Pyrazolo[1,5-a]pyrimidine compounds, pharmaceutical composition showing ability to inhibit gabaa receptors, and drug for treating and preventing disorders associated with gabaa receptor inhibition

FIELD: medicine, pharmaceutics.

SUBSTANCE: pyrazolo[1,5-a]-pyrimidine compounds according to the invention are specified in a group consisting of: N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-ethylmethanesulphonamide; {2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2,4-difluor-5-[3-(thiophene_2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide and N-{5-fluor-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide.

EFFECT: preparing pyrazolo[1,5-a]pyrimidine compounds, their pharmaceutically acceptable salts and hydrates showing an ability to inhibit GABAA receptors, and applicable for treating and preventing anxiety, epilepsy and sleeping disorders, including insomnia, as well as for inducing a sedative-hypnotic, analgesic and sleeping effects and myorelaxation.

14 cl, 6 tbl, 4 dwg, 22 ex

 

The technical field to which the invention relates.

The present invention relates to exhibiting affinity for GABAAndreceptors, specifically to compounds pyrazolo[1,5-a]pyrimidine, and more specifically N-{2-Deputy-5-[3-Deputy-pyrazolo[1,5-a]-pyrimidine-7-yl]-phenyl}-N-methylacetamide and N-{2-Deputy-5-[3-Deputy-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methane-sulfonamide.

The level of technology

GABAAnd-receptor (γ-aminobutyric acid (A) is pentamers protein, which forms a membrane ion channel. GABAAndthe receptor is involved in regulation of sedation, anxiety, muscle tone, activity, leading to epilepsy, and the functioning of memory. These effects are due to different subunits of the GABAAnd-receptor, especially α1and α2-subunits.

Sedative effect is modulated α1-subunit. Zolpidem is characterized by high affinity to α1-receptors and sedative and hypnotic effects caused by these receptors in vivo. Similarly widespread effects of zaleplon also mediated α1-receptors.

Neuroleptic effects of diazepam is mediated by increased GABA-ergicheskoe migration in a population of neurons expressing α2-receptors. This indicates that α2receptors of t is Auda highly specific targets in the treatment of anxiety.

Myorelaxation when receiving diazepam mainly mediated α2receptors, because these receptors are highly expressed in the spinal cord.

Anticonvulsant effect of diazepam partially mediated α1-receptors. When receiving diazepam component that reduces the memory, anterograde amnesia mediated α1-receptors.

GABAAnd-receptor and α1and α2-subunit described by möller and colleagues (J. Pharmacol. Exp. Ther., 300, 2-8, 2002; Curr. Opin. Pharmacol., 1, 22-25, 2001); Rudolph and colleagues (Nature, 401, 769-800, 1999) and Chickpeas and colleagues (Br. J. Psychiatry, 179, 390-396, 2001).

Diazepam and other classical benzodiazepines are widely used as sedative agents, hypnotic agents, anticonvulsant agents, and muscle relaxants. Their side effects include anterograde amnesia, depression of motor activity and enhanced activity of alcohol.

In this context, the compounds of the present invention are ligands α1and α2-GABAAndreceptors for clinical use in sleep disorders, preferably insomnia, anxiety and epilepsy.

Insomnia is a common disease. Chronic form affects 10% of the population and 30% short form of the disease. Insomnia is characterized by problems with falling asleep or Probus the situation and is associated with the manifestation of the effects the next day such as fatigue, weakness, poor concentration and irritability. Important social contribution of this disease and its contribution to health, which leads to the obvious socio-economic consequences.

Pharmacological therapy in the treatment of insomnia primarily includes barbiturates and chloral hydrate, but these medications have numerous side effects, such as poisoning, overdose, increase metabolism, and the development of dependence and improve sustainability. In addition, they affect the structure of sleep by reducing its total duration and number of stages of REM sleep. The benzodiazepines have important therapeutic advantage due to its low toxicity, but still not solved the serious problem of addiction, myorelaxation, amnesia and resume symptoms of insomnia after discontinuation of the drug.

The latest known therapeutic approach is the use of benzodiazepine hypnotics stimulants, such as pyrrolo[3,4-b]pyrazine (zopiclone), imidazo[1,2-a]pyridine (zolpidem) and pyrazolo[1,5-a]pyrimidines (zaleplon). Later started the development of two new pyrazolo[1,5-a]pyrimidines, indiplon and ocinaplon, the latter with a strong sedative effect. All these compounds cause a quick sleep and have less expressive, the negative effects the next day less risk of drug abuse and reduced the risk of a relapse of symptoms of insomnia compared with benzodiazepines. The mechanism of action of these compounds lies in the allosteric activation of GABAAndreceptors by joining the binding site of the benzodiazepine (C.F.P.George, The Lancet, 358, 1623-1626, 2001). While benzodiazepines are non-specific ligand binding site of the GABAAnd-receptor, zolpidem and zaleplon show greater selectivity for α1the subunit. Despite this, these drugs still affect the structure of sleep and may cause dependence with long-term treatment.

A number of related pyrazolo[1,5-a]pyrimidines have been described in patent publications US 178449, US 4281000, US 4521422 (2-pyridinyl-[7-(4-pyridinyl)pyrazolo[1,5-a]pyrimidine-3-yl]metano, ocinaplon), US 4576943, US 4626538 (N-{3-[3-(Cyanophyta[1,5-a]pyrimidine-7-yl]-phenyl}-N-ethyl-ndimethylacetamide, zaleplon), US 4654347, US 6399621 (N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl }-N-methyl-acetamide", she indiplon), WO 2005014596, WO 2005014597 and in WO 2006136530.

The search for new active compounds for the treatment of insomnia is necessary for health, because even the recently released hypnotics however, change the structure of sleep and may cause dependence with long-term treatment.

However, it is desirable to focus on the development of n is o sleeping drugs with fewer side effects.

