Valsartan salts, pharmaceutical composition based on thereof and method for preparing salts

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes valsartan salts chosen from the group involving monosodium, monopotassium, disodium, dipotassium, magnesium, calcium, bis-diethyl (or dipropyl, or dibutyl)-ammonium salts or their hydrates, and mixtures of these salts also. Also, invention relates to a method for their preparing and a pharmaceutical composition comprising thereof. Proposed salts can be in crystalline, partially crystalline, amorphous or polymorphous form. Prepared salts show high quality of crystalline lattices that is a base for chemical and physical stability of new compounds.

EFFECT: improved preparing method, improved and valuable properties of salts.

11 cl, 11 tbl, 16 ex

 

The invention relates to new salts antagonist AT1receptors, which represent (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine(valsartan) formula

The active substance of valsartan is a free acid, which is described in particular in EP 0443983, primarily in example 16; it has two acidic hydrogen atoms: (I) a hydrogen atom (atom N) carboxyl groups and (II) a hydrogen atom tetrazole rings. Therefore, one acid atom N (primarily atom N carboxyl group), or both acid atom N can be substituted monovalent or higher valency, for example, the divalent cation. It is also possible formation of mixed salts.

In EP 0443983 not described any specific salt of valsartan. The application does not contain any information about the specific properties of salts. At the same time in a number of countries active substance of valsartan used as an antihypertensive agent, marketed under the trademark DIOVAN.

Valsartan in the form of the free acid has a melting point in a closed crucible 80-95°and in an open crucible 105-110°C, and the enthalpy of melting of 12 kJ/mol. Optical rotation is [α]20D=(-70±2)° for a concentration of C=1 in methanol).

The density of the crystalline valsartan and hydrates of the salts was determined using a helium pycnometer (type Assiros 1330 company Micromeritics, NORCROSS, state of Georgia, USA). The density of the crystalline valsartan in the form of the free acid is 1.20±0,02.

Chart x-ray diffraction is essentially a very broad diffuse reflection of x-rays; therefore, according to x-ray analysis of the free acid is found in almost amorphous form. Data on the melting temperature along with the measured value of the enthalpy of melting component 12 kJ/mol, conclusively prove the presence of a significant residual structures in the form of particles or structural domains in the valsartan in the form of the free acid.

There is a need to create a more stable, for example, crystalline forms of valsartan, which are easier to expose the processes of drying or grinding after the final stage of the chemical process of receiving and processing at the stage of preparation of pharmaceutical compositions. There have been many futile attempts to create improved forms by obtaining salts, when this form should ideally be as close to the crystal, and possess physical and chemical stability. The desired improved properties and have only salt according to the invention, their solvate and polymorph forms.

It turned out that obtaining salts of valsartan having the desired preferred properties is a difficult task. In most cases receive, for example, amorphous salts with low stability (such as rigid foams, waxes or oils). Based on extensive research it was found that the greatest advantage compared with valsartan in the form of the free acid have the salt of valsartan according to the present invention.

Objects of the present invention are salts of valsartan, which is selected from the group comprising odnonatrieva salt, odnoklikovoy salt, dukelaw salt, magnesium salt, calcium salt, mediatraining salt, badprogramming salt, bodybuilding salt, mono-L-arginine salt, bis-L-arginine salt, mono-L-lysine salt, bis-L-lysine salt, and a mixture of salts, or respectively their amorphous form, a solvate, especially a hydrate, and their polymorphic forms, corresponding method of production and use and pharmaceutical compositions containing such salts.

Objects of the present invention are salts of valsartan, which is selected from the group comprising odnonatrieva salt, odnoklikovoy salt, dukelaw salt, magnesium salt, calcium salt, mediatraining salt, bisopropol moneynow salt, bodybuilding salt, mono-L-arginine salt, bis-L-arginine salt, mono-L-lysine salt, bis-L-lysine salt, or respectively their amorphous form, a solvate, especially a hydrate, and their polymorphic forms.

Mixtures of salts are (I) the form of simple salts containing different cations selected from the above group, or (II) a mixture of such forms of simple salts that exist, for example in the form of conglomerates.

The preferred salt is chosen, for example, from the group, including

odnonatrieva salt in amorphous form,

dukelaw salt of valsartan in amorphous or crystalline form, especially in the form of its hydrate,

odnoklikovoy salt of valsartan in amorphous form,

dukelaw salt of valsartan in amorphous or crystalline form, especially in the form of its hydrate,

calcium salt of valsartan in crystalline form, especially in the form of its hydrate, most preferably in the form of the tetrahydrate,

the magnesium salt of valsartan in crystalline form, especially in the form of its hydrate, most preferably in the form of uranyl,

a mixed calcium/magnesium salt of valsartan in crystalline form, especially in the form of its hydrate,

mediatraining salt of valsartan in crystalline form, especially in the form of its hydrate,

badprogramming with the eh of valsartan in crystalline form, primarily in the form of its hydrate,

bodybuilding salt of valsartan in crystalline form, especially in the form of its hydrate, most preferably in the form of its hemihydrate,

mono-L-arginine salt of valsartan in amorphous form,

bis-L-arginine salt of valsartan in amorphous form,

mono-L-lysine salt of valsartan in amorphous form,

bis-L-lysine salt of valsartan in amorphous form.

Salts according to the invention preferably are selected and practically purified form, for example, having a degree of purity >95%, preferably >98%, most preferably >99%. The degree of enantiomeric purity of the salts according to the invention is >98%, preferably >99%.

With the invention it has been unexpectedly found that the salts according to the invention or an amorphous form, a solvate, such as the hydrates of the salts and the corresponding polymorphic form, have the preferred properties compared to the free acid. Under given conditions the crystalline salts and hydrates are crystalline salts have a melting point that is associated with a specific endothermic enthalpy of melting. The crystalline salt according to the invention are stable and compared with valsartan have higher characteristics during storage and distribution of drugs is a war funds. Amorphous or partially amorphous salts have limited stability, i.e. being in solid form, they have a limited range of stability. For their stabilization requires certain conditions that can be achieved, for example, by preparation of galenical compositions.

In addition, both the crystalline and amorphous salts of the invention possess a high degree of dissociation in water and, therefore, significantly higher solubility in water. These properties are preferred because, on the one hand, the dissolution process occurs more quickly, and, on the other hand, such solutions require less water. In addition, in the case of solid dosage forms higher solubility in water under certain conditions may lead to a higher bioavailability of salts or hydrates of the salts. Improved properties, especially beneficial to the patients. In addition, it was found that certain salts according to the invention, first and foremost, salts of alkaline earth metals, have very high physical stability. For different values of relative humidity at room temperature and at slightly elevated temperatures, hydrates of the salts according to the invention practically does not absorb water or lose water is wide range of relative humidity for several hours, for example, four hours. For example, the melting point of the salts of the present invention does not change during storage at different relative humidity.

Improving physico-chemical properties of certain salts or hydrates of certain salts is of great importance both to receive them as having pharmaceutical activity of substances, and for preparation, storage and use of herbal compositions. Thus, due to the higher consistency of the physical parameters can provide even higher quality compositions. High stability salts or hydrates of the salts also allows you to have an economic advantage due to the fact that the process consists of simpler stages. A high degree of crystallinity certain hydrates of salts makes it possible to apply various analytical methods, primarily various x-ray methods by which you can make accurate and simple analysis of the output of these products. This factor is of great importance to ensure the quality of the active substance and its galenical forms during preparation, storage and injection of patients. In addition, it is possible to avoid the use of complex measures are taken to stabilize the active ingredient in the herbal compositions.

Thus, the invention relates to crystalline and semi-crystalline and amorphous salts of valsartan.

The invention relates also to a solvate such as a hydrate, and polymorphic forms of the salts according to the invention.

The solvate, as well as the hydrates of the salts according to the invention may constitute, for example, semi-, mono-, di-, tri-, Tetra-, Penta-, exacerbate or hydrates, respectively. In the crystal lattice can be included used for crystallization solvents, such as alcohols, especially methanol, ethanol, aldehydes, ketones, especially acetone, esters, such as ethyl acetate. The degree of solvation or hydration during crystallization and subsequent stages of the process, obtained using a specific solvent or water, or direct the formation of free acid, as a rule, are unpredictable and depend on a combination of conditions, which implement the process, and the various interactions between valsartan and specific solvent, especially water. The corresponding stability of the formed crystalline or amorphous solid products in the form of a salt, solvate and hydrate, as well as corresponding solvate salts or hydrates of the salts must be determined by experimental means. Thus, it cannot be limited to only the composition of the chemical composition and stoichiometric ratio of molecules in the formed solid product, since under these conditions can be obtained as various crystalline solid and amorphous substance.

As the corresponding hydrates can be described preferred hydrates of the salts, because the water molecules in the crystal structure associated large intramolecular forces and therefore a necessary element in the formation of the structure of such crystals, some of which has very high stability. However, water molecules are also present in certain crystalline lattices that are related to the relatively weak intermolecular forces. Such molecules to a greater or lesser extent integrated in the formed crystalline structure, but have a low energy action. The water content of amorphous solids, such as crystalline hydrates, as a rule, it is possible to define precisely, but it largely depends on the drying and environmental conditions. In contrast, in the case of stable hydrates exist exact stoichiometric ratio between the pharmaceutical active substance and water. In many cases, these ratios do not fully coincide with the stoichiometric quantities, as a rule, they are less than theoretical values due to the presence of certain defects in the crystal is E. The ratio of organic molecules and water molecules in the case, if the water is more loosely coupled, may vary considerably, for example, can produce di-, tri - or tetrahydrate. On the other hand, in the amorphous solid substances, the water content in the structure of the molecule is not stoichiometric, this ratio may be stoichiometric only randomly.

In some cases it is impossible to determine the exact stoichiometric content of water molecules, as are formed of the layered structure, for example, in the case of alkali metal salts, especially potassium salts, so it is impossible to determine the exact number of included water molecules.

For a crystalline solid substances with similar chemical composition, the existence of different generated lattices represent the General concept of polymorphism.

It should be borne in mind that any found above and below in the present description reference salts refer also to the corresponding solvate such as a hydrate, and polymorphic modifications, as well as amorphous forms, if it is necessary and appropriate.

Most preferred are the tetrahydrate of the calcium salt of valsartan and uranyl magnesium salt of valsartan.

On the chart the x-ray diffraction on powders of these two hydrates of the salts, there are a large number of discrete reflections of x-rays and almost no signs of non-crystalline or amorphous fractions. Thus, the degree of crystallization of these have a certain level of hydration of the salts is unexpectedly high. From certain hydrates of the salts can also be grown relatively large crystals, which from the viewpoint of crystallography are single crystals. For such crystals is possible to determine the structure of the solid substance. This is carried out based on a computerized analysis of the reflection intensities measured using x-ray diffractometer.

This method of determining crystal structure allows normal conditions, such as high physical, chemical and enantiomeric purity of the tested crystals, to make a precise determination of the structure at the molecular or atomic level, namely the symmetry and size of the unit cells, the provisions of atoms and temperature coefficients, and taking into account the estimated amount of cells measured optical density of the photographic image in x-rays allows us to estimate the molecular weight. At the same time, the structure definition based on the photos in x-rays gives information about the quality of the product.

