Novel crystalline forms of rosiglytasone, methods of their obtaining, pharmaceutical composition and based on them method of treatment

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to methods of obtaining rosiglytasone, rosiglytasone, obtained by said methods, and its pharmacological compositions and methods of treatment using it.

EFFECT: obtaining of new crystalline modifications of rosiglytasone, which have useful biological properties.

58 cl, 4 dwg, 2 tbl, 9 ex

 

The present invention relates to a method of receiving rosiglitazone, rosiglitazone, obtained by such methods, and pharmaceutical compositions and therapeutic use of rosiglitazone and methods of treatment using it.

Rosiglitazona maleate, malate 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dione, has the following General structural formula (I):

Rosiglitazone is representative of the class thiazolidinedione compounds and is one of the most potent compounds of this class. It was shown that antidiabetic class of preparations of thiazolidinediones, such as pioglitazone, englitazone, rosiglitazone, troglitazone and ciglitazone, reduce insulin resistance in people. Therefore, rosiglitazone is a known anti-diabetic compound, and more specifically is the preferred drug for non-insulin dependent diabetes mellitus (NIDDM). Diabetes is a complex chronic progressive disease that affects the kidneys, eyes, cardiovascular and nervous systems.

In the patent application PCT WO 94/05659 disclosed certain derivative thiazolidinedione with hypoglycemic and hypolipidemic activity, including the maleate 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazo the one-2,4-dione.

In patent applications PCT 99/31093, WO 99/31094 and WO 99/31095 disclosed various hydrates rosiglitazona maleate with non-stoichiometric water content.

In patent applications PCT WOOO/64893, WO 00/64896 and WO 02/026737 disclosed polymorphs rosiglitazona maleate. In the patent application WO 02/026737 revealed polymorphic forms I, II, III and IV rosiglitazona maleate, methods for their production and their pharmaceutical compositions.

The present invention offers additional ways to get rosiglitazone, including rosiglitazona maleate, as well as free base of rosiglitazone. As for receiving rosiglitazona maleate according to the present invention, described the receipt of two polymorphic forms, which are further designated as forms a and B. form a rosiglitazona maleate is thermodynamically stable and can be easily obtained from the form In rosiglitazona maleate or other anhydrous or hydrated polymorphs rosiglitazona maleate, described in the prior art.

Crystalline form And rosiglitazona maleate obtained according to the present invention has an x-ray or almost the same radiograph as shown in figure 1. More specifically, the crystalline form And rosiglitazona maleate can be characterized by the x-rays with characteristic peaks (2θ): 9,25°, 15,86°, 15,02&x000B0; , 17,00°, holds 18.52°, 21,99°, 23,58°, 25,06° and 26,55°.

Additional data of x-ray analysis, characterizing crystalline form And rosiglitazona maleate, shown in the following table 1.

5,88986
Table 1
no maximum2θ (grad)d (A)I/IIThe full width at half maximum (FWHM) (deg)The intensity (number of pulses)Integral intensity (number of pulses)
14,640019,0288880,253401101776
27,530311,7304050,2340064960
38,523910,3651360,25440811507
49,25549,54750100,259801251992
59,82168,9983340,52330481145
613,88626,3722540,2325054732
715,0298530,3292069314134
815,86785,580651000,29740129621662
917,00125,21108150,359702003772
1017,78264,9838140,2387057826
1118,52164,78659310,361704007774
1219,18004,6237440,3040050979
1319,95854,4451150,35710611319
1421,13124,2010040,2575057903
1521,99764,03746210,410602676470
1623,58263,76956150,362701984075
1724,50003,6304580,32880992208
25,06933,54928390,4030050111039
1926,12003,4088450,2500060878
2026,55873,35352110,482501413200
2127,24003,2711740,3422048901
2228,24003,1575740,54660581647
2330,07162,9692950,74330702483
2431,14002,8698040,2400047587
2531,46002,8413430,3934042753
2631,99162,7953340,44330521436
2733,97652,6364350,25700691236
2834,66942,5853150,1153063 384

Crystalline form And rosiglitazona maleate may also be characterized as having an infrared absorption spectrum or almost the same infrared absorption spectrum as shown in figure 2. Characteristic peaks are as follows: 1750, 1705, 1640, 1619, 1514, 1466, 1379, 1361, 1326, 1242, 1163, 866, 774, 715 and 669 cm-1. The infrared spectrum of a dispersion form And rosiglitazona maleate in mineral oil was removed spectrometer Perkin Elmer spectrum-1 FT IR.

Crystalline form In rosiglitazona maleate obtained according to the present invention has an x-ray or almost the same radiograph as shown in figure 3. More specifically, the crystalline form of the maleate of rosiglitazone may be characterized by the x-rays with characteristic peaks (2θ): 8,93°, shed 15.37°, 15,86°, 18,05°°, 20,24°, 22,28°, 23,51°, are 24.88°, 25,12°, 25,91°, 26,69° and 29,64°.

