Crystals of solvate of quinolinecarboxylic acid derivative

FIELD: chemistry.

SUBSTANCE: invention was targeted at obtaining crystals of acetonitrile solvate of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (compound B), which is an intermediate compound in obtaining crystals of 6-fluor-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of III type (compound A). Compound B crystals are mostly precipitated by regulation of super-saturation during crystallisation involving acetonitrile as a solvent. Then compound A crystals of III type are obtained crystal desolvation.

EFFECT: increased efficiency of compounds.

6 cl, 4 dwg, 4 tbl, 4 ex

 

The present invention relates to a crystal of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid (hereinafter referred to as compound A) combined acetonitrile MES (hereinafter referred to as compound B), to a method for producing crystals of compounds and to a method for producing crystals of connection And type III using crystal compounds Century

Connection And has excellent antibacterial activity (see, for example, patent document 1) and sold on the market as a synthetic antibacterial agent. It is known that there are 3 types of crystals (type I, type II and type III) compounds And which are referred to as type I, type II and type III in accordance with decrease of the melting temperature, measured by differential scanning calorimetry (hereinafter referred DSC) (see, for example, non-patent document 1). In addition, certain solubility, absorption capacity, therapeutic effect, etc., determine the presence of crystals of type III (see, for example, non-patent document 1).

It is known that crystals of the compound, type I, type II and type III is obtained by crystallization from acetonitrile, however, conditions of crystallization is not known and the existence of a connection also has not been proven (see, for example, non-patent document 1).

Patent document 1: JP-A-1-294680.

Non-patent document 1: Kazuro Kakemi and others (7, "Chemical Structure, physicochemical properties and stability of Prulifloxacin", IYAKUHIN KENKYU, vol. 28 (1), pp 1-11 (1997).

The aim of the present invention is the provision of raw materials for obtaining crystals of connection And type III, which have great pharmaceutical and pharmacological action, as well as the way they are received.

Hitherto it was believed that the crystals connection And type III is obtained directly from the solution of the compound in acetonitrile, as well as crystals of type I and type II. However, the authors of the present invention have found that the crystals of type III can be obtained not by direct recrystallization, as crystals of type I and type II, and by desolvation crystal connection (see experimental examples 1-3 described below). The authors of the present invention have found that the crystals connections are an important intermediate compound for obtaining a medicinal product (crystals connection And type III).

In addition, the authors of the present invention conducted intensive studies on the method of selective deposition of crystals connections, as a result it was found that these objectives can be achieved by adjusting the concentration of swarnakumari (see experimental example 1 described below).

That is, the authors of the present invention have found that the crystals connection can be selectively precipitated by adjusting the concentration of swarnakumari during crystallization using acetonitrile as solvent and then after desolvation crystals can be obtained crystals connection And type III, which is the subject of the present invention.

The present invention includes:

(1) crystal connection, having diffraction peaks at least at 7.3 for°, 14,7°and 19.2° and 22.3° in the spectrum of the powder rentgenodiffraction;

(2) the method of producing crystals connection, characterized in that the crystallization was carried out from a solution of the compound in acetonitrile, and during the formation of crystallization nuclei concentration swarnakumari (g/100 g) is in the range from 2.15 to 2.36;

(3) the method of producing crystals connection, characterized in that the crystallization was carried out from a solution of the compound in acetonitrile, and during the formation of crystallization nuclei concentration swarnakumari (g/100 g) is in the range from 0.41 to 2.36, and

(4) the production method, described in paragraph (3), where the temperature of the solution during the addition of the seed crystal is 70°With or below.

In the present invention, the term "spontaneous formation of crystallization centers" oznake the formation of crystallization centers, which occurs spontaneously when crystallization was carried out without the seed crystal.

In the present invention, the term "concentration swarnakumari: AU (g/100 g)" means the degree of swarnakumari and corresponds to the following formula:

CX=C-Cs

where C (g/100 g) represents the weight of the connection (in terms of desolat)dissolved in 100 g of solvent.

Cs (g/100 g) is a saturating mass (in terms of desolat) compounds, dissolved in 100 g of solvent at the temperature during the spontaneous formation of crystallization centers or adding the seed crystal.

That is, if Sh>0, the solution is swarnakumari, and if CX<0, the concentration of the solution reaches saturation.

In the present invention, the term "number in terms of desolat" refers to the weight, the resulting mass transformation connection (MES) in a lot of desolate. For example, if the weight of a connection is 502,5 g, then the number in terms of desolat is 461,5,

In the present invention, the term "desolate" means the removal of solvent from the MES. For example, if water is the solvent, as an example of the conversion of the hydrate to the anhydrous form by removal of water molecules.

Figure 1 shows the spectrum of the x-ray powder is directii crystals connection And type I. On the vertical axis intensity (imp./sec. (cps), and the horizontal axis is specified angle diraction processes (2Θ ± 0,2°).

