The method of obtaining d - 2 (6 --d - galactopyranosides -2) - 4,5-dihydrothiazolo-4 - carboxylic acid

 

(57) Abstract:

The invention concerns a carbohydrate, in particular ways to obtain D - 2 - (6 - b - D - galactopyranosides -2 ) 4,5 - dihydrothiazolo-4 - carboxylic acid used as substrate to determine the enzymatic activity of b-galactose, and may find application in enzyme analysis, DNA probes and genetic engineering. The goal is to create a new way to obtain this substance. Synthesis of lead by the reaction of 2,3,4,6-Tetra-0-acetyl - b-D-galactopyranoside 2-cyan-6-trimethylsilylcyanation in the environment of non-polar organic solvent (benzene) in the presence of epirate boron TRIFLUORIDE with separation and purification by chromatography intermediate 6-(2-cyanobenzoyl)-2,3,4,6-Tetra-0-acetyl - b-D-galactopyranoside with its subsequent dezazetilirovanie and condensation with D-cysteine. Product dezazetilirovanie can be subjected to purification by chromatography and crystallization. The new method allows to obtain from the available reagents in good yield (61%) of the target product, providing high sensitivity for the detection of b-galactosidase bioluminescent method. 1 Il.

The invention relates to carbohydrates and
used as substrate to determine the enzymatic activity of-galactosidase, which can find application in genetic engineering, enzyme analysis and DNA probes.

Known bioluminescent detection-galactosidase activity [1] . The best substrate for this method is o-nitrophenyl- -D-galactopyranoside, which is cleaved by the enzyme with the formation of o-NITROPHENOL and galactose. Galactose is determined by a complex multi-stage detection system comprising three sequential enzymatic reactions requiring the use of such substrates of enzymes as CR (nicotinamide adenine dinucleotide), FMN (playmonopolyonline), long-chain aldehyde. All of this adds cost and complexity to the analysis.

Known derivatives of luciferin with esterified phenolic group of the General formula

where R the rest of phosphoric, sulfuric or amino acids. In the patent [2] mentioned compounds, where R is a carbohydrate residue, in particular D-galactopyranosyl intended for bioluminescent detection of hydrolases (phosphatases, sulfates, proteases and field of glycosidase inhibition). However, the method of obtaining the compounds of formula I and a method of its use op is Wendy Erin with phosphorus oxychloride and subsequent hydrolysis of P-Cl-bonds in accordance with the following synthesis scheme [3]

< / BR>
The disadvantage of this method is that as the starting material used expensive luciferin. In addition, the enzyme has two functional groups, which may be the reaction of interaction of phenolic hydroxyl, and carboxy group. For this reason, the outputs of the derivative of luciferin on phenolic hydroxyl group are low and, for example, in the case of phosphates 29%. A significant drawback is that in the reaction mixtures is not included in the reaction of luciferin, which is extremely difficult to escape and preventing bioluminescent definition, creating a high background.

The aim of the invention is to develop a new method of obtaining the compounds of formula I, allowing high yield and available reagents to obtain the target product with a high sensitivity in the detection of the enzymatic activity of-galactosidase.

The proposed method for obtaining the compounds of formula I is that 2,3,4,6-Tetra-O-acetyl- -D-galactopyranoside subjected to interaction with 2-cyan-6-trimethylsilylcyanation in the environment of non-polar organic solvent, such as benzene, in the presence the cleaning of the intermediate 6-(2-cyanobenzoate (2,3,4,6-Tetra-O-acetyl- -D-galactopyranoside) with subsequent dezazetilirovanie and condensation with D-cysteine.

The scheme of synthesis of the proposed method is as follows:

< / BR>
+

___

The method is as follows.

