The method of obtaining 1,4,3,6-dianhydro-d-sorbitol dinitrate
(57) Abstract:The invention relates to a technology for 1,4,3,6-dianhydro-D-sorbitol dinitrate, which is the substance of the medicinal product "nitrosorbid". The method of obtaining 1,4,3,6-dianhydro-D-sorbitol dinitrate is in the nitration 5.1-6.9 wt.D. nitric acid at a temperature of 0-17oWith 1 wt. D. 1,4,3,6-dianhydro-D-sorbitol dinitrate containing 0.5 to 9.5% of the water supplied to the nitration temperature 40-80oC. after completing the reaction mass is diluted with wash water to a content of nitric acid, 20-25%, nitrosorbid filtered from the spent acid and washed with water. The proposed solution will reduce the consumption of nitric acid, to improve the performance of the nitration process, reduce the amount of waste nitric acid used for regeneration. table 1. The invention relates to a technology for 1,4,3,6-dianhydro-D-sorbitol dinitrate (nitrosorbid), which is the substance of a medicinal product under the name "nitrosorbid", which is used as a vasodilator to treat hypertension, angina and other cardiovascular diseases.NITR is known laboratory method of nitration of sorbed sulfuric-nitric mixture (melange), the proposed UNIFI them. S. Ordzhonikidze ( P. M. Kochergin, R. M. Titkov. The medical industry of the USSR, 8, 18, 1959), which requires validation in an industrial environment. Its disadvantages are the complexity of the regeneration of the mixed waste acid and wash water compared with the regeneration of one of nitric acid.Most noteworthy is the way nitration of sorbed nitric acid and allocation nitrosorbid by diluting the reaction mixture with water, which is implemented at a chemical plant in Krasnouralsk the Ekaterinburg region) and adopted for the prototype (Regulations for obtaining nitrosorbid in poltavtsom scale, UNIFI them. S. Ordzhonikidze, 1963).In this way nitrosorbid obtained by adding a concentrated aqueous solution of 1 weight. including carbide (syrupy liquid that contains 80-90% of sorbed) to fuming nitric acid at a temperature of 18-20oC for 1 -1 h 20 min Nitric acid taken in the quantity of 7.75 weight.h. 1 century including carbide. Instead of nitric acid as nitrouse agent can be applied melange (mixture of nitric and sulphuric acids) in the same ratio. At the end of dosing an aqueous solution of sorbide the reaction mass is maintained at 16-20oC for 30 min, and longer in the form of white crystals. The resulting suspension nitrosorbid in dilute nitric acid, filtered, the filter cake washed with water until neutral and sent for recrystallization in ethanol. Waste nitric acid (15-18% concentration) and wash water (1-4% concentration) is passed to regeneration.The disadvantages of the method are:
- high consumption of nitric acid in the nitration;
the low concentration of the spent nitric acid upon dilution of the reaction mixture with clean water;
the costs of regeneration of nitric acid after water leaching;
- reduced the productivity of the process.The aim of the present invention is to reduce the consumption of nitric acid, increasing productivity, reducing costs for the regeneration of spent acid and wash water.This goal is achieved by reducing additives water to carbide applied to the nitration, 0.5-9.5% and reduction of the nitric acid in the nitration with 7,75 wt.D. to 5.1-6.9 wt.D., replacement of pure water for dilution sour wash water, reducing the amount of spent acid used for regeneration.Nitration of sorbed nitrogen Kim, stirrer, water (brine) bath for cooling, download 510-690 g of 98.5% nitric acid, cooled her from minus 2oTo + 12oAnd when the agitator from a heated dropping funnel dispense heated to 40-80oWith sorbed in the number of 100.5-109,5 g containing 0.5 to 9.5% of water, maintaining the temperature in the reaction mass 0-17oC. Upon completion of the dosage sorbed give exposure 30 min at 10-17oWith, and then the resulting reaction mass slowly with stirring 12-17oWith poured in 2-2,3 l wash "acidic" water from the previous water leaching. Suspension nitrosorbid diluted in up to 20-25% nitric acid, filtered, nitrosorbid portions washed with water, which is used for