Figure 2 shows the spectrum of the powder rentgenodiffraction crystals connection And type II. On the vertical axis intensity (imp./sec. (cps), and the horizontal axis is specified angle diraction processes (2Θ ± 0,2°).

Figure 3 shows the spectrum of the powder rentgenodiffraction crystal compounds Century On the vertical axis intensity (imp./sec. (cps), and the horizontal axis is specified angle diraction processes (2Θ ± 0,2°).

Figure 4 shows the spectrum of the powder rentgenodiffraction crystals connection And type III. On the vertical axis intensity (imp./sec. (cps), and the horizontal axis is specified angle diraction processes (2Θ ± 0,2°).

Crystals connection can be obtained by precipitation from a solution in which the concentration of swarnakumari (g/100 g) during the spontaneous formation of crystallization nuclei is in the range from 2.15 to 2.36, and conducting crystallization from a solution of the compound in acetonitrile at suppressing the formation of crystals of the compound, type I and type II.

On the other hand, if the crystallization is carried out in terms of adding seed crystals, get crystals depending on the form of the seed crystals. So, during crystallization is here adding seed crystals, in contrast to crystallization, resulting in the spontaneous formation of centers of crystallization, the crystals connection can be obtained, even if the concentration of swarnakumari (g/100 g) is in the range from 0.41 to 2.36. It is preferable to add the seed crystals in a greater amount (not less than 0.004 g/100 g solvent)than usual (less than 0.004 g/100 g solvent). If you use a small amount of seed crystals added seed crystals become incentive and observed spontaneous formation of new centers of crystallization. However, if seed crystals are added in large quantities, mainly is the growth of the added seed crystals, and the spontaneous formation of crystallization nuclei is suppressed, whereby the formation of crystals of the compound, type I or type II can be reduced to the minimum level.

Crystals connections are exposed to solvent mediated transformation, therefore, the temperature of the solution during the spontaneous formation of crystallization centers and at the time of adding the seed crystal support at 70°With or below, preferably 67°With or below, more preferably 55°With or below.

In the present invention, the term "solvent mediated transformation" refers to the transformation of the crystal in another form in the presence of a solvent. For example, this means that when a predetermined temperature, the crystals of the compound In the solvent is transformed into crystals connection And type I.

Crystals connection And type III can be obtained by desolvation crystals connection Century. Desolvation can be performed by drying the crystals of MES in accordance with the traditional method; however, it is preferably carried out at 80°or lower under reduced pressure. In addition, as described above, the crystals of connection And type III are solvent mediated transformation, therefore, the temperature of the drying support at 70°With or below, preferably 67°With or below, more preferably 55°With or below.

More specifically, the crystals connection can be obtained, for example, as follows.

(1) stage of dissolution

Connection And dissolved in acetonitrile. Use such amount of the compounds a and acetonitrile, to obtain a given concentration of swarnakumari. The dissolution is preferably carried out under heating. The temperature of the heating is not limited, however, the dissolution is preferably carried out at a temperature close to the boiling point of acetonitrile. In addition, this stage is preferably carried out in a flow of inert gas, such as nitrogen or argon.

To remove undissolved substances is a, the solution can be filtered. To prevent the formation of crystals in the filtering process, the filtering is preferably carried out with the use of a filter provided with a heating device, and at high pressure. If the crystals are formed in the filtrate, these can be re-dissolved by re-heating the solution after filtering.

(2) stage cooling

The solution is cooled to precipitate crystals. It is necessary to control the temperature at which they begin to precipitate crystals, therefore, crystallization is carried out without the addition of seed crystals, requires special attention. After deposition of the crystals, the cooling rate is not limited, however, cooling is preferably at a rate of about 0,04°C/min or less, more preferably at a rate of about 0,22°C/min or faster. There is no specific limitation on the cooling temperature (temperature at the time of collecting the precipitated crystals), but it is preferably in the range from 0 to 45°S, more preferably from 0 to 25°C. the dwell Time after reaching the cooling temperature is not limited, but is preferably 30 minutes or more, more preferably 90 minutes or more. In addition, this stage should be undertaken in the Oka inert gas, such as nitrogen or argon.

(3) collection phase crystals

Precipitated crystals can be collected by a known method such as filtration or centrifugation, they can also be dried. Drying the precipitated crystals can be performed in the traditional way. To prevent solvent mediated transformation, the temperature in the drying process is set at 70°With or below, preferably at 67°With or below, more preferably at 55°With or below. In addition, it may desolvate crystals and in some cases formation occurs desolvation. To prevent desolvation, it is preferable to dry the crystals at ambient temperature or below and under reduced pressure. Crystals are used as raw material for the production of crystals connection And type III, as described below, therefore, they can be used without special drying.

