Thrombocyte aggregation-inhibiting n-carb(arginyl)oxymethylimidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane
SUBSTANCE: invention relates to N-carb(arginyl)oxymethylimidazo[4,5-e]benzo[1,2-c; 3,4-c']difuroxane of formula .
EFFECT: improved properties of the compound.
1 dwg, 1 tbl
The invention relates to the pharmacy, in particular to the synthesis of pharmacologically active compounds.
Cardiovascular diseases are the leading cause of deaths in Russia. Most often the basis for cardiovascular disease atherothrombosis is the pathological process of thrombosis, leading to myocardial infarction and stroke. Therefore, the development of new classes of drugs with antiplatelet activity is relevant.
The antiplatelet agents are drugs with different mechanism of action, belonging to different groups of chemical compounds.
It is known that as a result of the interaction of nitric oxide (NO) with platelets and leukocytes reduced their aggregation and adhesion to the walls of blood vessels, leading to inhibition of the processes of thrombosis. Disorders associated with the normal course of the above reactions are the basis of the pathophysiological processes specific to the development of various diseases of the cardiovascular system. When such diseases are observed multiple violations of the synthesis of endogenous NO, its reception soluble form of guanylyl cyclases (RGD), as well as the regulation of the level of cyclic nucleotides and calcium ions [Dessy S., Ferron O. Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature. Current Medical Chemistry - Anti-Inflammatory &Anti-Allergy Aents in Medicinal Chemistry. 2004. Vol.3. P. 207-216].
To date, proved the formation of nitric oxide as a result of the biotransformation of nitroglycerin and other nitrates, which are used for the treatment of cardiovascular diseases, as anti-ischemic and antianginal drugs. However, their significant drawback is the occurrence of tolerance and other side effects with long-term use [Granik V. G., Grigoriev N. B. Nitric oxide (NO). A new way to search for medicines: a monograph. - [Academic book. 2004, 360 p.].
In this regard, a search for new compounds able to form NO in vivo reanimations way. This approach is seen as relevant and promising direction of creating new, more effective in comparison with previously known antihypertensive and antiplatelet medicines that possess anti-anginal and anti-ischemic activity.
One of the classes of chemical compounds, derivatives of which are donors of nitric oxide, furoxone. Furoxone considered as a prodrug that implement its biological activity through the TWG-cGMP-path [Granik V. G., Grigoriev N. B. Nitric oxide (NO). A new way to search for medicines: a monograph. - [Academic book. 2004, 360 p.; Granik, V. G., Kaminka M. E., Grigoriev, M. B., Severina I. S., M. A. Kalinkina, �akirov V. A., Levin V. I. Furoquinoline as an exogenous donor of nitric oxide // Chem. Pharm. Log. 2002, Volume 36, No. 10, pp. 7-11].
In the patent US No. 2012/021007 2012 was held a screening of furoxans, but their antiplatelet activity has not been investigated.
In the patent RU 2123046 1998 and EN 2139932 1998 described furoxone as donors of nitric oxide and activators RHC, but the data on their antiplatelet activity is not presented.
In the patent US No. 7838023 2010 mentioned that the biologically active derivatives of furoxone possess antiplatelet activity, but no information on the studies is not given.
The object of the present invention is to provide a new and effective inhibitors of platelet aggregation.
The problem is solved N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxine, inhibiting platelet aggregation.
The synthesis of the target compounds
Synthesis of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime was performed on the solid phase under the conditions of automated peptide synthesizer ABI A PeptideSynthesizer (AppliedBiosystems, USA), using FastMoc 0.25-strategy. Strategy FastMoc 0.25 involves the consecutive addition of amino acid residues to an insoluble polymeric substrate. The base labile Fmoc group - 9-fluorenylmethoxycarbonyl - is used to protect the N-group of each amino acid OST�TKA. Residues that are potentially reactive side chains are protected kislotoneustoichiwami groups.
After removal of the Fmoc group with piperidine, the following protected amino acid is added, or using a coupling reagent, or pre-activated derivative of an amino acid.