The unique properties of these two hydrates of salts due to their crystalline structure, which in the formation of these salts are formed through the merger of four or six-and water molecules with the molecule of valsartan. As a result, formed a nearly perfect three-dimensional crystal lattice. These two salts have a solubility in water, several times higher than the solubility of valsartan in the form of the free acid, that is the most unexpected, given the high melting temperature and enthalpy of melting, in which eight or five times higher than the corresponding values characteristic of the free acid. Extremely high quality of the crystal lattices of these two hydrates of the salts is the basis of chemical and physical stability of these two compounds.

As a hydrate salt of particular note is the tetrahydrate of the calcium salt of valsartan. In a closed sample container (closed Cup) at a heating rate of Tr=10·min-1it has a melting point 205±1,5°and the enthalpy of melting point 98±4 kJ·mol-1. At elevated temperatures the tetrahydrate of the calcium salt of valsartan is stable both in terms of the content of hydrated water, and the structure of the molecule. This melting point is the melting point of the hydrate, which can be measured only in a closed container for samples. For this purpose, used gold containers having a wall thickness of 0.2 mm; after making inthey samples of hydrate salt mass from 2 to 4 mg were sealed by cold welding. These gold containers have internal free volume of approximately 22 mm. The number of sample should be adapted to the volume of the pressurized container to the process of measuring the melting temperature could not be a considerable dehydration of the hydrates of the salts. The partial pressure of water at 205°With approximately 18 bar, therefore, in the measurement of the melting temperature in an open container by using DSC (Differential Scanning Calorimeter) is turning into anhydrous compound. Extrapolating the data measured at multiple heating rates (Tr=10, 20, 40·min-1), infinitely greater heating rate, you get a melting point of 213±2°and the enthalpy of melting point 124±5 kJ·mol-1. As a high melting point, and the magnitude of the enthalpy of melting, characterized by extremely high stability of the crystal lattice of the tetrahydrate of the calcium salt of valsartan. These two thermodynamic characteristics indicate the preferred physical properties of the product compared to the free acid, for which the two corresponding values are: melting point in a closed crucible 90°C, the enthalpy of melting of 12 kJ·mol-1 . These thermodynamic data along with x-ray data prove the high stability of this crystal lattice. This is the reason for the high physical and chemical stability of the tetrahydrate of the calcium salt of valsartan.

Measurement of the infrared absorption spectrum of the tetrahydrate of the calcium salt of valsartan, is included in the compressed tablet containing potassium bromide were allowed to identify the presence of the following bands with significant intensity (data are given as the inverse values of the wavelength, i.e. in wave numbers (cm-1)): 3750-3000 (st); 3400-2500 (st); 1800-1520 (st); 1500-1380 (st); 1380-1310 (m); 1290-1220 (w); 1220-1190 (w); 1190-1160 (w); 1160-1120 (w); 1120-1050 (w); 1030-990 (m); 989-960 (w), 950-920 (w); 780-715 (m); 710-470 (m). The intensity of the absorption bands are indicated as follows: (w) = weak, (m) = medium, and (st) = strong intensity. Measurement of the infrared spectrum was performed using ATR-IR spectroscopy (Attenuated Total Reflection-Infrared Spectroscopy) using devices like Spektrum BX firm Perkin-Elmer Corp., Beaconsfield, Buckinghamshire, UK.

The tetrahydrate of the calcium salt of valsartan has the following absorption bands (data are given as the inverse values of the wavelength, i.e. in wave numbers (cm-1)):

3594 (w); 3306 (w); 3054 (w); 2953 (w); 2870 (w); 1621 (st); 1578 (m); 1458 (m); 1441 (m); 1417 (m); 1364 (m); 1336 (w); 1319 (w); 1274 (w); 1241 (w); 1211 (w); 1180 (w); 1149 (w); 113 (w); 1106 (w); 1099 (w); 1012 (m); 1002 (w); 974 (w); 966 (w); 955 (w); 941 (w); 863 (w); 855 (w); 844 (w); 824 (w); 791 (w); 784 (w); 758 (m); 738 (m); 696 (m); 666 (m).

The intensity of the absorption bands are indicated as follows: (w) = weak, (m) = medium, and (st) = strong intensity.

The most intense absorption bands obtained by ATR-IR spectroscopy, are characterized by the following values (the data is given as the inverse values of the wavelength, i.e. in wave numbers (cm-1)): 3306 (w); 1621 (st); 1578 (m); 1458 (m); 1441 (m); 1417 (m); 1364 (m); 1319 (w); 1274 (w); 1211 (w); 1180 (w); 1137 (w); 1012 (m); 1002 (w); 758 (m); 738 (m); 696 (m); 666 (m).

The error for all bands of absorption, as measured by ATR-IR, is ±2 cm-1.

theoretical water content for the tetrahydrate of the calcium salt of valsartan is 13.2%. Using TeraScale TGS-2 (firm Perkin-Elmer Corp., Norwalk, Connecticut, USA) it was found that the water content is at 12.9%. On the basis of this was derived the General formula (C24H27N5O3)2-CA2+·(3,9±0,1)N2O.

The mass loss, i.e. the reduction of water content in the tetrahydrate in an anhydrous atmosphere N2depending on time, was measured by thermogravimetric method at a heating rate of 10 K·min-1. The results are presented in table 1.

Table 1
Temperature [°]Weight loss (or water loss) in %
250
500
750,5
1003,5
12510,2
15012,4
17512,8
20012,9
22512,9
25013,0
27513,2

Table 2 presents data characterizing the solubility of the tetrahydrate of the calcium salt of valsartan in mixtures of water-ethanol at 22°C.

Table 2
The concentration of ethanol in water (vol.%)The solubility of the tetrahydrate of the calcium salt of valsartan in g/l solution at 22°
09 (pH 7.4)
109
3014
5046

Table 3 presents a comparison of the solubilities in distilled water two most important salts according to the invention and of the free acid.

Table 3
Connectionrastvorimosti in g/l solution at 22°
Valsartan0,17
The tetrahydrate of the calcium salt of valsartan9
The uranyl magnesium salt of valsartan59

Determining other characteristics of the tetrahydrate of the calcium salt of valsartan carried out on the basis of the distances between the planes of the crystal lattice, which is measured using the diagram of x-ray diffraction on the powder. A chart of x-ray diffraction on powder were obtained using camera Genie (type FR 552 company Enraf Nonius, Delft, the Netherlands) on x-ray film in passing rays using Cu-Ka1-radiation source at room temperature. The analysis of images to calculate the distances between the planes of the crystal lattice was performed both visually and with the help of the device type Line-Scanner (firm Johansson Täby, S), while simultaneously determined the intensity of the reflection.

Preferably characterization eragiketa the calcium salt of valsartan is produced by measuring the distance d between the planes of the crystal lattice diagram-based x-ray diffraction, the following average values and the proper limits of error.

d [Å]: 16,1±0,3, 9,9±0,2, 9,4±0,2, 8,03±0,1, 7,71±0,1, 7.03, you±0,1, 6,50&x000B1; 0,1, 6,33±0,1, 6,20±0,05, by 5.87±0,05, 5,74±0,05, 5,67±0,05, 5,20±0,05, of 5.05±0,05, 4,95±0,05, 4,73±0,05, 4,55±0,05, 4,33±0,05, 4,15±0,05, 4,12±0,05, 3,95±0,05, 3,91±0,05, a 3.87±0,05, 3,35±0,05.

Listed below are the distances between the planes of the crystal lattice for the most intense reflections on the chart, the x-ray diffraction:

d [Å]: 16,1±0,3, 9,9±0,2, 9,4±0,2, 7.03, you±0,1, 6,50±0,1, by 5.87±0,05, 5,74±0,05, 4,95±0,05, 4,73±0,05, 4,33±0,05, 4,15±0,05, 4,12±0,05, 3,95±0,05.

The preferred method of checking the above average values of the distances between the planes of the crystal lattice and of the intensities measured on the charts, x-ray diffraction, were obtained by the camera Genie for this substance, consists in calculating these distances and corresponding intensities on the basis of comprehensive data on the structure of the single crystal. This definition of structure allows to obtain the unit cell parameters and the position of the atoms, which allows the processing chart of x-ray diffraction for solid substances by means of computer methods of calculation (program CaRine Crystallography, Universitè de Compiègne, France). Table 4 presents a comparison of these data, namely the distances between the planes of the crystal lattice and the intensity is of ivesta, representing the largest value bands for the tetrahydrate of the calcium salt of valsartan, measured with the camera, hinge and calculated for the single crystal.

7,71
Table 4
MeasuredCalculatedMeasuredCalculated
d [Å]Intensityd [Å]Intensityd [Å]Intensityd [Å]Intensity
16,10very strong16,02very strong5,67very poor5,658very poor
9,89strong9,88very strong5,20very poor5,199very poor
9,38average9,37averageof 5.05very poor5,040very poor
8,03weak8,02average4,95average4,943weak
weak7,70weak4,73weak4,724weak
7,03average7,01average4,55weak4,539weak
6,50averageof 6.49average4,33weak4,338weak
6,33weak6,33weak4,15strong4,150strong
6,20very poorto 6.19very poor4,12weak4,114weak
by 5.87average5,862average3,95average3,941average
5,74average5,738average3,35weak3,349weak

The invention relates to the crystalline tetrahydrate of the calcium salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine, i.e. crystalline solid substance, which is passed fully characterized experimental data and parameters obtained on the basis of x-ray analysis of the single crystal and diagrams of x-ray diffraction on the powder. A detailed presentation of theory underlying the methods of analysis x-ray diffraction on a single crystal, and method of processing, the study of crystal structure data and parameters given in the work of Stout and Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. Chapter 3 (1968).

Table 5 presents the data and parameters obtained in the study using x-ray patterns of the single crystal tetrahydrate of the calcium salt of valsartan.

The unit cell is described by six parameters, namely the constant a, b and C lattice and angles with the optical axis, i.e. α, β and γ. These settings determine the unit cell volume Vc. A detailed description of these lattice parameters are given in Chapter 3 operation Stout and Jensen (see above). The data obtained for the tetrahydrate of the calcium salt of valsartan on the basis of measurements of a single crystal, first of all atomic coordinates, isotropic thermal parameters, the coordinates of the hydrogen atoms and the corresponding isotropic thermal couples the points that show that there exists a unit cell of the monoclinic type containing four units of the formula CA2+valsartan2-·4H2Oh, which is formed from two independent crystallographic point of view units, each of which is located in two positions.

For this centrically space group P21, which was established on the basis of determination of crystal structure using x-ray analysis, the racemates not exist. This proves the enantiomeric purity of S-configuration crystalline tetrahydrate of the calcium salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine.

An important quality characteristic of pure active substance from the point of view of physical-chemical processes such as drying, sieving, grinding, and processes of preparation of galenical compositions, which are performed with the use of pharmaceutical excipients, namely, mixing, granulation, spray drying, tabletting, is the dependence of the water absorption or loss of water considered active substance from temperature and relative humidity environment. It is obvious that in the preparation of certain songs free and bound water is brought together with the ex is piantoni and/or add in the processed mass in accordance with the conditions of the preparation process of the composition. As a consequence, the pharmaceutical active substance is exposed to free water for long periods of time, the activity of which depends on temperature (partial vapour pressure).

