The method of obtaining phosphoric esters thiamine
(57) Abstract:Usage: obtain phosphoric esters of thiamine. The inventive product fosfotiamina, exit 42 Reagent 1: thiamine-Mononitrate. Reagent 2: P2O5H3PO4Reaction conditions: in the presence of RCONH2where R is H, NH2C4H24+1when n=1-4 and at elevated temperatures. The invention relates to organic chemistry, specifically to methods of producing phosphoric esters of thiamine, which (namely fosfotiamina and cocarboxylase hydrochloride) is used in medicine as drugs.A method of obtaining phosphoric esters thiamine phosphorylation of thiamine-chloride-sodium pyrophosphate in the presence of an excess of phosphoric acid. Phosphorylation occurs indiscriminately, which formed as a result of the mixture of phosphate esters of thiamine, consisting of thiamine-0-monophosphate (phosphatemia), thiamine-0-diphosphate (acarboxy - LAZ) and thiamine-0-triphosphate. The mixture of phosphate esters of thiamine share chromatographytandem on ionoobmennoi resin. Fractions of the eluate containing, respectively, thiamine-0-monophosphate, thiamine-0-diphosphate and thiamine-0-triphosphate, evaporated and the residue Mine 
The disadvantage of this method is the use of sodium pyrophosphate, because pyrophosphoryl acid and its salts are easily available on an industrial scale.Also known is a method of obtaining phosphoric esters thiamine phosphorylation of thiamine-chloride phosphorus oxychloride in the presence of phosphoric acid. As with the previous method it is neselektivno phosphorylation process. The mixture of phosphate esters of thiamine can be separated into individual components by chromatographytandem on ion-exchange resin, as described above 
The disadvantage of this method is the use of significant quantities of phosphorus oxychloride as its interaction with phosphoric acid produces large volumes of gaseous hydrogen chloride.The closest to the technical nature of the claimed is a method of obtaining phosphoric esters thiamine phosphorylation of teminology fosforiliruyusciye mixture prepared from phosphoric anhydride and phosphoric acid. This phosphorylation process, as described above, also provides selectivity and leads to the formation of a mixture of phosphate esters of thiamine. The resulting mixture chromatograph is phat 
The disadvantage of this method is the use as feedstock thiamine-chloride, which refers to hard-to-reach products.The proposed solution allows to obtain a phosphoric ester of thiamine thiamine-Mononitrate phosphorylation mixture of phosphoric anhydride and phosphoric acid.This is achieved by the fact that the phosphorylation of thiamine-Mononitrate carried out in the presence of amides of carboxylic acids of General formula RCONH2where R is H, NH2CnH2n+1when n=1-4, when the molar ratio of amide carboxylic acid and thiamine-Mononitrate from 0.5:1 to 2:1.The use of thiamine-Mononitrate enables industrial production of phosphoric esters of thiamine (phosphatemia, cocarboxylase) more affordable raw materials than thiamine chloride. It is known that thiamine-Mononitrate used in industry as an intermediate for the production of thiamine-chloride.Amides of carboxylic acids prevent the oxidation of thiamine-Mononitrate and phosphoric esters of thiamine in the process of phosphorylation. It was established experimentally that the phosphorylation of thiamine-Mononitrate accompanied by the formation of oxides of nitrogen is ion environment. Thus the decomposition of nitric acid takes place at a high speed in the process of phosphorylation under the influence of increased temperature. The resulting nitrogen oxides easily react deamination of amides of carboxylic acids, during which they are associated and thus removed from the reaction medium. In the absence of amides of carboxylic acids under the influence of accumulating in the reaction medium of oxides of nitrogen flow in the deep oxidation of thiamine-Mononitrate and phosphoric esters of thiamin.Reduction of amide carboxylic acid in the reaction mixture below the lower limit leads to the phosphorylation process cannot be fully bind the formed nitrogen oxides and to prevent the oxidative degradation of thiamine-Mononitrate and phosphoric esters of thiamine. The use of quantities of carboxylic acid amide, exceeding the upper limit, it is impractical, because with smaller amounts result in almost complete suppression side of the oxidation process.The essence of the proposed method is that the mixture of phosphoric anhydride and phosphoric acid when heated add amide carboxylic acid and then gradual the mixture of phosphate esters of thiamine dissolved in distilled water and chromatographytandem on the ion exchange