Naphthyridine derivatives as potassium channel modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula I, wherein W and Z represent CH; Y represents CH2; wherein R1 and R2 independently represent H, halogen, CH2F, CHF2, CF3, CF2CF3, or C1-C6alkyl; R' represents H; R3 and R4 independently represent H, or C1-C3alkyl, all mentioned C1-C3alkyl groups and mentioned C1-C6alkyl groups are independently substituted by one or two groups independently substituted by one or two groups independently specified in OH, halogen, C1-C3alkyl, OC1-C3alkyl or trifluoromethyl; q=1 or 0; R5 represents C1-C6alkyl; and to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a composition, a tablet and pharmaceutical syrup having potassium channel modulation activity and containing the compound of formula I, to a method of preventing and treating diseases that are affected by the activation of potentially opened potassium channels.

EFFECT: there are prepared and described the new biologically active compounds which may be effective in the prevention or treatment of diseases or disorders that are affected by potassium channel activity.

21 cl, 2 ex, 1 tbl

 

The technical field to which the invention relates.

The invention relates to new compounds that modulate potassium channels. Compounds are applicable for the treatment and prevention of diseases and disorders that affect the activity of potassium ion channels. One such condition are seizures.

The level of technology

Discovered that retigabine (ethyl ester of N-[2-amino-4-(4-forbindelsen)phenyl]carbamino acid) (patent of the United States No. 5384330) is effective in the treatment of disorders of the type of convulsive seizures in children. Bialer, M. et al., Epilepsy Research 1999, 34, 1-41. Also found that retigabine is applicable in the treatment of pain, including neuropathic pain. Blackburn-Munro and Jensen, Eur. J. Pharmacol. 2003, 460, 109-116; Wickenden, A.D. et al., Expert Opin. Ther. Patents 2004 14(4).

Form of epilepsy known as benign hereditary neonatal seizures", is associated with mutations in the KCNQ channels 2/3. Biervert, S. et al., Science 1998, 27, 403-06; Singh, N.A. et al., Nat. Genet. 1998, 18, 25-29; Charlier, C. et al., Nat. Genet. 1998, 18, 53-55, Rogawski, Trends in Neurosciences 2000, 23, 393-398. Subsequent studies have established that the main place of action retigabine is the KCNQ channel 2/3. Wickenden, A.D. et al., Mol. Pharmacol. 2000, 58, 591-600; Main, M.J. et al., Mol. Pharmcol. 2000, 58, 253-62. It is shown that retigabine increases the conductivity of the channels at the membrane resting potential and connects the gate of the activation of KCNQ channel 2/3. Wuttke, T.V. et al., Mol. Phamacol. 2005, 67, 1009-1017. With increasing improvements in research in this area found that retigabine increases neuronal M-currents and increases the probability of opening channels of KCNQ 2/3. Delmas, P. and Brown, D.A. Nat. Revs Neurosci., vol. 6, 2005, 850-62; Tatulian, L. and Brown, D.A., J. Physiol., (2003) 549, 57-63.

Recognition retigabine as modulators of potassium channels has caused many to seek other modulators of potassium channels among compounds with different structural characteristics in common with retigabine.

Disclosure of inventions

In one embodiment, the invention provides a compound of formula I

where W and Z independently represent CH or N; Y is CH2, O or NH;

where R1and R2independently represent H, a halogen, CH2F, CHF2, CF3, CF2CF3C1-C6alkyl, C(=O)C1-C6alkyl, CH2C(=O)C1-C6alkyl, NH-C1-C6alkyl, NHC(=O)C1-C6alkyl, C(=O)N(CH3)2C(=O)N(Et)2With(=O)NH-C1-C6alkyl, C(=O)OC1-C6alkyl, OC(=O)C1-C6alkyl, OC1-C6alkyl, SC1-C6alkyl, C3-C6cycloalkyl, (CH2)mC3-C6cycloalkyl, C3-C6cycloalkenyl, (CH2)mC3-C6cycloalkenyl, C2-C 6alkenyl, C2-C6quinil, Ar1, (CH2)mAr1, phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mPersil, furyl, thienyl, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolin, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl or (CH2)mpyrimidyl where these cycloalkyl and cycloalkenyl groups optionally contain one or two heteroatoms independently selected from O, N and S, and alkyl, cycloalkyl, cycloalkenyl, alkeline, alkyline, imidazolidine, pyrazoline, oxazolidine, isoxazolidine, thiazolidine, isothiazolinone, phenyl, pyrrolidine, peredelnye or piramidalnyi group optionally substituted by one or two groups independently selected from HE, halogen, cyano, methyl, ethyl or trifloromethyl, where m is zero, 1 or 2; or R1and R2together with the carbon atoms of the ring to which they are attached, form a 5 - or 6-membered condensed ring which may be saturated, unsaturated or aromatic, which optionally contains one or two heteroatoms independently selected from O, N and S and which is optionally substituted with halogen, CF3or C1-C3by alkyl; R' submitted is a N, halogen, CF3or C1-C3alkyl; R3and R4independently represent H, NH2, (C1-C3alkyl)NH, CN, halogen, CF3, OCF3OC1-C3alkyl or C1-C3alkyl, all of these C1-C3the alkyl group and the specified C1-C6alkyl group optionally substituted by one or two groups independently selected from HE, halogen, C1-C3of alkyl, OC1-C3the alkyl or trifloromethyl; q=1 or 0; R5represents a C1-C6alkyl, (CHR6)wC3-C6cycloalkyl, (CHR6)wCH2C3-C6cycloalkyl, CH2(CHR6)wC3-C6cycloalkyl, CR6=CH-C3-C6cycloalkyl, CH=CR6-C3-C6cycloalkyl, (CHR6)wC5-C6cycloalkenyl, CH2(CHR6)wC5-C6cycloalkenyl, C2-C6alkenyl, C2-C6quinil, Ar1, (CHR6)wAr1CH2(CHR6)wAr1or (CHR6)wCH2Ar1where w=0-3, Ar1represents phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl or imidazolyl, where C1-C6alkyl group optionally substituted by hydroxy, methoxy, methylthio or halogen and where cycloalkyl and cycloalkenyl group neo is Astelin substituted by one or two groups independently selected from HE, halogen, cyano, methyl, ethyl or trifloromethyl; R6represents hydrogen, methyl, halogen or methoxy, and its pharmaceutically acceptable salts. Such compounds are modulators of potassium channels.

