Water-soluble complex of cis-diaminodichloroplatinum (2+) with isoniaside and method of preparing said complex

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining physiologically active compounds, particularly to a new water-soluble complex of cis-diaminodichloroplatinum (2+) with isonicotinic acid hydrazide of formula Pt(NH3)2Cl2·2L, where L=INH is isoniaside, isonicotinic acid hydrazide. The method of preparing the complex involves reacting cis-diaminodichloroplatinum (2+) with isonicotinic acid hydrazide with subsequent extraction of the end product.

EFFECT: compound widens the range of water-soluble anti-tumour and anti-metastatic preparations; can be used in medical practice as an analogue of cisplatin on therapeutic effect, but in a more convenient form of administration due to its high solubility and low toxicity.

3 cl, 6 dwg, 1 ex

 

The invention relates to physiologically active compounds and can be used in medical practice for the treatment of cancer as an independent drug and in combination with known drugs.

It is known that cisplatin (CIS-Diaminedichloroplatinum (2+)) (commercial synonyms: Platinum, Platidiam, Platinol) is widely used in practice for chemotherapy of cancer patients. Cisplatin is a crystalline powder from yellow to yellow-orange color, which slowly and very slightly soluble in water and isotonic sodium chloride (Mashkovsky PPM Drugs, ed. 12-E. - M.: Medicine, 1992, str-524).

Despite the poor solubility of compounds in water and aqueous solutions, the main method of use of cisplatin therapy is intravenous. For this purpose, the drug is dissolved 10 mg of dry matter per 10 ml of sterile water for injection, and the solution diluted in 1 l of isotonic sodium chloride solution or 5% glucose solution. To increase the solubility of cisplatin before the introduction of the solution recommended preheat temperatures of 30-36 degrees Celsius. The solution is injected jet (slow) or in the form of prolonged infusion (during onset 6 to 48 h).

A method of obtaining CIS-diaminedichloroplatinum is Tina (4+) of CIS-diaminedichloroplatinum (2+) by treating the suspension of cisplatin 30%hydrogen peroxide at 60-80°C, followed by separation of the solid residue (SU 1137698 A1, Jelihovsky NN. and others, 17.10.1983). It is shown that when carrying out chemical transformations embedded hydroxy-group do not affect the steric accommodation chlorine - and amino-groups.

Also known derivatives of cisplatin, where one of the ligands are replaced by other biogenic ligands for the purpose of lowering the overall toxicity of cisplatin (US6548541, Shaw, 15.04.2003; US7160908, Shaw, 09.01.2007) and the establishment of its soluble form (RU2151740 C1, Jelihovsky NN. and others, 27.06.2000).

The present invention is to develop a previously unknown complex compounds cisplatin (bivalent platinum), namely complex CIS-diaminedichloroplatinum (2+) with isonicotinic acid hydrazide (isoniazid), higher solubility and reduced toxicity, which allows you to refuse the stage of lyophilization in the process of getting the dosage form and facilitate its use, and method of its production.

The new compound is a derivative of cisplatin (CIS-diaminedichloroplatinum) formula: Pt(NH3)2Cl2·2L, where L=INH (isoniazid, isonicotinic acid hydrazide).

To obtain the compounds (1) one part of cisplatin mixed with 2 parts of the polymer, in solution, at the temperature of the solution in the range of 50-80°C with constant stirring for 48 hours before coord is a homogeneous solution. The compound obtained is filtered through standard microbiological filter with a pore size of 0.22 μm to remove insoluble fractions.

Patent-pending compound is new, not described in literature, is not known and the method of its production.

Below is a detailed description of the method of obtaining a patent pending compound - complex compounds CIS-diaminedichloroplatinum (2+) with isonicotinic acid hydrazide.

