Method of producing non-hydratable crystal form

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a non-hydratable crystal form (polymorph A) of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-[4-cyano-2-methyl-6-[(methylamino)-carbonyl]phenyl]-1H-pyrazole-5-carboxamide (compound 1), which is characterised by an X-ray diffraction pattern having reflection angle peaks given in the claim. According to the invention, the method involves heating a hydratable crystal form of compound 1 (polymorph B), having X-ray diffraction characteristics given in the claim, at temperature from about 40°C to the boiling point of the solvent of the mixture, which contains a solvent selected from a group consisting of water, n-heptane, 1-chlorobutane, toluene, 1-butanol and 1-pentanol.

EFFECT: obtaining a stable polymorph A of compound 1, which enables to obtain stable solid insecticide compositions.

15 cl, 2 dwg, 7 ex

 

The SCOPE of the INVENTION

This invention concerns a method of obtaining degidratirutego crystalline forms of gidratirutmi crystalline form of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide.

BACKGROUND of the INVENTION

PCT patent publication WO 04/067528 and WO 06/062978 disclose methods for the preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide (compound 1), and the use of this compound as an insecticide. Document WO 06/062978, in addition, discloses the purification of compound 1 by recrystallization from 1-propanol.

In the prior art it is well known that certain crystalline compounds may exist as polymorphs. The expression “polymorph” refers to a specific crystalline form of chemical compounds, which can crystallize in different crystal forms, which have different structures and/or conformations of the molecules in the crystal lattice. Although polymorphs can have the same chemical composition, they may also vary in composition due to the presence or absence of cocrystallization water or other molecules, which can be weakly or strongly coupled to the lattice. Polymorphs may differ such chemical, physical and biological properties of the mi, as the form of crystals, density, hardness, color, chemical stability, melting point, hygroscopicity, suspenderbelt, dissolution rate and bioavailability.

To date it has not been possible to provide the appearance and the number of crystalline polymorphs of any of the individual compounds and specific physico-chemical properties of any specific polymorph. It is important to emphasize that thermodynamic stability and potentially different behavior after the introduction in living organisms cannot be determined in advance.

A BRIEF DESCRIPTION of the INVENTION

This invention is directed to a method of producing polymorpha A connection 1, which is characterized by x-ray diffraction, which has at least the position of the maxima in the reflection angle, specified in degrees 2θ, 6,78, 11,09, 19,94, 20,99, 26,57, 26,98 and 31,52; comprising heating at a temperature of from about 40°C to the boiling point of the solvent mixture, which contains a solvent selected from the group consisting of water, n-heptane, 1-chlorobutane, toluene, 1-butanol and 1-pentanol, and polymorph B connection 1, which characterized by x-ray diffraction, which has at least the position of the maxima in the reflection angle, specified in degrees 2θ, 7,43, 9,89, 18,68, 19,36, 22,16, 23,09 and 25,70.

CRATAERINA GRAPHIC MATERIALS

Figure 1 shows the powder x-ray diffraction of polymorph A connection 1 and shows the calculation of the absolute intensity, plotted on a graph against the position of the maxima in the reflection angle, specified in degrees 2θ.

Figure 2 presents the powder x-ray diffraction of polymorph In compounds 1 and shows the calculation of the absolute intensity, plotted on a graph against the position of the maxima in the reflection angle, specified in degrees 2θ.

A DETAILED DESCRIPTION of the INVENTION

In the context of this description the expression “contains”, “containing”, “includes”, “including”, “has”, “having” or any other of their variation are intended to cover non-exclusive inclusion. For example, composition, process, method, article or apparatus that contains a list of elements is not necessarily limited to only those elements but may include other elements not specifically shown or not inherent to such a composition, process, method, article or apparatus. In addition, unless specifically indicated the opposite, “or” refers to an inclusive or, not XOR. For example, a condition A or B satisfies any one of the following: A is true (or present), and B - false (or not present), A - false (or not present)and B is true (which if present), and both A and B is true (or present).

Also, the singular element or component of the present invention is intended to be non-limiting as to the number of cases (events) of the element or component. Thus, the singular should be read as such, which includes one or at least one, and the singular form of the word element or component also includes the plural, unless the number is obviously not intended to be the only one.

Compound 1 is a 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide and has the following chemical structure:

Compound 1 can exist in more than one crystalline form (i.e polymorph). The person skilled in the art will appreciate that polymorph connection 1 can show beneficial effects (for example, suitability for obtaining useful compositions, improved biological characteristics) relative to another polymorph or a mixture of polymorphs of the same compound 1. Differences relative chemical stability, filterability, solubility, hygroscopicity, melting point, density, solids and yield can have a significant impact on the development of methods of production and composition and on the quality and e is the efficiency of processing plants.

Developed a way to get degidratirutego of polymorph connection 1 (polymorph A) of Gidrodinamika of polymorph connection 1 (polymorph B), usually derived according to the existing methods for obtaining compounds 1. The water content of polymorph B significantly changed under the influence of variations in atmospheric humidity. Unlike polymorph B polymorph A does not acquire or does not lose significant amounts of water when exposed to variations in atmospheric humidity. Moreover, polymorph A usually not into polymorph B during long storage. This surprising stability facilitates a more comparable analysis of compound 1. These characteristics also make polymorph A connection 1 very suitable for obtaining durable stable solid compositions which make it possible to determine a stable concentration of active ingredient.

In addition, polymorph has A physical form, providing the opportunity for more efficient filtering in comparison with polymorpha B. During the industrial synthesis and highlight the remarkable simplicity of the Department of polymorph A can reduce the cost of production.

Powder rentgenodiffraction used to determine the crystalline phases of both polymorphs A and B of compound 1. For the characterization of polymorphs A and B data were obtained with automatic powder is fractometer Philips X'pert, model 3040. The samples at room temperature drove in a batch mode on multi-changer sample model PW 1775 or model PW 3065. The diffractometer was equipped with an automatic removable slit, xenon proportional counter and a graphite monochromator. The radiation was Cu (Kα), 45 kV, 40 mA. The samples were prepared as dry smear on a low-background glass holder for samples. Data were collected in the 2θ angles from 2 to 60 degrees using a continuous scan with an equivalent step size of 0.03 degrees and time of calculating 2.0 seconds. Applied software MDI/Jade database of the International Committee for diffraction data for phase identification and comparison of the diffraction patterns of the samples with those of reference materials.

