Amorphous form of n-{2-fluorine-5-[3-(thiophen-2-carbonyl)-pirazolo[1,5-a]-pyrimidin-7-yl]-phenyl)-n-methyl-acetamide, method for preparing it, pharmaceutical composition (versions) containing said amorphous form and drug and method of treating and/or preventing nervous disorders

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an amorphous form of N-{2- fluorine-5-[3-(thiophen-2-carbonyl)-pyrazolo[1,5-a]-pyrimidin-7-yl]-phenyl}-N-methyl-acetamide, methods for preparing it.

EFFECT: preparing the pharmaceutical compositions for GABA-receptor inhibition containing said form, and also to using them as a drug for treating and/or preventing anxiety, epilepsy, sleeping disorder and sleeplessness, for induction of sedative-hypnotic effect, for anaesthesia and muscular relaxation and for time modulation required for sleep induction and duration.

12 cl, 4 dwg

 

The technical field to which the invention relates.

The present invention relates to N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a] pyrimidine-7-yl] -phenyl}-N-methyl-ndimethylacetamide in amorphous form, the methods of its production, its use as a therapeutically active agent and pharmaceutical compositions, including a new form of the above compounds.

The level of technology

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

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

The compound (I)described in the definitions above, is a crystalline material that has a melting point 165-167°C. However, the use of compound (I) in crystalline form is difficult due to its physical properties, such as its low solubility. In most cases the crystalline form of compound (I) is very lahoratory, what could affect its therapeutic applicability, as well as the manufacture of the aqueous compositions.

It is obvious that any improvement of physical properties of compound (I) could potentially provide more effective treatment and improved manufacturing capabilities.

Thus, it would be a significant contribution in the area of technology to provide solid amorphous form of compound (I), which has a high solubility, the means of its production, its use as a therapeutically active agent and pharmaceutical compositions comprising new forms.

Disclosure of inventions

The present invention discloses the compound (I) in amorphous form. Favorably, when the solubility of the amorphous form approximately two times higher than the one of crystalline products.

Accepted methods of obtaining amorphous substances include melting of these substances and rapid cooling of the melt. However, these methods are usually limited to laboratory scale, because they are not feasible and is hardly suitable for industrial applications.

In another aspect, the present invention also provides a method of obtaining an amorphous form, which comprises: (i) dissolving N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide in dichloromethane; (ii) the UE shall Rivonia solvent under vacuum, and (iii) drying the product to remove residual solvent.

In a preferred embodiment, the method corresponding to the present invention includes:

(i) dissolving N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a] pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide in dichloromethane;

(ii) adding to the solution of charcoal;

(iii) heating the mixture up to 30-50°C;

(iv) stirring the mixture for 20 to 45 minutes;

(v) cooling the suspension to 15-30°C;

(vi) the removal of the charcoal by filtration;

(vii) the evaporation of the solvent under vacuum; and

(viii) drying the product under vacuum at 40-60°C. to remove residual solvent.

In a preferred embodiment, the mixture of stage (iii) is heated to 40°C (±5°C).

In another embodiment, the mixture is stirred at stage (iv) within 30 minutes (±5 minutes).

In yet another embodiment, the suspension on the stage (v) is cooled to 20-25°C.

In one of the following embodiment, the product of stage (viii) dried at 50°C (±5°C).

Another aspect of the present invention is to enable the utilization of amorphous forms of compound (I) as a drug.

In another aspect of the present invention features a pharmaceutical composition comprising the amorphous form of compound (I) in a mixture with one or more pharmaceutically acceptable carriers, fillers, diluents is whether auxiliary components.

In another aspect of the present invention features a pharmaceutical composition comprising the amorphous form of compound (I)is intended for use for the treatment and/or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect, for anesthesia and relaxation of the muscles and to modulate the time required to induce sleep and its duration.

Pharmaceutical compositions include compositions suitable for oral, rectal and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable path will depend on the nature and severity of the condition being treated. The most preferred route is the oral route. The compositions can be conveniently presented in unit dosage form and received by any of the methods known in the field of pharmacy.