(4) the Method of producing crystals of connection And type III

Crystals connection And type III can be obtained by desolvate crystals connection using the traditional method. Drying conditions are not limited, provided that the solvent can be removed from the crystal MES, however, drying is preferably carried out at 80°or lower and under reduced pressure. In addition, to prevent indirect solution is Telem transformation drying is carried out in the period from several hours to several tens of hours at a temperature of 70°With or below, preferably 67°With or below, more preferably 55°With or below.

Hereinafter the present invention will be explained in more detail with reference to the comparison examples, examples and experimental examples. Needless to say, the present invention is not limited to the following examples.

In this description thermal analyses (analysis of DSC and TG analysis) is conducted using a differential scanning calorimeter with a heat flux DSC-50 thermal gravimetric analyzer TGA-50 and system thermal analysis TA-50, produced by Shimadzu, with a heating rate of 10°C/min, and an analysis of the powder rentgenodiffraction spend on powder roentgendifractometric, which is Rigaku Denki Co. Measurement error of this unit is ±0,2°.

Example comparison 1

Crystals of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid type I (compound A)

Connection And receive in accordance with the description of the patent document 1. The compound (7.0 g) was dissolved by heating at 560 g of acetonitrile. The solution is gradually cooled and when the temperature of the solution reaches 25°add to 0.022 g Crist is low type I as the seed crystals, to cause precipitation of crystals, resulting in a gain of 1.80 g of crystals connection And type I. the Crystals are subjected to DSC analysis and determine the melting temperature (endothermic peak), which is in the range from 213 to 225°C (decomposition).

In non-patent document 1 forms crystals are referred to as type I, type II and type III in accordance with decrease of the melting temperature, measured by DSC analysis. Comparison of the results of DSC analysis of the crystals obtained in example for comparison 1, the example comparison 2 and example 3 showed that the crystals obtained in this example, comparison, correspond to crystals connection And type I.

Spectrum powder rentgenodiffraction for the obtained crystals are shown in Fig. 1. Crystals connection And type I have distinctive peaks at 12,5°, 16,5°, 18,0° and 24.0°.

Example 2 comparison

Crystals of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid type II (compound A)

Connection And receive in accordance with the description of the patent document 1. The compound (14.4 g) was dissolved by heating at 560 g of acetonitrile. The solution is gradually cooled, and when the solution temperature reaches 25°add 0.02 g of crystals of type II as the seed crystals, so in order to call the deposition of crystals, resulting gain 10.8 g of crystals connection And type II. The crystals are subjected to DSC analysis and determine the melting temperature (endothermic peak), which is in the range from 179 to 189° (transformation of crystals of type I) and from 213 to 225°C (decomposition).

Comparison of the results of DSC analysis of the crystals obtained in example for comparison 1, the example comparison 2 and example 3 showed that the crystals obtained in this example, comparison, correspond to crystals connection And type II.

Spectrum powder rentgenodiffraction for the obtained crystals are shown in Fig. 2. Crystals connection And type II have distinctive peaks at 9,9°, 18,0°, 20,3° and 24.6°.

Example 1

Crystals combined acetonitrile MES 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid (compound)

Connection And receive in accordance with the description of the patent document 1. The compound (15.0 g) was dissolved by heating at 560 g of acetonitrile, and conducting crystallization without the addition of seed crystals, resulting in a gain 11,99 g of crystals of compound (in terms of desolat). The crystals are subjected to DSC analysis and determine the melting temperature (endothermic peak), which is in the range from usually the temperature to 130° (Desolace), from 134 to 149° (transformation) and from 213 to 225°C (decomposition).

(1) weight Reduction if desolvation according to the analysis of DSC and TG analysis shows that the composition of the MES includes one molecule of acetonitrile and one molecule of compound A. After reducing the mass of crystals analyze powder rentgenodiffraction and receive a range that is identical to the spectrum of the crystals connection And type III. (2) the results of the analysis of the crystals obtained by keeping crystals connection And type III in saturated vapor acetonitrile, powder rentgenodiffraction coincide with the spectral data obtained for crystals of example 1. In addition, (3) the crystals of which a thorough drying completely removed the attached solvent analyze by gas chromatography and find acetonitrile. Next, (4) for crystallization do not use solvents other than acetonitrile. The results described above, etc., demonstrate that the crystals obtained in example 1 are combined acetonitrile MES connection (connection).

Spectrum powder rentgenodiffraction for the obtained crystals are shown in Fig. 3. Crystals connections have distinctive peaks at 7,3°, 12,6°, 14,7°, 16,5°and 19.2°, 22,3° and 25.8°. Particularly characteristic are the IKI when 7,3° , 14,7°and 19.2° and 22.3°.