Additional data of x-ray analysis, characterizing crystalline form In rosiglitazona maleate, shown in the following table 2.

td align="center"> 22td align="center"> 887
Table 2
no maximum2θ (grad)d (A)I/IIThe full width at half maximum (FWHM) (deg)The intensity (the number of them is of alsow) Integral intensity (number of pulses)
14,681718,8594860,207901121615
28,92949,89532160,223102733878
39,31759,4840130,2750058806
412,03177,3499440,25000681071
513,98126,3291660,271801011604
614,82005,9727730,0900060649
715,37985,756611000,32560175929961
815,86395,58201100,402801823362
916,78045,2791490,245201662342
1018,05014,91055190,279403435704
118,7600 4,7263030,2000054572
1219,19344,6205490,349501582634
1319,66004,5119260,420001121883
1419,98004,4403890,203601641511
1520,24004,38392130,243002302888
1620,75394,2765190,258701622226
1721,17164,1930740,2433068834
1822,28473,98609230,315504047057
1923,12003,8439340,1000072498
2023,51403,78040170,437502945969
2124,06003,6958340,38280691193
24,28003,6628460,19400110901
2324,88003,57585160,370002835014
2425,12003,54223230,189203993534
2525,42003,5011040,22400711065
2625,91883,43484110,427701953233
2726,18003,4011640,2336063868
2826,69293,33696110,294101932721
2927,10843,2867560,306901121674
3028,14003,1685660,266601101517
3128,40003,1401440,1528069633
3228,73753,1040340,2350076
3329,28003,0477480,410001495056
3429,64003,01153150,000002560
3529,80002,9957390,252401592457
3630,21252,9557630,35500541367
3731,52032,8360440,43060692168
3833,18372,6975890,361701523225
3935,61752,5186330,28160531541
4038,64002,3282930,41340581132
4138,82002,3179140,45600661023

The crystalline form of the maleate of rosiglitazone may also be characterized as having an infrared absorption spectrum or almost the same infrared absorption spectrum, ka is shown in figure 4. Characteristic peaks are as follows: 1745, 1708, 1641, 1619, 1464, 1484, 1378, 1354, 1303, 1245, 1179, 1164, 1084, 1071, 862, 824, 778 and 719 cm-1. The infrared spectrum of the dispersion forms In rosiglitazona maleate in mineral oil was removed spectrometer Perkin Elmer spectrum-1 FT IR.

The present invention proposes a method of obtaining crystalline form And rosiglitazona maleate, characterized by radiograph with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55, which includes the preparation of a mixture, which contains the free base of rosiglitazone and maleic acid miscible with water, the solvent, the stirring of this mixture and heated, and thus, the solution, filtering, and thus, the transparent filtrate, and add to it water-immiscible solvent, followed by stirring and cooling, highlighting thus, crystalline form And rosiglitazona maleate.

In the above method suitable miscible with water solvent are1-4alcohols, preferably methanol usage.

The initial mixture, obtained as indicated above, is preferably heated to at least approximately at 45°With obtaining a solution more suitable to a temperature in the range of about 45-50°C.

Preferred is not miscible with water rest what realem is ethyl acetate, which is respectively added to the filtrate under stirring at a temperature in the range of about 25-30°C, followed by additional stirring, respectively, for about 1 hour while maintaining a temperature of about 30°C.

More specifically cooled to a temperature of about 5-10°With further stirring for about 1 hour while maintaining basically the above temperature. The resulting solid is filtered off, washed with ethyl acetate and dried in vacuum, obtaining forms And rosiglitazona maleate.

The present invention also offers a method of obtaining a crystalline form And rosiglitazona maleate, characterized by radiograph with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55, which includes the preparation of a mixture, which contains the free base of rosiglitazone and maleic acid in a solvent, boiling under reflux this mixture, filtration of this mixture and obtaining a filtrate, adding seed crystals of form a rosiglitazona maleate to the specified filtrate, followed by stirring and allocation of crystalline forms And rosiglitazona maleate.

Accordingly, the used solvent is acetone, and the seed crystals of form a rosiglitazona maleate was added when the temperature is round about 35-40° Since, typically, about 40°C, followed by stirring at low temperature (typically about 30° (C) for a long period of time, which is typically about 18 hours.

The method accordingly includes in addition to drying in a vacuum at a temperature of about 25-35°typically, about 30°and within about 5 hours, and then at a temperature in the range of about 45-55°typically, about 50°within about 6 hours, to obtain the forms And rosiglitazona maleate.

The present invention further provides a method of obtaining crystalline form And rosiglitazona maleate, characterized by radiograph with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55, which includes the preparation of a mixture, which contains the free base of rosiglitazone and maleic acid in a solvent, boiling under reflux this mixture, cooling this mixture and mixing, and thus, a solid precipitate, filtering the specified solid precipitate and drying to obtain the crystalline form And rosiglitazona maleate.

A suitable solvent is acetonitrile, and the cooling is usually carried out to a temperature of about 25-35°With more suitable about 30°C, followed by stirring for 5 h the owls at a temperature of 25-30° With obtaining a solid residue.