column is divided into separate components thiamine-0-monophosphate (fosfotiamina), thiamine-0-diphosphate (kokarboksilazu) and thiamine-0-triphosphate. When a sufficiently high degree of purity, the yield of the target products from diaminomaleonitrile not lower than thiamine-chloride, which is currently used as the initial product in the production of phosphatemia and cocarboxylase.P R I m e R 1. To 99 g of 85% orthophosphoric acid slowly with stirring was added 132 g of phosphoric anhydride, preventing temperature increase above the 100aboutWith, and maintained at a temperature of 100aboutC for 1 h To thus prepared fosforiliruyusciye mixture at the same temperature was added 9 g of urea is stirred until complete dissolution and then gradually add 38 g of thiamine-Mononitrate (36.5 g of 100% substance), incubated at 100aboutC for 1 h While experiencing the allocation colorless gas. Reaction mass takes a light-brown color. After exposure it is cooled in a bath of ice. When cooled it becomes viscous and difficult to stir. The cooled reaction mass is dissolved in 550 ml of cold distilled water, keeping the temperature when dissolved at 0aboutC.The resulting solution, containing a mixture of phosphoric epimeno cation exchanger KU-23 to N+-form. Flowing the solution through the column, put the phosphoric esters of thiamine on the cation exchanger. Chromatographic separation of the phosphoric esters of thiamine carried out, sequentially passing through the column of 0.05 N. acetate buffer solutions with a pH of 2.5 and 4.3. The first buffer solution aluinum column with thiamine-0-trisphosphate, a second thiamine-0-diphosphate. On the cation remains thiamine-0-monophosphate.The first fraction of the eluate evaporated in vacuum at a temperature not exceeding 20aboutWith, one stripped off the solution, add 10 times by volume the amount of absolute ethanol and incubated at a temperature of about 0aboutC. Precipitated precipitate was separated by filtration and dried in vacuum. Get 7,1 g thiamine-0-triphosphate (6 g 100% substance). The output of 10.7% of theoretical, counting on thiamine-Mononitrate.The second fraction of the eluate also evaporated in vacuum at a temperature not exceeding 20aboutWith one stripped off the solution acidified with concentrated hydrochloric acid, add 10 times by volume the amount of absolute ethanol and incubated at a temperature of about 0aboutC. Precipitated precipitate was separated by filtration and dried in vacuum. Obtain 13.8 g of thiamine hydrochloride-0-diphosphate (cocarboxylase hydrochloride) and m m e R 2. To 99 g of 85% orthophosphoric acid slowly with stirring was added 132 g of phosphoric anhydride, preventing temperature increase above the 100aboutS, and incubated at 100aboutC for 1 h To thus prepared fosforiliruyusciye mixture at the same temperature was added 7 g of formamide and then gradually add 38 g of thiamine-Mononitrate (36.5 g of 100% substance), maintained at a temperature of 100aboutC for 1 h While experiencing the allocation colorless gas. Reaction mass takes a light-brown color. After exposure it is cooled to 60aboutWith and dissolved in 550 ml of distilled water. The obtained acidic solution containing a mixture of phosphate esters of thiamine and phosphoric acid, is heated at a temperature of 90aboutC for 6 h to hydrolysis of thiamine-0-diphosphate and thiamine-0-triphosphate to thiamine-0-monophosphate. The hot solution lighten activated carbon, cooled to a temperature of 25aboutWith and add to 7-fold by volume quantity of acetone. After holding at a temperature of about 0aboutSkipped the precipitate was separated by filtration and dried in vacuum. The product is crystallized twice from 50% ethanol, using a 5-fold volume of colio thiamine-0-monophosphate (phosphatemia) or 20.7 g in terms of 100% substance. Exit 42% of theoretical, counting on thiamine-Mononitrate.P R I m e R 3. The process is conducted as described in example 2, with the same quantities of reagents and with the only difference that instead of 7 g of formamide using 15 g of amide valerianic acid. Obtain 17.3 g thiamine phosphate-0-monophosphate (phosphatemia) or 15.4 g in terms of 100% substance. Exit 31.2% of theoretical, counting on thiamine-Mononitrate. The METHOD of OBTAINING PHOSPHORIC ESTERS THIAMINE phosphorylation salt of thiamine mixture of phosphoric anhydride and phosphoric acid, characterized in that as the salt of thiamine is used thiamin-Mononitrate and phosphorylation is carried out in the presence of amides of carboxylic acids of General formula RCONH2where R is H, NH2CnH2n+1when n is 1-4, with a molar ratio of amide carboxylic acid and thiamine-Mononitrate from 0.5:1 to 2:1.
