Form vi of atorvastatin calcium and its hydrates

FIELD: pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to a novel crystalline form VI of atorvastatin calcium, or its hydrates. Invention proposes a picture of powdery roentgen diffraction with value 2Θ determined by using Shimadzu XRD-6000 with K-radiation of copper at λ = 1.5406 Å and with relative intensity >15%, 3.7365; 7.7200; 8.6985; 10.2185; 12.5933; 17.9103; 18.3600; 19.4031; 20.2800; 20.8200; 22.5122 and 25.5848. Also, invention describes methods for their preparing. Invention provides high purity, stability and solubility of proposed form.

EFFECT: improved and valuable properties of form VI.

22 cl, 2 tbl, 6 ex

 

The technical FIELD

This invention relates to the form VI of atorvastatin calcium or its hydrate, and the way they are received. In particular, this invention relates to a new crystalline form of atorvastatin calcium.

The LEVEL of TECHNOLOGY

Atorvastatin is a representative of a class of drugs called statins. Satinowye medicinal substances are currently the most therapeutically effective medicines available to reduce the concentration of particles of low-density lipoprotein (LDL) in the bloodstream of patients with risk of cardiovascular diseases. He also, apparently, reduces the total content of glycerides and total cholesterol. High levels of LDL in the bloodstream is associated with the formation of coronary lesions that obstruct the blood flow and can cause rupture and promote thrombosis. Goodman and Gilman. The Pharmacological Basis of Therapeutics 879 (9thed. 1996). The reduction of LDL levels in plasma have been shown to reduce the risk of clinical cases of patients with cardiovascular disease and patients who do not have cardiovascular disease but who have hypercholesterolemia [Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b].

Were studied in some details of the mechanism of action latinovich drugs. They serve tout the synthesis of cholesterol and other sterols in the liver by competitive inhibition of the enzyme 3-hydroxy-3-methylglutarylcoenzyme-A-reductase ("HMG-COA reductase"). HMG-COA-reductase catalyzes the conversion of HMG-COA in the mevalonata, which is determining the speed stage in the biosynthesis of cholesterol, and therefore, its inhibition leads to a decrease in the concentration of cholesterol in the liver. Lipoprotein very low density lipoproteins (VLDL) is a biological carrier for transfer of cholesterol and triglycerides from the liver to peripheral cells. Lonp catabolized in peripheral cells, which secrete an oily acid that can be stored in adipocytes or oxidized in the muscle. Lonp into medium-density lipoprotein (LSP), which is, or is removed by the LDL receptor, and / or converted to LDL. The decline in the production of cholesterol increases the number of LDL receptors and a corresponding decline in the production of LDL particles by the metabolism of LSP.

Atorvastatin is a common name of the substance with the chemical name [R-(R*,R*)]-2-(4-forfinal)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid. The free acid affected lactonization. The molecular structure of the lactone represented by the formula (1).

Atorvastatin comes to the market in the form of three-hydrate semi-calcium salt under the name lipitor (LIPITOR) Warner-Lambert Co. It is a synthetic inhibitor of HMG-COA reductase and is used to treat hyperli is idemia and hypercholesterolemia. The empirical formula of atorvastatin calcium is a (C33H34FN2About5)2Sa, and its molecular weight is equal to 1155,42.

Its structural formula is:

Figure 1

Atorvastatin calcium is a white to not-quite-white, amorphous or crystalline powder that is insoluble in aqueous solutions with pH 4 and below. It is very slightly soluble in distilled water, phosphate buffer with pH 7.4 and acetonitrile, slightly soluble in ethanol and freely soluble in methanol.

The lactone of atorvastatin was first presented to the public and claimed in U.S. patent No. 4681893. Semi-calcium salt represented by the formula (II) (hereafter "atorvastatin calcium"), the enantiomer having the R-form of the acid with an open ended ring described in U.S. patent No. 5273995. This patent States that this calcium salt is obtained by crystallization from a saturated salt solution, resulting in the conversion of sodium salt using CaCl2and further purify by crystallization from a mixture of 5:3 ethyl acetate and hexane. Both of these U.S. patents is included here by reference.

In U.S. patent numbers 5003080, 5097045, 5103024, 5124482, 5149837, 5155251, 5216174, 5248793, 5280132, 5342952, 5007080, 6274740, which are included here by reference, describes various methods and key intermediate connection is possible to obtain atorvastatin calcium. All of these methods give a mixture of crystalline and amorphous forms.

