Polymorphous crystalline forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

 

The technical field to which the invention relates.

This invention relates to a new polymorphic/pseudopolymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate and its stereoisomers having the formula (1). The invention also relates to pharmaceutical compositions containing the new polymorphic form, or a mixture thereof and a pharmaceutically acceptable carrier. Polymorphic forms of the present invention are more active as antidiabetic agents compared with currently known 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-Dion-maleate.

The present invention also relates to a method of obtaining different polymorphic/pseudopolymorphic 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione of maleato having the formula (1)below. The polymorphic form obtained in a way consistent with the present invention are more active as antidiabetic agents,

Polymorphic forms of 5-[4-[2-[N-methyl-n-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1)defined above, reduce the amount of glucose in the blood and give positive results in ischemic heart disease and atherosclerosis.

Of the many drugs that are useful in the treatment of diabete the definition of diseases, derivative thiazolidinedione widely known and regarded as much more efficient components than the sulfonylureas. 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione the maleate, which is one of the representatives of the preparations of thiazolidinediones, which showed applicationsi effect was reported in 1988 by a group Beecham, England (EP 0306228 A1) and since then in this area this substance has aroused interest.

New polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1)defined above, useful in the reduction of body weight in the treatment and/or prophylaxis of diseases such as high blood pressure, coronary heart disease, atherosclerosis, stroke, peripheral vascular disease and related disorders. New polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1)according to the present invention can be used in the treatment of certain renal diseases including glomerulonephritis, glomerular sclerosis, nephritic syndrome, nephrosclerosis for high blood pressure, nephropathy. New polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1) are also useful in the treatment and/or prevention of immunity to insulin (diabetes 2 t is PA) resistance to leptin, decreased glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders. These new polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1) can also be useful as inhibitors alsoreported, for improving cognitive functions in dementia, for treatment of complications of diabetes, disorders associated with activation of endothelial cells, treatment of psoriasis, polycystic ovaries (PCOS), inflammatory bowel disease, osteoporosis, motonishi dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthomas, inflammation and for the treatment of the cancer. New polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1)according to the present invention, useful in the treatment and/or prophylaxis of the aforementioned diseases in combination/conjunction with one or more inhibitors of HMG COA reductase, lipid/hypolipoproteinemia agents such as derivatives fibroeva acid, nicotinic acid, cholestyramine, colestipol, probucol.

The level of technology

The last trend that emerged recently in the farm is cautiously industry, focuses on the study of polymorphism and the study of differences in the activity of the various polymorphic forms of the drug. The term polymorphism according to the present invention, refers to a variety of physical forms, crystalline forms, crystalline/liquid crystalline/non-crystalline (amorphous) forms. This question has aroused the greatest interest after noticed that many antibiotics, antibacterial agents, tranquilizers, etc. exhibit polymorphism and several/one of the polymorphic forms of the drug are excellent bio-utility and, therefore, have much higher activity compared to other polymorphs. Sertraline, pentitol, ranitidine, sulfathiazole, indomethacin and other are some important examples of pharmaceutical preparations which exhibit polymorphism. Polymorphism in drugs is an area that is currently of great interest, as is clear from the many issued patents. As some of these may be mentioned the following: US patent 5700820 describes six polymorphic forms of troglitazone, in patent US 5248699 discussed five polymorphic forms of sertraline hydrochloride, patent EP 014590 describes four polymorphic forms of Francisella. In patents EP 490648 and EP 022527 considered polymor the ISM drugs these are discussed in six polymorphic forms of troglitazone, publication WO 97/27191 also concerns the question of polymorphism in drugs.

European patent No. 0306338, international publication number WO 94/25026 and application for US patent No. 5646169 describe that using x-ray crystallographic analysis were identified interrelated configuration diastereoisomers and that prepares a description of the crystal and molecular structure of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate. Presents information does not affect the question of the possibility/the observation that 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate exist in different polymorphic forms. To date there is no published work relating to such observations. The fact that the polymorphism of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate has not been studied previously, with the audience currently interest in the field of polymorphism in drugs, prompted the authors of the present invention to engage in this study.

Recent worldwide research for the prevention/treatment of chronic complications in diabetes. 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate is considered today as one of the most effect is the main anti-diabetic drugs, which as a multi-purpose active substance has an effect not only with diabetes, but also helps lower triglycerides and also helps with the above mentioned related complications. Indeed, the specified 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate acts as a second candidate for drug applicationscope class of antidiabetic drugs.