Accordingly, the method further includes drying in vacuum at a temperature of about 25-35°typically, about 30°C, for about 5 hours, and then at a temperature in the range of about 45-55°typically, about 50°C for about 6 hours with obtaining forms And rosiglitazona maleate.

The present invention also offers a method of obtaining a crystalline form And rosiglitazona maleate, characterized by radiograph with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55, which includes the suspension of polymorph rosiglitazona maleate or hydrate rosiglitazona maleate in a solvent and heated, and thus, the solution, cooling and mixing of the specified solution and isolating the crystalline form And rosiglitazona maleate.

The preferred solvent is C1-4alcohols, such as isopropyl alcohol, and a solution obtained by heating at a temperature of about 60-65°C. the Solution is accordingly cooled to a temperature of about 25-30°C and stirred for a long time, for example, within about 8 hours. The crystals obtained as a result of further cooling, is filtered off and dried in vacuum at a temperature of about 45-55°, 50°With, obtaining forms And maleate rosig is tizona.

Alternative solvent may preferably be ethyl acetate, and the solution obtained by heating to a temperature of about 60-65°C. Then cooling is carried out until a temperature of about 20-25°with stirring, and then further cooled to a temperature below about 10°usually about 5°C. the Resulting solid is filtered off, washed with ethyl acetate and dried in a vacuum at a temperature of about 45-55°With about 50°With, obtaining forms And rosiglitazona maleate.

The present invention also offers a method of obtaining a crystalline form of the maleate of rosiglitazone, characterized by radiograph with characteristic peaks (2θ): 8,93, 15,37, 15,86, 18,05, 20,24, 22,28, 23,51, 24,88, 25,12, 25,91, 26,69 and 29,64, which includes the suspension form And rosiglitazona maleate, characterized by radiograph with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 And 26,55 in the solvent and heated, and thus, the solution cooling and ageing when standing, and the allocation of crystalline forms In rosiglitazona maleate.

Preferably the solvent is1-4alcohols, such as isopropyl alcohol, and the solution, respectively, obtained by heating at a temperature of about 60-65°C. the Solvent may be tetrahydrofuran, and the solution get boiling is the group under reflux.

The resulting solution was incubated at standing at a temperature of from about 0 to -5°C for an extended period of time of at least about 48 hours, and the formed crystals are filtered and dried in vacuum at a temperature of about 45-55°With more suitable about 50°With receipt forms In rosiglitazona maleate.

The present invention also provides a method of obtaining the free base of rosiglitazone recovery 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidin-2,4-dione of the formula (II)

in the presence of ion cobalt ligand and a reducing agent, where:

cobalt ion can be in any form, such as dichloride cobalt diacetate cobalt and trichloride cobalt;

the ligand is chosen from the group consisting of dimethylglyoxime, 2,2'-bipyridyl and 1,10-penetralia;

the reducing agent is chosen from the group consisting of sodium borohydride, lithium borohydride, potassium borohydride, borohydride tetraalkylammonium and zinc borohydride;

and optionally converting the thus obtained free base of rosiglitazone in its pharmaceutically acceptable salt.

Preferably, the above method is carried out in the presence of cobalt dichloride as a source of ion cobalt and/or dimethylglyoxime as a ligand, and/ilibagiza sodium as a reducing agent. The compound of formula (II) can be easily obtained according to the methods of synthesis are well known in this field, for example as described in U.S. patent 5585495.

In addition, preferably, 5-[4-[2-(N-l-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidin-2,4-dione of the formula (II) suspended in tetrahydrofuran in the presence of a base, where base is a hydroxide of an alkali metal such as sodium hydroxide. Accordingly, the reaction mixture containing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidin-2,4-dione, cobalt dichloride, dimethylglyoxime and sodium borohydride in the presence of tetrahydrofuran as a solvent is stirred for an extended period of time, typically about 16 hours, at a temperature of about 20-30°C.

In addition to the stirring reaction mixture, respectively, is acidified, for example, by adding glacial acetic acid for about 1-2 hours. Preferably the resulting suspension was further stirred for about 1-2 hours, was filtered, the obtained solid substance was washed with water and dried in a vacuum at a temperature of about 55-65°typically, about 60°With, obtain the free base of rosiglitazone.

Appropriate pharmaceutically acceptable salt of rosiglitazone, the proposed method according to the SNO present invention, include salts formed with mineral acids such as Hydrobromic, hydrochloric and sulfuric acid, or organic acids such as methanesulfonate, tartaric and maleic acid. In particular, the free base of rosiglitazone obtained by the method according to the present invention, preferably in turn rosiglitazona maleate and, in particular, in the form a or form In rosiglitazona maleate, using stage of the method of obtaining these polymorphic forms, as basically described above.

The present invention additionally offers free base of rosiglitazone, shape And rosiglitazona maleate or form In rosiglitazona maleate mainly obtained by the method described above.