Atorvastatin receive in the form of its calcium salt. Calcium salt is desirable as it gives the opportunity to prepare suitable preparations with atorvastatin in accordance with the purposes of the introduction. In addition, there is a need for atorvastatin in pure and crystalline form, to make it able to meet strict pharmaceutical requirements and specifications.

In addition, it is necessary that the way in which get atorvastatin was suitable for large-scale production. In addition, it is desirable that the product was in the form that can easily be distinguished. Finally, economically it is desirable that the product had a longer shelf life without the need to comply with special conditions of storage.

In the methods presented above U.S. patents described amorphous atorvastatin, which has properties that are unsuitable for filtration and drying under conditions of large-scale production, and must be protected from heat, light, oxygen and moisture.

In U.S. patent No. 5969156 described three polymorpha atorvastatin indicated by the authors, opening them as forms I, II and IV. Although the authors claim certain benefits processing and therapeutic benefits of these forms over the amorphous atorvastatin the om calcium, advantages can be realized with the help of others, do not open earlier forms of atorvastatin calcium.

In PCT application WO 97/03960 and PCT application WO 00/71116 described method for the production of amorphous atorvastatin calcium.

In PCT application WO 97/03958 and U.S. patent No. 6121461 describes a method for form III crystalline atorvastatin calcium, and at the same time, in PCT application WO97/03959 reported the method to obtain forms I, II and IV of crystalline atorvastatin calcium.

In PCT application WO 01/36384 described form V atorvastatin calcium. In all of these patents claimed advantages over existing patents in one way or another.

This invention includes a new crystalline form of atorvastatin calcium in the form of the hydrate and the anhydrous state. Polymorphism is a property of some molecules and molecular complexes to take more than one crystalline or amorphous form in the solid state. The only molecule that is similar to the atorvastatin of formula (I) or a salt complex of the formula (II)may form a series of solid substances having specific physical properties such as solubility, stability, purity, picture x-ray diffraction and13From the NMR spectrum in the solid state. Differences in the physical properties of polymorphs is the result of orientation and intermolecular interactions neighboring the molecules (complexes) in the mass of solids. Accordingly, polymorphs are separate solid substances having the same molecular formula, which can be thought of as similar to the unit cell in metallurgy, even with a clear favorable and/or unfavorable physical properties compared to other forms of family polymorphs. One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, especially their solubility in the gastric juice of the patient. For example, when the absorption from the gastrointestinal tract is slow, often for drug substances which are unstable in the stomach or intestines of a patient, it is desirable to dissolve slowly, so that it does not accumulate in a hostile environment. On the other hand, when the effectiveness of the medicinal substance correlates with peak levels in the bloodstream, which is typical for latinovich medicinal substances, and provided that the drug is rapidly absorbed from the LCD system, then more rapidly dissolving form, likely to show increased efficiency compared with comparable number more slowly soluble form.

BRIEF DESCRIPTION of DRAWINGS

FIG. 1 is the structural formula of the new crystalline polymorphic form VI atorv the statin calcium of the present invention.

FIG. 2 is an x-ray powder diffraction pattern of atorvastatin calcium form VI.

FIG. 3 is13From the NMR spectrum in the solid state of atorvastatin calcium form VI.

The INVENTION

This invention is a new crystalline polymorphic form of atorvastatin calcium, designated as form VI,as in the anhydrous condition, and hydratewith the advantage of high purity, stability and solubility.

This invention, moreover, is a simple inexpensive way of obtaining a new form VI of atorvastatin calcium, which has the advantages of easy and quick separation and crystallization, not counting the purity, yield and stability. The number of stages is very small.

This invention also provides a high output and a very low content of residual solvents.

Accordingly, this invention relates to a crystalline polymorphic form VI of atorvastatin calciumas in the anhydrous state and in the form of a hydrate.