As an activator of the first amino acid Fmoc-strategy in the reaction of accession to the resin acts as dicyclohexylcarbodiimide (DCC). The reaction proceeds in the presence of 4-dimethylaminopyridine (DCC/DMAP), which plays a catalytic role.
As an activator of the second and subsequent amino acids Fmoc-strategy acts 1-hydroxy-benzotriazole in dicyclohexylcarbodiimide (HOBt/DCC). The reaction proceeds with the formation of the activated amino acid and N,N'-dicyclohexylamine (DCU).
All of these operations occur in a peptide synthesizer.
For removal of the peptide from the resin in the fume cupboard in a polypropylene test tube was prepared a mixture with the following ratio of components: TAN - 2.5%, TIPS - 2.5%, EDT - 5%, TFA - 90%. The prepared mixture was placed on ice to cool for 20-30 min. Then cool the mixture to remove the peptide was placed in the peptide-resin and stirred. Put the vial containing the peptide-resin in a polypropylene test tube, closed and kept on rocking for 4 hours.
Extraction of the peptide from the resin was carried out n� glass filter funnel in a fume hood. Funnel pre-rinsed out twice with MTBE (methyl tertiary butyl ether). After removing the fused mixture with the resin and the peptide on the filter SCHOTT. Washed the test tube, which was the reaction of the TFA, the flush was leaking at the filter. Was filtered under a slight vacuum to the drying of the resin. Added cold MTBE, washed thoroughly with resin and filtered before drying. Washed the test tube, which was the peptide-resin three times with cold MTBE and added washout to the main drain. Thoroughly mixed, the slurry was left for not less than 1 hour at -20°C. the Precipitate was filtered and dried.
The peptide purification was performed using preparative high-performance liquid chromatograph PuriFlash 450 (InterChim).
The HPLC conditions: cartridge Interchim PF-C18(20g), 15 μm. Can be used facing other cartridges C18 or C8.
a. The detector cell: preparative
b. Flow rate - 20.0 ml/min
c. Wavelength: range 200 - 400 nm
d. Range of detection: 2 AUFS
e. The value of the loop: 2 ml (injection volume 1.5-1.8 ml sample)
f. Eluent A: 5.0% acetonitrile, 0.1% trifluoroacetic acid in water
g. Eluent B: 0.1% trifluoroacetic acid in acetonitrile;
h. Gradient: 10-90% B over 12 min
The structure of synthesized compounds was confirmed by NMR1H and chromatography-mass spectroscopy. The NMR spectra of1H were recorded on the instrument Brker Avance 600 mhz; chemical shifts were measured relative to the solvent signal (DMSO-d6that δH2.5 M. D.).
Chromato-mass-spectrometric analysis was performed on a Waters instrument MSD SQD - ESI with UV and mass spectrometric detectors: wave length 220 nm, temperature probe 15°C, the temperature of the column thermostat at 40°C. MSD - parameters: source temperature 130°C, the gas temperature is 400°C, the voltage on the capillary 3kV; column Waters Acquity of 1.7 µm 2.1·50 mm. A gradient from 5 to 100% B over 4 min (A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile).
The NMR spectrum1H (δ, M. D.) of 1.52 (m, 2H, C(22)H2); 1,74 (m, 2H, C(21)H2); 3,10 (m, 2H, C(23)H2); to 4.28 (m, 1H, C(20)H); 5,31 (s, 2H, C(16)H2); 7.23 percent (ush. d, 5H, N(19)H, N(24)H, N(26)H, N(29)H2); 8,89 (m, 1H, C(11)H); 9,02 (s, 1H, COOH).
The mass spectrum of the [MS (ES)] m/z 449.35 [M+H]+
The pharmacological action.
Estimation of specific activity of antiplatelet action of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']Difenoxin conducted in vitro using the blood of healthy donors. Blood sampling was performed immediately before the study, using as anticoagulant sodium citrate (3.8%). The ratio of anticoagulant:blood corresponded to 1:9.
Antiplatelet activity of the obtained compounds was studied in platelet-rich plasma with the use of adenosine diphosphate (ADP) � as inducer of platelet aggregation.