Prepared in a solution 0.274 g (0.002 mole) of the hydrazide of isonicotinic acid in 5 ml of water. The resulting solution was heated to a temperature of 50°C and added to it 0.300 g (0.001 mol) of CIS-diaminedichloroplatinum (2+). After mixing of the reagents, the reaction mixture was stirred 48 hours at 50°C. the resulting solution was filtered through standard microbiological filter with a pore size of 0.22 μm (the company Millipore). The obtained filtrate was concentrated in vacuum. Received 0.563 g (98%) of a substance in the form of a glassy film of light-yellow color. The complex is soluble in water, which greatly simplifies the work with him on biological objects, and this is a technical result of invention.

The structure and composition of the obtained complex compounds were proved by UV and NMR spectroscopy and elemental analysis, and the resulting spectra are shown in figure 1-6:

figure 1 shows an NMR spectrum1N ishodnoj is isoniazid;

figure 2 is an NMR spectrum1N. a mixture of isoniazid + complex;

figure 3 is an NMR spectrum1N. a mixture of isoniazid + complex (through the year);

figure 4 is an NMR spectrum1N. a mixture of isoniazid + complex (80°C);

figure 5 is an NMR spectrum1N. a mixture of isoniazid + complex (after passing through the SiO2, eluent - Meon:N2O 3:1);

figure 6 - absorption spectra of a solution of 10-2M isoniazid in water (curve 1), solutions of the complex in water with a concentration of 5·10-2M (curve 2) and ≈10-2M (curve 3) (optical path of 0.1 cm).

It is seen that the NMR spectrum1N of the received complex compared with the spectrum of the source isoniazid observed shift of the signals of aromatic protons in the weaker field, which indicates the formation of new connections. The value of the constant of spin-spin interaction is 6.3 Hz, 1 Hz more than the original ligand.

The stability of the complex was confirmed by the preservation of the NMR spectrum after keeping the solution of the complex in the course of the year, heating the solution to a complex of up to 80°C and after passing a solution of the complex through the column with silicagel (SiO2), eluent CH3HE:N2O=3:1. The last shows the possibility of additional purification of the resulting complex.

Elemental analysis.

C12H20Cl2N8O2Pt

Found 1(%): 25.48; N, 3.6; CL 16.13; N, 12.80; Pt 32.29;.

Found 2(%): 25.18; N, 3.70; CL 14.00; N at 14.86; Pt 33.01;.

Calculated (%): 25.09; N, 3.48; CL 12.37; N 19.51; Pt 33.97.

Thus, the proposed method for obtaining compounds of formula (1) can achieve the goal of the invention and to obtain previously unknown water-soluble complex compound cisplatin, namely the complex CIS-diaminedichloroplatinum (2+) with isonicotinic acid hydrazide. The compound obtained can be used in medical practice as an independent antitumor and antimetastatic drugs and in combination with already known drugs.

Tests for acute toxicity was performed by intraperitoneal administration of a solution of the drug to mice BDFi. As the comparison drug used source cisplatin. Tests showed that the proposed complex when calculating the number of entered platinum has several times less toxicity compared to the original cisplatin, with activity against all species tested tumors, which operates cisplatin remains the same or increases.

These findings indicate that physiological activity of cisplatin bound to the complex in relation to neoplastic processes virtually unchanged, acute toxicity decreased, and ease of use with a Ter the FDI has increased significantly.

1. Water-soluble complex CIS-[diaminedichloroplatinum (2+)] isonicotinic acid hydrazide of the formula (1)

2. The method of obtaining water-soluble complex of General formula 1 according to claim 1, characterized in that the processing of CIS-diaminedichloroplatinum (2+) is conducted at a temperature of 50-80°C With a solution of the hydrazide of isonicotinic acid at a molar ratio of CIS-diaminedichloroplatinum (2+) / isonicotinic acid hydrazide, equal to 1:2, followed by the separation of the insoluble residue and the selection of the target product.

3. The method according to claim 2, characterized in that first prepare a 0.4 molar aqueous solution of the hydrazide of isonicotinic acid, is heated to a temperature of 50°C and add to 0.001 mole of CIS-diaminedichloroplatinum (2+) obtaining the reaction mixture, then the reaction mixture is stirred at a temperature of 50-80°C for 48 h and filtered, and the filtrate was concentrated in vacuo with the separation of the target product.



