N-acyl derivatives of biogenic amines - modulators of lipid peroxidation and method of production thereof
(57) Abstract:N-alaline derivatives of biogenic amines - modulators of the process of lipid peroxidation and the way they are received. Usage: the invention relates to the field of Bioorganic chemistry, and biology and medicine. The essence of the invention: N-alaline derivatives of biogenic amines of General formula X-CO-NH-Y, where X is-CO-residue amino or fatty acids, and-NH-Y-the balance of serotonin, tryptamine, histamine modulation of the process of lipid peroxidation. The method of obtaining compounds of formula XCONHY by arilirovaniya amino biogenic amine activated pentafluorophenyl esters of N-protected amino acids or anhydrides of fatty acids in an organic solvent, followed by purification by ion-exchange chromatography, isoelectric precipitation or re-extraction of water and organic solvents. 2 S. p. f-crystals. The invention relates to the field of Bioorganic chemistry, more specifically to the synthesis of pseudopeptides N-Alannah derivatives of biogenic amines that can be used in biology and medicine as modulators of the process of lipid peroxidation (LPO).Antioxidants (AO) westw are endogenous antioxidants, for example superoxide dismutase /1/, dipeptide carnosine (H-Ala-His-OH) /2/, decarboxylating similar carnosine (N-alaline derived histamine-b-Ala-HA) pseudopeptide carcinine /3/. In addition, exogenous SA: natural JSC tocopherol acetate and synthetic - BHT, emoxipin, Mexidol, opinon /1/.Closest to the claimed pseudopeptides on the structure and properties of an antioxidant peptide carnosine.The disadvantage of carnosine are high effective dose and a relatively low level of antioxidant activity, which greatly restricts the use of carnosine as a therapeutic drug /4/.The aim of the invention is the synthesis of new, more effective antioxidants N-Alannah derivatives of histamine analogues of carnosine and N-Alannah derivatives of biogenic amines serotonin and tryptamine with lower effective concentrations and, in addition, the increased lipophilicity
affinity to membranes.This goal is achieved near the N-acyl derivatives of biogenic amines of General formula X-CO-NH-Y, where X is-CO-residue g-aminobutyric (GABA), L-pyroglutamyl (pGlu), L - and D-glutamic (Glu), triptamine (TA); and retrieval method that involves acylation of biogenic amine activated at the carboxyl group derived fatty or N-substituted amino acids.The proposed synthesis of N-aminoaniline derivatives of biogenic amines perform classical methods of peptide chemistry with the use of activated pentafluorophenyl esters as the most active of the known.the a-Amino group of amino acids replace tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Z) protections a-carboxyl function of glutamic acid protects benzyl (Bzl) group. Pyroglutamic acid used in the synthesis without protecting minopoly.The synthesis is carried out according to the following scheme 1:
< / BR>H-D-Glu-OBzl-H-L-pGlu;
NH2-B HA, TA, 5-OBzl-TA;
NH2-A"-CO - L-Glu-; -D-Glu-NH-B-HA-TA, 5-HT.R2H HHal(HCl, HBr); CF3COOH; CF3SO3H; n is 1, 2, 3.Stage 2 is excluded in the case of R1Z stage 4 is carried out in the presence of the intermediate connection R1-A-CONH - BN-Z - Bzl-groups that otscheplaut catalytic hydrogenolysis. Stage 1 is conducted in the medium of anhydrous aprotic solvent, preferably dimethylformamide (DMF), 0.5 to 1.0 hour at work solvent, preferably methanol or triperoxonane acid (stage 2).The advantage of this method of synthesis is the implementation of cleaning and selection (phase 3) of the target product NH2-A-CONH-B, not containing carboxyl groups, in the stable crystalline form of the free bases in a single phase with high yield by passing the corresponding salt by ion exchanger with Quaternary ammonium groups, for example, ARA-10p (or 8s) NPO "Biolar" (Latvia) with elution of water with alcohol, mainly 60% methanol or 70% ethanol.So, in this method using Boc--Ala-OPfp and ion exchanger ARA-8s in OH--gain carcinine H-b-Ala-HA in the form of stable crystalline basement with high yield and high purity. Physico-chemical characterization posted in /3/ without