Accurate data relating to this subject, produced using the isothermal measurements conducted during predefined time intervals and predefined relative humidity based on dynamic vapor sorption (device type DVS-1 firm Surface Measurement Systems LTD, Marlow, Buckinghamshire, UK). Table 6 shows data on weight change, i.e., about the absorption or loss of water for 4 h, depending on the relative humidity at 25°for sample tetrahydrate of the calcium salt of valsartan weight of 9.5 mg Data for the following cycles of change relative humidity: 40-90; 90-0; 0-90; 90-0% relative humidity:

Table 6
Relative humidity in %The absorption or loss of water in %Relative humidity in %The absorption or loss of water in %
400,04100,00
500,040-0,01
600,03100,00
700,02200,00
800,02300,00
900,00400,00
800,02500,00
700,02600,01
600,02700,00
500,0280-0,01
400,0290-0,02
300,010-0,02
200,01(initial value)0,00

The measurement error is specified by means of sorption based on thermogravimetry is approximately 0.1%. Therefore we can assume that in the considered conditions, which are real from the point of view of the pharmaceutical preparation of galenic forms for the tetrahydrate of the calcium salt of valsartan is not observed appreciable absorption or loss of water. Totally unexpected is the fact that tetrahydrate containing the crystal structure approximately 13% of bound water, is completely newoption ivim to water even in conditions of very high relative humidity. This property is crucial in the final stages of chemical synthesis, and implementation of all stages of the process of preparation of herbal compositions for various dosage forms. A very high stability is also extremely beneficial for patients, as it provides a constant bioavailability of the active substance.

The rate of dissolution of the calcium salt of valsartan at pH 1 and 4.5 and 6.8 exceed the corresponding values for valsartan.

Very high stability of the calcium salt of valsartan, first of all its tetrahydrate in water can be illustrated by tests on stability evaluation. The results of these tests indicate that the water content of the tetrahydrate of the calcium salt of valsartan remains constant when stored for four weeks at 40°C and 75%relative humidity as an open container and in a sealed ampoule.

Because calcium salt, especially its tetrahydrate has better crystalline properties specified salt can be directly subjected to pressing to give the corresponding compositions in tablet form.

You can also provide improved dissolution profile of the tablets. In the study of the dissolution profile was set the Leno, from filmtablette release 100% of the calcium salt, primarily tetrahydrate, occurs within 15 minutes

Among crystalline solid compounds of a new type, it is preferable to hydrate the magnesium salt of valsartan, first of all, the uranyl. Thermal characterization of the hydrate salt in the region of the melting temperature indicates certain chemical and physical instability. Therefore, studies of thermal characteristics depend on the conditions under which performs the measurements. In the closed Golden sample container, having an internal volume of approximately 22 μl, for sample weighing 2-4 mg at a heating rate of Tr=10·min-1the melting point of uranyl magnesium salt of valsartan is 132±1,5°C and the enthalpy of melting is 56±3 kJ·mol-1. The enthalpy of melting, which is approximately 5 times greater than the corresponding value for valsartan in the form of free acid, and the higher melting point of uranyl magnesium salt of valsartan evidence of stability of the crystal lattice of a new type at a temperature close to the room.

Optical rotation for uranyl magnesium salt of valsartan in 1%solution in methanol at 20°is [α]20D=-14°.

Measurement of the infrared absorption spectrum of uranyl magnesium salt of valsartan, is included in the compressed tablet containing potassium bromide were allowed to identify the presence of the following bands with significant intensity (data are given as the inverse values of the wavelength, i.e. in wave numbers (cm-1)): 3800-3000 (st); 3000-2500 (st); 1800-1500 (st); 1500-1440 (m); 1440-1300 (m); 1280-1240 (w); 1240-1190 (w); 1190-1150 (w); 1120-1070 (w); 1050-990 (w); 990-960 (w); 960-920 (w); 920-700 (m); 700-590 (w); 590-550 (w).

The intensity of the absorption bands are indicated as follows: (w) = weak, (m) = medium, and (st) = strong intensity.

Measurement of the infrared spectrum was performed using ATR-IR spectroscopy (Attenuated Total Reflection-Infrared Spectroscopy) using devices like Spektrum BX firm Perkin-Elmer Corp., Beaconsfield, Buckinghamshire, UK.

The uranyl magnesium salt of valsartan has the following absorption bands (data are given as the inverse values of the wavelength, i.e. in wave numbers (cm-1)): 3378 (m); 3274 (m); 2956 (m); 2871 (w); 2357 (w); 1684 (w); 1619 (st); 1557 (m); 1464 (m); 1419 (m); 1394 (st); 1374 (m); 1339 (w); 1319 (w); 1300 (w); 1288 (w); 1271 (w), 1255 (w); 1223 (w); 1210 (w); 1175 (m); 1140 (w); 1106 (w); 1047 (w); 1024 (w); 1015 (w); 1005 (w); 989 (w); 975 (w); 955 (w); 941 (w); 888 (w); 856 (w); 836 (m); 820 (w); 766 (st); 751 (m); 741 (st); 732 (st).

The intensity of the absorption bands are indicated as follows: (w) = weak, (m) = medium, and (st) = strong intensity.

The most intense the main band absorption, obtained using ATR-IR spectroscopy, are characterized by the following values (the data is given as the inverse values of the wavelength, i.e. in wave numbers (cm-1)): 3378 (m); 3274 (m); 2956 (m); 1619 (st); 1557 (m); 1464 (m); 1419 (m); 1394 (st); 1271 (w); 1175 (m); 1015 (w); 975 (w); 836 (m); 766 (st); 751 (m); 741 (st); 732 (st).

The error for all bands of absorption, as measured by ATR-IR, is ±2 cm-1.

theoretical water content of the uranyl magnesium salt of valsartan is to 19.1%. With United devices based on thermogravimetric method and infrared spectroscopy with Fourier transform (TG-FTIR, device type IFS 28, issued by companies Netzsch Gerätebau GmbH, Selb, Bayern and Bruker Optik GmbH, Karlsruhe), which, by means of infrared spectroscopy allows to measure simultaneously the mass loss and to identify lost in this component (release of water), it was found that the water content of 18.5%, which is in good agreement with theoretical value. For uranyl this corresponds to a molar ratio of 5.8±0,2 mol H2About per mole of the magnesium salt.

Table 7 provides data on water loss by uranyl magnesium salt of valsartan depending on the temperature obtained in an atmosphere of N2using the device for thermogravimetric thermal analysis at a heating rate of 10 K·min-1 . Based on the measurements of TG-FTIR method was established that weight loss is only caused by the release of water.

Table 7
Temperature [°C]Weight loss or release of water in %
250
501,2
754,2
10011,0
12516,7
15017,7
17518,3
20018,5
22518,7
25018,9
27519,3

The uranyl magnesium salt of valsartan has a solubility in distilled water at 22°equal to 59 g per liter of the solution when the pH value of 9.3.

The crystalline form of uranyl magnesium salt of valsartan accurately characterized by the distances between the planes of the crystal lattice, calculated on the basis of the lines in the picture x-ray diffraction on the powder. For this purpose apply the same methods of measurement and analysis, and for the tetrahydrate of the calcium salt of valsartan.

Preferably characterization of uranyl magnesium salt of valsartan is obtained on the basis of the values rasstoianiia planes of the crystal lattice d, average values are presented below along with the corresponding errors:

d [Å]: 19,7±0,3, 10,1±0,2, 9,8±0,2, 7,28±0,1, 6,48±0,1, 6,00±0,1, 5,81±0,1, 5,68±0,1, 5,40±0,05, 5,22±0,05, 5,12±0,05, 5,03±0,05, 4,88±0,05, 4,33±0,05, 4,22±0,05, 4,18±0,5, 4,8±0,5, 3,5±0,5, 3,6±0,5, 3,2±0.5 in.

The greatest intensity of reflections on the chart, the x-ray diffraction correspond to the following distances between the planes of the crystal lattice:

d [Å]: 19,7±0,3, 10,11±0,2, 9,8±0,2, 7,28±0,1, 5,81±0,05, 5,68±0,05, 5,03±0,05, 4,88±0,05, 4,18±0,05, 4,08±0,05, of 3.46±0,05.

The preferred method of checking the above average values of the distances between the planes of the crystal lattice and of the intensities measured on the charts, x-ray diffraction, were obtained by the camera hinge for the considered substance is in the calculation of these distances and the corresponding intensities on the basis of comprehensive data on the structure of the single crystal. This definition of structure allows to obtain the lattice parameters and the position of the atoms, which allows the processing chart of x-ray diffraction for solid substances by means of computer methods of calculation (program CaRine Crystallography, Université de Copié gne, France). Table 8 presents a comparison of these data, namely the distances between the planes of the crystal lattice and intensities representing the highest value bands for uranyl magnesium salt of valsartan, obtained by the camera hinge and on the basis of calculations of a single crystal.

Table 8
MeasuredCalculatedMeasuredCalculated
d [Å]Intensityd [Å]Intensityd [Å]Intensityd [Å]Intensity
19,7very strong19,66very strong5,12weak5,124weak
10,11averageto 10.09average5,03strong5,032very strong
9,83average9,84very strong4,88strong4,878very strong
7,28average 7,27average4,33very poor4,341weak
6,48weak6,46weak4,22weak4,215weak
6,00weak6,00weak4,18average4,181average
of 5.81average5,805average4,08average4,079average
of 5.68average5,676strong3,95weak3,946weak
of 5.40very poor5,391very poorof 3.46average3,463average
5,22weak5,217weak3,42weak3,428weak

The invention relates primarily to the crystalline uranyl magnesium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine, i.e. crystalline solid, which is completely characterized by the experimental data and the parameters, obtained on the basis of x-ray analysis of the single crystal. A detailed presentation of theory underlying the methods of analysis x-ray diffraction on a single crystal, and method of processing, the study of crystal structure data and parameters given in the work of Stout and Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. Chapter 3 (1968).

Table 9 presents the data and the parameters obtained in the study by x-ray crystal structure of uranyl magnesium salt of valsartan.

The unit cell is described by six parameters, namely the constant a, b and C lattice and angles with the optical axis, i.e. α, β and γ. These settings determine the unit cell volume Vc. A detailed description of these lattice parameters are given in Chapter 3 operation Stout and Jensen (see above).

The data obtained for uranyl magnesium salt of valsartan on the basis of measurements of a single crystal, first of all atomic coordinates, isotropic thermal parameters, the coordinates of the hydrogen atoms and the corresponding isotropic thermal parameters, suggests that there is an element of the ary monoclinic cell type, containing four units of the formula Mg2+valsartan2-· 6N2O.

For this centrically space group C21, which was established on the basis of determining the structure of the single crystal, the racemates not exist. This proves the enantiomeric purity of S-configuration crystalline uranyl magnesium salt of valsartan.

Table 10 shows data on weight change, i.e., about the absorption or loss of water for 4 h, depending on the relative humidity at 25°for sample uranyl magnesium salt of valsartan weight of 9.5 mg Data for the following cycles of change relative humidity: 40-90; 90-0; 0-90; 90-0% relative humidity:

Table 10
Relative humidity in %The absorption or loss of water in %Relative humidity in %The absorption or loss of water in %
400,0610-0,12
500,140-4,3
600,1910-0,79
700,2520-0,14
800,4130to-0.05
900,58400,02
800,32500,09
700,22600,14
600,14700,20
500,08800,28
400,16900,51
30-0,030-3,68
20-0,07(initial value)-0,01

The measurement error is specified by means of sorption based on thermogravimetry is approximately 0.1%. In these circumstances, which are real from the point of view of the pharmaceutical preparation of galenic forms, it was found that for uranyl magnesium salt of valsartan at a relative humidity of 20-80% may be reversible weak water absorption or loss of water. Totally unexpected is the fact that the uranyl containing the crystal structure approximately 19% of bound water, reversibly absorbs or releases water only at very high values of relative humidity and is relatively insensitive at moderate values of the relative humidity. This is the property that allows the development of simple physico-chemical process of obtaining and allows you to create a dosage form, which are the most preferred for patients.