Example 2

Crystals combined acetonitrile MES 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid (compound)

Connection And receive in accordance with the description of the patent document 1. Connection (3,93 g) is dissolved by heating in 561,5 g of acetonitrile. The solution is gradually cooled, and when the solution temperature reaches 25°add 0,449 g connections as the seed crystals, to cause precipitation of crystals, resulting in a gain 0,70 g of crystals of compound (in terms of desolat). Physical data (results of DSC analyses and rentgenodiffraction) coincide with the data obtained for crystals of example 1.

Example 3

Crystals of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid type III (compound A)

The crystals of the compounds In (9.8 g) is dried for 24 hours at 50°and reduced pressure (20 mm RT. Art.) to desolvate (yield 9.0 g). The crystals are subjected to DSC analysis and determine the melting temperature (endothermic peak), which is in the range from 134 to 149° (transformation) and from 213 to 225°C (decomposition).

Comparison of the results of DSC analysis of crystals obtained from the example of comparison 1, example of comparison 2 and example 3 showed that the crystals obtained in this example, comparison, correspond to crystals connection And type III.

Spectrum powder rentgenodiffraction for the obtained crystals are shown in Fig. 4. Crystals connections have distinctive peaks at 7,5°, 8,1°, 13,7°and 17.5° and 26.1°. This spectrum coincides with the spectrum of rentgenodiffraction crystals connection And type III, are shown in non-patent document 1.

Experimental example 1

The effect of the concentration of swarnakumari on the crystallization

The specified number of connections And dissolve in a given amount of acetonitrile, crystallization was carried out at various concentrations of swarnakumari and the obtained crystals analyzed by powder roentgendifractometric. The results are shown in table 1.

Table 1
Concentration of power (C)Difficult-adjustment crystalsTemperature during spontaneous formation of crystallization centers or adding seed crystals (°C)Solubility during spontaneous formation of crystallization centers or adding seed crystals (Cs)The concentration of swarnakumari (Cx)View OSA-Slavist the x crystals
2,14No.250,291,85B+I
2,44No.250,292,15In
2,40No.170,19of 2.21In
2,40No.14,30,162,24In
2,68No.270,322,36In
3,66No.00,073,59II
2,32III501,001,32B+I
1,80III250,291,51B+I
1,89III250,291,60In
2,00III250,291,71In
2,14III250,291,85In
of 2.21III250,291,92In
2,39III302,01In
2,41III250,292,12In
2,68III250,292,39In
2,73III250,292,44In
2,36In702,360,00B+I
0,70In250,290,41In
2,36In651,920,44In
of 1.34In450,790,55In
1,07In300,380,69In
1,61In450,790,82In
1,25In250,290,96In
1,43In300,381,05In
2,36In551,251,11In
1,52In25 0,291,23In
1,75In300,381,37In
1,75In250,291,46In
2,36In450,79of 1.57In
1,96In250,291,67In
2,10In300,381,72In
2,14In250,291,85In
2,36In300,381,98In
2,36In250,292,07In
2,41In250,292,12In

In table 1 I denotes the crystals connection And type I, II denotes the crystals connection And type II, III denotes the crystals connection And type III, and refers to the crystals of the compounds Century

As shown in table 1, the crystals connection And type III are obtained by crystallization with spontaneous formation of crystallization centers or even with the addition of cu the growth of connections And type III as the seed crystals. In this way receive only the crystals of the compound, type I and type II crystals of compound C. Therefore, it was found that the crystals connection And type III can not be directly obtained by recrystallization.

In addition, if the seed crystals is not added, the crystals connection is obtained if the concentration of swarnakumari (g/100 g) during the spontaneous formation of crystallization nuclei is in the range from 2.15 to 2.36. However, if the concentration of swarnakumari exceeds the upper limit of the interval, there is a mixture of crystals of the compound, type II, and if it is below the lower limit of the interval, there is an admixture of crystals connection And type I.

In addition, if you add the crystals connection as the seed crystals, get crystals connection, even if the concentration of swarnakumari (g/100 g) while adding seed crystals is in the range from 0.41 to 2.12. I believe that the preferential deposition of crystals connection is the result of suppressing the formation of other centers of crystallization (crystal compound, type I) due to the addition of the seed crystals.

Experimental example 2

Desolat crystals connection

Crystals of the compound In the subject of desolvation by drying at 80°C for 24 the aces under reduced pressure and the obtained crystals analyzed by powder roentgendifractometric. The physical characteristics of the obtained crystals coincide with the characteristics of the crystals obtained in example 3. Therefore, it was found that the crystals connection And type III can be obtained by desolvation crystal compounds Century

Experimental example 3

Selection of the solvent for crystallization

(1) By adding 3 ml of solvent to 50 mg of the compounds And determine soluble compound in this solvent, or not.

(2) to investigate the stability of the compounds in the solvent to the compound And add 2 times the volume (volume of solvent (ml)/mass of solute (g)) of the solvent, the mixture is kept 1000 minutes at 50°and then investigate the stability of the compounds by high performance liquid chromatography.

