Polymorphic modification in n-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-2-fluoro-phenyl}-n-methyl-acetamide (versions), containing it pharmaceutical composition (versions), medication, method of obtaining said polymorphic modification (versions) and method of treatment and/or prevention of nervous disorders

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes novel polymorphic modification N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-2-fluoro-phenyl}-N-methyl-acetamide, methods of its obtaining, its application as medication, its application for preparation of medication and pharmaceutical compositions, including novel polymorphic modification.

EFFECT: obtaining novel polymorphic modification for preparation of medication and pharmaceutical compositions.

30 cl, 2 tbl, 24 ex, 7 dwg

 

The present invention relates to a new polymorphic modification of N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide, the means of its production, use as therapeutically active substances and pharmaceutical compositions, including a new polymorphic modification.

The level of technology

N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide is an active ligand-receptor γ-aminobutyric acid A (GABAAnd), which can be used for the treatment or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration as described in PCT/EP 2006/063243 and US 60/692866.

In the text of this application, the term "compound (I)" refers to N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide.

The compound (I) is structurally related N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide, also known as indiplon. This compound and its use as a sedative or hypnotic described in US 6399621. In contrast to the compounds (I), this compound is only monosubstituted by FeNi is gnome cycle.

Published to date the only crystalline form of compound (I), which is disclosed in the above description of the invention and shows a melting point 165-167°C. In this study, this form shows the curve of DSC (differential scanning calorimetry) with a sharp peak melting point between to 166.2 and 167,4°C. a Small discrepancy with previously published melting point is valid and is within experimental error. This form is referred to in this application as Polymorphic modification of A.

It is important that the medicinal substance was in the form that it would be convenient to handle and which it would be convenient to apply. This is important not only from the point of view of obtaining a commercially viable method of producing, but also from the point of view of the subsequent production of a pharmaceutical composition comprising an active connection. The medicinal substance and composition, including him, should have sufficient shelf life without any significant changes in the physico-chemical characteristics of the active component. Moreover, it is also important that the medication did in its purest form. The specialist will understand that if the drug can be easily obtained in a stable crystalline form, the above problems can be solved. Therefore,in the production of commercially viable and pharmaceutically acceptable pharmaceutical compositions preferably, when possible, get the medicine in almost crystalline and stable form. Thus, there is a need for a stable crystalline form of compound (I), which can be easily handled and with whom it would be easy to handle.

Disclosure of inventions

The authors of the present invention have discovered a new crystalline form of compound (I). This new form is designated as polymorphic modification of the Century

Polymorphs of compound (I) shows the curve of the powder x-ray diffractometry with the most intense peaks at 2θ=7,1°(±0,1°) and 21.4°(±0.1 degree); Fourier spectra Raman (FT-Raman Spectrum with characteristic signals 3107 cm-1, 1605 cm-1, 1593 cm-1, 1538 cm-1, 1336 cm-1and 102 cm-1and the curve of differential scanning calorimetry (DSC) peak melting at about 158°C.

Like polymorphic modifications And polymorphs In is an active ligand GABAAndand can be used for the treatment or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration.

Polymorphs of compound (I) ex is differs from indiplon fact, that parapolitica phenyl cycle substituted by fluorine atom. Polymorphic modification In exhibits unexpectedly high efficiency and unexpectedly improved margin of safety compared with the connection of the prototype indiplon, which is confirmed by the data given in the following detailed description, which, thus, makes the connection according to the invention is unexpectedly superior therapeutic drug to achieve the sedative/hypnotic effects.

Brief description of drawings

The invention is described using the drawings, in which:

Figure 1 represents a curve of the powder x-ray diffractometry for the polymorphic modifications A. the Intensity on the axis of ordinates are presented in counts per second (cps).

Figure 2 represents a curve of the powder x-ray diffractometry for the polymorphic modifications of the Century, the Intensity on the axis of ordinates are presented in counts per second (cps).

Figure 3 represents the Fourier transform of the Raman spectrum for polymorphic modifications A.

Figure 4 represents the Fourier transform of the Raman spectrum for polymorphic modifications Century

Figure 5 represents a curve of differential scanning calorimetry (DSC) for polymorphic modifications A.

6 represents a curve of differential scanning calorimetry (DSC) DL is polymorphic modifications Century

Fig.7 shows the results of the evaluation of the following parameters: the time of awakening, the phase of slow wave sleep and paradoxical phase of sleep for compounds of the present invention, and indiplon (US 6399621).

The implementation of the invention

The first aspect of the present invention is a new polymorphic modification of compound (I).

Polymorphs of compound (I) shows the curve of the powder x-ray diffractometry with the most intense peaks at 2θ=7,1°(±0,1°) and 21.4°(±0,1°); the specified polymorphic modification curve is characterized with powder x-ray diffractometry with specific peaks at 2θ=7,1°(±0,1°), 11,8°(±0,1°), 12,3°(±0,1°), 12,6°(±0,1°), 13,7°(±0,1°), 14,7°(±0,1°), 15,5°(±0,1°), 19,0°(±0,1°), 20,8°(±0,1°), 21,4°(±0,1°), 22,0°(±0,1°), 22,3°(±0,1°), 22,6°(±0,1°), 23,4°(±0,1°), 23,9°(±0,1°), 25,6°(±0,1°), 26,3°(±0,1°), 27,1°(±0,1°), 27,8°(+0,1°), 31,8°(±0,1°) and 36.5°(±0,1°). Polymorphs of compound (I) also shows the Fourier-transformed spectrum of the Raman scattering of the characteristic signals at 3107 cm-1, 1605 cm-1, 1593 cm-1, 1538 cm-1, 1336 cm-1and 102 cm-1and the curve of differential scanning calorimetry with a peak melting point of about 158°C.

The second aspect of the present invention is a method of obtaining polymorphic modifications In the compound (I) by suspension of Polym hnoi modification And the compound (I) at room temperature (20-25°C) in a solvent, selected from the group comprising From1-C6aliphatic alcohols1-C6aliphatic ketones, With1-C4alkyl esters With1-C4aliphatic acid, With4-C5saturated cyclic ethers, With1-C6aliphatic NITRILES, aromatic hydrocarbons and water, and a mixture selected from the group comprising From1-C6aliphatic alcohol and1-C6aliphatic organic acid, water and1-C6aliphatic alcohol and water, and With the4-C5saturated cyclic ether and subsequent selection of the obtained crystals.

