Fingolimod salts

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propan-1,3-diol salts specified in tartrate, lactate benzoate, succinate, malonate, acetate and propionate in the crystalline form. Each of the above salts is characterised by powder X-ray pattern data. Compounds in the therapeutically effective amount can be used in treating autoimmune diseases.

EFFECT: crystalline salts of the present invention possess higher stability, better solubility, more convenient to store and handle.

11 cl, 7 dwg, 1 tbl, 10 ex

 

The present invention relates to salts, such as crystalline salts of compound FTY720, and to their use.

Compounds 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol disclosed in application EP-A-0627406 that are relevant to the description of which is incorporated into this description by reference. Based on the observed activity, it was found that these compounds are suitable as immunosuppressants. Therefore, these compounds may be suitable for treatment or prevention of various autoimmune conditions, including multiple sclerosis. A specific compound of this class is FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol; fingolimod), which can be obtained in free base form or cleaners containing hydrochloride salt. FTY720 has the following structure:

Thus, the present invention relates to crystalline salts of FTY720, where salt is selected from tartrate, lactate, benzoate, succinate, malonate, acetate and propionate, and salt is not necessarily crystalline.

In one of the embodiments of the invention the salt is selected from tartrate, lactate, benzoate, succinate and malonate.

In another embodiment of the invention the salt is selected from tartrate, lactate, succinate and malonate.

In another one of the embodiments of the invention salt depict is to place a tartrate,

In a specific embodiment of the invention the salt is a tartrate characterized by powder x-ray having peaks at least two, preferably at least four and more preferably all, of the listed values of 2 Theta: about 3,1, 19,3, 21,7, 9,6, 17,2, 6,4, 22,6 and 20.8 degrees 2 Theta. Peaks at these values of 2 Theta have the following relative intensities: 3,1 (strong), and 19.3 (weak) 21,7 (weak) 9,6 (weak) 17,2 (weak) 6,4 (weak) 22,6 (weak) and 20.8 (weak). In the private version of the invention, the salt is a tartrate characterized by powder x-ray corresponding to essentially the radiograph shown in Fig.1.

In another embodiment of the invention the salt is calcium lactate.

In a specific embodiment of the invention the salt is lactate, which is characterized by a powder x-ray having peaks at least two, preferably at least four and more preferably all, of the listed values of 2 Theta: 4,3, 8,7, 20,8, 13,1, 10,3, 18,8, 8,1, 21,6, 21,9 and 19.6 degrees 2 Theta. Peaks at these values of 2 Theta have the following relative intensities: 4,3 (strong), and 8.7 (average), 20.8 (the average), 13,1(average), 10,3 (weak) 18,8 (weak), 8,1 (average), 21,6 (average), 21,9 (weak) and 19,6 (weak). In Astrom embodiment of the invention the salt is a lactate, characterized by powder x-ray corresponding to essentially the radiograph shown in Fig.2.

In another variant of the invention, the salt is a benzoate.

In a specific embodiment of the invention the salt is a benzoate, characterized by a powder x-ray having peaks at least two, preferably at least four and more preferably all, of the listed values of 2 Theta: 3,7, 7,5, 18,7, 19,8, 15,2, 19,4, 19,9, 6,0 and 21.9 degrees 2 Theta. Peaks at these values of 2 Theta have the following relative intensities: 3,7 (strong), and 7.5 (average), 18,7 (weak) 19,8 (weak) 15,2 (weak), and 19.4 (weak) 19,9 (weak) 6,0 (weak) and 21.9 (weak). In the private version of the invention, the salt is a benzoate, characterized by a powder x-ray corresponding to essentially the radiograph shown in Fig.3.

In another embodiment of the invention the salt is a succinate.

In a specific embodiment of the invention the salt is a succinate, characterized by a powder x-ray having peaks at least two, preferably at least four and more preferably all, of the listed values of 2 Theta: 3,2, 19,8, 20,7, 23,3, 26,2, 9,8, 19,4, 24,5, 33,4, 26,6 and 2.6 degrees 2 Theta. Peaks at these values of 2 Theta have the following relative intensities: 3,2 (strong) 19,8 (average), 20,7 (weak) 23,3 (weak) 26,2 (weak) 9,8 (weak), and 19.4 (weak) 24,5 (weak) 33,4 (weak) 26,6 (weak) and 22.6 (weak). In the private version of the invention, the salt is a succinate, characterized by a powder x-ray corresponding to essentially the radiograph shown in Fig.4.

In another variant of the invention, the salt is malonate.

In a specific embodiment of the invention the salt is malonate characterized by powder x-ray having peaks at least two, preferably at least four and more preferably all, of the listed values of 2 Theta: 2,5, 5,2, 8,0, 16,2, 17,0, 20,4 degrees 2 Theta. Peaks at these values of 2 Theta have the following relative intensities: to 2.5 (strong), and 5.2 (weak) 8,0 (weak) 16,2 (weak) 17,0 (weak) to 20.4 (weak). In the private version of the invention, the salt is malonate characterized by powder x-ray corresponding to essentially the radiograph shown in Fig.5.

In another embodiment of the invention the salt is an acetate.

In a specific embodiment of the invention salt depict is to place a acetate, characterized by powder x-ray having peaks at least two, preferably at least four and more preferably all, of the listed values of 2 Theta: 4,8, 8,4, 10,1, 11,5, 15,2, 17,7, 19,3, 20,1, 21,5, 21,9, 24,0, 25,4, 30,8 degrees 2 Theta. Peaks at these values of 2 Theta have the following relative intensities: 4,8 (strong), and 8.4 (weak) 10,1 (middle), and 11.5 (weak) 15,2 (average) of 17.7 (weak) 19,3 (weak), 20,1 (weak) 21,5 (weak) 21,9 (weak) 24,0 (weak) 25,4 (average), 30,8 (weak). In the private version of the invention, the salt is an acetate, characterized by a powder x-ray corresponding to essentially the radiograph shown in Fig.6.

In another variant of the invention, the salt is a propionate.

In a specific embodiment of the invention the salt is a propionate, characterized by a powder x-ray having peaks at least two, preferably at least four and more preferably all, of the listed values of 2 Theta: 4,8, 8,4, 9,8, 14,7, 16,8, 17,6, 19,7, 20,2, 22,6, 24,8, 29,8 degrees 2 Theta. Peaks at these values of 2 Theta have the following relative intensities: 4,8 (strong), and 8.4 (weak) 9,8 (average), 14,7 (weak) 16,8 (weak) 17,6 (weak) 19,7 (weak) 20,2 (weak) 22,6 (weak) 24,8 (weak) 29,8 (weak is). In the private version of the invention, the salt is a propionate, characterized by a powder x-ray, there is a corresponding x-ray, shown in Fig.7.