FIELD: coordination compounds synthesis.
SUBSTANCE: invention provides complex comprising calcium and [[(4R)-4[bis[carboxy.kappa.O)methyl]amino-.kappa.N]-6,9-bis[carboxy-.kappa.O)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecane-11-ylic acid-.kappa.N6,.kappa.N9,-kappa.011]-oxydato(6-)]-,6H, (MS-325) or its salt with physiologically acceptable cation in each case containing essentially no Gf-MS-325. Also described are pharmaceutical agent based on compounds according to claim 1 and a method for preparing galena composition, complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent reducing effect produced by heavy metals as well as complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent suitable for NMR diagnostics and/or diagnostic radiology, a method for amplifying patient's image in NMR tomography based on compounds according to claim 1 and above defined complex or its salt with physiologically acceptable cation in each case containing essentially no visualizing metal chelates and MS-325.
EFFECT: increased assortment of complexes with useful medicine-destination properties.
14 cl, 4 dwg, 30 ex
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):
or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:
wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
FIELD: molecular biology, biotechnology, biochemistry, pharmaceutical chemistry.
SUBSTANCE: invention relates to new unnatural substrates for enzyme terminal deoxynucleotidyl transferase that can be used as a tool for insertion of label by 3'-hydroxyl group of oligodeoxynucleotides and single-stranded DNA. Invention describes new substrates for terminal deoxynucleotidyl transferase of the general formula (I): wherein R represents a marker group chosen from dansyl, dinitrophenyl, fluorescein, fluorenylmethyloxycarbonyl, rhodamine B, tetramethylrhodamine, eosin, erythrosine, trioxalene, BODIPY, biotin, auramine, psoralene, pyrene, Texas red dye, actinomycin D, 7-methoxycoumarin and ellipticin; X is a linker representing a linear carbon chain that comprises heteroatoms, such as nitrogen and oxygen atoms, and this chain can comprise carbonyl and thiocarbonyl as functional groups. Invention provides preparing new effective substrate for enzyme.
EFFECT: valuable biochemical properties of substrates.
1 tbl, 2 dwg, 7 ex
FIELD: chemistry of organophosphorus compounds.
SUBSTANCE: invention relates to the improved method for synthesis phosphorus-chlorine-containing methacrylates that can be used in synthesis of polymeric, among them, uncolored, optically transparent and composition materials with reduced inflammability. Invention describes a method for synthesis of phosphorus-chlorine-containing methacrylates of the general formula:
wherein R means lower alkyl, chloroalkyl, alkoxyl, phenoxyl or group of the formula:
R1 means lower alkoxyl, phenoxyl or group of the formula:
Method involves interaction of phosphoric pentavalent acid chloroanhydrides with methacrylic acid glycidyl ester at heating in the presence of hexamethylenephosphorotriamide or dimethylformamide as a catalyst wherein catalyst is taken in the amount 0.3-0.6% of reagents mass, and process is carried out at rise of temperature from 40°C to 80°C in the presence of compound chosen from the group: alkyl- or alkoxy-substituted phenols taken in the amount 0.03-0.3% of reagents mass. Method provides decreasing water absorption of (co)polymerization products of synthesized phosphorus-chlorine-containing methacrylates and reducing retention time of surface stickiness of fiber glass synthesized on their basis and at retention the level of other properties, among them transparence and colorless.