Powder x-ray diffraction of polymorph A connection 1 shown in figure 1. The corresponding 2θ values are given in table 1.

Table 1
The peaks of x-ray radiation for reflection angle, specified in degrees 2θ, for polymorph And connections 1
of 6.7819,9427,5934,6441,5450,87
11,0920,9928,3935,2142,3851,77
11,8222,01increased by 28.7036,0242,9752,91
13,9022,53to 29.2736,3243,6253,60
of 14.7623,6029,9636,9844,6954,81
15,4224,1431,0438,0345,3255,73
15,7324,4431,5238,4245,62 56,21
16,6124,8932,1339,4446,4657,09
18,5526,0332,5939,7747,1658,64
rate 18.8926,5733,3040,1948,2959,00
19,3126,9833,8640,7050,24

Powder x-ray diffraction of polymorph In connection 1 is shown in figure 2. The corresponding 2θ values are given in table 2.

13,64
Table 2
The peaks of x-ray radiation for reflection angle, specified in degrees 2θ, for polymorpha In connection 1
4,6316,3823,0930,7739,9650,18
the 7.43the value of 16,8124,1131,3740,4351,68
the remaining 9.0817,4724,6333,1441,7251.89ˆ
9,8917,8425,70of 34.4042,6852,73
10,4218,1126,5134,9743,1956,80
12,3018,6827.05 per35,8144,2157,35
12,5919,3627,3536,8344,99
21,1728,7337,1646,88
13,9421,6829,2438,3747,30
15,2822,1630,5038,9649,76

Crystalline polymorphs of compound 1 can also be characterized by IR spectroscopy. IR spectra were measured on ICPF (infrared spectroscopy with Fourier transform) spectrometer FTS 3000 (Varian, USA) with the use of auxiliary equipment Golden Gate ATR for solids. IR spectra include the following band maxima shown in table 3 (polymorph A) and table 4 (polymorph B).

Table 3
The maxima of the bands of the IR spectrum for polymorph A connection 1
Wave number (cm-1)Wave number (cm-1)Wave number (cm-1)
14901074
312514561044
305114191024
22421357962
16911341814
16331302763
15871261
15771229
15441160
15161132

Table 4
The maxima of the bands of the IR spectrum for polymorpha In connection 1
Wave number (cm-1)Wave number (cm-1)Wave number (cm-1)
36111533801
33201467799
31441358752
30601303668
29661274
29421145
22271077
16721046
16351028
1594962

Crystalline polymorphs of compound 1 can also be characterized and differentiated from each other by Raman spectroscopy and spectroscopy near infrared region.

Embodiments of the present invention include:

An implementation option 1. The method described in the brief description of the present invention, where the solvent is n-heptane.

An implementation option 1a. The way in which approaches the implementation of the 1, where the temperature is from about 40 to about 100°C.

An implementation option 2. The method described in the brief description of the present invention, where the solvent is toluene.

An implementation option 2a. Method of option exercise 2, where the temperature is from about 40 to about 111°C.

An implementation option 3. The method described in the brief description of the present invention, where the solvent is 1-chlorobutane or 1-chloropentane.

An implementation option 3a. The method described in the brief description of the present invention, where the solvent is 1-chlorobutane.

An implementation option 3b. The method described in the brief description of the present invention, where the solvent is 1-chloropentane.

An implementation option 3c. Method of option exercise 3a, where the temperature ranges from approximately 40 to approximately 77°C.

An implementation option 4. The method described in the brief description of the present invention, where the solvent is 1-butanol or 1-pentanol.

An implementation option 4a. The method described in the brief description of the present invention, where the solvent is 1-butanol.

An implementation option 4b. The method described in the brief description of the present invention, where the solvent is 1-pentanol.

An implementation option 4c. The method of any one of the vari is now implementation 4-4b, where the temperature is from about 40 to about 100°C.

An implementation option 5. The method described in the brief description of the present invention, where the solvent is water.

An implementation option 5a. Method of option exercise 5, where the temperature is from about 60 to about 100°C.

An implementation option 5b. Method of option exercise 5a, where the temperature ranges from about 70 to about 100°C.

An implementation option 5c. Method of option exercise 5a, where the temperature ranges from about 70 to about 90°C.

An implementation option 5d. The method of any one of embodiments 5-5c, where the mixture is heated for at least about 2 hours.

An implementation option 5e. Method variant implementation 5d, where the mixture is heated for a period of not more than approximately 48 hours.

Option exercise 5f. Method of option exercise 5e, where the mixture is heated for a period of not more than approximately 24 hours.

An implementation option 5g. Method of option exercise 5f, where the mixture is heated for a period of not more than about 12 hours.

An implementation option 6. The method of any one of embodiments 5-5g, where the mixture contains at least about 30% water by weight.

An implementation option 6a. With the persons case for 6, where the mixture contains at least about 40% water by weight.

An implementation option 6b. Method of option exercise 6a, where the mixture contains at least about 80% water by weight.

An implementation option 6c. Method of option exercise 6b, where the mixture contains at least about 90% water by weight.

An implementation option 6d. Method of option exercise 6c, where the mixture contains at least about 95% water by weight.

An implementation option 6e. Method of option exercise 6d, where the mixture contains at least about 98% water by weight.

An implementation option 7. The method described in the brief description of the present invention or any one of embodiments 1-6e, where approximately 0.1-10% by weight of polymorph A (compound 1) relative to the weight of polymorph B add to the mixture before heating.

An implementation option 7a. Method of option exercise 7, where approximately 0.2 to 5% by weight of polymorph A (compound 1) relative to the weight of polymorph B add to the mixture before heating.

