�e factors such as the time, the composition of impurities, the shaking, the presence of primers and so forth, can also have an impact on what forms will appear. Thus, the methods described in this description of the invention, if necessary, can be adapted by the specialist for the purpose of obtaining a specific crystalline form of Compound I (e.g. A-form or D-form).

In addition, the drying temperature and drying time may affect the properties of the solid and/or solid form of the compounds according to the invention. For example, dehydration may occur due to low humidity, and/or at elevated temperatures and/or under reduced pressure. Therefore, the crystalline anhydrate compounds according to the invention can also be formed by dehydration of the hydrate.

As indicated earlier in this description of the invention, preferred compounds of the invention may also be characterized by x-ray powder diffraction pattern, which essentially corresponds to the shown in the attached Fig.1 or Fig.2, and/or, as shown in Table 1 or Table 2 below in this description of the invention (see Examples 1 and 2). Specialist it is obvious that the crystalline form anhydrate form of Compound I shows "essentially" the same x-ray powder diffraction pattern as the other, when at�th expert is apparent from the respective diagrams (i.e. the relative position of the peaks, admitting the error of the experiment, such as the preferred orientation of the sample and the corresponding settings of the instrument (for example type of device standardization and/or calibration)) that was formed the same crystalline form. Thus, there may be some error of the experiment for the value 2°theta, as may be specified in this description of the invention (such as a change up to ±0.5°2-theta).

The inventors found that the compounds of the invention have unexpectedly improved physical and/or chemical stability in comparison with other forms of Compound I, which could be obtained earlier.

The term "stable", as defined in this description of the invention, includes chemical stability and solid state stability.

The phrase "chemical stability" of the authors of the invention include the fact that the connection can be stored in a dedicated solid form or in the form of solid compositions in which it may be represented in a mixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal conditions of storage, with an insignificant degree of chemical degradation or separation.

In the expression "solid state stability", the authors of the invention include the fact that the connection can be stored in a dedicated solid forms� or in the form of solid compositions, in which it can be presented in a mixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, with an insignificant degree of change in the solid state (for example, crystallization, recrystallization, loss of crystallinity, solid-phase transition, hydration, dehydration, solvation or desolvation).

Examples of "normal storage conditions" include temperatures of between minus 80 and plus 50°C (in one aspect, from 0 to 40°C, and in another aspect at ambient temperature, such as from 15 to 30°C), pressure from 0.1 to 2 bar (from 104up to 2×105PA) (in one aspect at atmospheric pressure) and/or the influence of 460 Lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months). Under such conditions it is possible to detect that the compounds according to the invention are less than about 15%, in one aspect less than about 10% and in another aspect less than about 5% chemically decayed/decomposed, or have changed the solid state, according to circumstances. Specialist it is obvious that the above upper and lower limits of temperature and pressure mean limit values of normal storage conditions, and that some combination of these limits will not be encountered during normal storage�settings (for example, a temperature of 50°C and a pressure of 0.1 bar (10 4PA.

The term "normal storage conditions" may also include relative humidity 5% to 95% (in one aspect, from 10 to 60%). However, in the case of some of the crystalline forms according to the invention changes the conformation or crystal structure during hydration and/or dehydration may occur as a result of prolonged exposure to certain limit values of relative humidity at normal temperatures/pressures.

The preparation and characterization of compounds of the invention are described below in this description of the invention. Different crystalline forms of compounds according to the invention can be easily characterized using the methods of x-ray diffraction on the powder (XRPD), for example, as described later in this description.

Compounds according to the invention can be isolated using methods that are well known to those skilled in the art, such as desantirovaniya, filtration and/or centrifugation.

The inventors have discovered that by applying crystallization or transformation described in this description of the invention, it is possible to obtain compounds according to the invention with high chemical purity.

Upon receipt of the compounds according to the invention, as described in this description of the invention, the compound obtained is in the form�, which has improved chemical stability and solid state stability, as indicated earlier in this description of the invention, improved profiles of solubility and hygroscopicity in comparison with other previously known forms.

Although in one aspect, the compounds of the invention (i.e. crystalline form) are not in the form of salts, salts that may be mentioned include salts of accession acid salt and the base is connected.

Pharmaceuticals and medical use

Compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals.

In particular, the compounds of the invention find use in the treatment of diseases/conditions where the useful modulation of the activity of chemokine receptors, especially CXCR2.

The term "modulate" can refer to any measurable reduction and/or prevention of the relevant activity (activity against chemokine receptor). The modulating activity of a chemokine receptor can be measured by comparing the activity of the chemokine receptor in the sample containing the compound according to the invention, in the sample and in the absence of compounds according to the invention (as will be obvious to the person skilled in the technical field). Measurable from�enemie can be objective (e.g. measurable by using some test or marker for example in the analysis or in vitro test or in vivo, such as described below in this description of the invention, or by other suitable analysis or test, known to those skilled in the art) or subjective (for example, the subject indicates the effect of or feels an effect).

The compound of formula (1) or pharmaceutically acceptable salts may be useful in the treatment (therapeutic or prophylactic) of conditions/diseases in human and animal, not human, which is exacerbated or caused by excessive or unregulated chemokines produced. Examples of such conditions/diseases include (each taken independently):

(1) airway - obstructive Airways diseases, including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, hereditary, acquired and dust asthma, particularly chronic or inveterate asthma (for example late asthma and airway hyperactivity); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis, chronic rhinitis including education kawasmeh masses, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and rhinitis medication; bronchiectasis; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and rhinitis children with scrofula; CE�ssion rhinitis, including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, allergic alveolitis among agricultural workers and related diseases, pulmonary fibrosis and idiopathic interstitial pneumonia;

(2) bones and joints - rheumatoid arthritis, the seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's syndrome), Behcet's disease, Sjogren's syndrome and systemic sclerosis;

(3) skin - psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus vulgaris, bullous pemphigus, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, dermal eosinophilia, uveitis, alopecia areata and vernal conjunctivitis;

(4) gastrointestinal tract - celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, undifferentiated colitis, microscopic colitis, inflammatory bowel disease, irritable bowel syndrome, non-inflammatory diarrhea, food allergies which have effects remote from the digestive tract, for example migraine, rhinitis and eczema;

(5) the Central and peripheral nervous system neurodegenerative diseases and dementia disorders, e.g. bol�of SNL Alzheimer's, amyotrophic lateral sclerosis and other motor neuron disease, a disease of Creutzfeldt-Jakob and other prion diseases, HIV encephalopathy (AIDS dementia), Huntington's disease, fronto-temporal dementia, dementia with Lewy bodies and vascular dementia; polyneuropathies, e.g. Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, plexopathies; CNS demyelination, e.g. multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders, such as severe myasthenia gravis and the syndrome of Eaton-Lambert; spinal disorders for example tropical spastic paraparesis syndrome and muscle stiffness: paraneoplastic syndromes, e.g. cerebellar degeneration and encephalomyelitis; CNS trauma; migraine; and stroke.

(6) other tissues and systemic disease - atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematous, systemic lupus erythematous, Hashimoto's thyroiditis, type 1 diabetes, nephrotic syndrome, eosinophilia fasciitis, syndrome Hyper-lgE, lepromatous leprosy, and idiopathic thrombocytopenic purpura; post-operative adhesions, and sepsis.