Rosiglitazone obtained according to the present invention are useful for the treatment of diabetes mellitus type II. Rosiglitazone obtained according to the present invention can also be recommended for special use in the treatment and/or prevention of other diseases, including hyperlipidemia, hypertension, and cardiovascular disease, especially atherosclerosis. In addition, it is believed that rosiglitazone obtained according to the present invention may be useful in the treatment of certain eating disorders, in particular, regulation of appetite and food intake in subjects suffering is non disorders associated with malnutrition, such as anorexia nervosa, disorders associated with eating, such as obesity and anorexia with bulimia.

Therefore, the present invention accordingly provides the use of rosiglitazone, obtained according to the present invention, for treatment.

Accordingly, the present invention provides the use of rosiglitazone, obtained according to the present invention, for the treatment and/or prevention of hyperglycemia. In particular, it is proposed rosiglitazone obtained according to the present invention, for use in the treatment of diabetes.

The present invention additionally provides the use of rosiglitazone, obtained according to the present invention, for the treatment and/or prevention of hyperlipidemia.

The present invention also provides the use of rosiglitazone, obtained according to the present invention, for the treatment of hypertension, cardiovascular disease and certain eating disorders. Cardiovascular disease includes in particular atherosclerosis. Certain eating disorders include the regulation of appetite and food intake in patients suffering from disorders associated with malnutrition, such as anorexia nervosa, disorders associated with obesity, such as air the tion and anorexia with bulimia.

Accordingly, the present invention also provides a pharmaceutical composition comprising rosiglitazone obtained according to the present invention, and a pharmaceutically acceptable carrier for her. In particular, the shape And rosiglitazona maleate obtained according to the present invention, suitable for use in pharmaceutical compositions, as it is anhydrous, crystalline and non-hygroscopic. Preferably the composition proposed by the present invention, can be used for oral administration. The pharmaceutical compositions of the present invention, however, may be introduced by any convenient means and in any convenient form, for example, orally in the form of tablets, capsules, liquid preparations, granules, pellets, or parenterally in the form of solutions or suspensions for injection or infusion.

The pharmaceutical compositions of the invention can be obtained by traditional methods in this area. For example, tablets can be obtained by mixing the active ingredient with conventional excipients and/or diluents and further compressing the mixture in a conventional tablet press machine. Examples of excipients and diluents may include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum and the like. Any other functional the Chairman substances or additives dyes, flavors, preservatives or the like can also be used, provided their compatibility with rosiglitazone, obtained according to the present invention.

Injectable solutions can be obtained by dissolving rosiglitazone obtained according to the present invention, and possible additives in a part of the solvent for injection, usually sterile water, bringing the solution to the desired volume, the sterilization solution and filling the respective ampoules or vials. May be entered in any acceptable additive usually used in this field, such as toning agents, preservatives, antioxidants and the like.

The present invention additionally provides a method of treatment and/or prevention of hyperglycemia in a patient, which provides for the introduction of a therapeutically effective amount of rosiglitazone, obtained according to the present invention, the patient with hyperglycemia who needs it. In particular, the present invention provides a method of treatment and/or prevention of diabetes mellitus in a patient, which includes the introduction of a therapeutically effective amount of rosiglitazone, obtained according to the present invention, to a patient suffering from or Prednisolonum to diabetes.

The present invention additionally provides a method L. the treatment of hyperlipidemia the patient, which includes the introduction of a therapeutically effective amount of rosiglitazone, obtained according to the present invention, the patient with giperlipedemia in need.

The present invention additionally provides a method of treating hypertension, cardiovascular disease or certain eating disorders described above, including the introduction of a therapeutically effective amount of rosiglitazone, obtained according to the present invention, to a patient in need of it.

As an additional aspect of the present invention provides the use of rosiglitazone, obtained according to the present invention, for manufacturing a medicinal product for the treatment and/or prevention of hyperglycemia. In particular, the present invention provides the use of rosiglitazone, obtained according to the present invention, for manufacturing a medicinal product for the treatment and/or prevention of diabetes.

The present invention also provides the use of rosiglitazone, obtained according to the present invention, for preparing a medicinal product for the treatment and/or prevention of hyperlipidemia.

The present invention also provides the use of rosiglitazone, obtained according to the present invention, for the manufacture of Lekarstvo is the first drug for treatment and/or prevention of hypertension, cardiovascular disease or certain eating disorders.

The choice of specific dosage forms of rosiglitazone, obtained according to the present invention, for therapeutic use or treatment in accordance with the present invention will depend on being treated with specific painful conditions, symptoms and severity of the disease. Preferably, the route of administration and frequency of dosing are the responsibility of the treating physician.

The present invention will be further illustrated by the following drawings and examples, which in no way limit the scope of the invention.

Figure 1 shows a specific x ray powder form And rosiglitazona maleate.

Figure 2 shows the IR spectrum of form a rosiglitazona maleate.

Figure 3 shows a specific x ray powder form In rosiglitazona maleate.

Figure 4 shows the IR spectrum of form In rosiglitazona maleate.