The active compound can be combined with a pharmaceutical carrier according to conventional methods of preparing pharmaceutical preparations. The carrier may take a wide variety of forms depending on the form of preparation is required for administration, e.g. oral, or parenteral (including intravenous injections or infusions). Upon receipt of the compositions for oral, in addition to the state forms you can use any of the usual pharmaceutical media. Conventional pharmaceutical environment include, for example, water, glycols, oils, alcohols, flavoring components, preservatives, dyes, etc. in the case of oral liquid preparations (such as, for example, suspensions, solutions, emulsions and elixirs, aerosols, or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, sliding agents, binder components, leavening agents, etc. in the case of oral solid preparations (such as powders, capsules and tablets), with the oral solid preparations are preferred to oral liquid preparations.

In another aspect, the present invention proposes a method of treatment and/or prevention of anxiety, epilepsy, sleep disorders and insomnia, induction of sedative-hypnotic effect, for anesthesia and relaxation of the muscles and to modulate the time required to induce sleep and its duration in human or mammal other than human, which includes the introduction of this person or mammal other than human a therapeutically effective amount of an amorphous form together with one or more pharmaceutically acceptable carriers, fillers, diluents or auxiliary components.

Due to the ease of use of tablets and capsules represent the most favorable oral unit dosage form, and in this case, use solid pharmaceutical carriers. If necessary, the tablets can be coated using standard aqueous or anhydrous ways.

An appropriate range of doses for use is from 0.01 mg to about 100,00 mg total daily dose proposed for a once-daily injection, or, if required in divided doses.

In another aspect of the present invention features the use of an amorphous form of compound (I) for the preparation of drugs for the treatment and/or prevention of anxiety, epilepsy, sleep disorders and insomnia, induction of sedative-hypnotic effect, for anesthesia and relaxation of the muscles and to modulate the time required to induce sleep and its duration.

Amorphous compound (I)corresponding to the present invention can be characterized by the powder x-ray diffraction. On the accompanying Figure 1 shows a typical x-ray diffraction pattern characterized by a broad halo, which is a characteristic of any amorphous material in x-ray diffraction.

FT-Raman spectrum of amorphous compound (I), see Figure 2, demonstrates a characteristic feature of the enhanced signals.

Similarly, the spectrum of Raman, ATR-IR spectrum of the amorphous material, see Figure 3, dem will strirred significantly broader signals, than the signals of crystalline materials. Particularly intense absorption discover at 1099 cm-1.

After receiving the in situ amorphous form shows a Tg (glass transition temperature) is 61.3°C. However, the DSC curve aged amorphous sample, see Figure 4, shows a slightly higher TD 64°C. the Sample with higher TD recrystallized with an exothermic peak at 117°C and again melted at 167°C.

Like crystalline compound (I) in amorphous form is strong (active) ligand GABAAndand its use for the treatment and/or prevention of anxiety, epilepsy, sleep disorders, insomnia, induction of sedative-hypnotic effect, for anesthesia and relaxation of the muscles and to modulate the time required to induce sleep and its duration.

Brief description of drawings

The Figure 1 shows the powder x-ray diffraction of compound (I) in amorphous form. The intensity on the axis of ordinate is expressed in pulses per second.

The Figure 2 shows the spectrum of the Fourier transform (FT) - Raman compounds (I) in amorphous form.

The Figure 3 shows damped total reflection (ATR)-IR spectrum of the compound (I) in amorphous form.

The Figure 4 shows the differential scanning calorimetry (DSC) of the compound (I) in amorphous form.

For a more complete p the understanding of the invention the following examples are presented only for illustrative purposes.

The implementation of the invention

Preparation of the analytical sample (example): Amorphous form of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]-pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide.

N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide (200 mg) is melted in an aluminum pan on thermostal of Kofler. The pallet is removed after a few minutes and put on a cold thermostal. The sample hardens within a few minutes, and lightly crushed in a mortar for analysis. Characteristics of the resulting product, including powder x-ray diffraction, FT-Raman spectroscopy, ATR-IR spectroscopy and DSC, as described in "Characterization of amorphous form.