(7) ottorini� allograft - acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft-versus-host;

(8) cancer - especially non-small cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous sarcoma, and metastasis of tumors, non-melanoma skin cancer and prevention of metastasis;

(9) diseases in which angiogenesis is associated with elevated levels of CXCR2 chemokines (e.g. NSCLC, diabetic retinopathy);

(10) the cystic fibrosis;

(11) burn wounds & chronic skin ulcers;

(12) diseases of the reproductive system - e.g. disorders of ovulation, menstruation and implantation, pre-term labour, endometriosis;

(13) reperfusion injury in heart, brain, peripheral limbs and other organs, inhibition of atherosclerosis.

Thus, the present invention provides a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description of the invention, for use in therapy.

Compounds according to the invention can be applied for the treatment of diseases in which chemokinesis receptor is a receptor CXCR2,

Specific condition that can be treated by the compounds according to the invention, are p�to, diseases in which angiogenesis is associated with elevated levels of CXCR2 chemokines, and inflammatory diseases such as asthma, allergic rhinitis, COPD, bronchiectasis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, osteoarthritis or osteoporosis.

In another aspect, the specific condition that can be treated by the compounds according to the invention, are asthma, COPD and bronchiectasis.

As another aspect of the present invention, the compound of formula (1) can be used as antagonists of the receptor CX3CR1. It is assumed that such compounds will be particularly useful in the treatment of disorders of the Central and peripheral nervous system and other conditions characterized by activation of microglia and/or infiltration of leukocytes (e.g. stroke/ischemia and head trauma). In particular, the compounds are indicated for use in the treatment of neurodegenerative disorders or demyelinizing diseases in mammals, including humans. More specifically, the compounds are indicated for use in the treatment of multiple sclerosis. The connection is also shown to be useful in the treatment of pain, rheumatoid arthritis, osteoarthritis, stroke, atherosclerosis and pulmonary arterial hypertension.

In another aspect the present invention provides a compound of formula (1) or pharmacist�Cesky acceptable salt, as defined above in this description of the invention, for use as a medicament.

In another aspect the present invention provides use of a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description of the invention, for use as a medicament for the treatment of diseases or States of the person for whom the modulating activity of a chemokine receptor is beneficial.

In another aspect the present. the present invention provides use of a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description of the invention, for use as a medicament for the treatment of asthma, allergic rhinitis, cancer, COPD, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, osteoarthritis or osteoporosis.

In another aspect the present invention provides use of a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description of the invention in the manufacture of a medicament for use in therapy.

In another aspect the present invention provides use of a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description of the invention in the manufacture of a medicine for the treatment of diseases or States rights, for example a modulating activity of a chemokine receptor is beneficial.

In another aspect the present invention provides use of a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description of the invention in the manufacture of a medicine for the treatment of asthma, allergic rhinitis, cancer, COPD, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, osteoarthritis or osteoporosis.

In the context of the present description of the invention the term "therapy" also includes "prophylaxis" unless there is a specific indication to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

The invention also provides a method of treatment mediated by chemokines of the disease, where the chemokine binds to a chemokine receptor (especially CXCR2), comprising administering to the patient a therapeutically effective amount of a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description.

The invention also provides a method for the treatment of inflammatory diseases, especially asthma, allergic rhinitis, COPD, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, osteoarthritis or osteoporosis, in a patient suffering from, or have�risk of the disease, comprising administering to the patient a therapeutically effective amount of a compound of formula (1) or pharmaceutically acceptable salt as defined above in this description.

More specifically, the compounds of the invention may be useful in the treatment of asthma, allergic rhinitis, COPD, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer.

Compounds according to the invention is shown in both a therapeutic and/or prophylactic treatment of the above conditions.

Specialist in the art it is clear that the term "atherosclerosis" includes any disease characterized by the accumulation of cholesterol and formation of foam cells, inflammation, and cell proliferation in a blood vessel, especially in the artery wall.

According to another aspect of the invention proposes a method for the treatment of the disease/condition for which the modulating activity of a chemokine receptor is useful (e.g. a specific disease/condition specified in this description of the invention), comprising introducing the compound according to the invention to a patient in need of such treatment.

"Patients" include mammalian patient (including humans). Therefore, the method of treatment described above, �may include treatment of the human or animal body.

The term "effective amount" refers to the amount of the compound which has a therapeutic effect on a treated patient. This effect may be objective (e.g. measurable by some test or marker) or subjective (for example people reported the symptom or feelings effect).

Compounds according to the invention can be administered orally, intravenous, subcutaneous, buccal, rectal, dermaline, nasal, tracheal, bronchial, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form. For example, pharmaceutical compositions can be entered locally (e.g. to the lungs and/or Airways or to the skin) in the form of solutions, suspensions, heptapteridae aerosols and dry powder compositions;

or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. In one aspect, the compounds of the invention are administered orally.

Compounds according to the invention can be entered by themselves, but in one aspect of the invention, they are administered in the form of a known pharmaceutical pre�herdsmen, includes tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. Type pharmaceutical composition may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have harmful side effects or toxicity under the conditions of use.

Such compositions can be obtained in accordance with standard and/or accepted pharmaceutical practice. Or obtaining of the suitable compositions may be made by a specialist without inventive approach, with the use of regular operations and/or in accordance with standard and/or accepted pharmaceutical practice.

Thus, according to another aspect of the invention proposed pharmaceutical composition, comprising a compound according to the invention, as defined above in this description of the invention, in admixture with pharmaceutically acceptable auxiliary substance, diluent and/or carrier, Such compositions can be entered as described above in this description of the invention. The connection according to the invention (that is, crystalline form), which is a m�is the active ingredient of the pharmaceutical composition, may be ground or milled into smaller particles.

Depending, for example, the effectiveness and physical characteristics of the compounds according to the invention (i.e. active ingredient), pharmaceutical compositions that may be mentioned include those in which the active ingredient (i.e. the compound of the invention) is present in amounts of at least 1% of the mass.(or at least 10%, at least 30% or at least 50% wt.). That is, the ratio of active ingredient to other components (i.e. the addition of an auxiliary substance, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, 30:70 or at least 50:50) by weight.

The number of compounds according to the invention in the composition will depend on the severity of the condition and patient being treated, and the compound(s) that(s) used, but may be determined by a specialist without inventive approach.

The invention also provides a method of obtaining pharmaceutical compositions, as defined above in this description of the invention, comprising combining the compound according to the invention, as defined above in this description of the invention with pharmaceutically acceptable auxiliary substance, diluent or carrier.

Connections Fig�structure can also be combined with other therapeutic agents, for example with those who are also useful in the treatment of the disease/condition for which the modulating activity of a chemokine receptor is beneficial (e.g. diseases/conditions specified in this description of the invention). Compounds according to the invention can also be combined with other therapies.

According to another aspect of the invention proposes a combined product containing:

(A) a compound of the invention, as defined above in this description of the invention; and

(B) another therapeutic agent that is useful in the treatment of the disease/condition for which the modulating activity of a chemokine receptor is beneficial (e.g. disease/condition described in this description of the invention, where each of the components (A) and (B) is prepared as a pharmaceutical preparation in admixture with pharmaceutically acceptable auxiliary substance, diluent or carrier.