Disclosure of inventions

The authors present invention has opened new pyrazolo[1,5-a]-pyrimidines, which have activity against GABAAndand especially against its α1and α2-subunits. Therefore, the compounds of the present invention is effective for the treatment and prevention of diseases mediated and α2the subunits GABAAnd-receptor. Examples, not limiting the invention are sleep disorders, especially insomnia, anxiety and epilepsy. Not limiting the invention, examples of the relative indications of the compounds described herein are diseases and conditions, such as insomnia or anesthesia, require the induction of sleep, induction of sedation or induction of myorelaxation.

Structure zaleplon, the primary connection in a series of pyrazolo[1,5-a] pyrimidines, which is similar to the structure of the compounds of the present invention. However, zaleplon causes intense biotransformation by aldehides (B.G.Lake et al., Metabolism of zaleplon by human liver: evidence for involvement of aldehyde oxidase, Xenobiotica, 2002, Oct; 32 (10): 835-47; and K.Kawashima et al., Aldehyde oxidase-dependent marked species difference in hepatic metabolism of the sedative-hypnotic zaleplon, between monkeys and rats, Drug Metab Dispos. 1999 Mar; 27 (3): 422-8). Although the literature describes different pyrazolo[1,5-a]pyrimidine, more metabolically stable compared the Yu with zaleplon, this connection has the disadvantage of its toxic effect above that was shown in experiments on cell viability.

The sensitivity of the connections to the biotransformation is associated with their metabolic stability, i.e. the half-life of the drug in the body and the possibility of formation of metabolites. These parameters are important to evaluate the bioavailability, toxicity, and the possibility of dosing for interaction with other drugs, which in turn is an important parameter in the determination of their possible application for the treatment of humans. From this point of view, the connection with the maximum metabolic stability minimize possible interactions with other drugs and require more rarely receive doses of the drug.

Compounds of the present invention are less susceptible to spontaneous biotransformation, i.e. their metabolic stability is higher in comparison with other known related pyrazolo[1,5-a]-pyrimidine, which improves the pharmacokinetic profile, helping to keep pharmacological effect, and allows you to maintain sleep throughout the night for various indications. This property is connected with substitution of the phenolic ring, i.e. the substituents R3and R4. Particularly effective are compounds that are electron received from the remote will replace the lei in the phenolic ring.

In addition, the compounds of the present invention possess a strong sedative/hypnotic effect, as shown in the examples, and low toxicity, which has been shown in experiments on cell viability.

Thus, the present invention relates to compounds covered by the General formula (I):

and their pharmaceutically acceptable salts and hydrates, which are ligands GABAAnd-receptor, where R and R1represent alkyl(C1-C6), R2selected from the group consisting of cyano, a nitro-group and thiophene-2-carbonyl, R3selected from the group comprising hydrogen and halogen, R4selected from the group comprising hydrogen, halogen, alkyl(C1-C6), R5selected from the group comprising hydrogen and alkyl(C1-C6and Y vybivaetsja from the group consisting of-CO - and-SO2-; and pharmaceutically acceptable salts and hydrates.

Another object of the present invention is a new method of treatment or prophylaxis of anxiety, epilepsy and sleep disorders, including insomnia, and induction of sedative-hypnotic, anesthetic, hypnotic effects and myorelaxation by introducing a therapeutically effective quantities of these compounds or their pharmaceutically acceptable salts or hydrates.

The implementation of the image is etenia

As indicated above, the present invention relates to compounds of General formula (I):

and their pharmaceutically acceptable salts and hydrates, where R, R1, R2, R3, R4, R5and Y are as described above.

Used herein, the term "pharmaceutically acceptable salt" means any salt formed of organic or inorganic acid, such as Hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, Benzenesulfonic, benzoic, citric, econsultancy, formic, fumaric, glutamic, lactic, maleic, malic, malonic, almond, methansulfonate, 1,5-naphthalenesulfonate, oxalic acid, pavalova, propionic, p-toluensulfonate, succinic, tartaric acid and others.

Specific compounds according to formula (1) are selected from the group including:

N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,

N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,

N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,

N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,

N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,

N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylethanol is named,

N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,

N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,

N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,

N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,

N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide,

N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide,

N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-acetamide", she

N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-acetamide", she

N-{2,4-debtor-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide and

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

The following scheme of reactions illustrate the formation of compounds of the present invention.

Scheme 1

where R, R1, R2, R3, R4, R5and Y are such as defined above, and Q is the corresponding leaving group selected from the group comprising N(dialkyl(C1-C6)), alkylthio(C1-C6)and alkoxy(C1-C6)group. Preferably, Q is selected from the group comprising Dima is ylamino-, methylthio and methoxy group.

The reaction aminopyrazole General formula (III) with the compound, suitably substituted 1-aryl-2-propen-1-group, is carried out in an inert polar solvent, whether or not containing protons, such as glacial acetic acid, ethanol, methanol, dimethylformamide or dimethylsulfoxide at a temperature of from 50 to 130°C. after a few hours (the reaction time), the solvent removed and the resulting residue is separated and placed in an aqueous solution of sodium bicarbonate and dichloromethane. Coarse residue after evaporation of the organic layer to dryness can be cleaned using one of the following methods: (a) chromatography on silica gel in the presence of ethyl acetate or dichloromethane/methanol as eluent or (b) crystallization in a suitable solvent (ethyl acetate, ethanol, methanol etc).

The intermediate compound of formula (II), if Q is dimethylaminopropoxy [intermediate compound (VI)] can be obtained in the following sequence of reactions presented in figure 2:

where R, R1, R2, R3, R4, R5and Y are as described above. Intermediate compounds of formula (IV), where Y is sulfonyloxy group are in accordance with the method described R.H.Uloth et al. (J. Med. Chem. 9, 88-96, 1966).

Enaminone formula (V') and (VI) receive, in accordance with the traditional methods of synthesis of enamines described in J..Domagala et al. (J. Heterocyclic Chem., 26 (4), 1147-58, 1989) and K.Sawada et al. (Chem. Pharm. Bull., 49 (7), 799-813, 2001) by reacting the acetophenone with N,N-dimethylformamide by dimethylacetate (DMFDMA) or a reagent of Bredereck (tert-butoxybis(dimethylamino)methane).