Example: Amorphous form of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide.

A vessel with a capacity of 250 ml washed with nitrogen and make it 9,23 g (0,023 mol of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide and dichloromethane (92,3 ml, 10 volumes). The mixture was kept under stirring to ensure complete dissolution, then add charcoal (0,92 g) and the mixture is heated to 40°C. and stirred for at least 30 minutes. The suspension is cooled to 20-25°C. and the resulting mixture is filtered to remove the charcoal, which flushing is t additional dichloromethane (2×18,5 ml). The dichloromethane extracts are combined and evaporated under vacuum, and optionally dried under vacuum at 50°C (±5°C) to remove residual solvent. N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo-[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide receive in the form of a solid (7.9 g), which was identified is an amorphous material. The yield is 85%. Purity is >95%.

Data1H NMR (400 MHz, CDCl3): δ to 1.98 (3H, s), and 3.3 (3H, s), 7,13 (1H, d, J=4 Hz), 7.18 in-7,20 (1H, m), 7,42 (1H, t, J=8,8 Hz), 7,71 (1H, d, J=5,2 Hz), 8,02-8,08 (2H, m)to 8.12 (1H, dd, J=2,4 and 7.6 Hz), 8,71 (1H, s), 8,82 (1H, d, J=4 Hz).

MS (ES) m/z=395 (MN+).

Characteristics of the resulting product is fully consistent with the obtained in the reference example.

Example song 1: 5 mg tablets

The amorphous form of compound (I)5.0 mg
Colloidal silicon dioxide0.6 mg
Croscarmellose 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
The amorphous form of compound (I)10.0 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, sufficient
the number before155,0 mg

An example of a song 3: oral drops
The amorphous form of compound (I)0.5 g
Propylene glycol10.0 g
Glycerin5.0 g
Saccharin sodium0.1 g
Polysorbate 801.0 g
Lemon flavoring0.2 g
Ethanol25,0 ml
Purified water, a sufficient quantity to100,0 ml

Example compositions 4: tablets 2.5 mg
The amorphous form of compound (I)2.5 mg
Colloid is silicon dioxide 0.6 mg
Croscarmellose 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, sufficient mg amount125,0

Example compositions 5: capsules 5 mg
The amorphous form of compound (1)5.0 mg
Colloidal silicon dioxide0.6 mg
Crosspovidone12,0 mg
Talc4.0 mg
Article is Arat magnesium 1.5 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
The amorphous form of compound (I)0.25 g
Propylene glycol10.0 g
Glycerin5.0 g
Saccharin sodium0.1 g
Polysorbate 801.0 g
Lemon flavoring0.2 g
Ethanol25,0 ml
Purified water, a sufficient quantity to100,0 ml

Characterization of amorphous form.

The amorphous form of compound (I) is characterized using the following methods.

Equipment and experimental conditions

X-ray powder diffraction: Bruker D8 Advance. Radiation Cu Kalfa; power x-ray tube 35 kV/45 mA; VANTEC detector 1; step size of 0.017° 28θ, 105±5 s/step, the scan interval is 2 deg-50° 2θ (print interval may be different). Use silicone holders for the sample as a single crystal, the sample diameter is 12 mm, a depth of 0.1 mm

FT-Raman spectroscopy: Bruker RFS100. Nd:YAG 1064 nm excitation, the laser power of 100 mW, Ge detector, 64 scan interval 50-3500 cm-1, resolution 2 cm-1. Aluminum holder for a sample.

DSC: Perkin Elmer DSC 7. Gold containers, the heating rate of 2°C min-1or 10°C min-1the variation of the initial and final temperatures.

Characteristics of the amorphous form.

Powder x-ray diffraction: X-ray diffraction pattern shows a broad halo, which is a characteristic of any amorphous material in x-ray diffraction. X-ray diffraction pattern shown in Figure 1. The intensity on the axis of ordinate is expressed in counts.