Polymorph B of compound 1 can be converted into polymorph A connection 1 by heating in the presence of a liquid phase containing the solvent is selected from certain organic solvents (i.e. solvents whose molecules contain at least one carbon atom). That is are certain organic solvents are suitable for this conversion, and forecasting outside of close homologues is impossible, and thus, the identification of suitable classes of organic solvents requires experiment. However, classes of organic solvents, which usually are good at converting polymorph B in polymorph A, as found, include C3-C8 n-alkalemia alcohols (for example, n-propanol, n-butanol, n-pentanol), C4-C6 n-alkylchloride (for example, n-butyl chloride or n-pantellaria), C6-C10 alkanes (such as n-hexane, hexane, n-heptane, heptane), C6-C10 cycloalkanes, optionally substituted up to 2 substituents independently selected from C1-C2 alkyl (e.g., cyclohexane, methylcyclohexane, Cycloheptane), and benzene, optionally substituted by not more than 3 groups independently selected from C1-C2 alkyl (e.g., benzene, toluene, xylene). Because polymorph B typically contains water (as water of hydration and the residual water is present, for example, in the wet sediment), and polymorph A is anhydrous, water is released during the conversion. Azeotropic distillation can often be applied to remove water from the mixture transformation of polymorphs.

It is remarkable that water, as detected at this time, works very well as a solvent in the heated liquid phase to convert polymorph B in polymorph A. This is particularly unexpected because polymorph B, which may contain significant amounts of water in its crystal lattice, can have, as expected, the advantage over anhydrous polymorphs A in the aquatic environment. However, water was found at this time, particularly suitable for the formation of a liquid phase to convert polymorph B in polymorph A. Conversion goes up to approximately 100% implementation and high outputs for commercially suitable periods of time at temperatures that do not exceed approximately 100°C (i.e. the normal boiling point of water). Not only due to the fact that water is much cheaper than organic solvents, but also because of polymorph has A small solubility in water, it can easily be distinguished by filtration. Alternatively, if polymorph A is found in high concentrations in water, polymorph A can be isolated by evaporation of water. Unlike organic solvents, water, evaporated from the mixture, does not require capture.

In one embodiment, this method blend including polymorph B and water (together with increasing quantities of polymorph A), contains a solid phase, which includes decreasing the number of polymorph B and the increasing number of polymorph A, together with the liquid phase, which contains water and optionally other solvents. Typically, the optional other rest ritali selected from organic solvents, soluble in water, although organic solvents that have a low solubility in water, may also be used. Normally, therefore, the liquid phase of the mixture in this embodiment, this method comprises at least about 50%, and more usually at least about 80%, 90% or 95%, and most typically at least about 98% water by weight.

Method variant implementation, described above, provides a means of converting polymorph B connection 1 in polymorph A connection 1 by heating the mixture, which contains polymorph B connection 1 and water. Usually, a mixture of solid polymorph B connection 1 and water in the form of a slurry or suspension is placed inside a vessel of suitable size, provided with means for mixing and heating the mixture. The mixture is then heated with mixing over a period of time long enough to effect the conversion of polymorph B in polymorph A. Methods of mixing can be internal (e.g., magnetic stirrer or verhneprivodnaya stirrer) or external (for example, the reaction vessel which is rotated or shaken). Usually it is advantageous to add the seed crystals polymorpha to A mixture that contains polymorph B, prior to heating. Adding seed crystals reduces the total conversion time and in some slucajenim temperature, necessary to implement the conversion. After conversion polymorph B in polymorph a mixture is cooled and the product isolated. Depending on the relative amounts of solid and liquid phases highlighting product may further include drying the suspension, or, if the mixture is a slurry, filtering, followed by optional washing, and then drying.

The amount of water in the mixture can be varied to adapt to different technological equipment. For example, the use of a large excess of water (i.e., where water is a liquid phase in which the suspended crystals polymorpha B) provides relief mixing with traditional equipment, such as verhneprivodnaya stirrer. Such suspension, however, requires significant energy to heat to the desired temperature. After conversion in polymorph A connection 1 slurry may be filtered for separation of the solid product. This wet solid product or wet sludge can be further dried to obtain a crystalline product suitable for the preparation of the compositions that do not include water or used directly for the preparation of compositions of water composition (e.g. concentrates) aqueous suspensions).

The predominant variant of this with the person includes the production of a mixture of polymorph B connection 1 and water in the form of mist, which contains only the amount of water necessary to facilitate blending. Mainly to use less water because less energy is necessary to heat the suspension to the desired temperature. In addition, a separate stage of filtration for separation of crystals polymorph A is not necessary, because the crystals polymorph A can be easily separated by drying the suspension. Depending on the configuration of the vessel, which is used to convert polymorph B in polymorph A, primarily to carry out this drying process directly in the vessel. In industrial commercial ways of eliminating the need of transferring solids from one container to another leads to significant savings. Alternatively, the crystals polymorph A can be transferred to another vessel, suitable for further drying.

Thus, in the overwhelming embodiment of the present invention, the crystals polymorph B compound 1 combined with water to form a suspension, which typically contains about 20-60% by weight water content, more typically 30-50% by weight water content, and most typically about 40% by weight water content.

Without further elaboration, it is considered that a person skilled in the art using the preceding description can be used on the TES invention to the full extent. The following examples, therefore, should be interpreted only as illustrative, and not limiting the disclosure in any way. It is not necessary that the source material for any of the example was obtained in the same way obtain. Percentages are by weight, except when specified otherwise.

Specific examples of conversion polymorph B connection 1 in polymorph A connection 1 below.