The interaction of 2,3,4,6-Tetra-O-acetyl- -D-galactopyranoside with trimethylsilyloxy ether 2-cyan-6-hydroxybenzothiazole get galactopyranoside (IV) yield 77%. Dezazetilirovanie galactoside (V) get off exit 86% by removing the protective acetyl groups derived from (IV) by the action of catalytic amounts of sodium methylate in methanol. The compound (V) is transformed into the target galactoside D-luciferin by condensation with D-CIS - theine in water-methanol medium using sodium carbonate as the condensing means. The compound (I) is recovered from the reaction mixture with a yield of 61% by crystallization. Use as a starting compound 2-cyan-6-trimethylsilylacetamide, not luciferin, as in the method-analogue has a number of advantages.

In particular, in the proposed method, derivatives IV and V can easily be purified by chromatography and crystallization from possible impurities 2-cyan-6-hydroxy-benzothiazole, from which the final stage of the synthesis can be formed free luciferin, preventing bioluminescent detection-GA) is not expensive D-luciferin, and its predecessor - 2-cyano-6-hydroxybenzothiazole, which is cheaper and more stable.

Synthesis of compound (III) is conducted by sililirovanie 2-cyan-6-hydroxybenzothiazole mixture of hexamethyldisilazane-trimethylchlorosilane when heated. The interaction of fluoride (II) derivatives of (III) is carried out in an environment of benzene using as a condensing agent epirate boron TRIFLUORIDE at room temperature. The obtained compounds were characterized by values of the melting point and specific rotation. Their structure is proved using the 13With NMR spectroscopy. So, in the spectrum of compound (IV) have the necessary signals galactopyranosyl residue, linked-glycosidic bond, the signals of acetyl groups, CN groups, and aromatic carbon atoms of benzothiazole. In the spectrum of compound (V), on the contrary, there are no signals of acetyl groups, are required signal CN-group, benzothiazole residue and dezazetilirovanie-D-galactopyranoside. In the spectrum of galactoside D-luciferin (I) no signal CN-group, there are 6 signals - -D-galactopyranoside and 11 signals corresponding D-ljutsiferinom residue.

P R I m e R 1. Synthesis of D-galactoside D-luciferin (I).

Synthesis of 2-cyan-6-trimethylchlorosilane heated under reflux. After about 0.5 h, the mixture becomes homogeneous, the refrigerator is deposited precipitate of ammonium chloride. The residue is carefully removed, the excess similitude mixture is distilled off under reduced pressure, the residue is crystallized from hexane. Allocate 0.17 g (81%) of compound (III), so pl. 68-69aboutC.

Synthesis of 6-(2-cyanobenzoyl)-2,3,4,6-Tetra-O-acetyl- -D-galactopyranoside (IV). To a solution of 0.25 g (1.01 mmol) of the ester (III) and 0.40 g (1.15 mmol) of compound (II) in 2.0 ml of abs. benzene is added a solution of 0.13 ml (1.0 mmol) of epirate boron TRIFLUORIDE in 1 ml of benzene. The addition of exercise dropwise and with stirring. After adding (5-10 min) the mixture was stirred at room temperature for 4 hours Diluted with chloroform, washed with water, chromatographic sorbent Silpearl (Czechoslovakia) in the solvent system ether-benzene 1:3. Allocate 0.39 g (77%) of the compound (IV). After crystallization from ethanol so pl. 160-161aboutC [ ]D+2o(0.5, chloroform).

13With NMR (CDCl3, , M. D.): 99,6 (C1); 68,5 (C2); 70,7 (C3); 68,8 (C4); 71,7 (C5); 61,4 (C6) signals the rest of galactopyranose, 20,6-20,7 (CH3) ; 169,3-170,2 (CH3CO); 112,9 (CN-group); 107,9; 119,4; 126,2; 137,5; 149,0; 157,7 - the signals of the carbon atoms of the benzothiazole.

Synthesis of 6-(2-cyanobenzoate the sodium in absolute methanol. After 1 h, neutralized with cation exchange resin CRS-2P, evaporated. Crystallization from 4 ml of ethanol emit 0.12 g (86%) of compound (V), so pl. 188-190aboutC [ ]D-56o(0.5, pyridine),13With NMR (pyridine-d-5): 102,9 (C1); 72,0 (C2); 75,2 (C3); 70,1 (C4); 77,9 (C5); 62,4 (C6) signals galactopyranosyl residue; 114,0 - (CN-group); 108,1; 119,9; 125,8; 137,9; 147,8; 158,9; 170,2- signals benzthiazole kernel.

