6-(moselhotel-l-prolyl-l-arginyl)-aminonaphthalene-1-isobutyl - sulphonamide as a substrate for fluorescent determination of thrombin

 

(57) Abstract:

Usage: in biochemistry as a substrate for fluorescent determination of thrombin. The inventive 6-(moselhotel-L-prolyl-L-arginyl)-aminonaphthalene-1-isobutylamine. Reagent 1: tos-Gly-L ProOH. Reagent 2: bromohydrin - 6-L-organisationally-1-isobutylamine. The process is conducted in dry DMF in the presence of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide. Yield 75%, []2D0-38,0 (C1, DMSO), So pl. 156 to 160oC. Describe the substrate exceeds a known substrate for the determination of thrombin (Chromozym TH) is almost 3 times by the time 10% hydrolysis. table 2., 1 Il.

The invention relates to the field of Bioorganic chemistry, namely to a new 6-(moselhotel-L-prolyl - L-arginyl)aminonaphthalene-1-isobutylamino formula:

< / BR>
as a substrate for the determination of thrombin.

For these purposes, a widely used commercial substrate Tos-Gly-Pro-Arg-pNA(pNH p-nitroanilide) (Chromozym TH). However, this substrate is not effective enough, because it has a low rate of hydrolysis in the interaction with thrombin.

The aim of the invention is to increase the efficiency peptidyl substrates.

The goal of DOS is D. To establish the effectiveness of this compound as a substrate to carry out the hydrolysis by thrombin and determine the catalytic constant (Kcat), the constant Michael-Menten (KM) and their ratio (Kcat/KM)/1/. As is known, the higher the Kcat/KMthe more effective the substrate, i.e., a shorter time of hydrolysis.

The invention is illustrated in the examples.

Example 1. 6-Phthalimidomethyl-1-isobutylamine.

Dissolve 11 ml (0.11 mol) of isobutylamine and 14 ml (0.1 mol) of triethylamine in 500 ml of acetone and portions over 10 min add to 37.1 g (0.1 mol) phthalimidomethyl-1-sulphonylchloride. The reaction mixture is stirred at 20oC for 4 h, the Acetone is distilled off, the residue is poured 1 liter of water, the product is sucked off, washed with water, dried and recrystallized from methanol. Get 32,4 g (yield 79.4 per cent) of the product so pl. 150-153oC.

Found, C 64,71; H Is 4.85; N 6,98; S 7,25. C22H20N2SO4.

Calculated C 64,69; H 4,94; N 6,86; S A 7.85

Example 2. 6-Aminonaphthalene-1-isobutylamine.

Pour 40,8 g (0.1 mol) of 6-phthalimidomethyl-1-isobutyramide 500 ml of methanol, was added dropwise 5 mol (0.1 mol) of hydrazine hydrate is added and heated for 4.5 hours, the Methanol is distilled off, the residue is ucaut of 20.3 g (yield 73,1%) of the product so pl. 48-50oC, Rfof 0.56 (ethyl acetate-chloroform 1:1). PMR (DMSO) 0,70 (CH3), 1,45(CH), 2,48(CH2).

Found, C60,58; H 6,60; N 10,06; S 11,21. C14H18N2SO2.

Calculated C 60,41; N. OF 6.52; N 10,06; S TO 11.52

Example 3. Bromohydrin 6-(N-benzyloxycarbonyl)-L-organisationally-1-isobutyramide.