The date of preparation of platelet-rich plasma blood immediately after receiving centrifuged for 10 minutes at 1000 rpm, after which the top layer of plasma was transferred to another tube, and the residue was centrifuged for 20 min at 3000 rpm to obtain estramboticos plasma. All procedures were performed in polystyrene dishes with thromboresistant properties. During the entire study period is rich and estrambotica plasma was at room temperature, and the entry of platelet aggregation was performed at 37°C.
For the study of specific antiplatelet activity of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime was guided by the requirements for pre-clinical pharmacological substances of this class, approved Pharmacological service on surveillance in healthcare and social development.
Platelet aggregation was studied by turbidimetric method of born (Born, 1962), based on the change of transmittance of light (540 nm) is studied using the plasma under constant stirring (1000 rpm). As a sample comparison, estrambotica plasma. Light transmission through estrambotica plasma was taken as 100%, and the light transmission through platelet-rich plasma was taken as 0%. The end�centration of platelets was adjusted in platelet-rich plasma to 2.5·10 -8cells/ml using dilution of platelet-poor plasma.
To conduct the study used a two-channel laser analyzer platelet aggregation/counter 230LA-2 (SPC "Biola"). The sample volume was 300 μl. The measuring times - 8 minutes as the inductor used ADP at a concentration of 50 μm. Get agregarme represent the dependence of the degree of aggregation of the time elapsed after addition of the inducer of aggregation. Studying the connection (in the form of an aqueous solution, optionally containing DMSO 0.2%) in different concentrations (0.1·10-6, 0.2·10-6, 0.3·10-6, 0.4·10-6, 0.5·10-6M) was added to the sample prior to the introduction of aggregation inducer (ADP). The results of studies on the blood of healthy donors are presented in table 1.
Table 1. The results of the study specific antiplatelet activity of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime
|The concentration of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']Difenoxin, M||% aggregation in the presence of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']cefuroxime|
In the study of the inhibitory action of N-carb(arginyl)oxymethylene[4,5-e]benzo[1,2-c;3,4-c']Difenoxin on platelet aggregation in healthy donors was discovered the effect of inhibition of ADP-induced platelet aggregation. The dependence of platelet aggregation on the concentration of the compounds is presented in Fig.1.
The compound inhibited ADP-induced platelet aggregation with IC500.25 μm, which shows a pronounced antiplatelet effect. Shown by the connection antiplatelet activity of higher antiplatelet activity of similar compounds described in patent RU 2502739 2012 (IC500.41 µm).
inhibits platelet aggregation.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula and to its pharmaceutically acceptable salts, stereoisomers and isomers, wherein T: N, U: N, X: CR3 and Y: N; or T: CR6, U: CR4, X: CR3 and Y: N; or T: CR6, U: N, X: NR3 and Y: C; or T: O, U: N, X: CR3 and Y: C; or T: NR6, U: N, X: CR3 and Y: C; and R1, R2 and R5: H, heteroaryl substituted by 1-2 substitutes; or T: CR6, U: N, X: CR3 and Y: N; or T: N, U: CR4, X: CR3 and Y: N; and R1 and R2: H, heteroaryl substituted by 1-2 substitutes; R5: heteroaryl substituted by 1-2 substitutes; R3: H, bridging (C7-C10)cycloalkyl; (C1-C8)alkyl optionally substituted by 1 substitute; (C3-C10)cycloalkyl optionally substituted by 1 substitute; (C6-C8)cycloalkenyl substituted by two (C1-C6)alkyl; (C6)aryl optionally substituted by 1-2 substitutes; heteroaryl optionally substituted by (C1-C6)alkyl; heterocyclyl optionally