Synthesis of D-2-(6--D-galactopyranosides-2)-4,5 - dihydrothiazolo-4-ka-Borovoy acid (I) - - -D-galactopyranoside D-luciferin. A mixture of 0.04 g of compound (V), 0.02 g of D-cysteine hydrochloride (hydrochloride of 2-amino-3-mercaptopropionic acid) in a mixture of 1 ml of methanol and 1 ml of water is stirred in a stream of argon. Added 0.025 g of sodium carbonate and continue stirring for 1.5 hours Neutralized with 0.2 N. HCl until acidic and leaves at a temperature of 5-6aboutWith 10-15 h, Allocate to 0.032 g (61%) of crystalline-D-galactopyranoside D-luciferin fireflies (I), which is a white substance, soluble in water, so pl. 250-260aboutC (decomp. ). When thin-layer chromatography on Silufol (Czechoslovakia) in the system ethyl acetate-methanol (3:1) Rf=0,25 (relative to luciferin).

13With NMR (dimethylsulfoxide-d6): 101,4 (C1); 73,3 (C2); 75,8 (C3); 70,3 (C4); 78,2 (C5); 60,4 (C6) - signals the OS is P> UV spectrum: three maximum absorption: at 330, 260 and 220 nm (0.1 M phosphate buffer, pH 7,3).

Spectra fluorescence: fluorescence maximum at 435 nm (excitation at 355 nm, 0.1 M Tris-acetate buffer, pH 7,8). The content of luciferin obtained in the substance of 0.13%.

P R I m m e R 2. Synthesis of D-galactoside D-luciferin carried out according to example 1, except that 6-(2-cyanobenzoyl)- -D-galactopyranoside (compound V) immediately before the condensation with D-cysteine is subjected to additional purification by the method of column chromatography on silica gel Silpearl (Czechoslovakia) in the organic solvent ethyl acetate-ethanol, followed by crystallization from ethanol. Obtained-D galactopyranoside D-luciferin contains 0.02% D-luciferin.

P R I m e R 3. Use the-D-galactoside D-luciferin as a substrate for the bioluminescent determination of activity of-galactosidase.

To 1.0 ml of 0.8 mm solution of D-galactoside of luciferin in 0.1 M phosphate buffer, pH of 7.3, containing 1 mm MgSO4, 0.1 M NaCl, add 1-20 ml-galactosidase in the same buffer. Incubate the mixture at 37aboutC for 100 min, then take 20 ál of the reaction mixture, and determining the concentration of luciferin in this mixture bioluminescent the 7,8, containing 2 mm EDTA, 10 mm MgSO4, 0.3 mm solution of ATP in the same buffer, 10 μl of a solution of luciferase fireflies with specific activity of 108-109srvc.ed./ml (1 srvc. unit corresponds to the intensity of bioluminescence 109quantum/sec). The cuvette is placed in the sample compartment of a luminometer to measure background luminescence (Ibackground) injected 20 μl of the reaction mixture with an unknown concentration of luciferin (see above) and measure the intensity of the I1. Then add 10 ál of the solution luciferin known concentration ("internal standard") and measure the intensity of the I2. An unknown concentration of luciferin in the reaction mixture are calculated according to the formula

Cx= , where Cxthe unknown concentration of luciferin; Nx- dilute the reaction mixture with an unknown concentration of luciferin in luminometric cell; C - concentration of luciferin in the internal standard solution in a ditch; Nc- dilution of the internal standard solution in a ditch.