The results of the above studies (1) are shown in column *1 of table 2, and the results of the above studies (2) are shown in column 2 table 2.

Table 2
SolventSolubility (*1)Chemical stability (*2)
acetonitrileabout
petroleum etherx-
naphthax-
hexanex-
benzenex-
heptanex-
methylcyclohexanex-
toluenex-
xylenex-
p-Cemalx-
carbon tetrachloridex-
chloroformx-
trichloroethylenex-
tetrachlorethylenex-
diisopropyl etherx-
tetrahydrofuranx-
dioxanex-
disutility etherx-
diphenyl etherx-
the ethyl acetatex-
the acetatex-
isopropylacetatex-
acetonex-
methyl ethyl ketonex-
ethanolx-
methanolxx
2-propanolx-
isobutyl alcoholx-
1-butanolx-
glycerinx-
the cresolx-
formamidx-
pyridine▵ --
nitromethane▵ --
chloroacetonitrile▵ --
N,N-dimethylformamide▵ --
formic acid▵ x-
acetic acid▵ x-
aniline▵ x-
2-ethoxyethanolξ x-
phenolξ x-
acetic anhydrideξ x-

In column *1 table 2 "ξ", if the solvent has a boiling point of 130° (C or above, corresponds to the solvent in which the compound And restore is carried out at 130° And if the solvent has a boiling point of 130°or lower corresponds to the solvent in which the compound a is dissolved at boiling point (solvents that are suitable for crystallization), "▵" corresponds to the solvent in which the compound a is dissolved at ordinary temperature (solvents that can be used for crystallization), and "x", if the solvent has a boiling point of 130° (C or above, corresponds to the solvent in which the compound a is not soluble in 130°and if the solvent has a boiling point of 130°or lower corresponds to the solvent in which the compound a is not soluble at boiling point (solvents, which are not suitable for crystallization). In addition, in the column *2 table 2 "ξ" means that there are no peaks, no peculiar connection (product degradation is absent), "x" means that there is a peak other than the peaks of compound A (present product degradation), and "-" means not tested.

As shown in column *1 of table 2, for the crystallization of compounds In addition to acetonitrile can be used 7 more solvents, namely pyridine, nitromethane, chloroacetonitrile, N,N-dimethylformamide, formic acid, acetic acid and aniline. However, in the 3 types of plants is aricela, namely formic acid, acetic acid and aniline, there is a decomposition product of the compound And, therefore, 3 of the above types of solvents are not suitable for crystallization.

Accordingly, use of the other 4 types of solvents, and the specified number of connections And add to a given amount of solvent, dissolve, increasing the temperature to 78°With or above and the mixture is cooled to 25°C. the Precipitated crystals are filtered and analyzed by powder roentgendifractometric. The results are shown in table 3.

Table 3
SolventThe amount of
The amount of solute (g)The amount of solvent (ml)The crystal type
pyridine467I
nitromethane350II
chloroacetonitrile15I
N,N-dimethylformamide650I

In table 3, I denotes the crystals connection And type I, II denotes the crystals connection And type II.

As for Asano in table 3, when using the 4 studied species solvents cannot be obtained crystals perfect crystals connection And type I and type II.

Experimental example 4

Study of solvent mediated transformation

Crystals connection is added to the acetonitrile in an amount that is not less than the amount needed to obtain the concentration of swarnakumari at a given temperature (in a state where not all the added crystals are dissolved and a number of crystals is undiluted), stirred for 30 minutes, after which the crystals are filtered and analyzed by powder roentgendifractometric. The results are shown in table 4.

Table 4
temperature (°)View crystal
25Unchanged
40Unchanged
55Unchanged
67Unchanged
80The impurity crystals connection And type I

As shown in table 4, it was found that 67°With or below the transformation of the crystal connections to other crystals is not observed, however, at 80°With some soy is inane In transformed into crystals connection And type I.

Therefore, it is considered that it is preferable to choose such conditions of crystallization, in which the crystals connections do not leave in acetonitrile at a temperature of 70°or better, to the extent possible.

Industrial application

Crystals of compounds In accordance with the present invention represent an important intermediate compound for obtaining crystals of connection And type III. Using crystals connection can preferably be obtained crystals connection And type III.

In addition, the crystals connection can be obtained by adjusting the concentration of swarnakumari therefore, the method of obtaining this compound is an excellent way to obtain large quantities of medicinal substances (i.e. crystals connection And type III) high quality.

1. Crystal combined acetonitrile MES 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)-methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid, having diffraction peaks at least at 7.3 for°, 14,7°and 19.2° and 22.3° in the spectrum of the powder rentgenodiffraction.