substituted by (C1-C6)alkyl or heteroaryl; or R3: -A-D-E-G, wherein: A: a bond or (C1-C6)alkylene; D : (C1-C2)alkylene optionally substituted by (C1-C6)alkyl, bridging (C6-C10)cycloalkylene optionally substituted by (C1-C6)alkyl, (C3-C10)cycloalkylene optionally substituted by 1-2 substitutes, (C4-C6)cycloalkenylene optionally substituted by (C1-C6)alkyl, (C6)arylene, heteroarylene or heterocyclylene optionally substituted by one (C1-C6)alkyl; E: a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)O-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-N(Ra)C(O)ORe- or -Re-N(Ra)S(O)2-Re-; wherein in each case, E is bound to either a carbon atom, or a nitrogen atom in D; G: H, -N(Ra)(Rb), halogen, -ORa, S(O)2Ra, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -C(O)Ra, -CF3, N(Ra)S(O)2Rb, -(C1-C6)alkyl optionally substituted by 1-3 substitutes; -(C3-C6)cycloalkyl optionally substituted by CN; -heteroaryl optionally substituted by 1-2 halogens, CN, -C(O)NH2 or -CF3; -heterocyclyl optionally substituted by 1-5 substitutes, -(C6-C10)aryl optionally substituted by 1-3 substitutes; wherein in a fragment containing -N(Ra)(Rb), nitrogen, Ra and Rb can form a ring so that -N(Ra)(Rb) represents (C3-C6)heterocyclyl optionally substituted by 1 substitute, wherein said (C3-C6)heterocyclyl is bound through nitrogen; R4 and R6: H, (C1-C4)alkyl optionally substituted by -OH, -COOH; (C3-C8)cycloalkyl, phenyl, optionally substituted by -SO2CH3 or -NHSO2CH3, halogen or -J-L-M-Q; wherein: J: (C2-C6)alkenylene; L: a bond; M: a bond; Q: -C(O)ORa; Ra and Rb: H, (C1-C4)alkyl optionally substituted by cyano, -CF3 or cyclopropane; (C6)aryl optionally substituted by halogen or -O(C1-C4)alkyl; and Re: a bond, (C1-C4)alkylene or (C3)cycloalkylene. Besides, the invention refers to specific compounds, a pharmaceutical composition based on the compound of formula I, using the compound of formula I for treating and using the compounds of formulas 2-6
for preparing the compound of formula I.
EFFECT: prepared are the new compounds effective in treating a condition mediated by Jak1, Jak3 or Syk protein kinase activity.
51 cl, 34 tbl, 44 ex
SUBSTANCE: invention relates to a method of producing N-carboxymethylimidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane by hydrolysis of N-carbethoxymethylimidazo[4,5-e]benzo[1,2-c;3,4-c']difuroxane with 10% aqueous hydrochloric acid solution.
EFFECT: high output of the end product.
SUBSTANCE: invention relates to N-carb(glutaminyl)oxymethylimidazo[4,5-e]benzo[1,2-c; 3,4-c']difuroxane of formula .
EFFECT: obtaining a novel compound which can be used as a medicinal preparation which inhibits thrombocyte aggregation.
1 dwg, 1 tbl
SUBSTANCE: invention relates to a compound of formula (I) or (I'): Z-X1-(-CH2-CH2-O-)n-Yp-D (I), D-Yp-(-CH2-CH2-O-)n-X1-Z (l'), where: Z is a reactive carboxylic ether selected from a group consisting of N-succinimidyl, N-sulphosuccinimidyl, N-phthalimidyl, N-sulphophthalimidyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3-sulpho-4-nitrophenyl, 3-carboxy-4-nitrophenyl and a trifluorophenyl ester, or haloacetamide; D is maytansinoid; X is an aliphatic structural unit; Y is an aliphatic structural unit linked to the maytansinoid through a thioether bond; where said aliphatic structural unit, represented by X or Y, is a simple or branched alkyl group with 1-20 carbon atoms in the chain, a cyclic alkyl group having 3-10 carbon atoms, a simple or branched alkenyl group, having 2-15 carbon atoms in the chain or a simple or branched alkynyl group, having 2-15 carbon atoms in the chain; 1 equals 0 or 1; p equals 0 or 1; and n is an integer from 1 to 2000. The invention also relates to a conjugate of a cell-binding agent, and cytotoxic maytansinoid, where the cell-binding agent is an antibody.