In another embodiment, this invention provides or is considering a composition comprising a pharmaceutically acceptable carrier, excipient or diluent and at least one of the following components: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex and iv) its pharmaceutically acceptable MES.

In another embodiment, this invention provides or is considering a method of treatment or prevention of diseases or disorders affected by increased neuronal M-streams containing the introduction to the patient in need, one or more of the following components: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex and iv) its pharmaceutically acceptable MES.

In another embodiment, the invention provides a method of preventing or treating diseases or disorders which tion, affected by activation of potentially open potassium channels containing the introduction to the patient in need, one or more of the following components: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex and iv) its pharmaceutically acceptable MES.

In another embodiment, this invention provides or is considering a method of treating or preventing a seizure of the person introducing the patient who is affected or has the potential to defeat such a breach, one or more of the following components: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex and iv) its pharmaceutically acceptable MES.

In another embodiment, this invention provides or is considering a pharmaceutical preparation for oral administration containing a therapeutically effective amount of the compounds of formula I and any suitable tabletroute agent, or a suitable syrup for pediatric use.

In another embodiment, this invention provides or is considering a tablet for Perera inogo introduction, containing a therapeutically effective amount of the compounds of formula I and a suitable tabletroute agent.

In another suitable embodiment, this invention provides or is considering syrup for pediatric use, containing a solution or dispersion, or suspension of the compounds of formula I and a suitable syrup.

In another embodiment, this invention considers a pharmaceutical preparation for administration to animals, including animal companions (dogs and cats) and livestock containing a therapeutically effective amount of the compounds of formula I and a veterinary acceptable carrier.

In another embodiment, this invention considers a method of preventing or treating diseases or disorders that affect the activation of potentially open potassium channels, introducing an animal that is affected or has the potential to defeat such a breach, one or more of the following components: i) a pharmaceutically effective amount of the compounds of formula I; (ii) its pharmaceutically acceptable salts; (iii) pharmaceutically acceptable ether complex and iv) its pharmaceutically acceptable MES.

This invention includes all tautomers, salts and stereoisomeric forms of the compounds of formula I. This and the finding also includes all the compounds of this invention, in which one or more atoms replaced by their radioactive isotopes.

In more specific ogrodowa embodiment, this invention provides a compound of formula IA

In another more specific ogrodowa embodiment, this invention provides a compound of formula IB

In another more specific ogrodowa embodiment, this invention provides a compound of formula IA, in which W and Z both represent n

In another even more specific ogrodowa embodiment, this invention provides a compound of formula IA, in which W represents N and Z represents CH.

In another even more specific ogrodowa embodiment, this invention provides a compound of formula IA, in which W represents CH and Z represents N.

In another more specific ogrodowa embodiment, this invention provides a compound of formula IA in which R' represents H, halogen, CF3or methyl.

In another more specific ogrodowa embodiment, this invention provides a compound of formula IA, in which W and Z both represent N and R' represents H, F or methyl.

In another more to kratom ogrodowa embodiment, this invention provides a compound of formula IB, in which W and Z both represent n

In another more specific ogrodowa embodiment, this invention provides a compound of formula IB, in which W represents N and Z represents CH.

In another more specific ogrodowa embodiment, this invention provides a compound of formula IB, in which W represents CH and Z represents N.