dilution, and nitrosorbid dried at a temperature of 50-60oWith and analyze the requirements of the Federal Assembly of 42-422-92. Waste nitric acid regenerate known methods. The content of the basic substance in carbide 98-99% define chromatographic, and when the content of the basic substance 95-97% sorbed again distilled under a residual pressure of 1-5 kPa and a temperature of 165-195oC.The hallmark of this method is the reduction of water content in carbide impede the process of nitration and Spole to reduce the consumption of nitric acid, to increase the productivity of the process nitrile, reduce the amount of waste nitric acid for regeneration. Mobility "syrup" carbide for dosing with a reduced water content reached by raising its temperature with a water content of 0.5% to 75-80oWith due to its melting point, when the water content of 6-9,5% to 40-45oWith the expense of increasing the solubility and fluidity.The results of the experiments presented in the table. The method of obtaining 1,4,3,6-dianhydro-D-sorbitol dinitrate by nitration with nitric acid flooded 1,4,3,6-dianhydro-D-sorbitol, containing not less than 98% of the basic substance, and separating it from the reaction mixture by dilution with water, characterized in that the 5.1-6.9 wt. D. nitric acid is dosed 1 wt. D. with a temperature of 40-80oWith 1,4,3,6-dianhydro-D-sorbitol containing 0.5 to 9.5% of water, maintaining the temperature of the reaction mass 0-17oAnd for dilution of the reaction mixture to 20-25% concentration of nitric acid used water after washing, isolated from the reaction mass 1,4,3,6-dianhydro-D-sorbitol dinitrate.
< / BR>where X 0;
R1a hydrogen atom;
R2-R4the atom of hydrogen or halogen, C1-C6alkyl or C1-C6alkoxygroup, the nitro-group;
R5, R6, R7the atom of hydrogen or C1-C6alkyl,
that exhibit fluorescent properties and are used as dyes for dyeing films and aminomethylating fibers (DOS 2942931 (1980), BASF, Erf
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new bis-tetrahydrofuranbenzodioxolyl sulfonamide compounds of the formula (I): , its salts, stereoisomers and racemates that are effective inhibitors of protease activity. Also, invention relates to pharmaceutical preparations, methods for inhibition of retrovirus proteases, in particular, to resistant retrovirus proteases, to many drugs, methods for treatment and prophylaxis of infection or disease associated with retrovirus infection in mammals and to methods for inhibition of retrovirus replication. Invention provides preparing new derivatives of bis-tetrahydrofuranbenzodioxalyl sulfonamides eliciting the valuable pharmaceutical properties.
EFFECT: valuable medicinal properties of compound and composition, improved treatment method.
16 cl, 2 dwg, 3 tbl
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:
wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.
EFFECT: valuable medicinal properties of compound.
13 cl, 1 dwg, 4 tbl, 16 ex
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to a novel method for preparing 14β-hydroxy-1,4-carbonate-desacetylbaccatin III and intermediate substances used in preparing new derivatives of taxane and possessing an antitumor activity. Method involves the following stages: a) protection of hydroxyls at positions 7 and 10 in 10-desacetylbaccatin III wherein R and R1 are taken among hydrogen atom, (C1-C10)-alkyl or aryl, (C1-C10)-alkyl- or aryl-carbonyl, trichloroacetyl, (C1-C4)-trialkylsilyl; preferably, when R and R1 are similar then they represent trichloroacetyl; when they are different then, preferably, R represents trichloroacetyl and R1 represents acetyl; or R represents triethyl or trimethylsilyl and R1 represents acetyl; b) two-stage oxidation to yield a derivative oxidized to carbonyl at position 13 and hydroxylated at position 14; c) carboxylation of vicinal hydroxyls at positions 1 and 14 to yield 1,14-carbonate derivative; d) reduction of carbonyl at position 13; e) removal of protective groups at positions 7 and 10. Also, invention relates to intermediate substances. Invention provides preparing intermediate substances used in synthesis of taxane.
EFFECT: improved preparing method.