The activity of-galactosidase is proportional to the concentration of luciferin formed by the action of this enzyme on-D-galactoside D-luciferin within 100 minutes of the Calibration graph to determine galactosidase shown in the drawing, where [luciferin]100the concentration of luciferin, microns after 100 min of incubation of the substrate with a-galactosidase. Conditions: 0.1 M phosphate buffer, pH of 7.3, containing 1 mm MgSO4, 0.1 M NaCl; 0.8 mm-D-galactoside D-luciferin, 37about. Drug-D-galactoside D-luciferin contains 0.02% D-luciferin. The limit of detection of-galactosidase by this method is 10-16M, i.e., is not inferior to the sensitivity of the bioluminescent method of detection of-galactosidase, as described in [1]. When this detection technique is simplified by the use not of three enzymes, as one.

Thus, the proposed new method of obtaining-D-galactoside D-luciferin formula (I) allows to obtain a product of the available reagents, with a good yield. Moreover, the feature of the proposed method is the possibility of purification of the compounds of formula (I) at least two preliminary stages, which provides high sensitivity in the detection of-galactosidase bioluminescent method.

1. The METHOD of OBTAINING D-2(6 - D-GALACTOPYRANOSIDES-2)-4,5-DIHYDROTHIAZOLO-4-CARBOXYLIC ACID of the formula

< / BR>
characterized in that 2,3,4,6-Tetra-O-acetyl- -D-galactopyranoside subjected to interaction with 2-risotti epirate boron TRIFLUORIDE as a condensing reagent to extraction and purification by chromatography intermediate 6-(2-cyanobenzoyl)-2,3,4,6-Tetra-O-acetyl- -D-galactopyranoside formula

< / BR>
then dezazetilirovanie and condensation with D-cysteine.

2. The method according to p. 1, characterized in that the product dezazetilirovanie purified by chromatography and crystallization.

 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles of formula I , containing in substituted alkyl residues in 2-posiiton, as well as physiologically accepted salts thereos, having anorexia action. In formula Y is direct bond; X is CH2; R1 and R1' are independently H, Cl; R2 and R3 are H; R4 is (C8-C16-cycloalkyl, (CH2)n-A-R8, wherein n = 1-6, excepted group of formula -CH2-O-CH2-phenyl with unsubstituted phenyl; A is O, S; R8 is methyl or (CH2)m-aryl, where in m = 0-6; and aryl may represent phenyl, wherein aryl group may be optionally substituted with one or two substituents, selected from Cl, O-(C1-C6)-alkyl or (C1-C6)-alkyl. Also disclosed is method for production thereof.

EFFECT: new anorexia pharmaceuticals.

5 cl, 4 ex, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to polycyclic dihydrothiazoles and their physiologically acceptable salts and physiologically functional derivatives. Invention describes compounds of the formula (I): wherein r1 and R1' mean independently of one another atoms H, F, Cl, Br and J; R2 means hydrogen atom (H); R3 means chlorine (Cl), bromine (Br) atom; R4 means phenyl, and a method for their preparing. Compounds can be used, for example, as anorectics for prophylaxis or obesity treatment.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 2 tbl, 1 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to polycyclic dihydrothiazole and to their physiologically acceptable salts and physiologically functional derivatives. Invention describes compounds of the formula (I): wherein R1 and R1' mean independently of one another atoms of hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) and iodine (J); R2 and R3 mean hydrogen atom (H); R4 means (CH2)n-R5 wherein n can be = 0-6; R5 means phenyl that can be substituted with NH-SO2-(C1-C6)-alkyl, NH-SO2-phenyl being phenyl ring up to twice-fold can be substituted with chlorine atom (Cl), (CH2)m-SO2-NH2, (CH2)-SO2-NH-(C1-C6)-alkyl, (CH2)m-SO2-N-[(C1-C6)-alkyl]2 or (CH2)m-SO2-N-[=CH-N(CH3)2] wherein m can be = 0-6, and a method for their preparing. Compounds are useful, for example, as anorexic agents used in prophylaxis or treatment of obesity.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 12 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted 8,8a-dihydro-3aH-indeno[1,2-d]thiazoles and to their physiologically acceptable salts and physiologically functional derivatives also. Invention describes compounds of the formula (I): wherein R1 and R1' mean independently of one another H, F, Cl, Br, J; R2 and R3 means H; R4 means phenyl hat can be replaced with hydroxyl group (OH); R5 means hydrogen atom (H); R6 means OH. Also, invention describes a method for preparing these compounds. Compounds can be used as anorexic agents for prophylaxis and treatment of obesity.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