New polymorphic crystalline form VI of atorvastatin calcium differs following the pattern of the powder x-ray diffraction, expressed as 2 theta d-spacing and relative intensities with a relative intensity of >15%, determined on a Shimadzu XRD-6000 c To radiation is the group of copper with lambda 1,5406 Å :

DRelative intensity (>15%)
3,736523,458423,0
7,720011,442536,0
8,698510,157474,0
10,21858,649757,0
12,59337,023419,0
17,91034,948547,0
18,36004,828320,0
19,40314,5710100,0
20,28004,375329,0
20,82004,263048,0
22,51223,946324,0
25,58483,492325,0

In addition, the crystalline form VI of atorvastatin calcium or its hydrates under item I have peaks of powder x-ray diffraction at 2Θ 3,7; 8,6; 10.2 and 20.9 degrees and a broad peak at 2Θ 19.5 degrees.

In addition, this invention relates to a crystalline form VI of atorvastatin and its hydrates, differing in the following range13Nuclear magnetic resonance (NMR) in the solid state, where the chemical shift is expressed in ppm (ppm)defined n the spectrophotometer Varian.

δ (ppm)
21,898
24,294
27,767
29,368
33,939
38,275
42,836
45,980
68,932
71,266
73,617
119,357
122,987
131,214
137,515
162,696
169,066
179,540
186,890
190,640

The crystalline form VI of atorvastatin calcium or its hydrates under paragraph 1 are signals13With NMR in the solid state at about 162,689 ppm, 169,066 ppm, 179,54 ppm, 186,89 ppm and 190,64 ppm

In a preferred embodiment of the present invention, crystalline form VI of atorvastatin calcium contains up to 8 mol of water per mol of atorvastatin calcium.

In yet another preferred embodiment of the present invention, crystalline form VI of atorvastatin is Alicia is a trihydrate.

This invention also provides a method of obtaining a new crystalline polymorphic form VI of atorvastatin calciumas in the form of the hydrate and the anhydrous state,[R-(R*,R*)]-2-(4-forfinal)-beta,Delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid semi-calcium salt (2:1), having the formula, which is presented in figure 1:

a) dissolving the calcium salt of any form of atorvastatin inorganic solvent, such asaliphatic ketone, to obtain a transparent solution of salt of atorvastatin

b)optionally, removal of impurities,

(C) adding demineralized water,

d) isolation of the crystalline polymorphic form VI of atorvastatin calcium and drying, if desired, to capture the required water of crystallization.

In addition, this invention is also a method of obtaining a new crystalline polymorphic form VI of atorvastatin calcium is [R-(R*,R*)]-2-(4-forfinal)-beta,Delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid semi-calcium salt (2:1), having the formula 1, which includes:

a) dissolving the lactone form of atorvastatin in an organic solvent, preferably in an aliphatic ketone, to obtain a transparent solution,

b) adding an aqueous solution of the hydroxide of alkaline-earth metal and demineralized water with stirring,

(C) allocation of crystalline polymorphic form VI of atorvastatin calcium and drying, if desired, to capture the required water of crystallization.

In one of the embodiments of the present invention used atorvastatin calcium may be amorphous or crystalline forms I, II, III, IV and V of atorvastatin calcium or mixtures thereof.

In an additional embodiment used atorvastatin calcium may be in the anhydrous state or in the form of a hydrate containing up to 9 water molecules.

In yet another additional embodiment of the used organic solvent may be selected from aliphatic ketones containing from 1 to 3 carbon atoms. Used aliphatic ketones can be acetone, methyl ethyl ketone, diethylketone, methylpropylketone, preferably, acetone.

In yet another embodiment of the used organic solvent may be 100-kratom, preferably 15-fold, more preferably 10 times the number from the original connection.

In accordance with another aspect of the present invention, the dissolution can be carried out by heating the suspension of atorvastatin calcium in an organic solvent to the boiling point of the used solvent, preferably, to a temperature above 40°s and 80°more preferably, from 40°C to 50°C.

When one of the additional embodiments of the impurities are removed by filtering.

In yet another additional embodiment, the number of DM water can be up to 100 times, preferably 10 times greater than the number of the original connection.

In another embodiment of DM water can be added dropswhile maintaining the temperature.

Additionally, the hydroxide of alkaline-earth metal may be calcium hydroxide. An aqueous solution of hydroxide of alkaline-earth metal may be preferably added at an elevated temperature, preferably at temperatures above 40°s and 80°S, more preferably at a temperature of from 40°C to 50°C.

The hydroxide of alkaline-earth metal may be added in 50-fold, preferably 10-fold amount of the parent compound, more preferably, in a ratio of 1:1.