FT-Raman spectroscopy: FT-Raman spectrum is shown in F. the góra 2.

ATR-IR spectroscopy: a Particularly intense absorption is detected at 1099 cm-1. ATR-IR spectrum is shown in Figure 3.

DSC: After receiving the in situ amorphous form shows TD 61,3°C. the DSC Curve aged amorphous sample shows a higher TD 64°C with a pronounced peak in the relaxation of about 7 j/g At higher Th sample is recrystallized from an exothermic peak at 117°C and again melted at 167°C. the melting Temperature and enthalpy of melting show that recrystallization occurs in the crystalline material. You may notice that the enthalpy of recrystallization from 61 j/g to 67 j/g more than 10% lower than the enthalpy of melting. It largely suggests that some additional formation of an ordered structure already exists in the glassy state, in comparison with the melt above 167°C. One possible explanation could be that the education diameter has already happened in glassy "amorphous" state, but without any long-term formation of ordered structures in the sample. The assumption of a certain formation of an ordered structure in the glassy state is confirmed by the evaluation value Δ. Δ Dt comes up to 0.3 j/(g K), whereas for her, as a rule, expect a value close to 0,j/(g K) for avrprog the low molecular weight compounds. In addition, Δ associated with quantities melting peak at 167°C to more than 0.4 j/(g K), and it is known that the values Δ while the peak melting and glass transition are very close. From the above it should be concluded that the so-called amorphous state includes (precrystallizer fraction, which is not involved in the transition and reduces the released energy of recrystallization. DSC curve shown in Figure 4.

1. Amorphous form of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a] pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide.

2. The amorphous form according to claim 1, which shows x-ray diffraction pattern shown in figure 1.

3. The way to obtain the amorphous form according to any one of claims 1 and 2, comprising dissolving N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo-[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide in dichloromethane, evaporation of the solvent under vacuum and drying the resulting product to remove residual solvent.

4. The method according to claim 3, in which after dissolving M-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide in dichloromethane to the resulting solution add charcoal, the mixture is heated to 30-50°C, stirred for 20-45 minutes, then the obtained suspension is cooled to 15-30°C, remove from it the charcoal by filtration, then the solvent evaporated under vacuum and done is make drying the obtained product under vacuum at 40-60°C. to remove residual solvent.

5. The method according to claim 4, in which the mixture obtained after adding charcoal to the solution of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide in dichloromethane, heated to 40°C (±5°C).

6. The method according to claim 4, in which the mixture obtained after adding charcoal to the solution of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo-[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide in dichloromethane, stirred for 30 min (±5 min).

7. The method according to claim 4, in which the resulting suspension is cooled to 20-25°C.

8. The method according to claim 4, in which the product obtained after evaporation of the solvent under vacuum, dried at 50°C (±5°C).

9. The use of the amorphous form according to claim 1 as a drug for the treatment and/or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing a sedative-hypnotic effect, for anesthesia and relaxation of the muscles and to modulate the time required to induce sleep and its duration.

10. Pharmaceutical composition for the inhibition of the GABA-a receptor, comprising the amorphous form according to claim 1 in a mixture with at least one pharmaceutically acceptable carrier, excipient, diluent, or auxiliary agent.

11. Pharmaceutical composition for treatment and/or prevention of anxiety, epilepsy, sleep disorders and insomnia, for inducing egative-hypnotic effect, for anesthesia and relaxation of the muscles and to modulate the time required to induce sleep and its duration, comprising the amorphous form according to claim 1.