Intermediates of formula (II), where Q is dimethylaminopropoxy, Y sulfonium, a R1- stands (VII)can be obtained in accordance with an alternative Scheme 3:

where R, R3and R4are as described above.

The conversion of (IV) to (VII) leads to the formation of enaminone and simultaneously to the formation of N-methylsulfonylamino as a result of the use of the properties of N,N-dimethylformamide of dimethylacetate as meteorologi agent.

Intermediates of formula (II), where Q is dimethylaminopropoxy, R1is stands (X)can also be obtained in accordance with Scheme 4:

where R, R3, R4and Y are as indicated the above.

The advantage of this method lies in the fact that education sulfonamida or carboxamide occurs at the last stage of the process. The result is the total number of steps of the method decreases when receiving large quantities of product. Moreover, as shown in the diagram, the conversion of (VIII) (IX) leads to the three subsequent reactions that occur simultaneously: (a) formation of enaminone, (b) methylation of trifurcated and (c) diallylamine, resulting in the formation of N-methylated amine. Subsequent reaction of (IX) with the corresponding sulfonic acid chloride or-carboxylic acid chloride leads to the production of intermediate products (X).

Compounds of the present invention or their pharmaceutically acceptable salts or hydrates may be used for the preparation of a medicine for the treatment and prevention of diseases associated with modulation of GABAAndreceptors in humans and other mammals. More specifically, for treating diseases associated with modulation of GABAAndreceptors, which are the diseases associated with modulation of α1-GABAAnd-receptor and/or α2-GABAAnd-receptor. The list of such diseases is not limited to anxiety, epilepsy, sleep disorders, including insomnia, and the like.

The fit is accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of drugs for the treatment of and prevention of anxiety in humans and other mammals.

In accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of a medicine for the treatment and prevention of epilepsy in humans and other mammals in need.

In accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of a medicine for the treatment and prevention of sleep disorders in humans and other mammals in need.

In accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of a medicine for the treatment and prevention of insomnia in humans and other mammals in need.

In accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of drugs for the induction of sedative-hypnotic effect in humans and other mammals need.

In accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of drugs for induction of anesthesia in humans and other mammals in need.

In accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of drugs for modulating the time required to induce sleep and its duration in humans and other mammals in need.

In accordance with another embodiment of the invention features the use of compounds of the present invention or their pharmaceutically acceptable salts or hydrates for the preparation of drugs for the induction of myorelaxation in humans and other mammals in need.

The present invention also relates to a method of treatment or prevention of diseases associated with modulation of GABAAndreceptors of humans and other mammals, which is the introduction to a specified person or other mammal, in need, a therapeutically effective quantity is of the compounds of the present invention or its pharmaceutically acceptable salt or hydrate together with pharmaceutically acceptable diluents or carriers. More specifically, diseases associated with modulation of GABAAndreceptors include diseases associated with changes in α1-GABAA-receptor and/or α2-GABAAnd-receptor. The list of such diseases is not limited to anxiety, epilepsy, sleep disorders, including insomnia, and the like.

The term "mammal" refers here representatives of Mammals are higher vertebrates. The term "mammal" includes humans, but not not limited to.

In accordance with another embodiment of the invention features a pharmaceutical composition comprising the compound of the present invention or its pharmaceutically acceptable salts or hydrates together with therapeutically inert carriers.

The composition of the invention may include carriers suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable mode of administration depends on the nature and severity of the condition of the patient undergoing treatment. The most preferred method of administration of the compounds of the present invention is the oral route of administration. The composition can be easily presented in the form of dosage form and prepared Lubims known in the pharmaceutical literature methods.

The active compound can be combined with a pharmaceutical carrier according to conventional pharmaceutical methods of preparation of medicines. The carrier may take a number of forms depending on the form of a medicinal product, it is necessary to incorporate, for example, oral or parenteral (including intravenous injection or infusion). In the preparation of compositions for oral administration can apply any of the usual pharmaceutical media. Traditional pharmaceutical environment include, for example, water, glycols, oils, alcohols, flavoring, preservatives, dyes, etc. in the case of oral liquid compositions (such as, for example, suspension, solution, emulsion or elixir), aerosols, or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating substances, sliding substances, binders, dezintegriruetsja substances and other, in the case of solid oral preparations (such as powders, capsules and tablets), and hard drugs are more preferable in comparison with liquid.

Because of the ease of introduction of the patient tablets and capsules represent the most preferred pharmaceutical dosage form for a drug, in this case, use solid pharmaceutical is e media. If necessary, the tablets may be coated in accordance with the water or waterless methods.

A suitable interval of dosage for use is from about 0.01 mg to about 100,00 mg daily, the dose is given once a day or divided into subdata, if required.

Compounds of the present invention have a high affinity for α1and α2-GABAAnd-receptors. The results obtained in vitro are consistent with the results obtained in vivo, in sedative-hypnotic research.

The pharmacological activity of the compounds of the present invention was determined, as described below.

a) Analysis of binding ligands. Determination of affinity of the analyzed compounds to α1and α2-GABAAndthe receptor.

In the experiment we used male rats Sprague-Dawley weighing 200-250 g After decapitate animal was removed cerebellum (fabric, containing mainly α1-GABAAnd-receptors) and spinal cord (fabric, containing mainly α2-GABAAnd-receptors). Membranes were prepared in accordance with the methodology proposed J.Lameh et al. (Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 24, 979-991, 2000) and H.Noguchi et al. (Eur. J. Pharm., 434, 21-28, 2002) with slight modifications. Weighed tissue suspended in 50 mm Tris-HCl (pH 7.4), 1:40 (vol./about.) or sucrose 0,32 M in the case of the spinal cord, homog who was nezirovi and then centrifuged at 20000 g for 10 minutes at 7°C. The precipitate resuspendable in the same conditions and centrifuged. Finally, the precipitate resuspendable a minimum and kept at -80°C overnight. The next day the procedure was repeated, sediment resuspendable at a ratio of 1:10 (vol./about.) in the case of procedures with the cerebellum and in the ratio of 1:5 (vol./about.) in the case with the spinal cord.