In yet another embodiment, the solution can be slowly cooled to a temperature in the range from -20°to 20°C (room temperature), preferably in the range from 15°to 20°for the implementation of crystallization. Cooling can be performed with a speed of 2-3°in a minute.

The selection can be carried out by any conventional methods, such as filtration, vacuum filtration, decantation, centrifugation.

Drying can be a wasp who Astley using known means, such vacuum tray dryer, drum vacuum dryer, and the temperature is above 50°s and 80°C, preferably at 55°With over 12 to 30 hours to regulate the amount of water in the molecules. The person skilled in the art will understand that by adjusting the temperature and time of these stages it is possible to optimize the yield of the desired product.

A new crystalline form VI of atorvastatin calcium has potential application for the treatment of hyperlipidemia,NCEP, hypocholesterolemia, Alzheimer's disease, atherosclerosis, xanthomas, and synergism with other drugs, to treat deficiency of lipase by phytosterolemia, and the like.

DETAILED description of the INVENTION

X-ray powder diffraction pattern of the new polymorphic crystalline form VI (Fig. 2) has an average peaks at 2Θ 3,7±0,2; 8,6±0,2; 10,2±0,2 and 20.9±0.2 degrees and one large peak at 2Θ 19,5±0.2 degrees.

This picture of x-ray radiation is very different from the picture to the known crystalline forms I, II, III, IV, V, and from x-ray diffraction pattern of the amorphous form, which is characterized by two broad peaks in the range of 2Θ 8-14 degrees and 2Θ 15-26 degrees.

X-ray diffraction pattern of figure 2 was obtained by the known methods using Scimadzu XRD-6000, applied radiation copper λ=1,5406 Å. The measurement interval 2Θ 3-40 degrees. Table 1 lists 2Θ, d-inteval and relative intensities with a relative intensity of >15%.

TABLE 1
DRelative intensity (>15%)
3,763523,458423,0
7,720011,442536,0
8,698510,157474,0
10,21858,649757,0
12,59337,023419,0
17,91034,948547,0
18,36004,828320,0
19,40314,5710100,0
20,28004,375329,0
20,82004,263048,0
22,51223,946324,0
25,58483,492325,0

Range13With NMR in the solid state of new polymorphic form is characterized by the following chemical shifts.

δ (ppm)
21,898
24,294
27,767
29,368
33,939
38,275
42,836 (strong)
45,980
68,932
71,266
73,617
119,357
122,987
131,214 (strong)
137,515
162,696
169,066
179,540
186,890
190,640

Range13With NMR in the solid state is very different from the known spectra of forms I, II, III, IV, V, and amorphous forms, which gives a different picture with shifts significantly different from the picture of the new polymorphic form VI, appearing in 162,698 ppm, 169,066 ppm, 179,54 ppm, 186,89 ppm and 190,64 ppm, which corresponds With the12or25carbon atoms of the compounds of formula with Fig. 1. Range with Fig. 3 was obtained by the spectrometer Varian 300 MHz (megahertz). The device is equipped with13JV head for sample weight and the sample was moved at speeds of 7.0 kHz. Magic in the ol and the effectiveness of the decoupling of the protons were optimized prior to registration data.

RD and NMR were performed on unground samples.

A new polymorphic form exists in the anhydrous state, as well as in the form of a hydrate. It contains up to 9 water molecules. However, the preferred trihydrate form.

The invention is further illustrated by the following examples which do not limit the actual scope of the claims.

EXAMPLE 1:

Atorvastatin calcium (100.0 g) was added to an acetone (1 l) at room temperature. The mixture was heated to 50°C for 30 minutes to obtain a transparent solution. To this solution was added dropwise DM water (500 ml) at 50°C. the Solution was slowly cooled to room temperature at a speed of 2°C/min, crystallized a new polymorphic form of atorvastatin calcium. The product was filtered vacuum filtration and then dried in tray vacuum dryer at 50-55°With within 24 hours.

Output: 90.0 g (90,0%)

The relative purity (HPLC): 99,63%

Residual solvent:

Acetone: not more than 0.2%

EXAMPLE 2:

Atorvastatin calcium (100.0 g) was added in acetone (100,0 ml) at room temperature. The mixture was heated to 50°C for 30 minutes to obtain a transparent solution. To this solution was added dropwise DM water (100 ml) at 50°C. the Solution was slowly cooled to room temperature at a speed of 2°C/min, which was crystallizability new polymorphic form of atorvastatin calcium. The product was filtered vacuum filtration and then dried in tray vacuum dryer at 55-60°C for 28 hours.