Such combined products offer for the introduction of compounds according to the invention in combination with another therapeutic agent, and may thus be presented either as separate compositions, where at least one of these compositions contain the compound of the invention and at least one contains a different therapeutic agent, or they can be performance�HN (that is made in the form of the drug) in the form of a combined preparation (i.e. presented as a single composition, comprising a compound of the invention and another therapeutic agent). Thus, it is also proposed:

(1) pharmaceutical composition, comprising a compound according to the invention, as defined above in this description of the invention, the other therapeutic agent that is useful in the treatment of the disease/condition for which the modulating activity of a chemokine receptor is beneficial, and a pharmaceutically acceptable excipient, diluent or carrier; and

(2) a list containing components:

(a) a pharmaceutical composition comprising a compound according to the invention, as defined above in this description of the invention, in admixture with pharmaceutically acceptable auxiliary substance, diluent or carrier; and

(b) a pharmaceutical composition comprising another therapeutic agent that is useful in the treatment of the disease/condition for which the modulating activity of a chemokine receptor is beneficial, in admixture with pharmaceutically acceptable auxiliary substance, diluent or carrier, where each of the components (a) and (b) is offered in a form that is suitable for administration in combination with another.

The invention also provides a method of obtaining a combination product, as defined above in this description image�etenia, comprising combining the compound according to the invention, as defined above in this description of the invention with another therapeutic agent that is useful in the treatment of cancer and/or proliferative disease, and at least one pharmaceutically acceptable auxiliary substance, diluent or carrier.

By "Association", the inventors mean that the two components lead to a condition that is suitable for administration in combination with each other.

Thus, in relation to the method of producing a set of components, as defined above in this description of the invention, by "merging" two components with each other, the inventors mean that these two components can be set:

(1) presented as separate formulations (i.e. independently of one another), which then take however for use in combination with each other in combination therapy; or

(2) packaged and presented together as separate components of a "combination pack" for use in combination with each other in combination therapy.

Depending upon the disorder and patient to be treated and the route of administration, the compounds according to the invention can be administered in different therapeutically effective doses to a patient in need of it. However, the dose imposed by melicope�ment, especially the person in the context of the present invention, should be sufficient to cause a therapeutic response in the mammal within an acceptable period of time. The person skilled in the art understands that the choice of an accurate dose of the composition and the most appropriate mode of delivery will also be influenced, inter alia, the pharmacological properties of the composition, nature and severity of the condition being treated, the physical condition and clarity of mind of the patient, and the effectiveness of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of disease.

Administration may be continuous or intermittent (for example by bolus injection). The dosage can also be determined by time and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg of the compounds according to the invention in a day.

In any case, a medical practitioner or other specialist, can easily determine the actual dosage which will be most suitable for an individual patient. The above dosages are exemplary for the average case; there may, of course, be some instances when useful higher or lower ranges of dosages, and includes any � scope of this invention.

Wherever the word "about" was not used in this description of the invention, for example in the context of quantities (such as values, mass, volume, moles, temperature, degree of crystallinity, degree of destruction, the degree of purity, degree of dissolution and doses of active ingredients, it will be obvious that such variables are approximate and as such may vary by ±10%, for example ±5%, ±2% or ±1% of the numbers specified in this specification.

Compounds of the invention have the advantage that they are in a form that provides improved ease of handling, and can be obtained in forms which have improved chemical stability and solid state stability compared with the forms obtained earlier. Thus, the compounds can be stable when stored for extended periods. In particular, the D-form (see Example 2 below in this description of the invention) may have improved thermodynamic stability in comparison with forms of Compound I obtained earlier.

Compounds according to the invention also have improved solubility profiles and hygroscopicity in comparison with previously available forms.

Compounds according to the invention may also have the advantage that they can be obtained with good yields, with higher �istoday, within less time, more conveniently and at lower cost, than forms obtained earlier.

Compounds according to the invention may also have the advantage that they can be more effective, less toxic, have a more prolonged action, to be more effective, cause fewer side effects, easier to absorb, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), and/or have other useful pharmacological, physical or chemical properties compared to known compounds (for example previously known forms of Compound (I), for use in the aforementioned indications and other.

The invention is illustrated but not limited by them, the following examples with reference to the attached figures, where:

Fig.1 shows x-ray powder diffractogram of the crystalline form A of anhydrate of Compound I using a wavelength of x-rays 1,5418 Å obtained by Example 1 (the amount of pulses/second (intensity) is applied on the graph depending on the values of °2-theta).

Fig.2 shows x-ray powder diffractogram of the crystalline form D of anhydrate of Compound I using a wavelength of x-rays 1,5418 Å, obtained simply�PTO of Example 2 (the amount of pulses/second (intensity) is applied on the graph depending on the values of °2-theta).

Fig.3 shows the DSC of the crystalline form of anhydrate of Compound I obtained by means of the Example 2.

A common methodology for the description of the method of x-ray diffraction on powder

It is known that it is possible to obtain x-ray powder diffraction pattern which consists of one or more measurement errors depending on measurement conditions (such as used appliance or device). In particular, it is well known that the intensity of the x-ray powder diffraction pattern may fluctuate depending on measurement conditions. Therefore, it should be understood that the Forms A and D of the present invention is not limited to the crystals that exhibit x-ray powder diffraction patterns identical to the x-ray powder diffraction pattern shown in Fig.1 and 2, and any crystals showing x-ray powder diffraction pattern essentially the same as shown in Fig.1 and 2, are included in the scope of the present invention. A specialist in the field of x-ray diffraction on the powder is able to draw a conclusion about the identity essentially x-ray powder diffraction patterns.

A specialist in the field of x-ray diffraction on the powder realizes that the relative intensity of peaks can be affected, for example, the grains larger than 30 microns and varies the ratio of the geometry�die sizes which may affect analysis of samples. The specialist also understands that the position of reflections can influence the exact height at which the sample is placed in the diffractometer and the zero calibration of the diffractometer. Playmost the sample surface can also have a small effect. Consequently, the diffraction pattern data presented should not be taken as absolute values.

Typically, the measurement error of a diffraction angle in an x-ray powder diffractogram is about 5% or less, in particular plus or minus 0.5° 2-theta. Usually plus or minus 0.2° 2-theta. Such degree of a measurement error should be taken into account when considering the x-ray powder diffraction pattern in Fig.1 and 2 and looking at Tables 1, 2 and 2A. In addition, it should be understood that intensities might fluctuate depending on experimental conditions and sample preparation (preferred orientation).

Analysis of x-ray diffraction on the powder (XRPD) was performed on samples prepared by standard methods, for example described in Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. &Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.

Analyses of x-ray diffraction was performed, �using Then-No. ARL X'tra (wavelength of x-rays 1,5418 Å , the radiation source of Cu, a voltage of 45 kV, the emission of the filament 44 mA) within 152 minutes 2 to 40°. Perform calculations of the provisions of the peaks (°2-theta), they may vary in the range of ±0.5° 2-theta. However, the data presented in Table 2A for Form D, obtained using the device Bruker D4 and wavelength 1,5418 Å.

Specialist in the art it is obvious that the intensity of the XRPD may vary when measured for essentially the same crystalline form, such as preferred orientation.

Differential scanning calorimetry

Analytical instrument: TA Instruments Q1000 DSC. Usually less than 5 mg of the substance contained in 40 ál aluminum cuvette, fitted with a glass lid, heated in the temperature range from 25°C to 300°C at a constant heating rate of 10°C per minute. Used nitrogen as the purge gas flow rate of 100 ml per minute.

Referential Example 1

(R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)ethanol

1) 5,6-O-isopropylidene-L-ascorbic acid

To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and 2,2-dimethoxypropane (46 kg, 443 mol) was uploaded steam-toluensulfonate acid (1.1 kg, 5.5 mole). The temperature was adjusted to 25±5°C. the Slurry was stirred for 2 hours, during which nitrogen is often passed through a bottom valve for prevented�I deposition of the substance on the bottom of the reactor. Subsequent analysis by NMR (solvent: D2O) showed 98.5% conversion.