With the aim of developing new polymorphic forms to lower cholesterol and reduce body weight, which are useful in the treatment and/or prevention of diseases associated with elevated lipids, atherosclerosis, coronary artery disease, syndrome-X, reduced glucose tolerance, resistance to insulin, resistance to insulin, leading to diabetes type 2 and related complications in diabetes, for the treatment of diseases in which insulin resistance is the pathophysiological mechanism and treatment of high blood pressure, with improved efficiency, activity and lower toxicity, the authors filed his research on the receipt of new polymorphic forms, effective in the treatment of the aforementioned diseases. Efforts in this direction have resulted in polymorphic forms having the formula (1)

Another objective of the present invention is to develop polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, their stereoisomers, their pharmaceutically acceptable solvate and pharmaceutical compositions containing them or their mixtures, which may have agonist activity against PRARα and/or PRARγand optional extras to inhibit HMG COA reductase.

Another objective of the present invention is the development of new polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, their stereoisomers, their pharmaceutically acceptable solvate and pharmaceutical compositions containing them or their mixtures, which have increased the intensity and do not have toxic effects or have a reduced toxic effect.

Another objective of the present invention is to develop a method of obtaining new polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, their stereoisomers, pharmaceutically acceptable solvate.

Another objective of the present invention is to develop pharmaceutical compositions containing the new polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, a solvate, or a mixture thereof in combination the appropriate media solvents, diluents and other media, which are usually used in the preparation of such compositions.

The invention

The present invention is connected with the observation that 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate exhibits polymorphism, which is not reported until the present time. Polymorphic forms I, II, III, IV are obtained from different solvents like ethyl alcohol, acetone, methyl alcohol and 1,4-dioxane.

Using studies of x-ray diffraction method on the powder was found that the forms I, II, III, IV are crystalline in nature.

Differential scanning calorimetry polymorphic form I shows a melting endotherm at 100.53°C. Form II shows a melting endotherm at 127.67°C. Form III shows a melting endotherm at 126.41°and form IV shows a melting endotherm at 125.39°C.

All polymorphic forms were identical in solution, which is evident from the data of nuclear magnetic resonance (NMR)data, UV spectra and mass spectra. On the other hand the methods used to study solids, such as differential scanning calorimetry (DSC), x-ray diffractometry for powder (RDP) and infrared spectroscopy (IR) find the differences between these forms.

Briefly the description of figures

X-ray diffraction lines on the powder got on the diffractometer Rigaku model D/Max 2200, which was equipped with a horizontal goniometer Θ/2 Θ configuration. Used radiation of copper To α(λ=A) and the sample was scanned between 3-45 degrees 2Θ.

For differential scanning calorimetry used the instrument Shimadzu DSC-50, equipped with a regulator. Data were processed on a personal computer with a Pentium processor using software Shimadzu TA-50. Samples suspended in aluminum cups, was heated from room temperature to 220°With the heating rate was 5°/min. Empty aluminum Cup was used for comparison. In the analysis cell DSK was constantly purged with dry nitrogen, and the rate of the purge was 30 ml/min

Figure 1 shows a typical thermogram of form I, obtained by differential scanning calorimetry.

Figure 2 shows a typical thermogram of form II obtained by differential scanning calorimetry.

Figure 3 shows a typical thermogram of form III obtained by differential scanning calorimetry.

Figure 4 shows a typical thermogram of form IV obtained by differential scanning calorimetry.

Figure 5 depicts is characteristic is Yu x-ray diffraction pattern of form I.

6 depicts a characteristic x-ray diffraction pattern of form II.

Fig.7 depicts the characteristic x-ray diffraction pattern of form III.

Fig depicts the characteristic x-ray diffraction pattern of form IV.

Figure 9 presents the joint chart of x-ray diffraction patterns of forms I, II, III, IV.

Figure 10 shows a typical absorption spectrum of infrared rays form I in the bromide of potassium.

11 shows a typical absorption spectrum of infrared rays form II potassium bromide.

Fig shows a typical absorption spectrum of infrared rays form III in the bromide of potassium.

Fig shows a typical absorption spectrum of infrared rays form IV in the bromide of potassium.

Information confirming the possibility of carrying out the invention

One of the objects of the present invention is a new polymorphic form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate and its stereoisomers having the formula 1, which is characterized by the following data:

DSC: melting endotherm at 100.53°With (since 88.65° (C) (1).