Examples

Getting 1 of the prior art

Rosiglitazona maleate was obtained according to the description of WO 94/05659, where 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dione (470 g) and maleic acid (137 g) was dissolved in ethanol (4 l) at boiling. The hot solution was filtered through diatomaceous earth and were then given an opportunity to cool down slowly with mild stirring. After you remove the air traffic management in the refrigerator at 0-5° With in a few hours maleate was filtered, washed with ethanol and dried in vacuum at 50°and receiving a result of 446 g rosiglitazona maleate, as proposed in WO 94/05659. The product is identified as a form In the x-ray and IR spectrum, as can be seen in figure 3 and 4 respectively.

Example 1

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidin-2,4-dione (10 g) suspended in water (30 ml) and tetrahydrofuran (30 ml) and the resulting suspension was added 25 ml of 4% sodium hydroxide. The resulting mixture was cooled to 10°and added to it a solution of a catalyst obtained by dissolving 1.88 g of dimethylglyoxime and 0.200 g of cobalt dichloride in 30 ml of tetrahydrofuran. Then was slowly added a solution of 3.2 g of sodium borohydride in 30 ml of water and 9.4 ml of 4% sodium hydroxide at 10°C for 90 minutes. The resulting reaction mixture was stirred at 25°C for 16 hours and then acidified 60% glacial acetic acid, which was added very slowly over 1-2 hours. The resulting suspension was further stirred for 1.5 hours. The resulting solid (free base form of rosiglitazone) was filtered, washed with water and dried in vacuum at 60°and receiving a result of 9.3 g of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dione.

Example 2

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)the toxi]benzyl]thiazolidin-2,4-dione (free base of rosiglitazone, 50 g 0,140 mol) were loaded in 100 ml of methanol, was added a solution of maleic acid (18.7 g, 0.16 mol) in methanol (50 ml) under stirring, and optionally heated to 45-50°obtaining a transparent solution. The resulting solution (hot) was filtered through celite, was slowly added to the clear filtrate in ethyl acetate (500 ml) under stirring at 25-30°and was further stirred for 1 hour at 30°C, then cooled to 5-10°C and stirred at this temperature for 1 hour. The obtained solid substance was filtered in an atmosphere of argon and washed with 50 ml of ethyl acetate. The solid was dried in vacuum at 50-55°receiving in the form And rosiglitazona maleate (60 g) with a yield of 90%.

Example 3

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dione (free base of rosiglitazone, 100 g, 0,280 mol) is suspended in 500 ml of dry acetone and the solution was added maleic acid (38,99 g, 0,336 mol) in 200 ml of dry acetone at 27°obtaining a transparent solution. Added activated charcoal (5 g) and boiled under reflux for 30 minutes. The hot solution was filtered through celite. To the clear filtrate was added seed crystals of form a at 40°and was stirred for 18 hours at 30°C. the Precipitated solid was filtered in an atmosphere of argon, etc is mawali 100 ml of dry acetone. The obtained solid was dried in vacuum at 30°C for 5 hours and at 50°C for 6 hours, getting in the form And rosiglitazona maleate (95 g) with a yield of 72%.

Example 4

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dione (free base of rosiglitazone, 50 g, 0,140 mol) was stirred with 250 ml of dry acetonitrile and added to a suspension of maleic acid (19,50 g has 0.168 mol) in 100 ml of dry acetonitrile at 27°C to obtain a clear solution, followed by boiling under reflux for 30 minutes at 80-82°C. the Reaction mass was given to gradually cool to 30°and was stirred for 5 hours at 25-30°C. the Precipitated solid was filtered in an atmosphere of argon and washed with 50 ml of dry acetonitrile. The obtained filtered solid was dried in vacuum at 30°C for 5 hours and at 50°C for 6 hours, getting in the form And rosiglitazona maleate (45 g) with 71%yield.

Example 5

The form In rosiglitazona maleate (50 g, 0,105 mol) is suspended in 1500 ml of isopropyl alcohol and heated to 60-65°obtaining a transparent solution. The solution was gradually cooled to 27°and was stirred for 8 hours. The obtained crystals were filtered and dried in vacuum at 50°receiving in the form And rosiglitazona maleate (0 g) with a yield of 80%.

Example 6

5- [4- [2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidin-2,4-dione (free base of rosiglitazone, 25 g, 0.07 mol) is suspended in 900 ml of acetone, was added dropwise a solution of maleic acid (9,74 g, 0,083 mol) in 25 ml of methanol for 20 minutes at 25°C. To the above clear solution was added activated charcoal (5.0 g), stirred at 25°C for 20 minutes and then filtered through celite. The obtained clear filtrate was stirred for 12 hours at ambient temperature. The precipitated solid was isolated by filtration and dried in vacuum at 50°With, resulting in obtaining a desired shape In rosiglitazona maleate (20 g).

Example 7

The form And rosiglitazona maleate (20 g, 0,105 mol) is suspended in 600 ml of isopropyl alcohol and heated to 60-65°obtaining a transparent solution. The solution was kept when standing at a temperature of from 0 to -5°C for 48 hours. The obtained crystals were filtered and dried in vacuum at 50°receiving in the form In rosiglitazona maleate (15.0 g).