The affinity was determined using a competitive analysis using flumazenil with radioactive labeled as a ligand. Studies were performed in accordance with the techniques described S.Arbilla et al. (Eur. J. Pharmacol., 130, 257-263, 1986) and Y.Wu et al. (Eur. J. Pharmacol., 278, 125-132, 1995) 96-well microplate. Incubated the membrane containing the analyzed receptors, flumazenil (final concentration of radioactive label 1 nm) and increasing concentrations of these compounds (in total volume of 230 μl of 50 mm [pH 7,4] Tris-HCl). Simultaneously incubated alone membrane with flumazenil with a radioactive label (total binding 100%) and in the presence of increasing concentrations of flumazenil without radioactive label (nonspecific binding, the ligand with a radioactive label). Reactions were started by addition of the ligand with a radioactive label, and incubated for 60 minutes at 4°C. At the end of the incubation period, 200 μl of the reaction mixture was transferred to a tablet for micrometrology (Millipore) and Phi is trevali using a vacuum pump and then washed three times with cold buffer for the study. Tablets for micrometrology supplied filter GF/B filter remained membranes containing the receptor and the ligand with a radioactive label, which is associated with the receptor. After washing the plates were allowed to dry. The next day was carried out by counting using a scintillation counter, Perkin-Elmer Microbeta.

For analysis of the results was calculated the percentage of specific binding for each concentration of the analyzed compounds according to the formula:

% specific binding=(X-N/T-N)·100,

where

X - the amount of bound peroxidase ligand for each concentration of the compound,

T is the total binding, the maximum number of contacting the ligand containing radioactive tag,

N - non-specific binding amount of the ligand with a radioactive label, who contacted nonspecific, regardless of what was used receptor.

Each concentration of the studied compounds was analyzed three times and the average values were used to determine the experimental values of the percentage of specific binding, depending on the concentration of the compound. Data on the affinity expressed in % inhibition at concentrations of 10-5M and 10-7M for α1-subunit and 10-5M for α2-subunit. The results of these studies are presented in Tables 1 and 2 for the NGO.

Table 1
Affinity for α1the subunit of the GABAAndreceptor
Connection% inhibition of 10-5M% inhibition of 10-7M
The experimental sample 5of 98.242,3
The experimental sample 698,136,4
The experimental sample 1197,741,8
Experimental model 1398,739,8
Experimental model 1497,331,9
Zaleplon97,226,1

Table 2
Affinity for α2the subunit of the GABAAndreceptor
Soy is inania % inhibition of 10-5M
The experimental sample 594,5
The experimental sample 687,5
Connection% inhibition of 10-5M
The experimental sample 1195,0
Zaleplon77,4

b) determining the prognostic sedative-hypnotic activity in vivo.

The activity of these compounds in vivo was assessed using predictive sedative-hypnotic studies in mice (D.J.Sanger et al., Eur. J. Pharmacol., 313, 35-42, 1996 and G.Griebel et al., Psychopharmacology, 146, 205-213, 1999).

For studies used groups of 5-8 male CD1 mice weighing 22-26 g of the Investigated compounds were administered intraperitoneally one equimolecular dose, dissolved in 0.25% agar with a drop of Tween 80 in the volume of 10 ml/kg For each method of administration were analyzed by two doses. Control animals received only the carrier. Using the Smart System (Panlab, S.L., Spain) recorded the distance traveled in cm for each mouse at five-minute intervals for 30 minutes after intraperitoneal and is jaczie. Calculate the percentage of inhibition on distance travelled in animals treated vs. control (the first 5 minutes was discarded) and the values of the ED50. The results of this analysis are presented in Tables 3 and 4.

Table 3
The definition of sedative-hypnotic activity in vivo in mice
Connection% inhibition of motor activity
98 (μm/kg)
The experimental sample 589,0
The experimental sample 676,3
The experimental sample 11is 83.8
Experimental model 1395,6
Experimental model 1489,6
Zaleplon84,9

Table 4
The determination of the values of ED50when induction sedating the effect in mice
ConnectionED50(μm/kg)
The experimental sample 1116,9
Example 2 of WO 20051459630,1
Example 18 of WO 200514596to 19.9

Compared to other members of the pyrazolo[1,5-a]-pyrimidines as described in the literature, the compound of example 11 of the present invention has a significantly lower ED50. This means that the compound of example 11 is more active in vivo, because for the induction of therapeutic effect require a lower dose.

C) Determination of metabolic stability in vitro in the cytosolic fraction of human hepatocytes

Compounds were dissolved in dimethyl sulfoxide so that the initial concentration was 10 mm. This stock solution is then diluted with a solvent and a buffer to obtain a final concentration for the analysis of 5 μm. Compounds were analyzed at a single concentration of 5 µm twice incubare with 1.0 mg/ml polerowanie cytosole person (obtained from Xenotech plc) at 37°C. Metabolism was evaluated in the presence or absence of cofactors and measured as the flow of the original connection by means of the analysis of LC/MS in the time t is the customs 0, 60 and 120 minutes. Then calculate the percentage remaining of the original connection. The results are presented in Table 5. Used General LC method:

Mobile phase: A=0.1% of formic acid in water

In=0,1% formic acid in acetonitrile

Column for HPLC: Higgins Clipius C18 5 μm, 50×3 mm

Flow rate: 2 mlmin-1.