Very high stability magnesium salt of valsartan, foremost of uranyl in water can be illustrated by tests on stability evaluation. The results of these tests indicate that the water content of the uranyl magnesium salt of valsartan remains constant when stored for four weeks at 40°C and 75%relative humidity as an open container and in a sealed ampoule.

Due to the fact that magnesium salt, especially uranyl has better crystalline properties specified salt can be directly subjected to pressing to give the corresponding compositions in tablet form.

In addition, it allows to provide an improved dissolution profile of the tablets. In the study of the dissolution profile was determined that from filmtablette release 100% of a magnesium salt, first of all, it uranyl, occurs within 15 minutes

In addition, the magnesium salt of valsartan, especially uranyl, has a preferred profile of the resistance of the seal.

Mixed calcium/magnesium salt of valsartan also possess valuable properties, for example, they can form a homogeneous crystalline conglomerates. They can, preferred is compulsory to apply in the preparation of galenical composition.

The rate of dissolution, which has Duklja salt of valsartan at pH 1, 4.5 and pH 6.8, exceed the corresponding values characteristic of valsartan.

The next object of the invention is a method of obtaining salts according to the invention.

Salts according to the invention, including amorphous or crystalline form, can be obtained as follows:

For the formation of salts of the process is carried out in the solvent system, in which two reactant, namely valsartan in the form of acid and the corresponding base, have sufficient solubility. For the implementation of crystallization or precipitation, it is advisable to use a solvent or mixture of solvents in which(Oh) formed salt is poorly soluble or completely insoluble. In one embodiment, obtaining the salts according to the invention is applied solvent in which the salt is soluble, and then to this solution add antibacterial, resulting in a gain of a solvent in which the resulting salt has a low solubility. In another embodiment, the salt crystallization is performed with the concentration of the salt solution, for example, by heating, optionally under reduced pressure, or by slow evaporation of the solvent, for example, at room temperature, or by adding seed crystals or by means of regulating the water project activity, required for hydrate formation.

As solvents can be used, for example, With1-C5the alkanols, preferably ethanol and isopropanol, as well as With1-C5dialkylamide, preferably acetone, and mixtures thereof with water.

Antibacterial for crystallization of salt can represent, for example, With3-C7alternately, especially acetonitrile, esters, primarily With1-C5-alkilany broadcast With2-C7alkenylboronic acid, such as ethyl - or isopropylacetate, simple di(C1-C5alkalemia) esters, such as methyl tert-butyl ether, or tetrahydrofuran, and C5-C8alkanes, primarily pentane, hexane or heptane.

To obtain a hydrate is used, first of all, the process of dissolution and crystallization or crystallization under conditions of trim of water.

The process of dissolution and crystallization differs in that

(I) carry out interaction valsartan and the appropriate base, preferably in a water-containing organic solvent,

(II) a solvent system concentrate, for example, by heating, optionally under reduced pressure, and by adding seed crystals or slow evaporation, for example, at room temperature, then initiate crystallization or p is ecipitation and

(III) allocate the resulting salt.

Used for the process of dissolution and crystallization water-containing system organic solvent preferably is a mixture of alcohols, such as ethanol, and water, or alkynylaryl, especially acetonitrile, and water.

The crystallization process by balancing used to produce hydrates, characterized in that

(I) valsartan and the corresponding base is added to water-containing organic solvent

(II) the solvent is concentrated, for example, by heating, optionally under reduced pressure, or by slow evaporation, for example, at room temperature

(III) the residue obtained after evaporation, balance the right amount of water through

(a) the suspension of the residue obtained by evaporation, preferably still warm and which still contains some water, in an appropriate solvent or

(b) trim the excess water in the solvent;

at stages a) and b) available or added water is present in the amount in which water is dissolved in an organic solvent and does not form an additional phase; and

(IV) allocate the resulting salt.

The solvent system used as containing the water of an organic solvent, preferred is a mixture of the corresponding alcohols, such as C1-C7the alkanols, especially ethanol, and water.

As a suitable solvent for equilibration is used, for example, esters, such as1-C7alkilany broadcast With1-C7alkenylboronic acids, especially acetate, or a ketone, such as dis1-C5alkylation, primarily acetone.

The process of equilibration is distinguished, in particular, that allows to obtain high outputs and has a high reproducibility.

When receiving a monobasic alkali metal salts of the present invention, generally formed of an amorphous form. At the same time can also be obtained in crystalline form and in the form of hydrates dibasic alkali metal salts and salts of alkaline earth metals according to the present invention from the corresponding solvents commonly used in the production process, such as esters, for example, With1-C7alkalemia esters With1-C7alkenylboronic acids, especially acetate, ketones, such as, dis1-C5alkylene, primarily acetone, With3-C7alternately, especially acetonitrile, or ethers, for example, di(C1-C5alkalemia) esters, such as methyl tert-butyl is a new ether, and tetrahydrofuran, or a mixture of solvents. Using the process of dissolution and crystallization or crystallization in terms of the water balance can be obtained in a reproducible manner defined hydrates are crystalline or polymorphic forms.

Getting UN-hydrated bestialitymovies salts of the present invention is preferably carried out in one stage, using an appropriate solvent, optionally mixed with Antibacterials. In this way receive a crystalline salt.

Typically, amino acid salts of the present invention receive in amorphous form.

Methods of obtaining salts are also objects of the present invention.

Such salts or hydrates of the salts according to the invention receives, for example, by neutralization of valsartan in the form of acid base, bearing the appropriate cation. Such neutralization is advisable to be implemented in the aquatic environment, for example, in water or in a mixture of water and solvent, in which valsartan more soluble than in water. Salts of weak bases can be converted into other salts or by treatment with strong bases, or by treatment with acid and subsequent neutralization other grounds.

Crystallization, first of all hydrates of salts of alkaline earth IU allow, carried out in water or in an aqueous medium consisting of water and at least one solvent which can be mixed or partially mixed with water, i.e., the polarity of which is not too small, for example, alkanol, such as methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl ethyl ketone, acetonitrile, DMF, DMSO. Alkananda fraction is approximately 10-90, or 20-70, preferably 30-50%. In the case of the use of higher alkanols less polar solvent may be present in lower concentrations. Due to the limited solubility of valsartan in the water process is often carried out in suspension or in solution, if valsartan soluble in the other components of the solvent.

According to one of embodiments, for example, to obtain the calcium salt of valsartan, an aqueous solution of valsartan is neutralized with a solution of calcium hydroxide at room temperature and the solution is kept for crystallization. According to a preferred variant of the method, the crystallization is carried out from a solvent mixture of water/ethanol, where the share of ethanol is approximately 30-50%. According to the most preferred option crystallization is carried out in a closed system using a low temperature gradient (preferably 1-2°s at 40° (C) in a solution containing 30 vol.% of ethanol.

In the preferred embodiment, it is possible to optimize the crystallization process, for example, to speed it up, by adding at least one seed crystal.

Salts according to the invention can be applied, for example, in the form of pharmaceutical compositions which contain the active substance, for example, a therapeutically effective amount of the active substance, optionally in combination with a pharmaceutically acceptable carrier, for example, inorganic or organic, solid or optional liquid pharmaceutically acceptable carrier suitable for enteral, e.g. oral, or parenteral administration.

The invention relates in particular to pharmaceutical compositions, primarily in the form of a solid dosage form, preferably for oral administration, optionally containing pharmaceutically acceptable carrier.

Such pharmaceutical compositions can be used, for example, for the prevention and treatment of diseases or conditions that can be alleviated through the blockade AT1-receptor, for example,

disease or condition selected from the group including

(a) hypertension, congestive heart failure, renal failure, especially chronic renal failure, restenosis after percutaneous Nutripro svetnoi angioplasty and restenosis after surgery, related coronary artery;

(b) atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renal failure, hypothyroidism, post-myocardial infarction (MI), coronary heart disease, hypertension, associated with age, family dyslipidemias hypertension, increased formation of collagen, fibrosis and hypertension arising after remodeling (antiproliferative effect of the combination), all these diseases or conditions associated with hypertension or linked;

(C) endothelial dysfunction with or without associated hypertension,

(g) the giperlipedemia, hyperlipoproteinemy, atherosclerosis and hypercholesterolemia and

(d) glaucoma.

The composition of the invention preferably is used to treat high blood pressure and congestive heart failure, and post myocardial infarction.

The person skilled in the art can select the appropriate standard model for testing using animals to assess therapeutic indications and positive impacts above and below in the present description.

Pharmaceutical actions that occur when entered and compounds from among the salts of the present invention or the combination of active substances according to the present invention, it is possible to demonstrate, for example, by appropriate pharmacological models known in the art. The person skilled in the art can select the appropriate standard model for testing using animals to assess therapeutic indications and positive impacts above and below in the present description.

These positive steps can be demonstrated, for example, model for testing, are described in G.Jeremic and others, J.Cardovasc. PharmacoL, 27:347-354, 1996.

For example, having great importance to the possibility of using salts or compositions of the present invention for the prevention and treatment of myocardial infarction can be identified using the following model to test.

The scheme experience

In an ongoing study as a model of acute myocardial infarction using chronic obstruction of the coronary artery (KAO) in rats. Experiments conducted on 5 groups of animals, which are subjected to a variety of the following treatments:

animals treated with placebo

- KAO + media

- KAO + salt of the present invention, optional

- KAO + salt of the present invention + component included in the composition.

During the study measured the following parameters:

- the size of the infarct

chamber size l of the first ventricle (LV)

- the density of the interstitial and perivascular collagen in the affected myocardium of the left ventricle

- protein content COL-I and COL-III in the affected myocardium of the left ventricle (by Western blotting)

- the cross-sectional area and the length of cardiomyocytes in the slices of the LV myocardium

- the concentration of renin and aldosterone in plasma

- the concentration of sodium, potassium and aldosterone in urine

blood pressure in conscious animals

- blood pressure in the left ventricle and the carotid artery have shot animals.

The method

The size of the infarct: Transverse histological sections of the left ventricle thickness of 6 μm dye dye tetrazolium nitrosolobus and recorded by a CCD-camera (camera on charge-coupled devices) type B/W XC-77CE (Sony). The resulting image is treated using a system image analysis type KS 300 (Carl Zeiss Vision) using specially developed for this purpose software (Porzio and others, 1995). One operator involved in the experience of "flying blind" in interactive mode determines the boundaries of the interventricular septum and on each slice of semi-automatically identifies the area of infarct, an area of unstained tissue of the ventricle. The program automatically calculates the number of geometric parameters for each component cutoff Zheludok is a, namely for the camera, partitions, the area of the infarct region of the myocardial wall of the left ventricle and a living wall of LV (Porzio and others, 1995).

Histology: Heart fixed in situ by the upward perfusion buffered 4%formaldehyde after the heart stops in systole, which is carried through i.v. injection of 0.5 m KCl. After fixing determine separately the mass of the left ventricle (LV) and free wall of the right ventricle; the greatest diameter of the left ventricle is measured using a compass. Designed for histology slices of the left ventricle stained with hematoxylin and eosin for qualitative analysis and quantitative assessment of the cross-sectional area of cardiomyocytes using a semi-automated procedure of image analysis. The accumulation of interstitial collagen in LV assess painted on Sirius red slices using a semi-automated procedure of image analysis (Masson and others, 1998).