EFFECT: obtaining compounds and conjugates, as well as pharmaceutical compositions based thereon, which can be used in medicine to treat tumours, autoimmune diseases, graft rejection, graft-versus-host disease, viral infections and parasitic infections.
20 cl, 38 dwg, 10 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of formula (I) where values of the substitutes are disclosed in the patent claim.
EFFECT: compounds can be applied for treating the infections caused by Pneumovirinae subfamily viruses (RSV, PCB).
53 cl, 502 ex, 11 tbl
SUBSTANCE: invention relates to products of oxidative decomposition of atorvastatin calcium, specifically to 4-[6-(4-fluorophenyl)-6-hydroxy-1b-isopropyl-6a-phenyl-1a-phenylcarbamoylhexahydro-1,2-dioxa- 5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid, phenylamide 4-(4-fluorophenyl)-2,4-dihydroxy-2-isopropyl-5-phenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxylic acid and 4-[1b-(4-fluorophenyl)-6-hydroxy-6-isopropyl-1a-phenyl-6a-phenylcarbamoylhexahydro-1,2-dioxa-5a-azacyclopropa [a]inden-3-yl]-3-(R)-hydroxybutyric acid. The invention also relates synthesis methods thereof, based on oxidation of an atorvastatin salt.
EFFECT: disclosed are products of oxidative decomposition of an atorvastatin salt, which can be used to identify impurities or a product of decomposition of an atorvastatin salt in accordance with approved analytical procedures.
15 cl, 5 tbl, 9 ex
SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.
EFFECT: wider field of use of the compounds.
16 cl, 4 tbl, 29 ex
SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.
EFFECT: compound with antagonistic effect on vasopressin V1A receptor.
73 cl, 133 ex
FIELD: organic chemistry, pharmaceuticals.
SUBSTANCE: invention relates to D-proline derivatives of formula I or IA wherein R1 and R2 are independently lower alcoxy, lower alkenyloxy, hydroxy, -OCH(CH3)OC(O)-lower alkyl or -OCH2C(O)N(R3)N(R4), with the proviso, that only one from R1 and R2 represent hydroxy; R3 and R4 are independently hydrogen, lower alkyl? Lower alkenyl, or cycloalkyl; or R1 and R2 together with carbon atom to which they are attached form linkage group X, wherein X represents -O(CH2)nCH=CH(CH2)nO- or -O(CH2)mO-; n = 1, 2 or 3; m = 4-8.
EFFECT: new prodrugs.
14 cl, 1 tbl, 25(29) ex
FIELD: organic chemistry.
SUBSTANCE: invention relates to derivatives of general formula I , wherein R1, R2 and R3 are independently H or C1-C4-alkyl; Ar is condensed thiophene or pyridine ring optionally substituted with one or more substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkyloxy(C1-C4)-alkyl, CF3, halogen, nitro, cyano, NR4R5 NR4COR6 and CONR4R5 (R4 and R5 are independently H or C1-C4-alkyl; or R4 and R5 together with adjacent nitrogen atom form 5- or 6-membered saturated heterocyclic ring; R6 is C1-C4-alkyl): A is residue of 4-7-membered saturated heterocyclic ring optionally containing nictogen atom and optiomally substituted with 1-3 substituents selected from C1-C4-alkyl, C1-C4-alkyloxy, hydroxyl, halogen, and alkoxy; and pharmaceutical composition based on the same; with the proviso, that compound of formula I wherein A represents condensed [3,2-f]pyridine ring; each R1, R2 and R3 represents H, and A represents (CH2)3. Also described are application of abovementioned derivatives, pharmaceutical composition enhancing of synaptic response mediated with AMPA receptors in CNS based on the same, and method for treatment of neurological diseases or mental disorders.
EFFECT: new compounds with value biological properties.