Dissolve to 3.89 g (0.01 mol) of bromhidrosis N-benzyloxycarbonyl-L-arginine and 2,78 g (0.01 mol) of 6-aminonaphthalene-1-isobutyramide in 15 ml of dry pyridine, add 30 ml of dry toluene and the latter is distilled off. The reaction mixture is cooled to -20oC and add a solution 2,02 g (0.01 mol) of dicyclohexylcarbodiimide (DCC) in 6 ml of dry pyridine. The reaction mixture was kept at -20oC for 0.5 h, at 4oC for 1 h and at 20oC for 20 hours Sucked off the fallen dicyclohexylamine, pyridine evaporated and the residue is dissolved in 40 ml of a mixture of chloroform-propanol (3:1). The solution was washed with 15 ml of water, 15 ml of saturated NaCl containing 1 ml of conc. HCl, 15 ml of 2% aqueous ammonia and 15 ml of water, dried over anhydrous Na2SO4. The solvent is distilled off, the residue is triturated with ether, sucked off, dried and recrystallized from propanol. Get 6,17 g (yield 95%) about the20-13,5 (c 1, MeOH). PMR (DMSO) 0,70(CH3), 1,50(CH), 2,45(CH2).

Found, C 51,62; H 5,88; N 13,07; S 4,12; Br 11,84

Calculated C 51,77; H 5,74; N 12,94; S 4,94; Br 12,30. C28H37N6BrSO5.

Example 4. Bromohydrin 6-L-organisationally-1-isobutyramide.

Dissolve 6.50 g (0.01 mol) of bromhidrosis 6 - N-benzyloxycarbonyl)-L-organisationally-1-isobutyramide in 10 ml of 3h. HBr in glacial acetic acid and incubated at 20oC for 1.5 h, the Reaction mixture was poured into 100 ml of dry ether, the precipitated precipitate is sucked off, washed with ether and dried. The dry residue is dissolved in 10 ml of water, add 50 ml of butanol and with shaking portions of 15 ml of 5% aqueous NaHCO3to pH 7.5 aqueous layer. The organic layer was washed with 210 ml of water, butanol evaporated, the residue triturated with ether, sucked off, washed with ether, dried and recrystallized from methanol. Gain of 4.95 g (yield 96%) of the desired product with so pl. 158-165 (in Russian)oC []2D0-2,0 (c 1; DMSO), Rf0,47 (PDR 412). PMR (DMSO) 0,70(CH3), 1,50(CH), 2,50(CH2).

Found, C of 46.68; H 5,94; N 16,38; S 6,12; Br 16,11

Calculated C 46,60; H The 6.06; N 16,30; S 6,22; Br 15,50. C20H31SBrO3.

Example 5. 6-(Moselhotel-L-prolyl-L-arginyl)amine and 0.51 g (2.5 mmol) DCC in 18 ml) cooled to -20oC dry dimethylformamide (DMF). The reaction mixture was kept at -20oC for 0.5 h, at 4oC for 1 h and poured chilled to 4oC a solution of 1.29 g (2.5 mmol) of bromhidrosis 6-L-organisationally-1-isobutyramide. Stirred at 20oC for 20 h, sucked off the fallen dicyclohexylphosphino, the filtrate is poured into 125 ml of water and the resulting suspension extracted with CH ml of a mixture of ethyl acetate: butanol (1 1). The organic layer was washed with I ml of 5% aqueous NaHCO3, 10% aqueous KHSO4and water, the solvent evaporated, the residue triturated with ether, sucked off and dried. Obtain 1.40 g (yield 75%) of chromatographically pure target product with so pl. 156 - 160oC []2D0-38,0 (1; DMSO), Rf0,61 (PDR 412). PMR (DMSO) 0,65 (CH3), 1,50(CH), 2,50(CH2), 2,3(CH3, Tos), 7,28(C6H4, Tos), 7,63(C6H4Tos).

The new peptidnogo substrate for the analysis of thrombin and the establishment of its effectiveness in comparison with the known compound are given in examples 6, 7 and 8.

Example 6. The definition of time 10% hydrolysis of 6-(tosyl-glycyl-shed-arginyl)aminonaphthalene-1-isobutyramide.

A. Definition of intensity fluoresc the jut of 0.02 N. Tris-HCl buffer, pH of 7.4, containing 0.15 M NaCl to a concentration of 1 μm and placed in a cuvette of fluorimetry. Record the height of the bar fluorescence maximum ,wosb.=352 nm on an "Hitachi MPF-4 (Japan). The height of the peak fluorescence of 6-aminonaphthalene-1-isobutyramide take 1.