Example 8

The form And rosiglitazona maleate (20 g, 0,105 mol) is suspended in 400 ml of tetrahydrofuran and boiled under reflux, to obtain a transparent solution. The solution was kept when standing at a temperature of from 0 to -5°in a few days. Receiving the data crystals were filtered and dried in vacuum at 50° C receives in the form In rosiglitazona maleate (16.0 g).

Example 9

The form In rosiglitazona maleate (50 g) is suspended in 500 ml of ethyl acetate and heated to 60°in an inert atmosphere, the resulting solution was rapidly cooled with stirring to 25°C, then cooled to 5°C. the Obtained solid substance was filtered off, washed with chilled ethyl acetate and dried in vacuum at 50°receiving in the form And rosiglitazona maleate.

1. The method of obtaining crystalline form And rosiglitazona maleate, characterized by x-ray diffraction pattern with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55 comprising preparing a mixture which contains the free base of rosiglitazone and maleic acid miscible with water solvent, mixing the mentioned mixture and heated to form a solution, filtering to obtain a clear filtrate and adding to it is not miscible with water solvent, followed by stirring and cooling to allocate crystalline form And rosiglitazona maleate.

2. The method according to claim 1, in which the named miscible with water solvent are1-4the spirits.

3. The method according to claim 2, in which named With the1-4alcohol is methanol.

4. The method according to any one of claims 1 to 3, in which the name is the mixture is heated to a temperature at least about 45°to obtain the above solution.

5. The method according to any one of claims 1 to 3, in which the mentioned water-immiscible solvent is ethyl acetate.

6. The method according to claim 5, in which the named add ethyl acetate to the filtrate under stirring at a temperature of about 25-30°C, followed by stirring.

7. The method according to any one of claims 1 to 3, in which cooling is performed to a temperature of about 5-10°With additional stirring while maintaining the above temperature.

8. The method according to claim 7, in which the obtained solid substance in addition to the above cooling is filtered off, washed with ethyl acetate and dried in vacuum to obtain forms And rosiglitazona maleate.

9. The method of obtaining crystalline form And rosiglitazona maleate, characterized by x-ray diffraction pattern with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55 comprising preparing a mixture which contains the free base of rosiglitazone and maleic acid in a solvent, the reflux named mixture, filtering the mentioned mixture and obtaining a filtrate, adding seed crystals of form a rosiglitazona maleate to the above filtrate, followed by stirring and allocation of crystalline forms And rosiglitazona maleate.

p> 10. The method according to claim 9, in which the mentioned solvent is acetone.

11. The method according to any of PP and 10, which is called the seed crystals of form a rosiglitazona maleate added at a temperature of about 35-40°C, followed by stirring at low temperature for an extended period of time.

12. The method according to claim 11, which further comprises drying in a vacuum at a temperature of about 25-35°and then at a temperature of about 45-55°obtaining forms And rosiglitazona maleate.

13. The method of obtaining crystalline form And rosiglitazona maleate, characterized by x-ray diffraction pattern with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55 comprising preparing a mixture which contains the free base of rosiglitazone and maleic acid in a solvent, heating named mixture under reflux, cooling named mixture and mixing to obtain the precipitated solid substance, called filtering the precipitated solid and drying to obtain the crystalline form And rosiglitazona maleate.

14. The method according to item 13, which is called the solvent is acetonitrile.

15. The method according to any of PP and 14, in which cooling is performed to a temperature of about 25-35°C, followed by stirring for receiving the Oia settled solids.

16. The method according to any of PP and 14 which further includes drying in vacuum at a temperature of about 25-35°and then at a temperature of about 45-55°to obtain forms And rosiglitazona maleate.

17. The method of obtaining crystalline form And rosiglitazona maleate, characterized by x-ray diffraction pattern with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55, which includes the suspension of polymorph rosiglitazona maleate or hydrate rosiglitazona maleate in a solvent and heating to obtain a solution, cooling and stirring the above solution, and the allocation of crystalline forms And rosiglitazona maleate.

18. The method according to 17, in which the mentioned solvent are C1-4the spirits.

19. The method according to p, in which the solvent is isopropyl alcohol.

20. The method according to any of PP-19, in which a solution obtained by heating to a temperature of about 60-65°C.

21. The method according to any of PP-19, in which the solution is cooled to a temperature of about 25-30°C and stirred for a long time.

22. The method according to any of PP-19, in which the obtained crystals in addition to the above cooling is filtered off and dried in vacuum at a temperature of about 45-55°to obtain forms And rosiglitazona maleate.

23. The method according to 17, in which restorealiases ethyl acetate.

24. The method according to item 23, in which a solution obtained by heating to a temperature of about 60-65°C.

25. The method according to any of PP and 24, in which cooling is performed to a temperature of about 20-25°with stirring, and then further cooled to a temperature lower than about 10°C.

26. The method according A.25, in which the formed solid is filtered, washed with ethyl acetate and dried in a vacuum at a temperature of about 45-55°to obtain forms And rosiglitazona maleate.