Preferably the solvent is selected from the group comprising methanol, ethanol, 1-methoxy-2-propanol, methyl ethyl ketone, ethyl acetate, dioxane, acetonitrile, toluene, water, a mixture of ethanol and acetic acid, a mixture of water and ethanol, and a mixture of water and tetrahydrofuran. When you apply a mixture of ethanol and acetic acid, the volume ratio of ethanol and acetic acid preferably ranges from 90:10 to 98:2, respectively. More preferred is a ratio of 95:5. Alternatively, when using a mixture of water and ethanol, volume ratio of water and ethanol is preferably lies in the range from 5:95 to 95:5, respectively. More preferably the ratio is in the range from 10:90 to 90:10. If used, see the camping water and tetrahydrofuran, the volumetric ratio of water and tetrahydrofuran is in the range from 85:15 to 95:5, respectively. More preferred is a ratio of 90:10. The obtained crystals can be allocated using conventional procedures such as filtration, filtration under reduced pressure or filtered in a centrifuge, followed by washing if necessary, and drying, getting polymorphic modification of the compound (I) of the present invention.

In the second aspect of the invention disclosed variant of the previous method in which a mixture of polymorphic modifications And the compound (I) and polymorphic modifications In the compound (I) suspendered in an aromatic solvent at a temperature from 80°C to the boiling temperature, and then the obtained crystals are highlighted. The weight ratio in the mixture of polymorphic modifications and polymorphic modification lies in the range from 25:75 to 75:25, preferably 50:50. Preferred aromatic rhetorical represents toluene, and the preferred temperature range is from 95 to 105°C.

Another aspect of the present invention is the method of obtaining polymorphic modifications In the compound (I) by dissolving polymorphic modifications And the compound (I) in a suitable solvent; filtering and keeping up until dissolve the spruce is not completely evaporated. Preferred solvents. are acetone and tetrahydrofuran.

Another aspect of the present invention is the method of obtaining polymorphic modifications In the compound (I) by dissolving polymorphic modifications And the compound (I) in a mixture of water and tetrahydrofuran at room temperature; and allocating the resulting crystalline precipitate. The volumetric ratio of water and tetrahydrofuran preferably ranges from 5:95 to 15:85, respectively. A more preferred ratio is a 10:90. The resulting crystalline precipitate can be isolated as described above.

Another aspect of the present invention is the method of obtaining polymorphic modifications In the compound (I) by dissolving polymorphic modifications And the compound (I) in a solvent selected from the group comprising From1-C6aliphatic sulfoxidov, aromatic amines, With1-C6aliphatic organic acids and mixtures With1-C2halogenated aliphatic hydrocarbon and C1-C6aliphatic alcohol; filtering the solution; adding the solution to antibacterial selected from the group comprising From1-C6aliphatic alcohols and C1-C4alkyl esters With1-C4aliphatic acids; and vyd the population of the obtained crystals.

Preferably, the solvent is selected from the group comprising dimethyl sulfoxide, pyridine, acetic acid and a mixture of dichloromethane and 2-propanol. The volume ratio of dichloromethane and 2-propanol are preferably ranges from 0.5:10 to 2:10, respectively, when using a mixture of dichloromethane and 2-propanol. A more preferred ratio is a 1:10. Antibacterial is selected from the group comprising ethanol, 2-propanol and ethyl acetate.

To ensure that controlled turns polymorphic modification, it is strongly recommended to apply the seed. This can be the seed of the equilibrium of the suspension, during the precipitation or crystallization from hot solution. Accordingly, polymer modification In the compound (I) can be obtained by adding crystals of the specified polymorphic modifications for the seed to a solution of compound (I) in a suitable solvent of crystallization and isolation of the obtained crystals using known chemistry procedures.

Another aspect of the present invention is to propose the use of polymorphic modifications In the compound (I) as a drug.

Another aspect of the present invention is to propose a pharmaceutical composition comprising a polymorphic modification In the unity (I) in a mixture with one or more pharmaceutically acceptable carrier, filler, diluent, or auxiliary agent.

Another aspect of the present invention is to propose a pharmaceutical composition comprising a polymorphic modification of the compound (I), for use in the treatment or prophylaxis of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic action, anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration.

The invention also relates to a method of treatment and/or prevention of mammals, including humans, suffering from or prone to anxiety, epilepsy, sleep disorders, to induce a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration, this method includes the introduction of said patient a therapeutically effective amount of the polymorphic modifications In the compounds of formula (I) together with a pharmaceutically acceptable diluent or excipient.

Pharmaceutical compositions include compositions for oral, rectal and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route of administration will depend on the nature and severity of the disease, which p is estoit to treat. The most preferred route of administration of the present invention is an oral way. The compositions can be conveniently presented in the form of a single pharmaceutical dosage forms and received by any of the methods well known in the pharmaceutical industry.

The active compound can be combined with a pharmaceutical carrier according to conventional pharmaceutical techniques of mixing. The carrier may take a wide variety of forms depending on the form of the desired drug for administration, for example oral, or parenteral (including intravenous injections or infusions). When preparing the compositions for oral dosage form may be any of the usual pharmaceutical media. Conventional pharmaceutical carrier includes, for example, water, glycols, oils, alcohols, aromatic substances, stabilizers, dyes, etc. in the case of oral liquid preparations (such as, for example, suspensions, solutions, emulsions and elixirs; aerosols; or extenders, such as starches, sugars, microcrystalline cellulose, diluents, granulating substances, lubricants, binders, dezintegriruetsja substances, etc. in the case of solid oral preparations (such as powders, capsules and tablets), with the solid oral por the drugs are preferred in compared to liquid oral preparations.

Because of the simplicity of the introduction of tablets and capsules represent the most preferred oral dosage form, in such cases, use solid pharmaceutical carriers. If desired, tablets may be coated using standard aqueous or nonaqueous techniques.

The limits of acceptable dosages for use are from about 0.01 mg to about 100,00 mg total daily dose, given either once daily or, if necessary, broken up into several methods.

Another aspect of the present invention is to propose the use of polymorphic modifications In connection (I) for the preparation of medicinal products intended for use in the treatment or prophylaxis of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration.

Projected sedative-hypnotic effect of polymorphic modifications In the compound (I) was determined as shown below, and compared with the effect produced indiplon (the closest connection of the prototype described in US 6399621).

Influence indiplon, and compounds of the present invention applied orally, SPSS is annoy locomotor activity in mice is an established model for evaluating induce a sedative effect, this experiment is considered to be predictive for the efficacy of hypnotic action. In this experiment, ED50, i.e. the dose that induces a sedative effect in 50% of animals was calculated. The connection of the prototype (indiplon), described in US 6399621 showed ED50=0.2 mg/kg, while the connection of the present invention showed ED50=0.13 mg/kg, which was 35% more active.