 

Same patents:

FIELD: process engineering.

SUBSTANCE: invention relates to complete methane oxidation catalysts and can be used in industries using diesel fuel. Invention covers complete methane oxidation catalysts based on strontium hexaferrites of the following composition: SrMnxFe12-xO19, where x=0, 1, 2, 6. Proposed method comprises settling catalyst components with the help of NH4HCO3 solution at constant pH equal to (7.1 to 8.0) and temperature not lower than 70°C with subsequent stages of filtration, rinsing, drying and roasting. Proposed method comprises also the stage of heat treatment at 800° to 1000° C and is realised in the presence of above described catalysts.

EFFECT: high degree of methane conversion at relatively low temperatures.

6 cl, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: method of obtaining palladium acetate involves dissolving palladium metal in concentrated nitric acid, evaporation of the obtained solution and reaction with acetic acid, where the palladium nitrate solution after evaporation, before crystallisation of palladium (II) nitrate salt, is treated with nitrogen (II) oxide or a mixture of nitrogen (II) and (IV) oxides containing not more than 30% nitrogen (IV) oxide and acetic acid at temperature of the solution of 40-90°C with glacial acetic acid consumption of 1.5-2.5 l per kg of palladium in the solution and nitrogen (II) oxide or mixture of nitrogen (II) and (IV) oxides consumption of 1.0-2.0 m3 at normal conditions per 1 l of the initial palladium nitrate solution for 0.5-1.5 hours and the formed solution is heated in a nitrogen atmosphere at 110-140°C for not less than 2 hours with consumption of elementary nitrogen of approximately 30 m3 per 1 m3 of the formed solution.

EFFECT: obtaining palladium acetate in monophase state and avoding formation of impurities of insoluble palladium catena-poly-acetate.

3 cl, 35 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a polyolefin synthesis method and more specifically to a polyethylene synthesis method. Polyethylene is a copolymer of ethylene with 1-alkenes. The invention also relates to polyethylene synthesis catalyst systems. The catalyst system is a mixture of metallocenes: hafnocene and an iron-based complex, an activating compound and a support. The invention also relates to films made from polyethylene and packets made from the said films.

EFFECT: disclosed catalyst system enables production of polyethylene with given molecular weight distribution in a single reactor.

16 cl, 3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a polyolefin synthesis method and more specifically to a polyethylene synthesis method. Polyethylene is a copolymer of ethylene with 1-alkenes. The invention also relates to polyethylene synthesis catalyst systems. The catalyst system is a mixture of metallocenes: hafnocene and an iron-based complex, an activating compound and a support. The invention also relates to films made from polyethylene and packets made from the said films.

EFFECT: disclosed catalyst system enables production of polyethylene with given molecular weight distribution in a single reactor.

16 cl, 3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: method involves reaction in aqueous medium of a diaquaplatinum or bis(nitrato)platinum complex in a mixture with dihalogenoplatinum with a block-copolymer of formula (1): or (2):, where R1 represents hydrogen or C1-C12-alkyl, L1 and L2 - connecting groups, R3 - hydrogen, a protective group for amino groups, a hydrophobic or polymerised group, R4 represents hydroxy-, carboxy- or a hydrophobic group, R5 represents hydrogen, an alkali metal ion or a protective group for the carboxylic group, m=5-20000, n=10-60, under the condition that, R5 - hydrogen or an alkali metal ion constitutes 50% or more in n links.

EFFECT: obtaining a conjugate which does not contain silver ions, the solution of which has lower particle-size distribution.

17 cl, 11 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organometallic chemistry, specifically to a method of preparing a catalyst for metathesis polymerisation of dicyclopentadiene -[1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-N,N-dimethylaminomethylphenyl methylene)ruthenium. The method involves reacting a triphenylphosphine complex of ruthenium with 1,1-diphenyl-2-propin-1-ol in tetrahydrofuran while boiling in an inert atmosphere, and then with tricyclohexylphosphine at room temperature in an inert atmosphere. The indenylidene ruthenium complex formed is separated and successively reacted in a single reactor with 1,3-bis(2,4,6-trimethylphenyl)-2-trichloromethylimidazolidine and 2-(N,N-dimethylaminomethyl)styrene in toluene while heating in an inert atmosphere.