In another more specific ogrodowa embodiment, this invention provides a compound of formula IB, in which R' represents H, halogen, CF3or methyl.

In another more specific ogrodowa embodiment, this invention provides a compound of formula IB, in which W and Z both represent N and R' represents H, F or methyl.

In more specific ogrodowa embodiment, this invention provides or is considering a compound of the formula IA, in which R5represents a C1-C6alkyl, (CHR6)wC3-C6cycloalkyl, (CHR6)wCH2C3-C6cycloalkyl or CH2(CHR6)wC3-C6cycloalkyl.

In more specific ogrodowa embodiment, this invention provides or is considering a compound of the formula IB, in which R5is Soboh the C 1-C6alkyl, (CHR6)wC3-C6cycloalkyl, (CHR6)wCH2C3-C6cycloalkyl or CH2(CHR6)wC3-C6cycloalkyl.

In even more specific ogrodowa embodiment, this invention provides or is considering a compound of the formula IA, in which R5represents a C1-C6alkyl, (CHR6)wC3-C6cycloalkyl, (CHR6)wCH2C3-C6cycloalkyl or CH2(CHR6)wC3-C6cycloalkyl and R1represents H, CF3or halogen.

In even more specific ogrodowa embodiment, this invention provides or is considering a compound of the formula IA, in which R5represents a C1-C6alkyl, substituted methoxy, methylthio or halogen; R' represents a methyl or H and R1represents H, CF3or halogen.

In another ogrodowa embodiment, this invention provides or is considering a compound of the formula I, in which R5represents CR6=CH-C3-C6cycloalkyl, CH=CR6-C3-C6cycloalkyl, (CHR6)wC5-C6cycloalkenyl, CH2(CHR6)wC5-C6cycloalkenyl, C2-C6alkenyl or C2 -C6quinil; R' represents a methyl or H and R1represents H, CF3or halogen.

In another more specific ogrodowa embodiment, this invention provides or is considering a compound of the formula IA in which R' represents a methyl or H; R1represents H, CF3or halogen; R3and R4represent methyl, aminomethyl or chlorine and R5represents Ar1, (CHR6)wAr1CH2(CHR6)wAr1or (CHR6)wCH2Ar1.

In another more specific ogrodowa embodiment, this invention provides or is considering a compound of the formula IA in which R' represents a methyl or H; R1represents H, CF3or halogen; R3and R4are methyl and R5represents a C1-C6alkyl, (CHR6)wC3-C6cycloalkyl, (CHR6)CH2C3-C6cycloalkyl or CH2(CHR6)C3-C6cycloalkyl.

In another more specific ogrodowa embodiment, this invention provides or is considering the connection of either formula IA or formula IB, in which R2represents H or F; R' represents H or halogen; R3and R4are METI and R 5represents a C1-C6alkyl, (CHR6)wC3-C6cycloalkyl, (CHR6)wCH2C3-C6cycloalkyl or CH2(CHR6)wC3-C6cycloalkyl.

In another more specific ogrodowa embodiment, this invention provides or is considering a compound of formula IA or formula IB, in which R5represents CHZCHZ-cyclopentyl or one of the following groups:

In another more specific ogrodowa embodiment, this invention provides or is considering a compound of the formula IA or IB, in which R1represents a halogen or halogenmethyl; R2represents H or halogen and R5represents one of the groups listed above.

In another more specific ogrodowa embodiment, the invention is redstavlyaet or consider a compound of the formula IA or IB, in which R1represents phenyl, pyridyl, pyrrolyl, (CH2)mimidazolyl, (CH2)mPersil, (CH2)moxazolyl, (CH2)misoxazolyl, (CH2)mthiazolyl, (CH2)misothiazolin, (CH2)mphenyl, (CH2)mpyrrolyl, (CH2)mpyridyl or (CH2)mpyrimidyl and R5represents a C5-C6alkyl or CH2-C3-C6cycloalkyl.

The following examples are provided to show - but no way to limit the various possible embodiments of this invention.

The implementation of the invention

During the development of compounds with therapeutic properties, superior therapeutic properties retigabine

the authors of the present invention found that a para-N-1,2,3,4-tetrahydroisoquinoline and carbamates of the formula I

have unexpected and unusual activity in relation to potassium channels, proving their high activity, measured in the following analysis of the outflow of rubidium.

Used in context, the term "modulator of potassium channels" refers to a compound that can cause increased flows of potassium channels. He also refers to the connection that can increase the probability of opening of the KCNQ channel 2/3. For preliminary testing compounds for their ability to modulate potassium channels, the inventors used the following test to the outflow of rubidium ions.