7 cl, 1 tbl, 12 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the field of pharmaceutics and represents a medication, possessing venomotor and anticoagulant action, which includes a dry extract of vine leaves, a base, preservatives, solvents, and is characterised by the fact that it additionally contains heparin in the form of a pharmaceutically acceptable salt, as the base it contains a hydrophilic gel-generating agent, as the solvents it contains purified water, propyleneglycol, ethyl alcohol rectified 95%, as the preservatives it contains nipagin, nipasol, with the following component ratio, wt %: dry extract of vine leaves with the content of the sum of flavonoides counter per rutin no less than 8% - 0.1-30.0; heparin in the form of a pharmaceutically acceptable salt - 100-1000 Units, hydrophilic gel-generating agent - 0.2-20.0; nipagin - 0.01-0.2; nipasol - 0.01-0.2, propyleneglycol - 3.0-70.0; ethyl alcohol rectified 95% - 3.0-70.0; purified water - the remaining part.
EFFECT: invention provides the creation of the medication in the form of a gel with good absorption, fast soaking, storage stability and acceptable organoleptic properties.
4 cl, 8 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.
EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.
SUBSTANCE: invention concerns preparing systemic and topical solid and soft dosage forms for external application in the form of a 1.5% hydrophilic gel and rectal capsules containing a 7.5% hydrophilic gel 1.9 g (in terms of the amount of the active substance of 0.14 g/capsule), for preventing and treating chronic venous insufficiency possessing anticoagulant, antithrombotic, anti-inflammatory, antiexudative and antitranssudative, capillary protective activities and improving haemorheology. An active pharmacologically active substance is presented by a substance of a potassium salt of sulphated arabinogalactan; a hydrophilic base is Aerosil, glycerol and pure water; the ingredients of the agent are taken in certain proportions, wt %.
EFFECT: invention provides the effective prevention and treatment of chronic venous insufficiency, has a broad spectrum of therapeutic action, improves haemorheology, tones the vessels and can be used in particular for treating varicose veins, thrombosis and posttraumatic oedema.
5 cl, 7 ex, 8 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a dosage form of Clopidogrel presented in the form of a solid gelatine capsule. The dosage form contains Clopidogrel hydrogen sulphate, lactose anhydride, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide and magnesium stearate.
EFFECT: according to the invention, the dosage form of Clopidogrel contains a high amount of the active ingredient; it is prepared without the use of a wet granulation technique, and provides the more accurate dosage of the ingredients and the stability of the substances used.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to field of immunology and biotechnology. Claimed is monoclonal antibody or its functional fragment, where said antibody and fragment bind with activated protein C and inhibit anticoagulant activity, but do not bind and do not inhibit activation of inactivated protein C, where said antibody is obtained by immunisation of mammal by APC and screening of binding ability of said antibody with APC, but not with protein C. Also described is pharmaceutical composition for treating diseases associated with anticoagulation activity of APC, including said antibody in effective amount and pharmaceutically acceptable carrier. Claimed are: method of inhibiting anticoagulation activity of activated protein C in subject, method of inhibiting amidolytic activity of activated protein C in subject, method of treating subject, requiring blood coagulation; method of treating subject with haemophilia; method of modulating haemostasis in subject; as well as method of modulating thrombogenesis in subject, which include introduction of effective quality of said antibody to subject. In addition, described is method of treating subject with sepsis, including introduction of effective quality of said antibody and activated protein C.
EFFECT: invention makes it possible to obtain monoclonal antibody or its functional fragment, where said antibody and fragment bind with activated protein C and inhibit anticoagulation activity, but do not bind and do not inhibit activation of inactivated protein C.
17 cl, 11 dwg, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine. What is described is a system of the transdermal delivery of a drug containing an effective dose of an antithrombotic agent, such as tirofiban, or its pharmaceutically acceptable salt. A dose of the delivered drug is proportional to an applied plaster size and reaches 60-85% of thrombocyte inhibition. The system enables providing the individualised treatment of patients. There are presented methods of treating various disorders, when the thrombocyte inhibition is required.
EFFECT: transdermal delivery system can deliver the drug to the patient for the prolonged period of time.
25 cl, 12 ex
SUBSTANCE: invention refers to medicine, namely to surgery, and can be used for treating trophic ulcers and purulonecrotic involvements of lower extremities in diabetic patients. That requires a baseline therapy and a regional fibrinolytic therapy. Conducting the regional fibrinolytic therapy following applying a rubber bandage on the lower one-third of the shin is accompanied by administering Urokinase medac in a dose of 100 thousand units into the heel bone once a day within 5 days.