Such sedative-hypnotic effect was confirmed by electroencephalographic (EEG) study in mice, which was estimated cycle recording of sleep-Wake. Doses were selected based on previous experiments, and both compounds were tested in pharmaceutical dosage corresponding to the same activity (ED50, 3-fold and 6-fold in both cases). The compound of the present invention showed a statistically significant improvement in all three estimated parameters (time, Wake-up phase of slow wave sleep and paradoxical phase of sleep), as shown in figure 7, while the connection of the prototype indiplon was effective only on one parameter (slow-wave sleep).

7, the results are presented as the average time (min ± SEM)spent in each state during the study period of 6 h in the same animals (n=9). The highest dosage of the compounds of this izaberete the Oia (GF-015535-00) resulted in the increase phase of slow wave sleep (SWS, up to 140 min) and paradoxical sleep (PS), and reduction of Wake (W), while the connection of the prototype (indiplon) increased only slow SWS sleep for a shorter period of time compared to our compound (140 min), which clearly showed the best effect on the sleep of the compounds of the present invention.

Finally, it was performed a third experiment in order to assess side effects. The model served as a two-day test active avoidance, which is a behavioral test used to assess learning and memory in mice. In this case, was received on the exposure index amnesia. Since it was published that drugs like benzodiazepine, cause amnesia, this index allows you to define the boundary between preclinical effective dosages that cause sedation, and the minimum effective dose that causes a statistically significant memory impairment in mice (MED amnesia/ED50 sedative action). Therefore, the exposure index amnesia was calculated for both compounds. The results obtained are included in Table 1.

Table 1
The exposure index amnesia (MED amnesia / ED50 of Sedat the main action) in mice after oral administration of connections
ConnectionMED amnesiaED50 sedative actionThe exposure index amnesia
Indiplon10 mg/kg0.20 mg/kg50-fold limit
The compound (I)10 mg/kg0.13 mg/kg75-fold limit

As a result, the compound of the present invention shows a 25-fold higher limit between induced sedative and amnesic than the connection of the prototype indiplon.

In conclusion, the compound of the present invention clearly shows unexpectedly higher efficiency and improved border security, compared with the connection of the prototype Indiana.

Polymorphic modification of the present invention is obtained in accordance with the following examples which are given only for illustrative purposes.

Preparative example 1: Original material, polymorphs And was obtained in accordance with Example 2 of the specification of PCT/EP 2006/063243 and US 60/692866.

Preparative example 2: Obtaining polymorphic modifications of polymorphic modifications And in methanol

Polymorphic mod is the qualification, And (to 151.8 mg) suspended in methanol (2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered by centrifugation (0.22 μm filter) and dried in vacuum at room temperature for 15 minutes was obtained polymorphic modification (95 mg).

Preparative example 3: Obtaining polymorphic modifications of polymorphic modifications And acetonitrile

Polymorphic modification And (to 151.8 mg) suspended in acetonitrile (2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered by centrifugation (0.22 μm filter) and dried in vacuum at room temperature for 15 minutes was obtained polymorphic modification In (90 mg).

Preparative example 4: Obtaining polymorphic modifications of polymorphic modification A in ethanol

Polymorphic modification And (153,3 mg) suspended in ethanol (2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered by centrifugation (0.22 μm filter) and dried in vacuum at room temperature for 15 minutes was obtained polymorphic modification In (110 mg).

Preparative example 5: Receiving polymorphic modifications of polymorphic modifications And 1-methoxy-2-propanol

Polymorphic modification And (152,4 mg) suspended in 1-methoxy-2-propanol (2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered by centrifugation (Phil is Tr 0.22 μm) and dried in vacuum at room temperature for 15 minutes Was obtained polymorphic modification In (90 mg).

Preparative example 6: obtain the polymorphic modifications of polymorphic modifications And methylethylketone

Polymorphic modification And (to 150.6 mg) suspended in methyl ethyl ketone (2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered by centrifugation (0.22 μm filter) and dried in vacuum at room temperature for 15 minutes was obtained polymorphs (100 mg).

Preparative example 7: Getting polymorphic modifications of polymorphic modifications And acetate

Polymorphic modification And (150,0 mg) suspended in ethyl acetate (2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered by centrifugation (0.22 μm filter) and dried in vacuum at room temperature for 15 minutes was obtained polymorphic modification In (105 mg).

Preparative example 8: Getting polymorphic modifications of polymorphic modifications And toluene

Polymorphic modification And (150,0 mg) suspended in toluene (2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered by centrifugation (0.22 μm filter) and dried in vacuum at room temperature for 15 minutes was obtained polymorphic modification In (90 mg).

Preparative the initial example 9: Getting polymorphic modifications of polymorphic modification And in a mixture of ethanol/acetic acid 95:5

Polymorphic modification And (156,0 mg) was stirred with a mixture of ethanol/acetic acid 95:5 (2 ml) for 8 days at room temperature. The sample was filtered and dried under vacuum for 10 minutes was obtained polymorphs (100 mg).

Preparative example 10: Getting polymorphic modifications of polymorphic modifications And in acetone

Polymorphic modification And (157,9 mg) was dissolved in acetone (8 ml). The solution was filtered and left to evaporate at room temperature. After complete evaporation of the solvent for a few days formed yellow crystals, corresponding polymorphic modifications Century

Preparative example 11: Obtain polymorphic modifications of polymorphic modifications And tetrahydrofuran

Polymorphic modification And (157,8 mg) was dissolved in tetrahydrofuran (5 ml). The solution was filtered and left to evaporate at room temperature. After complete evaporation of the solvent for a few days formed yellow crystals, corresponding polymorphic modifications Century

Preparative example 12: Getting polymorphic modifications of polymorphic modification And in a mixture of water/ethanol 10:90

Polymorphic modification And (148 mg) suspended in H2O (0.2 ml) and ethanol (1.8 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered and you who left the house taking in vacuum for 10 minutes Was obtained polymorphic modification In (110 mg).

Preparative example 13: Getting polymorphic modifications of polymorphic modification And in a mixture of water/ethanol 90:10

Polymorphic modification And (146 mg) suspended in N2(1.8 ml) and ethanol (0.2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered and dried in vacuum for 10 minutes was obtained polymorphic modification In (160 mg, wet).

Preparative example 14: Getting polymorphic modifications of polymorphic modification And in a mixture of water/tetrahydrofuran 10:90

Polymorphic modification And (154 mg) was dissolved in N2O (0.2 ml) and tetrahydrofuran (1.8 ml) and stirred at room temperature for 3 days. A solid precipitate formed during this time was filtered and dried in vacuum for 10 minutes was obtained polymorphic modification In (40 mg).

Preparative example 15: Getting polymorphic modifications of polymorphic modification And in a mixture of water/tetrahydrofuran 90:10

Polymorphic modification And (151 mg) suspended in H2O (1.8 ml) and tetrahydrofuran (0.2 ml) and stirred at room temperature for 3 days. The solid precipitate was filtered and dried in vacuum for 10 minutes was obtained polymorphic modification In (165 mg, wet).