EXAMPLE 1

Getting polymorpha A connection 1 (using a suspension in water)

In a 250 ml flat-bottomed cylindrical reactor tube (inner diameter of approximately 6 cm, Wilmad-LabGlass) downloaded moistened with water the precipitate of polymorph B connection 1 (67,8 g, obtained by the method of example 15 in PCT patent publication WO 06/062978, except that the selected residue product was washed with additional water; hydrated with water the precipitate dried and used without additional processing). Water-wetted sediment had a total moisture content of approximately 40% by weight, including about 1% residual acetonitrile. Then the reactor was added as seed crystals of 2.0 g of polymorph A connection 1 (obtained by heating and azeotropic drying the suspension of polymorph B in heptane; 97.4% of polymorph A analysis in the near infrared region of the spectrum). Verhneprivodnaya shaking installed with the application with clanlogo four-bladed, with a 45-degree angle of the impeller with a total diameter of 4.5 cm and a projection height of the blade approximately 2.2 see the Cover of the reactor was added and thermocouple was inserted through one hole of the cover. All other openings in the cover corked to prevent evaporation of moisture from the mixture. The shaking began at approximately 21 revolutions per minute. Hot oil recirculating heater/chiller installed on maintaining 83°C was circulated through the reactor vessel, and the contents of the reactor were allowed to be heated and mixed for at 6.25 hours, after which the contents of the reactor were cooled and allowed to settle without mixing during the night. The next day again started heating and mixing using the same conditions and supported within of 7.25 hours. Samples were removed from the reactor during heating after stopping stirring and removal of the reactor cover. Before sampling, each sample the contents of the reactor were thoroughly mixed manually with a spatula to ensure homogeneity. Received a sample weighing from 1 to 3 g, and then placed in a vacuum oven and dried overnight at about 50°C and 17-40 kPa under a gentle stream of nitrogen. The sample was then analyzed for crystalline form analysis in the near infrared region of the spectrum. The results of the analysis of crystalline formula samples were as follows:

Table 5
Convert polymorph B in polymorph A
Time (hours)% Polymorph A (a)
229,8
360,1
6,2585,5
8,596,1
10,596,9
13,597,2
(a) as determined by analysis in the near infrared region of the spectrum.

After heating for a total of 13.5 hours the reactor was cooled to 25°C, and the contents of the reactor were transferred to a bowl for drying and dried overnight in a vacuum oven at 50°C and 17-40 kPa under a gentle stream of nitrogen to obtain of 28.2 g of dry polymorpha A connection 1 (92,3% purity according to the method of high performance liquid chromatography (HPLC), 0,1% H2O according to the titration according to Karl Fischer).

EXAMPLE 2

Getting polymorpha A connection 1 (using a suspension in water)

In a 100 ml round bottom flask was loaded polymorph B is connected to the I 1 (5,00 g, prepared according to the method of example 15 in PCT patent publication WO 06/062978 without recrystallization from 1-propanol, 4.2% polymorpha A according to the analysis in the near infrared region of the spectrum), polymorph A compound 1 (prepared by the method of example 15 in WO 06/062978, including recrystallization from 1-propanol, 0.05 g, 97,0% polymorpha A according to the analysis in the near infrared region of the spectrum) and water (15 ml). The mixture was spun for 4 hours in a water bath heated to 70°C. After cooling to 25°C the mixture was filtered, washed with several small portions of water and dried in a vacuum oven at 60°C and 17-40 kPa to obtain polymorph A connection 1 (96.8 per cent of polymorph A according to the analysis in the near infrared region of the spectrum), 4,74 g (93,9% yield), melting 218-220°C.

EXAMPLE 3

Getting polymorpha A connection 1 (using a suspension in n-heptane)

6 l cylindrical reactor with a glass casing, equipped verhneprivodnaya stirring, a thermocouple, immersion pipe for sampling the input of nitrogen, cylinder, back-flow distillation and reflux condenser, cooled closed circulation refrigerator, liquid filled 50:50 glycol:water, loaded with polymorpha B connection 1 (906,1 g moistened with water sludge, approximately 40% moisture, determined by weight loss after drying; prepared by the method of example 15 in PCT patent the th publication WO 06/062978 without recrystallization from 1-propanol and without drying; polymorph B, as defined by rentgenodiffraction). The refrigerator temperature was set at 5°C. After purging the reactor with nitrogen, the reactor was filled with 500 ml of fresh n-heptane and 2000 ml of n-heptane filtrate, recycled by identical methods as described in this example. The reactor was again purged with nitrogen, began stirring and the reaction mixture was heated to the setpoint casing 97,5°C. the Reaction mixture began to boil when the temperature of the mixture reached approximately 80°C at atmospheric pressure, and the condensate (i.e. condensed evaporation) sent from the output of a column in a 1000 ml measuring cylinder, modified lower output. The condensate formed two separate transparent liquid layers. The bottom layer of the condensate, which consisted of water were periodically removed from the measuring cylinder and weighed. Approximately 350 ml of fresh n-heptane was added back to the reactor to compensate for the loss of n-heptane, remote through the cylinder for collecting condensate. The temperature of the reaction mixture gradually increased as water was removed from the system. When the temperature of the reaction mixture reached 90°C, the setpoint of the casing raised to 110°C and the reaction mixture was heated to reflux distilled for about two hours. Samples of the reaction mixture were periodically collected through the immersion pipe. These samples ochiltree and, seized educated wet sediment was dried in a vacuum oven and analyzed using analysis in the near infrared region of the spectrum. The results of the analysis of the crystalline forms for the samples were as follows:

Table 6
Convert polymorph B in polymorph A
Time (minutes) (a)Temperature suspended solids (°C)% Polymorph A (b)
28987,582,8
319for 95.285,5
34997,996,1
40998,797,4
(a) as determined from the onset of condensation.
(b) as determined by analysis in the near infrared region of the spectrum.

The total volume of the aqueous layer, remote from the distillate amounted to 363 ml. Reactor was cooled to 25°C and was kept in over night. The reaction mixture is mixed for a short time, to help bring a suspension of crystals in which the CMB with large porous glass filter, and the suspension was filtered under vacuum. The filtrate is recycled and used to flush the residual product from the reactor to the filter. The wet precipitate was dried in a vacuum oven overnight at 80°C under a gentle stream of nitrogen to obtain 529,5 g of the product. The dried product was polymorph A, as found by analysis in the near infrared region of the spectrum and rentgenodiffraction (97.1% of polymorph A through analysis in the near infrared region of the spectrum).