Similarly determine the fluorescence intensities of known detectable group (1-aminonaphthalene-5-sulfonic acids), which accounted for only 0.12 part of the fluorescence intensity detected group proposed substrate.

B. In the same buffer to prepare 100 μm substrate solution of 6-(tosyl-glycyl-shed-arginyl)aminonaphthalene-1-isobutyramide add 1 nm thrombin in the same buffer and determine the time required to achieve the same fluorescence as in part a of experience, i.e. 10% hydrolysis of the substrate. Time is 155 C.

C. determination of the time 10% hydrolysis of the substrate 6-(moselhotel-L-prolyl-L-arginyl)-aminonaphthalene-1-isobutyramide. In the cell of fluorimetry place of 1.8 ml of 1 μm of substrate solution of 6-(tosyl-glycyl-L-prolyl-L-arginyl)-aminonaphthalene-1-isobutyramide in the same buffer, add 0.2 ml of a 1 nm solution of thrombin in the same buffer and measure the growth of intensive the aqueous hydrolysis. The degree of hydrolysis is determined by the fluorescence of the resulting 6-aminonaphthalene-1-isobutyramide. 10% hydrolysis defined 0,3 min.

Example 7. The definition of time 10% hydrolysis of 4-(tosyl-glycyl-propyl-arginyl)nitroanilide.

Prepare 100 μm substrate solution 4-(tosyl-glycyl-shed-arginyl)nitroanilide in the same buffer as in example 6, add the thrombin concentration in the solution is 1 nm and 405 nm is measured increase in optical density of the solution to 0,098, i.e., to achieve a 10 μm concentration of p-nitroaniline, which corresponds to a 10% increase hydrolysis of the substrate. The time required for this is 460 C.

From examples 6 and 7 shows that the proposed substrate is almost 3 times according to the time of hydrolysis exceeds the prototype.

Example 8. Defining constants Michael-Menten (KM) and catalytic constant (Kcat) Chromazum TH in the reaction with thrombin.

Prepare solutions Chromozym TH different concentration (S) in 0.02 M Tris-HCl buffer, pH of 7.4, 0.15 M NaCl. 2 ml thermostatic at 25oC cuvette spectrophotometer, add I nm thrombin in the same buffer, measure the length of the optical density at 405 nm over time and from this determine the speed of the re is W). The intersection of the obtained straight line with the abscissa gives the value of 1/Kmand y is 1/Vmax.

As you can see from the chart

From: Km=13.8 m vmax=14,1 nm-1S.

By the formula where E is the concentration of thrombin (mol/l) and equal to 1 nm, receive the amount of catalytic constants:

Kcat14,1-1C.

Similarly calculate these constants for the substrate. Only the reaction rate of hydrolysis by thrombin determine fluorescent method as in example 6.

Constants KM, Kcatand their ratio are shown in table. 2.

A new substrate for the determination of thrombin fluorescent method outperforms well-known almost 3 times by the time 10% hydrolysis (examples 6 and 7) (see 155 and 460, respectively).

Efficiency the ratio of the constants Kcat/KMincreased 3.6 times (example 8, table. 2) (cf. 3,85106and 1,02106respectively).

6-(Moselhotel-L-prolyl-L-arginyl)-aminonaphthalene-1-isobutyl sulphonamide of the formula

< / BR>
as a substrate for fluorescent determination of thrombin.