Loaded heptane (222 kg) and the temperature was adjusted to 5±5°C. the Reaction mixture was stirred for at least 30 minutes before filtering. The remains acetonide product in the reactor was washed away in the residue on the filter, using the mother liquors. The residue on the filter was washed with heptane (111 kg) and dried at 50°C with obtaining 5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) in the form of almost white powder. Yield: 91%.

1H NMR (400 MHz, d6-DMSO, with maleic acid and TFA (trifluoroacetic acid)) δ 4.71 (d, J=3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J=7,0, 8.4 Hz, 1H), 3.90 (dd, J=6,3, 8.4 Hz, 1H), 1.27 (s, 6H).

2) (R)-Methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)-2-hydroxyacetate

5,6-O-Isopropylidene-L-ascorbic acid (to 58.8 kg, 272 mol) was charged to a solution of sodium hydroxide (27.5 kg, 50%, 340 mol), diluted with water (294 kg) and the temperature was adjusted to 30±5°C. was Loaded with sodium bicarbonate (57 kg, 680 mol) and the mixture was stirred for 15 minutes, then temperature increased to 40±5°C. hydrogen Peroxide 35% (55 kg, 562 mol) was added to the mixture at 35-60°C for a period of time longer than 60 minutes. The reaction mixture was stirred for two hours before NMR analysis (solvent: D2O), which showed <1% remaining starting material.

Sodium sulfate (4.2 kg, 33 mol) was charged to a reactor and �after stirring for 30 minutes the test for peroxide is negative.

After loading the additional amount of sodium bicarbonate (34 kg, 408 mol), the mixture was heated to 70±5°C and was stirred for at least one hour before NMR analysis (solvent: D2O), showed 98.5% conversion in the following intermediate compound, (2R)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](hydroxy)acetic acid.

Approximately 150 l of water was separated under reduced pressure before filtering out salts. The residue on the filter was washed with water (30 l).

NMP (N-methylpyrrolidone) (330 kg) were loaded into the combined mother liquors/wash water and the temperature was adjusted to 30±5°C. was Loaded methyl iodide (83 kg, 585 mol) and the reactor was closed. The temperature was adjusted to 55±5°C and the reaction mixture was allowed to interact for a period of at least 120 minutes before NMR analysis (solvent: D2O), which showed 6% of the remaining intermediate connections, hydroxiacetic.

Uploaded sodium sulfite (56 kg, 446 mol) dissolved in water (147 kg) and the mixture was stirred for 30 minutes. The solution was extracted with four times for 10 minutes at 30±10°C, using 406 kg of toluene in each extraction. The combined organic phase was concentrated by removing the solvent under reduced pressure and a maximum temperature of 70°C to achieve a residual volume of approximately 350 l. the Solution was cooled to t�of mperature below 30°C and transferred in steel barrels on a Millipore filter to obtain a solution of (R)-methyl-2-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)-2-hydroxyacetate in toluene (359 kg, 9,4%, 177 mol). Yield: 65%.

1H NMR corresponds to a commercially available sample specified in the subtitle product.

3) (R)-Methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)-2-(tosyloxy)acetate

From a solution of (R)-methyl-2-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)-2-hydroxyacetate in toluene (359 kg, 9.4 per cent, 177 mol) toluene was distilled off under reduced pressure and a maximum temperature of 70°C to stop the condensation.

Uploaded acetonitrile (153 kg) and the temperature was adjusted to 25±5°C. was Added triethylamine (41 kg, 405 mol), 4-(dimethylamino)pyridine (1.12 kg, 9,2 mol) and then, after about 30 minutes, a solution of para-toluensulfonate (52,5 kg, 276 mol) in acetonitrile (146 kg) at 25±5°C. After stirring the reaction mixture for another three hours analysis of NMR analysis (solvent: d6-DMSO) showed an acceptable conversion (94%).

Uploaded MTBE (methyl tert-butyl ether) (235 kg) and water (326 kg) and the two-phase system was stirred for about 3 hours, after which HPLC analysis showed the level of para-toluensulfonate less than 0.1% of the total peak area. The temperature was adjusted to 25±5°C and then the mixture was allowed to separate for 15 minutes. The aqueous phase was collected and was extracted with additional MTBE (156 kg) before discarding. Combined together 2 organic phase was washed with water (326 kg). Then the organic phase was washed 4 times with a solution of chloride �extended to every portion 16 kg) in water (each serving is 140 kg), each time for 5-10 minutes at 25±5°C. Then the organic phase was washed twice with water (185 kg per serving) each time for 5-10 minutes at 25±5°C. Then NMR analysis (solvent: d6-DMSO) showed less than 2% NMP (remaining from the initial solution) in moles relative to the intermediate sulfonate ester.

Loaded activated carbon (6.0 kg) and the suspension was stirred for 15 minutes at 25±5°C, then filtered coal on two parallel bag filters. After the bag filters used cluster filter of 0.6 μm. Filters and tubes were washed with MTBE (27 kg).

The mother liquors and washings were combined and the volume reduced by separation of the solvent under reduced pressure and a maximum temperature of 50°C until the termination of condensation. Loaded heptane (106 kg) and the volume of the solution was lowered again by separation of the solvent under reduced pressure and a maximum temperature of 50°C until the termination of the condensation, leaving about 60 liters of solution in the reactor. Uploaded MTBE (185 kg), then after adjusting the temperature to 25±5°C was added heptane (75 kg). The solution was cooled to 0-5°C for at least 30 minutes and added heptane (150 kg) for another 20 minutes. The slurry was stirred for one hour at 0-5°C and then filtered. The residue on the filter was washed with a mixture of MTBE (16 kg) and heptanol (30 kg). The wet product was loaded into vacuu�ing shelf dryer and dried at 35°C (pressure less than 100 mbar (10 4PA)) to give (R)-methyl-2-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)-2-(tosyloxy)acetate (51,3 kg, 154 mol) as a light brown powder. Yield: 87%.

1H NMR (400 MHz, CDCL3) δ 7.83 (m, 2H), 7.35 (m, 2H), 4.84 (d, J=4,8 Hz, 1H), 4.46 (m, 1H), 4.04 (dd, J=6,6, to 9.1 Hz, 1H), 3.97 (dd, J=5,2, of 9.1 Hz, 1H), 3.70 (s, 3H), 2.45 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H).

4) (S)-2,2-Dimethyl-4-((R)-oxirane-2-ol)-1,3-dioxolan

(R)-Methyl-2-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)-2-(tosyloxy)acetate (76,1 kg, 221 mol) was dissolved methanol (57 kg) and dichloromethane (208 kg).

Methanol (14 kg), dichloro methane (53 kg) and one third of the initial solution of the substance (74 mol) were loaded into the reactor. The solution was adjusted to 10-15°C. Then sodium borohydride (6.3 kg, 169 mol) 18 portions were loaded into the reactor, maintaining the temperature of 8-15°C. the Mixture was stirred for half an hour after the upload completes. Downloaded following one third of the initial solution of the substance (74 mol) and then sodium borohydride (6,3 kg, 169 mol), followed by the half-hour stirring, using the same method as before. This procedure was repeated again with the last one-third of the initial solution of the substance (74 mol) and additional sodium borohydride (6,3 kg, 169 mol). Then analysis by HPLC showed greater than 99.9% conversion to the intermediate compound, (S)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)-2-hydroxyethyl-4-methylbenzenesulfonate.