Consider this invention the compounds of formula I developed for oral or intravenous doses up to approximately 1200 mg per day. Thus, the present invention deals with the solutions or suspensions of the compounds of formula I, prepared for intravenous administration. Similarly, among many other examples are also discussed solutions or suspensions, containing in addition to the compounds of formula I, syrup, such as sorbitol or propylene glycol, are suitable for oral administration to the sick child. In addition, are also considered as pills taken with re what avyayam, and the tablets are taken without chewing, containing the compounds of formula I together with pharmaceutically acceptable tabletiruemye agents and other pharmaceutically acceptable carriers and excipients. Used in context, the term pharmaceutically acceptable carrier contains such excipients, binders, lubricants, tabletiruemye agents and dezintegriruetsja agents that are typically used in the manufacture of pharmaceuticals. Examples of such agents include, but are not limited to - microcrystalline cellulose, lactose, starch and dicalcium phosphate and provide. It also covers dezintegriruetsja agents, such as sodium salt glycolate, starch, lubricants such as stearic acid and SiO2and means to improve the solubility, such as cyclodextrins, among many other examples for each group. Such substances and methods of their use are well known in the pharmaceutical field. Additional examples are provided in Kibbe, Handbook of Pharmaceutical Excipients, London, Pharmaceutical Press, 2000.

The invention also covers pharmaceutical preparations comprising vaccinal preparations for the introduction of animals, including animal companions (dogs and cats) and livestock, such as cows, pigs, is the traders and horses, containing a therapeutically effective amount of the compounds of formula I and a veterinary acceptable carrier. However, any animal that is susceptible to convulsive attacks, included in the scope of this invention. A typical method of introduction may be intramuscular, oral administration or subcutaneous injection of from about 0.05 ml to 25 ml of vaccine preparation. However, as indicated above, the compounds of formula I developed for a dose of up to about 1200 mg per day. Vaccination can be performed by a single inoculation or through several inoculate. Consider vaccine compositions used in the methods of the present invention, may include one or more veterinary acceptable carriers. "Veterinary acceptable carrier" includes any and all solvents, dispersion medium, shell, adjuvants, stabilizing agents, diluents, excipients, preservatives, isotonic agents. The solvent may include water, saline, dextrose, ethanol, glycerol and the like. Isotonic agents may include, for example, sodium chloride, dextrose, mannitol, sorbitol and lactose. Adjuvants addressed by the present invention include saponin, cholesterol, gel, aluminum hydroxide, complete and incomplete adjuvants's adjuvant. In the present invention R is smatrivayutsya also vaccine preparations containing from about 1 mg/ml to about 2000 mg of adjuvant per dose of vaccine composition.

General schema

Part I. the formation of compounds of formula V are shown in figure 1.

Part II. Obtaining compounds of formula VII shown in scheme 2.

DMF - DMF

Part III. Obtaining compounds of formula IX are shown in figure 3.

base - base

Part IV. Obtaining compounds of formula X shown in scheme 4 Scheme 4:

Lawesson''s reagent is the reagent of Losona

Part V. the formation of compounds of the formula XI is shown in scheme 5.

Lawesson''s reagent is the reagent of Losona

Part VI. Obtaining compounds of formula XIII is shown in scheme 6.

Getting specific compounds

Synthesis of N-[2,6-dimethyl-4-(2-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthiridine-6-yl)phenyl]-3,3-dimethylbutyramide (11)

1-Benzyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (3)

A solution containing N-benzylpiperidine 1 (5 g of 26.4 mmol) and pyrrolidine 2 (2,82 g, to 39.6 mmol) in toluene (60 ml), was heated to boiling under reflux with azeotropic removal of water. The reaction mixture was then cooled and concentrated under reduced pressure. The resulting oil is astoral in the air, was dried over magnesium sulfate and concentrated under reduced pressure. The crude enamine 3 was used in the next stage.

6-Benzyl-2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthiridine (5)

To a solution of crude enamine 3 (500 mg, 2.1 mmol) in dioxane (5 ml) was added compound 4 (0.3 ml, 2.1 mmol) and the mixture was stirred at room temperature over night. Then was added ammonium acetate (20 mg) and the mixture was heated at the boil under reflux for 18 hours. The reaction mixture was then cooled to room temperature, acidified with 10% HCl, and was extracted with dichloromethane and concentrated. Purification preparative thin-layer chromatography (5% solution of DCM/MeOH) gave compound 5.

2-Trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthiridine (7)

To a solution of 5 (500 mg, 1.7 mmol) in dichloromethane (8 ml) was added compound 6, 3-chloropropionitrile (to 0.22 ml, 2.1 mmol) and the reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was then cooled to room temperature and concentrated. The resulting residue was dissolved in methanol (16 ml) and stirred at 40°C for 3 hours. The mixture was then cooled to room temperature and concentrated.

N-(4-Bromo-2,6-dimetilfenil)-3,3-dimethylbutyramide (8)

3,3-Dimethylbutanoate (3,37 g, 3.5 ml, 25 mmol) and triethylamine (2,53 g, 3.5 ml, 25 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)is nilina (5.0 g, 25 mmol) in acetonitrile (30 ml). The reaction mixture was stirred at room temperature for 4 hours. To the mixture was added water and the formed precipitate was collected, thus obtaining specified in the title compound in the form of powder (7,46 g, yield 100%).