X-ray diffraction on the powder (2Θ): 10.90, 14.54, 15.96, 18.46, 18.60, 19.76, 20.72, 21.84, 22.36, 22.46, 23.90, 24.04, 24.72, 25.30, 25.98, 27.44, 29.70 (figure 5).

IR (cm-1): 3435 (cf), 2997 (CL), 2773 (cf), 1750 (cf), 1701 (s), 1620 (cf), 1510 (cf), 1362 (cf), 1332 (cf), 1237 (CL), 1165 (cf), 864 (C), 764 (CL), 717 (cf), 654 (cf), 540 (CL), (figure 10).

Another object of the present invention is a new polymorphic form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate and its stereoisomers having the formula 1, which is characterized by the following data:

DSC: melting endotherm at 127.67°With (since 123.17° (C) Fig.2.

RDP (2Θ): 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80, 25.10, 25.84, 26.72, 27.18 per, 29.30, 29.54, 29.84, at 33.26 (6).

IR: 3424 (CL), 3040 (CL), 2947 (cf), 2720 (cf), 1751 (cf), 1702 (s), 1641 (cf), 1618 (cf), 1574 (CL), 1541 (CL), 1412 (CL), 1382 (CL), 1359 (cf), 1326 (cf), 1265 (CL), 1242 (s), 1213 (CL), 1162 (s), 1067 (CL), 1031 (SL), 865 (s), 773 (s), 713 (s), 667 (cf), 576 (CL), 539 (cf), (11).

Another object of the present invention is a new polymorphic form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate and its stereoisomers having the formula 1, which is characterized by the following data:

DSC: melting endotherm at 126.41°With (since 122.06° (C) (3).

RDP (2Θ): 4.60, 8.46, 9.24, 14.98, 15.86, 17.02, 18.60, 21.92, 23.50, 25.00, 25.44, 26.00, 26.38, 28.34, 33.90 (Fig.7).

IR: 3429 (cf), 2949 (cf), 2738 (cf), 1747 (CL), 1704 (s), 1641 (cf), 1617 (cf), 1513 (s), 1464 (cf), 1352 (cf), 1244(s), 1178 (s), 1069 (cf), 862 (CL), 777 (forces), 717 (cf), 657 (cf), 589 (CL) (Fig).

Another object of the present invention is a new polymorphic form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate and its stereoisomers having the formula 1, which is characterized SL is blowing data:

DSC: melting endotherm at 125.39°With (since 121.03° (C) (4).

RDP (2Θ): 7.4, 8.8, 9.54, 14.98, 15.32, 15.82, 16.90, 17.70, 18.40, 18.54, 19.08, 19.72, 20.22, 20.48, 21.36, 21.66, 22.18, 22.58, 23.32, 23.96, 24.52, 25.38, 26.48, 27.00. 27.58, at 27.94, 28.34, 28.54, 28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84, 31.40, 31.94 (Fig).

IR: 3433 (cf), 2930 (cf), 1753 (CL), 1705 (s), 1642 (CL), 1617 (cf), 1512 (s), 1467 (CL), 1351 (cf), 1244 (cf), 1162 (cf), 1061 (CL), 864 (C), 765 (s), 714 (CL), 658 (cf), 526 (CL) (Fig).

Another object of the present invention is a method of obtaining a new polymorphic form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, having the formula 1, the characteristics of which are described above, comprising the following stages:

(i) synthesis of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate using known methods and dissolution in ethanol,

(ii) heating the solution on a steam bath until until the solid has dissolved completely,

(iii) filtering a clear solution and cooled to room temperature for 18 hours,

(iv) the allocation of the received form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.

Another object of the present invention is a method of obtaining a new polymorphic form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, having the formula 1, the characteristics of which are described above, including follow what their stage:

(i) synthesis of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate using known methods and dissolution in acetone,

(ii) heating the solution on a steam bath until until the solid has dissolved completely,

(iii) filtering a clear solution and cooled to room temperature for 18 hours,

(iv) the allocation obtained form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.

Another object of the present invention is a method of obtaining a new polymorphic form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, having the formula 1, the characteristics of which are described above, comprising the following stages:

(i) synthesis of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate using known methods and dissolution in methanol,

(ii) heating the solution on a steam bath until until the solid has dissolved completely,

(iii) filtering a clear solution and cooled to room temperature for 18 hours,

(iv) the allocation obtained form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.