Preferably the various salt forms of the present invention can possess one or more desired properties compared with the free base or cleaners containing hydrochloride form of FTY720. For example, salt can be more stable and have better quality than the free base, in particular during storage and distribution. In addition, salts may have a high degree of dissociation in water and, therefore, improved solubility in water. Salt of the present invention can also be preferred because they exhibit negligible moisture absorption or wear.

The crystalline form may be characterized by the main peaks of the powder x-rays, as shown in the examples. Also crystalline forms may be different thermodynamic stability, physical parameters such as absorption spectrum in the infrared spectroscopy (IR) or the peaks of the phase transition in differential scanning calorimetry (DSC). Preferably salts of the present invention are essentially pure crystalline form. The term "essentially pure", use is Amy in this application, relates to crystalline forms, polymorphic purity of more than 90%, more preferably 95%, more preferably 96%, more preferably 97%, more preferably 98%, more preferably 99%, as determined, for example, powder x-ray diffraction, Raman spectroscopy or infrared spectroscopy.

Salt of the present invention can be in the form of a solvate, including hydrates, and can exhibit polymorphism.

Salt of the present invention can be obtained from the free base of traditional chemical methods. In principle, these salts can be obtained by reaction of the free base FTY720 with the appropriate acid in water or in an organic solvent, or mixtures thereof. In many cases, can be used non-aqueous environment, such as ethyl acetate, ethanol or isopropanol. FTY720 and acid combine in the desired stoichiometric ratio, such as 1:1 or 1:2. Then salt can crystallize, or initiate the crystallization, or it forms an amorphous solid, not necessarily before the crystallization. After that, the solid salt can be dried, for example, by heating under reduced pressure. For illustration purposes, without any limitation, and various salt forms of the present invention can be obtained in accordance with the method of the kami, presented in the examples.

Also the present invention relates to pharmaceutical compositions comprising a crystalline salt of the present invention. The pharmaceutical composition of the invention preferably contains 0.01-20% wt. salt, more preferably 0.1 to 10 wt. -%, for example, 0.5 to 5 wt. -%, based on the total weight of the composition.

The pharmaceutical composition can be a solid pharmaceutical composition in a form suitable for oral administration, for example in the form of tablets or capsules. The composition can be obtained in the traditional way, for example by mixing the salt of the present invention with a pharmaceutically acceptable carrier or diluent.

In the private embodiment of the invention the composition is a solid pharmaceutical composition comprising the salt of the invention and a sugar alcohol. Compositions of this type are disclosed in the application WO 2004/089341, the contents of which are incorporated in the present description by reference.

Solid compositions disclosed in this publication, are particularly suitable for oral administration of salts of the present invention. The compositions provide a convenient tool for the systematic introduction of compounds, for which there is no inherent shortcomings of liquid compositions for injection or oral administration, and have good physical and chemical properties of well-kept. In particular, the compositions of the present invention can show a high level of uniformity in the distribution of compounds in the composition, as well as high stability. In addition, the composition can be obtained on high-speed automated equipment and, thus, no manual encapsulation.

The sugar alcohol may act as a diluent, carrier, filler or onyemaobi agent and preferably represents mannitol, ▫ maltitol, Inositol, xylitol or lactic, preferably essentially non-hygroscopic sugar alcohol such as mannitol (D-mannitol). Can be used as a single sugar alcohol, or a mixture of two or more sugar alcohols, for example, a mixture of mannitol and xylitol, for example, in a ratio of from 1:1 to 4:1.

In a particular preferred variant of the invention, the sugar alcohol is prepared from the spray dried compositions, for example compositions mannitol having a specific surface area. The use of this type of composition mannitol contributes to the promotion of uniform distribution of the compound and mannitol composition. High surface area can be achieved by obtaining a sugar alcohol such as mannitol, containing particles having a small size and/or uneven surface of each particle. To whom it was established, the use of spray dried sugar alcohol such as mannitol, for example, with a particle size of 300 μm or less, improves compressibility and strength of tablets prepared from the composition.

Preferably the surface area of the drug, a sugar alcohol such as mannitol, measured in one point, is 1-7 m2/g, for example, 2-6 m2/g or 3-5 m2/, Preferably the drug mannitol may have a particle size of 100-300 μm, for example 150-250 microns, and a bulk density of 0.4-0.6 g/ml, for example of 0.45-0.55 g/ml Suitable mannitol with high surface area is Parteck M200, commercially available from E. Merck.

The composition preferably contains 75-99,99% of the mass. sugar alcohol, more preferably 85-99,9 wt. -%, for example 90-99,5 wt. -%, based on the total weight of the composition.

The composition preferably further comprises a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium fumarate, canola oil, gidrirovannoe vegetable oil, such as gidrirovannoe castor oil (for example, Cutina® or Lubriwax® 101), mineral oil, sodium lauryl sulphate, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer, or CME is ü any of the above. Preferred lubricants include magnesium stearate, gidrirovannoe castor oil and mineral oil. Colloidal liquid and the polyethylene glycol is less desirable as lubricants.

Preferably the composition contains 0.01-5% wt. lubricant, more preferably 1-3 wt. -%, for example, about 2 wt. -%, based on the total weight of the composition.

The composition may contain one or more additional excipients, such as carriers, binders or diluents. In particular, the composition may contain microcrystalline cellulose (such as Avicel®), methylcellulose, gidroksipropilzelluloza, starch (e.g. corn starch) or dicalcium phosphate, preferably in quantities of from 0.1 to 90 wt. -%, for example 1-30 wt. -%, based on the total weight of the composition. In case of using a binder, such as microcrystalline cellulose, methylcellulose, gidroksipropilzelluloza, its content is from 1 to 8%, for example 3-6 wt. -%, based on the total weight of the composition. Application of the binder increases the strength of the granules of the composition, which is particularly important in fine granulation. Microcrystalline cellulose and methylcellulose are the most preferred in the case if you want high strength tablets and/or the longer the time of disintegration. Hydroxypropylcellulose preferable if you want a fast disintegration. If necessary, as additional binders may also be added xylitol, for example, in addition to microcrystalline cellulose, for example in an amount up to 20% of the mass. sugar alcohol such as xylitol.