N-[2,6-Dimethyl-4-(2-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthiridine-6-yl)phenyl]-3,3-dimethylbutyramide (11)

Bis(dibenzylideneacetone)palladium (15 mg, was 0.026 mmol) and (2'-dicyclohexylphosphino-2-yl)dimethylamine (40 mg, 0.1 mmol) was added to dry toluene (5 ml), purged with argon for 30 min) and the mixture was stirred for an additional 30 minutes at room temperature in argon atmosphere. Then was added tert-piperonyl potassium (188 g, 71 mmol), compound 7 (191 mg, 0.8 mmol) and compound 8 (200 mg, 0.67 mmol); the reaction mixture was stirred at 80°C over night. The reaction mixture was then cooled to room temperature, filtered through a bed of silica gel and was purified preparative TLC (5% solution of DCM/MeOH), while receiving the connection 11.

N-(2,6-dimethyl-4-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthiridine-6(5H)-yl)phenyl)-3,3-dimethylbutyramide

Bis(dibenzylideneacetone)palladium (4 mg, 0.069 mmol) and (2'-dicyclohexylphosphino-2-yl)dimethylamine (7 mg, 0.015 mmol) was added to dry toluene (1 ml, purged with argon and was stirred for 15 minutes in an argon atmosphere. Then to allali tert-piperonyl potassium (36 mg, 0.32 mmol), N-(4-bromo-2,6-dimetilfenil)-3,3-dimethylbutyramide (52 mg, 0,17 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthiridine (WO/04069162) (40 mg, 0.15 mmol) and the reaction mixture was stirred at 80°C over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% mixture of ethyl acetate:hexane), thus obtaining the desired compound in the form of solids.1H NMR (DMSO-d6, 400 MHz) δ of 1.05 (s, N), 2,11 (C, 6N), 2,17 (s, 2H), is 3.08 (t, J=5.6 Hz, 2H), to 3.64 (t, J=5,9 Hz, 2H), 4,48 (s, 2H), 6,76 (s, 2H), 8,08 (s, 1H), up 8.75 (s, 1H), 8,90 (1H).

The synthesis of other substituted tetrahydro-1,6-naphthirydines

Substitution in positions 2 and 3 tetrahydro-1,6-naphthirydines can be accomplished by condensation of 1-benzyl-4-piperidinol with the corresponding 3-aminoindane with subsequent dibenzylammonium (scheme II).

Alkylation of 5 - or 8-position tetrahydro-1,6-naphthirydines can be performed by chemical modification of the pyridine derivatives (see scheme III).

Biological results

Compounds of the formula this invention were evaluated as modulators of potassium channels by measuring the release of rubidium ion in the following analysis.

Methods: cells PC-12 were grown at 37°C and 5% CO2in the DMEM/F12, supplemented with 10% horse serum, 5% fetal calf serum, 2 mm glut is mine, 100 U./ml penicillin, 100 Units/ml streptomycin. They were seeded in covered D-lysine 96-well microplate for cell cultures at a density of 40,000 cells per well and were differentiated with 100 ng/ml NGF-7 within 2-5 days. To analyze the medium aspirated and cells were washed once with 0.2 ml of buffer for rinsing (25 nm HEPES, pH 7.4, 150 mm NaCl, 1 mm MgCl2, 0.8 mm NaH2PO4, 2 mm CaCl2). The cells were then loaded with 0.2 ml of a buffer to load Rb+(the buffer for washing plus 5.4 mm RbCl2, 5 mm glucose) and incubated at 37°C for 2 hours. Attached cells were rapidly washed three times with buffer (the same buffer as for the load Rb+but containing 5.4 mm KCl instead of RbCl) to remove extracellular Rb+. Immediately after washing, cells were added 0.2 ml of depolarization buffer (buffer for washing plus 15 mm KCl) without adding to the cells of the compounds or by adding compounds to activate the outflow channels potassium ions. After incubation for 10 min at room temperature, the supernatant was carefully removed and collected. Cells were literally by adding 0.2 ml of buffer for lysis (buffer depolarization plus 0.1% of Triton X-100) and also collected lysates of cells. If samples are not immediately analyzed for the content of Rb+atomic absorption spectroscopy (see below), they were stored at 4°C without any negative effects the subsequent analysis of the Rb +.

The concentration of Rb+in supernatant (Rb+sup) and cell lysates (Rb+Lys) quantitatively determined using plasma atomic absorption spectrometer ICR8000 (Aurora Biomed. Inc., Vancouver, B.C.) under the conditions specified by the manufacturer. Samples of 0.05 ml of titration microplate automatically processed breeding equal volume of buffer for analysis of the sample Rb+and injected into the flame air-acetylene. The quantity Rb+the sample was measured by absorption at 780 nm using a hollow electron beam lamp as light source and detector RMT. A calibration curve, which includes the range 0-5 mg/l Rb buffer analysis of the sample, were built for each set of tablets. The percentage of outflow Rb+(F) defined by the equation

F=[Rb+sup/(Rb+sup+Rb+Lys)]×100%.