The content of collagen in the affected myocardium of the left ventricle: the Fabric of the affected myocardium of LV homogenized, subjected to electrophoresis in SDS page-ordinator and electroblotting on the nitrocellulose. The blots treated with the primary antibodies, i.e. rabbit anticorodal to rat collagen type I or type II (company Chemicon). For detection of primary antibodies used secondary antibodies conjugated with alkaline phosphatase (for collagen type I or type peroxidase (collagen type II).

The chamber volume of the left ventricle: LV chamber Volume to determine hearts stopped in diastole (KCl) and fixed in formalin under hydrostatic pressure equivalent to the measured end-diastolic pressure in the left ventricle. For measuring the length of the internal cavity of the LV in LV immerse the measuring rod. The transverse diameters of the camera measure of LV on two transverse slices with a thickness of 1 mm, taken near the base and apex of the ventricle (Jeremic and others, 1996). The chamber volume is calculated by integrating equation, which includes the transverse diameter and the length of the inner cavity.

Systemic hemodynamics and hemodynamics of the left ventricle For measurement of systolic and diastolic blood pressure in the right carotid artery enter micromattic pressure (type Millar SPC-320)connected to a recording device (type Windograf, the company Gould Electronics). The pressure sensor is pushed into the left ventricle for measurement of systolic (SDLG) and end-diastolic (CDLI) pressure in the left ventricle, the first derivative of the pressure in the left ventricle over time (+dP/dt) and heart rate.

Non-invasive measurement of blood pressure: Systolic blood pressure and heart rate measured at two in the minds of rats using the cuff for tail (type Letica LE 5002).

The electrolytes, hormones in urine: Rats from which eljnosti placed into the cells for metabolism studies and collected within 24 h urine 1 ml of 6N. HCl. Measure the absorption of water. Contained in the urine catecholamines extracted on columns of type Bondelut 18 (firm Varian), share with GHUR (Apex-II 18, 3 ám analytical column 50×4.5 mm, firm Jones Chromatography) and quantitatively evaluated using an electrochemical detector (type Coulochem II, the firm ESA) (Goldstein and others, 1981). The content of aldosterone in plasma and urine and angiotensin II in plasma was determined by specific radioimmunoassay analyses (Aldoctk-2, DiaSorin and Angiotensin II, the firm Nichols Diagnostics). The content of sodium and potassium in the urine is measured by flame photometry.

The size of the sample:

To identify reliable biological differences enough to have in each of the processing groups of 10 animals subjected to analysis. For the final analysis selected only those rats the size of a heart attack is at least 10% of the area of the slice of the left ventricle.

It is known that endothelial dysfunction is a factor of decisive importance for vascular diseases. The endothelium plays a dual role, providing a source of various hormones or products with opposite actions: vasodilatation and vasoconstriction, inhibition or stimulation of growth, fibrinolysis or thrombogenesis, the production of oxidants or oxidizers. Genetically predisposed to hypertension animal is, with endothelial dysfunction, represent a suitable model for evaluating the effectiveness of cardiovascular therapy.

Endothelial dysfunction is characterized, for example, increased oxidative stress, leading to reduction of the level of nitric oxide, elevated levels of factors involved in coagulation or fibrinolysis, such as platinochloride inhibitor 1 (PAI-1), tissue factor (TF), tissue plasminogen activator (tPA), elevated levels of factors intercellular adhesion, such as ICAM and VCAM, elevated levels of growth factors such as bFGF (b-fibroblast growth factor), TGFb (b, a growth factor for T cells), PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor), all factors that cause associated with cell proliferation, inflammation and fibrosis.

The effectiveness of the treatment, for example, endothelial dysfunction can be demonstrated by the following pharmacological test:

Materials and methods

20-24-week-old male rats of the SHR received from the company RCC Ltd. (Fullinsdorf, Switzerland), contain in a room with controlled temperature and light regime, providing free access to feed for rats (Nafag 9331, Gossau, Switzerland) and tap water. The experiment is carried out according to the instructions NIH (national Institute of health)approved by the Board is binarnoi service of the Canton (Bew 161, Kantonales Veterinäramt, Liestal, Switzerland). All rats treated with the inhibitor of NO-synthase L-NAME (firm Sigma Chemicals), which is administered in drinking water (50 mg/l) for 12 weeks. The average daily dose of L-NAME, calculated on the amount of absorbed water is 2.5 mg/kg/day (range of 2.1 to 2.7).

Rats can be divided into 2 or 3 groups: group 1, control (n = 40); group 2, treatment salt of the present invention (n = 40); group 3 (test compounds), the processing component within the composition (n is, for example, 30). Drugs injected into the liquid for drinking. Pressor action of Ang II, used in a concentration of 1 mg/kg obtained for the control normotensive rats, may be reduced after treatment with salt according to the present invention (Gervais and others, 1999).

Every week, measure the weight of the body. For 3 and 2 weeks before the start of the experiment and after 2 weeks after administration of the medicinal product register systolic blood pressure and heart rate using plethysmograph with cuff covering the tail. Rats were kept in individual cells for metabolism studies), collect urine for 24 h before treatment and after 4 and 12 weeks and standard laboratory methods to measure the volume and analyzed for protein, creatinine, sodium is I and potassium. At the same time take samples of blood from retroorbital plexus (maximum 1 ml) for analyses on the content of creatinine, Na+and+.

After 4 weeks of kill ten rats from each group and allocate kidneys and heart for morphological analysis. The rest of the rats killed after 12 weeks. Measure the weight of the heart and kidneys. The last blood samples taken after 4 (morphometric analysis) and 12 (end of study) weeks containing 5% add use to assess the level of aldosterone using radioimmunoassay analysis using the kit for radioimmunoassay analysis of aldosterone (RIA) type DPC coat-a-count (firm Bühlmann, Switzerland).

Statistical analysis:

All results are presented as median values ±RMSE. Statistical analysis carried out using one-way analysis of variance, and then apply the analysis using multiple criteria Duncan and criteria Newman-Keuls for comparing the data from different groups. Statistically significant results are with high probability less than 0.05.

Accelerated regression of atherosclerosis, not accompanied by effects on the lipid levels in the serum, can be demonstrated, for example, on models with animals, according to the method described in NCAP and others, Biochemical and Biophysical Research Communications, 259, 414-419 (1999).

The fact that salt or combination of the present invention can be applied to achieve regression of atherosclerosis induced by a diet high in cholesterol can be demonstrated by using the model for testing, are described, for example, .Jiang and others in Br.J.Pharmacol. 104, 1033-1037(1991).

The fact that salt or combination of the present invention can be used for the treatment of renal failure, especially chronic renal failure, can be demonstrated using the model for testing, are described, for example, D.Cohen and others in the Journal of Cardiovascular Pharmacology, 32: 87-95 (1998).

Compositions of the present invention, which optionally can contain other with pharmacological activity of a substance, get a well-known method, for example by means of conventional mixing, granulation, coating, dissolving or lyophilization, and they contain from about 0.1 to 100%, preferably from approximately 1 to approximately 50% of liofilizatow, including up to 100% active ingredient.

The invention relates also to compositions containing salts according to the invention.

The invention relates also to the use of the salts according to the invention preferably for the preparation of pharmaceutical compositions intended primarily for the prevention and treatment of diseases or conditions that can be facilitated by the blockade AT1-receptor. They are used primarily to treat high blood pressure and congestive heart failure, and post myocardial infarction.

The invention relates also to the use of the agents according to the invention for the prevention and treatment of diseases or conditions that can be facilitated by the blockade AT1-receptor, which differs in that the patient, including humans, in need of such treatment is administered a therapeutically effective amount of the salt according to the invention optionally in combination with at least one composition for the treatment of cardiovascular diseases and related conditions and diseases listed above or below.

The invention also relates to combinations, such as pharmaceutical combinations containing salt according to the present invention, or in each case a pharmaceutically acceptable salt in combination with at least one composition intended for the treatment of cardiovascular diseases and related conditions and diseases listed above or below, or in each case its pharmaceutically acceptable salt. The combination of the agent according to the invention or in each case its pharmaceutically acceptable salts of the other compositions, intended for the treatment of cardiovascular diseases and related conditions and diseases listed above or below, are also objects of the present invention.

The combination may include, for example, the following composition selected from the group including:

(I) an inhibitor of HMG-Co-A reductase inhibitor or its pharmaceutically acceptable salt,

(II) an inhibitor of angiotensin converting enzyme (ACE) or its pharmaceutically acceptable salt,

(III) calcium channel blocker or its pharmaceutically acceptable salt,

(IV) inhibitor aldosteroneinduced or its pharmaceutically acceptable salt,

(V) aldosterone antagonist or its pharmaceutically acceptable salt,

(VI) dual inhibitor of angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) or its pharmaceutically acceptable salt,

(VII) endothelin antagonist or its pharmaceutically acceptable salt,

(VIII) a renin inhibitor or its pharmaceutically acceptable salt,

(IX) a diuretic or its pharmaceutically acceptable salt.

In the context of the present description, the notion of inhibitors of HMG-Co-A-reductase (also called inhibitors β-hydroxy-β-methylglutaryl-coenzyme-A-reductase) applies to such active substances that can be applied to lower levels of lipids, including cholesterol, in the blood is I.

Class of inhibitors of HMG-Co-A reductase inhibitor comprises compounds with different structural features. It should be noted, for example, compounds selected from the group including atorvastatin, tseriwastatina, compactin, dalvastatin, dihydrocoumarin, plugindomain, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, mevastatin, simvastatin and melastatin, or in each case their pharmaceutically acceptable salts.

Preferred inhibitors of HMG-Co-A-reductase are marketed agents, the most preferred are fluvastatin and pitavastatin or in each case their pharmaceutically acceptable salts.

Termination of the enzymatic degradation of angiotensin I, resulting in the formation of angiotensin II, with the help of the so-called ACE inhibitors (also called angiotensin-converting enzyme inhibitors) is a promising way to regulate blood pressure and also allows you to create a therapeutic method, suitable for the treatment of congestive heart failure.

The class of ACE inhibitors include compounds with different structural features. It should be noted, for example, compounds selected from the group consisting of alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, EN is prelat, fosinopril, imidapril, lisinopril, moltopren, perindopril, inapril, ramipril, spirapril, temocapril and trandolapril, or in each case their pharmaceutically acceptable salts.

Preferred ACE inhibitors are marketed agents, the most preferred are benazepril and enalapril.

Class CERs (calcium channel blockers) includes, first of all, the dihydropyridine (DHP) and compounds that are not related to BPH, such as CERs type of diltiazem and verapamil.

As CERs in the specified composition is preferably applied related to BPH compounds selected from the group including amlodipine, felodipine, residin, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, nimodipine, nimodipine, nisoldipine, nitrendipin and niguldipine, and not related to BPH compounds preferably are selected from the group including flunarizin, prenilamin, diltiazem, fendilin, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, their pharmaceutically acceptable salts. All of these CERs are used for therapeutic purposes, for example, as antihypertensive drugs, medicines for angina or antiarrhythmic drugs.

It is preferable CERs include amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimadi is in, nisoldipine, nitrendipin and verapamil, or, for example, depending on the specific CERs, its pharmaceutically acceptable salt. As BPH most preferred is amlodipine or its pharmaceutically acceptable salt, especially besilate. A preferred representative of the compounds that are not related to BPH, is verapamil or its pharmaceutically acceptable salt, especially the hydrochloride.