disclosure of the method of synthesis. The advantages of this method of synthesis carcinine visible when compared to the known method thereof, which consists in the condensation of histamine with Nps-b-Ala-OH N,N ' -dicyclohexylcarbodiimide (DCGK) method.The disadvantages of this method of synthesis is the instability of the Nps - b-Ala-OH in the free state and the necessity of its use in Nps-protection from Nps - b-Ala-HA, as well as possible adverse reactions on the imidazole histamine under the action DCGK, cause, apparently, the need for repeated purification by recrystallization of dichlorhydrate carcinine, which affects the magnitude of the yield and purity of the target product /5/. In addition to the above deficiencies proposed by the authors /5/ a method, there are no characteristics of the final substance and the value of its output.Another advantage of the proposed method for the synthesis of pseudopeptides formula NH2-A-CONH-B containing carboxyl group (glutaradehyde compounds) is one-step purification method and selection of the target product in the form of a free base by electrophoretic deposition from an organic solvent, preferably ethanol.Synthesis of fatty acid derivatives of biogenic amines is carried out by acylation of the amino group of biogenic amine with the acid chloride of the fatty acid, for example, laureillard.The synthesis is carried out according to scheme 2:
X-CO-Cl+NH2B _ XCONHB,
where X is-CO-Cl laureillard,
the reaction is carried out in an environment aprotic organic solvent, mainly DMF, in the presence of 1.1 equiv. the basis is a simple method of purification of the target product X is-CONH-B by re-extraction, using the difference in solubility of the target product, the original compounds and impurities in water and organic solvents.The proposed pseudopeptide N-acyl derivatives of biogenic amines obtained with high yields and high purity and characterized by IR, NMR spectroscopy, elemental analysis, TLC and HPLC.The proposed method of obtaining pseudopeptides N-acyl derivatives of biogenic amines is illustrated by the following examples.The individuality of the obtained compounds is checked by TLC on plates Alufol (neutrons. Germany) in methanol (1), plates Silufol UV-254 (Czechoslovakia) systems: methanol (2), isopropanol-water-25% ammonia 6:1:3 (3), chloroform-methanol-25% ammonia 5:3:1 (4), butanol-acetic acid-water 8:3:29 (5), chloroform-methanol 8:2 (6), chloroform-methanol 19:1 (7), chloroform-methanol 9:1 (8), chloroform-methanol 95:5 (9).Chromatogram showing chlorthalidone reagent, reagent Pauli, Ehrlich reagent, ninhydrin and glow in UV light.The melting point of a substance is determined on the device Boetius (Germany).IR spectra shoot in the vaseline on the instrument Shimadzu YR-35.The specific angles of rotation are measured on spectropolarimetry Perkin-Elmer400 (Japan) in deuterated solvents.Analytical reversed-phase HPLC performed under conditions (1): column Separon C-18 (250 mm 3,0), elute with 0.1 M Na2HPO4(pH 2.7, and the bring. H3PO4), the rate of elution of 0.2 ml/min; (2): column Separon C-18 (3.0 x 250 mm), elute with 0.1 M Na2HPO4(pH 2,4, bring. H3PO4), the rate of elution of 0.2 ml/min; (3): column Silasorb C-18 (4,0 x 125 mm), elute 70% acetonitrile in 0.05% solution heptacosanoic acid in water; (4): column Hipersil ODS (250 x 3 mm), elute with a gradient from 0% to 30% acetonitrile in water over 30 min, the rate of elution of 1.0 ml/min Preparative reversed-phase HPLC is carried out in conditions (5): column Silasorb C-18 (250 x 10 mm), elute with a gradient of acetonitrile in water from 0% to 99% for 30 min; the rate of elution of 5.0 minutesExample 1. -Alanylhistidine ( b-Ala-HA).1.1. Na-tert. Butyloxycarbonyl-alanylhistidine (Boc - b-Ala-HA).To a solution of 1.75 g (4.9 mmol) of Boc - b-Ala OPfp in 4 ml of anhydrous DMF was added to 0.60 g (5.0 mmol) of histamine and stirred for 0.5 h at 20oC and 24 h at 0oC. the Solvent is removed in high vacuum. The residue is dried in vacuum over P2O5. Receives a yellow amorphous substance. The output of 1.38 g (86%), so pl. 130 139oC, Rf 0,78 (2). The infrared spectrum, cm-1:1650 (amide I), 1560 (amide II).