EFFECT: improved method of synthesis, improved and valuable properties of compounds.
2 tbl, 10 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.
EFFECT: valuable medicinal properties of salts and drug.
14 cl, 1 tbl, 8 ex
FIELD: organic chemistry, chemical technology, pharmacy.
SUBSTANCE: invention relates to a new method for synthesis of water-soluble formulations of pharmaceutical preparations containing a blocked aromatic hydroxyl group. Invention describes a method for synthesis of water-soluble phosphonooxymethyl derivatives involving the following steps: step (1): wherein R-OH is converted to R-O-CH2Cl, and step (2): wherein compounds synthesized in the first step is used and wherein R-O-CH2Cl reacts with the phosphoric acid molar excess and a base in suitable polar aprotonic solvent, and wherein R-OH represents a drug containing alcohol or phenol; n = 1 or 2; R1 means hydrogen atom, alkaline metal ion or pharmaceutically acceptable cation; R2 means hydrogen atom, alkaline metal ion or pharmaceutically acceptable cation. Also, Invention describes a method for synthesis of water-soluble phosphonooxymethyl-propofol. Invention provides simplifying the process for synthesis of water-soluble formulations of pharmaceutical preparations.
EFFECT: improved method of synthesis.
26 cl, 4 ex
SUBSTANCE: scope of invention covers production of complexes of Sn or Ti chlorides or of Si phenyltrichloride with common formula 2(RO)3P=O·ER1Cl3, where E = Sn, Ti or Si; R = -CH2CH2Cl, -CH2CH(Cl)CH3, -CH2CH(Br)CH2(Br); R1=Cl or -C6H5, suitable for use as catalysts in organic synthesis. The method includes interaction of tris(halogenalkyl)phosphates with Sn or Ti tetrachlorides or Si phenyltrichloride at ambient temperature and mole ratio phosphate: chloride 2 : 1.
EFFECT: production of new complexes of chlorides with orto-phosphate acid esters.
5 ex, 2 tbl
SUBSTANCE: mixture of monoalkyldiphenylphosphates and dialkylmonophenylphosphates is obtained from reacting phosphorous oxychloride with phenol, after which dichloromonophenylphosphate and monochlorodiphenylphosphate are reacted with aliphatic alcohol in the presence of catalyst - Lewis acid in the absence of a solvent at temperature 60-200°C and pressure from 0.001 to 1.1 bar abs.
EFFECT: design of a new method of producing alkylphenylphosphates and their mixtures, suitable for use plasticisers, lubricants and fireproofing compositions.
16 cl, 17 ex, 5 tbl
SUBSTANCE: invention relates to a method of producing polymer material, enriched with phosphorus, which is used as a fireproof additive. A method is described for producing fireproof polymer material in two stages by reacting initial reagents in a reactor. The first stage involves reacting anhydrous phosphorous pentoxide with a second reagent, chosen from a group consisting of (a) diol, which is 1,3-propanediol and 1,4-butanediol, and (b) a mixture of cyclic ether and alcohol, obtaining polymer precursor material. The second stage involves reacting polymer precursor material with cyclic ether, for example ethylene oxide, propylene oxide and/or glycidol, obtaining the final product. Described also is a fireproof composition, which contains polymer material in form of a salt, obtained by reacting phosphoric ester with an amine, chosen from melamine and polyethylenimine.
EFFECT: obtaining water-insoluble intumescent polymer material which promotes reduction of flammability.