5 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula II as neuropeptide FF receptor antagonist, their pharmaceutically acceptable acid-additive salts, medication based on them, as well as their application. Compounds can be applied for treatment and prevention of diseases mediated by activity of neuropeptide FF receptor, such as pain, hyperalgesia, enuresis, for elimination of syndromes arising in case of alcohol, psychotropic and nicotine addiction, for regulation of insulin release, digestion, memory functions, blood pressure or electrolytic and energy exchange. In general formula II , A together with thiazole ring forms 4,5,6,7-tetrahydrobenzothiazole, 5,6,7,8-tetrahydro-4H-cycloheptathiazole, 5,6-dihydro-4H-cyclopentathiazole fragments; R1 represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tret-butyl, 1,1-dimethylpropyl or phenyl; R2-R6 each represents hydrogen or methyl.

EFFECT: obtaining solutions, which ca be used for treatment and prevention of diseases, mediated by activity of neuropeptide FF receptor.

6 cl, 4 tbl, 106 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-acyl-2-aminothiazoles of formula (I) and their pharmaceutically acceptable salts as antagonist of adenosine receptor A2B and to a pharmaceutical composition based on the said compounds. In formula (I) X is -CH2-, -CH2CH2-, -(CH2)3- and O(CH2)-; R is a 5- or 6-member saturated or unsaturated carbocyclic or heterocyclic ring system, which can optionally contain one or more heteroatoms, chosen from N, O and S, where the said ring system is optionally substituted with one or more substitutes, chosen from a group consisting of halogen, hydroxy, lower alkyl, nitrile group, sulfonamide, aminosulfonyl, lower alkoxycarbonyl, lower alkylsufonyl, benzyl, benzoyl, phenylsulfonyl, and the said benzyl, benzoyl or phenylsulfonyl are optionally substituted with a halogen, trihalogeno-lower alkyl group; R1 is chosen from a group consisting of hydrogen, halogen or lower alkoxy group.

EFFECT: obtaining compounds which can be used for treating and preventing diseases caused by adenosine receptors A2B, such as diabetes, diabetic retinopathy, asthma and diarrhea.

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 5-member azacyclic compounds of formula

,

where X denotes S; Y denotes O; Q denotes O; R1 denotes methyl or, together with R2, forms a 6-member aliphatic ring, R2 denotes methyl or, together with R1, forms a 6-member aliphatic ring; R3 denotes hydrogen; R4 denotes benzyl; Z- is a pharmaceutically acceptable acid radical. The invention also relates to a pharmaceutical composition, use of formula (I) compounds, which are active in destruction of advanced glycosylation end products (AGE), to obtain a medicinal agent and a method producing formula (I) compounds.

EFFECT: obtaining compounds of formula (I) which are active in destruction of advanced glycosylation end products (AGE).

6 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R denotes a substituted or unsubstituted thiazolyl group of formula or ; R4 and R5, each independently, are selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl; iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteratoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; or R4 and R5 can be taken together to form a saturated or unsaturated ring, having 5-7 atoms; said substitutes are independently selected from one or more groups, selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R6 denotes a group selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteroatoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R1 is selected from i) hydrogen; ii) C1-C6 linear or C3-C6 branched alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted benzyl; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R2 is selected from i) C1-C6 linear or C3-C6 branched alkyl or ii) C1-C6 linear or C3-C6 branched alkoxy; R3 denotes hydrogen or C1-C4 linear or C3-C6 branched alkyl.

EFFECT: compounds of formula (I) are effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

20 cl, 10 tbl, 8 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

Up!