Crystalline forms of fingolimod hydrochloride

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new hydrate of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol hydrochloride salt in the crystalline form with the characteristics below. The hydrate can be used for producing a drug or for treating or preventing a transplanted organ or tissue rejection, or autoimmune diseases in a therapeutically effective amount. The above hydrate is characterised by an X-ray powder diffractogram having peaks at approximately 2.9, 17.2, 30.6, 28.2, 24.4, 8.6 and 25.9 degrees 2-Theta with a limit of error of ±0.2 degrees for each value of 2θ, having a purity of 90% or more, and containing 5.2 to 5.9% of water.

EFFECT: invention also characterises a pharmaceutical composition with using the above hydrate.

4 cl, 4 dwg, 8 tbl, 14 ex

 

The present invention relates to crystalline forms and hydrates of FTY720 hydrochloride and their application.

Compounds 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propane-1,3-diol disclosed in the 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 the 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 from the free base or hydrochloride salt. FTY720 has the following structure:

The present invention is based in part on the discovery that FTY720 hydrochloride exhibits polymorphism. As shown in the application examples, FTY720 hydrochloride at room temperature exists in a specific crystalline form (hereinafter Form I). Crystalline Form I is undergoing a transformation in an alternate crystal form (Form II) with a transition temperature of approximately 40°C. additionally, crystalline Form II undergoes a transition to a third crystalline form (Form III) at temp�a temperature of approximately 66°C. At a temperature of approximately 107°C FTY720 hydrochloride forms a phase with low crystalline order.

Thus, the present invention relates to new crystalline forms of FTY720 hydrochloride, including their solvates, especially the hydrates.

Crystalline Form I of FTY720 hydrochloride characterized by x-ray powder diffraction pattern having peaks at least two, preferably at least four, and more preferably all of the listed values of 2-Theta: 3,6, 7,1, 10,7, 12,5, 15,4 and 20.6 degrees 2-Theta. Peaks at these values of 2-Theta have the following relative intensities: 3,6 (strong) and 7.1 (weak) to 10.7 (weak) 12,5 (weak) to 15.4 (average) and 20.6 (average).

In one of the embodiments of the invention, this crystalline form is characterized by x-ray powder diffraction pattern having peaks at least two, preferably at least four, and more preferably all of the listed values of 2-Theta: 3,55, 7,12, 10,71, 12,48, 15,42 and and 20.59 degrees 2-Theta. Peaks at these values of 2-Theta have the following relative intensities: 3,55 (strong), 7,12 (weak), and 10.71 (weak) 12,48 (weak), for 15.42 (middle) and and 20.59 (average).

In the private embodiment, this crystalline form is characterized by x-ray powder diffractogram�my appropriate essentially the diffraction pattern shown in Fig.1.

Crystalline Form II of FTY720 hydrochloride characterized by x-ray powder diffraction pattern having peaks at least two, preferably at least four, and more preferably all of the listed values of 2-Theta: 3,5, 6,9, 10,4, 14,6, 19,2, 20,3 and 20.9 degrees 2-Theta. Peaks at these values of 2-Theta have the following relative intensity: 3,5 (strong), 6,9 (strong), 10,4 (weak) 14,6 (weak) 19,2 (weak) 20,3 (weak) and 20.9 (weak).

In one of the embodiments of the invention, this crystalline form is characterized by x-ray powder diffraction pattern having peaks at least two, preferably at least four, and more preferably all of the listed values of 2-Theta: 3,47, 6,92, 10,38, 14,58, 19,20, 20,34 and 20,86 degrees 2-Theta. Peaks at these values of 2-Theta have the following relative intensities: 3,47 (strong), at 6.92 (weak) to 10.38 (weak) 14,58 (weak), 19,20 (weak) 20,34 (weak) and 20,86 (weak).

In the private embodiment, this crystalline form is characterized by x-ray powder diffraction pattern corresponding to essentially the diffraction pattern shown in Fig.2.