2. The crystal according to claim 1, having diffraction peaks at least at 7.3 for°, 12,6°, 14,7°, 16,5°and 19.2°, 22,3° and 25.8° in the spectrum of the powder rentgenodiffraction.

3. A method of obtaining a crystal combined acetonitrile Sol is wool 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid, characterized in that the crystallization was carried out from the combined acetonitrile solution of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid, maintaining the concentration of swarnakumari (g/100 g) in the range from 2.15 to 2.36 during the spontaneous formation of crystallization centers.

4. A method of obtaining a crystal combined acetonitrile MES 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid, characterized in that the crystallization was carried out from the combined acetonitrile solution of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid, maintaining the concentration of swarnakumari (g/100 g) in the range from 0.41 to 2.36 while adding seed crystals.

5. The method according to claim 4, where the temperature of the solution during the addition of the seed crystals is 70°With or below.

6. A method of obtaining a crystal of 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid type III, characterized in that conduct desolvation crystals combined acetonitrile MES 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl-1-piperazinil]-4-oxo-4H-[1,3]Tiesto[3,2-a]quinoline-3-carboxylic acid.



 

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12 cl, 166 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the general formula (I): wherein R1 is chosen from group consisting of hydrogen atom (H), -(CH2)3-, -(CH2)4-, -CH2-S-CH2-, -S-CH2-CH2-; R2 is chosen from group consisting of nitrogen (N), sulfur (S) atom; n = 0 or 1; Z is chosen from group consisting of (C2-C10)-alkyl; R3 is chosen from group consisting of H; m = 0-2; R4 is chosen from group consisting of oxygen atom (O), -CH2-; R5 is chosen from group consisting of the following groups:

wherein R6 is chosen from group consisting of H, alkyl-(C1-C5)-alkoxyl; W is chosen from group consisting of -NH wherein each "alkyl" can be linear or branched and can be also cyclic or linear, or branched and comprises such cyclic residues, and each "aryl" comprises monocyclic aromatic group comprising 5-12 carbon atoms bound with one or some heteroatoms chosen from N, O or S atoms, and to their salts and solvates. Also, invention relates to a pharmaceutical composition, to a method for their synthesis and using compounds by claims 1-6. Invention provides synthesis of novel active compounds and pharmaceutical compositions based on thereof that possess affinity to serotonin receptors of subtype 5-HT1A.

EFFECT: valuable medicinal properties of compounds, improved method of synthesis.

10 cl, 4 tbl, 26 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention proposes use of 2-amino-7-bromo-4-acetylazo[5,4-b]indol depicted by formula: against hyperbaric and hematic hypoxia and protection of liver against carbon tetrachloride poisoning. Use of this compound reduces concentration of AlAT by a factor of 2.6 and that of AcAT by a factor of 1.67.

EFFECT: increased therapeutic activity.

3 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds of formula I , or stereoisomers, or pharmaceutically acceptable salts thereof, wherein Q is SO2; n = 2 or 3; each R1 and R2 is independently H, halogen, OR22 or C1-C6-alkyl; each R3 and R4 is H; each R5 and R6 is independently H or C1-C6-alkyl optionally substituted with phenyl or R5 and R6 together with together with atom to which they are attached may form 5-7-membered ring optionally containing N as the second heteroatom optionally substituted with COOH or C1-C6-alkyl; R7 is H; R7 is optionally substituted 8013-membered bicyclic or tricyclic ring system, containing N in bridge bond and optionally 1, 2 additional heteroatoms selected from N, S wherein substituent represent 1 or 2 halogen atoms; R22 is H or C1-C6-phenyl optionally substituted with C1-C6-alkyl. Compounds of present invention specifically bond to 5-HT6 receptor and are useful in pharmaceutical compositions.

EFFECT: compounds with specific bonding to 5-HT6 receptor.

10 cl, 3 tbl, 45 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and pharmaceutically acceptable salt thereof, wherein R1, R3, R4, R5, and R10 are independently H, halogen, C1-C4-alkyl, etc.; R2 is H, halogen, NO2, etc.; R6 is H, C1-C6-alkyl, C1-C6-alkoxy-substituted C1-C4-alkyl, etc.; R7 is H, C1-C4-alkyl or C2-C4-alkenyl, optionally substituted with halogen; R8 and R9 are H, R11 and R12; meanings of the rest substituents are as define in specification.

EFFECT: new compounds with value biological properties and useful as drug having activity in relates to progesterone receptor.

15 cl, 3 tbl, 80 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to bicyclic 1,4-piridotiazine-1,1-dioxides of general formula I wherein R1 is chlorine or fluorine; R2 is linear or branched alkyl, cycloalkyl, optionally reduced aryl or heteroaryl, etc. Method for production of said compounds includes reaction of acyclic sulfones with primary alcohols, preferably in presence of inorganic or organic such as carbonates or alkali metal hydroxides tertiary organic amines or base mixtures, preferably in aprotic bipolar media without solvents, or mixture thereof with water.