8 cl, 8 ex
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to a method for synthesis of new compounds, namely, 1,11-dialkyl-3,5-dihydrofuro-[2',3':3,4]-cyclohepta[c]isochromens of the formula: (Ia-f): wherein (Ia): R means hydrogen atom (H); R1 means hydrogen atom (H); (Ib): R means bromine atom (Br); R1 means hydrogen atom (H); (Ic): R means chlorine atom (Cl); R1 means hydrogen atom (H); (Id): R means hydrogen atom (H); R1 means bromine atom (Br): (Ie): R means hydrogen atom (H); R1 means chlorine atom (Cl); (If): R means methoxy-group (-OCH3); R1 means hydrogen atom. Method involves formation of condensed tetracyclic system as result of the successive recyclization reactions of furan ring of derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol and the secondary cyclization of formed isochromen ketone in boiling of solution containing derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol of the formula: in ethanol medium in the presence of hydrogen chloride alcoholic solution for 15-40 min. Invention provides synthesis of new derivatives of isochromens possessing the potential anti-inflammatory activity.
EFFECT: improved method of synthesis, valuable medicinal properties of compounds.
1 cl, 2 tbl, 5 ex
FIELD: organic chemistry of natural compounds, medicine, oncology.
SUBSTANCE: invention relates to a novel crystalline form of (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)ethylideneoxy]-5,20-epoxy-1-hydroxytax-11-ene-13-yl-(2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate that shows the diffraction picture of roentgen rays in powder with characteristic peaks at diffraction angles (θ)= 6.2o, 10.3o, 10.7, 11.4o and 12.0, and a method for its preparing. Method involves carrying out the crystallization step by using organic solvent chosen from group consisting of ketone type solvent, nitrile solvent type and their mixture, or mixture of said solvent and water. Also, invention relates to an antitumor agent based on the prepared crystalline form. Invention provides the stable quality of a medicinal agent based on its lower hygroscopicity.
EFFECT: improved and valuable properties of compounds.
8 cl, 5 ex
FIELD: organic chemistry, chemical technology, medicine, oncology.
SUBSTANCE: invention relates to a method for isolation of epotilons used in medicine in treatment of cancer diseases. Method for desorption of epotilons A, B, D and/or E from synthetic resin is based on using low-polar or nonpolar solvent chosen from the group comprising (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Used aromatic solvent is chosen from the group including naphthalene, benzene or naphthalene and benzene substituted with one or some substitutes chosen from the following group: (lower)-alkyl, (lower)-alkoxy-group, halogen atom, nitro-group and (lower)-alkoxy-(lower)-alkyl wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Solvent is removed to the required level but up to preparing a dry residue preferably. If necessary, residue is dissolved in mixture alcohol/hydrocarbon in the corresponding volume ratio. Alcoholic phase is evaporated until dry and then alcoholic extract is crystallized from mixture alcohol and hydrocarbon. Then formed crystallized product is dissolved in mixture nitrile/water but preferably in mixture acetonitrile/water taken in the ratio = 2:3 (vol./vol.). Formed solution is applied on column (if necessary, after separation for some distillates) for preparative chromatography in reversed phase followed by elution with mixture nitrile/water, removing nitrile and extraction of an aqueous phase with ester. Ester extract is evaporated and formed product is subjected for crystallization. Method for preparing epotilons A, B, D and/or E from resin or reaction mixture involves the following steps: (a) desorption of epotilons with low-polar or nonpolar solvent chosen from the group including (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents being the desorption step can be repeated up to achievement of the more complete desorption; (b) removal of solvent used in desorption from formed solutions by evaporation; (c) optional crystallization of epotilon(s) after desorption and first of all for crystallization of epotilon B by addition of mixture of alcohol with hydrocarbon and the following evaporation of alcoholic phase until dry and crystallization of epotilon B from the corresponding mixture of solvents; (d) (obligatory step) separation of epotilons by method of chromatography in reversed phase and the following dissolving a residue obtained in previous step in suitable solvent, elution with mixture nitrile/water and removing nitrile from epotilon-containing fractions by evaporation. If necessary, water remained with epotilon is extracted with ester followed by evaporation of epotilon-containing ester phase until dry; (e) optional purification by adsorption chromatography method, and final recrystallization of purified epotilon from corresponding solvents or mixture of solvents. If necessary, in this process between each step formed solutions or suspensions are concentrated, and/or liquid or solid components are separated of one another. Separation of epotilons A and B is carried out by chromatography method based on a mobile layer modeling. Invention provides simplifying methods for preparing large amounts of epotilons for satisfying requirement in these agents.