Preparative example 16: Getting polimorfnoyadernami In from polymorphic modifications And dioxane

Polymorphic modification And (151 mg) suspended in dioxane (1 ml). The suspension was stirred at room temperature for 6 days. Then the solid was filtered and dried in vacuum for several minutes, the substance is identified as polymorphic modification Century

Preparative example 17: Getting polymorphic modifications of a mixture of polymorphic modifications And/polymorphic modifications In 50:50 toluene

A mixture of polymorphic modifications (75,7 mg) and polymorphic modifications (75,3 mg) suspended in toluene (1 ml) and stirred at 99°C for 1 day. From the hot solution sample was collected, which was immediately identified as polymorphic modification of the Century

Preparative example 18: Getting polymorphic modifications of polymorphic modification And in a mixture of dimethylsulfoxide/2-propanol 1:10

Polymorphic modification And (180,0 mg) was dissolved in dimethyl sulfoxide (1.5 ml). The filtered solution was dropwise added to 2-propanol (15 ml). A few minutes after completion of addition, the solution began precipitate formation. After 10 min stirring, the precipitate was filtered, washed with 2-propanol and dried in vacuum for 15 min, receiving 75 mg of polymorphic modifications Century

Preparative example 19: Obtaining polymorphic modifications of polymorphic modification And in a mixture of pyridine/2-PR is panel 1:10

Polymorphic modification And (182,8 mg) was dissolved in pyridine (1 ml). The solution was filtered and dropwise added to 2-propanol (10 ml). Closer to the completion of addition, the solution began precipitate formation. The suspension was stirred 5 min, the solid precipitate was filtered, washed with 2-propanol and dried in vacuum for 15 min, receiving 90 mg polymorphic modifications Century

Preparative example 20: Obtaining polymorphic modifications of polymorphic modification And in a mixture of acetic acid/2-propanol 1:10

Polymorphic modification And (180,9 mg) was dissolved in acetic acid (1 ml). The solution was filtered and dropwise added to 2-propanol (10 ml). After 1-2 min after the end of addition, the solution began precipitate formation. The suspension was stirred 5 min, the solid precipitate was filtered, washed with 2-propanol and dried in vacuum for 15 min, receiving 95 mg polymorphic modifications Century

Preparative example 21: Getting polymorphic modifications of polymorphic modification And in a mixture of acetic acid/ethanol 1:10

Polymorphic modification And (155 mg) was dissolved in acetic acid (1 ml). The filtered solution was dropwise added to ethanol (10 ml). After 5 min after the end of addition, the solution began to crystallize. The suspension was stirred 1 h, the crystals were filtered and dried in vacuum, obtaining 75 mg polymorphic modifications the AI Century

Preparative example 22: Obtaining polymorphic modifications of polymorphic modification And in a mixture of acetic acid/ethyl acetate 1:10

Polymorphic modification And (158 mg) was dissolved in acetic acid (1 ml). The filtered solution was dropwise added to ethyl acetate (10 ml). After 2 min after the end of addition, the solution began to crystallize. The suspension was stirred for 2 h, the crystals were filtered and dried in vacuum, obtaining 45 mg polymorphic modifications Century

Preparative example 23: Obtaining polymorphic modifications of polymorphic modification And in a mixture of dichloromethane/2-propanol 1:10

Polymorphic modification And (177,4 mg) was dissolved in dichloromethane (1.5 ml). The solution was filtered and dropwise added to 2-propanol (15 ml). After about 3 min after the end of addition, the solution began precipitation, the amount of which over time slowly increased. The suspension was stirred for another 30 min, the solid precipitate was filtered and dried in vacuum for 15 min, after receiving 80 mg of polymorphic modifications Century

Preparative example 24: Getting polymorphic modifications of polymorphic modification And water

Polymorphic modification And (149 mg) suspended in water and stirred at room temperature for 5 days. These crystals were identified as polymorphic mod the qualification Century

Example song 1: 5 mg tablets

Polymorphs of compound (I)5.0 mg
Colloidal silicon dioxide0.6 mg
Crosscarmellose sodium12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Polysorbate 801.0 mg
Lactose75,0 mg
The hypromellose3.0 mg
Polyethylene glycol 40000.5 mg
Titanium dioxide E1711.5 mg
Microcrystalline cellulose, enough to125,0 mg

Example composition 2: capsules 10 mg

Polymorphs of compound (I)10.0 mg
Colloidal silicon dioxide 0.6 mg
Crosspovidone12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Sodium lauryl sulfate1.5 mg
Lactose77.0 mg
Gelatin28.5 mg
Titanium dioxide E1711.5 mg
Indigotin e0.02 mg
Microcrystalline cellulose, enough to155,0 mg

An example of a song 3: oral drops

Polymorphs of compounds (1)0.5 g
Propylene glycol10.0 g
Glycerin5.0 g
Saccharin sodium0.1 g
Polysorbate 801.0 g
Lemon flavour02 g
Ethanol25,0 ml
Purified water, a sufficient quantity to100,0 ml

Example compositions 4: tablets 2.5 mg

Polymorphs of compound (I)2.5 mg
Colloidal silicon dioxide0.6 mg
Crosscarmellose sodium12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Polysorbate 801.0 mg
Lactose75,0 mg
The hypromellose3.0 mg
Polyethylene glycol 40000.5 mg
Titanium dioxide E1711.5 mg
Microcrystalline cellulose, enough to125,0 mg

Example compositions 5: capsules 5 mg

Polymorphs of compound (I)5.0 mg
Colloidal silicon dioxide0.6 mg
Crosspovidone12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Sodium lauryl sulfate1.5 mg
Lactose77.0 mg
Gelatin28.5 mg
Titanium dioxide E1711.5 mg
Indigotin e0.02 mg
Microcrystalline cellulose, enough to155,0 mg

Example compositions 6: oral drops

Polymorphs of compound (I)0.25 g
Propylene glycol10.0 g
Glycerin5.0 g
Saccharin sodium 0.1 g
Polysorbate 801.0 g
Lemon flavour0.2 g
Ethanol25,0 ml
Purified water, a sufficient quantity to100,0 ml

Characterization of polymorphic modifications

Polymorphic modifications of compound (I) were characterized using the following procedures.