Crystalline Form III of FTY720 hydrochloride characterized by x-ray�coy powder diffraction pattern, having peaks at least two, preferably at least four, and more preferably all of the listed values of 2-Theta: 3,5, 6,9, 10,3, 14,4, 18,9, 20,3, 20,7 and 24.2 degrees 2-Theta. Peaks at these values of 2-Theta have the following relative intensity: 3,5 (strong), 6,9 (strong), 10,3 (weak) 14,4 (weak) 18,9 (weak) 20,3 (weak) 20,7 (weak) and 24.2 (weak).

In one of the embodiments of the invention, this crystalline form is characterized by x-ray powder diffraction pattern having peaks at least two, preferably at least four, and more preferably all of the listed values of 2-Theta: 3,46, 6,88, 10,32, 14,41, 18,94, 20,26, 20, 73 and 24.23 degrees 2-Theta. Peaks at these values of 2-Theta have the following relative intensities: 3.46 in (strong), to 6.88 (weak) of 10.32 (weak), 14,41 (weak) of 18.94 (weak), 20,26 (weak) is 20.73 (weak) and 24.23 (weak).

In the private embodiment, this crystalline form is characterized by x-ray powder diffraction pattern corresponding to essentially the diffraction pattern shown in Fig.3.

In addition, the invention relates to a method for producing crystalline Form I of FTY720 hydrochloride, comprising cooling the crystalline Form II or Form III FTY720 hydrochloride to a temperature less than 40°C., Prefer�till then the method includes cooling to a temperature of 30°C or less more preferably up to 20°C or less, more preferably at least 10°C or less, for example, at least up to 8°C or less, for example up to 2-8°C, in order to ensure the transformation to crystalline Form I.

It was also found that FTY720 hydrochloride can exist essentially in the form of a hydrate. In one of the embodiments of the invention, the hydrate is characterized by an x-ray powder diffraction pattern having peaks at least two, preferably at least four, and more preferably all of the listed values of 2-Theta: 2,9, 17,2, 30,6, 28,2, 24,4, 8,6 and 25.9 degrees 2-Theta. Peaks at these values of 2-Theta have the following relative intensities: 2,9 (strong), 17,2 (middle) 30,6 (weak) 28,2 (weak) 24,4 (weak) to 8.6 (weak) and 25,9 (weak). In the private embodiment of the invention relates to a hydrate of FTY720 hydrochloride characterized by x-ray powder diffraction pattern corresponding to essentially the diffraction pattern shown in Fig.4.

For illustration and without limitation, various crystal forms and hydrates of FTY720 hydrochloride can be obtained in accordance with the methods provided in the examples of the present description. In particular, interconversion of the various polymorphic forms of FTY720 hydrochloride can be carried out by heating �whether cooling FTY720 hydrochloride in accordance with the procedures described in the examples.

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

A crystal form characterized by main peaks of x-ray powder difractogram, as shown in the examples of the present application. Also the crystal forms may be different thermodynamic stability, physical parameters, such as absorption spectrum in infrared spectroscopy (IR) or phase transition peaks in the differential scanning calorimetry (DSC).

In one embodiment, the implementation of the various crystalline salt forms of the present invention are essentially pure crystalline form. The term "substantially pure" as used in the present application, relates to crystalline polymorphic forms with a purity of more than 90%, more preferably 95%, more preferably 96%, more preferably 97%, more preferably 98%, more preferably 99%, as determined, for example, x-ray powder diffraction, Raman spectroscopy or IR spectroscopy.

The present invention also relates to pharmaceutical compositions containing the 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%, e.g. 0.5 to 5 wt.%, based on the total weight of the composition.

Pharmaceutical compositions may 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 salts of the present invention with a pharmaceutically acceptable carrier or diluent.

In the private embodiment, the composition is a solid pharmaceutical composition containing a salt of the invention and a sugar alcohol. Compositions of this type are disclosed in the application WO 2004/089341, the content of which is incorporated into this description by reference. Solid compositions disclosed in this publication, and particularly suitable for oral administration of salts of the present invention. The compositions provide a convenient means DL� systematic introduction of compounds which is not characterized by the disadvantages of liquid formulations for injection or oral use, and have good physicochemical properties and well kept. In particular, the compositions of the present invention can demonstrate a high level of homogeneity in the distribution of compounds in the composition, as well as high stability. In addition, the composition can be obtained by high speed automated equipment and, thus, no manual encapsulation.