2O5. The output of 0.77 g (89,5%) of a brown oily product. Purified on a column of anion exchange resin ARA-8s (Cl--form), elwira 60% solution of methanol in water. Combine fractions with Rf of 0.3 (3). The solvent is removed in vacuum. The oily residue lyophilized. Dried in vacuum over P2O5. Receive an amorphous vitreous substance is yellow. The yield of 0.47 g (61%), so pl. 181 183oC, Rf 0,3 (3), 0,56 (1). The infrared spectrum, cm-1: 1660 (amide I), 1560 (amide II). Found, C 37,71; H 6,33; N 21,16; Cl 26,39. C8H16N4C12O. Calculated,C 37,76; H 6,32; N 21,26; Cl 27,79.1.3. b-Alanylhistidine ( b-Ala-HA).On a column of anion exchange resin ARA-8s (OH)--form) is applied to 0.47 g b-Ala-HA2HCl and elute 60% aqueous solution of methanol. Combine fractions with Rf of 0.34 (3). The solvent is removed in vacuo, the residue lyophilized. Dried in vacuum over P2O5. Get transparent crystalline substance. Yield 0.14 g ( 43,3% ), so pl. 115 117oC, Rf 0,34 (3), 0,11 (1). IR spctr, cm-1: 1650 (amide I), 1570 (amide II), 1086 (C-N). Range of H1NMR spectrum (CD3OD), DM.D. of 2.34 (t, 2H, b-CH2); 2,87 (t, 2H, a-CH2-HA); 3,30 (t, 2H, b-CH2-HA); 3,45 (but C 51,22; H OF 7.70; N 29,05. HPLC under the conditions (3): output time of an individual peak of 14.9 minutesExample 2. g-Aminobutyrate.2. 1. Na-tert-Butyloxycarbonyl- -aminobutyrate.To 1,80 g (4,65 mmol) Boc-GABA-OPfp are added a solution of 0.52 g (4,65 mmol) of histamine in 20 ml of anhydrous dimethylformamide. Stirred for 1 h at 20oC. Left for 24 h at 0oC. the Solvent is removed in high vacuum. The oily residue is crystallized from a mixture of pentane and ether (10:12 ml). Incubated 24 h at 0oC. the Solvent is separated by decantation. The residue is dried in vacuum over P2O5. Get transparent crystalline substance. Yield 1.35 g ( 92,47% ), so pl. 125 127oC, Rf 0.5 In (5). H1NMR spectrum (CB3OD), d M. D. of 1.45 (s, 9H, CH3-Bu); of 1.78 (m, 2H, b-CH2); 2,22 (t, 2H, a-CH2); 2,82 (t, 2H, a-CH2-HA); of 3.12 (t, 2H, b-CH2-HA); to 3.52 (m, 2H, g-CH2); 6,85 (s, 1H, CH-4-Im); at 7.55 (s, 1H, CH-2-Im). Found, C 55,01; H To 7.84; N 17,87. C14H22N4O30.5 H2O. Calculated, C 55,72; H 7,66; N 17,80.2.2. g-Aminobutyrate.To 1.05 g of 3.33 mmol) of Boc-GABA-HA was added to 4.0 ml of 4n. solution of HCl in anhydrous methanol. Leave for 1 h at 20oC. the Solvent is removed in vacuum. The obtained yellow oily substance aciduria in vacuum at 40oC. the Residue lyophilized. Dried in vacuum over P2O5. Get hygroscopic amorphous, glassy substance. The output of 0.61 g (at 90.77%), so pl. 132 134oC, Rf Of 0.45 (4). IR range, cm-1: 1590 (amide I); 1465 (amide II); H1NMR spectrum (CD3OD), d M. D. 1,90 (m, 2H, b-CH2); to 2.35 (m, 2H, a-CH2), 2,95 (t, 2H, a-CH2-HA); 3, 30 (t, 2H, b-CH2-HA); to 3.50 (t, 2H, g-CH2); 7,30 (c, 1H, CH-4-Im); 8,65 (s, 1H, CH-4-Im); 8,65 (c, 1H, CH-2-Im). Found, C 55,69; H 8,07; N Weighing 28.32. C9H16N4O. Calculated, C 55,08; H By 8.22; N 28,55. HPLC under the conditions (2): time out of individual peak 6,41 minutesExample 3. L-Pyroglutamate (L-pGlu-HA).To a solution of 2.00 g (15,4 mmol) L-pyroglutamic acid and 2.85 g (15,49 mmol) pentafluorophenol in 20 ml of anhydrous dimethylformamide at -10oC and vigorous stirring was added 3,29 g (15.9 mmol) of N,N"-dicyclohexylcarbodiimide. Stirred for 2.5 h at -10oC. Leave for 48 h at 0oC. the Precipitate of dicyclohexylamine separated. To the solution was added 1,72 g (15.9 mmol) of histamine. Stirred for 1 h at 20oC and leave for 24 at 0oC. the Solvent is removed in high vacuum. The oily residue is crystallized from 7 ml of dry ethanol. Leave for 20 h at 0oC. the