47 cl, 3 dwg, 5 tbl, 13 ex
SUBSTANCE: agricultural finished form of composition contains at least one agricultural active ingredient and at least one agricultural adjuvant or auxiliary agent. Adjuvant includes at leasdt one phosphatised 2-propyl heptanol, phosphatised alkoxylate of 2-propyl heptanol or their mixture. Composition contains 0.1-30% of weight of adjuvant. Alkoxylate includes in average 1-20 ethyleneoxy units and 0-3 propyleneoxy and/or butyleneoxy units. Method of plant processing includes contacting of plants with agriculturally efficient quantity of agricultural finished form.
EFFECT: invention allows to increase stability and activity of composition.
15 cl, 8 tbl, 1 dwg
FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR4 2, -CONR4 2, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR4 2, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR4 2, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR9 2, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR4 2, -CN, -NR9 2, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R2 2; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR2 2 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).
EFFECT: valuable medicinal and biochemical properties of compounds.
69 cl, 7 tbl, 64 ex
SUBSTANCE: description is given of a hetero-aromatic compounds with a phosphonate group with formula (I) and their pharmaceutical salts, radicals of which are given in the formula of invention. The compounds are inhibitors of fructose-1,6-bisphosphotase. Description is also given of pharmaceutical compositions based on compounds with formula (I) and (X) and the method if inhibiting fructose-1,6-bisphosphotase, using the compound with formula (I).
EFFECT: obtaining of new biologically active substances.
184 cl, 52 tbl, 62 ex
FIELD: medicine; pharmacology.
SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.
EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.
46 cl, 1 tbl, 233 ex
SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.
EFFECT: high-yield end product.
26 cl, 5 tbl, 50 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to derivatives of Ice formula and the use thereof in treating the diseases associated with thrombocyte aggregation ICE', wherein P(O)R5R8 is specified in R1 is specified in phenyl; W is specified in a bond, -O-, -NR3-; R2 is specified in alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, phenyl, heterocyclyl, or heteroaryl, alkoxycarbonyl alkyl, carboxyalkyl or phenyl alkyl; R3 is specified in hydrogen or alkyl; or R2 and R3 form a ring together with a nitrogen atom; Ra is specified in hydrogen or methyl; R4 is specified in alkoxy; n is from 0 to 3; m is from 0 to 1; V is specified in a bond and phenyl; R5 and R8 are specified in hydroxyl, phenyloxy, benzyloxy, -O-(CHR6)-O-C(=O)-R7, -O-(CHR6)-O-C(=O)-O-R7, -O-(CHR6)-C(=O)-O-R9, -NH-(CHR10)-C(=O)-O-R9, -NH-C(CH3)2-C(=O)-O-R9; q is equal to 2; R6 is specified in hydrogen and alkyl; R7 is specified in alkyl or cycloalkyl; R9 is specified in alkyl; R10 is specified in hydrogen, alkyl, phenyl or benzyl; and R11 is specified in hydrogen, alkyl or alkoxy.
EFFECT: new P2Y12 receptor antagonists are produced.
25 cl, 126 ex, 5 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to 2-amino-1-((phosphonoxy)methyl)-3-(3-((4-((2-pyridinyloxy)methyl)phenyl)methyl)-5-isoxazolyl)pyridinium of formula: and salts thereof effective as an antimycotic agent, and to pharmaceutical compositions and therapeutic agents based on it and the use thereof in treating mycotic diseases.
EFFECT: what is presented is the new effective antimycotic agent with improved water solubility and safety.
6 cl, 16 dwg, 3 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of general formula 1 or their stereoisomers or pharmaceutically acceptable salts possessing the properties of inhibitors of RNA polymerase HCV NS5B, and to methods for producing them. In general formula 1 R1 represents C1-C4alkyl; R2 and R3 represents fluorine, or R2 represents fluorine, while R3 represents methyl; one of R4 and R5 represents hydrogen, and the other of R4 and R5 represents C1-C6acyl optionally substituted by α-aminoacyl specified in a group containing (dimethylamino)acetyl, 1-tert-butoxycarbonylamino-2-methyl-propylcarbonyl, 1-methylpyrrolidine-2-carbonyl, 1-methylpiperidine-3-carbonyl and 1-methylpiperidine-4-carbonyl, R6 represents hydrogen, methyl, methoxy and halogen.