Output: 92,0 g (92.0%)

The relative purity (HPLC): 99,68%

Residual solvent:

Acetone: not more than 0.2%

EXAMPLE 3:

Atorvastatin calcium (10.0 g) was added to an acetone (1 l) at room temperature. The mixture was heated to 45°C for 20 minutes to obtain a transparent solution. To this solution was added dropwise DM water (1.0 l) at 45°C. the Solution was slowly cooled to room temperature at a speed of 2°C/min, crystallized a new polymorphic form of atorvastatin calcium. The product was filtered vacuum filtration and then dried in tray vacuum dryer at 55-60°With within 24 hours.

Output: 90.0 g (90,0%)

The relative purity (HPLC): 99,61%

Residual solvent:

Acetone: not more than 0.2%

EXAMPLE 4:

The lactone form of atorvastatin calcium (100.0 g) was added in acetone (1 l) at room temperature. To this solution was added calcium hydroxide (10.0 g), suspended in DM water (100 ml)in one portion. The reaction mass was stirred at 45-46°to the disappearance of the lactone form of atorvastatin calcium (TLC, 2.0 hours). On drops) was added DM water (400 ml) at 45°C. the Solution was slowly cooled to room temperature with near the STU 2° C/min, crystallized a new polymorphic form of atorvastatin calcium. The product was filtered vacuum filtration and then dried in tray vacuum dryer at 50-55°C for 20 hours.

Output: 100.0 g (90,0%)

The relative purity (HPLC): 99,31%

Residual solvent:

Acetone: not more than 0.2%

EXAMPLE 5:

The lactone form of atorvastatin calcium (10.0 g) was added in acetone (10.0 ml) at room temperature. To this solution was added calcium hydroxide (1.0 g), suspended in DM water (5.0 ml), in one piece. The reaction mass was stirred at 50°to the disappearance of the lactone form of atorvastatin calcium (TLC, 2.0 hours). Was added dropwise DM water (5 ml) at 50°C. the Solution was slowly cooled to room temperature at a speed of 2°C/min, crystallized a new polymorphic form of atorvastatin calcium. The product was filtered vacuum filtration and then dried in tray vacuum dryer at 55-60°With within 24 hours.

Yield: 10.0 g (90,0%)

The relative purity (HPLC): 99,20%

Residual solvent:

Acetone: not more than 0.2%

EXAMPLE 6:

The lactone form of atorvastatin calcium (10.0 g) was added in acetone (1.0 l) at room temperature. To this solution was added calcium hydroxide (1.0 g), suspended in DM water (100,0 ml)in one portion the Reaction mass was stirred at 45-46° With to the disappearance of the lactone form of atorvastatin calcium (TLC, 2.0 hours). Was added dropwise DM water (900 ml) at 45-46°C. the Solution was slowly cooled to room temperature at a speed of 2°C/min, crystallized a new polymorphic form of atorvastatin calcium. The product was filtered vacuum filtration and then dried in tray vacuum dryer at 55-60°With within 24 hours.

Yield: 10.2 g (92,0%)

The relative purity (HPLC): 99,22%

Residual solvent:

Acetone: not more than 0.2%

Although this invention has been described on the basis of its specific embodiments, certain modifications and equivalents will be apparent to experts in the field, and, it is understood that they are included in the scope of this invention.

1. The crystalline form VI of atorvastatin calcium or a hydrate, a different pattern x-ray powder diraction processes by values of 2Θdetermined using a Shimadzu XRD-6000 with radiation of copper with λ 1,5406Å and with a relative intensity of >15%

3,7365; 7,7200; 8,6985; 10,2185; 12,5933; 17,9103; 18,3600; 19,4031; 20,2800; 20,8200; 22,5122 and 25,5848.

2. The crystalline form VI of atorvastatin calcium or its hydrate according to claim 1, having peaks of x-ray powder diraction processes at 2Θ 3,7; 18,0 and 20.9° and large peaks at 2Θ 8,6; 10,2 and 19.5°.