Another object of the present invention is a method of obtaining a new polymorphic form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]TIA who alidin-2,4-dione maleate, with formula 1, the characteristics of which are described above, comprising the following stages:

(i) synthesis of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate using known methods and dissolved in 1,4-dioxane,

(ii) heating the solution on a steam bath until until the solid has dissolved completely,

(iii) filtering a clear solution and cooled to room temperature for 18 hours,

(iv) the allocation obtained form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.

The stereoisomers of the compounds included in the scope of the present invention, can be obtained by the use of chemicals in their pure enantiomeric form in accordance with the method allows such a possibility, or they can be obtained by the reaction of the reactants in the presence of catalysts in their pure enantiomeric form or by separation of mixtures of the stereoisomers by conventional means. Some preferred methods include the use of microbial separation. Separation of the diastereomeric salts occurs where applicable, using chiral acids, such as mandelic acid, camphorsulfonic, tartaric acid, lactic acid and the like or by using chiral bases such as brucine, peninnah alkaloids and their derivatives podobnych substances. Commonly used methods are described Jaques and others in the publication "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). For the conversion of the acid amide can be used the usual conditions of the reactions; diastereoisomer may be separated or using fractional crystallization or chromatography and the stereoisomers of the compounds of formula (1) can be obtained by hydrolysis of pure diastereomeric amide.

The present invention also relates to pharmaceutical compositions containing any of the polymorphic form I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1) and a pharmaceutically acceptable carrier.

The present invention also relates to pharmaceutical compositions containing a mixture of any of the polymorphic forms I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate of the formula (1) and a pharmaceutically acceptable carrier.

The pharmaceutical composition may be commonly used forms such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain substances that give some smell, sweeteners and so on, such substances may be contained in suitable solid or liquid carriers or diluents, or in suitable sterile media to get a solution or suspension suitable for any is of capabilities. Such compositions typically contain from 1 to 25%, preferably from 1 to 15% by weight of the active component, and the remainder of the composition is a pharmaceutically acceptable carriers, diluents or solvents.

Polymorphic forms of the formula (1)defined above, in clinical conditions were applied to mammals, including humans, using oral, nasal, pulmonary, transdermal or parenteral, rectal, delayed release, subcutaneous, intravenous, be, intramuscular, vnutrenniy route of administration or through the ophthalmic solutions, ointments. Introduction oral route is preferred because it is more convenient and excluded possible pain and irritation that occurs when the injection. However, if the patient is unable to swallow medication or poor absorption for oral use because of illness or other violation, you must provide the parenteral drug. Daily dosage is from about 0.01 to 100 mg/kg body weight of the patient, or preferably from 0.01 to about 30 mg/kg of body weight, regardless of the route of administration, when this medication is used or once or in several stages. However, the optimal dose for the treatment of a particular patient will be determined by the physician responsible for Uchenie, usually first apply small doses, which then increases, and thus determined the most appropriate dose.

Suitable pharmaceutically suitable carriers are solid fillers or diluents and sterile aqueous or organic solutions. The active component is present in such pharmaceutical compositions in amounts sufficient to provide the desired dose in the range specified above. Thus, for oral administration of polymorphic form can be mixed with a suitable solid or liquid carrier or diluent to obtain capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions can, if desired, contain additional components such as sweeteners, flavorings, fillers and the like. For parenteral administration polymorphic forms may be mixed with sterile aqueous or organic medium in order to get a solution or suspension suitable for injection. For example, can be used solutions in sesame or peanut oil, aqueous propylene glycol and the like, and aqueous solutions of pharmaceutically acceptable acid additive salts, soluble in water, or salts with bases of these compounds. Also for injection can be used water is diversified solutions in which the active ingredient is dissolved in polyhydroxyalkane castor oil. The solutions prepared in this manner can then be injected intravenously, administered intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration is preferred.

For nasal administration of composition may contain polymorphic forms of the present invention dissolved or suspended in a liquid carrier, in particular in aqueous media. Apply the composition in aerosol form. The carrier may contain additives such as dissolving agents, such as propylene glycol, surfactants, amplifiers suction, such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives, such as parabens.

Tablets, coated tablets or capsules containing talc and/or binder containing carbohydrates or anything like that, are most suitable for any oral administration. Preferably, the carriers for tablets, coated tablets or capsules include lactose, corn and/or potato starch. You can use syrup or elixir when you can use sweetened filling.