Sugar alcohol may act as a diluent, carrier, filler or bulking agent, and preferably represents mannitol, maltitol, Inositol, xylitol or lactitol, preferably, essentially nephroscopy sugar alcohol, e.g. mannitol (D-mannitol). Can be used as a single sugar alcohol, and 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 embodiment the sugar alcohol is prepared from spray-dried compositions, for example compositions of mannitol having a high-specific surface area. The use of this type of composition mannitol contributes to the promotion of a homogeneous distribution of the compound and mannitol in the composition. High surface area �can be achieved by obtaining a sugar alcohol, for example mannitol containing particles having a small size and/or uneven surface of each particle. As it was established, the use of spray dried sugar alcohol, for example mannitol, for example, with particle sizes of 300 μm or less, improves the compressibility and strength of the tablets obtained from the composition.

Preferably, the surface area of the drug, a sugar alcohol, e.g. mannitol, measured in one point, is 1-7 m2/g, for example 2-6 m2/g or 3-5 m2/g. Preferably, the drug mannitol may have a particle size of 100-300 μm, for example 150-250 microns, and bulk density of 0.4-0.6 g/ml, for example between 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. a sugar alcohol, more preferably 85-99,9%, e.g., 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, colloids�th silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer or a mixture of any of the foregoing. Preferred lubricants include magnesium stearate, gidrirovannoe castor oil and mineral oil. Colloidal liquid and the less preferred polyethylene glycol as a lubricant.

Preferably the composition contains 0.01-5 wt%. the 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 (e.g. Avicel®), methylcellulose, hydroxypropyl cellulose, starch (e.g. corn starch) or dicalcium phosphate, preferably in an amount of from 0.1 to 90 wt.%, for example 1-30% wt., based on the total weight of the composition. In the case of using a binder, such as microcrystalline cellulose, methylcellulose, hydroxypropyl cellulose, the content is 1 to 8%, e.g. 3-6% wt., based on the total weight of the composition. The application of the binder increases the strength of the granules of the composition, which is particularly important when thin granulation. Microcrystalline cellulose� and cellulose are the most preferred in the event that if you want high strength of the tablet and/or a longer disintegration time. Hydroxypropyl cellulose is preferred in that case, if you want a fast disintegration. Optionally, as an additional binder may also be added xylitol, for example, in addition to microcrystalline cellulose, for example, in an amount up to 20 wt.%, a 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 range from 0.1 to 30%, preferably 1-20 wt%.

The composition may be in the form of powder, granules, flakes or metered dosage form, e.g. as tablets or capsules. The compositions of the present invention are well adapted for encapsulation in a shell capsules for oral administration, in particular in a shell of hard gelatin capsules.

Alternatively, the composition can be compressed into tablets. The tablets can optionally be coated, for example coating with talc or polysaccharide (e.g., cellulose) or methylcellulose.

In that case, if the composition is a metered dosage form, each dosage form may contain, for example, tokolo 0.5 to about 10 mg of a salt of the invention.

The compositions of the present invention demonstrate good performance of stability according to the standard stability tests, for example, have high storage stability one, two or three years and even more. Stability can be determined, for example, through measuring decomposition products by HPLC after storage at certain time intervals, at a certain temperature, for example 20, 40 or 60°C.

Pharmaceutical compositions of the present invention can be obtained by standard methods, e.g. conventional mixing, granulating, sugar coating, dissolving or lyophilization. Used methods known in the art (see, e.g., L. Lachman et al. theory and Practice of Industrial Pharmacy, 3rd ed., 1986, H Sucker et al., Pharmazeutische Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen Praxis, 4th ed. (Springer Veriag, 1971) and Remington's Pharmaceutical Sciences, 13th ed., (Mack Publ., Co., 1970) or later editions).