The effect (E) of the compounds were determined by the equation: E=[(Fc-Fb)/(Fs-Fb)]×100%, where Fcrepresents the outflow in the presence of compounds in the buffer depolarization, Fbrepresents outflow in basal buffer, Fsrepresents a reversal in the buffer depolarization and F represents the outflow in the presence of compounds in the buffer depolarization. Build the graph of the action (S) connections from its concentration to calculate the value of the EU50 concentrations of compound for 50% of the maximum outflow Rb+. The results are shown below. Explanation of symbols:

And: EU50= 1 nm - 50 nm; In: EC50= 50 nm - 100 nm;: E50= 100 nm - 500 nm.

Activity approximate connection
CONNECTIONACTIVITY
And

retigabine

1. The compound of the formula I

where W and Z are CH; Y is CH2;
where R1and R2independently represent H, a halogen, CH2F, CHF2, CF3, CF2CF3or C1-C6alkyl;
R' represents H;
R3and R4independently represent H, or C1-C3alkyl, all of these C1-C3the alkyl group and the specified C1-C6alkyl group optionally substituted by one or two groups independently selected from HE, halogen, C1-C3of alkyl, OC1-C3the alkyl or trifloromethyl;
q=1 or 0;
R5represents a C1-C6alkyl;
and FA is matemticas acceptable salt.

2. The compound according to claim 1, which is a compound of formula IA

3. The compound according to claim 1, where R3and R4independently represent methyl.

4. The compound according to claim 1, where R3and R4both represent methyl and R5is neopentyl.

5. The compound according to claim 4, where R1represents F or CF3and R2represents H or F.

6. A compound selected from the group consisting of:


and

7. The composition having modulating activity against potassium channels, which contains a pharmaceutically acceptable carrier and at least one of the following components: i) a pharmaceutically effective amount of the compounds of formula I; and (ii) a pharmaceutically acceptable salt of the compounds of formula I.

8. The composition according to claim 7, in which the pharmaceutically acceptable carrier is microcrystalline cellulose.

9. The method of prevention or treatment of diseases or disorders that affect the activation of potentially open potassium channels containing the introduction to the patient in need, a therapeutically effective amount of the compounds of formula I according to claim 1 or the pharmaceutical preparations is automatic acceptable salt.

10. The method according to claim 9, where the disease or disorder is a seizure.

11. The method according to claim 10 where the compound of formula I is a compound of formula IA.

12. The method according to claim 9, where the compound of formula I selected from the group consisting of:


and

13. The method according to any of PP-12, where therapeutically effective amount is from about 300 mg to about 2000 mg per day.

14. The way to increase the probability of opening channels KCNQ2/3 mammal, introducing causing increased activity of the channels KCNQ2/3 mammal amount of the compounds of formula I or its salts.

15. The method according to 14, where the compound of formula I is a compound of formula IA.

16. A method of increasing neural M-threads in a mammal, containing the introduction to the specified mammal an effective amount of the compounds of formula IA or its salts.

17. Tablet for oral dosage administration, having modulating activity against potassium channels, which contains a pharmaceutically acceptable carrier and from about 100 to about 700 mg of the compounds of formula IA or its salts.

18. Tablet 17, further containing a lubricating substance./p>

19. Tablet 17, additionally containing disintegrity agent.

20. Tablet 17, where a tablet is a tablet taken projivaniem.

21. Pharmaceutical syrup for pediatric use with modulating activity against potassium channels, which contains per dose from about 100 to about 700 mg of the compounds of formula IA or its salts.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline modification of para-methoxyanilide of 6-hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo-[3,2,1-ij]quinoline-5-carboxylic acid of formula: (I) , which is obtained by crystallisation from ethyl acetate, where values of interplanar distance (d) and relative reflection intensities (Irel) are given in claim 1.

EFFECT: novel crystalline modification exhibits a high diuretic effect.

2 dwg, 9 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: chemistry.

SUBSTANCE: invention relates to complexes of lanthanides and organic ligands which are luminescent in the visible spectrum and are used in electroluminescent devices, means of protecting security paper and documents from falsification etc. Disclosed are novel luminescent coordination compounds of lanthanides of formula: where Ln is Eu3+, Tb3+, Dy3+, Sm3+, Gd3+.

EFFECT: said compounds have high luminescence intensity and considerable thermal tolerance of up to 400°C, which enables use thereof in modern production of light-emitting diodes.