In one of the embodiments of the invention the composition further comprises a stabilizer, preferably glycine·HCl or sodium bicarbonate. The amount of stabilizer may vary from 0.1 to 30%, preferably 1-20 wt%.

The composition may be in the form of powder, granules, flakes or dosage forms, such as tablets or capsules.

Compositions of the present invention is well adapted to encapsulate in a shell capsules for oral administration, particularly in the hard shell capsules.

Alternatively, the composition can be compressed into tablets. Tablets may not necessarily have a coating, e.g. a coating of talcum powder, or a polysaccharide (e.g., cellulose), or hypromellose.

If the composition is a dosage form, each dosage form may contain, for example, from about 0.5 to about 10 mg salt of the invention.

Compositions of the present invention exhibit x is good stability indicators according to the standard stability studies, for example have the storage stability of one, two or three years and even more. Stability indicators can be defined, for example, by determining the degradation products by HPLC after storage at certain intervals of time, at a certain temperature, for example 20, 40 or 60°C.

The pharmaceutical compositions of the present invention can be obtained by standard methods, such as conventional mixing, granulating, coating sugar, dissolution or lyophilization. Methods known from the prior art (see, for example, L. Lachman et al. theory and Practice of Industrial Pharmacy, 3eed., 1986, H Sucker et al., Pharmazeutische Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen Praxis, 4eed. (Springer Veriag, 1971) and Remington's Pharmaceutical Sciences, 13eed., (Mack Publ., Co., 1970) or later edition).

In yet another embodiment of the invention the pharmaceutical composition was prepared in the following way, includes the following stages:

(a) a mixed salt of the present invention and a sugar alcohol;

(b) obtained in stage (a) a mixture of crushed and/or granularit and

(C) powdered and/or granulated at the stage (b) the mixture is mixed with the lubricant.

When using this way we obtain a composition with a high level of content and uniformity of mixing (i.e., essentially homogeneous R is Opredelenie salt in the composition), the time of dissolution and stability.

The method can be carried out by the dry mixing of the components. In this embodiment of the invention stage grinding (b) may include passing the mixture obtained in stage (a), through a sieve, which preferably has a cell size of 400-500 μm. Stage of the method (a) may include the stage of mixing the total quantity of salt in the beginning with a small amount of a sugar alcohol, for example from 5 to 25 wt. -%, based on the total weight of the sugar alcohol, to obtain a pre-mixture. Then to the pre-mixture add the remaining amount of the sugar alcohol. Stage (a) can also include stage adding to the mixture of binder solution, such as methylcellulose and/or xylitol, for example in aqueous solution. Alternatively, a binder is added to the dry mixture, and water is added at the stage of granulation.

Obtained in stage (b) the crushed mixture is optionally stirred again before mixing with the lubricant. Lubricant, for example magnesium stearate, before mixing preferably pre-screened, for example, through 800-900 µm sieve.

An alternative method used wet granulation. In this embodiment of the invention the salt is preferably initially in a dry form is mixed with the desired sugar alcohol, e.g. the mannitol, and then the resulting mixture of sugar alcohol/salt in dry form is mixed with a binder such as hydroxypropylcellulose or hypromellose. Then add water and mix granularit, for example, using automatic pellet mill. The obtained granulate is dried and pulverized.

Optionally, in stage (C) to the mixture obtained in stage (b), may be added an additional amount of the binder.

The method may include the additional step tableting or encapsulating the mixture obtained in stage (b), for example, hard gelatin capsules, using automatic encapsulating device. Capsules can be painted or marked to give an individual appearance and instant recognition. The use of dyes improves appearance, and is also used to identify the capsules. Dyes suitable for use in the pharmaceutical industry, typically include carotenoids, oxides of iron and chlorophyll. Preferably the capsules of the present invention labeled by code.

Salt of the present invention may be used:

a) to treat or prevent rejection of transplanted organ or tissue, for example for the treatment of recipients of heart transplant, lung, heart and lungs together, liver, kidneys, pagelog who offered gland, skin or cornea, and to prevent reactions "graft versus host", such as occasionally occurring reaction after bone marrow transplantation; in particular, for the treatment of acute or chronic rejection of ALLO - and xenograft, or by transplantation of cells that produce insulin, for example cells of the islets of Langerhans; and

b) to treat or prevent autoimmune diseases or inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, diabetes type I or type II and related disorders, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriasis, graves ' ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally on the basis of aberrant reactions, e.g. inflammatory bowel disease, Crohn's disease or ulcerative colitis, internal asthma, inflammatory lung damage, inflammatory lesions biscuits, inflammatory kidney damage, atherosclerosis, irritant contact dermatitis, and other eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologic the Ki-mediated diseases, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

For the above-mentioned applications the required dosage will vary depending on the type of introduction, the specific conditions treated, and the desired result. In General satisfactory results are achieved with a daily dose comprising from about 0.1 to about 100 mg/kg of body weight. Nominal daily dosage for the larger mammal, e.g. humans, is in the range from about 0.5 mg to 2000 mg, for convenience of administration, for example, divided into doses up to four per day, or in the form of delayed release.

Salt can be introduced by any suitable means, such as orally, for example in the form of tablets or capsules, tapicerki or parenterally, for example intravenously. Pharmaceutical compositions containing the salts of the present invention together with at least one pharmaceutically acceptable carrier or diluent, can be obtained by conventional methods by mixing with a pharmaceutically acceptable carrier or diluent. Dosage forms for oral administration include, for example, from about 0.1 mg to about 500 mg of active substance.

Salt can be introduced as the sole active ingredient or together with other lekarstvennihe in immunomodulating regimens or other anti-inflammatory agents, for example, for the treatment or prevention of acute or chronic allograft rejection, inflammatory or autoimmune diseases. For example, salt can be used in combination with calcineurin inhibitors such as cyclosporin a, cyclosporin G, FK-506, ABT-281, ASM 981; an mTOR inhibitors such as rapamycin, 40-O-(2-hydroxy)atrribution, CCI779, AT or AR and others; corticosteroids; cyclophosphamide; azathioprene; methotrexate; other receptors of the S1P agonist, e.g. FTY720 or its equivalent; Leflunomide or its equivalent; miraibio; mycophenolate acid; mycophenolate mofetil; 15-deoxynivalenol or its equivalent; immunosuppressive monoclonal antibodies, for example, monoclonal antibodies to receptors of cells; e.g., MHC, CD2, CD3, CD4, CD11a/CD18, CD7, CD25, CD27, B7, CD40, CD45, CD58, CD137, ICOS, CD150 (SLAM), OX40, 4-W or their ligands, such as CD 154; or with other immunomodulators, such as recombinant binding molecule that contains at least a portion of the extracellular domain of CTLA4 or a mutant, for example at least extracellular portion of CTLA4 or a mutant associated with a non-CTLA4 protein sequence, e.g. CTLA4Ig (for example, designated as ATSS 68629) or a mutant, e.g. LEA29Y, or other inhibitors of the adhesion molecules, such as mAbs, or inhibitors with a small mole is Blarney mass, including antagonists of LFA-1, selectin antagonists and antagonists of VLA-4.