EXAMPLE 4

Getting polymorpha A connection 1 (using a suspension of 1-chlorobutane)

Glass vial with screw cap filled with polymorpha B connection 1 (0,509 g), polymorphum A connection 1 (0,503 g, prepared from polymorph B using a method similar to example 3) and 1-chlorobutane (5.8 g). Added magnetic stirrer and the flask was closed. The vial was placed in an aluminum pan on top of the hot plate magnetic stirrer. An aluminum pan was heated to 45°C and the reaction mixture was stirred at this temperature for about 27 hours. Then the reaction mixture was filtered through a Buchner funnel using vacuum. The filter cake was dried in air for about 30 minutes and then transferred to a new glass vial. The vial was covered with a cloth and placed in a vacuum oven that was maintained at 60-70°C and 17-40 kPa in accordance with the s approximately 3 days. The dried solids were analyzed in the near-infrared region of the spectrum and found 97.4% of polymorph A.

EXAMPLE 5

Getting polymorpha A connection 1 (using a suspension in toluene)

1000 ml cylindrical reactor with a glass casing, equipped verhneprivodnaya mixing, trap Dean-stark and reflux condenser, thermocouple, and addition funnel was filled with polymorpha B of compound 1 (100 g, obtained by the method of example 15 in PCT patent publication WO 06/062978, except that the selected residue product was processed in a suspension in a mixture of acetonitrile with water, filtered and dried; polymorph B confirmed using rentgenodiffraction). After purging the reactor with nitrogen, the reactor was filled with 500 ml of toluene and the contents of the reactor were mixed to form a suspension. The suspension was heated by raising the temperature of the liquid in the casing to 120°C. the Condensate, which began to gather when the suspension reached 102.6°C, collected in the trap Dean-stark. After approximately one hour at reflux distilled 4.4 g of the lower (aqueous) layer was removed from the trap. After another twenty minutes the suspension was more liquid and consisted of large solid particles that quickly settled to the bottom of the reactor, when the mixing is temporarily stopped. After approximately two hours total time at reflux distilled, the reaction mixture was cooled d is 20°C. The reaction mixture was removed and filtered using vacuum to obtain a wet sludge, which had the appearance of sand. The precipitated product is washed in a total of 150 ml of fresh toluene two portions, and then moved in a Cup to dry. The precipitated product was dried in a vacuum oven at 100°C and 17-40 kPa with a slight stream of nitrogen for three days. The dried product was identified as polymorph A connection 1 (92,2 grams) by rentgenodiffraction; analysis in the near infrared region of the spectrum showed that the product is 95.6% of polymorph A.

EXAMPLE 6

Getting polymorpha A connection 1 (using a suspension in 1-butanol)

Glass vial with screw cap filled with polymorpha B connection 1 (0,572 g), polymorphum A connection 1 (0,578 g, prepared from polymorph B using a method similar to example 3) and 1-butanol (4.0 g). Added magnetic stirrer and the flask was closed. The vial was placed in an aluminum pan on top of the hot plate magnetic stirrer. An aluminum pan was heated to 60°C and the reaction mixture was stirred at this temperature for approximately 24 hours. Then the reaction mixture was filtered through a Buchner funnel using vacuum. The filter cake was dried in air for about 30 minutes and then transferred to a new glass vial. The vial was covered with a cloth and put in coumou oven, which is maintained at 60°C and 17-40 kPa for about 3 days. The dried solids were analyzed in the near-infrared region of the spectrum and found 96,7% polymorpha A.

EXAMPLE 7

Getting polymorpha A connection 1 (using a suspension of 1-pentanol)

Glass vial with screw cap filled with polymorpha B connection 1 (0,611 g), polymorphum A connection 1 (0,605 g, made of polymorph B using a method similar to example 3) and 1-pentanol (4.0 g). Added magnetic stirrer and the flask was closed. The vial was placed in an aluminum pan on top of the hot plate magnetic stirrer. An aluminum pan was heated to 60°C and the reaction mixture was stirred at this temperature for approximately 24 hours. Then the reaction mixture was filtered through a Buchner funnel using vacuum. The filter cake was dried in air for about 30 minutes and then transferred to a new glass vial. The vial was covered with a cloth and placed in a vacuum oven that was maintained at 60°C and 17-40 kPa for about 3 days. The dried solids were analyzed in the near-infrared region of the spectrum and found 97,2% polymorpha A.

1. The method of producing polymorpha And 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide, Hara is terisolasi x-ray diffraction, which has, at least, the position of the maxima in the reflection angle, specified in degrees 2θ,

of 6.78
11,09
19,94
20,99
26,57
26,98
31,52

comprising heating at a temperature of from about 40°C. to the boiling point of the solvent mixture containing a solvent selected from the group consisting of water, n-heptane, 1-chlorobutane, toluene, 1-butanol and 1-pentanol, and polymorph 3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide, characterized by x-ray diffraction, which has at least, the position of the maxima in the reflection angle, specified in degrees 2θ,
the 7.43
9,89
18,68
19,36
22,16
23,09
25,70

2. The method according to claim 1, where the solvent is n-heptane.

3. The method according to claim 1, where the solvent is toluene.

4. The method according to claim 1, where the solvent is 1-chlorobutane.

5. The method according to claim 1, where the solvent is 1-butanol or 1-pentanol.

6. The method according to claim 1, where the solvent is water.

7. The method according to claim 6, where the temperature is from about 60 to about 100°C.

8. The method according to claim 7, where the temperature ranges from about 70 to about 100°C.

9. The method of claim 8, where the temperature ranges from about 70 to about 90°C.

10. The method according to claim 6, where the mixture is heated for at least about 2 hours

11. The method according to claim 10, where the mixture is heated for a period of not more than approximately 48 hours

12. The method according to claim 11, where the mixture is heated for a period of not more than approximately 24 hours

13. The method according to item 12, where the mixture is heated for a period of not more than about 12 hours

14. The method according to claim 6, g is e, approximately 0.1-10 wt.% polymorpha And relative to the weight of polymorph To add to the mixture before heating.