GradientTime% A% B
0,00955
2,00595
2,50595
2,60955
3,00955

Table 5
Metabolic stability in a fraction of cytosol Hepatol the s man
Connection% the original (parent)
60 minutes120 minutes
The experimental sample 68681
The experimental sample 118882
Zaleplon7968
Example 18 of WO 2005145967346

Suddenly compounds in experimental examples 6 and 11, it was observed that percentage (10-20%), the remaining parent compound compared to zaleplon and connection WO 200514596 was higher after incubation for 60 and 120 minutes. On the other hand, for zaleplon it was shown that the percentage of remaining connections at any point in time below, and biotransformation between 60 and 120 minutes above.

g) Determination of toxicity to cells in vitro in HepG2 cells, Cho-K1 and HeLa within 24 hours.

HepG2 (hepatocellular carcinoma cells) and CHO-K1 cells Chinese hamster ovary), obtained from the collection of the American Round Culture Collection (ATSS). HpG2 were cultured in minimum essential medium (MEM), containing saline Earl with 1,87 mm Glutamax®and supplemented with 1 mm sodium pyruvate, 0.1 mm nonessential amino acids, 100,000 Units/l penicillin, 10000 U/l streptomycin and 10% fetal bovine serum. SKO-K1 maintained in the medium ham's F-12 containing 1 mm Glutamax®and supplemented with 1 mm L-glutamine, 10000 U/l penicillin, 10000 μg/l streptomycin and 10% fetal bovine serum. System analysis Promega CellTiter 96®Aqueous One Solution Cell Viability contains salt tetrazole (MTS), which under the action of the enzyme with dehydrogenase activity in metabolically active cells is transformed into a soluble product formazan. The number of formazan in proportion to the number of living cells in culture.

Compounds were dissolved in DMSO so that the initial concentration was 100 mm. From this solution was preparing a series of dilutions in DMSO so that the concentration range was from 50 to 0.25 mm. Stock solution and a series of dilutions were then diluted 1:100 of the respective cultural environment. In the case of Cho-K1 cells were prepared in the concentration 1000, 500, 250, 100, 50, 25, 10, 5 and 2.5 μm in order to evaluate the IC50whereas in the case of HepG2 cells was analyzed target concentration of 1000, 100, 10 and 1 μm, in order to calculate a percentage of cells. The final concentration of DMSO in all wells was 1% (vol./vol.). Both cell lines were incubated with the test compounds at t the value of 24 hours. Relative cell viability was determined spectrophotometrically at 490 nm after adding dye MTS and subsequent incubation for 1 hour. As a positive control was used tamoxifen.

A similar Protocol was used to determine the toxicity to the cells in the experiment with HeLa cells for 24 hours. The results are presented in Table 6.

Table 6
Cytotoxicity to HepG2 cells, Cho-K1 and HeLa 24 hours
Connection% viable cellsIC50
HepG2 at 100 µmHeLa at 100 µmCHO
The experimental sample 1184,5%83,9%185,6 mcm
Example 1 (according to US 6399621 (indiplon)70%67,9%108,4 mcm

These results show that the compound of example 11 of the present invention are less toxic than the control connection indiplon, pascalc the survival of cells to compounds of example 11 above, compared with indiplon (84,5% vs. 70%) in the culture of HepG2 cells. These results are also confirmed by two other analyzed cell lines. Experimental example 1:

N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide

The mixture 0,048 g (0.38 mm) 4-nitro-2H-pyrazole-3-ylamine and 0.1 g (0.38 mm) of N-[5-(3-dimethylamino-acrolein)-2-forfinal]-N-methylacetamide 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness to obtain an oil, which was subjected to chromatography (on silica gel) using acetate-dichloromethane as eluent, thereby obtaining 61 mg (yield 49%) of solid N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide.

1H NMR (400 MHz, CDCl3): δ of 1.97 (3H, s), 3,29 (3H, s), 7,29 (1H, d, J=4.4 Hz), was 7.45 (1H, t, J=8,4 Hz), 7,89-8,02 (1H, m), 8.07-a of 8.09 (1H, m), 8,83 (1H, s), and 9.0 (1H, d, J=4.4 Hz).

MS (ES) m/z=330 (MH+).

HPLC=95,7%.

Experimental example 2:

N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide

The mixture 0,041 g (0.38 mm) of 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mm) of N-[-(3-dimethylamino-acrolein)-2-forfinal]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 95 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide (yield 81%).

1H NMR (400 MHz, CDCl3): δ a 1.96 (3H, s), or 3.28 (3H, s), 7,18 (1H, d, J=4.4 Hz), 7,42 (1H, t, J=8,8 Hz), 7,99-8,02 (1H, m), 8,09-to 8.12 (1H, m), 8,42 (1H, s), 8,79 (1H, d, J=4.4 Hz).

MS (ES) m/z=310 (MH+).

HPLC=97.8 per cent.

Experimental example 3:

N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide

The mixture 0,054 g (0,43 mm) 4-nitro-2H-4-pyrazole-3-ylamine and 0,120 g (0,43 mm) of N-[5-(3-dimethylamino-acrolein)-2-forfinal]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing the th dichloromethane, evaporated to dryness to obtain an oil, which was subjected to chromatography (on silica gel) using acetate-dichloromethane as eluent, thereby obtaining 35 mg (yield 24%) of solid N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide.

1H NMR (400 MHz, CDCl3): δ 1,90 (3H, s), 3,26 (3H, s), 7,30 (1H, d, J=4.4 Hz), to 7.77 (1H, t, J=8 Hz), to 7.93 (1H, dd, J=2.4 and 8.4 Hz), 8,08 (1H, d, J=2 Hz), 8,83 (1H, s), 9,01 (1H, d, J=4,8 Hz).

MS (ES) m/z=346 (MH+).

HPLC=91%.

Experimental example 4:

N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide

The mixture 0,046 g (0,43 mm) 5-amino-1H-pyrazole-4-carbonitrile and 0,120 g (0,43 mm) of N-[5-(3-dimethylamino-acrolein)-2-chlorophenyl]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 108 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide (yield 77%).

1H NMR (400 MHz, CDCl3): δ 1,90 (3H, s), of 3.25 (3H, s), 7,20 (1H, d, J4,4 Hz), 7,74 (1H, t, J=8,8 Hz), 7,94 (1H, dd, J=2.4 and 8.4 Hz), 8,10 (1H, d, J=2 Hz), 8,43 (1H, s), 8,80 (1H, d, J=4,8 Hz).