Dichloro methane (200 kg) was charged into the reaction mixture. The solution �of ethylate sodium in methanol (43 kg 30%, 239 mol) was added in portions at 20-25°C for 60 minutes. After about half an hour, HPLC analysis showed 99.7% of the expenditure of the intermediate alcohol.

A solution of sodium acetate (25 kg) in water (230 l) was charged into the reaction mixture. The mixture was stirred for 10-15 minutes at 20-25°C. After separation for 15 minutes and the lower organic phase was removed. The upper aqueous phase was extracted with dichloromethane (376 kg). The lower organic phase was removed by combining with the first organic phase and the aqueous phase was discarded.

Water (359 l) was charged to a combined organic phase. After stirring for 10-15 minutes at 20-25°C and standing for 15 minutes and the lower organic phase was transferred into a reactor containing sodium sulfate (63 kg).

Volume of the mixture was reduced to 310 l by separating the solvent and then filtered sodium sulfate. The residue on the filter was washed with dichloromethane (94 kg). The United liquids are thoroughly mixed and then discharged into steel drums through a polypropylene bag filter to obtain a solution of (S)-2,2-dimethyl-4-((R)-oxirane-2-ol)-1,3-dioxolane in DCM (467,5 kg and 6.2%, 203 mol) in the form of a clear yellow liquid. Yield: 91%.

A sample that does not contain solvents, it was possible to allocate in a small volume by evaporation of solvent and then distillation under vacuum.

1H NMR (vydeleny�th sample, 400 MHz, d6-DMSO) δ 4.01 (dd, J=6,6, 8,2 Hz, 1H), 3.92 (m, 1H), 3.72 (dd, J=5,8, 8,2 Hz, 1H), 3.03 (ddd, J=2,6, and 4.1, and 5.2 Hz, 1H), 2.77 (dd, J=4,1, 5,0 Hz, 1H), 2.58 (dd, J=2,6, and 5.0 Hz, 1H), 1.34 (s, 3H), 1.27 (s, 3H).

5) (R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)ethanol

From a solution of (S)-2,2-dimethyl-4-((R)-oxirane-2-ol)-1,3-dioxolane in dichloromethane (465 kg and 6.2%, 200 mol) of dichloro methane was distilled at 41-42°C and replaced by THF (tetrahydrofuran) (129 kg). Distillation was continued at 60°C to achieve a given volume in the reactor (235 l). The solution of the case of lithium (LAH) in THF (26,4 kg, 10%, 70 mol) was added portionwise into the reactor at 22°C and after subsequent stirring at 25°C for about one hour OS(gas chromatography) analysis showed more than 99.9% of the expenditure of the initial substance.

Small portions of water were added through the hopper at a speed which is regulated to control the temperature and foaming. Just added 2.6 liters of water (1 litre per kg LAH). A solution of sodium hydroxide (2.6 kg, 15%,1 l per kg LAH) was added in the same manner as described for the water. Water (7.9 l, 3 l per kg LAH) was uploaded again through the hopper, using the same method as before.

The slurry was filtered and the residue on the filter was washed with THF (36 kg). The filtrate is concentrated by the separation of THF at a maximum temperature of 85°C until the termination of condensation. Uploaded 2-MeTHF (129 kg) to the reactor and then the solvent was distilled before of�I volume of solution approximately 120 liters. Analysis by KF (Karl Fischer) showed less than 0.1% water. The solution was discharged through a filter cassette to the drum, lined with PE (polyethylene), to obtain a solution of (R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-ol)in ethanol (103 kg, 27%, 187 mol) in the form of transparent light yellow liquid. Yield: 94%.

A sample that does not contain solvents, it was possible to allocate in a small volume by evaporation of the solvent and subsequent distillation under vacuum.

1H NMR (selected sample, 400 MHz, d6-DMSO) δ mn-14.77 (d, J=5.1 Hz, 1H), 3.95 (dd, J=8,0, a 6.2 Hz, 1H), 3.76 (dd, 8,0, 6,0 Hz, 1H), 3.70 (m, 1H), 3.46 (m, 1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.07 (d, J=6.2 Hz, 3H).

Example 1: form a - anhydrate of Compound I

Compound I, i.e. N-[2-[[(2,3-differenl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl"] oxy}-4-pyrimidinyl]-1-azetidin-sulfonamide (obtained for example in accordance with Example 47 in WO 2006/024823) used in the following way.

1. Download MAPI Connection I (43,94 g, 100% wt. = 40,0 g) and acetonitrile (160 ml, 4,0 relative volume) in the vessel 1 and stirred at 20°C.

2. The mixture was filtered into a vessel and washed with 2 vessel 1 and the production lines acetonitrile (20 ml, 0,50 relative volumes). Was stirred and heated to 55°C.

- Used Whatman filter paper, grade 3 (pore size of 6 microns, the diameter of the circular area of the filter 32 mm).

Filter paper can be replaced by a clean (if �the rate of filtration using suction slows down).

After filtration the solution was weighed and found that its mass is less than the estimated. It topped a small portion of acetonitrile (10 ml, 0,25 relative volumes) to correct obvious losses by evaporation.

3. Download phosphoric acid (8,80 g, 0,22 relative mass), then water (20 ml, 0,50 relative volumes) in a stirred solution in vessel 2, to dissolve and change the set value of 51°C.

- Acid and water can be downloaded together, if this is more convenient.

4. Take a sample of the reaction mixture for determination of transformation through 10 and 35 minutes.

- It is important to dilute the samples for HPLC analysis as soon as possible after their selection, specifying the time at which dilution were actually made.

- The transformation was 45, 81 and 93% after the 10.5, 32 and 57 min, respectively. Move on to stage 5 at t=135 min.

5. Heated to 71°C.

Stage 6 should be started as soon as possible after reaching about 68°C.

6. Charged water (204 ml, 5.1 m relative volumes), slowly enough to keep the temperature above 67°C.

7. Cooled to 65°C.

- It is important that the temperature of the reaction mixture was as close as possible to the specified value before continuing. Temperatures were 2-3°C lower can lead to very rapid crystallization and related issues. Temperature 3°C above could exceed preelementary transparency and crystallization will not be able to start.

8. If necessary, create a seed for crystallization by dilution of the sample solution (0,48 ml 0,012 relative volumes) of water (1.44 ml relative volume of 0.036). Well mixed and then loaded liquid mixture back into the solution.

9. Support at 65°C for 40 min.

10. Cool to 6°C at a rate of 3°C/h (65-59°C for 2.0 hours, then at 8°C at a rate of 4°C/h (59-51°C) and finally to 20°C at a rate of 6°C/h (51-20°C for 5.2 h).

11. Check that crystallization has reached an appropriate balance.

12. Filtered, the residue washed twice with a mixture of 3:2 vol.:about water:acetonitrile. (2×120 ml, 2×3,00 relative volume), including rinsing of the vessel 2 for each rinse, and then dried at 60°C to constant weight.

Alternatively, a Form can be obtained in the following way:

1. Download N-[2-[[(2,3-differenl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidin-sulfonamide (obtained for example in accordance with Example 47 in WO 2006/024823) (43,94 g, 100% wt. = 40,0 g) and acetonitrile (160 ml, 4,0 relative volumes) in the vessel 1 and stirred at 20°C.

2. Filter the mixture into a vessel and washed with 2 vessel 1 and the production lines acetonitrile (20 ml, 0,50 relative volumes). Was stirred and heated to 55°C.