15. The method according to 14, where approximately 0.2 to 5 wt.% polymorpha And relative to the weight of polymorph To add to the mixture before heating.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(azacycloalkyl)benzene-1,3-diol compounds of general formula (I) given below:

,

where: R1 is: - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom or a trifluoromethyl group, - aralkyl radical, - C1-C5-alkoxy radical, -amine radical, having the structure (a):

,

where R2 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6- cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical of the structure (b):

,

where p is equal to 1 or 2, - a radical of the structure (c):

,

where R4 is: - carboxymethyl, -COOCH3, or carboxyethyl, -COOEt, radical, - C1-C3-alkyl radica, - hydrogen, and R5 is: - an unsubstituted aryl radical or an aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, fluorine atom or a trifluoromethyl group, - C3-C6-cycloalkyl radical, - pyridyl, and R3 is: - hydrogen, - C1-C5-alkyl radical; or R1 can also be a radical of formula (d):

,

where R6 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical, R7 is: - hydrogen, - C1-C5-alkyl radical, and R8 is: - hydrogen, - hydroxyl, - amine radical, - C1-C3-alkoxy radical; Y is hydrogen or fluorine, and m and n are equal to 0, 1 or 2, as well as isomeric and enantiomeric forms of compounds of formula (I). The invention also relates to use of said compounds as a drug for treating pigmentation disorders.

EFFECT: novel compounds, which can be used in pharmacology or cosmetology to treat or prevent pigmentation disorders, are obtained and described.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 4-(4-cyano-2-thioaryl)- dihydropyrimidin-2-one derivatives of formula (I), a method for preparing and using them. In formula , , both A and E mean C-R7, wherein R7 mean hydrogen, Z means O, n means the number 0,1 or 2, R1 means (C1-C6)-alkyl which may be substituted by the group hydroxy, (C1-C4)-alkoxy,(C3-C6)-cycloalkyl, phenyl or 5- or 6-member heteroaryl with two heteroatoms specified in nitrogen or sulphur, or may be substituted up to three times by fluorine, or means (C3-C6)-cycloalkyl or phenyl, R2 means hydrogen, R3 means cyano or a group of formulas -C(=O)-R8, -C(=O)-O-R8 or -C(=O)-NH2, wherein R8 means (C1-C6)-alkyl or (C3-C6)-alkenyl, R4 means methyl or ethyl, or R3 and R4 are linked to each other and together form an annulated group of formula (II), R9 means hydrogen, (C1-C6)-alkyl or (C3-C6)-cycloalkyl with (C1-C6)-alkyl may be substituted by a hydroxy group, aminocarbonylamino or (C1-C4)-acylamino, R5 means hydrogen or (C1-C6)-alkyl. The other group and radical values are specified in the patent claim.

EFFECT: compounds possess the properties of a neutrophil elastase (HNE) inhibitor and can find application in treating and/or preventing pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary emphysema, mediated by neutrophil elastase (HNE) activity.

16 cl, 4 tbl, 10 dwg, 202 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein: X and Y independently mean a nitrogen atom or the chain -CR4-, wherein R4 means a nitrogen atom; A means an aryl or heteroaryl group, with the above aryl or heteroaryl groups are optionally substituted by one or more groups specified in a halogen atom, a hydroxyl group, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkoxy group optionally substituted by (C1-C4)alkoxy group, a halogen alkyl group, a halogen alkoxy group; W means a halogen atom; Z means (C1-C4)alkylene group optionally substituted by one or more groups specified in a halogen atom and (C1-C4)alkyl group; B means the group -NR4R5, wherein R4 and R5 independently mean (C1-C4)alkyl group; R1 and R2 mean: - or R1 means a hydrogen atom and R2 mean (C1-C4)alkyl group, - or R1 and R2 together with a carbon atom whereto attached form a mono- or polycyclic system specified in: (C3-C8)cycloalkyl group, a bicyclic bridge group or a tetracyclic bridge group; the above system may be substituted by one or more hydroxyl groups; R3 means either the group C(O)R5, wherein R5 means (C1-C4)alkoxygroup optionally substituted by (C1-C4)alkoxygroup, or the group NR6R7, wherein R6 and R7 independently mean a hydrogen atom, (C1-C4)alkyl group, (C3-C5)cycloalkyl group, (C1-C4)alkylsulphonyl group, a halogenalkyl group, or the group -CH2XR8, wherein: - X means an oxygen atom and R8 means a hydrogen atom or (C1-C4)alkyl group, - or the nitrile group (CN); p means an integer equal to 0 or 1; the aryl group represents an aromatic monocyclic group containing 5 or 6 carbon atoms; the above cycle may be fused with a partially saturated heterocyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as an oxygen atom; the heteroaryl group represents an aromatic cyclic group containing 5 or 6 atoms, including one or two heteroatoms, such as nitrogen; in the form of a base or an additive salt with an acid or base, as well as to their enantiomers and diastereoisomers, including to their racemic mixtures. Besides, the invention refers to methods for preparing the compound of formula I, as well as to a therapeutic agent and a pharmaceutical composition which possess antagonist action on an urotensin II receptor and contain the compound of formula I.

EFFECT: there are prepared and described the new compounds which possess urotensin II receptor antagonist action.

9 cl, 44 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel carboxyl- or hydroxyl-substituted benzimidazole derivatives of formula (I), or pharmaceutically acceptable salts thereof, where R1 is selected from and , R2 is hydrogen; R3 is cyclohexyl or bicyclo[2.2.1]heptyl; R4 is phenyl, which is substituted in the 4th position with a halogen or a lower fluoroalkyl, or a pyridyl, which is substituted with 1 or 2 substitutes independently selected from halogen and a lower alkoxy group; R5 and R6 independently denote hydrogen or fluorine; R7 and R9 are independently selected from a group consisting of hydrogen, lower alkyl, halogen, lower alkoxy group, lower fluoroalkyl, lower fluoroalkoxy group and cyano group; R8 is -(CR12R13)n-COOH, where n equals 0, 1 or 2, and R12 and R13 are independently hydrogen or lower alkyl, or -O-(CR14R15)p-COOH, where p equals 1 or 2, and R14 and R15 are independently hydrogen or lower alkyl, or R14 and R15 together with the carbon atom with which they are bonded form a cycloalkyl ring, or R8 is tetrazole; R10 is a hydroxy group or -(CH2)p-COOH, where p equals 0 or 1; m equals 0 or 1; R11 is -COOH. The invention also relates to specific carboxyl- or hydroxyl-substituted benzimidazole derivatives and a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel carboxyl- or hydroxyl-substituted benzimidazole derivatives, having selective activity with respect to farnesoid X receptor, are obtained.