Below is an example of a typical method of tabletting:

Example tableting:

a) 1) active ingredient30 g
2) lactose95 g
3) corn starch30 g
4) carboxymethylcellulose44 g
5) magnesium stearate1 g
200 g per 1000 tablets

Components 1 to 3 are uniformly mixed with water and granularit after drying under reduced pressure. Components 4 and 5 are thoroughly mixed with the granules, compress teletrauma machine and get 1000 tablets, each tablet contains 30 mg of the active component.

b) 1) active ingredient30 g
2) calcium phosphate90 g
3) lactose40 g
4) corn starch30 g
5) polyvinylpyrrolidone3.5 g
6) magnesium stearate1.5 g
200 g per 1000 tablets

Components 1-4 are evenly moistened with an aqueous solution of the component 5 and granularit after drying under reduced pressure. Next add the component 6, granules shrink teletrauma machine and get 1000 tablets, each tablet contains 30 mg of the active component.

Infusion is her invention is described in detail in the examples, the following, which are given for illustration only and in no way should be construed as limiting the scope of invention.

Examples

Example - 1

A mixture of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate (60 g, M) and maleic acid (22.8 g, 0.19 M) is heated under reflux with stirring in isopropanol (1.0 l) until then, until you have a clear solution (1-2 hours). The reaction mass allow to cool to room temperature while stirring for 15-20 hours. White or white crystalline substance is filtered off, washed with isopropanol (3×100 ml) and petroleum ether (2×100 ml), then dried to yield a white or white tinged with substances (84.5 g; yield 92%).

Example 2

1 g of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate obtained by the method described in example 1, add 10 ml of ethanol and heated on the steam bath until then, until completely dissolved solids. Transparent solution allow to cool to room temperature for 18 hours to obtain polymorphic form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, with yields of 80% and a purity >99%.

Example 3

1 g of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, obtained what about the way described in example 1, add 50 ml of acetone and heated on the steam bath until then, until completely dissolved solids. Solution allow to cool to room temperature for 18 hours to obtain polymorphic form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, with the release of 60% and a purity >99%.

Example 4

1 g of 5-[4-[2-[N-methyl-N - (2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate obtained by the method described in example 1, add 10 ml of methanol and heated on the steam bath until then, until completely dissolved solids. Transparent solution allow to cool to room temperature for 18 hours to obtain polymorphic form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, with a yield of 75% and a purity >99%.

Example - 5

1 g of 5-[4-[2-N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate obtained by the method described in example 1, add 10 ml of 1,4-dioxane and heated on the steam bath until then, until completely dissolved solids. Transparent solution allow to cool to room temperature for 18 hours to obtain polymorphic form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, with an output of 70% and a purity >99%.

1. Polymorphic crystalline form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, having the formula

and its stereoisomers, characterized by endothermal melting at 100,53°With (since 88,65° (C) according to differential scanning calorimetry (DSC) and x-ray difractograms on the powder (RDP)containing peaks at (2Θ): 10,90, 14,54, 15,96, 18,46, 18,60, 19,76, 20,72, 21,84, 22,36, 22,46, 23,90, 24,04, 24,72, 25,30, 25,98, 27,44, 29,70.

2. Polymorphic form according to claim 1, characterized by the spectrum of the IR-absorption with peaks 3435, 2997, 2773, 1750, 1701, 1620, 1510, 1362, 1332, 1237, 1165, 864, 764, 717, 654, 540 cm-1.

3. Polymorphic form according to claim 1, characterized in that its production includes the following stages:

(i) mixing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] benzyl]thiazolidin-2,4-dione maleate with ethanol and heated to form a solution,

(ii) filtering the solution and cooling to room temperature, and (iii) isolation of crystals of form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.

4. Polymorphic crystalline form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, having the formula

and its stereoisomers, characterized by the following data DSC: melting endotherm pri,67° (Since is 123.17° (C), and the fact that there are peaks RDP (2Θ): 8,90, 15,40, 18,06, 19,20, 22,30, 23,40, 23,62, 24,80, 25,10, 25,84, 26,72, 27,18, 29,30, 29,54, 29,84 and of 33.26.

5. Polymorphic form according to claim 4, characterized in that it has the peaks of the spectrum of the IR absorption: 3424, 3040, 2947, 2720, 1751, 1702, 1641,1618,1574,1541,1412, 1382,1359,1326,1265,1242, 1213, 1162, 1067, 1031, 865, 773, 713, 667, 576 and 539 cm-1.

6. Polymorphic form according to claim 4, characterized in that its production includes the following stages:

(i) mixing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate with acetone and heated to form a solution,

(ii) filtering the solution and cooling to room temperature, and

(iii) isolation of crystals of form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.