3. Crystalline form VI atorvas the Atina calcium or its hydrate according to claim 1, characterized by the following range of13Nuclear magnetic resonance (NMR) in the solid state, and the chemical shift is expressed in ppm (ppm):

δ (ppm)
21,898
24,294
27,767
29,368
33,939
38,275
42,836
45,980
68,932
71,266
73,617
119,357
122,987
131,214
137,515
162,696
169,066
179,540
186,890
190,640

4. The crystalline form VI of atorvastatin calcium or its hydrate according to claim 1, having a signal13With NMR in the solid state at about 162,689 ppm, 169,066 ppm, 179,54 ppm, 186,89 ppm and 190,64 ppm

5. The crystalline form VI of atorvastatin calcium according to claim 1, which contains up to 8 mol of water per mol of atorvastatin calcium.

. The crystalline form VI of atorvastatin calcium according to claim 1, which contains up to 3 mol of water per mol of atorvastatin calcium.

7. The crystalline form VI of atorvastatin calcium according to claim 1, which has a melting point in the range from 177 to 182°C.

8. A method of obtaining a crystalline form VI of atorvastatin calcium according to claim 1 in the form of the hydrate and the anhydrous state, [R-(R*,R*)]-2-(4-forfinal)-beta, Delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid polyallelic salt (2:1), having the formula

which includes

a) dissolving the calcium salt of any form of atorvastatin in an organic solvent such as an aliphatic ketone, preferably at a temperature in the range from room temperature up to the boiling temperature to obtain a transparent solution of salt of atorvastatin

b) optionally, removal of impurities,

c) adding demineralized water, while maintaining the same temperature,

d) isolation of the crystalline polymorphic form VI of atorvastatin calcium and drying, if desired, to capture the required water of crystallization.

9. The way to get a new polymorphic crystalline form VI of atorvastatin calcium is [R-(R*,R*)]-2-(4-forfinal)-beta,Delta-dihydroxy-5-(1-methylethyl)-phenyl-4-[(phenylamino)-Carboni is]-1H-pyrrol-1-heptane acid calcium salt (2:1), those having the formula :

which includes

a) dissolving the lactone form of atorvastatin in an organic solvent, preferably an aliphatic ketone, at a temperature in the range from room temperature up to the boiling temperature to obtain a transparent solution,

b) adding an aqueous solution of hydroxide of alkaline earth metal and demineralized water with stirring while maintaining the same temperature,

c) isolation of the crystalline polymorphic form VI of atorvastatin calcium and drying, if desired, to capture the required water of crystallization.

10. The method of claim 8, where used atorvastatin calcium amorphous or crystalline forms I, II, III, IV and V of atorvastatin calcium or mixtures thereof.

11. The method of claim 8, where used atorvastatin calcium is in the anhydrous state or in the form of hydrate content up to 9 water molecules.

12. The method according to PP and 9, where the used organic solvent selected from aliphatic ketones containing from 1 to 3 carbon atoms.

13. The method according to item 12, where used aliphatic ketones represented by acetone, methyl ethyl ketone, diethylketone, methylpropylketone, preferably acetone.

14. The method according to PP and 9, where the organic solvent used in 100-fold, preference is sustained fashion 15-fold, more preferably 10 times the number from the original connection.

15. The method of claim 8, where the dissolution is carried out by heating the suspension of atorvastatin calcium in an organic solvent to a temperature above 40°s and 80°more preferably, from 40 to 50°C.

16. The method according to PP and 9, where impurities are removed by filtering.

17. The method according to PP and 9 where the use of demineralized (DM) water 100-fold, preferably 10-fold, more preferably 5 times the number from the original connection.

18. The method according to claim 9, where the used alkali earth metal hydroxide is calcium hydroxide.

19. The method according to claim 9, where add the alkali earth metal hydroxide in 50-fold, preferably 10-fold amount of the parent compound, more preferably in a ratio of 1:1.

20. The method according to PP and 9, where the cooling is carried out slowly to a temperature of from -20 to 20°C (room temperature), preferably from 15 to 20°for the implementation of crystallization, and the specified cooling can be carried out with a speed of 2-3°in a minute.

21. The method according to PP and 9, where the selection is carried out by conventional methods such as filtration, vacuum filtration, decantation, centrifugation.