26 cl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

Organic compounds // 2491285

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein V is specified in -O- or a single bond; W is specified in -N(R5)C(O)-, -S(O)t- and -C(O)O-; X is specified in C(H) or N; Y is specified in S, N(H) or N(CH3); p means 0 or 2; t means 1 or 2; R1 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by 1 or 2 halogroups, C3-7cycloalkylC1-6alkyl, 2,3-dihydro-1H-indenyl, C6arC1-6alkyl optionally substituted by one or two halogroups and heteroarylC1-6alkyl, wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen optionally oxidated, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9-member bicyclic heteroaryl containing 1 or 2 heteroatoms independently specified in a group consisting of nitrogen, oxygen and sulphur, wherein monocyclic heteroaryl of the heteroarylalkyl group may be optionally substituted by one or two substitutes independently specified in a group consisting a halogroup, a cyanogroup, C1-6alkyl, haloC1-6alkyl and C1-6alkyl-O-C(O)-; R2 is specified in a group consisting of hydrogen, C1-6alkyl optionally substituted by phenoxy, hydroxy C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, phenyl optionally substituted by a halogroup, haloC1-6alkyl, C6arC1-6alkyl (optionally substituted by a halogroup, haloC1-6alkyl or haloC1-6alkoxygroup), 2-oxo-imidazolidinyl, heterocyclylC1-6alkyl and heteroarylC1-6alkyl, wherein heterocyclyl of heterocyclylalkyl means 5- or 6-member monocycle containing oxygen, and wherein a heteroaryl fragment of the heteroarylalkyl group means 5-6-member monocycle containing 1-3 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, or a heteroaryl fragment of the heteroarylalkyl group means 9- or 10-member bicycle containing 1 to 2 heteroatoms specified in a group consisting of nitrogen and sulphur, wherein monocyclic heteroaryl of the heteroaryl alkyl group may be optionally substituted by 1 or 2 substitutes independently specified in a group consisting of a halogroup, C1-6alkyl, haloC1-6alkyl and phenyl optionally substituted by a halogroup; R3 is specified in a group consisting of hydrogen and alkyl; two adjacent R4 groups together with carbon atoms whereto attached can form phenyl; R5 means hydrogen; or a pharmaceutically acceptable salt thereof.

EFFECT: preparing the heterocyclic derivatives which modulate activity of stearoyl CoA desaturase, methods of using the above derivatives for modulating activity of stearoyl CoA desaturase and pharmaceutical compositions containing the above derivatives.

26 cl, 1 tbl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).

EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.

11 cl, 1 tbl, 104 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted quinoxaline-type piperidine compounds of formula or to a pharmaceutically acceptable derivative thereof, wherein: Y1 represents O; Q is specified in condensed benzo or pyridino; each R2 is independently specified in: (a) -halogen or -CN; (b) -(C1-C6)alkyl; a is an integer specified in 0, 1 or 2; a dash line in a 6-member ring containing a nitrogen atom which is condensed with Q group means the presence or absence of a bond, and when the dash line means the absence of the bond, then R3, and one R4 are absent; R3 is specified in: (a) -H; each R4 is independently specified in: (a) -H; or (b) - halogen or CN; or (c) -X, -(C1-C6)alkyl-X, -(5- or 6-member)heterocyclyl-X or -(5- or 6-member)heterocyclyl-(C1-C6)alkyl-X; or (d) -C(=Y)X, -C(=Y)T3, -C(=Y)YX, - C(=Y)YT3, -C(-Y)N(T1)(T2), -C(=Y)N(R9)CN, -C(=Y)N(R9)X, -C(=Y)N(R9)YH, -C(=Y)N(R9)YX, -C(=Y)N(R9)YCH2X, -C(-Y)N(R9)YCH2CH2X or -C(=Y)N(R9)S(K))2T3; or (e) -N(R9)X, -N(R9)-CH2X, -N(R9)-CH2CH2X, -N(R9)CH2N(R9)C(=N(R12))N(R12)2, -N(R9)-CH2CH2N(R9)C(=N(RI2))N(R12)2, -N(T1)(T2), -N(T3)C(=Y)T3, -N(T3)C(=Y)YT3, -N(T3)C(=Y)N(T1)(T2), -N(T3)S(=O)2T3 or -N(T3)S(=O)2N(T1)(T2); X represents: (a) -H, -( C1-C6)alkyl, -(C2-C6)alkenyl, -(C1-C6)alkoxy, -(C3-C7)cycloalkyl, -(5- or 6-member)heterocycle or -(7-10-member)bicycloheterocycle each of which is unsubstituted or substituted with 1, 2 or 3 of optionally substituted R8 groups; or (b) -phenyl, -naphthalenyl, or -(5- or 6-member)heteroaryl each of which is unsubstituted or substituted with 1 or 2 of independently specified in R7 groups; each Y is independently specified in O; A and B are independently specified in: (a) -H; or (c) A-B together can form a (C2-C6)bridge each can optionally contain -HC=CH- or -O- in a (C2-C6)bridge; wherein the 6-member ring containing a nitrogen atom which is condensed with Q group can be found in the endo- or exo- configuration in relation to the A-B bridge; or (d) A-B together can form the -CH2-N(Ra)-CH2- bridge wherein the 6-member ring containing a nitrogen atom is condensed with Q group, and can be found in the endo- or exo- configuration in relation to the A-B bridge; Ra is specified in -H or -(C1-C6)alkyl; Z represents -[(C1-C10)alkyl optionally substituted with R1]h-, wherein h is equal to 0 or 1; each R1 is independently specified in: (b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl3 -(C3-C7)cycloalkoxy, -(C6-C14)bicycloalkyl, -(C8-C10)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C7-C14)bicycloalkenyl, -(3-7-member)heterocyclyl each of which is unsubtituted or substituted with 1, 2 or 3 of independently specified in R8 groups;