 

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FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

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106 cl, 9 tbl, 61 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of acetylamidiniophenylalanylcyclohexylglycilpypidinioalanin amides of formula I , wherein X anions are physiologically acceptable anions, and analogous thereof. Said compounds are effective inhibitors of fibrillation factor Xa and are useful, for example, in prevention of thrombosis. Claimed method includes coupling of 2-[2-acetylamino-3-(4-amidinophenyl)-propionylamino]-2-cyclohexylacetic acid, obtained from 2-[2-acetylamino-3-(4-cyanophenyl)acryloylamino]-2-cyclohexylacetic acid by assimetric hydration and converting of cyano group to amidine, or salt thereof with 3-(2-amino-2-carbamoylethyl)-1-methylpyridinic acid or salt thereof. Also are disclosed starting materials and intermediated used in this method, process for production the same and acetyl-(S)-4-amidiniophenylalanyl-(S)- cyclohexylglycil-(S)-(1-methyl-3-pypidinio)alanin amide in form of ditosylate.

EFFECT: simplified method; increased commercial availability of compounds with applicable anion.

14 cl, 16 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. 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EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

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EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.

20 cl, 48 tbl

FIELD: biotechnology, medicine, oncology.

SUBSTANCE: invention proposes peptide of the structure Tyr-Ser-Leu and a pharmaceutical composition based on thereof that is used for stimulating antitumor immune response. Also, invention proposes methods for treatment of mammal and for modulation of the immune response. Proposed inventions expand assortment of agents used in treatment of cancer diseases.

EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.

20 cl, 48 tbl

FIELD: biochemistry.

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7 cl, 8 ex

FIELD: medicine, biochemistry.

SUBSTANCE: invention describes compounds that inhibit function of NS3-protease encoded by hepatitis C virus.

EFFECT: valuable medicinal properties of inhibitors.

6 cl, 2 tbl, 472 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes heterocyclic compounds represented by the general formula (I): and possessing elastase-inhibitory activity, and intermediate compounds for synthesis of such compounds. In the formula (I) R1 represents heterocyclic group represented by the formula (II): wherein A represents presence or absence of benzene ring; X represents oxygen atom, sulfur atom or -NH; Y represents nitrogen atom or -CH. Indicated heterocyclic group can be substituted with 1-3 substitutes that can be similar or different and they are chosen from group consisting of lower alkyl, lower alkoxy group and phenyl that can be optionally substituted with halogen-containing lower alkyl, lower alkoxy group or halogen atom; each among R2 and R3 represents hydrogen atom or hydroxyl, or R2 and R3 can be combined to form oxo group under condition that both are not hydrogen atoms.

EFFECT: valuable biochemical property of compounds.

8 cl, 7 tbl

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SUBSTANCE: invention relates to immunology. Described is tripeptide-L-Tyrosyl-L-Seryl-L-Valine and its application in pharmaceutical composition and in production of food additive. Discovered is method of relieving state of human disease, where disease is selected from group, which consists of states which can be relieved by stimulation of T-lymphocytes transformation, and fault of cell proliferation, which includes introduction of described pharmaceutical composition. Claimed invention gives short peptides which possess biological activity.

EFFECT: obtaining short peptides which possess biological activity.

8 cl, 5 dwg, 1 tbl, 6 ex

FIELD: medicine, oncology, molecular pharmacology.

SUBSTANCE: invention relates to a method and set for identifying the individual subjected to risk for arising in it the vascular and cancer disease. Method involves stages for the quantitative determination of the analyte concentration, i. e. pepsinogen I (PGI), in serum sample taken in the personal individual; comparison of the analyte concentration determined by the proposed method with a method-specific boundary value for this analyte; determination of the homocysteine concentration in a serum sample taken in this individual. The set comprises the combination of separate components that are necessary for the quantitative determination of the PGI concentration. Method provides the early detection of the possibility for arising the vascular and cancer disease in the patient.

EFFECT: improved method for assay.

4 cl

FIELD: production methods.

SUBSTANCE: method is based on the capability of defibrotide to increase the fermentation activity of plasmin and foresee the stages: a) making the contact in reactional area defibrotide, plasmin and substrate specific for plasmin which, because of reaction, provides the defined product b) the definition of the amount of obtained product in temporary points.

EFFECT: invention allows to define the biological activity of defibrotide in comparison with standard etalon with height accuracy and big repeatability.

9 cl, 6 dwg, 4 tbl, 1 ex

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