If salt is administered in conjunction with other immunomodulatory or anti-inflammatory agent, the dosage of the agent will vary depending on the type of the jointly-used drug, condition treated, and so on

The present invention also applies to:

1. Method of treating or preventing rejection of transplanted organ or tissue, comprising introducing to a subject a therapeutically effective amount of a crystalline salt of the invention.

2. The method of treatment or prevention of autoimmune diseases or inflammatory conditions, comprising introducing to a subject a therapeutically effective amount of a crystalline salt of the invention.

3. Salt of the present invention, for example, a crystalline salt of the invention for use as a pharmaceutical product.

4. Pharmaceutical compositions containing the salt of the invention, for example, a crystalline salt of the invention and a pharmaceutically acceptable diluent or carrier.

5. The use of salts of the invention, for example a crystalline salt of the invention, for obtaining a medicinal product, for example, in the above-described methods.

6. Pharmaceutical compositions containing (a) a salt of the invention on the example of the crystalline salt of the invention, and (b) a second drug, this drug is suitable for the prevention or treatment of the above conditions.

7. The method described above comprising co-administration, e.g., simultaneously or sequentially, (a) a crystalline salt of the invention and (b) a second drug, this drug is suitable for the prevention or treatment of the above conditions.

The following examples illustrate the present invention. In examples 1-29 references to the connection A, FTY720 or cleaners containing hydrochloride salt FTY720 also include a reference to any salt of the present invention.

Example 1

Microselectron connection And, for example cleaners containing hydrochloride salt of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), sift and of 116.7 g of sifted compounds mixed with 9683,3 g microcrystalline cellulose. The mixture is then milled in the device Frewitt MGI (Key International Inc., USA) using a 30 mesh sieve. Magnesium stearate is screened through a 20 mesh and 200 g of sifted compounds mixed with FTY720, receiving the composition of the product.

After that, the composition of the product is placed on a tablet press using a 7 mm molds and receive tablets of 120 mg each tablet contains:

Connection And for example FTY720* 1.4 mg
Microcrystalline cellulose such as Avicel PH 102to 116.2 mg
Magnesium stearate2.4 mg
Total120 mg
* 1 mg compounds And free-form equivalent of 1.12 mg FTY720.

Example 2

In this example, using the method of example 1, except that magnesium stearate is replaced by Cutina® (gidrirovannoe castor oil).

Example 3: FTY720 tartrate

Ttrat analyzed by powder x-ray diffraction (XRPD). In this and subsequent examples, the powder x-ray register between 2° and 35° (2 Theta) using CuKα-radiation and x-ray diffraction system Scintag XI, equipped with temperature controls and humidity.

Powder x-ray FTY720 tartrate shown in Fig.1, the characteristic peaks below:

2 Theta (deg)d-step (Å)Relates. intensity
3,128,664Strong
19,34,596 Weak
21,74,092Weak
9,69,221Weak
17,25,158Weak
6,413,906Weak
22,63,931Weak
20,84,258Weak

Example 4: FTY720 lactate

Powder x-ray FTY720 lactate shown in Fig.2, the characteristic peaks below:

2 Theta (deg)d-step (Å)Relates. intensity
4,320,493Strong
8,710,183Average
20,84,272Average
13,16,768Average
10,38,587Weak
18,84,717Weak
8,110,878Weak
21,64,102Weak
of 21.94,051Weak
19,64,527Weak

Example 4: FTY720 benzoate

Powder x-ray FTY720 benzoate is shown in Fig.3, the characteristic peaks below:

2 Theta (deg)d-step (Å)Relates. intensity
3,723,816Strong
7,511,762Average
18,74,743Weak
19,84,490Weak
15,25,842Weak
19,44,583Weak
to 19.94,446Weak
6,014,709Weak
of 21.94,051Weak

Example 6: FTY720 succinate (2:1)

Powder x-ray FTY720 succinate (2:1) shown in Fig.4, the characteristic peaks below:

2 Theta (deg)d-step (Å)Relates. intensity
3,227,952Strong
19,84,476Average
20,74,294Weak
23,33,810Weak
26,23,403Weak
9,8 8,986Weak
19,44,571Weak
24,53,626Weak
the 33.42,681Weak
26,63,354Weak
22,63,929Weak

Free base FTY720 (1,63 mmole) was dissolved in i-D (6 ml) at 82°C. Then at 82°C. add a solution of malonic acid (0,815 mmole) in i-D (1 ml). Directly after the addition begins crystallization of the product. The resulting suspension is cooled to room temperature. The product is collected by filtration and washed with i-D (2 ml). After drying at 50°To give the product as white crystals with a yield of 92.3 per cent.

In an alternative method the free base FTY720 of 2.27 mmole) is dissolved in ethyl acetate (16 ml) at a temperature of from 88 to 90°C. and Then at 75°C. add a solution of malonic acid (1,14 mmole) in ethyl acetate (3 ml), immediately after add begins crystallization of the product. The resulting suspension is cooled to room temperature. The product is collected filter is a Finance and washed with ethyl acetate (2 ml). After drying at 50°To give the product (788 mg) as white crystals.

Powder x-ray FTY720 of malonate (2:1) shown in Fig.5, the characteristic peaks below:

2 Theta (deg)Relates. intensity
2,5Strong
5,2Weak
8,0Weak

2 Theta (deg)Relates. intensity
16,2Weak
of 17.0Weak
20,4Weak

Example 8: FTY720 acetate

Free base FTY720 (1,63 mmole) was dissolved in i-D (6 ml) at 82°C. Then at 82°C. add a solution of acetic acid (1,79 EQ.) in i-D (1 ml). A clear solution is cooled to room temperature, resulting in crystallization of the product. The resulting suspension is stirred for another 15 min, the product is collected by filtration and washed with i-D (4 ml). After drying at 50°To give the product as white crystals with in the course of 83%. The product is then recrystallized from a mixture of i-D/acetic acid and the output is 90,6%.