- Used Whatman filter paper grade 3 (pore size of 6 microns, the diameter of the circular area of the Fi�tra 32 mm).

Filter paper can be replaced by a clean (if the filtration rate using the suction slows down).

After filtration the solution was weighed and found that the weight is less than estimated. It topped a small portion of acetonitrile (10 ml, 0,25 relative volumes) to correct obvious losses in evaporation of acetonitrile.

3. Download phosphoric acid (8,80 g, 0,22 relative mass), then water (20 ml, 0,50 relative volume) in a stirred solution in vessel 2 change setpoint at 51°C.

- Acid and water can be downloaded together, if this is more convenient.

4. Take a sample of the reaction mixture for determination of transformation through 10 and 35 minutes.

- It is important to dilute the samples for HPLC analysis as soon as possible after their selection, specifying the time at which dilution were actually made.

- The transformation was 45, 81 and 93% after the 10.5, 32 and 57 min, respectively. Proceed to stage 5 at t=135 min.

5. Heated to 71°C.

- Stage 6 should be started as soon as possible after reaching about 68°C.

6. Charged water (204 ml, 5.1 m relative volumes) slowly enough to keep the temperature above 67°C.

7. Cooled to 65°C.

- It is important that the temperature of the reaction mixture was as close as possible to the specified value before continuing the method. Temperatures were 2-3°C below may Pref�STI to very rapid crystallization and related issues. Temperature 3°C above can go beyond the transparency and temperature of crystallization will not be able to start.

8. Support at 65°C for 40 min.

9. Cool to 6°C at a rate of 3°C/h (65-59°C for 2.0 hours, then at 8°C at a rate of 4°C/h (59-51°C) and finally to 20°C at a rate of 6°C/h (51-20°C for 5.2 h).

10. Check that crystallization has reached an appropriate balance.

11. Filtered, the residue washed twice with a mixture of 3:2 vol.:about. water:acetonitrile (2×120 ml, 2×3,00 relative volume), including rinsing of the vessel 2 for each rinse, and then dried at 60°C to constant weight to produce a Compound I Form A.

Alternatively, the form can be obtained by dissolving N-[2-[[(2,3-differenl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl"] oxy}-4-pyrimidinyl]-1-azetidin-sulfonamide (obtained from N-[2-[[(2,3-differenl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-4-pyrimidinyl]-1-azetidin-sulfonamida in accordance with Example 47 in WO 2006/024823) in water (6,2 relative volumes) and acetonitrile (5 relative volumes) by heating to 70°C. once this temperature is reached and the solution became transparent, the solution was slowly cooled to 20°C. Crystallization usually starts at a temperature of about 60°C to obtain Form A.

The XRPD diffraction pattern for Form A using wavelength 1,5418 And on at�Corder Thermo ARL X'tra XRD shown in Fig.1 and presented in Table 1 below.

Table 1
Angle (°2-theta)Relative intensity (%)
approximately 25-100%="vs", approximately 10-25%="s", approximately 3-10%="m" and about 1-3%="w"
4,4vs
8,7vs
9,7s
9,9vs
11,4vs
13,1vs
14,8s
15,5s
15,9m
16,3s
17,6vs
of 17.8vs
18,2s
18,5s
19,0m
19,2vs
19,5vs
19,9vs
20,1m
21,9m
22,4vs
23,8s
24,1vs
24,4s
24,9m
26,1s
26,5s

This agitata form of Compound I was vysokomaslichnoy.

Example 2: Form D - anhydrate of Compound I

Form a of Compound I are obtained, for example, the method described in Example 1 above, was transformed into the Form of D.

Form a of Compound I was suspendirovanie in methanol at 50°C for 6 weeks with receiving the D-form.

You can also obtain the form D by suspendirovanie product from Example 47 in WO 2006/024823 in methanol at 50°C for 6 weeks.

According to DSC of form D had a melting point 152,7°C (onset). See Fig.3 below.

The XRPD diffractogram of form D with the wave-length of 1,5418 Å, Thermo ARL X'tra XRD pok�Zana Fig.2 and presented in Table 2 below.

/tr>
Table 2
Angle (°2-theta)Relative intensity (%)
approximately 25-100%="vs", approximately 10-25%="s", approximately 3-10%="m" and about 1-3%="w"
4,4vs
8,7vs
9,7vs
11,5s
12,9vs
13,1vs
14,5s
18,0vs
19,0vs
19,1vs
19,3s
19,5s
19,9vs
21,0s
21,9^s
22,5vs
23,9s
24,5s
25,1s
25,3s
27,0s
28,6m
28,8s
29,1s
30,4s
34,6m
by 36.4m

The XRPD diffractogram of form, obtained according to Example 1 using wavelength 1,5418 Å on the device Bruker D4 XRD are presented in Table 2A below.

Table 2A
The value of D°2-theta%
d=20,0094,485,3
d=10,0688,8100,0
d=9,0299,873,9
d=8,42810,512,4
d=7,63011,623,4
d=6,822of 13.058,5
d=6,72513,268,4
d=6,08814,511,8
d=5,64715,712,9
d=5,49316,111,4
d=5,04817,614,7
d=4,89918,194,3
d=4,73118,717,0
d=4,64719,127,9
d=4,61419,227,7
d=4,57719,426,5
d=4,52719,631,0
d=4,43420,055,3
d=4,35620,419,2
d=4,30520,614,8
d=4,21921,014,9
d=4,155a 21.413,1
d=4,04921,924,4
d=4,039 units22,026,5
d=3,94222,551,0
d=3,78123,516,3
d=3,70624,038,4
d=3,61824,623,4
d=3,52925,233,0
d=3,50625.4 mmthe 38.2
d=3,42126,08,5
d=3,36826,4a 16.4
d=3,29727,014,1
d=3,10928,79,7
d=3,090of 28.9the 16.2
d=3,06429,118,4
d=2,96230,112,9
d=2,93330,424,8
d=2,88930,911,6
d=2,77032,39,1
d=2,72832,88,4
d=2,63834,08,5
d=2,58834,615,2
d=2,46136,510,9
d=2,36338,06,0
d=2,329the 38.611,6

This agitata form of Compound I was also vysokomaslichnoy and also was more thermodynamically stable than the A-form is obtained by means of the Example 1 (see Example 3 below).

Example 3: Form D - anhydrate of Compound I

Modification of D can be obtained by using crystallization with Antibacterials, using ethanol as solvent and water as antibacterial.

Get rich 80% solution of the compound in ethanol, e.g.� by dissolving 1 relative mass of the compound in 83 relative volumes of ethanol at 25°C (equivalent to 12 mg AZD 5069 in 1 ml of ethanol). The solution can be obtained from crystalline substances form A or amorphous substances. To this solution was added 166 relative volumes of water (double the volume of water relative to ethanol), or continuously for some period of time, or multiple aliquots. When water is added the compound crystallizes in the form D versions, and can be separated from the slurry by filtering.

Example 4: Form D Connection 1 anhydrate (method using priming)

Form D was also obtained with a yield of 80% by the use of priming, which comprises dissolving Compound I (e.g. one relative "mass") in a solvent (such as alcohol, for example isopropanol; for example 30 relative volumes, or ethanol; 15 relative volumes); stirring at elevated temperature (e.g. 70°C), for example within a time period (which can amount to several hours) to achieve complete dissolution; continuation of stirring at an elevated temperature (e.g. 55°C; i.e. at a temperature below that required to achieve dissolution) within a few hours (e.g. over night); the introduction of priming of Form D of Compound I (e.g. 0.1 wt.%); cooling to a lower temperature (e.g. 20°C) and filtering.