Instrumental and experimental conditions

Powder x-ray diffractometry: Bruker D8 Advance. Cu α radiation; power x-ray tube 35 kW/45 mA; detector VANT1; of 0.017° 2θ step size, 105±5 with a step of 2°-50° 2θ scanning range (recorded range may be different). Used holder for samples with single crystal silicon, the sample diameter is 12 mm, a depth of 0.1 mm

Raman spectroscopy with Fourier transform: Bruker RFS100. Nd:YAG 1064 nm excitation laser power of 100 mW, Ge detector, 64 scanning range 50-3500 cm-1, resolution 2 cm-1aluminum holder for a sample.

Differential scanning calorimetry: Perkin Elmer DSC 7. Gold crucibles, heating rate 2°C min-1or 10°C min-1variable initial and final rate is atory.

X-ray analysis of single crystals: Crystal was measured on the diffractometer Nonius Kappa CCD at 173°To using GRAFITO-monochromomania Mo α-radiation with λ=0,71073 Å. Set the COLLECT was used for data collection and integration. The structure was determined by direct methods using SIR92. All non-hydrogen atoms were processed by the method of least squares relative to F c using CRYSTALS. Sheldrick weight was used for final processing. Graphics were obtained using ORTEP III for Windows.

Characteristics of the polymorphic modifications And

Powder x-ray diffraction: X-ray diffraction pattern is characterized by an intense peak at 2θ=5,7°. Whereas vysokoelastichny the form of crystals, it can be expected that such a high intensity is observed due to the preferential orientation of crystals. X-ray diffraction pattern shown in figure 1.

Raman spectroscopy with Fourier transform. The characteristic signals of the Raman spectra represent the most intense peak in the region of C-H at 3073 cm-1peaks at 1616 cm-1, 1590 cm-1, 1544 cm-1, 1326 cm-1and a double peak at 117 cm-1/79 cm-1. The Fourier transform of the Raman spectrum shown in IG.

Differential scanning calorimetry: Differential scanning calorimetry DSC showed a sharp melting peak between to 166.2 and 167,4°C (small differences, depending on the scan speed) with ΔfusH=85 j/g Substance is not crystallized again when cooled, even when the cooling rate is only 2°C/min, instead she steklobalans when 61,3°C. the DSC Curve is shown in figure 5.

Characteristics of the polymorphic modifications In

Powder x-ray diffractometry: the Most intense peaks in an x-ray diffraction pattern are located at 2θ=7,1° and 21.4°. X-ray diffraction pattern shown in figure 2.

Raman spectroscopy with Fourier transform: Characteristic signals Raman spectra of polymorphic modifications found at 3107 cm-1(the most intense peak in the region of the C-H), 1605 cm-1, 1593 cm-1, 1538 cm-1, 1336 cm-1and 102 cm-1. The Fourier transform of the Raman spectrum shown in Figure 4.

Differential scanning calorimetry: DSC Measurement showed a sharp melting peak at about 158°C With enthalpy of melting ΔfusH=104 j/, the DSC Curve is shown in Fig.6.

The structure of the single crystal: the Compound crystallizes in the axial space group P-1. The structure shows two molecules in asymmetric the civil code, unrelated in space group symmetry. These two molecules can almost perfectly overlap during rotation around the axis "a", but the unit cell cannot be converted, so that the crystal lattice of higher symmetry.

The structure can be interpreted as a connection based on dimers. The driving force behind the formation of these dimers, the most likely represents a π-π interaction between the phenyl cycle and thiophene cycle, on the one hand, and N-heterocycles, on the other hand. Two different types of molecules in the unit cell form two different types of dimers with several different short distances between the condensed N-heterocycles (3,348 Å and 3,308 Å for very short distances, respectively). The dimers are arranged in layers like structure of fish bones. Two types of dimers always alternate in the structure of fish bones, as they alternate from one layer to another. The crystal structure is described in Table 2.

Table 2
The crystalline characteristics of the polymorphic modifications In
Molecular formulaC20H15FN4O 2S
Molecular weight394,43 g/mol
The number of molecules in the unit cell Z4
The calculated density1,478 g/cm3
The number of electrons in the unit cell F(000)816
The crystal size0,14×0,18×0.24 mm3
The absorption rate0,218 mm-1
Min./Max. transmission0,96/0,97
Temperature173°K
Radiation (wavelength)Mo α (α=0,71073 Å)
Crystal systemtriclinic
Space groupR-1
and8,9236(2) Å
b14,0292(3) Å
15,6218(3) Å
α65,3449(14)°
β 87,0440(14)°
γ86,0799(14)°
The volume of the elementary cell1772,69(7) Å3
Min./.θ1,435°/27,883°
The number of collected reflections16548
The number of independent reflections8448 (merging r=0,034)
The number of observed reflections (I>2.00 σ(I))5430
The number of refined parameters506
r (observed data)0,0455
rW (all data)0,0734
Compliance0,9980
residual electron density-0,37/0,39 e Å-3

1. Polymorphs of N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide, curve characterized by powder x-ray diffractometry with specific peaks at 2θ=7,1°(±0,1°) and 21,4°(±0,1°).

2. Polymorphic modification according to claim 1, characterized by the powder curve the x-ray diffractometry, with specific peaks at 2θ=7,1°(±0,1°), 11,8°(+0,1°), 12,3°(±0,1°), 12,6°(±0,1°), 13,7°(±0,1°), 14,7°(±0,1°), 15,5°(±0,1°), 19,0°(±0,1°), 20,8°(±0,1°), 21,4°(±0,1°), 22,0°(±0,1°), 22,3°(±0,1°), 22,6°(±0,1°), 23,4°(±0,1°), 23,9°(±0,1°), 25,6°(±0,1°), 26,3°(±0,1°), 27,1°(±0,1°), 27,8°(±0,1°), 31,8°(±0,1°) and 36,5°(±0,1°).

3. Polymorphs of N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-acetamide", she characterized the Fourier spectrum of Raman scattering, which has the characteristic signals at 3107 cm-1, 1605 cm-1, 1593 cm-1, 1538 cm-1, 1336 cm-1and 102 cm-1.

4. Polymorphs of N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide, characterized by differential scanning calorimetry, having a peak melting point of about 158°C.

5. The method of obtaining polymorphic modification according to any one of claims 1 to 4, which is suspended polymorphic modification And N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide at room temperature in a solvent selected from the group comprising C1-C6aliphatic alcohols, C1-C6aliphatic ketones, C1-C4alkyl esters With1-C4aliphatic acids, With4-C5saturated cyclic ethers, C1-C6aliphatic NITRILES, aromatic hydrocarbons and water, and mix, using the data from the group including C1-C6aliphatic alcohol and C1-C6aliphatic organic acid, water and C1-C6aliphatic alcohol and water, and With the4-C5saturated cyclic ether, and then allocate the resulting crystals.