12. The use of the amorphous form according to claim 1 for preparing a medicinal product intended for the treatment and/or prevention of anxiety, epilepsy, sleep disorders and insomnia, induction of sedative-hypnotic effect, for anesthesia and relaxation of the muscles and to modulate the time required to induce sleep and its duration.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted pyrazolopyrimidines derivatives of formula , wherein Y1, Y2, Y3, Y4 represent N or C-, wherein at least, two groups of Y1-Y4 represent carbon atom, R1 represents chlorine or bromine, R2-R7 represent, e.g. hydrogen, methyl or ethyl; and R10 and R11 independently represent, e.g. hydrogen or C1-C6alkyl, their optical isomers and pharmaceutically acceptable salts. Also, the invention refers to using said compounds for treating and preventing a number of acute and chronic mGluR5 related neurological disorders, such as, e.g. pains of various character, dyskinesia, Parkinson's disease, anxiety disorder, Alzheimer's disease and others, a pharmaceutical composition containing specified compounds and methods for preparing them.

EFFECT: compounds are strong mGluR5 modulators.

21 cl, 2 tbl, 274 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I): X denotes a single bond or a binding group selected from -CO, -SO2-, -CS- or -CH2-; Y denotes a single bond or a divalent binding group obtained from a cyclic structure selected from benzene, pyridine, pyrimidine, pyrazole, imidazole, thiazole, thiophene, quinoline, benzoimidazole, benzothiazole, benzopyrazole, naphthalene and benzothiophene; X and Y are simultaneously single bonds; Z denotes a hydrogen atom or a substitute selected from a group A; m equals 1 or 2; n equals 0-3; in group A and group B, R, R' and R" can, respectively and independently, be identical or different and denote a hydrogen atom or -C1-6-alkyl; said -C1-6-alkyl can be substituted with a group selected from -OH, -O(C1-6-alkyl),-CONH2, -CONH(C1-6-alkyl), -CON(C1-6-alkyl)2, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2); Sus denotes a C3-C7 saturated or a C5-C10 unsaturated hydrocarbon ring or a nitrogen-containing C3-C7 heterocyclic ring containing 1-4 nitrogen atoms or containing an additional O, S atom; said C1-6 alkylene in groups A and B can be substituted in positions 1-3 with a -N(C1-6- alkyl)2 group, values of radicals R1, A1, T, B and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a PI3K inhibitor and a medicinal agent having PI3K inhibitor properties against a proliferative diseases such as a malignant tumour.

EFFECT: high efficiency of using the compounds.

21 cl, 645 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to polymorph of 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazol-1-yl]ethanol, particularly to a new crystalline phosphate salt of 2-[4-(3-quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)pyrazol-1-yl]ethanol.

EFFECT: preparing the pharmaceutical composition and using the new salt in treating cell growth abnormalities, such as cancer in mammals.

10 cl, 10 dwg, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I in which: X8 denotes N, and X5 and X6 denote CH; R7 denotes phenyl or C5-6-heteroaryl group which is optionally substituted with one or more groups selected from halogen, hydroxy group, nitro group, cyano group, carboxy group and thiol, or phenyl or a methoxy group -C(=O)CH3, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)N(CH2CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -N(CH2CH3)2 or C1-4-alkyl, optionally substituted with a hydroxy group; RN3 and RN4, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperidinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; R2 denotes NRN5RN6, where RN5 and RN6, together with the nitrogen atom with which they are bonded, form a heterocyclic ring selected from morpholine, thiomorpholine, piperdinyl, piperazinyl, homopiperazinyl and a pyrrolidinyl ring, optionally substituted at the carbon atom with one or two C1-4-alkyl groups; or a pharmaceutically acceptable salt thereof, and where "C5-6-heteroaryl" denotes a heteroaryl group selected from furan, thiophene, pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tetrazole, octatriazole, isoxazine, pyridine, pyridazine, pyrimidine, pyrazine and triazine; and where "C3-5-heterocyclyl", as used here, relates to a univalent structure obtained by removing a hydrogen atom from the ring of the heterocyclic compound, where that structure contains 5 or 6 ring atoms, 1-4 of which are ring heteroatoms selected from oxygen, nitrogen and sulphur; and under the condition that when R2 denotes an unsubstituted morpholine group, RN3 and RN4, together with the nitrogen atom with which they are bonded, form a morpholine group, R7 does not denote an unsubstituted phenyl, and when R2 denotes an unsubstituted piperidinyl, RN3 and RN4, together with the nitrogen atom with which they are bonded, form an unsubstituted piperidinyl, R7 does not denote unsubstituted phenyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having mTOR inhibiting activity.