Example 5: Thermodynamic stability

Vol�lnai comparative tests of suspended matter And form (obtained according to Example 1) and D-forms (obtained according to Example 2).

Compare suspension containing the A-form and D-form in methanol maintained at any temperature in the range from about 5°C to about 50°C. it is Found that the D-form is stable under these conditions. However, the A-form is transformed into a D-shape.

Complete metamorphosis A-form to D-form occurs when the slurry is maintained at a specific temperature for a sufficient period of time.

This indicates that the D-form is thermodynamically more stable form than the A-form, at least in specific relevant temperature range, and therefore the D-form may be more desirable than A-form, for use as a medicament.

1. Crystalline form of N-[2-[[(2,3-differenl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl"] oxy}-4-pyrimidinyl]-1-azetidin-sulfonamida, characterized by x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å, containing at least one crystalline peak with a value of 2-theta (degrees) 21,0, is 28.8 and/or 29.1.

2. The crystal form according to claim 1, wherein the x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å, containing at least 2 crystal peak value of 2-theta (degrees) 21,0, is 28.8 and/or 29.1.

3. Cristalli�by technical form according to claim 2, wherein the x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å, containing at least 3 crystalline peak with a value of 2-theta (degrees) 21,0, is 28.8 and/or 29.1.

4. The crystal form according to claim 1, wherein the x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å, containing additional crystalline peak with a value of 2-theta (in degrees) selected from the 12.9 and 18.0.

5. The crystal form according to claim 1, wherein the x-ray powder diffraction pattern, measured using a wavelength of x-rays 1,5418 Å containing crystalline peaks with a value of 2-theta (in degrees) 12,9, 13,1, 18,0, 21,0, 22,5, 25,1, 25,3, 28,8, 29,1 and 30.4.

6. Crystalline form of N-[2-[[(2,3-differenl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl"] oxy}-4-pyrimidinyl]-1-azetidin-sulfonamida, which has a melting point (onset) 152,7°C.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: medicine, pharmaceutics.

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

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

21 cl, 3 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to specific compounds or to their therapeutically acceptable salt presented in the patent claim and representing sulphonyl benzamide derivatives. The invention also refers to a pharmaceutical composition inhibiting the activity of anti-apoptotic proteins of the family Bcl-2, containing an excipient and an effective amount of a specific sulphonyl benzamide derivative.

EFFECT: sulphonyl benzamide derivatives inhibiting the activity of anti-apoptotic Bcl-2 proteins.

2 cl, 3 tbl, 558 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula OR or its pharmaceutically acceptable salt or solvate. The radical values are as follows: Rt - H, C1-C8 alkyl group, ammonium ion, alkali or alkali-earth ion; R84 - substituted C1-8 alkyl; R - C1-8 hydroxyalkyl, C1-8 alkoxyalkyl, C1-8 aminoalkyl, (CH2)8(NHC(S)NH)Ph(SO2NH2), (CH2)dPh(SO2NH2), (CH2)5C(O)NH-(1-acetylpyrrolidin-2-yl)boric acid, (1-acetylpyrrolidin-2-yl)boric acid, (CH2)4CH(NH2)CO2H, (CH2)3CH(NH2)CO2H, (CH2)2CH(NH2)CO2H, -(CH2)d-R80, -C(O)(CH2)d-R80, or amino acid radical; R80 is carboxylate, C6-10 aryl, 3-6-merous heterocyclyl, amino acid; d represents an integer within 0 to 12 inclusively; and R82, R83, R85 and R86 are hydrogen, substituted or unsubstituted alkyl, ether, ester, CH2CH2OCH2CH3, CH2CH(OCH3)2, -(CH2)d-R80, or (CH2)dR87; wherein R87 represents phosphonate or phosphorinate. What is also presented is a complex containing the above compound and a radionuclide.

EFFECT: compound can be used as diagnostic or therapeutic agents.

11 cl, 13 dwg, 10 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , II or IV , wherein the radical values W, V, Ra, Rb, X, L, Rt, A are presented in the patent claim.

EFFECT: declared compounds identify and bind the CA-IX protein; they can contain a radioactive element for radionuclide imaging or therapeutic application.

27 cl, 1 tbl, 5 dwg, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.

EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.

18 cl, 12 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, including: i) opening of epoxy cycle of Compound 3 by means of methylamine with obtaining compound 4, ii) separation of Compound 4 by means of chiral acid, selected from L-(-)-malic acid and L-(-)-pyroglutamic acid with obtaining Compound 5A or 5B, or iii protection of secondary amine of Compound 5A or 5B with tert-butoxycarbonyl protective group with obtaining compound 6 iv) methylation of free hydroxyl group of Compound 6 with methylating agent, v) removal of protection from amino groups by means of monohydrate of p-toluenesulphonic acid with obtaining Compound 8 and vi) interaction of Compound 8 with compound 10 with the following obtaining (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid.

EFFECT: method improvement.

29 cl, 3 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to oncology, and can be applied for the treatment of adenogenous locally advanced cancer of the rectum. For this purpose chemotherapy with 5-fluorouracil, medical therapy, gamma-therapy are realised by a method of dynamic fractioning of a dose. 5-fluorouracil is introduced into the pararectal cellular tissue, adjacent to a tumour, in a volume of 5-15 ml 5-15 min before an irradiation session of before the first three large fractions. As the drug therapy realised is infusion introduction of Mabthera in a dose of 50-70 70 mg/m2 50-60 minutes before radiotherapy on the 1, 7 and 14 days of treatment. From the 1 to 12 days from the treatment beginning radiotherapy is performed on the tumour zone and the zone of regional metastases from 2-4 fields in a mode of dynamic fractioning with SFD=3.6 Gy 3 times and further with SFD=2.2-2.4 Gy 9 times to TFD=32.4-34.8 Gy.

EFFECT: method ensures the reduction of the volume and size of the initial tumour, transfer of non-operable and conditionally operable stages of the disease into the operable state and a possibility of carrying out radical operations with an increase of therapy tolerance as a result of reduction of toxic and cytotoxic effects of the treatment, increase of protective powers of the organism and a possibility of carrying of radiotherapy in the total volume.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to immunology. What is described is an immunoconjugates targeting CD138-expressing cells containing: IgG4 anti-CD138 antibody containing a heavy chain having CDRs from SEQ ID NO: 1 presented in the description and at least 70% identical to SEQ ID NO: 1, and a light chain having CDRs from SEQ ID NO: 2 presented in the description and at least 70% identical to SEQ ID NO: 2; and an effector molecule presenting a tubulin polymerisation inhibitor, and wherein the effector molecule is attached to the above engineered target antibody through a cleaved linker containing a disulphide bond. Besides, disclosed are a pharmaceutical composition and a kit for inhibition, delaying and/or prevention of tumour growth and/or CD138-expressing tumour cell propagation, wherein the composition contains the above immunoconjugate in an effective amount, and one or more pharmaceutically acceptable excipients; the kit comprises pharmaceutical compositions in independent containers, wherein one container comprises an effective amount of the pharmaceutical composition according to the present invention, while the other container contains a second pharmaceutical composition containing an effective amount of a co-drug, preferentially a cytotoxic agent, and one or more pharmaceutically acceptable excipients. There are presented the following methods implying administering the above immunoconjugate: a) a method of treating multiple myeloma in an individual; b) a method for immunoconjugate-mediated drug delivery; c) a method for inhibition, delaying and/or prevention of CD138-expressing tumour cell growth in a cell culture; d) a method for inhibition, delaying and/or prevention of the growth of a tumour containing CD138 tumour cells, and/or propagation of the tumour cells of this tumour in the patient; e) a method for inhibition, delaying and/or prevention of the tumour growth and/or propagation of CD138-expressing tumour cells in the patient; f) a method of treating the individual suffering a condition expected to be improved by suppressing myeloma cell survival; g) a method for inhibition, delaying and/or prevention of the growth of the tumour containing CD138 tumour cells, and/or propagation of the tumour cells in the individual; h) a method for reducing a cell count in a direct or mediated contact to the CD138-expressing tumour cells in the individual; i) a method for reducing a cell count in a direct or mediated contact to the CD138-expressing tumour cells.