EFFECT: safe method for production of new compounds useful as drugs.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: medicine.

SUBSTANCE: group of inventions concerns medicine and can be applied in treatment of bacterial infections caused by gram-positive bacteria. The methods involve administration of dalbavancin for treatment of bacterial infections, particularly of gram-positive bacterial infections of skin and soft tissues. Dosage schemes include administration of dalbavancin once a week, which would sustain therapeutic drug level in plasma for at least 1 week. The claimed pharmaceutical compositions include single dalbavancin dose sufficient for sustaining therapeutically effective level of dalbavancin in plasma.

EFFECT: prolonged therapeutic effect against gram-positive bacterial infection.

86 cl, 13 dwg, 17 tbl, 10 ex

FIELD: medicine; urology.

SUBSTANCE: method includes making a diagnosis, allocating originators from the primary and secondary centres of patient's infection, and, after definition , using cultural method, of their sensitivity to the most effective etiotropic preparation, injecting it to a patient. After taking the blood from the patient, separating it into plasma, suspension erythrocytes and phagocytes by means of consecutive rotation with the rate of 2100 rpm for 10 minutes, cooling them preliminary to the temperature of +5°C, the method further includes deleting toxic blood plasma and replacing, in peer quantity, with Ringer solution and, with the suspension of erythrocytes entered into this solution, driply parenterally injecting in a vascular bed of a patient. The suspension of phagocytes, after being irradiated with emission of helium-neon laser of λ=0.63 mcm for 10-15 minutes power to 15 MW, is saturated with a solution of etiotropic ofloxacin preparation in a dose of 400 mg and, being sustained for 30 minutes, the solution obtained is injected parenterally intravenously to a patient. Nifuratel is injected perorally to a patient in a dose of 400 mg. A course comprises 12 procedures daily.

EFFECT: raised efficiency of treatment; reduced terms of treatment and decreased by-effects.

2 ex

FIELD: medicine.

SUBSTANCE: essence of the invention lies in a composition which, after introduction to an individual, is capable of inducing a humoral immune response at the given individual the humoral immune response performing bactericidal effect against two or three of supervirulent rows of generations A4, ET5 and a number of generations of the 3rd serogroup in N.meningitidis. of an external membrane. Five albuminous antigens are used, i.e. (1) protein "NadA"; (2) protein "741"; (3) protein "936"; (4) protein of "953" and (5) protein "287".

EFFECT: development of a vaccine against two or more rows of supervirulent meningococcus generations.

29 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is intended for preventive treatment of nosocomial peritonitis in patients with already developed peritonitis, after applying laparostomy. Stage-by-stage sanation of an abdominal cavity is performed introducing at each sanation, 400 ml of a preparation of bacteriophage active against a potential originator of nosocomial peritonitis. Daily, before putting off laparostomy, 2 times a day 200 ml of the same preparation of bacteriophage is introduced into a gastroenteric tract, at a colon lesion it is introduced through a probe, at a lesion of the top department of a gastroenteric tract through rectum. Additionally, kypherone rectally to all patients in the quantity of 1 suppository 2-3 times a day for 5-10 days.

EFFECT: effective preventive treatment of nosocomial peritonitis due to complex etipathogenic influences on development of infectious process.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of bis(4-alkylaminopyridine-1) alkanes of formula I where R1 -s linear or branched alkyl, cycloalkyl or arylalkyl groups having from 4 to 18 carbons, preferably from 8 to 12 carbons, ideally - normal octyl, R2 - linear or branched alkylene groups having from 4 to 18 carbons, preferably from 8 to 14 carbons, ideally - 1,10 decandyl, X1, X2 - halogenanions (identical or diverse): fluoride-, chloride-, bromide-, iodideanions, ideally - chlorideanions through interreacting of 4-alkylaminopyridine of formula II with disubstituted alkylene of formula III X1-R2-X2 in a solvent at increased temperature with mole ratio of formula II compound to formula III compound equals 2:1, the process is carried out in anoxic environment, acetic acid or its mixture with water is used as a solvent, meanwhile the compound of formula II is treated with the compound of formula III in gradual and continuous way or portionwise, ensuring the reaction at temperature ranging from 90° to 130°C, ideally from 100 to 105°C.

EFFECT: preparation of bis(4-alkylaminopyridine-1) alkanes of high quality with higher yield at essential saving of expandable materials.

6 cl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention claims application of starches substituted by quarterly ammonium groups with substitution degree of 0.4 to 3.0 with the help of a linker, in infection diseases treatment. Suppression of 1 type herpes virus replication by the claimed starches is demonstrated, in comparison to zero antivirus effect of non-modified starches. Minimal inhibiting concentration for staphylococci and mycobacteria is 5-60 g/l.

EFFECT: efficient infection disease treatment by the claimed starches.