EFFECT: method increases output of product.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing iron (II) oxalate by directly reacting metal with acid in the presence of atmospheric oxygen and a liquid phase while stirring. The process is carried out in a bead mill. The liquid phase solvent used is water with mass ratio of the liquid phase to glass beads equal to 1:1, content of oxalic acid in the initial load is between 0.5 and 2.0 mol/kg, and content of stimulating sodium chloride additive is between 0.02 and 0.10 mol/kg. Crushed grey cast iron which is stirred by a blade mixer is taken in amount of 30% of the mass of the rest of the load. The process is started and carried out at temperature in the interval from (50±2) to (93±2)°C while bubbling air under conditions for stabilising temperature using a heated liquid bath and controlling using a sample taking method and determination of content of iron (II) and (III) salts in the samples, and residual quantity of acid up to virtually complete conversion of the latter into salt. After that air bubbling, external heat supply for stabilising temperature and stirring are stopped. The suspension of the reaction mixture is separated from the glass beads and particles of unreacted metal alloy and filtered. The filtration residue is washed with distilled water and taken for further purification through recrystallisation, while the filtrate and the washing water are returned to the load for the repeated process. Iron (II) oxalate, which is separated from the reaction mixture by traditional filtering, is virtually the only product of conversion.

EFFECT: liquid phase used together with the sodium chloride additive can be repeatedly returned to the process.

10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: catalysts for metathesis polymerisation of dicyclopentadiene are described, which are represented by [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-N,N-diethylaminomethylphenylmethylene)ruthenium of formula (1) or [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-N-pyrrolidinylmethylphenylmethylene)ruthenium of formula (2) . A method is described for producing a catalyst of formula (1), involving successively reacting a first generation Grubb catalyst with 1,3-bis-(2,4,6-trimethylphenyl)-2-trichloromethylimidazolidine and N,N-diethyl-(2-vinylbenzyl)amine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. In another version of the said method, a second generation Grubb catalyst is reacted with N,N-diethyl-(2-vinylbenzyl)amine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. A method is described for producing a catalyst of formula (2), involving successively reacting a first generation Grubb catalyst with 1,3-bis-(2,4,6-trimethylphenyl)-2-trichloromethylimidazolidine and 1-(2-vinylbenzyl)pyrrolidine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. In another version of the method, a second generation Grubb catalyst is reacted with 1-(2-vinylbenzyl)pyrrolidine in an inert atmosphere at temperature between 40 and 70°C in the presence of a solvent. A method is described for metathesis polymerisation of dicyclopentadiene, involving polymerisation using catalysts of formulae (1) or (2) in molar ratio monomer:catalyst ranging from 70000:1 to 100000:1.

EFFECT: increased output of catalyst and simpler synthesis due to less number of stages, obtaining polydicyclopentadiene with good application properties with low catalyst consumption.

7 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: iron (II) fumarate can be used in different fields of chemical practice, in analytical control and in scientific research, through direct reaction of iron with fumaric acid in the presence of a catalyst, where the catalyst used is molecular iodine in amount of 0.025 to 0.1 mol/kg of the initial load, iron is taken in large excess in form of shells on the entire height of the reactor, false bottom and blade mixer, as well as in form of crushed cast iron and(or) reduced iron powder, the liquid phase solvent used is butylacetate, in which iodine and fumaric acid are at least partially dissolved, where fumaric acid is taken in amount of 0.8 to 1.2 mol/kg of the initial load, loading is done in the sequence: glass beads, liquid phase solvent, fumaric acid, iodine, and then crushed cast iron and(or) reduced iron powder; the process is started at room temperature and is carried out in a vertical type bead mill with ratio of mass of beads to mass of crushed cast iron and(or) reduced iron powder equal to 4:1, at temperature ranging from 18 to 45°C while bubbling air with flow rate of 0.95 l/min-kg of the liquid phase and using forced cooling and controlling using a sampling method until complete exhaustion of the loaded acid for formation of salt, after which stirring and cooling are stopped, the reaction mixture is separated from glass beads and unreacted crushed cast iron and(or) reduced iron powder and filtered, the residue is washed with butylacetate and taken for recrystallisation, and the filtrate and washing butylacetate are returned to the repeated process. Amount of acid used in extracting the product (without loss during purification) ranges from 89 to 96.5%, which depends on conditions for carrying out the process.