In yet another embodiment the pharmaceutical composition is prepared by a method comprising the following steps:

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

(b) obtained in stage (a) the mixture is milled and/or granulated and

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

When using this method, yielding�t composition, with a good level of content and uniformity of mixing (i.e. essentially uniform distribution of salt in the composition, the time of dissolution, and stability.

Salt can optionally be micronized, and/or pre-sifted, for example, through a sieve with cell size of 400-500 μm, before step (a) to remove lumps. Stage of mixing (a) may include mixing of the salt and the sugar alcohol, e.g. mannitol in any suitable blender or mixer, for example, 100-400 rpm.

The method may be carried out by dry mixing the components. In this embodiment of the invention: the stage of milling (b) may include passing the mixture obtained at stage (a), through a sieve, which preferably has a cell size of 400-500 μm. Stage method (a) may include the step 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 preliminary mixture. Then prior to the mixture add the remaining amount of the sugar alcohol. Stage (a) may also include the step of adding a binder to the mixture solution, for example methylcellulose and/or xylitol, for example, in the form of an aqueous solution. Alternatively, a binder is added to the dry mixture and water is added at the stage of granulation

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

Alternative use the method of wet granulation. In this embodiment, the salt is preferably in the beginning in dry form is mixed with the desired sugar alcohol, e.g. mannitol, and then the resulting mixture is a sugar alcohol/salt in dry form mixed with a binder such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose. After that, water was added and the mixture granulated, for example, using automated pellet mill. The resultant granulate is dried and pulverized.

If required, at the 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 of tableting or encapsulating the mixture obtained in stage (b), for example, in a hard gelatin capsule using an automated encapsulation device. Capsules may be colored or labeled to impart an individual appearance and instant recognition. The application of dyes improves the appearance and is also used for �automatically recognized capsules. Dyes suitable for use in pharmacy typically include carotinoids, iron oxides, and chlorophyll. Preferably the capsule of the present invention labeled by the code.

Salts 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, kidney, pancreatic, skin or corneal, and to prevent reaction "transplant against host" such as occasionally occurring reaction after bone marrow transplantation; particularly for the treatment of acute or chronic rejection of ALLO - and xenotransplantation, or 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, e.g. rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes type I or type II and related disorders, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriasis, graves ' ophthalmopathy, of alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergies and other respiratory�technical 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 cookies, inflammatory kidney damage, atherosclerosis, irritant contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically mediated diseases, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

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

Salt can be introduced by any appropriate means, for example orally, for example in the form of tablets or capsules, topically or parenterally, for example intravenously. Pharmaceutical compositions containing the salts of the present and�gaining 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. Metered dosage form for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance.

Salt can be administered as the sole active ingredient or together with other drugs in immunomodulating modes or with other anti-inflammatory agents, e.g. 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, e.g. rapamycin, 40-O-(2-hydroxy)atrribution, CCI779, AVT or AR, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; other receptors of the S1P agonist, e.g. FTY720 or its analogues; Leflunomide or analogs; miraibio; mycophenolic acid; mycophenolate of mofetil; 15-deoxynivalenol or its analogues; immunosuppressive monoclonal antibodies, for example, monoclonal antibodies to receptors of white blood cells; for example MHC, CD2, CD, CD4, CDlla/CD18, CD7, CD25, CD27, B7, CD40, CD45, CD58, CD137, ICOS, CD150 (SLAM), OH, 4-1 BB or their ligands, such as a CD 154; or with other immunomodulators, e.g. a recombinant binding molecule containing at least part 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 ATS 68629) or a mutant, e.g. LEA29Y, or other inhibitors of adhesion molecules, such as mAbs or inhibitors with small molecular weight, 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, undergoing treatment, etc.

The present invention also relates to:

1. A method for the treatment or prevention of rejection of transplanted organ or tissue comprising administering to the subject a therapeutically effective amount of a crystalline salt of the invention.

2. A method for the treatment or prevention of autoimmune disease or inflammatory condition, comprising administering to the subject a therapeutically effective amount of crystal�tion salts of the invention.