5 cl, 7 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: mentioned medicinal preparations (versions) include immunogenic protein or nucleic acid, coding the corresponding immunogenic protein (the sequences are presented in sequences list). Medicinal preparations, based on immunogenic protein or protein coding nucleic acid, are used in immunogenic formulation for humoral immunity induction, applied as pharmaceutical means. The invention also covers method of infectivity neutralisation of mentioned bacteria and method of patient immunisation against Chlamydia trachomatis infection by applying immunogenic compositions.

EFFECT: applying antigens and immunogens, identified by the invention, provides producing of more effective vaccines, diagnostic and treatment preparations.

7 cl, 162 dwg, 2 tbl, 44 ex

FIELD: medicine.

SUBSTANCE: invention refers to anti-infective materials (agents) and methods of production thereof, characterised by biocompatibility with animal or human body liquids and tissues. Invention concerns method of production of anti-infective agent, production of anti-infective agent implying modification of inorganic mineral with silico- and alumooxycompounds, namely, Na-shaped bentonite, inorganic metal salts in polar solvent, followed by bentonite keeping in salt solution, isolation of promodified bentonite from solution and drying at temperature not higher 100°C. Before being modified bentonite is enriched with Na+ ions through processing with 3-10% aqueous solution of chloride sodium with following washing and filtering of produced semiproduct thereafter modified by 10-20% inorganic metal salts solution represented with silver nitrate or copper sulphate. Modified bentonite is kept in specified salt solutions within 12-24 hour. Then promodified bentonite is cleared from sodium salts through washing and filtration. After being dried made agent is milled to particle dispersion 20-150 nm. Thus inorganic mineral are processed with specified solutions in ratio, weight fraction bentonite:solution, as 1: (10-40).

EFFECT: production of agent with higher anti-infective efficiency using simple and cheap methods and materials.

7 cl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new nucleoside analogues characterised as inhibitors of purinephosphoribosiletransferase, purinenucleosidephosphorylase, 5 '-methylthioadenosinephosphorylase, 5 '-methylthioadenosinenucleosidase and/or nucleosidehydrolase and can be applied for treatment of malignant neoplasm, bacterial infections, protozoal infections, T- cell mediated diseases. In formula V is selected of CH2 and NH, and W is selected of NR1 and NR2; X is selected of CH2 and CHOH in R or S - configurations; Y is selected of hydrogen and hydroxy; Z is selected of hydrogen, halogen and hydroxy, SQ and Q where Q is optionally substituted with halogen C1-C6alkyl or benzyl group; R1 is radical of formula ; R2 is radical of formula ; A is selected of N, CH; B is selected of OH, NH2 and halogen; D is selected of NH2 and hydrogen; E means N; G is selected of CH2 or G is absent. Invention also refers to based pharmaceutical composition, methods of disease or condition treatment requiring inhibition of purinephosphoribosiletransferase, purinenucleosidephosphorylase, 5 '-methylthioadenosinephosphorylase, 5 '-methylthioadenosinenucleosidase and/or nucleosidehydrolase, and to application of invention compounds for medical product preparation.

EFFECT: products are characterised with increased efficiency.

30 cl, 6 tbl, 19 dwg, 51 ex

FIELD: medicine.

SUBSTANCE: group of inventions concerns veterinary microbiology and immunology. Method of vaccine production includes cultivation of strain B.necrophomm "0-1" "ВИЭВ" on nutrient medium, inactivation with formalin, biomass isolation from culture fluid by centrifugation, centrifugate isolation and exotoxin ultrafiltration concentration to protein content 5.5-6.0 mg/ml (by Lowry). Exotoxin B.necrophomm of molecular weight 18000-20000 D is produced. It is added with formalin solution to end concentration 0.4% and inactivated within 15 days. Formalin inactivated exotoxin is mixed with oily adjuvant at the following component proportions (mass%): formalin inactivated exotoxin B.necrophorum - 60.0-67.0, oily adjuvant - 33.0-40.0. Then produced suspension is homogenised and end vaccine is packed up. A vaccine is injected intradermally in single or twice dosage 0.2-0.4 ml. Invention enables to simplify method of production of highly effective vaccine, to produce vaccine of reactogenity, as well as to lower vaccination dose and increase convenience of introduction.

EFFECT: development of effective method of necrobacteriosis vaccination in veterinary science.

10 cl, 4 ex

FIELD: medicine, dermatology.

SUBSTANCE: atopic dermatitis is suggested to be treated using "day" tranquilliser grandaxin (tofisopam) and anti-depressant - selective inhibitor of serotonin re-uptake trittico (trazodone). Invention ensures prolonged remission period during a year and longer for 75.6% of patients against similar index of 45.4% for patients with standard scheme of treatment.

EFFECT: increased efficiency of treatment.

5 tbl

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