EFFECT: improved method of producing said product.

8 ex

FIELD: pharmacology.

SUBSTANCE: invention can be applied in medicine and pharmaceutics. Bioactive cis-dichlorodimethylaminoplatinum (II) is obtained by heating aqueous solution containing potassium tetrachloroplatinate (II), methylaminochloride and potassium acetate to 80°C for 4 hours.

EFFECT: cis-dichlorodimethylaminoplatinum (II) output reaching 69%, admixtures not detected.

4 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: disclosed are bis(oxymethyl)phosphinic acid salt of formula I and method for production thereof.

EFFECT: antituberculosis agent of decreased toxicity without losses of therapeutic activity.

3 cl, 3 dwg, 9 tbl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: the present innovation deals with identifying isoniazide, pyridine derivative, applied to control the quality of production manufactured by pharmaceutical enterprises and prepared by drug stores. One should detect by treating the sample under investigation with freshly prepared 10%-hydroxylamine hydrochloride alkaline solution at obtaining the color. The method creates minimal duration for detection.

EFFECT: higher sensitivity and specificity of the method.

1 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described is a compound of formula

or its pharmaceutically acceptable salt, where m, p, q, Ar, R1 and R2 are as given in the description, as well as a pharmaceutical composition with selective affinity to 5-HT receptors which contains a formula (I) compound.

EFFECT: obtained compounds have selective affinity to 5-HT receptors and can be used, as expected, in treating certain central nervous system disorders.

21 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide salts of formula I , containing an anion selected from a group consisting of phosphate, sulphate, succinate, malate, citrate, fumarate, maleate and edisilate. The invention also relates to a method for synthesis of salts in paragraph 1, to a pharmaceutical composition, a method of inhibiting monoamine receptor activity, as well as to use of at least one salt in paragraph 1.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors or inverse agonists of the monoamine receptor.

50 cl, 9 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and their acid-additive and basic salts as FAAH enzyme inhibitors, method of producing said compounds, a pharmaceutical composition based on said compounds and their use, as well as to intermediate compounds of formula (IIa). In general formula (I) , m is an integer ranging from 1 to 4; n is equal to 1 or 2; o is equal to 1 or 2; A is selected from one or several groups X, Y; X denotes a methylene group optionally substituted with one group which is C1-6-alkyl; Y denotes a C2-alkynylene group; B denotes a covalent bond or C1-6-alkylene group; G denotes a covalent bond, an oxygen atom; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, quinolinyl, isoquinolinyl; R5 denotes a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluroalkoxy, NR7R8; R6 denotes a phenyl group, phenyloxy or pyrimidinyloxy; where R6 group(s) can be substituted with one or two R5 groups which are identical or different from each other; R7 and R8 independently denote a C1-6-alkyl group; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or C1-C6-alkyl group. In general formula (IIa) , m is an integer ranging from 1 to 2; n equals 2, o equals 2; A denotes X, X denotes a methylene group; B denotes a C1-6-alkylene group; G denotes a covalent bond; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes phenyl; R5 denotes a halogen atom, C1-6alkoxy; R6 denotes a phenyl group; R2 denotes a hydrogen atom.

EFFECT: compounds can be used for treating and preventing diseases mediated by FAAH enzyme activity, such as acute and chronic pain, dizziness, vomiting, nausea, disrupted eating behaviour, neurologic and psychiatric pathologies, acute and chronic neurodegenerative diseases etc.

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

Up!