7. Polymorphic crystalline form III of 5-[4-[2-[N-methyl-]-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, having the formula

and its stereoisomers, characterized by the following data DSC: melting endotherm at 126,41°With (since 122,06° (C), and the fact that there are peaks RDP (2Θ): 4,60, 8,46, 9,24, 14,98, 15,86, 17,02, 18,60, 21,92, 23,50, 25,00, 25,44, 26,00, 26,38, 28,34 and 33,90.

8. Polymorphic form according to claim 7, characterized in that it has the peaks of the spectrum of the IR absorption: 3429, 2949, 2738, 1747, 1704, 1641, 1617, 1513, 1464, 1352,1244, 1117, 1069, 862, 777, 717, 657 and 589 cm-1.

9. Polymorphic form pop, characterized in that its production includes the following stages:

(i) mixing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate with methanol and heated to form a solution,

(ii) filtering the solution and cooling to room temperature, and

(iii) isolation of crystals of form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.

10. Polymorphic crystalline form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate, having the formula

and its stereoisomers, characterized by the following data DSC: melting endotherm at 125,39°With (since 121,03°) and what has peaks RDP (2Θ): 7,40, 8,80, 9,54, 14,98, 15,32, 15,82, 16,90, 17,70, 18,40, 18,54, 19,08, 19,72, 20,22, 20,48, 21,36, 21,66, 22,18, 22,58, 23,32, 23,96, 24,52, 25,38, 26,48, 27,00, 27,58, 27,94, 28,34, 28,54, 28,84, 29,10, 29,86, 30,02, 30,40, 30,52, 30,84, 31,40 and 31,94.

11. Polymorphic form of claim 10, characterized in that it has the peaks of the spectrum of the IR absorption: 3433, 2930, 1753, 1705, 1642, 1617, 1512, 1467, 1351, 1244, 1162, 1061, 864, 765, 714, 658 and 526 cm-1.

12. Polymorphic form of claim 10, characterized in that its production includes the following stages:

(i) mixing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate with 1,4-dioxane and heated to form a solution,

(iii) filtration is the situation of the solution and cooling to room temperature; and

(iii) isolation of crystals of form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidin-2,4-dione maleate.



 

Same patents:

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology.

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: medicine, in particular methods (variants) for prophylaxis and treatment of disorders associated with abnormal lipid carbohydrate metabolism or circulatory disturbances associated therewith in mammalian.

SUBSTANCE: claimed methods includes administration of pioglytazone or pharmaceutically acceptable salt thereof in combination with at least one member selected from group containing alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanide, statin derivative, squalene, fibrate compound, enhancer of low density lipoprotein catabolism and inhibitor of angiotensine converting enzyme to mammalian. Alternatively method includes administration of pioglytazone or pharmaceutically acceptable salt thereof in combination with enhancer of insulin secretion and/or insulin preparation.

EFFECT: synergic effect in relation to lowering of glucose levels in blood, body mass losses, with decreased amount of side effects.

13 cl, 8 tbl

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with obtaining preparations for treating diabetes mellitus based upon medicinal plants. The suggested antidiabetic species contains the folds of kidney beans fruits, goat's rue grass (Galega officinalis), Leonorus grass, leaves of common nettle and leaves of green tea at equal ratios. The suggested innovation could be presented as phyto-tea in filter-packs per 2.0 g. At applying the present species blood level of sugar is decreased, and in case of light form of diabetes mellitus - it is normalized that enables to decrease the dosages of antidiabetic preparations.

EFFECT: higher efficiency of application.

2 ex, 2 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a hydrophilic pharmaceutical composition with hypoglycemic effect comprising nateglinide crystals of B-type as an active component. The composition has edge angle to water surface 111 degrees or less. This edge angle is created by addition at least one hydrophilic substance to the composition chosen from groups comprising of hydrophilic polymers, surfactants, sugars and sugar-alcohols. Invention provides easy method for preparing the composition, its high solubility and rather rapid release of nateglinide.

EFFECT: improved and valuable properties of pharmaceutical composition.

13 cl, 8 dwg, 4 tbl, 6 ex

FIELD: medicine, endocrinology.