EFFECT: improved isolating method.
12 cl, 2 ex
FIELD: organic chemistry, medicine, gynecology.
SUBSTANCE: invention relates to novel tetracyclic heterocompounds of the formula (I): wherein X, Y, Z, R1 - R4, n and m has values given in the invention description and used as selective modulating agents for estrogen receptors. Also, invention relates to a method for synthesis of these compounds and pharmaceutical compositions comprising thereof, and their using in treatment and/or prophylaxis of disorders mediated by one or more estrogen receptors. Proposed compounds are useful in treatment and/or prophylaxis of disorders associated with depleting estrogen and comprising such disorders as rush of blood, vaginal dryness, osteopenia and osteoporosis, hormone-dependent cancer and hyperplasia of breast, endometrium, uterus cervix and prostate, endometriosis, uterus fibroma, osteoarthritis that can be used as contraceptive agents both separately and in combination with progestogen or progestogenous antagonist.
EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.
25 cl, 7 tbl, 171 ex
FIELD: organic chemistry, medicine, endocrinology.
SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.
EFFECT: valuable medicinal properties of compounds.
11 cl, 41 tbl, 243 ex
FIELD: organic chemistry, medicine, biochemistry, pharmacy.
SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra 1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.
35 cl, 16 sch, 13 tbl, 43 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to heterocycle-substituted tricyclic compounds of the formula (I): or their pharmaceutically acceptable salts wherein R means hydrogen atom; R1 and R2 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R3 means hydrogen atom; n1 and n2 = 0-3 independently under condition that they both do not mean 0; Het means pyridyl wherein pyridyl is added to B through cyclic carbon atom and it comprises from 1 to 4 substitutes (W) chosen independently from group comprising -NR4R5, -NHCOR26, -NHSO2R16; R21 means aryl and R21 means heteroaryl wherein heteroaryl represents furyl, thienyl, pyridyl, thiazolyl, pyrrolidinyl, azethidinyl; R4 and R5 mean hydrogen atom or alkyl comprising 1-6 carbon atoms, or R4 and R5 mean in common -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)2NR7-(CH2)2- wherein R7 means hydrogen atom or alkyl comprising 1-6 carbon atoms; R8, R, R10 and R11 mean hydrogen atom; B means -(CH2)n4CR12=CR12a(CH2)n5 wherein n4 and n5 = 0-2 independently; R12 and R12a are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R21 means from 1 to 3 substitutes chosen independently from group comprising hydrogen atom, trifluoromethyl, trifluoromethoxy, halogen atom, cyano, alkyl comprising 1-6 carbon atoms, alkoxy group comprising 1-6 carbon atoms, or -CR29(=NOR28); R22 means -COR23, -S(O)R31, -S(O)2R31 or -COOR27; R23 means cycloalkyl comprising 3-7 carbon atoms, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, cycloalkyl comprising 3-7 carbon atoms containing from 1 to 3 substitutes chosen from group comprising halogen atom, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy group and alkoxy group comprising 1-6 carbon atoms, aryl, aryl-(C2-C6)-alkyl; R27 means alkyl comprising 1-6 carbon atoms, phenyl or benzyl; R28 and R29 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R31 means alkyl comprising 1-6 carbon atoms, halogenalkyl comprising 1-6 carbon atoms, aryl, aryl-(C1-C6)-alkyl. Also, invention relates to pharmaceutical compositions containing these substances and their using for preparing a drug used in treatment of thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, heart failure and cancer.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
10 cl, 11 tbl, 9 ex