In an alternative method the free base FTY720 of 2.27 mmole) is dissolved in ethyl acetate (16 ml) at a temperature of 88-90°C. and Then at 75°C. add a solution of acetic acid (2.5 EQ.) in ethyl acetate (3 ml), immediately after add begins crystallization of the product. The resulting suspension is cooled to room temperature. The product is collected by filtration and washed with ethyl acetate (2 ml). After drying at 50°To give the product as white crystals with a yield of 99.4%.

Powder x-ray FTY720 acetate is shown in Fig.6, the characteristic peaks below:

2 Theta (deg)Relates. intensity
4,8Strong
8,4Weak
the 10.1Average
11,5Weak
15,2Average
17,7Weak
19,3Weak
Weak
a 21.5Weak
of 21.9Weak
24,0Weak
25,4Average

2 Theta (deg)Relates. intensity
30,8Weak

Example 8: FTY720 propionate

Free base FTY720 (1,63 mmole) was dissolved in i-D (6 ml) at 82°C. Then at 82°C. add a solution of acetic acid (1,79 EQ.) in i-D (1 ml). A clear solution is cooled to room temperature, resulting in crystallization of the product. The resulting suspension is stirred for another 15 min, the product is collected by filtration and washed with i-D (2 ml). After drying at 50°To give the product as white crystals with a yield of 68%. The product is then recrystallized from a mixture of i-D/propionic acid and the output is 90,6%.

In an alternative method the free base FTY720 of 2.27 mmole) is dissolved in ethyl acetate (16 ml) at a temperature of 88-90°C. and Then at 75°C. add a solution of propionic acid (2.5 EQ.) in ethyl acetate (3 ml), while directly n the following add begins crystallization of the product. The resulting suspension is cooled to room temperature. The product is collected by filtration and washed with ethyl acetate (2 ml). After drying at 50°To give the product as white crystals with a yield of 96.9 percent.

Powder x-ray FTY720 propionate shown in Fig.7, the characteristic peaks below:

2 Theta (deg)Relates. intensity
4,8Strong
8,4Weak
9,8Average
14,7Weak
16,8Weak
17,6Weak
19,7Weak
20,2Weak
22,6Weak
24,8Weak
29,8Weak

Example 10: a Study of solubility

Determine the solubility of various salts, and the resulting Dan is haunted in the following table (approximate values at 25°C, g/100 ml %):

SolventFree baseHydrochlorideTartrateLactateBenzoateSuccinate
HCl 0.1 N.>2>2>2
Water0,02>100,04>100,040,09
Ethanol3,68>7,940,07>7,940,970,27
Isopropanol2,034,510,092,750,350,23
Acetone0,520,08 0,061,30,360,09
The octanol1-21-2<0,1
The ethyl acetate0,450,030,050,310,080,07
Phosphate buffer (pH 6,88)<0,001<0,001<0,001

1. Salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720), a tartrate, where the salt is in crystalline form characterized by a powder x-ray having peaks at 2θ values (Theta) about 3,1, 19,3, 21,7, 9,6, 17,2, 6,4, 22,6 and 20.8 degrees.

2. Salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720), a lactate, where the salt is in crystalline form characterized by a powder x-ray having peaks at 2θ values (Theta) about 4,3, 8,7, 20,8, 13,1, 10,3, 18,8, 8,1, 21,6, 21,9 and 19.6 degrees.

3. Salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720), a benzoate, where the salt is in crystalline form characterized by a powder x-ray having peaks at 2θ values (Theta) about 3,7, 7,5, 18,7, 19,8, 15,2, 19,4, 19,9, 6,0 and 21.9 degrees.

4. Salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720), a succinate, where the salt is in crystalline form characterized by a powder x-ray having peaks at 2θ values (Theta) about 3,2, 19,8, 20,7, 23,3, 26,2, 9,8, 19,4, 24,5, 33,4, 26,6 and 22.6 degrees.

5. Salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720), representing malonate where the salt is in crystalline form characterized by a powder x-ray having peaks at 2θ values (Theta) about 2,5, 5,2, 8,0, 16,2, 17,0, 20,4 degrees.

6. Salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720), an acetate, where the salt is in crystalline form characterized by a powder x-ray having peaks at 2θ values (Theta) about 4,8, 8,4, 10,1, 11,5, 15,2, 17,7, 19,3, 20,1, 21,5, 21,9, 24,0, 25,4, 30,8 degrees.

7. Salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720), a propionate where the salt is in crystalline form characterized by a powder x-ray having peaks at 2θ values (Theta) is Kolo 4,8, 8,4, 9,8, 14,7, 16,8, 17,6, 19,7, 20,2, 22,6, 24,8, 29,8 degrees.

8. Sol according to any one of the preceding paragraphs for use in obtaining medications for the treatment of autoimmune diseases.

9. Sol according to any one of paragraphs.1-7 for use for the treatment of autoimmune diseases,

10. Pharmaceutical composition for treatment or prevention of autoimmune diseases, containing salt according to any one of paragraphs.1-7 together with a pharmaceutically acceptable carrier or excipient.