6. The method according to claim 5, in which the solvent is selected from the group comprising methanol, ethanol, 1-methoxy-2-propanol, methyl ethyl ketone, ethyl acetate, dioxane, acetonitrile, toluene, water, a mixture of ethanol and acetic acid, a mixture of water and ethanol, and a mixture of water and tetrahydrofuran.

7. The method according to claim 6, in which a mixture of ethanol and acetic acid in the following ratio of components,%:

ethanol90-98
acetic acid2-10

8. The method according to claim 7, in which the content of ethanol and acetic acid in a mixture of 95 and 5% vol. respectively.

9. The method according to claim 6, in which a mixture of water and ethanol in the following ratio of components,%:

water5-95
ethanol5-95

10. The method according to claim 9, in which a mixture of water and ethanol at the next appropriate is Oseni components, vol.%:

water10-90
ethanol10-90

11. The method according to claim 6, in which a mixture of water and tetrahydrofuran in the following ratio of components,%:

water85-95
tetrahydrofuran5-15

12. The method according to claim 11, in which the ratio of water and tetrahydrofuran in the mixture is 90 and 10% vol. respectively.

13. The method of obtaining polymorphic modification according to any one of claims 1 to 4, in which is suspended a mixture of polymorphic modifications And N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide and polymorphous modifications of N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl)-N-methyl-ndimethylacetamide in an aromatic solvent at a temperature from 80°C to the boiling point, and then allocate the resulting crystals.

14. The method according to item 13, in which a mixture of polymorphic modifications and polymorphic modifications In the following ratio, wt.%:

polymorphic modification And 25-75
polymorphic modification25-75

15. The method according to 14, in which the contents of the polymorphic modifications and polymorphic modifications in the mixture is 50 and 50 wt.% respectively.

16. The method according to item 13, in which the aromatic solvent is a toluene.

17. The method according to item 13, in which the mixture is suspended at a temperature of from 95°C to 105°C.

18. The method of obtaining polymorphic modification according to any one of claims 1 to 4, in which polymorphic modification And N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide dissolved in a solvent selected from the group comprising acetone and tetrahydrofuran, then sucked her and incubated until complete evaporation of the solvent.

19. The method of obtaining polymorphic modification according to any one of claims 1 to 4, in which polymorphic modifications And N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide dissolved in a mixture of water and tetrahydrofuran at room temperature, and then allocate the resulting crystalline precipitate.

20. The method according to claim 19, in which a mixture of water and tetrahydrofuran in the following ratio of components,%:

water5-15
tetrahydrofuran85-95

21. The method according to claim 20, in which the content of water and tetrahydrofuran in the mixture is 10 and 90 vol.% respectively.

22. The method of obtaining polymorphic modification according to any one of claims 1 to 4, in which polymorphic modification And N-{5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-2-fluoro-phenyl}-N-methyl-ndimethylacetamide dissolved in a solvent selected from the group comprising From1-C6aliphatic sulfoxidov, aromatic amines, C1-C6aliphatic organic acid and a mixture of C1-C6halogenated aliphatic hydrocarbon and C1-C6aliphatic alcohol, then the solution is filtered, add the resulting solution to antibacterial selected from the group comprising C1-C6aliphatic alcohols and C1-C4alkyl esters of C1-C4aliphatic acids, and then allocate the resulting crystals.

23. The method according to item 22, in which the solvent is selected from the group comprising dimethyl sulfoxide, pyridine, acetic acid and a mixture of dichloromethane and 2-propanol.

24. The method according to item 23, in which a mixture of dichloromethane and 2-propanol in a volume ratio of components (0.5 to 2):10.

25. The method according to paragraph 24, in which the volume ratio of dichloromethane and 2-propanol in the mixture is 1:10.

26. The method according to the .22, in which antibacterial selected from the group comprising ethanol, 2-propanol and ethyl acetate.

27. The use of polymorphic modification according to any one of claims 1 to 4, as a drug for the treatment or prophylaxis of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration.

28. Pharmaceutical composition for treatment or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration, including polymorphic modification according to any one of claims 1 to 4, together with at least one pharmaceutically acceptable carrier, excipient, diluent, or auxiliary agent.

29. Pharmaceutical composition for the treatment or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration, including polymorphic modification according to any one of claims 1 to 4.

30. The use of polymorphic option the requirements according to any one of claims 1 to 4 for the preparation of a medicinal product, intended for the treatment or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect of anesthesia and muscle relaxation and to modulate the time required for the onset of sleep and its duration.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel acetylenyl-pyrazole-pyrimidine derivatives of general formula (I), having mGluR2 (metabotropic glutamate receptor) antogonist properties). In compounds of general formula (I): either E and J denote N, G denotes C and L denotes N, M denotes CH, or M denotes N, L denotes CH; or L and G denote N, E denotes C, and J and M denote CH; or J, G and L denote N, E denotes C, and M denotes CH; or E and L denote N, J and M denote CH, and G denotes C; R1 denotes H, halogen, CF3, CHF2 or C1-6alkyl; R2 denotes H, halogen, C1-6-alkyl, C1-6-alkoxy, CF3 or CHF2, wherein R1=R2≠H; R3 denotes H; -C(CH3)2OH; linear C1-4-alkyl or C3-4-cycloalkyl, which are possibly substituted with one or more substitutes selected from a group comprising 1-3 F and 1-2 OH; A is selected from a group comprising phenyl or a 5- or 6-member heteroaryl having in the ring 1-2 heteroatoms selected from nitrogen, sulphur or nitrogen and sulphur in the 5-member ring, and 1-2 nitrogen atoms i the 6-member ring, and possibly substituted with 1-3 Ra; Ra denotes halogen; hydroxy; cyano; CF3; NReRf; C1-C6-alkyl, possibly substituted amino or hydroxy; ; C1-6-alkoxy; C3-4-cycloalkyl; CO-NRbRc, SO2-NRbRc; or SO2-Rd-; Rb and RC can be identical or different and are selected from a group comprising H; normal or branched C1-6-alkyl, possibly substituted with one or more substitutes selected from a group comprising F, cyano, hydroxy, C1-6-alkoxy, -NH-C(O)-O-C1-6-alkyl, amino, (C1-6-alkyl)amino, di(C1-6-alkyl)amino, heterocycloalkyl having 6 ring atoms, from which 1-2 heteroatoms are selected from nitrogen or nitrogen and oxygen, or a 6-member heteroaryl with one nitrogen heteroatom in the ring; or a 6-membeer heteroaryl with one nitrogen heteroatom in the ring; or Rb and Rc, together with the nitrogen atom with which they are bonded, can form a heterocyclic ring having 6 members in the ring, from which 1-2 atoms are selected from nitrogen and/or oxygen, and which can be substituted with C1-6-alkyl; Rd denotes OH or C1-6-alkyl; Re and Rf denote H, C1-6-alkyl, possibly substituted hydroxy, -C(O)- C1-6-alkyl; S(O)2-C1-6-alkyl.