4 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazo[4,5-b]pyrazine derivatives of general formula or to its pharmaceutically acceptable salt wherein: R1 represents either aryl unsubstituted or substituted by one of the groups: halogen, hydoxyl, C1-6alkyl, C1-6alkoxyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC1-6alkylC1-6alkoxy, C1-6alkylhydroxy, -C(O)NH2, -C(O)OC1-6alkyl, -C(O)NH C1-6alkyl, cyano, carboxy, heteroaryl and heterocycloalkyl; or heteroaryl unsubstituted or substituted by one of the groups: C1-6alkoxy, hydroxy, -C1-6alkyl, NH2 and NHC1-6alkyl; heterocycloalkyl unsubstituted or substituted by one group =O; and R2 represents H; unsubstituted C3-4alkyl; C1-4alkyl substituted by C5-6cycloalkyl unsubstituted or substituted by one group specified in amino, hydroxyl, C1-6alkoxy, or heterocycloalkyl unsubstituted or substituted by 1-2 groups specified in =O, C1-6alkyl; or C5-6cycloalkyl substituted by one group specified in hydroxyl, C1-6alkoxyl, C1-6alkylC1-6alkoxy, C1-6alkylhydroxy, CONH2; or substituted ir unsubstituted heterocycloalkyl; wherein aryl represents an aromatic structure consisting of 6-10 carbon atoms containing one ring or two condensed rings; wherein heteroaryl represents a 5-10-member aryl ring system containing 1-2 heteroatoms specified in nitrogen, oxygen and sulphur; wherein heterocycloalkyl represents a 5-9-member nonaromatic cycloalkyl wherein 1-2 heteroatoms specified in nitrogen and oxygen; provided the compound does not represent 1,3-dihydro-5-phenyl-2H-imidazo[4,5-b]pyrazin-2-one. Also, the invention refers to the specific imidazo[4,5-b]pyrazine derivatives, to a based pharmaceutical composition, to a method of treating or preventing cancer, inflammatory conditions, immunological diseases, metabolic conditions, and to a method of kinase inhibition in a cell expressing said kinase.

EFFECT: there are produced new imidazo[4,5-b]pyrazine derivatives showing effective biological properties.

17 cl, 2 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a phenylpyrazol derivative presented by formula (1) or to its pharmaceutically acceptable salt: wherein R1 and R2, which may be identical or different, each represents C1-C6 alkyl, or R1 and R2 are coupled together with an adjacent nitrogen atom to form a 5-6-merous saturated heterocylic ring (wherein the mentioned saturated heterocylic ring may be substituted by halogen or C1-C6 alkyl), n represents an integer 0 to 2, T represents a hydrogen atom, halogen or C1-C6 alkyl, and R has one of formulas (I)-(V), (VII) or (VIII):

(wherein Z1 and Z2, which may be identical or different, each represents -CH2-, -O- or -NR11-, p represents an integer 0 to 3, q represents an integer 0 to 1, r and s which may be identical or different, which represents an integer 0 to 2, R3 represents halogen, C1-C6 alkyl, or hydroxy, R4 and R5 which may be identical or different, each represents a hydrogen atom, C1-C6 alkyl (wherein said C1-C6 alkyl may be substituted by hydroxy, hydroxy- C1-C6 alkoxy, C2-C7 alkoxycarbonyl or carboxy), or formula -(CH2)m-Ar1 (wherein Ar1 represents wherein (wherein said phenyl is substituted by halogen or C1-C6 alkyl), and m represents an integer 0 to 1), R6 represents oxo, R7 represents a hydrogen atom or C1-C6 alkyl, R8 represents C1-C6 alkyl (wherein said C1-C6 alkyl may be substituted by halogen), C1-C6 alkoxy (wherein said C1-C6 alkoxy is substituted by halogen) or formula -(CH2)1-Ar2 (wherein Ar2 represents phenyl (wherein said phenyl is substituted by C1-C6 alkoxy, hydroxyl or cyano) or pyridinyl, and 1 represents an integer O to 1), G represents -CO- or -SO2-, R9 represents C1-C6 alkyl, C1-C6 alkoxy, phenyl (wherein said phenyl may be substituted by halogen or pyridinyl, and R11 represents C1-C6 alkyl)}.

EFFECT: there are produced new compounds and a preventive or therapeutic agent on the basis of said compounds which can find application in medicine for treating dementia, Alzheimer's disease, attention deficit/hyperactivity disorder, schizophrenia, epilepsy, convulsions of central genesis, eating behaviour disorders, obesity, diabetes, hyperlipidemia, sleep disturbances, narcolepsy, sleeping apnoea syndrome, circadian rhythm disorder, depression or allergic rhinitis.

12 cl, 3 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine and medical technology. A patient is exposed to electrical stimulation generated by the 'simpaticor-01' apparatus. A one-element electrode is placed in a projection of cervical ganglia, while a multiple-element electrode - on a patient's neck. The exposure to the field is paused. A convulsive readiness threshold is assessed. Neurometabolic preparation dosage is specified in accordance with age, while anticolvulsants are dosed as per manufacturer's recommendations. Amplitude, frequency and length of the current pulse field, length of exposure and pauses are specified individually for each patient so that in the process of treatment and later on, the convulsive readiness threshold tends to decrease in the form of reducing a number of paroxysmal sharp and slow waves, as well as elimination of epileptoid activity.