MS (ES) m/z=326 (MH+).

HPLC=97,7%.

Experimental example 5:

N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide

The mixture 0,043 g (0.33 mm) 4-nitro-2H-4-pyrazole-3-ylamine and 0.1 g (0.33 mm) of N-[5-(3-dimethylamino-acrolein)-2-forfinal]-N-methylmethanesulfonamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane.

The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness to obtain an oil, which was subjected to chromatography (on silica gel) using acetate-dichloromethane as eluent, thereby obtaining 58 mg (yield 48%) of solid N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide.

1H NMR (400 MHz, CDCl3): δ to 3.02 (3H, s), 3,39 (3H, s), 7,29 (1H, d, J=4.4 Hz), 7,38-7,42 (1H, m), 8,05-8,13 (2H, m), 8,83 (1H, s), 8,98 (1H, d, J=4.4 Hz).

MS (ES) m/z=366 (MH+).

HPLC=97,6%.

Experimental example 6:

N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide

The mixture 0.036 g (0.33 m the) 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mm) of N-[5-(3-dimethylamino-acrolein)-2-forfinal]-N-methylmethanesulfonamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane.

The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 81 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide (yield 70%).

1H NMR (400 MHz, CDCl3): δ 3,01 (3H, s), to 3.38 (3H, s), 7,29 (1H, d, J=4.4 Hz), of 7.36-7,41 (1H, m), 8,08-of 8.15 (2H, m), 8,42 (1H, s), 8,77 (1H, d, J=4.4 Hz).

MS (ES) m/z=346 (MH+).

HPLC=99,1%.

Experimental example 7:

N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide

The mixture 0,050 g (0,39 mm) 5-nitro-2H-pyrazole-3-ylamine and 0.124 g (0,39 mm) of N-[5-(3-dimethylamino-acrolein)-2-chlorophenyl]-N-methylmethanesulfonamide in 12 ml of glacial acetic acid was heated for 1.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. With the Oh, containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 56 mg of N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide (yield 77%).

1H NMR (400 MHz, CDCl3): δ is 3.08 (3H, s), to 3.38 (3H, s), 7,30 (1H, d, J=4.4 Hz), 7,71 (1H, d, J=8,4 Hz), of 8.04 (1H, dd, J=2 and 8.4 Hz), 8,14 (1H, d, J=2.4 Hz), 8,83 (1H, s), 8,99 (1H, d, J=4.4 Hz).

MS (ES) m/z=382 (MH+).

HPLC=98,5%.

Experimental example 8:

N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide

The mixture 0,042 g (0,39 mm) 5-amino-1H-pyrazole-3-carbonitrile and 0.124 g (0,39 mm) of N-[5-(3-dimethylamino-acrolein)-2-chlorophenyl]-N-methylmethanesulfonamide in 12 ml of glacial acetic acid was heated for 1.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 99 mg of N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide (yield 70%).

1H NMR (400 MHz, CDCl3): δ is 3.08 (3H, s), 3,37 (3H, s), 7,20 (1H, d, J=4.4 Hz), 7,69 (1H, d, J=8,8 Hz), with 8.05 (1H, dd, J=2.4 and 8.8 Hz), 8,16 (1H, d, J=1.6 Hz), 8,42 (1H, s), 8,78 (1H, d, J=4.4 Hz).

MS (ES) m/z=362 (MH+).

HPLC=93,7%.

Experimental example 9:

N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide

The mixture 0,046 g (0,39 mm) 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mm) of N-[5-(3-dimethylamino-acrolein)-2-forfinal]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 92 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide (yield 75%).

1H NMR (400 MHz, CDCl3): δ to 1.98 (3H, s), 2,61 (3H, s), and 3.3 (3H, s), to 7.09 (1H, d, J=4 Hz), 7,39-7,44 (1H, m), 7,89-8,02 (1H, m), 8,08-8,11 (1H, m), to 8.70 (1H, d, J=4.4 Hz).

MS (ES) m/z=324 (MH+).

HPLC=98,4%.

Experimental example 10:

N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl ndimethylacetamide

The mixture to 0.055 g (0,43 mm) 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0,120 g (0,43 mm) of N-[5-(3-dimethylamino-acrolein)-2-chlorophenyl]-N-methylate the foreign Ministry in 12 ml of glacial acetic acid was heated for 1.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 106 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide (yield 73%).

1H NMR (400 MHz, CDC3): δ at 1.91 (3H, s), 2,61 (1H, s), of 3.25 (3H, s), 7,10 (1H, d, J=4,8 Hz), 7,73 (1H, d, J=8,4 Hz), of 7.97 (1H, dd, J=2 and J=8 Hz), 8,08 (1H, d, J=2.4 Hz), 8,71 (1H, d, J=4.4 Hz).

MS (ES) m/z=340 (MH+).

HPLC=99,6%.

Experimental example 11:

N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]passedin-7-yl]-phenyl}-N-methyl-methanesulfonamide

The mixture 0,041 g (0.33 mm) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mm) of N-[5-(3-dimethylamino-acrolein)-2-forfinal]-N-methylmethanesulfonamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml in the water and was dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 66 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl }-N-methyl-methanesulfonamide (yield 55%).

1H NMR (400 MHz, CDCl3): δ 2,78 (3H, s), 3,17 (3H, s), of 3.54 (3H, s), 7,24 (1H, d, J=4.4 Hz), 7,51-7,56 (1H, m), 8,25-8,31 (2H, m), 8,84 (1H, d, J=4.4 Hz).

MS (ES) m/z=360 (MH+).

HPLC=98,9%.

Experimental example 12:

N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide

The mixture 0,048 g (0,39 mm) 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.124 g (0,39 mm) of N-[5-(3-dimethylamino-acrolein)-2-chlorophenyl]-N-methylmethanesulfonamide in 12 ml of glacial acetic acid was heated for 1.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 89 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide (yield of 60.5%).