EFFECT: novel compound which can be suitable for treating malignant growths is obtained and described.

10 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, particularly to application of an antiviral agent - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-7-one dehydrate sodium salt (hereinafter - the Agent) for preventing and treating viral diseases caused by a tick-borne encephalitis virus. Also, there is described method for preventing and treating conditions caused by the tick-borne encephalitis virus in humans and animals involving introduction of the Agent presented above to humans and animals.

EFFECT: extended range of the drug preparations possessing a wide spectrum of action and used for treating and preventing tick-borne encephalitis.

20 cl, 2 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolo-[1,2-a]benzimidazole derivatives of formula I , where NR2 assumes morpholino or diethylamino values, and Ar is 4-methoxyphenyl or 4-chlorophenyl, having antioxidant and antiradical properties.

EFFECT: obtaining novel sulphates possessing useful biological properties.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a pharmaceutical composition for depression and anxiety disorder (versions). Pharmaceutical composition for at least one of depression and anxiety disorder containing ginsenoside Rg1 and Rb1; a glycyrrhizic acid derivative being an acid specified in a group consisting of glycyrrhizic acid, glycyrrhetinic acid and combinations thereof; and cyclic adenosine monophosphate of jojoba (cAMP of jojoba), taken in certain amount. The pharmaceutical composition for treating at least one of depression and anxiety disorder containing ginsenoside Rg1 and Rb1; and a glycyrrhizic acid derivative being specified in a group consisting of glycyrrhizic acid, glycyrrhetinic acid and their combination taken in specific proportions.

EFFECT: compositions are effective for treating depression and anxiety disorder.

7 cl, 6 dwg, 19 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered an anxiolytic and/or antidepressant drug which contains vitamin K2 in the amount of 10 mcg to 100 mcg as an active component, a food additive for the same application and an appropriate method of treating.

EFFECT: vitamin K2 (preferentially - menaquinone-4 and/or menaquinone-7) is safe to use for a long period of time and shows tranquilising action, particularly bland, antidepressant and antistress action.

4 cl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a composition for treating anxiety disorder. The pharmaceutical composition for treating anxiety disorder containing ginsenoside having Rg1 and Rb1; and a glycyrrhizic acid derivative being specified in a group consisting of glycyrrhizic acid, glycyrrhetinic acid and their combination taken in specific proportions. The pharmaceutical composition for treating anxiety disorder containing ginseng and liquorice taken in certain proportions.

EFFECT: compositions are effective for treating anxiety disorder.

8 cl, 6 dwg, 2 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, cardiology and cardiac surgery, and can be used for psychological rehabilitation of patients with prosthetic heart valves (PHV). Method includes studying index of development of anxious disorders in pre-operational and post-operational periods and carrying out procedures for patients who have undergone cardiosurgical operations, including drug therapy. In determination of anxiety higher level is considered to be from 31 points and higher, additionally performed are point massage and muscular relaxation successively with groups of muscles of arms, forearms, face, neck, shoulder girdle, abdomen, hips, ankles and feet. Relaxation with each group of muscles is performed for 5-10 seconds 2-3 times per week.

EFFECT: method improves results of treatment of patients with PHV due to complex impact taking into account reactive and personality anxiety.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, in particular to pharmacy. A composition for injections exhibiting tranquilising action contains the ingredients in the following proportions, wt %: crystalline β-modification of 7-brom-1,3-dihydro-5-(2-chlorphenyl)-2H-1,4-benzodiazepin-2-one - 0.05-0.15, polyvinylpyrrolidone - 0.50-1.20, "Tween-80" - 2.00-10.00, glycerine - 5.00-15.00, sodium pyrosulphite - 0.30-1.20, sodium hydrate solution - to pH 6.0-7.5, water - the rest. A method for preparing the composition consist in the fact that "Tween-80" and glycerine are mixed, heated to 70-90°C, and crystalline β-modification of 7-brom-1,3-dihydro-5-(2-chlorphenyl)-2H-1,4-benzodiazepin-2-one is dissolved. The prepared mixture is poured in the mixed aqueous solution of sodium pyrosulphite and polyvinylpyrrolidone heated to 40-90°C, cooled to room temperature, filtered, reduced to pH 6.0-7.5 with sodium hydrate solution, bottled and sterilised.