11. A method of treating or preventing an autoimmune disease in a patient, comprising the introduction of a salt according to any one of paragraphs.1-7, the medicines at 8 p. or pharmaceutical composition according to p. 10 in therapeutically effective amounts.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a free-running form of powdered choline chloride from an aqueous solution thereof. Squeezed beet pulp with moisture content of 82…84% is preheated in a heating chamber to temperature of 80…90°C, and then dried in a vibration drier which is superheated with steam at atmospheric pressure with temperature of 135…140°C and speed of 1.5 m/s. Drying is carried out in a pulsed vibrofluidised bed to moisture content of 12…13%, wherein in the working chamber of the vibration drier, the layer of the product is brought into a vibrofluidised state for 3 s every 60 s by a gas-distributing array. The array has amplitude and frequency of vibration of 7 mm and 12.5 Hz, respectively. Spent superheated steam at temperature of 105…110°C from the vibration drier is first fed into a cyclone purifier for purification from a fine fraction which is combined with dried beet chips, and the purified spent superheated steam is then divided into two streams. One stream, formed when drying the product, is fed into a calorifier, where it is condensed and atmospheric air is heated through the separating wall of the calorifier to temperature of 65…70°C. The other stream is fed by a fan into a steam superheater in order to be superheated to temperature of 13.5…140°C with heating steam obtained in a steam generator at temperature of 150…155°C, and then into the vibration drier to form a recirculation loop. The condensate of the heating steam at temperature of 140…145°C, after the steam superheater, is combined with the condensate of the spent superheated steam at temperature of 95…100°C after the calorifier and fed into a condensate collecting tank. The obtained condensate mixture at temperature of 120…125°C from the condensate collecting tank is fed into the heating chamber for preliminary heating of the squeezed beet pulp, followed by returning into the steam generator to form a recirculation loop and removing excess condensate from the recirculation loop. The obtained dried beet pulp is ground to particle size of 1 mm and fractionated on a sieving machine. Sieve screenings are taken for regrinding, and the substance passing through the sieve is mixed with the starting 70% aqueous choline chloride solution, preheated to temperature of 35…40°C, in ratio of 2:3. The obtained mixture with moisture content of 47…50% is fed into the drier, where it is dried in a fluidised bed to final moisture content of 10% with atmospheric air, which is heated in the calorifier to temperature of 65…70°C with air flow rate in the working chamber of the drier of 0.8…1.0 m/s. Spent atmospheric air at temperature of 40…45°C from the drier is first fed for purification into the cyclone purifier, and then into the heater for heating the starting choline chloride solution before feeding into the mixture. The fine fraction of choline chloride obtained after purification is combined with a stream of ready powdered choline chloride after drying and taken for cooling.

EFFECT: method enables to obtain powdered choline chloride of high quality, enables preservation of vitamin B4 in the end product and prevents thermal decomposition of vitamin B4 in the initial 70% aqueous solution.

1 dwg

FIELD: food industry.

SUBSTANCE: invention relates to methods for manufacture of a free-flowing form of powdered choline chloride produced from a water solution having a biological action. The method envisages mixing 70% water solution of choline chloride with an active adsorbent. The adsorbent is represented by dry apple refuses produced as a result of two-stage drying process implementation in the two-sectional dryer. At the first stage apple refuses with moisture content equal to 65…70% are subjected to drying in a pulse vibrofluidised layer with atmospheric pressure superheated steam with a temperature equal to 130…135°C at a rate of 1.5…2 m/sec till moisture content is equal to 45…50%. The product layer is brought into a vibrofluidised state for 3 sec every 60 sec with an air distributor plate having oscillation amplitude and frequency equal to 5…7 mm and 10…12.5 Hz respectively. At the second stage apple refuses are dried in a pseudofluidised layer with superheated steam with decreased pressure equal to 0.02…0.04 MPa and temperature equal to 80…100°C at a rate of 1.0…1.5 m/sec till the final moisture content is equal to 8…10%. The exhaust superheated steam from the first dryer section, with a temperature equal to 105…110°C, is divided into two flows. One flow is supplied into an atmospheric pressure steam superheater for superheating up to a temperature equal to 130…135°C with heating steam by way of recuperative heat exchange and then is returned into the first section with a recirculation loop formation. The other steam flow in the amount generated in the product drying process at the first stage is supplied into a decreased pressure steam superheater where steam condensation takes place while condensation heat is used for superheating decreased pressure steam up to a temperature equal to 80…100°C due to recuperative heat exchange. The exhaust superheated steam from the second section of the dryer (having a decreased pressure and temperature equal to 65…80°C) is divided into two flows; one of them is supplied by a blower into the decreased pressure steam superheater for superheating up to 80…100°C and then is returned into the second section with a recirculation loop formation. The other seam flow in an amount generated in the apple refuses drying process at the second stage is supplied through the separating wall of the condenser into the condenser where steam condensation and atmospheric air preliminary heating up to a temperature equal to 45…50°C take place. The produced heating steam condensate with a temperature equal to 125…130°C from the atmospheric pressure steam superheater and exhaust atmospheric pressure superheated steam condensate with a temperature equal to 100…105°C from the decreased pressure steam superheater are supplied through the separating wall of the calorifier into the calorifier for final heating of atmospheric air up to a temperature equal to 65…70°C. Produced dry apple refuses are milled into particles sized 1 mm, fractionated; the sieve overtail is supplied for additional milling while the sieve undersize is mixed with choline chloride water solution preliminarily heated up to 35…40°C at a ratio of 2:3. Then the produced mixture with moisture content equal to 47…50% is supplied into the drier where the mixture is dried in the fluidised layer, till the final moisture content is equal to 10%, with atmospheric air heated up to 65…70°C at airflow rate in the drier operation chamber equal to 0.8…1.0 m/sec. The exhaust atmospheric air with a temperature equal to 40…45°C is supplied at first from the drier for purification into the purifier cyclone and then - into the heater for heating the initial choline chloride solution before supplying it into the mixer. Then the finely dispersed choline chloride fraction produced after purification is combined with a flow of the ready powdered choline chloride released from the dryer and is supplied for cooling.

EFFECT: invention allows to produce powdered choline chloride with high quality and high nutritional value and ensure vitamin B4 preservation in the ready product and enhance energy efficiency of the ready product production method.

1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing biologically active pluripotential compounds - 2-methyl-4-halogen-phenoxyacetates of tris-(2-hydroxyethyl)-ammonium of general formula given below referred to as chlorocresacin and bromocresacin respectively, by reacting 4-halogen-substituted 2-methyl-phenoxyacetic acid, where the halogen is chlorine or bromine, with triethanolamine. 4-halogen-substituted 2-methyl-phenoxyacetic acid is obtained via chlorination with sulphuryl chloride, where catalyst used is aluminium powder in an ester solution and bromation is carried out using elementary bromine in a glacial acetic acid medium. The obtained compounds have proven to be highly efficient biologically active substances with unique physiological action, for example as biostimulators or adaptogen. The method is characterised by replacement of chlorine gas with sulphuryl chloride which is more suitable for use in preparations. .

EFFECT: method enables to obtain desired products with high degree of purity.

2 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel salt clusters of ammonium salt and mineral salt with dibasic acid anions of formula (I) which are resistant and stable during storage and can be used for pain relief in case of inflammation of nerve fibres. In formula (I) • x moles of mineral salt R1, R2, R3 and R4, together with the nitrogen atom in the cluster are derivatives from bases, as components of the active substance, wherein the bases of the active substance are procaine, substituted procaines, adrenalin, tetracaine, lidocaine, bupivacaine, pontocaine, propoxycaine, octacaine, mepivacaine, prilocaine, dibucaine, isocaine, marcaine, etidocaine, piridocaine, eucaine, butacaine, cocaine, articaine, N,N-diethylaminoethanol, N,N-dimethylaminoethanol, N-ethyl-N-methylaminoethanol or N,N-diethylaminopropagyl with free or protected alcohol groups, which can be esterified into esters or converted to ethers, Y denotes CO32-, corresponding HY- = HCO3-, and x=0.5-30 denotes the number of molecules of the mineral salt for formation of the cluster.