1H NMR (400 MHz, CDCl3): δ 2,61 (3H, s), is 3.08 (1H, s), 3,66 (3H, s), 7,10 (1H, d, J=4,8 Hz),7,68 (1H, d, J=8,8 Hz), of 8.04 (1H, dd, J=2.4 and J=8,8 Hz), 8,15 (1H, d, J=2.4 Hz), to 8.70 (1H, d, J=4.4 Hz).

MS (ES) m/z=376 (MH+).

HPLC=98,1%.

Experimental example 13:

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

The mixture 0,074 g (0.38 mm) (5-amino-1H-pyrazole-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mm) of N-[5-(3-dimethylamino-acrolein)-2-were]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 132 mg of N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide (yield 88%).

1H NMR (400 MHz, CDCl3): δ of 1.87 (3H, s), is 2.37 (3H, s), of 3.25 (3H, s), 7,13 (1H, d, J=4 Hz), 7.18 in-7,20 (1H, m), 7,54 (1H, D, J=7,6 Hz), of 7.70 (1H, d, J=5,2 Hz), 7,94-7,98 (2H, m), 8,08 (1H, d, J=2,8 Hz), 8,71 (1H, s), 8,81 (1H, d, J=4 Hz).

MS (ES) m/z=391 (MN+).

HPLC=98,3%.

Experimental example 14:

N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide

The mixture 0,070 g (0.36 mm) (5-amino-1H-pyrazole-4-yl)-t is open-2-yl-methanone and 0.1 g (0.38 mm) of N-[5-(3-dimethylamino-acrolein)-2-methoxy-phenyl]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed to 135 mg of N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide (yield 92%).

1H NMR (400 MHz, CDCl3): δ 1,90 (3H, s), 3,23 (3H, s), of 3.97 (3H, s), 7,13 (1H, d, J=4,8 Hz), 7,17-7,21 (2H, m), of 7.70 (1H, D, J=4.4 Hz), 8,02 (1H, S), OF 8.09 (1H, d, J=4 Hz), 8,15 (1H, d, J=8,8 Hz), 8,71 (1H, s), 8,79 (1H, d,, J=4.4 Hz).

MS (ES) m/z=407 (MH+).

HPLC=100%.

Experimental example 15:

N-{2,4-debtor-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimid in-7-yl]-phenyl}-N-methyl-ndimethylacetamide

The mixture 0,217 g (1,12 mm) (5-amino-1H-pyrazole-4-yl)-thiophene-2-yl-methanone and 0.3 g (1,12 mm) of N-[5-(3-dimethylamino-acrolein)-2,4-differenl]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The body is ical layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 320 mg of N-{2,4-debtor-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide (yield 69%).

1H NMR (250 MHz, CDCl3): δ equal to 1.82 (3H, s), 3,11 (3H, s), of 6.96-7,06 (3H, m), 7,55 (1H, d, J=4.9 Hz), 7,76 (1H, t, J=8,2 Hz), to $ 7.91 (1H, dd, J=1 and 3.6 Hz), charged 8.52 (1H, s), 8,68 (1H, d, J=4,1 Hz).

MS (ES) m/z=413 (MH+).

HPLC=99,0%.

Experimental example 16:

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

The mixture 0,180 g (0,93 mm) (5-amino-1H-pyrazole-4-yl)-thiophene-2-yl-methanone and 0,275 g (0,93 mm) of N-[3-(3-dimethylamino-acrolein)-5-fluoro-2-methoxyphenyl]-N-methylacetamide in 10 ml of glacial acetic acid was heated for 2.5 hours, then the solvent was removed by evaporation under reduced pressure. To the resulting precipitate was added 15 ml of dichloromethane and 10 ml saturated sodium bicarbonate solution. Two layers were separated, the aqueous layer was washed twice with 10 ml dichloromethane. The organic layers were washed with 10 ml water and dried over magnesium sulfate. The layer containing dichloromethane, evaporated to dryness, to obtain the oil, which in the presence of ethyl acetate was formed 160 mg of N-{5-fluoro-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-ndimethylacetamide (yield 40%).

1H NMR (250 MHz, CDCl3): the 2,04 (3H, s)of 3.32 (3H, s), of 3.56 (3H, s), 7,09-of 7.25 (3H, m), 7,35 (1H, dd, J=2.2 and J=7,1 Hz), 7,72 (1H, d, J=4,9 Hz)to 8.12 (1H, d, J=3,8), 8,68 (1H, s), cent to 8.85 (1H, d, J=4 Hz).

MS (ES) m/z=425 (MH+).

HPLC=98,4%.

Example composition 1: tablets 5 mg

The active ingredient5.0 mg
Colloidal silicon dioxide0.6 mg
Crosscarmelose 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 to125,0 mg

Example composition 2: capsules 10 mg

The active ingredient 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
Indigotine E1320.02 mg
Microcrystalline cellulose to155,0 mg

An example of a song 3: oral drops

The active ingredient0.5 mg
Propylene glycol10.0 mg
Glycerin5.0 mg
Saccharin sodium0.1 mg
Polysorbate 80 1.0 mg
Flavoring Lemon0.2 mg
Purified water to100 ml

Example compositions 4: tablets 2.5 mg

The active ingredient2.5 mg
Colloidal silicon dioxide0.6 mg
Crosscarmelose 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 to125,0 mg

Example compositions 5: capsules 5 mg

The active ingredient5.0 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
Indigotine E1320.02 mg
Microcrystalline cellulose to155,0 mg

Example compositions 6: oral drops

The active ingredient0.25 mg
Propylene glycol10.0 mg
Glycerin5.0 mg
Saccharin sodium0.1 mg
Polysorbate 801.0 mg
Flavoring Lemon25.0 mg
Purified water to100 ml

1. Connection pyrazolo[1,5-a]pyrimidine selected from the group including:
N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
N-{2-chloro-5-[3-cyano-pyrazolo[l,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
N-{2-fluoro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,
N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,
N-{2-chloro-5-[3-nitro-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,
N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,
N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide,
N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide,
N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
N-{2,4-debtor-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide and
N-{5-fluoro-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylacetamide,
and their pharmaceutically acceptable salts and hydrates.