22. The method according to PP and 9, where the drying is performed by conventional means, such as vacuum l is Dova dryer, drum vacuum dryer at a temperature above 50 and below 80°C, preferably at 55°C for 12 to 30 hours



 

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FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

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9 cl, 1 tbl, 41 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

The invention relates to new tetrahydropyridine - or 4-hydroxypiperidine-alkylation formula I, where R1, R2, R3and R6denote hydrogen, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, C1-C6-alkoxyl or two adjacent radicals can form precondensation benzene ring, And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of coupling, n = 2 to 6, Z1, Z2and Z3represent a nitrogen atom or a substituted carbon atom, or a physiologically favourable salts, which possess antipsychotic or anxiolytic activity

The invention relates to 1-(21oksifenil)-2-methylpyrrole that exhibits antimicrobial activity and may find application in medicine as an antimicrobial agent in the local destination

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

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

9 cl, 1 tbl, 41 ex

FIELD: pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to a novel crystalline form VI of atorvastatin calcium, or its hydrates. Invention proposes a picture of powdery roentgen diffraction with value 2Θ determined by using Shimadzu XRD-6000 with K-radiation of copper at λ = 1.5406 Å and with relative intensity >15%, 3.7365; 7.7200; 8.6985; 10.2185; 12.5933; 17.9103; 18.3600; 19.4031; 20.2800; 20.8200; 22.5122 and 25.5848. Also, invention describes methods for their preparing. Invention provides high purity, stability and solubility of proposed form.

EFFECT: improved and valuable properties of form VI.

22 cl, 2 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula (1) , in form of trans- or cis-isomers, or their mixture, where R1 is selected from , and ; R7 stands for lower alkyl; R8 stands for lower alkyl; X represents >C=O or >SO2; R9 and R11 represent hydrogen or together form double bond; R10 and R12 are independently selected from hydrogen or lower alkyl; m stands for 1 or 2; n stands for 0, 1 or 2 and their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition and to application of said compounds, as well as compounds of formula (I), where R1 represents (R2, R3, R4, R5 and R6 each is independently selected from hydrogen, lower alkyl, lower alkoxy group or halogen; on condition that R2, R3, R4, R5 and R6 do not represent hydrogen), for treatment and/or prevention of DPP-IV-associated diseases.

EFFECT: obtaining novel compounds for treatment and/or prevention of DPP-IV-associated diseases.

14 cl, 1 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: in formula (I') , R5 is any group selected from a group comprising C1-C6 alkoxy group, which can be substituted with one group selected from a group of β substitutes, phenyloxy group which can be substituted with one group selected from a group of γ substitutes, C1-C6 halogenalkoxy group and C3-C6 cycloalkyloxy group; R6 is a substitute in a benzene ring which is selected from a group of α substitutes; R7 is a hydrogen atom, C1-C6 halogenalkyl group, C1-C6 hydroxyalkyl group which can be substituted with a hydroxy-protective group, C1-C6 alkyl group which can be substituted with one group selected from a group of β substitutes, or a phenyl group which can be substituted with one hydroxy group; m equals 1; n equals 1 or 2; numbers in each benzene ring denote the number of the position of each substitute; the group of substitutes includes hydroxyl groups, nitro groups, cyano groups, C1-C6 dialkylamino groups, acetamide groups, halogen atoms, C1-C6 alkyl groups, which can be substituted with one group selected from a group of β substitutes, C1-C6 halogen alkyl groups, C3-C10 cycloalkyl groups, 6-member heterocyclic groups with an N atom or O atom as a heteroatom, C3-C6 cycloalkenyl groups, phenyl group which can be substituted with one group selected from a group of γ substitutes, 5-6-member heteroaryl groups with 1-3 N atoms as heteroatoms which can be substituted wit one or more groups selected from a group of γ substitutes, C1-C6 alkoxy groups, C1-C6 halogenalkoxy groups, C3-C10 cycloalkoxy groups, phenyloxy group, C1-C6 alkylthio groups, C1-C6 halogenalkylthio groups, C1-C6 alkylsulphonyl groups and C1-C6 alkylcarbonyl groups; the group of β substitutes includes C1-C6 alkoxycarbonyl groups, C3-C10 cycloalkyl groups which can be substituted with one group selected from a group of γ substitutes, C3-C6 cycloalkenyl groups, C6-C10 aryl groups which can be substituted with one or more groups selected from a group of γ substitutes, 5-6-member heteroaryl groups with one N, O or S heteroatom, 9-member heteroaryl groups with two heteroatoms selected from N and S, C1-C6 alkoxy group and C6-C10 aryloxy group; and the group of γ substitutes include cyano groups, C1-C6 dialkylamino groups, C1-C6 cyclic amino groups, halogen atoms, C1-C6 alkyl groups, C3-C10 cycloalkyl grous, C1-C6 halogenalkyl groups, C1-C6 alkoxy groups and C1-C6 alkylenedioxy groups. The invention also relates to compounds or pharmaceutically acceptable salts thereof, selected from: 4-(2-cyclopropylethoxy)-N-(2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide, 4-(2-cyclopropylethoxy)-N-(2-[4-(difluoromethoxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}-vinyl)-benzamide. Other compounds are given in the formula of invention. The invention also relates to a pharmaceutical composition which can inhibit bone resorption, which contains the disclosed compound, to use of the disclosed compound as a medicinal agent for inhibiting bone resorption, for preparing a medicinal agent for lowering concentration of calcium in the blood, for preparing a medicinal agent for inhibiting reduction of bone mass, to a medicinal agent for inhibiting bone resorption in form of the disclosed compound, to a method of inhibiting bone resorption, a method of lowering concentration of calcium in the blood, a method of inhibiting reduction of bond mass, involving addition of an effective amount of the disclosed compound.