EFFECT: compounds can be used in preparing medicinal agents for treating central nervous system (CNS) disorders, such as Huntington's chorea, amyotrophic lateral sclerosis, dementia caused by AIDS, parkinsonism etc.

55 cl, 6 dwg, 321 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the 2,9-disubstituted imidazo[1,2-a]benzimidazole family, specifically to water-soluble salts of 9-aminoethyl-substituted 2-(4-fluorophenyl)imidazo[1,2-a]benzimidazole of general formula I:

,

where NR2 = pyrrolidine-, piperidine-, morpholine-; Y=HBr, H2SO4, (CH2COOH)2 and [CH(OH)COOH]2; n=1, 2.

EFFECT: novel compounds have analgesic action.

2 cl, 2 tbl, 15 ex

Pyrazolepyrimidines // 2412186

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat tumourous diseases, such as solid tumours, breast, lung, large intestine or prostate gland tumours. In compounds of formula

: R1 is selected from a group comprising: (a) saturated cyclic radical containing 3-8 ring atoms, from which 1-3 atoms are N atoms, which can contain up to four substitutes independently selected from a group comprising: (i) lower alkyl; and (ii) CO2R3, OR7 or S(O)nR8; (b) C6-C10aryl, which can contain up to four substitutes independently selected from a group comprising: (i) S(O)nR8, lower alkyl; OR7 and halogen; (c) C3-C8cycloalkyl, which can be substituted with NR5R6; and (d) lower alkyl, which can be substituted: (i) OR7, NR5R6; R2 is selected from a group comprising: (i) H; (ii) lower alkyl; (iii) C6-C10aryl which can be substituted with a halogen, lower alkyl, lower alkoxy group; R3 is selected from a group comprising: (i) H; (ii) lower alkyl; (iv) C3-C8cycloalkyl; R5 and R6 are independently selected from a group comprising: (i) H; (ii) lower alkyl; (iii) C3-C8cycloalkyl; (v) SO2R3; and (vi) CO2R3; R7 is selected from a group comprising H and lower alkyl; R8 is selected from a group comprising: (iii) NR5R6; (iv) lower alkyl; and n equals 1 or 2.

EFFECT: capacity to inhibit activity of cyclin-dependant kinase.

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I and to their pharmaceutically acceptable salts exhibiting inhibitory activity in relation to kinases chosen from Abl, Bcr-Abl, Bmx, BTK, b-RAF, c-RAF, CSK, cSRC, Fes, FGER3, Elt3, 1KKα, 1KKβ, JNK1α1, JNK2α2, Lck, Met, MKK4, MKK6, p70S6K, PAK2, PDGFRα, PKA, PKCα, PKD2, ROCK-II, Ros, Rsk1, SAPK2α, SAPK2β, SAPK3, SAPK4, SGK, Syk, Tie2 and TrkB. In compounds of formula I , n is equal to 1, m is equal to 0, Y1 is chosen from N and CR5, and R5 represents hydrogen, Y2 represents O, R1 represents hydrogen, R2 is chosen from hydrogen and C1-C6alkyl, R3 is chosen from a group including hydrogen, C1-C6alkyl, C1-C6alkoxy, R4 is chosen from NR5C(O)R6 and -C(O)NR5R6 where R5 is chosen from hydrogen and C1-C6 alkyl, and R6 represents phenyl optionally substituted with 1-3 radicals chosen of a group including NR3R3, halogen-substituted C1-C6alkyl, C5-C6heteroaryl(C0-C4)alkyl where heteroaryl contains 1-2 heteroatoms chosen from N and O, C5-C6heterocyclo(C0-C4)alkyl, where heterocyclyl contains 1-2 heteroatoms of N, and C5-C6heterocyclo(C0-C4)alkoxy where heterocyclyl contains 1-2 heteroatoms of N, and any heteroaryl or heterocyclyl contained in R6 is optionally substituted by 1-3 radicals independently chosen from a group including C1-C6alkyl and hydroxy(C1-C6)alkyl.

EFFECT: producing the compounds which can find application for treatment or prevention of diseases or disorders associated with abnormal or unregulated kinase activity, such as proliferative diseases, diseases of immune and nervous system.

8 cl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel chemical compound - 1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo [3,2-d]pyrimidin-4-one and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds and use thereof. Disclosed compound has myeloperoxidase enzyme inhibiting properties.

EFFECT: compounds are especially useful in treating and preventing neuroinflammatory disorders such as Parkinson's disease, cardiovascular disorders and respiratory disorders.

3 cl, 1 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazopyrazines of formula where Q1 and R1 have the values specified in the patent claim, and to their pharmaceutically acceptable salts showing IGF-1R enzyme inhibiting activity and applicable for treatment and/or prevention of various diseases and conditions which are sensitive to tyrosine kinase inhibition.

EFFECT: preparation of the compounds showing IGF-1R enzyme inhibiting activity.

27 cl, 294 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where R is methyl and R1 is 4-methyl-oxy-piperazin-1-yl; or R is CH2OH and R1 is 4-methyl-piperzin-1-yl or 4-methyl-4-oxy-piperazin-1-yl; and to pharmaceutically acceptable acid addition salts thereof, as well as to a medicinal agent based on said compounds, having NK-1 receptor antagonist activity and to use of said compounds in treating NK-1 receptor associated diseases.

EFFECT: compounds can be used in medicine.

9 cl, 2 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 8-sulphonyl-2,3,4,5-tetrahydro-1H-γ-carbolines of general formula 1 or pharmaceutically acceptable salts thereof, which are ligands with a wider range of simultaneous activity towards alpha adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors, sigma receptors, norepiniphrine receptors and serotonin receptors. In compounds of general formula 1 R1 is an amino group substitute selected from hydrogen; C1-C3alkyl optionally substituted with phenyl; C1-C4alkyloxycarbonyl; R2 is a cyclic system substitute selected from hydrogen, C1-C3alkyl optionally substituted with phenyl, pyridin-(3- or 4-yl), (6-methylpyridin-3-yl); C1-C3alkenyl substituted with phenyl; or optionally substituted phenylsulphonyl; R3 is an optionally halogen-substituted phenyl, six member aromatic azaheterocycle, mono- or di-C1-C3alkylamino group, phenylamino group which is optionally substituted with halogen atoms on the phenyl ring, or a substituted six member azaheterocycle containing an additional nitrogen atom, substituted with C1-C3alkyl.

EFFECT: compounds can be used in treating and preventing diseases and pathological conditions of the central nervous system, such as anxiety disorders, cognitive disorders, neurodegenerative diseases and depression.