Inhibitor aldosteroneinduced is an enzyme that converts corticosterone to aldosterone by hydroxylation of corticosterone with the formation of 18-Oh-corticosterone and turning 18-Oh-corticosterone to aldosterone. Class of inhibitors aldosteroneinduced, which, as is well known, is used to treat hypertension and primary aldosteronism, includes both steroidal and nonsteroidal inhibitors aldosteroneinduced, the latter are the most preferred.

Preferred are inhibitors aldosteroneinduced, which go on sale, or inhibitors aldosteroneinduced, the use of which is permitted by the health authorities.

Class of inhibitors aldosteroneinduced includes compounds with different structures. It should be noted, for example, compounds selected from the group comprising non-steroidal aromatase inhibitors of anast the ozol, fadrozole (including (+)-enantiomer), and steroidal aromatase inhibitor exemestane, or in each case, if this gets possible, their pharmaceutically acceptable salts.

The most preferred non-steroidal inhibitor aldosteroneinduced is (+)-enantiomer hydrochloride fadrozole (U.S. patent 4617307 and 4889861) formula

Preferred steroid aldosterone antagonist is eplerenone formula

or

spironolactone.

Preferred dual inhibitor of angiotensin-converting enzyme/neutral endopeptidase (ACE/NEP) is, for example, omapatrilat (see EP 629627), fasidotril or fasidotril or, if applicable, pharmaceutically acceptable salts.

The preferred endothelin antagonist is, for example, bosentan (see EP 526708 A)and tezosentan (see WO 96/19459), or in each case their pharmaceutically acceptable salts.

The renin inhibitor is, for example, ones renin inhibitor, such as a compound of the formula

having the chemical name 2(S), 4(S)5(S), 7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxypropane)phenyl]octanamide. This representative compound specifically described in EP 678503 A. the Most is her preferred is its profumata.

As a diuretic it is possible to apply, for example, a thiazide derivative selected from the group comprising chlorothiazide, hydrochlorothiazide, methylclothiazide and chlorthalidone. Most preferred is hydrochlorothiazide.

Owning therapeutic efficacy of the number of active substances, comprising in combination according to the invention, it is possible to introduce preferably simultaneously or sequentially in any order, separately or in the form of a fixed composition.

Information about the structure of active substances indicated by their generic names or trademarks, you can find the modern edition of "The Merck Index" or in databases, e.g. Patents International (e.g., IMS World Publications). Their content related to this question are included in the present description by reference. The person skilled in the art can select the active substances and on the basis of these links to get them and test on the standard models in experiments in vitro and in vivo for their pharmaceutical properties and actions.

The relevant active substances or their pharmaceutically acceptable salts can also be used in the form of MES, such as hydrates, or include other solvents used for crystallization.

Compounds intended for inclusion in the composition, could the t to be in the form of pharmaceutically acceptable salts. If these compounds are, for example, at least one basic center, they can form acid additive salt. If there are additional major centre, if necessary, to obtain the corresponding acid salt additive. Compounds bearing an acid group (for example COOH) can also form salts with bases.

One of the variants of the present invention also refers to "the set of components, for example, consisting of components for the Association in accordance with the present invention, which can be entered independently or in the form of different fixed combinations, including different numbers of components, i.e. simultaneously or at different points in time. While the components of the kit can be entered, for example, simultaneously or after a certain period of time, i.e. at different time points and with equal or different time intervals for any component set. Preferably the time intervals chosen so that the effects of the disease or condition to be treated, in the case of a combination of components exceed exposure that can be obtained when using only one of any component.

In addition, the invention relates to intended for sale packaging, with the composition containing a series of the present invention together with instructions for simultaneous, separate or sequential use.

The dose may depend on various factors such as route of administration, species of animal, age and/or condition of the individual. By oral administration, the daily dose is from about 0.25 to 10 mg/kg, and for warm-blooded animal weighing approximately 70 kg, preferably from about 20 to 500 mg, preferably 40, 80, 160 and 320 mg in terms of free acid.

The invention is illustrated in the examples and under its scope are also new compounds listed in the examples, as well as their use and methods for their preparation.

The following examples serve to illustrate the invention and in no way limit the scope of the invention.

For example, the described method of obtaining dallievas salt of valsartan, first of all its hydrate. It should be noted dukelaw salt because of its high solubility in water. It should also be noted crystalline tetrahydrate dallievas salt of valsartan, having a melting point 135,0°C. According to the elementary analysis of certain samples of hydrate content of water, comprising 3,72 mole per mole dallievas salt. At room temperature, at high values of relative humidity is formed tetrahydrate, and at low values of relative humidity is formed besod the traveler Duklja salt.

Similarly receive the magnesium salt of valsartan, for example, in the form of an amorphous solid product containing 3,4% H2O. the glass transition Temperature represents the average value of a phase transition in the specific heat of 0.85 j·[g·0S]-1is 167°C. Not established the existence of the melting temperature. Both facts, namely, the existence of the glass transition and the absence of the melting temperature, together with the measured value changes specific heat indicate that the magnesium salt of valsartan almost 100% is amorphous. Based on the analysis using stereospecific chromatography, it was found that the enantiomeric purity of such amorphous magnesium salt is 83%.

Example 1:

Obtaining in situ tetrahydrate of the calcium salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine

21,775 g (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine are dissolved at room temperature in 300 ml of ethanol. By cautious addition of 300 ml of water the concentration of ethanol is reduced to 50 vol.%. Using a magnetic stirrer to this transparent slightly acidic solution (pH 4) is added slowly in small portions to 3.89 g of CA(Oh)2so that the pH value in any the time is no more than approximately 8. Due to the absorption of CO2from the air used CA(Oh)2contains trace amounts of caso3; therefore it is added a 5%excess. After adding the stoichiometric amount of CA(Oh)2the pH value becomes equal to approximately 6, and after adding excess increases to 7. The solution becomes turbid due to the presence of small amounts of fine, caso2which is removed by filtration through a folded filter cloth. After removing the alcohol component is a continuous crystallization contained in the solution of the product during its curing at room temperature. The process can be accelerated by using a flat pan in an air dryer with air circulation at 40°C. After concentration to approximately half of the volume of the alcohol content is reduced to about 10 vol.% and most of the product goes into the crystalline state. It is filtered, washed in a short period of time 10% vol. ethanol and dried at 40°until reaching constant weight. The result is the tetrahydrate of the calcium salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine.

It is established that the melting temperature of the tetrahydrate of the calcium salt of valsartan, receive the frame according to the method described in example 1, when heated at a rate of 10 To·min-1in a closed container for a sample having a small internal volume, 205°C and the enthalpy of melting is 92 kJ·mol-1.

The density of crystals tetrahydrate of the calcium salt of valsartan obtained according to the method described in example 1, measured using a helium pycnometer is 1,297 g·cm-3. This value is consistent with the value 1,298 g·cm-3theoretically calculated for single-crystal structure.

Optical rotation for the tetrahydrate of the calcium salt of valsartan obtained according to the method described in example 1, measured in 1%solution of methanol, is [a]20D=+1°.

The enantiomeric purity of hydrate salts obtained according to the method described in example 1, determine the method of stereospecific GHUR.

Stereospecific separation carried out on a chiral column (type Chiral AGP). It is established that the enantiomeric purity is its = 100%.

Listed below are the distances between the planes of the crystal lattice, calculated for the lines with the greatest intensity on the basis of the measurement pattern x-ray diffraction using a camera Genie for the considered sample of the tetrahydrate of the calcium salt in Sartana:

d [Å]: 16,27, 9,90, 9,39, 8,04, 7,71, 7,05, 6,49, 6,34, 6,2, 5,87, 5,75, 5,66, 5,20, 5,05, 4,95, 4,73, 4,55, 4,33, 4,15, 4,12, 3,95, 3,91, 3,87, 3,35.

On the basis of elemental analysis, the following data about the content of the elements present in the tetrahydrate of the calcium salt of valsartan, and water. Determination of the amount of water carried out after its removal at 130°C. According to the elementary analysis within error the product has the General formula (C24H27N5About3)-2CA2+·4H2O.

Found (%)Calculated (%)
C52,8252,83
H6.42 per6,47
N12,9112,83
O20,2020,53
Water13,2513,21
Ca7,037,35

Example 2:

Obtaining in situ uranyl magnesium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine

43,55 g of valsartan, ie [(S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine], dissolved at room temperature in 600 ml of 50 rpm. %aqueous solution of ethanol (obtained from absolute ethanol (see the right is nick Merck) and double-distilled using quartz water). Slightly cloudy solution becomes clear after adding 50 ml of 50%ethanol. To the specified weakly acidic solution having a pH value of 4, add using a magnetic stirrer in small portions is 4.03 g or 0,1M MgO (Merck R.A.). When the pH value increases to approximately 6. The process is carried out using a 10%excess, i.e. add 0.40 g of MgO. This excess does not dissolve completely and the pH value rises to 7.5. A small amount of residue is filtered over a folded filter cloth and washed with 50 ml of 50%ethanol.

United clear solution is carefully concentrated at 40°under stirring with a magnetic stirrer in a large pan for crystallization. As you approach the end of this process, the solution begins to thicken, turning into the vitreous gel. In this phase by pokropivny with a glass rod to induce crystallization in situ, which can be identified by the white color of the resulting crystalline solid product. The product is dried at 50°in an air dryer air circulation until reaching constant weight. The output of uranyl magnesium salt of valsartan is 53.7 g or 95% in terms of valsartan used in the form of free acid.

The measured melting point of the hydrate salt, is received according to the method described in example 2, namely uranyl magnesium salt of valsartan, at a heating rate of 10 K·min-1in a closed container with a small volume to sample mass of 2.24 mg, is 132°C and the enthalpy of melting is 64 kJ·mol-1.

The density of crystals of uranyl magnesium salt of valsartan obtained according to the method described in example 2, measured using a helium pycnometer, is 1,273 g·cm-3. This value is consistent with the value 1,256 g·cm-3theoretically calculated for single-crystal structure.

Optical rotation for uranyl magnesium salt of valsartan obtained according to the method described in example 2, measured in 1%solution of methanol, is [a]20D=-14°

The enantiomeric purity of hydrate salts obtained according to the method described in example 2, was determined by stereospecific GHUR. Stereospecific separation carried out on a chiral column (type Chiral AGP). It is established that the enantiomeric purity is its = 99,6%,

Listed below are the distances between the planes of the crystal lattice, calculated for the lines with the greatest intensity on the basis of the measurement pattern x-ray diffraction using a camera Genie for the considered sample of Gex the hydrate magnesium salt of valsartan:

d [Å] 19,78, 10,13, 9,84, 7,28, 6,00, 5,81, 5,67, 5,21, 5,04, 4,88, 4,21, 4,18, 4,08, 3,95, 3,46, 3,42.

Below is measured on the basis of elemental analysis of the content of the elements present in the uranyl magnesium salt of valsartan, and water. Determination of the amount of water carried out after its removal at 130°C. According to the elementary analysis within error the product has the General formula (C24H27N5O3)2-Mg2+·6N2O.

Found (%)Calculated (%)
51,0350,94
H7,006,95
N12,4512,38
025,0225,44
Water19,0819,10
Mg4,354,29

Example 3:

Getting hydrate dallievas salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine (3,5±1,0 mol H2O)

5 g of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine are dissolved with gentle heating in 11.5 ml of 2n. the potassium hydroxide solution and mixed with 320 ml of acetonitrile. The mixture is heated for 5 min before the temperature of the reflux distilled (formed a cloudy solution), stand without stirring for 3 days at room temperature (formation of seed crystals) and then incubated for 24 h at 0°C. the mother liquor is removed by decantation. The crystalline product is washed twice with acetonitrile and then dried in air for 36 h until constant weight. The result hydrate dallievas salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine (3,7 mol of water per mol of dallievas salt). The melting temperature in a closed sample container 135°C.