EFFECT: more effective use of the compounds.

22 cl, 6 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II-A) or pharmaceutically acceptable salt thereof: [in which symbols denote the following: R10-R12: are identical or different and each denotes halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, ring B: benzene ring or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N, R14: R0, halogen or -OR0, R0: are identical or different and each denotes H or lower alkyl, Y1: a single bond, lower alkylene, lower alkenylene or O-lower alkylene-, and Z1: -CO2R0 or -C0-NH-SO2-lower alkyl]. The invention also relates to a pharmaceutical composition based on the said compound, having antagonistic effect on the EP1 receptor.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in a medicinal agent for treating lower urinary tract symptoms.

6 cl, 56 tbl, 231 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula I: , where values of R1-R4, R7, R8 are given in claim 1. Compounds of formula I exhibit antagonistic activity on MR steroid receptors, which enables their use to produce a pharmaceutical composition and drugs with MR steroid receptor antagonist properties.

EFFECT: improved method.

95 cl, 26 dwg, 2 tbl, 32 ex

FIELD: pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to a novel crystalline form VI of atorvastatin calcium, or its hydrates. Invention proposes a picture of powdery roentgen diffraction with value 2Θ determined by using Shimadzu XRD-6000 with K-radiation of copper at λ = 1.5406 Å and with relative intensity >15%, 3.7365; 7.7200; 8.6985; 10.2185; 12.5933; 17.9103; 18.3600; 19.4031; 20.2800; 20.8200; 22.5122 and 25.5848. Also, invention describes methods for their preparing. Invention provides high purity, stability and solubility of proposed form.

EFFECT: improved and valuable properties of form VI.

22 cl, 2 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compositions of general formula (I): where R1 and R2 mean H; R3 means H; R4 means lower alkyl; n is equal to 1-6; X means O; formula group =N-D (where D means H, lower alkyl); Y means ethylene group, ethynylene group, formula group -E-CH2 - (where E means carbonyl, formula group -CH(OH)-), C6-C10arylen C6-C10arylen group substituted with 1-3 substitutes, selected from Group (a) of substitutes; Z means single bond, C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain; R5 means H, C3-C10cycloalkyl group, C6-C10aryl, C6-C10aryl group substituted with 1-3 substitutes selected from Group (a) of substitutes; R6 and R7 are identical or different and represent each H, lower alkyl; Group (a) of substitutes represents group consisting of halogen, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylthio group; provided when R5 represents H, Z represents branched C1-C10alkylen group or C1-C10alkylen group containing oxygen atom in specified carbon chain or on the end of specified carbon chain, or it pharmacologically acceptable salt.

EFFECT: high immunosuppressive activity of compounds and their effective application for pharmaceutical compositions and for methods of preventive rheumatoid arthritis treatment.

51 cl, 13 tbl, 91 ex

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