EFFECT: compounds can be used for treating and preventing viral infections, including hepatitis C, optionally with additional agents specified in an inhibitor of inosin-5-monophosphate dehydrogenase, eg Ribamidine, an inhibitor of hepatitis C protease C NS3, eg Asunaprevir (BMS-650032), an inhibitor of hepatitis C protease C NS3/4A, eg Sofosbuvir (TMC435), an inhibitor of RNA-polymerase NS5A, eg Daclatasvir (BMS-790052) or Ledipasvir (GS-5885).
18 cl, 1 tbl, 14 ex
SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of formula (I) or its racemate, enantiomer, diastereoisomer and their mixture, as well as to their pharmaceutically acceptable salt, where A is selected from the group, consisting of carbon atom or nitrogen atom; when A represents carbon atom, R1 represents C1-C6-alkoxyl; R2 represents cyano; when A represents nitrogen atom, R1 hydrogen atom or C1-C6-alkoxyl; where said C1-C6-alkoxyl is optionally additionally substituted with one C1-C6-alkoxyl group; R2 is absent; R3 represents radical, which has the formula given below: or , where D represents phenyl, where phenyl is optionally additionally substituted with one or two halogen atoms; T represents -O(CH2)r-; L represents pyridyl; R4 and R5 each represents hydrogen atom; R6 and R7 each is independently selected from hydrogen atom or hydroxyl; R8 represents hydrogen atom; R9 represents hydrogen atom or C1-C6-alkyl; r equals 1 and n equals 2 or 3. Invention also relates to intermediate compound of formula (IA), method of obtaining compound of formulae (I) and (IA), pharmaceutical composition based on formula (I) compound and method of its obtaining and to application of formula (I) compound.
EFFECT: novel heterocyclic compounds, inhibiting activity with respect to receptor tyrosine kinases EGFR or receptor tyrosine kinases HER-2 are obtained.
18 cl, 12 ex, 4 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.
EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.
20 cl, 42 ex, 8 tbl, 3 dwg
SUBSTANCE: present invention relates to a novel (2R,3R,5R)-3-hydroxy-(5-pyrimidin-1-yl)tetrahydrofuran-2-ylmethyl aryl phosphoramidate of general formula I or a stereoisomer or a pharmaceutically acceptable salt thereof, having properties of nucleoside inihibitors of RNA polymerase NS5B of the hepatitis C virus. The invention also relates to a method of producing compounds, pharmaceutical compositions and a medicinal agent based on said compounds. In general formula 1 , R1 is hydrogen, (CH3)2[(CH3)3C]Si, C2-C6acyl, optionally substituted with a benzyloxy group, NR5R6 group, wherein R5 and R6 are independently hydrogen or C1-C4alkyl; 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl or piperidin-4-ylcarbonyl; R2 and R3 are F or R2 is F or OH and R3 is CH3; R4 is hydrogen or methyl; Ar is phenyl, pyridyl or naphthyl, where the phenyl, pyridyl or naphthyl is optionally substituted with at least one of C1-3alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, F, Cl, Br, I, nitro, cyano, -N(C1-3alkyl)2; Pm is 2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl or 4-(4-amino-2-oxo-2H-pyrimidin-1-yl), wherein the amino group is optionally substituted with 1-pyrrol-2-ylcarbonyl, piperidin-3-ylcarbonyl, piperidin-4-ylcarbonyl or a C(O)R8 radical, where R8 is C1-C4alkyl, optionally substituted with a NR6R7 group, where R6 and R7 are independently hydrogen or C1-C4alkyl; C1-3alkoxy, optionally substituted with a phenyl; X is O or N-R9, where R9 is C1-C4alkyl, optionally substituted with OH or OCH3; n=1, 2 or 3.
EFFECT: compounds can be used to prevent and treat viral infections, including hepatitis C.
12 cl, 1 tbl, 11 ex