EFFECT: presented group of inventions provide a composition exhibiting improved anxiolytic action and decreased sedation in comparison with the composition based on pharmacopoeial phenazepam.

2 cl, 2 tbl, 4 ex

Mglur5 modulators // 2439068

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel compounds of general formula I:

(where values R1-R5, X and Z are defined in invention description), pharmaceutical composition, which contains them, and application of claimed compounds as MGLUR5 modulators for inhibition of transient relaxations of lower esophageal sphincter or for treatment or prevention of gastroesophageal reflux disease.

EFFECT: obtaining compounds for treatment or prevention of gastroesophageal reflux disease.

14 cl, 87 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is a biologically active substance showing 5-HT3-serotonin receptor antagonist properties, 1-piperidinopropyl-2-(4-fluorophenyl)imidazo[1,2-a]benzimidazole of formula I. The compound has been known as a local anaesthetic. There are shown evident 5-HT3-antagonist properties of the compound in the macromolar concentration equal to the reference preparation ondansetron with the compound of formula I being safer.

EFFECT: new properties of the compound can be used for creating the effective agents exhibiting antiemetic, anxiolytic and analgesic activities.

2 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and medicine. Claimed is application of N-carbamoyl-4-(n-methoxyphenyl)-2-pyrrolidone of structural formula as means possessing antidepressive, anxiolytic and nootropic action. This low-toxic compound (LD50 2263.88 mg/kg) possesses high antidepressive, anxiolytic and nootropic activity, affect of which is not accompanied by hypnosedative phenomena, or reduction of mental and physical work ability.

EFFECT: demonstrated is antidepressive and anxiolytic action of compound already in its single application, which makes the medication different from most known antidepressants, requiring at least one-week long intake to develop their effect.

7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where X denotes S; R1 and R2 taken together with atoms to which they are bonded form a 5-member carbocycle, substituted with up to two substitutes selected from alkyl and CF3; R3 is selected from a group consisting of a hydrogen atom and C1-8-alkyl; R3a denotes a hydrogen atom; R4 denotes a hydrogen atom; R4a denotes a hydrogen atom; R5 denotes a hydrogen atom; R5a denotes a hydrogen atom; R6 denotes a hydrogen atom; R6a denotes a hydrogen atom; R7 denotes a hydrogen atom; or pharmaceutically acceptable salts thereof. The invention also relates to compounds of the given formula, compounds selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which modulate serotonin receptor activity.

6 cl, 19 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described is a novel crystalline β-modification of 7-bromo-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one (phenazepam) and synthesis method thereof, which can be used in pharmaceutical industry and medicine as a tranquilliser. Said novel crystalline β-modification of 7-bromo-1,3-dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one is characterised by certain interplanar spacing (A0) and corresponding intensity and parameters of the crystal lattice, given in the claims.

EFFECT: marked muscle relaxant, soporific, anticonvulsant and anxiolytic action.

2 cl, 7 ex, 2 tbl, 9 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine and offers a new pharmaceutical composition for treatment of depression; the composition includes therapeutically efficient quantity of compound of the formula (I) or its pharmaceutically acceptable salt; and therapeutically efficient quantity of the selective serotonin reuptake inhibitor; the application of the compound of the formula (I) is offered for production of the medications to cure depressions.

EFFECT: invention provides the composition suitable for treatment of depressions without undesirable side effects associated with nonselective interaction of the receptors.

16 cl, 1 dwg

Up!