EFFECT: invention enables preparing a homogenously targeted agent for treating the CD138-related diseases.

45 cl, 13 dwg, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to immunology. Presented are variants of anti-CD20 modified antibody or its antigen-binding fragment. Each of the variants is characterised by the fact that it contains a variable light and heavy chain domain, and induces a higher apoptosis level as compared to anti-B-Ly1 chimeric antibody. There are presented: a mixture of antibodies, wherein at least 20% of oligosaccharides in Fc domain have a branched chain and are not fucosylated, as well as a pharmaceutical composition for producing a therapeutic agent for a malignant haematological or autoimmune disease by using the antibodies or the mixture of antibodies. Described are: an expression vector, a based host cell, variants of coding polynucleotides, as well as a method for producing the antibody in the cell.

EFFECT: using these inventions provides the new antibodies with the improved therapeutic properties, including with increased binding of Fc receptor, and with the increased effector function that can find application for treating the malignant haematological or autoimmune disease.

32 cl, 3 ex, 9 tbl, 26 dwg

FIELD: medicine.

SUBSTANCE: present invention refers to immunology. Presented is a molecule of bispecific single-chain antibody containing a first binding domain able to bind to epitope of CD3-epsilon-chain of human and Callithrix jacchus (tamarin), Saguinus oedipus (cotton-top tamarin) and Saimiri sciureus (squirrel monkey), and a second binding domain able to bind to an antigen specified in a group consisting of: PSCA, CD19, C-MET, endosialin, EGF-like domain 1 EpCAM coded by exon 2, FAP-alpha or IGF-IR (or IGF-1R) or a human and/or a primate. The epitope CD3e contains an amino acid sequence disclosed in the description. Disclosed are a nucleic acid coding the above molecule of the bispecific single-chain antibody, an expression vector, a host cell and a method for producing the antibody, as well as the antibody produced by the method. Described is a based pharmaceutical composition containing the molecule of the bispecific single-chain antibody and a method for preventing, treating or relieving cancer or an autoimmune antibody. Presented is using the above molecule of the bispecific single-chain antibody for making the pharmaceutical composition for preventing, treating or relieving cancer or the autoimmune disease.

EFFECT: using the invention provides the clinical improvement in relation to T-cell redistribution, reducing it, and the improved safety profile.

23 cl, 74 dwg, 17 tbl, 33 ex

FIELD: medicine.

SUBSTANCE: invention refers to biotechnology, more specifically to biospecific antibodies, and can be used in medicine. Constructed is an antibody containing one of the following groups of six hypervariable region (HVR) sequences: (a) HVR-L1 containing the sequence NIAKTISGY; (b) HVR-L2, containing the sequence WGSFLY; (c) HVR-L3 containing the sequence HYSSPP; (d) HVR-H1 containing the sequence NIKDTY; (e) HVR-H2 containing the sequence RIYPTNGYTR; and (f) HVR-H3 containing the sequence WGGDGFYAMD; or (a) HVR-L1 containing the sequence NIAKTISGY; (b) HVR-L2 containing the sequence WGSFLY; (c) HVR-L3 containing the sequence HYSSPP; (d) HVR-H1 containing the sequence NISGTY; (e) HVR-H2 containing the sequence RIYPSEGYTR; and (f) HVR-H3 containing the sequence WVGVGFYAMD. The produced antibody specifically binds human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) The invention also refers to a recovered Fab fragment of the above antibody, a polynucleotide coding it, to an expression vector, a host cell, a method for producing it, as well as to using it for treating HER2-mediated diseases.

EFFECT: present invention enables producing the bispecific high-affinity antibody able to bind VEGF and HER2 simultaneously.

14 cl, 65 dwg, 16 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, specifically to a fused protein containing a variant of rodostomin, and can be used in medicine. An ανβ3 integrin selective polypeptide consisting of an amino acid sequence SEQ ID NO:1 conjugated on the N terminal by a linker amino acid sequence containing a combination of the amino acids glycine and serine with a variant of a human serum albumin (HSA) with SEQ ID NO:4.

EFFECT: invention enables the higher therapeutic effectiveness in the diseases related to ανβ3 integrin.

12 cl, 14 dwg, 2 tbl, 7 ex

Csf-1r antibody // 2547586

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. There are presented an antibody and its antigen-binding fragment specifically binding human colony-stimulating factor-1 receptor (CSF-1R) characterised by sequences of complementary-determining regions (CDR). There are also disclosed a nucleic acid coding the antibody according to the invention or its antigen-binding fragment, a vector providing the expression of the antibody and its antigen-binding fragment, and a pharmaceutical composition applicable in treating the diseases associated with an inflammation or an autoimmunity, or cancer.

EFFECT: invention can find further application in diagnosing and therapy of the CSF-1 associated diseases.

23 cl, 18 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a therapeutic agent for cerebral tumour containing a complex compound of metal-salen of formula (I) possessing a crystalline structure with the following properties as a main ingredient: the crystalline system is monoclinic; lattice spacings represent a=14.34(6)E, b=6.907(16)E, c=14.79(4)E, β=96.73(4) degrees and V=1455(8)E3; a space group represents P21/n (#14), wherein M represents Fe, and X represents halogen atom, and a method for its delivery involving administering a drug into the body, and feeding into brain tunics by an external magnetic field.

EFFECT: invention provides preventing side effects and conducting the effective treatment of malignant tumours.

3 cl, 6 dwg

FIELD: medicine.

SUBSTANCE: first stage of the treatment in the patients with a primary inoperable form of uterine cancer involves a neoadjuvant polychemotherapy combined with a session of therapeutic plasmapheresis. The chemotherapy is preceded with a session of discrete gravity plasmapheresis by means of MCS apparatus + PPP (platelet-poor plasma) Hemonetics. The chemotherapeutic agents are administered on the day following the plasmapheresis session.

EFFECT: method enables overcoming the tumour resistance to cytostatics, reducing the number of the pre-operative chemotherapeutic courses, downsizing the tumour and improving the tumour process respectability, reducing toxic and side chemotherapeutic responses, and reducing cytostatic doses.

1 ex

FIELD: medicine.

SUBSTANCE: method involves administering a combination of pharmacological agents into a laboratory animal after simulating osteoporosis by a bilateral ovariectomy and osteoporotic femoral fracture in female Wistar rats. This agents represent a combination of L-arginine 200mg/kg and losartan 6mg/kg, which is intragastrically administered daily into a laboratory animal once a day with underlying stimulating osteoporosis for eight weeks, and in fractures- with underlying simulating osteoporosis for twelve weeks.

EFFECT: using the declared invention provides the synergetic action and positive effect on the bone microcirculation in osteoporosis and in an osteotylus in osteoporotic fractures.

1 ex

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