SUBSTANCE: invention proposes a medicinal agent for reducing the blood sugar content after food intake and representing a compound included in meglytinides and, if necessary, a pharmaceutically acceptable carrier. Nateglynide is the preferable compound. The complication associated with diabetes mellitus is chosen among nephropathy, retinopathy, neuropathy and angiopathy. At least one agent chosen among antihypertensive agent, vasodilating agent and antihyperlipidemic agent can be used with agent used simultaneously for reducing the blood content after food intake. Invention provides realization of indicated prescription.

EFFECT: valuable medicinal properties of drugs.

15 cl, 2 dwg, 5 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to improved methods for modulation of diabetes mellitus type II in mammal and modulation of resistance to insulin. Methods involve administration to indicated mammal needing in this treatment of (-)-stereoisomer of compound of the formula (I): wherein R is chosen from group including hydroxy-, lower araloxy-, d-(lower)-alkylamino-(lower)-alkoxy-, (lower)-alkylamido-(lower)-alkoxy-, benzamido-(lower)-alkoxy-, ureido-(lower)-alkoxy-, N'-(lower)-alkyl-ureido-(lower)-alkoxy-, carbamoyl-(lower)-alkoxy-, halophenoxy-substituted lower alkoxy-, carbamoyl-substituted phenoxy-group; or R represents hydrolysable ester group; each X represents independently halogen atom; or its pharmaceutically acceptable salt wherein (-)-stereoisomer doesn't comprise conceptually (+)-stereoisomer. Also, invention relates to pharmaceutical compositions comprising (-)-stereoisomer of compound of the formula (I) and wherein compositions show significantly reduced inhibitory effect on activity of cytochrome P-450 2C9 as compared with racemic composition having 0% enantiomeric excess of (-)-stereoisomer.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition, improved preparing methods.

59 cl, 21 dwg, 8 tbl, 18 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology.

SUBSTANCE: invention relates to a method for preparing an antidiabetic agent pioglitazone of the formula (I): . Method involves condensation of 4-substituted phenol or phenolate of the general formula (II): wherein R represents organic radical comprising amino-group and chosen from group comprising group of the general formula: -NHRa (IIa) wherein Ra means hydrogen atom or protective group that is removed before the following treatment, and group of the general formula: wherein Rb represents carboxyl group as free acid or as salt or ester; M represents hydrogen atom or alkaline metal with pyridine base of the general formula (III): wherein Z means a removing group distinguishing from halogen atom and wherein the following steps are carried out: (a) diazotization reaction of amino-group as a moiety of organic radical R; (b) conversion of diazotized radical R to derivative of 2-halogenpropionate or 2-halogenpropionitrile of the formula: wherein Rb is determined above; X represents halogen atom; (c) cyclization of derivative of 2-halogenpropionate or 2-halogenpropionitrile with thiourea, and (d) hydrolysis of imine prepared. In case when R represents group of the formula (IIa) method involves firstly carrying out the condensation reaction followed by carrying out steps (a)-(d) to obtain agent of the formula (I); or in case when R represents group of the formula (IIb) then method involves firstly carrying out steps (a)-(d) followed by condensation with pyridine base of the general formula (III) to obtain agent of the formula (I). Also, invention describes compounds of the formula (V): wherein Ra represents a protective group chosen from group comprising acyl, n-alkoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-cyanoethoxycarbonyl as an intermediate substance in synthesis of compound of the formula (I).

EFFECT: improved preparing method of agent.