or or (d) -phenyl, -naphthalenyl each of which is unsubstituted or substituted with R7 group; each R6 is optionally specified in -H; each R7 is independently specified in -(C1-C4)alkyl, -OR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, -halogen, -N(R9)2, -C(=O)OR9; each R8 is independently specified in -(C1-C4alkyl, tetrzolyl, imidazolyl, furanyl, -(C1-C6)alkylCOOR9, -OR9, -SR9, -C(halogen)3, -CH(halogen)2, -CH2(halogen), -CN, =O, -halogen, -N(R9)(C1-C6)alkylCOOR9, -N(R9)2, -N(R9)S(=O)2R12, -N(R9)C(=O)R12, -N(R9)C(=O)OR12, -C(=O)R9, -C(=O)N(T1)(T2), -C(=O)OR9, -OC(=O)R9, or -S(=O)2R9; each R9 is independently specified in -H, -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -phenyl, -benzyl, -(5- to 6-member)heterocycle, -C(halogen)3; -CH(halogen)2 or -CH2(halogen); if h is equal to O, then R11 can be specified in -H, -C(=O)OR9 or -C(=O)N(R6)2 or R11 can be -(C1-C4)alkyl; if h is equal to 1, then R11 can be specified in -H; each R12 is independently specified in -H or -(C1-C4)alkyl; m is equal to an integer specified in 3, 4, 5, 6, 7, 8 or 9; each e and f is equal to an integer independently specified in 0 or 1, provided 2≤(e+f)≤5; each j and k is equal to an integer independently specified in 0 or 1, provided 1≤(j+k)≤4; each p is equal to an integer independently specified in 0 or 1; each T1, T2, and T3 is independently specified in -H or -(C1-C10)alkyl which is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups, or T1 and T2 together can form 5- to 8-member ring wherein the number of ring atoms contains a nitrogen atom wherein T1 and T2 are bound; the above 5- to 8-member ring is unsubstituted or substituted with 1, 2 or 3 from independently specified R8 groups and optionally any carbon atom in the above 5- to 8-member ring is independently substituted with O or N(R6); each halogen is independently specified in -F, -CI, -Br or -I.

EFFECT: invention refers to the intermediate compounds of formula

, , for preparing the above compounds of formula (II), compositions containing the above compounds and to a method of treating or preventing a diseased state, such as a pain.

36 cl, 58 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new antibacterial agents. Invention describes cycloalkyl-substituted derivatives of aminomethylpyrrolidine represented by the general formula (I): wherein each among R1 and R2 represents hydrogen atom; n represents a whole number from 1 to 4; Q represents structural moiety represented by the following formula (Ia): wherein R3 represents cyclic alkyl group comprising from 3 to 6 carbon atoms that can be substituted; R4 represents hydrogen atom; R5 represents hydrogen atom or amino-group; X1 represents halogen or hydrogen atom; A1 represents nitrogen atom or structural moiety represented by the formula (II): wherein X2 represents hydrogen, halogen atom or alkyl group comprising from 1 to 6 carbon atoms, or alkoxyl group comprising from 1 to 6 carbon atoms; X2 and R3 can form a ring structure in common with part of the parent skeleton optionally comprising oxygen, nitrogen or sulfur atom as a ring-forming atoms and optionally comprising alkyl group comprising from 1 to 6 carbon atoms as a substitute; Y represents hydrogen atom. Also, invention describes an antibacterial an agent containing compound by cl. 1. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds and agent.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

Substituted indoles // 2255087

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to new substituted indoles of the formula (I): and/or stereoisometic form of compound of the formula (I) and/or physiologically acceptable salt of compound of the formula (I) wherein R3 means residue of the formula (II): wherein D means -C(O)-; R7 means hydrogen atom (H) or -(C1-C4)-alkyl; R8 means (a) typical residue of amino acid among the group: phenylalanine or homophenylalanine wherein phenyl residue is unsubstituted or substituted with halogen atom; or (b) -(C1-C4)-alkyl wherein alkyl is a linear or branched and (b) 1) mono- or multi-substituted independently of one another with pyrrole residue wherein this residue is unsubstituted or substituted with halogen atom; (b) 2) mono- or bi-substituted independently with residue -S(O)x-R10 wherein x = 0, 1 or 2, or (b) 3) mono- or bi-substituted independently of one another -N(R10)2 wherein R10 means (a) hydrogen atom (H); (b) means -(C1-C6)-alkyl wherein alkyl is unsubstituted or substituted with halogen atom from 1 to 3 times; (c) phenyl wherein phenyl is substituted or substituted with halogen atom from 1 to 3 times; in the case (R10)2 residues R10 have values independently of one another (a), (b), (c); Z means (a) residue of heterocycles group comprising benzothiadizine, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, oxadiazolone, triazole being heterocycles are unsubstituted or substituted with -NH2=, =O, alkoxycarbonyl or aminocarbonyl from 1 to 3 times, or (b) means -C(O)-R11 wherein R11 means 1. -O-R10 or 2. -N(R10)2; R9 means (a) hydrogen atom (H); (b) means (C1-C6)-alkyl wherein alkyl is unbranched or branched and substituted with phenyl or =O independently of one another from 1 to 3 times; (c) phenyl wherein phenyl is unsubstituted or substituted with halogen atom; R1, R2 and R4 mean hydrogen atom (H); R5 means hydrogen atom (H); R6 means (a) phenyl wherein phenyl is unsubstituted or substituted with -NH2; (b) pyridine, or (c) pyrimidine being pyridine or pyrimidine is unsubstituted or substituted with groups -NH2, -NH-CH3. Compounds of the formula (I) are specific inhibitors of IkB kinase.

EFFECT: valuable biochemical properties of compounds.

3 cl, 3 tbl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

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