3. Crystalline salt of the invention for use as a pharmaceutical product.

4. Pharmaceutical compositions comprising the crystalline salt of the invention and a pharmaceutically acceptable diluent or carrier.

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

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

The following examples illustrate the present invention. In examples 1-13 references to the connection A, FTY720 or hydrochloride salt of FTY720 also include links to any of various crystalline salt forms of the present invention.

Example 1

Microselectron compound A, for example, hydrochloride 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), is screened and 116,7 g of the screened compound is mixed with 9683,3 g microcrystalline Zell�vines. The mixture is then milled in the device Frewitt MGI (Key International Inc., USA) using sieves with mesh size of 30 mesh. Magnesium stearate is sifted through a sieve with cell size of 20 mesh and 200 g of the screened compound is mixed with the mixture of FTY720, getting the composition of the product.

After that, the composition of the product is placed in a tablet press, containing 7 mm of the mold, and get tablets 120 mg, each tablet contains:

Compound A, e.g. FTY720*1.4 mg
Microcrystalline cellulose, e.g. Avicel PH 102USD 116.2 mg
Magnesium stearate2.4 mg
Total120 mg

*1 mg of compound A in free form is equivalent to 1.12 mg FTY720.

Example 2

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

Example 3

Compound A, e.g. FTY720, and microcrystalline cellulose, e.g. Avicel PH 102, individually sieved through a sieve with cell size of 18 mesh. 1.9 g sifted FTY720 are mixed with 40 g of sieved microcrystalline cellulose within 120 rpm in a mixer at 32 R/�in. After that, the FTY720 mixture was sieved through a sieve with cell size of 35 mesh.

Screened FTY720 mixture is placed in a granulator together with an additional amount (340,1 g) microcrystalline cellulose, e.g. Avicel PH 102, and 12 g of hydroxypropyl cellulose. The mixture was stirred for 3 min. Then at a rate of 100 ml/min water was added and the mixture granulated for 2 min Granulate is transferred to a centrifugal dryer and dried at 50°C for 150 min.

Thereafter, the mixture was pulverized in a device Frewitt MGI using sieves with mesh size of 35 mesh. Magnesium stearate is sieved and 6 g of the screened compound is mixed in the mixer for 90 rpm 32 rpm with the mixture of FTY720, with the composition of the product, demonstrating the essentially uniform distribution of the receptor agonist S1P in microcrystalline cellulose, e.g. Avicel PH 102.

Then the composition of the product fill hard gelatin shell size 3 on the device to encapsulate the H&K 400. Each capsule is placed 120 mg composition of the product. Thus, each capsule contains:

FTY720*0.56 mg
Microcrystalline cellulose114,04 mg
Hydroxypropyl cellulose 3.6 mg
Magnesium stearate1,8 mg
Total120 mg

Example 4

In this example, repeating the method of example 3, except that the magnesium stearate is replaced by Cutina® (gidrirovannoe castor oil).

Example 5

In this example, repeating the method of example 3, except that hydroxypropyl cellulose substituted with hydroxypropyl methylcellulose.

Example 6A

Microselectron compound A, e.g. FTY720, sieved through a sieve with cell size of 400 microns (40 mesh.). 58,35 g of the screened compound is mixed with 4841,65 g of microcrystalline cellulose, e.g. Avicel PH 102, 25 l of the mixer Bohle bin for 240 full speed. Thereafter, the mixture was pulverized in a device Frewitt MGI using sieves with mesh size of 425 μm, and the milled mixture is stirred again. Magnesium stearate is screened and 100 g of the screened compound is mixed with the mixture of FTY720, with the composition of the product, demonstrating the essentially uniform distribution of the receptor agonist S1P in the mixture.

Then the composition of the product fill hard gelatin shell size 3 on the device to encapsulate the H&K 400. Each capsule is placed 120 mg composition of the product. Thus, each capsule contains:

FTY720*1.4 mg
Microcrystalline celluloseUSD 116.2 mg
Magnesium stearate2.4 mg
Total120 mg

Example 6b

In an alternative embodiment, the capsules are prepared using the components and amounts described in example 6A, but FTY720 in the beginning mixed with 14 mg mannitol (before sieving). The mixture is then sieved as described above. Sieved mixture is mixed with the remaining amount of mannitol and add to it magnesium stearate, and then mixed again and fill with a mixture of capsules.