Elementary analysis: C24H27N5O3K2·3,72H2O, molecular weight 578,72

Found (%)Calculated (%)
49,9049,81
Nof 5.926,00
N12,1412,10
O18,5518,58
Water11,5811,58
To13,5013,51

A chart of x-ray diffraction was measured using a diffractometer company Scintag Inc., Cupertino, California, CA 95014, USA, using CuKα-source irradiation is Oia.

Below is the line of reflection and intensity characteristics of the most important lines to hydrate dallievas salt of valsartan, numerical data given in the form of 2θ°:

2θ°Intensity
4,6strong
8,8average
9,2strong
11,1weak
12,5weak
14,8strong
15,3weak
16,4average
17,8strong
18,2average
18,4average
18,9average
20,4average
21,1weak
21,3average
22,3weak
22,5strong
23.1average
23,9strong
25,6weak
26,6strong
26,9average
28,1average

Preference is sustained fashion are hydrates, characterized by peaks of moderate to severe intensity.

Example 4:

Getting dallievas salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine

25 g of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine are dissolved in 200 ml of ethanol. Add 50 ml of water, the solution is cooled to 0°and then mixed with 57.4 ml of 2n. solution of potassium hydroxide. The mixture is concentrated by evaporation on a rotary evaporator and evaporated again in the presence of toluene and acetonitrile and dried in high vacuum for 15 min at 50°C. the Product is dissolved in 290 ml of hot mixture of acetonitrile/water (95:5), is mixed with an additional portion of acetonitrile (110 ml), allowed to cool and carry the seed at about 30°C. the Mixture is allowed to stand for 4 days at room temperature and then subjected to vacuum filtration. The residue is washed with a mixture of acetonitrile/water (95:5) and dried in high vacuum at 80°C. the result dukelaw salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine in the form of a white powder. Melting point >300°C.

Elementary analysis: the Obtained product is gignosko the ranks and it is possible to balance in the air (C 24H27N5O3K2, 3,96 moles of H2O).

Found (%)Calculated (%)
49,1549,44
N6,026,04
N11,9112,01
OMT 19 : 1819,1
water12,2312,24
Tothe 13.413,41

Example 5:

Getting disodium salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine

1 g (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine dissolved in 50 ml of ethanol, mixed with 2.3 ml of 2n. the sodium hydroxide solution, concentrated by evaporation and the residue is evaporated in the presence of ethanol and ethyl acetate. The balance of white mixed with hot acetonitrile and subjected to vacuum filtration at room temperature. After drying overnight in a high vacuum at 80°get the disodium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine in the form of a white powder. The melting point is more than 260°With, at 295°occurs staining is brown.

Elementary analysis: the Obtained product (hygroscopic) can be balanced in the air (C24H27N5O3Na2, are 5.36 moles of H2Oh, molecular weight 576,05)

Found (%)Calculated (%)
of 49.7950,04
N6,516,60
N12,0012,16
O23,4423,22
water16,7516,76
Na8,097,98

Example 6:

Obtaining the magnesium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine

5 g of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine is added to the suspension containing 0,666 g of magnesium hydroxide in 20 ml of water. Add 40 ml of methanol, the mixture is then stirred for 2 h at room temperature and concentrate. The residue is dissolved in methanol, filtered through a coarse filter, concentrate and evaporated in the presence of acetonitrile. The product is stirred with hot acetonitrile, and subjected to vacuum filtration at room temperature and dried overnight in high vacuum p and 90° C. the result of the magnesium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine in the form of a white powder. Melting point: when heating the sample acquires a brownish color and turns into a glassy state at 300°C.

Elementary analysis: C24H27N5O3Mg, 0,89 moles of H2Oh, molecular weight: 473,85

Found (%)Calculated (%)
61,2660,83
N6,136,12
N14,8814,78
O13,13
water3,393,38
Mg4,745,13

Example 7:

Getting the calcium salt of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine

5 g of (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine is added to the suspension containing 0,851 g of calcium hydroxide in 20 ml of water, and then mixed with 200 ml of ethanol. The mixture is stirred for one hour at room temperature, concentrated by evaporation to dryness (repeated evaporation with Aceto what trilam), mix with hot acetonitrile (in the presence of trace amounts of ethanol and water) and subjected to vacuum filtration at room temperature.

0.95 g of salt is heated to a temperature of reflux distilled in 20 ml of a mixture acetonitrile/water (1:1), and the product is almost dissolved. Mixture is allowed to cool to room temperature, mixed with 20 ml of acetonitrile, and subjected to vacuum filtration and washed twice with a mixture of acetonitrile/water (1:1) and dried overnight in high vacuum at 80°C. melting point: above 300°C (decomposition).

Elementary analysis: C24H27N5O3Ca, 1,71 moles of H2Oh, molecular weight 504,39 (determination of water content is carried out after its removal at 150°).

Found (%)Calculated (%)
a 56.8857,15
N6,13between 6.08
N13,8913,88
O14,94
water6,126,11
CA7,947,95

Example 8:

Getting odnoklikovoy salt (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine

2G (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine are suspended in 20 ml of water and mixed with 2,296 ml of 2n. solution of potassium hydroxide. The mixture is stirred for 30 min and mixed with 50 ml of ethanol, resulting in a gain colorless solution. The mixture is concentrated by evaporation, the evaporated once more in the presence of acetonitrile and lyophilizers of tert-butanol (in the presence of trace amounts of water).

Elemental analysis (after equilibration in air). C24H27N5O3Ca, 1,69 moles of H2Oh, molecular weight 504,06 (determination of water content is carried out after its removal at 150°).

Found (%)Calculated (%)
57,3057,19
N6,356,27
N13,6113,89
O14,5814,89
water6,046,04
To7,727,76

Example 9:

Getting uranyl magnesium salt of valsartan using the process of equilibration of the water.

In the container for the mixture is mixed at room temperature to 1600 g of valsartan and 6820 g of isopropanol to the formation of the suspension and contribute in a glass tank volume 80 l equipped with a stirrer. Container for mixing washed what orciani isopropanol, the total number of which is 3919 g, and the washing solution is added to the basic mixture. After adding 3800 g of deionized water with stirring, the mixture becomes a homogeneous solution. Then add 156.3 g of magnesium oxide, suspended in 1520 g of deionized water, and suspendee add 1000 g of deionized water. With slow stirring at room temperature, the dissolution of magnesium oxide. The pH value of the resulting solution is approximately a 7.2. Adding small portions of 2.5 g of magnesium oxide, the pH value increases to approximately 8,3. The resulting mixture is turbid due to the presence of nerastvorim particles of unknown type, present in the magnesium oxide.

The resulting mixture was applied with the use of the filter has a cylindrical shape of the porous material in the enamel evaporator volume 35 and the glass tank and pickup tube is washed 885 g of isopropanol and 1122 g of deionized water. For moderate concentration in the evaporator create a vacuum corresponding to the initial theoretical value 89-100 mbar. When the coolant temperature of 45-50°and the boiling temperature of the mixture 37-40°To carry out the distillation of an aqueous solution of isopropanol in the total number of 13,66 kg lowering the pressure at which the distillation, to a final value of 10 mbar and while increasing the temperature to 65°With the total amount of distillate increases to 17,12 kg. content of the evaporator with stirring 9300 g of ethyl acetate, and then 14.9 g of uranyl magnesium salt of valsartan as the seed crystals. In conclusion, dissolved in a mixture even 6680 g of ethyl acetate and carry out cooling at room temperature under stirring. The mixing process continued for at least 24 hours Then the suspension is filtered through a filter funnel. The result is a moist residue on the filter. The evaporator washed 1171 g of ethyl acetate and wash the mixture is used to wash the precipitate on the filter. After drying, a certain part of the product on metal trays in a vacuum dryer at a pressure of 50 mbar and the temperature of the furnace 40°C for 6.5 h before reaching the constant weight gain dry substance.

Physical data, primarily chart of x-ray diffraction correspond to characteristics of uranyl magnesium salts obtained according to the method described in example 2.

Example 10:

Getting the tetrahydrate of the calcium salt of valsartan.

1600 g of valsartan and 7000 g of ethanol is stirred until the formation of the suspension in the container for mixing at room temperature and contribute to emalon the bath evaporator with a capacity of 35 litres, equipped with a mixer. Container for mixing washed with portions of ethanol with a total weight of 2000 and the washing solution is added to the basic mixture. After adding under stirring at 9000 g of deionized water, the mixture becomes a homogeneous solution. Then add 272 g of calcium hydroxide suspended in 1500 g of deionized water, and the suspension contribute 1300 g of deionized water.

With slow stirring at room temperature, the dissolution of calcium hydroxide. The pH value of the resulting solution is approximately 6,9. Adding small portions of 9.6 g of calcium hydroxide, the pH value increases to about 10.6. The resulting mixture is turbid due to the presence of nerastvorim particles present in the calcium hydroxide (calcium carbonate). The resulting mixture was applied with the use of the filter has a cylindrical shape of the porous material in the enamel evaporator with a capacity of 35 l glass tank and pickup tube is washed with a solution containing 1048 g of ethanol and 1000 g of deionized water. For moderate concentration in the evaporator create the vacuum corresponding to theoretical value of 100 to 120 mbar. When the coolant temperature of approximately 50°and a maximum boiling point 44°To carry out the distillation of water restoreuserprofile in the total number of 11,32 kg In the distillation process is spontaneous crystallization of dissolved salts. The suspension remaining after the distillation, cooled with stirring to about 5°C and stirred for approximately 16 h at 5°C. Then the suspension was filtered through a filter funnel. The evaporator is washed with a mixture containing 3600 ml of deionized water and 400 ml of ethanol, the mixture is cooled to 5°and washing the mixture is used to wash the precipitate on the filter. The result is a moist residue on the filter. After drying, a certain part of the product on metal trays in a vacuum dryer at a pressure of 50 mbar and the temperature of the furnace 40°C for 24 h until constant weight gain dry substance.

Physical data, primarily chart of x-ray diffraction, correspond to the characteristics of the tetrahydrate of the calcium salt obtained according to the method described in example 1.