27. A method of obtaining a crystalline form of the maleate of rosiglitazone characterized by x-ray diffraction pattern with characteristic peaks (2θ): 8,93, 15,37, 15,86, 18,05, 20,24, 22,28, 23,51, 24,88, 25,12, 25,91, 26,69 and 29,64, which includes the suspension form And rosiglitazona maleate, characterized by x-ray diffraction pattern with characteristic peaks (2θ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55, in a solvent and heating to obtain a solution, cooling and curing, and the allocation of crystalline forms In rosiglitazona maleate.

28. The method according to item 27, in which the solvent is1-4the spirits.

29. The method according to p, in which the solvent is isopropyl alcohol.

30. The method according to any of PP-29, in which a solution obtained by heating to a temperature of about 60-65°C.

31. The method according to item 27, in which the solvent is tetrahydro the uranium.

32. The method according to p, in which a solution obtained by heating under reflux.

33. The method according to item 27, in which the solution is maintained at a temperature of from about 0 to -5°C for an extended period of time, the resulting crystals are filtered and dried in vacuum at a temperature of about 45-55°to obtain forms In rosiglitazona maleate.

34. The way to obtain the free base of rosiglitazone recovery 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidin-2,4-dione of the formula (II)

in the presence of ion cobalt ligand and a reducing agent, in which the cobalt ion can be in any form dichloride cobalt diacetate cobalt and trichloride cobalt;

the ligand is chosen from the group consisting of dimethylglyoxime, 2,2'-bipyridyl and 1,10-penetralia;

the reducing agent is chosen from the group consisting of sodium borohydride, lithium borohydride, potassium borohydride, borohydride tetraalkylammonium and zinc borohydride;

and optional transformation thus obtained free base of rosiglitazone in its pharmaceutically acceptable salt.

35. The method according to clause 34, in which the cobalt ion is in the form of cobalt dichloride.

36. The method according to any of PP and 35, in which the ligand is dimethylglyoxime.

37. The way is about 34, in which the reducing agent is sodium borohydride.

38. The method according to clause 34, which is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidin-2,4-dione of the formula (II) is suspended in tetrahydrofuran in the presence of a base.

39. The method according to 38, in which the base is a hydroxide of an alkali metal.

40. The method according to 39, in which the alkali metal hydroxide is sodium hydroxide.

41. The method according to clause 34, in which the reaction mixture containing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidin-2,4-dione, cobalt dichloride, dimethylglyoxime and sodium borohydride in the presence of tetrahydrofuran as a solvent, is stirred for an extended period of time at a temperature of about 20-30°C.

42. The method according to paragraph 41, in which in addition to the above stirring the reaction mixture is acidified.

43. The method according to 42, in which the acidification involves adding glacial acetic acid for about 1 to 2 hours

44. The method according to item 43, in which the resulting suspension in addition to the above acidification is stirred for about 1 to 2 hours, the obtained solid is filtered off, washed with water and dried in a vacuum at a temperature of about 55-65°to obtain the free base of rosiglitazone.

45. The form of the maleate of rosiglitazone characterized by x-ray diffractor Moi with characteristic peaks (2θ ): 9,5, 15,86, 15,02, 17,00, 18,52, 21,99, 23,58, 25,06 and 26,55 obtained by the method according to any one of claims 1 to 26.

46. The form of the maleate of rosiglitazone characterized by x-ray diffraction pattern with characteristic peaks (2θ): 8,93, 15,37, 15,86, 18,05, 20,24, 22,28, 23,51, 24,88, 25,12, 25,91, 26,69 and 29,64 obtained by the method according to any of PP-33.

47. Pharmaceutical composition comprising rosiglitazone on any of PP and 46 and a pharmaceutically acceptable carrier.

48. The method of treatment and/or prevention of hyperglycemia, diabetes mellitus, hyperlipidemia, hypertension, cardiovascular disease or eating disorders in a patient, comprising introducing a therapeutically effective amount of rosiglitazone on any of PP and 46 to the needy in this patient.



 

Same patents:

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) HetAr represents pyrimidinyl or thiadiasolyl; R1 and R2 represent H; A represents C1-C2-alkyl; B represents aryl(CH2)0-3-O-C(O)-or arylcyclopropyl-C(O)-, in which aryl can be substituted with 1-5 substituents, each substituent represents C1-C4-alkyl. Invention also relates to pharmaceutical composition and to application of compounds of item 1. Obtaining novel compounds, as well as pharmaceutical composition possessing NMDA/NR2B antagonist activity.

EFFECT: increase of composition efficiency.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: described is obtaining and pharmaceutical application of substituted derivatives of arylalkane acid of formula I , where ring A, ring B, R1, R2, R3, R4, R5, X, Alk1, Alk2, Ar1 and Ar2 are such as determined in said description. Said compounds, as selective agonists activating (RAPPs) receptors, activated by peroximal proliferator, in particular, RXRs/RAPPs-alfa, RXRs/RAPPs-gamma and RXRs/RAPPs-delta heterodimers, are applied in treatment and/or prevention of type 2 diabetes and connected with it metabolic syndrome, such as hypertension, obesity, insulin-resistence, hyperlipidemia, hyperglycemia, hyperolesterinemia, artheriaslerosis, coronary artery disease, and other cardio-vascular disorders, and possess improved profile of side effects, connected with common RAPPs-gamma agonists.