Examples 7 and 8

In these examples, the capsule receive as described in example 6, except that the capsule contains each component in the following amounts:

Example 7Example 8
FTY720*2.8 mg5,6 mg
Microcrystalline cellulose114,8 mg112 mg
Magnesium stearate 2.4 mg2.4 mg
Total120 mg120 mg

Examples 9-11

In these examples, the capsules get a as described in examples 6-8, except that the magnesium stearate is replaced by Cutina® (gidrirovannoe castor oil).

Examples 12 and 13

Capsules containing the following components, obtained by weighing each component and mixing the components in a mortar, and then filling the mixture obtained capsules:

Example 12Example 13
FTY7205 mg1 mg
D-mannitol83,7 mg117 mg
Corn starch24 mg-
Avicel® RN12 mg-
Hydroxypropyl cellulose0.3 mg7 mg
Talc3 mg 3 mg
Lubriwax®1012 mg2 mg
Total130 mg130 mg

Example 14: Polymorphs and hydrates of FTY720 hydrochloride

The curves of differential scanning calorimetry (DSC) register using the system PerkinElmer DSC-7 and Pyris 1.

Heating curves of DSC show three characteristic transition at approximately 40°C, 66°C and 107°C. the First endothermic peak at 40°C, followed by a small endothermic peak indicates the melting of Form I and subsequent recrystallization into Form II. The second transition between Form II and Form III represents the transition between solid phases. The third transition is observed at 107°C. to About 10°C x-ray powder difractogram almost disappears and there is only one strong peak at 2,9°, what is believed, indicates the formation at a given temperature phase with nizkoglikemichesky structure. Thermomicroscopy shows double refraction at about 107°C, which disappears only at a temperature of about 230°C, which is below the decomposing observed at about 260°C.

This is followed by a powder x-ray diffraction at different temperatures to study the nature of various perehod�, observed in DSC. For each experiment, the heating rate is 10 K/min, and the time of the study - 5 min. X-ray powder diffraction pattern is recorded between 2° and 35° (2-Theta) with CuKα radiation using a Scintag diffraction system X1. Powder x-ray diffraction at different temperatures and levels of humidity is carried out using a system Scintag XDS 2000; equipped with control units for temperature and humidity.

In accordance with the data of powder x-ray diffraction at different temperatures FTY720 hydrochloride exists in at least four different crystalline forms. At about 107°C almost all the diffraction peaks disappear and there is only one strong peak at 2,9°. These results are consistent with the DSC results. However, another crystalline form (Form IV), observed at 0°C, detected only by x-ray powder diffraction, but not revealed DSC. Since x-ray powder diffraction pattern of Form IV is very similar to the diffraction pattern of Form I, and in the DSC thermal process is not observed, it is believed that the properties of crystals of Form IV is very similar to the properties of the Form I.

X-ray powder diffraction pattern of Form I of FTY720 hydrochloride is shown in Fig.1, characteristic peaks given below:

°degrees 2θd-step (Å)The relative intensity
3,5524,875Strong
7,1212,394Weak
And 10.718,255Weak
12,487,090Weak
For 15.425,742Average
And 20.594,309Average

In a separate embodiment the x-ray powder diffraction pattern of Form I of FTY720 hydrochloride has the following characteristics:

°degrees 2θd-step (Å)Relative intensity (%)
3,5524,875100
7,1212,3944
And 10.71 8,25510
12,487,0907
For 15.425,74215
And 20.594,30920

X-ray powder diffraction pattern of Form II of FTY720 hydrochloride is shown in Fig.2, the characteristic peaks of the following:

°degrees 2θd-step (Å)The relative intensity
3,4724,467Strong
At 6.9212,756Weak
To 10.388,513Weak
14,586,070Weak
19,204,617Weak
20,344,362Weak
20,864,254 Weak