EFFECT: invention also relates to a method of producing said clusters, a product for medical and pharmaceutical purposes and a pain relief method.

7 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: method involves reacting triethanol ammonium salts of o-cresoxyacetic and p-chloro-o-cresoxyacetic acid with the corresponding metal salt in alcohol or aqueous medium preferably at room temperature for 1-48 hours. The three-component complexes are extracted through solvent distillation with subsequent washing of the formed powder with ether and drying in a vacuum. The said complexes can be used as a base for making medicinal drugs.

EFFECT: design of a method of preparing complexes of o-cresoxy- and p-chloro-o-cresoxyacetic acid, triethanolamine and metals having formula n[R(o-CH3)-C6H3-OCH2COO-•N+H(CH2CH2OH)3]•MXm, where R = H, p-Cl; M = Mg, Ca, Mn, Co, Ni, Cu, Zn, Rh, Ag; X = CI, NO3, CH3COO; n = 1, 2; m = 1-3.

2 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: phosphoric and/or hypophosphorus acid and a basic compound are added to triethanolamine, where the basic compound is selected from a hydroxide of alkali metals, a hydroxide of alkali-earth metals and [R1R2R3(2-hydroxyethyl)ammonium]hydroxide, where R1, R2 and R3 independently denote an alkyl having 1-30 carbon atoms, or hydroxyalkyl having 2-10 carbon atoms. If a hydroxide of alkali metals is used as the basic compound, molar ratio of acid (acids): hydroxide ranges from 1:0.1 to 1:1, and if hydroxide of alkali-earth metals is used as the basic compound, molar ratio of acid (acids): hydroxide ranges from 1:0.05 to 1:0.5. Phosphoric and/or hypophosphorus acid and the basic compound are added before and/or during distillation of triethanolamine. The invention also relates to triethanolamine containing 0.01-2 wt % (in terms of pure triethanolamine) phosphoric and/or hypophosphorus acid and the corresponding hydroxide.

EFFECT: stability of improved chromaticity of triethanolamine during storage and increased output during distillation of the triethanolamine.

15 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to preparing biologically active compounds used in agriculture and animal husbandry. Tris-(2-hydroxyethyl)-ammonium-o-cresoxyacetate is prepared by interaction of triethanolamine with o-cresozyacetic acid in the solvent medium under conditions of three-stage temperature effect. At the first stage the process is carried out at the solvent boiling point, at the second stage at temperatures 81-85°C, and at the three stage at temperatures 73-77°C. The process is carried out in the vertical device fitted with three heating zones and rotor with control number of revolution and consisting of shaft with movable vanes. Invention provides simplified method due to diminishing number of the process stages.

EFFECT: improved preparing method.

2 cl, 3 ex

The invention relates to a static composition of the respective components are mixed with each other, as well as chemically bound to the composition of surface-active substances comprising at least one aromatic acid and at least one alkoxycarbonyl Amin

The invention relates to new salts of the compounds of formula [(H-B)+]nAnwhere ANDnrefers to the structure of formula (IIb) or (IIIb), where each of the radicals R independently of one another selected from the group including1-C24alkyl and C7-C24alkylaryl, m denotes a number from 0 to 5, n represents a number from 1 to 3, R represents a number from 0 to 3, q represents a number from 0 to 3 and r represents a number from 0 to 4, s represents a number from 1 to 3 and (H-B)+denotes the cation of the formula (I), where R4selected from the group including7-C19alkyl and C7-C19alkenyl-CH2- each radical R5independently from each other represents C2-C4alkylen straight or branched chain, and x denotes a number from 1 to 50 and y denotes a number from 0 to 50

FIELD: chemistry.

SUBSTANCE: matrix can be used in purification of proteins, where protein represents antibody, fragment of antibody or antibody-containing fused protein. Ligand corresponds to the following formula (I): R1-R2-N(R3)-R4-R5, where R1 represents non-substituted phenyl group; R2 represents hydrocarbon chain, containing 0-4 carbon atoms, preferably 1-4 carbon atoms; R3 represents hydrocarbon chain, containing 1-3 carbon atoms; R4 represents hydrocarbon chain, containing 1-5 carbon atoms; and R5 represents OH or H. As base matrix contains particles, in fact representing spherical particles, or has membranous or porous structure. Method of obtaining separation matrix includes immobilisation of said ligand on base mainly through amine group. Obtained matrix is placed into chromatographic column and after that sterilised if necessary. In order to separate one or more antibodies from one or more other compounds in liquid sample mobile phase, containing said antibodies and compound(s), are brought into contact with separation matrix. Liquid sample can contain supernatant, obtained in cell fermentation or unprocessed nutritional substance. In the process of application of chromatographic column mobile phase passes through column under impact of gravity and/or rocking, and antibodies are obtained in flow liquid of column. Invention also described set for purification of antibodies from one or more other components in liquid, containing in separate compartments chromatographic column, filled with separation matrix, one or more than one buffer and written instructions.

EFFECT: claimed invention relates to novel separation matrix, containing ligand, bound to base.

20 cl, 6 dwg, 4 tbl, 4 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to new amine derivatives of the following structural formula:

(A),

which have properties of an inhibitor of isomerase activity of a retinoid cycle. In formula (A) Z represents -C(R9)(R10)-C(R1)(R2)- or -X-C(R31)(R32); X represents -O-, -S-, -S(=O)-, -S(=O)2- or -N(R30)-; G is chosen from -C(R41)2-C(R41)2-R40, -C(R42)2-S-R40, -C(R42)2-SO-R40, -C(R42)2-SO2-R40 or -C(R42)2-O-R40; R40 is chosen from -C(R16)(R17)(R18), C6-10aryl; each R6, R19, R34, R42 has been independently chosen from hydrogen or C1-C5alkyl; each R1 and R2 has been chosen independently from each other from hydrogen, halogen, C1-C5alkyl or -OR6; or R1 and R2 together form oxo; each R3, R4, R30, R31, R32, R41 represents hydrogen; each R9 and R10 has been chosen independently from each other from hydrogen, halogen, C1-C5alkyl or -OR19; or R9 and R10 form oxo; or possibly R9 and R1 together form a direct link to provide a double link; or possibly R9 and R1 together form a direct link and R10 and R2 together form a direct link to provide a triple link; n is equal to 0 or 1; values of radicals R11, R12, R16-R18, R23, R33 are given in the formula of the invention. The invention also relates to a pharmaceutical composition containing the above compounds, to application of compounds for production of a medicinal agent for treatment of a retinal ophthalmological disease, reduction of a lipofuscin pigment accumulated in an eye, for inhibition of dark adaptation of rod photoreceptor cell of retina, inhibition of regeneration of rhodopsin in the rod photoreceptor cell of retina or inhibition of degeneration of a retinal cell in retina.