EFFECT: obtaining compunds, which possess improved profile of side effects, connected with common RAPPs-gamma agonists.

22 cl, 38 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: in compound of formula (I): , R1 represents C1-4-alkoxy C3-6cycloalkyl optionally substituted with atom of halogen, hydroxyl, trifluoromethyl, optionally substituted with halogen atom 5-6-member heterocyclyl, in which heteroatoms are selected from oxygen, optionally substituted with halogen atoms phenyl or optionally substituted with halogen atoms 5-6-member heteroaryl, in which heteroatoms are selected from nitrogen and/or sulfur; R2 represents hydrogen or trifluoromethyl; R3 represents hydrogen, optionally substituted with atom of halogen, C3-6cycloalkyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkyl phenyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkoxy heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, or optionally substituted with C1-4-alkyl 5-6-member heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen or oxygen, R4 and R5 independently represent hydrogen; X represents covalent bond or lower alkylene; X1 represents covalent bond or lower alkylene, Y represents covalent bond or lower alkylene, optionally substituted with hydroxy or cycloalkyl; and Z represents -C=C-, -R6C=CR7- or -CHR6CHR7-, where R6 and R7 in each position represent hydrogen or lower alkyl.

EFFECT: antilipolytic effect of compounds.

30 cl, 7 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: in substituted aromatic derivatives of formula (Ib) R1 and R2 independently represent H or F, one of R1 or R2 residues must represent F; R3 - OH; A represents O; R4 - hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or OH; R5 -hydrogen, (C1-C6)-alkoxy or halogen; R6 - hydrogen, halogen or OH; B - (C1-C6)-alkandiyl, -CO-NH-CH2-, -O- or -CO-CH2-CH2-; R7 - hydrogen; R8 - hydrogen, OH, (C1-C6)-alkyl, halogen or (C1-C6)-alkoxy, which is optionally single- or multi- substituted with fluorine; R9 - hydrogen; or R8 and R9 together represent -CH=CH-O- or -CH2-CH2-O-,forming together with carbon atoms to which they are bound, Cyc2 -furanyl or dihydrofuranyl, respectively; as well as to their pharmaceutically acceptable salts.

EFFECT: compounds are suitable for preparation of medications for reduction of sugar level in blood.

5 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: substituted with sulfamides xantine derivaives of formula I or their pharmaceutically acceptable salts, where R1, R2 and R3 are such as given in invention description. Compounds of formula (I) and their pharmaceutically acceptable salts display activity as gluconeogenesis modulators and can be used for obtaining pharmaceutical compositions, which can be useful for treatment of type 2 diabetes.

EFFECT: increase of compound efficiency.

35 cl, 98 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention concerns substituted heterocyclic fluorglucoside derivatives of the formula (I) , where R1 and R2 are independently F, H, or one of R1 or R2 residues is OH; R3 is OH or F, so that at least one of R1, R2, R3 residues is F; R4 is OH; A is O; X is C or N, so that if Y = S, X should be C; Y is N or S; m = 1; R5 is hydrogen, OH or (C1-C6)-alkyl optionally mono- or polysubstituted by fluorine; R6 is H or (C1-C6)-alkyl, if required; or, if Y = S, R5 and R6 form phenyl together with carbon atoms to which they are linked; B is (C1-C6)-alcandiyl or -CO-NH-CH2-; n = 2 or 3; Cyc1 is phenyl or thiophenyl; R7 is hydrogen, F, CI, Br, J, (C1-C6)-alkyl or (C1-C6)-alkoxy optionally mono- or polysubstituted by fluorine; R8 is hydrogen or halogen; R9 is hydrogen; or R8 and R9 together mean -CH=CH-CH=CH-, -CH=CH-C((C1-C6)-alkoxy)=CH- or -OH=CH-O- and together with carbon atoms to which they are linked form Cyc2, which is phenyl, optionally substituted (C1-C6)-alkoxy or furanyl respectively; and their pharmaceutically acceptable salts.

EFFECT: obtaining efficient medicine for sugar level decrease in blood.

7 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: medicine; oncology.

SUBSTANCE: 4 courses of neoadjuvant polychemotherapies are carried out and at decrease of the lung primary tumour by 1/2 of its size and at absence of the remote metastasises - to brain, skeleton bones, aliver, adrenals, the surgical treatment is carried out consisting of removal of the lung primary tumour with lympho dissection of the mediastinum and the neck. In 4 weeks after the operation polychemotherapy is carried out, and at absence of a pathomorphism or pathomorphism of degree I-II in the postoperative period drugs for carrying out of polychemotherapy are replaced and at tumour pathomorphism of III degree in the postoperative period polychemotherapy is caried out with similar preparations.

EFFECT: increase of treatment efficiency of parvicellular lung cancer due to augmentation of operation ablasticity at carrying out of neoadjuvant polychemotherapy and prescrption of polychemotherapy sensitive to tumour in postoperative period by results of pathomorphism examination.

2 ex

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