EFFECT: in the setting of reducing the total dosage of the preparation, the invention enables providing the high concentration of Urokinase medac in a pathological centre, improving microcirculation and metabolic processes in the involved tissues, accelerating the wound healing and reducing the length of hospital admission of the patients suffering from diabetic foot syndrome.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a pharmaceutical composition containing a thrombosis inhibitor. Active substances of the above inhibitor are Triflusal and clopidogrel bisulphate with Triflusal:clopidogrel bisulphate ratio of (100-650):(30-150), preferentially (1-20):1, more preferentially (3-6):1, and most preferentially 3:1 or 6:1. The composition is applied in treating cardiovascular and cerebrovasacular disorders.
EFFECT: inhibiting thrombosis and thrombocyte aggregation using the combination has been more effective, than using Triflusal and clopidogrel bisulphate individually; six-month monitoring has shown that the stability of the combined drug preparation of Triflusal and clopidogrel bisulphate is higher than that of the combined drug preparation of Triflusal or clopidogrel bisulphate.
20 cl, 2 dwg, 4 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa 2 represents CR5; Wa 3 represents CR6; Wa 4 represents N or CR7; in compound IX, Wa 1 and Wa 2 independently represent CR5, N or NR4, and Wa 4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb 5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.
EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.
68 cl, 11 dwg, 7 tbl, 55 ex
SUBSTANCE: group of inventions refers to medicine, and concerns using tetrapeptide Pro-Gly-Pro-Val as an agent for preventing or treating lipid storage disease; a method for preventing or treating lipid storage disease involving the intranasal administration of a therapeutic agent containing tetrapeptide Pro-Gly-Pro-Val in an effective amount; to a pharmaceutical composition for preventing or treating lipid storage disease, containing peptide Pro-Gly-Pro-Val with the anticholesteremic and triglyceridemic action as an active substance, and an auxiliary substance as a preserving agent.
EFFECT: group of inventions provides the more effective prevention and treatment of lipid storage disease as compared to natural tripeptide Pro-Gly-Pro.
6 cl, 4 ex, 5 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts, wherein A is thiazolyl, oxazolyl, thienyl, furyl, imidazolyl, pyrazolyl or oxadiazolyl (structures of which are presented in cl.1 of the patent claim), R1 represents C1-6alkyl; R2 represents (i) phenyl substituted by halogen; C1-6alkyl optionally substituted by morpholine or C1-6dialkylamino; C1-6alkoxy optionally substituted by halogen; or heterocyclyl, wherein a heterocyclyl substitute is specified in morpholine; pyrazolyl optionally substituted by C1-6alkyl; piperidinyl; pyrrolidinyl; oxadiazolyl substituted by C1-6alkyl; furyl substituted by C1-6alkyl; dioxydoisothiazolidinyl; triazolyl; tetrazolyl substituted by C1-6alkyl, tridiazolyl substituted by C1-6alkyl; thiazolyl substituted by C1-6alkyl; pyridyl; or pyrazinyl; (ii) substituted or unsubstituted heterocyclyl specified in quinolinyl; pyridyl substituted by C1-6alkoxy or morpholinyl; or benzo [d] [1, 2, 3] triazolyl substituted by C1-6alkyl; R3 represents phenyl substituted by 2 or 3 substitutes specified in halogen; C1-6alkyl; C1-6alkoxy optionally substituted by halogen; hydroxy group; cyano; or -C(=O)ORa, wherein Ra represents phenyl; R4 represents hydrogen, C1-6alkyl or C1-6halogenalkyl. The invention also refers to a pharmaceutical composition containing the compounds of formula (I), a method for PDE10 inhibition, a method of treating neurological disorders, and to intermediate compounds: 2-(4-chlor-3,5-dimethoxyphenyl)furan and 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde.
EFFECT: compounds of formula (I) as PDE10 inhibitors.
39 cl, 13 ex, 2 tbl, 77 dwg