18 cl, 2 dwg, 6 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: there are described compound of formula, its pharmaceutically acceptable salt or their mixture, enentiomerically pure 4-{(R)-(3-aminophenyl)[4-(4-fluorobenzyl)pyperazin-1-yl]-N,N-diethylbenzamide or its pharmaceutically acceptable salt. Also described are method of anxiety therapy, method of pain therapy and method of depression therapy in animal.

EFFECT: compounds are of use in therapy, in particular for elimination of pain, depression and anxiety.

5 cl, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology and concerns application of derivatives of gamma-aminobutyric acid in the form of 4-amino-3-phenyl butane acid salts of general formula

as an anxiolytic and cerebroprotective agent reducing inclination to alcohol.

EFFECT: preparation of the agent with reduced by-effects.

2 cl, 10 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antagonists of serotonin 5-HT6 receptors - substituted 2-amino-3-sulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of general formula 1 and substituted 2-amino-3-sulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of general formula 2 or their pharmaceutically acceptable salts and/or hydrates, method of producing said compounds and pharmaceutical compositions, medicinal agents and treatment method. In compounds of formula 1 and general formula 2 , Ar is phenyl which is possibly substituted with halogen atoms, or a 6-member nitrogen-containing heteroaryl; R1 is a hydrogen atom, C1-C3alkyl which is possibly substituted with phenyl, C1-C5alkoxycarbonyl; R2 is a hydrogen atom, halogen or C1-C3alkyl; R13 and R23 are optionally identical substitutes selected from a hydrogen atom, optionally substituted C1-C3alkyl or R13 and R23 together with the nitrogen atom with which they are bonded form a nitrogen-containing 6-member saturated heteroaryl optionally substituted with C1-C5alkoxycarbonyl, where the said heteroaryl has 1-2 heteroatoms selected from nitrogen.

EFFECT: compounds can be used to prevent and treat diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors for enhancing mental capacity.

14 cl, 3 tbl, 19 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to compound of formula I wherein X represents -S- or -NH-; R1 represents C1-12alkyl, C2-12alkenyl, phenyl C1-12alkel, phenyl C2-12alkenyl or phenyl-O-C1-12alkyl and wherein said phenyl groups are optionally substituted with one or two assistants chosen from the group consisting of lower C1-7alkyl, C C1-7alkoxy and halogen C1-7alkyl; R2 represents hydrogen, lower C1-7alkyl or C3-6cycloalkyl; R3/R4 together with N-atom whereto attached, form nonaromatic 5,6-members heterocyclic ring system which optionally contains in addition to N-atom one additional heteroatom chosen from the group, consisting of O or N and where the ring system is optionally substituted group lower C1-7alkyl, lower C1-7alkoxy, -NR2, -CONR2; or R3/R4 together with N-atom whereto attached, can form heterocyclic ring system which contains at least two rings and which optionally contains one or two additional heteroatoms chosen from group, consisting of N and O; R represents hydrogen or lower C1-7alkyl; R5 represents hydrogen or lower C1-7alkyl; or to pharmaceutically acceptable additive salts with acid of this compound. The invention also concerns a medical product.

EFFECT: improved clinical effectiveness.

16 cl, 4 dwg, 3 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) , where R1 is hydrogen, C1-C7 alkyl; R2 is C1-C7 alkyl, aryl, C1-C7 haloalkyl or C3-C8 cycloalkyl; R3, R4 each independently represents hydrogen, halogen, C1-C7 alkoxy, C1-C7 alkylsuphonyl; R5 is hydrogen, halogen, C1-C7 alkyl, C1-C7 haloalkoxy, or aryloxy, or is -NR7R8, where R7 and R8 represent C1-C7 alkyls, or R7 and R8 together with the nitrogen atom to which they are bonded can form a 4-7-member heterocycloalkyl group, which can be substituted with one or more substitutes selected from a group consisting of halogen, C1-C7 alkyl, C1-C7 alkoxy, hydroxyl, phenyl and di(C1-C7)alkylamino; R6 is hydrogen or together with R5 can form a 5- or 6-member heterocycloalkyl group which can be substituted with one or more halogens; and their pharmaceutically acceptable salts of acid compound, except the range of compounds given in paragraph 1 of the formula of invention. The invention also relates to medicine based on said compounds, with activity of allosteric enhancer of GABA-B receptors and use of compounds of the formula to prepare medicines used in treating central nervous system disorders, including anxiety and depression.

EFFECT: novel compounds are obtained and described, which can be used for preparing medicines used in treating central nervous system disorders, including anxiety and depression.

14 cl, 58 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular to pharmaceutics, and concerns pharmaceutical compositions, which contain as active substance therapeutically effective quantity of ladasten, and as target additives - starch, stearic acid and/or its salt or ludipress and stearic acid and/or its salt with definite ratio of said components. Composition is made in form of pills, contains optimal quantity of target additives, which allows to obtain easy swallowed pills. Pills meet all requirements of State Pharmacopoeia XI edition.

EFFECT: medication form easily releases active substance, which provides its high bioaccessibility.

13 cl, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention is related to antagonists of serotonin 5-HT6 receptors of common formula 1 and their pharmaceutically acceptable salts and/or hydrates, pharmaceutical compositions, dosage forms and methods of production. Invention also includes new compounds of formula 1.1. In formulae 1 and 1.1 , Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur and heteroatom; R1 represents atom of hydrogen, unnecessarily substituted C1-C5 alkyl; Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur as heteroatom; R1 represents atom of hydrogen, which is unnecessarily substituted C1-C5 alkyl; R21,R22, R31, R32 independently from each other represent atom of hydrogen or substituent of aminogroup, selected from unnecessarily substituted C1-C4 alkyl, unnecessarily substituted phenyl, or R31 and R32 together with atom of nitrogen, to which they are bound, create unnecessarily substituted saturated 6-member heterocycle, possibly containing atom of nitrogen in cycle; or R1 together with atom of nitrogen, to which it is bound, and R21 and R22 together with atom of nitrogen, to which they are bound, create substituted pyrimidine cycle. In formula 1.1 R4, R5 and R6 independently from each other represent atom of hydrogen, unnecessarily substituted C1-C3 alkyl or phenyl.

EFFECT: compounds of invention may find application for treatment and prevention of development of conditions and disorders of central nervous system.

13 cl, 11 dwg, 4 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: there is claimed method of prevention and treatment of neurasthenia, somatoform disorder of post-traumatic stress, in which patient intakes perorally lavender oil in form of capsule and means of the same purpose in form of capsule, which contains lavender oil, introduced perorally.

EFFECT: there is shown considerable reduction of pathology with specified symptoms.

2 cl, 1 tbl, 3 ex

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