EFFECT: improved properties of derivatives.

18 cl, 2 dwg, 17 tbl, 195 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel cyclic compounds of general formula which possess properties of CaSR modulator. In general formula I group represents cycloalkyl, which contains 4-7 carbon atoms, optionally substituted with one or several similar or different substituents, selected from R2, R3, R4 or R5; A represents 1-naphthyl; R1 represents methyl, ethyl or n-propyl, each of which is optionally substituted with one or several, similar or different substituents, selected from halogen and hydroxy; R2 and R3 represent hydrogen; R4 represents hydrogen, halogen, hydroxy or C1-6alkyl; each R5 represents independently one or several similar or different substituents, represented by hydrogen or C1-6alkyl; G represents -C(O)NH2, C3-8cycloalkyl, C1-6heterocycloalkyl, C1-6heterocycloalkenyl, C3-8cycloalkenyl, C6-14aryl, C1-10heteroaryl, C6-10arylamino, hydroxyaminocarbonyl, C6-10arylaminocarbonyl, C1-4aminocarbonyl, C1-6heterocycloalkylcarbonyl, C1-10heteroarylaminocarbonyl, C6-10arylsulfonylaminocarbonyl, C6-14aryloxy, or C1-4alkoxycarbonyl, where said substituents are optionally additionally substituted with one or several, similar or different substituents. Other values of radicals are given in the formula of invention.

EFFECT: compounds can be applied in treatment, relief or prevention of physiological disorders or diseases, associated with impairment of activity of CaSR, such as hyperparathyreosis, and other diseases.

23 cl, 9 dwg, 3 tbl, 315 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 5-amino-1-pentene-3-ol of the general formula (I)

as a free form or as their physiologically compatible salts possessing the analgesic effect. In general formula (I) each R1 and R2 means independently of one another (C1-C6)-alkyl that can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or multi-substituted; or R1 and R2 form in common -(CH2)2-9-mono- or bicyclic ring; each R3 and R4 means independently of one another (C1-C6)-alkyl, or R3 and R4 form in common a ring and mean the group -CH2CH2NR22CH2CH2 wherein R22 represents (C1-C10)-alkyl; R5 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched, mono- or multi-substituted or unsubstituted, (C3-C9)-cycloalkyl that is saturated or means phenyl, heteroaryl that can be condensed with benzene ring and chosen from 5-membered heteroaryl with sulfur or oxygen atom as a heteroatom bound through saturated (C1-C3)-alkyl, phenyl bound through saturated (C1-C3)-alkyl-(C3-C10)-cycloalkyl wherein each among all these alkyl, phenyl, heteroaryl and cycloalkyl residues and independently of others can be unsubstituted or mono- or multi-substituted residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, groups -OR18, (C1-C3)-alkyl) that is saturated or branched or unbranched, mono- or multi-substituted halide, or unsubstituted and wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or unbranched; R6 means (C1-C10)-alkyl that is saturated or unsaturated, branched or unbranched and unsubstituted, phenyl or heteroaryl that is chosen from 5-membered heteroaryl with oxygen atom as a heteroatom wherein each of them is unsubstituted or mono- or multi-substituted as indicated above; R7 means H. Also, invention relates to a medicinal agent based on proposed compounds and to a method for their synthesis.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

10 cl, 493 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the formula (I):

and their pharmaceutically acceptable salts wherein R1 means hydrogen (H), chlorine or bromine atom; R2 means electron-acceptor groups -CF3, -CN, fluorine atom, -COSO3H, -CF3SO3 and -NO2; R3 means linear or branched alkyl comprising from 2 to 10 carbon atoms, linear or branched alkoxyalkyl, aliphatic alcohol comprising from 1 to 10 carbon atoms or cycloalkyl comprising from 3 to 6 carbon atoms. Also, invention relates to methods for preparing indicated compounds and to a pharmaceutical composition comprising thereof. Compounds of the present invention are agonists of β2-receptor and can be used in treatment of asthma and bronchitis.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 1 tbl, 48 ex

-(tertiary aminomethyl)benzoimidazole and pharmaceutical composition based on them" target="_blank">

The invention relates to new derivatives-(tertiary aminomethyl)benzoimidazole, which have pharmacological properties, and to methods for their preparation

The invention relates to (S) enantiomers of new substituted-3-amino-chromanol, thiochroman and tetralines and their salts, processes for their preparation, pharmaceutical compositions containing the therapeutically active compounds and to novel intermediate compounds used in the preparation of therapeutically active compounds and to the use of said active compounds in therapy

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutically acceptable crystalline or amorphous salts of D-isoglutamyl-D-tryptophan, methods of their obtaining, pharmaceutical compositions, containing them, and their application for obtaining pharmaceutical compositions for treatment of different conditions and/or diseases. In particular claimed invention relates to potassium salt of D-isoglutamyl-D-tryptophan (1:1) and magnesium salt of D-isoglutamyl-D-tryptophan (2:1).

EFFECT: obtaining pharmaceutically acceptable crystalline or amorphous salts of D-isoglutamyl-D-tryptophan.

22 cl, 15 dwg, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to immunology and biotechnology. There are presented variants of antagonist antibodies binding to the interleukin-7 receptor (IL-7R). There are described: variants of nucleic acids coding the antibodies; a host cell recombinant producing the antibody; a pharmaceutical composition inhibiting the human IL-7R function, and methods of treating and/or preventing: an autoimmune disease specified in the group of type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis; type 2 diabetes or graft-versus-host disease based on using the antibody.

EFFECT: invention provides the antagonist anti-IL-7R antibodies that can find application in medicine.

17 cl, 15 dwg, 8 tbl, 13 ex

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