In a separate embodiment the x-ray powder diffraction pattern of Form II of FTY720 hydrochloride has the following characteristics:

°degrees 2θd-step (Å)The relative intensity
3,4724,467100
At 6.9212,7565
To 10.388,5139
14,586,0706
19,204,6179
20,344,3628
20,864,25413

X-ray powder diffraction pattern of Form III FTY720 hydrochloride is shown in Fig.3, characteristic peaks given below:

°degrees 2θd-step (Å)Relative intensity�
3,4625,467Strong
To 6.8812,826Weak
Of 10.328,559Weak
14,416,138Weak
Of 18.944,679Weak
20,264,378Weak
Is 20.734,279Weak
24,233,668Weak

In a separate embodiment the x-ray powder diffraction pattern of Form III FTY720 hydrochloride has the following characteristics:

°degrees 2θd-step (Å)Relative intensity (%)
3,4625,467100
To 6.8812,826 6
Of 10.328,55911
14,416,1386

°degrees 2θd-step (Å)Relative intensity (%)
Of 18.944,6798
20,264,3787
Is 20.734,27914
24,233,6686

For each value of the angle 2θ can be made minimal margin of error of approximately ±0.2°.

Isotherms of sorption/desorption was measured using a Dynamic Vapor System (DVS-1). The measurement is performed at 25°C and 40°C.

According to the isotherm of desorption of water registered at 25°C and relative humidity (RH) between 90% and 60% of them observed a nearly constant water content of 5.2 to 5.9%. The data obtained indicate the formation of hydrate (theoretical water content of the monohydrate 4,98%). According to water sorption isotherm obtained at 40°C, see the first value�tive absorption of water already at RH 80%, while according to the isotherm recorded at 25°C, the first absorption observed at RH 90%. For samples of Form I, stored for 1 month at 60°C and RH 75% and for 1 month at 80°C and RH 75%, characterized by the transformation in hydrated form with a water content of 10.2% to 10.6%, which is close to the computed water content 9,48% for two moles of water.

X-ray powder diffraction pattern of the hydrate is shown in Fig.4, the characteristic peaks of the following:

°degrees 2θd-step (Å)The relative intensity
2,930,298Strong
17,25,160Average
30,62,921Weak
28,23,161Weak
24,43,651Weak
8,610,280Weak
25,9UAH 3,438Weak

In a separate embodiment the x-ray powder diffraction pattern of the hydrate has the following characteristics:

°degrees 2θd-step (Å)Relative intensity (%)
2,930,298100
17,25,16026
30,62,9216
28,23,1615
24,43,6514
8,610,2804
25,9UAH 3,4384

1. Pharmaceutical composition for use in treating or preventing rejection of transplanted organ or tissue or autoimmune diseases containing crystalline hydrochloride salt of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY720) in the form of a hydrate characterized by x-ray powder dif�the actogram, having peaks at about 2,9, 17,2, 30,6, 28,2, 24,4, 8,6 and 25.9 degrees 2-Theta, with a limit of error ±0.2 ° for each value of the angle 2θ, having a purity of 90% or more, and with a water content of from 5.2 to 5.9%.

2. Use of the composition according to claim 1 for obtaining a medicinal product for the treatment or prevention of rejection of transplanted organ or tissue or autoimmune diseases.

3. A method of treating or preventing rejection of a transplanted organ or tissue or autoimmune diseases in a patient, comprising administering a therapeutically effective amount of a salt according to claim 1.

4. Hydrate hydrochloride salt 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol in crystalline form characterized by x-ray powder diffraction pattern having peaks at about 2,9, 17,2, 30,6, 28,2, 24,4, 8,6 and 25.9 degrees 2-Theta, with a limit of error ±0.2 ° for each value of the angle 2θ, having a purity of 90% or more and a water content, which ranges from 5.2 to 5.9 percent



 

Same patents:

Fingolimod salts // 2543621

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

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

Fingolimod salts // 2543621

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

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

Fingolimod salts // 2543621

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

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

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