EFFECT: method provides higher clinical effectiveness ensured by combining drug-induced therapy with electrical stimulation of the vegetative nervous system.

7 dwg, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition contains a biologically active substance presented by 2-ethyl-6-methyl-3-oxypyridine succinate sorbed on a polymer carrier which is presented by polybutylcyanoacrylate nanoparticles or lactic and glycolic acid copolymer nanoparticles, and pharmaceutically acceptable substances in the following proportions, wt %: polymer carrier - 0.1-10, 2-ethyl-6-methyl-3-oxypyridine succinate - 0.1-5, excipients - the rest.

EFFECT: composition is high-effective in treating paroxysmal conditions; it has mild side effects.

6 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition showing anticonvulsant activity on the basis of phenobarbital and a non-steroidal anti-inflammatory agent (fenamate) taken in molar ratio 23:5. The pharmaceutical composition is presented in the form of a dosage form for parenteral introduction and contains sodium phenobarbital 233 mg, sodium mefenamate 31.0 mg or sodium tolfenamate 33.5 mg, 1,2-propylene glycol 400 mg and ethanol 100 mg as stabilisers and hydroxypropyl-β-cyclodextrin 200 mg as an agent for prolonged release and reduced irritation, and distilled water for injections.

EFFECT: anticonvulsant composition possess high protective anticonvulsant efficacy in emergency management of convulsant poisoning, storage stability, low toxicity, high therapeutic range, prolonged action and minimally manifested local irritant action in parenteral introduction.

3 dwg, 7 tbl, 8 ex

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

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention discloses applying 3-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid or its pharmaceutically acceptable salt in preparing a drug for treating or preventing restless leg syndrome in a patient or for improving sleep in a patient suffering restless leg syndrome. There are also described pharmaceutical compositions for treating or preventing restless leg syndrome and for improving sleep in a patient with restless leg syndrome, containing a therapeutically effective amount of 3-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid or its pharmaceutically acceptable salt.

EFFECT: preparing the pharmaceutical compositions for treating or preventing restless leg syndrome and improving sleep in a patient with restless leg syndrome.

31 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neurology, and can be used in treatment of muscle spasticity in patients with spinal cord injury. For this purpose botulotoxin is introduced into iliolumbar muscle under control of X-ray computer tomography. Introduction of preparation is performed by dorsal access into proximal part of iliolumbar muscle at the level of LII-LIII vertebrae, 2-3 cm more laterally than spinous process. Depth of introduction is 8-10 cm.

EFFECT: method makes it possible to ensure efficient relief of local spasticity of iliolumbar muscle with absence of botulotoxin effect on other groups of muscles due to accurate introduction of preparation into definite region of said muscle.

2 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: present invention refers to new compounds of formula (I) or to its stereoisomers, or to a pharmaceutically acceptable salt, wherein Ra represents H or (C1-C6)alkyl; Rb is specified in an optionally substituted group consisting of -(CH2)n-aryl, -CH(CH3)-aryl, -(CH2)n-arylaryl, -(CH2)n-arylheteroaryl, -(CH2)n-(C3-C8) cycloalkyl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl and -(C3-C8) cycloalkylaryl; or Ra and Rb taken together with a nitrogen atom form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl; Y is specified in an an optionally substituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl, -NH-(CH2)n-heterocyclyl, wherein NH is attached to carbonyl, and -heterocyclylaryl, wherein heterocyclyl is attached to carbonyl; and n is equal to 0, 1 or 2; wherein each heterocyclyl represents an independent non-aromatic ring system containing 3 to 12 ring atoms, and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; wherein each heteroaryl represents an independent non-aromatic ring system containing 3 to 12 ring atoms and at least one ring atom specified in a group consisting of nitrogen, oxygen and sulphur; and wherein the optional substitutes are independently specified in a group consisting of C1-C6-alkyl, C1-C6-alkoxy, halogen, CN, CF3, OCF3, NH2, NH(CH3), N(CH3)2, hydroxy, cyclohexyl, phenyl, pyrrolidinyl, -C(O)-piperidinyl, -N(H)-C(O)-C1-C6-alkyl and N(H)-S(O)2-C1-C6-alkyl. The invention also describes a pharmaceutical composition having chemokine receptor antagonist activity and a method of treating such diseases, such as rheumatoid arthritis, psoriasis, lupus, etc.

EFFECT: there are prepared and described new chemical compounds that can be used as chemokine receptor antagonists and, as such, may be used in treating certain pathological conditions and diseases, particularly inflammatory pathological conditions and diseases and proliferative disorders and conditions, eg rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

23 cl, 59 ex, 2 tbl

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