12 cl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (1): wherein R1 means (C1-C6)-alkyl that can be substituted with phenyl; R2, R3, R4 and R5 represent independently each of other hydrogen halogen atom, nitro-group, (C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-, (C6-C10)-aryloxy-group, (C6-C10)-aryl that can be mono-, di- or tri-substituted with halogen atom; 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 under condition that R2, R3, R4 and R5 can't mean simultaneously hydrogen atom and at least one residue among R2, R3, R4 and R5 represents 2-oxopyrrolidine-1-yl, 2,5-dimethylpyrrole-1-yl or -NR6-A-R7 at value R6 - hydrogen atom, (C1-C4)-alkyl or (C6-C10)-aryl-(C1-C4)-alkyl wherein aryl can be substituted with halogen atom; A means a simple bond, -COn, -SOn or -CONH; n = 1 or 2; R7 means hydrogen atom; (C1-C18)-alkyl or (C2-C18)-alkenyl that can be substituted from one to three times with (C1-C4)-alkyl, (C1-C4)-alkyloxy-group, -N-((C1-C4)-alkyl)2-group, -COOH, (C1-C4)-alkyloxycarbonyl, (C6-C12)-aryl, (C6-C12)-aryloxy-group, (C6-C12)-arylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkoxy-group, halogen atom, -CF3 or oxo-group wherein aryl, in turn, can be substituted with halogen atom, (C1-C)-alkyl, aminosulfonyl- or methylmercapto-group; (C6-C10)-aryl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl-(C1-C4)-alkyl, (C5-C8)-cycloalkyl, (C6-C10)-aryl-(C2-C6)-alkenyl, (C6-C10)-aryl, diphenyl, diphenyl-(C1-C4)-alkyl, indanyl that can be mono- or di-substituted with (C1-C18)-alkyl, (C1-C18)-alkyloxy-group, (C3-C8)-cycloalkyl, hydroxy-group, (C1-C4)-alkylcarbonyl, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C4)-alkyloxy-group, (C6-C10)-aryloxy-group, nitro-, cyano-group, (C6-C10)-aryl, fluorosulfonyl, (C1-C6)-alkyloxycarbonyl, (C6-C10)-arylsulfonyloxy-group, pyridyl, -NHSO2-(C6-C10)-aryl, halogen atom, -CF3 or -OCF3 wherein alkyl can be substituted once again with halogen atom, -CF3 or (C1-C4)-alkyloxy-group; or group Het-(CH2)r wherein r = 0, 1, 2 or 3 wherein Het means saturated or unsaturated 5-7-membered heterocycle comprising atoms nitrogen (N), oxygen (O) or sulfur (S) and can be condensed with benzene and substituted with (C1-C4)-alkyl, (C6-C10)-aryl, halogen atom, (C1-C4)-alkyloxy-group, (C6-C10)-aryl-(C1-C4)-alkyl, (C6-C10)-aryl-(C1-C)-alkylmercapto- or nitro-group and wherein aryl condensed with benzene can be, in turn, substituted with halogen atom, (C1-C4)-alkyloxy-group; and to their pharmacologically acceptable salts and additive salts of acids, and to a method for their preparing. Proposed compounds show inhibitory effect on activity of hormone-sensitive lipase.

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

14 cl, 199 ex

FIELD: medicine.

SUBSTANCE: method involves administering Nateglynid and Glytazon in pharmaceutically permissible carrier. The combination is optionally administered as combined preparation or pharmaceutical composition. The pharmaceutical composition (the second version) has Nateglynid and Methformin as the second anti-diabetic agent enclosed into the pharmaceutical carrier.

EFFECT: enhanced effectiveness of synergetic preparations action upon diabetes II; prolonged therapeutic drug action time; postponed insulin administration.

13 cl, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means phenyl or naphthyl comprising the following substitutes: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl (-CF3), phenyl or heteroaryl representing aromatic 5-membered ring that comprises sulfur atom; each among R2, R3, R4 and R6 and independently of one another means hydrogen atom, hydroxy-group, (lower)-alkenyl, halogen atom, (lower)-alkyl or (lower)-alkoxy-group wherein at least one radical among R2, R3, R4 and R6 doesn't mean hydrogen atom, or R3 and R4 are bound and also bound with carbon atoms to which they are bound and form ring, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-O-, -O-CH=CH-, -CH=CH-CH=CH-, -(CH2)3-5-, -O-(CH2)2-3 or -(CH2)2-3-O- wherein R2 and R6 have above given values; R5 means (lower)-alkoxy-, (lower)-alkenyloxy-group, or ; R7 means hydrogen atom or (lower)-alkyl; R8 means (lower)-alkyl; R9 means hydrogen atom; R10 means phenyl or naphthyl that can be mono- or poly-substituted with -CF3; n means 1, 2 or 3, and wherein the bond between Ca carbon atom and Cb carbon atom represents carbon-carbon single or double bond, and to their pharmaceutically acceptable salts and esters also. Indicated compounds can be used as therapeutically active substances in treatment and/or prophylaxis of diseases mediated by agonists of PPAR-α and/or PPAR-γ receptors, for example, in treatment of diabetes.

EFFECT: valuable medicinal properties of compounds.

24 cl, 167 ex

FIELD: medicine.

SUBSTANCE: method involves using dipeptidyl peptidase IV (DP IV or CD 26) or DP IV-like enzyme for producing drug for treating stress or anxiety cases. Inhibitors are usable in combination with neuropeptides Y. The inhibitors are transported in physiologically compatible carriers. The inhibitors are also produced as prodrugs.

EFFECT: enhanced effectiveness of treatment.

6 cl, 11 dwg, 2 tbl

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