2. Compounds according to claim 1, selected from the group including:
N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methylmethanesulfonamide,
N-{2-chloro-5-[3-cyano-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide,
N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide,
N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidine-7-yl]-phenyl}-N-methyl-methanesulfonamide,
and their pharmaceutically acceptable salts and hydrates.

3. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment or prevention of diseases associated with inhibition of GABAAndreceptors in in need of such treatment of a human or other mammal.

4. The use according to claim 3, in which the GABAAndthe receptor is an α1-GABAAndthe receptor.

5. The use according to claim 3, in which the GABAAndthe receptor is an α2-GABAAndthe receptor.

6. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment or prevention of anxiety, mediated by the activity of HA IS TO Andreceptors in in need thereof of a human or other mammals.

7. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment or prevention of epilepsy, mediated by the activity of GABAAndreceptors, in need thereof of a human or other mammals.

8. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment or prevention of sleep disorders mediated by the activity of GABAAndreceptors, in need thereof of a human or other mammals.

9. The use of compounds according to claim 1 for preparing a medicinal product intended for the treatment or prevention of insomnia, mediated by the activity of GABAAndreceptors, in need thereof of a human or other mammals.

10. The use of compounds according to claim 1 for preparing a medicinal product intended for the induction of sedative-hypnotic effect, mediated by the activity of GABAAndreceptors, in need thereof of a human or other mammals.

11. The use of compounds according to claim 1 for preparing a medicinal product intended for the induction of anesthesia is mediated by the activity of GABAAndreceptors, in need thereof of a human or other mammals.

12. The use of compounds according to claim 1 for preparing a medicinal product intended for modulating the time required to induce sleep and its duration, mediated by the activity of GABAAndreceptors, in need thereof of a human or other mammals.

13. The use of compounds according to claim 1 for preparing a medicinal product intended for the induction of myorelaxation, mediated by the activity of GABAAndreceptors, in need thereof of a human or other mammals.

14. Pharmaceutical composition having the ability to inhibit GABAAndreceptors, and comprising a therapeutically effective amount of a compound according to claim 1 and an acceptable number of pharmaceutical excipients or carriers.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of general formula (I):

in the form of a separate stereoisomer or mixed stereoisomers or in the form of its pharmaceutically acceptable salt wherein R1 is indazolyl or substituted indazolyl; R6 is C6aryl or C6-12aryl substituted by halogen, hydroxy, cyano and C1-6alkoxy; or C6heterocyclyl containing 1-2 heteroatoms specified in nitrogen or oxygen; each X2 and X3 independently mean hydrogen, hydroxy or phosphate.

EFFECT: prepared compounds may be used for preparing a drug preparation for treating or preventing cancer, particularly acute myeloid leukemia.

6 cl, 6 tbl, 8 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

EFFECT: compounds of formula (I) are effective active agents for treating Hepatitis C viral (HCV) infection.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 4-amino-3-arylamino-6-arylpyrazolol[3.4-d]-pyrimidine derivatives showing antiviral activity. In formula I: the groups A and B independently represent phenyl, naphthyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, pyrazolyl, triazinyl, imidazolyl, furanyl, thienyl, and in each of these groups one to three hydrogen atoms can be independently substituted by the radical R1; R1 can be NO2, CN, CONR22, COOR2, CHO, CONH2, halogen, saturated or unsaturated, linear or branched alkyl with a number of atoms in the chain 1 to 7, saturated or unsaturated, linear or branched alkanole with a number of atoms in the chain 1 to 8, OR2, SR2, NR22, SO2NR32, di- or trifluoromethyl, phenyl; R2 represents hydrogen, CF3, and linear or branched alkyl with a number of atoms in the chain 1 to 7; the radical R3 represents H, benzyl, or linear or branched alkyl with a number of atoms in the chain 1 to 7; the radicals R4 and R5 represent hydrogen.

EFFECT: developing the method for preparing the compound of formula (I) and applying the compounds of the present invention as a biological agent exhibiting antiviral activity, eg for treating picornavirus infections.

9 cl, 6 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a novel compound - 6-(2'-amino-2'-carboxyethylthio)-2-methylthio-4-pivaloyloxy-methyl-1,2,4-triazolo[5,1-c] 1,2,4-triazin-7(4H)-one of formula having antiviral action and low toxicity.

EFFECT: compound can be used in medicine.

1 cl, 1 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and synthesis of heterocyclic compounds - 5,6-dihydro-7H-pyrrolo[1,2-d][1,4]benzodiazepin-6-one derivatives of formula 1a-e by boiling 2-amino-N-(2-furan-2-yl-phenyl)-acetamides in a mixture of glacial acetic acid and concentrated hydrochloric acid with subsequent treatment with sodium bicarbonate while boiling.

EFFECT: method is characterised by simple execution.

2 tbl, 5 ex

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

EFFECT: production of compounds possessing inhibition activity with regard to HIV reverse transcriptase.

22 cl, 3 tbl, 29 ex

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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide, and/or their mixture, as well as to applying it in a pharmaceutical composition, a method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease. Also, the invention refers to methods for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide and its intermediate compounds. .

EFFECT: developing the method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease.

12 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

Phytotranquiliser // 2452507

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry for the purpose of preparing drugs. The drug contains powdered herbs (valerian, motherwort, melissa, Greek valerian) and/or their dry concentrates and Vitamin C.

EFFECT: drug extends the range of tranquilisers for compensation of individual intolerance to certain components of known preparations and provides body recovery from stress consequences, enhances immunity, protects against free radicals accompanying stress.

3 cl, 3 ex

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

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: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

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