Example 11:

Hydrate disodium salt of valsartan (2,4±1,0 mol H2(O):

50 ml of 2n. the sodium hydroxide solution is added dropwise at about 25°With the solution containing a 21.5 g of valsartan in 200 ml of isopropanol. Clear solution (pH approximately 7,2) was concentrated in vacuo at about 40°C. Amorphous residue disodium salt are suspended in 100 ml of isopropanol idleout water with the help of one stage of concentration in vacuum at approximately 40° With and degassing. The amorphous residue is suspended in 75 ml of acetone and 2 ml of water at approximately 40°C. When the temperature is approximately 25-30°add 200 ml of methyl tert-butyl ether, and the components, which initially are fatty substances, gradually transformed into a crystalline suspension. After stirring overnight at about 25°the suspension is cooled to 10°and after approximately 1 h and subjected to vacuum filtration to remove atmospheric moisture. Then rinse with 20 ml of methyl tert-builbot ether. Wet the filter cake is dried overnight at approximately 30 mbar and 30°C. the result is a colorless crystalline powder with low hygroscopicity. Elementary analysis: C24H27N5O3Na2, 2,44 mol H2About

Found (%)Calculated (%)
55,0355,07
N6,166,14
N13,3813,38
O16,63
Water8,40to 8.41
Na8,678,78

Negativety data chart, x-ray diffraction (reflection line and the intensity of the most important lines) crystalline hydrate disodium salt of valsartan, obtained by measurement using a diffractometer company Scintag Inc. Cupertino, California, CA 95014, US, using as a radiation source CuKα:

Intensity
the 4.7strong
9,1strong
13,3weak
13,7weak
the 15.6average
16,4average
17,2average
17,9average
18,7average
19,6average
21,3average
of 21.9average
22,8strong
24,0weak
24,8weak
25,5weak
26,5average
26,8weak
27,3weak
27,8weak
28,6weak
29,4weak
29,9average

Example 12:

Hydrate dallievas salt shaft is of Arcana (3,4± 1,0 mol H2(O):

of 6.9 g of potassium carbonate was added when about 25°With the solution containing of 21.7 g of valsartan in 150 ml of acetone and 20 ml of water. After stirring for 2 h at about 25°get an almost clear solution, which was concentrated in vacuo with a bath temperature of about 50°C. To the residue (29.3 g), which contains a residual amount of water, add 55 ml of acetone and within about 2 h at about 35°To make methyl tert-butyl ether in the total number of 250 ml. After stirring at about 25°With easy-to-stirring suspension of crystals is cooled to 10°With, stirred for at least 1 h, and subjected to vacuum filtration and washed with 20 ml of methyl tert-butyl ether. Wet the filter cake is dried overnight at a pressure of about 30 mbar and at a temperature of 30°C. the result is colorless with low hygroscopic crystalline powder.

Elementary analysis: C24H27N5O3K2, 3,42 mol H2About

Found (%)Calculated (%)
50,3750,28
Nby 5.875,95
N 12,2412,22
O17,92
Water10,7610,75
Tothe 13.413,64

A chart of x-ray diffraction obtained by measuring using a diffractometer company Scintag Inc. Cupertino, California, CA 95014, US, using as a radiation source CuKα.

Below is the line of reflection and intensity characteristics of the most important lines to hydrate dallievas salt of valsartan, numerical data given in the form of 2θ°:

average
2θ°Intensity
a 4.9strong
9,4strong
11,4weak
12,8weak
14,0weak
15,0weak
the 15.6weak
16,6average
18,0weak
18,5weak
18,9weak
20,7weak
a 21.5weak
22,0weak
22,7
23,3weak
24,1average
25,6weak
25,8weak
27,1average
29,4weak

Preferred hydrates are characterized by the presence of peaks of moderate to severe intensity.

Example 13:

Mixed calcium/magnesium salt of valsartan:

of 21.5 g of valsartan in 200 ml of isopropanol and 100 ml of water is stirred for approximately 3 h at about 25°With 1.5 g of magnesium hydroxide and 1.9 g of calcium hydroxide. Almost clear solution was concentrated in vacuo at about 50°C. To warm semi-solid residue, which contains a residual amount of water, add with stirring a total of 240 ml of ethyl acetate. After stirring overnight at about 25°With components that are initially located in a viscous state into a homogeneous suspension. The suspension is subjected to vacuum filtration and washed with 20 ml of ethyl acetate. Wet the filter cake is dried in vacuum at 30-40°C. Receive a colorless crystalline powder.

Chart x-ray diffraction corresponds to a conglomerate of tetrahydrate of the calcium salt and hexahydro is the magnesium salt, described in examples 1 and 2.

Example 14:

Mediterania salt of valsartan:

1.5 g of diethylamine added dropwise at about 25°With the solution containing 4.35 g of valsartan in 60 ml of acetone. After a short period of time starts slow crystallization. After stirring overnight, the crystalline product is subjected to vacuum filtration at about 20°C, washed with cold acetone and dried in vacuum at about 50°C. Receive a colorless crystalline powder.

Elementary analysis: C32H51N7O3, 0,1 mol H2O

Found (%)Calculated (%)
65,8265,84
N8,908,84
Nof 16.84Ls 16.80
Ocharged 8.52
water0,340,34

Below are the data on the chart, the x-ray diffraction (reflection line and the intensity of the most significant lines) for crystalline mediatraining salt

Intensity
the 4.7 weak
8,5strong
9,3strong
10,8strong
11,3weak
the 13.4strong
14,0average
14,3weak
14,9average
17,1average
17,4average
17,6average
18,3weak
19,0average
20,0weak
of 21.2average
21,6weak
22,4average
22,7weak
24,9average
25,2weak
27,0weak

Example 15:

Bitteprofilloschen salt of valsartan:

2.1 g of dipropylamine added dropwise at 25°With the solution containing 4.35 g of valsartan in 60 ml of acetone. After the onset crystallization temperature increase within a short period of time up to 40°and then go down for about 2 hours to room temperature. After stirring for whom the night crystalline product is subjected to vacuum filtration, washed with twice 15 ml of acetone and dried in vacuum at about 40°C. Receive the product in the form of crystalline granules.

Elementary analysis: C36H69N7O3, 0.05 m H2O

Found (%)Calculated (%)
67,7467,69
Hto 9.32was 9.33
N15,3615,35
Oof 7.64
water0,130,14

Below are the data on the chart, the x-ray diffraction (reflection line and the intensity of the most significant lines) for crystalline badeparadies salt

Intensity
8,5strong
8,9weak
9,4strong
10,0average
11,2weak
the 11.6weak
12,5weak
13,2weak
13,9strong
14,3weak is I
14,7weak
15,1weak
the 15.6weak
16,0weak
of 17.0average
17,9average
18,7strong
19.9weak
20,4weak
20,6weak
21,0strong
21,7weak
22,3average
23,1strong
24,5weak
25,5average
25,8weak
26,7weak
28,6weak

Example 16:

Bodybuildin salt of valsartan:

The solution containing 2.15 g of valsartan in 30 ml of acetone, mixed with 1.4 g of dibutylamine at about 25°C. After a short period of time starts crystallization and heavy suspension for about 1 hour and gradually diluted with 20 ml of isopropylacetate. After stirring for 4 h at about 25°the crystals are separated by vacuum filtration, washed with twice 10 ml of isopropylacetate and su is at in a vacuum at 50° C. the result is a colorless crystalline powder with low hygroscopicity.

Elementary analysis: C40H67N7O3and 0.5 mole of N2About

Found (%)Calculated (%)
68,2568,30
N9,799,75
N13,8913,94
O8,01
Water1,331,33

Below are the data on the chart, the x-ray diffraction (reflection line and the intensity of the most significant lines) for crystalline bodybuilding salt

Intensity
7,5very strong
8,5average
the 9.7strong
a 12.7strong
13,3weak
14,1strong
15,1average
16,4strong
17,7weak
18,2weak
19,5strong
to 19.9average
20,5average
21,4average
of 21.9average
22,2average
22,6average
23,0strong
23,7weak
24,2weak
24,7average
25,7average
26,0weak
26,5weak
28,8weak

Example composition 1:

The tablet obtained by direct pressing:

5
no.IngredientThe number of the party [g]The number on the core tablets [mg]
1The tetrahydrate of the calcium salt of valsartan134,2480
2Avicel PH-102 (microcrystalline cellulose)60,40836
3Lactose (crystalline)96,149457,3
4Crosspovidone7,5514,5
Aerosil 200 (silica, colloidal anhydrous)0,8390.5
6Magnesium stearate (vegetable)6,20863,7

Ingredient No. 1 sieved through a sieve with mesh size of 0.5 mm and mixed for 15 min in the device type with the turbula ingredients 1-6. Tablets are made by pressing using a press tablet press with one punch, the diameter of which is 8 mm

Example composition 2:

Tablets produced by roller compaction:

No.IngredientThe number of the party [g]The number on the core tablets [mg]
1The uranyl magnesium salt of valsartan40080
2Avicel PH-102 (microcrystalline cellulose)27054
3Crosspovidone7515
4Aerosil 200 (silica, colloidal anhydrous)7,51,5
5Magnesium stearate153
6Magnesium stearate7,51,5

The ingredient is No. 1-5 are mixed for 50 min and compacted using a roller compactor's adjuvant. The resulting strip is milled and mixed with the ingredient 6, pressed into tablets using a tablet press press with one punch, the diameter of which is 8 mm

1. Salt of valsartan selected from the group comprising odnonatrieva salt, odnoklikovoy salt, disodium salt, dukelaw salt, magnesium salt, calcium salt, mediatraining salt, badprogramming salt, bodybuilding salts or their hydrates, and mixtures of these salts.

2. Salt according to claim 1, in crystalline, partially crystalline or amorphous form.

3. Calcium or magnesium salt of valsartan according to claim 1.

4. The tetrahydrate of the calcium salt of valsartan according to claim 1.

5. Tetrahydrate according to claim 4, characterized in that

(I) has a chart of x-ray diffraction on the powder obtained with the camera, hinge, which is characterized by the following distances between the planes of the crystal lattice:

d [Å]: 16,1±0,3, 9,9±0,2, 9,4±0,2, 7.03, you±0,1, 6,50±0,1, by 5.87±0,05, 5,74±0,05, 4,95±0,05, 4,73±0,05, 4,33±0,05, 4,15±0,05, 4,12±0,05, 3,95±0,05; or

(II) has an ATR-IR spectrum contains absorption bands that correspond to the following inverse wavenumber (cm-1):

1621 (st); 1578 (m); 1458 (m); 1441 (m); 1417 (m); 1364 (m); 1012 (m); 758(m);738(m);696(m);666(m).

6. The uranyl magnesium salts valsartan who according to claim 1.

7. The uranyl according to claim 6, characterized in that

(I) has a chart of x-ray diffraction on the powder obtained with the camera, hinge, which is characterized by the following distances between the planes of the crystal lattice:

d [Å]: 19,7±0,3, 10,11±0,2, 9,8±0,2, 7,28±0,1, 5,81±0,05, 5,68±0,05, 5,03±0,05, 4,88±0,05, 4,18±0,05, 4,08±0,05, of 3.46±0,05; or

(II) has an ATR-IR spectrum contains absorption bands that correspond to the following inverse wavenumber (cm-1):

3378 (m); 3274 (m); 2956 (m); 1619 (st); 1557 (m); 1464 (m); 1419 (m); 1394 (st); 1374 (m); 1175 (m); 836 (m); 820 (s); 766 (st); 751 (m); 741 (st); 732 (st).

8. Sol according to any one of claims 1 to 7 in the form of MES.

9. Sol according to any one of claims 1 to 8 in the form selected from the group including

(I) crystalline form;

(II) a partially crystalline form;

(III) amorphous form and

(IV) polymorphic form.

10. Pharmaceutical composition having antagonistic activity against AT1-and receptor-containing compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or additive.

11. The method of obtaining salt according to claim 1, characterized in that valsartan and the corresponding base is added to the polar organic solvent, optionally containing water, the solvent is concentrated by heating to 40-50°when red is the necessity under reduced pressure or by slow evaporation, for example, at room temperature, obtained after evaporation of warm residue containing some water, suspended in an organic solvent such as ester alkenylboronic acid or ketone (a), or balance the excess water in the solvent (b), despite the fact that at the stages a) and b) available or added water is present in the amount in which water is dissolved in an organic solvent and does not form an additional phase, and allocate the resulting salt.



 

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< / BR>
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3 tbl, 3 ex

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