Precipitate was separated by filtration and added 25 ml of a suspension of any the th control conditions (1). The solution containing the substance with Rf of 0.67 (1), separated from the ion exchanger by filtration. The solvent is removed in vacuo, the residue lyophilized. Transparent amorphous substance dried over P2O5in a vacuum. Get colorless crystalline substance. The output of 1.59 g ( 79.5% ), so pl. 206 209oC, Rf 0,67 (1), 0,44 (2), [a]D-6,0 (Cl, methanol). The infrared spectrum, cm-1: 1664 (amide I), 1550 (amide II), 1264 (C-O-). H1NMR spectrum (D2O), DM.D. 2,0 (m, 2H, b-CH2; of 2.45 (m, 2H, a - CH2); 2,95 (t, 2H, a-CH2-HA); to 3.50 (t, 2H, b-CH2-HA); 4,30 (m, 1H, a-CH); 7,00 (s, 1H, CH-4-Im); 7.75 (s, 1H, CH-2-Im). Found, C 53,76; H 6,48; N 24,59. C10H14N4O2. Calculated, C 54, 05; H 6,35; N 25,22. HPLC under the conditions (1): time out of individual peak of 10.5 minutesExample 4. g-D-glutamylcysteine (g-D-Glu-HA).4.1. Na-Benzyloxycarbonyl--benzyl - g-D-glutamylcysteine (Z-D-Glu(HA)-OBzl.To 580 mg (1 mmol) of Z-D-Glu(OPfp)-OBzl, dissolved in 1 ml DMF, was added 110 mg (1 mmol) of histamine under vigorous stirring. Once dissolved, add 0.2 ml (2 mmol) N-methylmorpholine. The reaction mixture is left at 18 of the 22oC for 48 hours. The solvent is removed in vacuum. The oily residue is purified column chromatography on silica gel 40/100, elute with a mixture of chloroform-methanol (8:2). Fractionate oil. Output 0,232 g ( 50% ). Rf 0,46 (6).4.2. g-D-glutamylcysteine (g-D-Glu-HA).To 190 mg (0.41 mmol) of Z-D-Glu(HA)-OBzl, dissolved in 3.0 ml of methanol, add 2)) mg of 10% Pd/C under vigorous stirring. Hydronaut in a stream of hydrogen for 3 hours. The reaction mixture is filtered. The solvent of the filtrate is removed in vacuo. Get transparent crystalline substance. Yield 80 mg (81% ). Rf 0.26 (4), so pl. 184 190oC. H1NMR spectrum (D2O), d M. D. 1.77 in (K, 2H, b-CH2); 2,07 (t, 2H, a-CH2-HA); 2,52 (t, 2H, g-CH2); 3,17 (t, 2H, b-CH2-HA); 3,40 (t, 1H, a-CH); to 6.67 (s, 1H, CH-4-Im); 7,47 (s, 1H, CH-2-Im). Mass spectrum m/z: [M+1H]+241,3. HPLC under the conditions (1): time out of individual peak of 7.4 minutesExample 5. g-L-glutaminate.5.1. Na-tert-Butyloxycarbonyl- -benzyl - g-L-glutaminate (Boc-L-Glu(TA)OBzl).To 503 mg (1 mmol) of Boc-L-Glu(OPfp)OBzl dissolved in 1 ml DMF, was added 160 mg (1 mmol) of tryptamine with vigorous stirring. After complete dissolution of the added 0.3 ml (3 mmol) of N-methylmorpholine. The reaction mixture is left at 18 of the 22oC in the dark for 48 hours. The solvent is removed in vacuum. The oily residue is purified column chromatography on silica gel 40/100, elute with chloroform. The fractions containing the target about% ). Rf 0,51 (7).5.2. a-Benzyl - g-glutamylcysteine (H-L-Glu(TA)OBzl).To 125 mg (0.45 mmol) of Boc-L-Glu(TA)OBzl was added 1.0 ml of 4n. HCl/dioxane, intensively mixed, rinsed with nitrogen. After 30 min to the reaction mixture was added 5 ml of diethyl ether. Fallen oily precipitate is separated from the solution by decantation and washed with 5 ml of diethyl ether. To the precipitate 0.1 ml of triethylamine and 5 ml of ethyl acetate, intensively stirred, and then the reaction mixture is filtered. The solvent of the filtrate is removed in vacuo. The oily residue is purified column chromatography on silica gel 40/100. Elute with chloroform, a mixture of chloroform-methanol (23:2). The fractions containing the desired product with a Rf of 0.27 (8) are pooled, the solvent is removed in vacuum. Get a clear oil. Yield 50 mg ( 31% ). Rf 0,27 (8).5.3. g-Glutamylcysteine (H-L-Glu(TA)-OH).To 40 mg (0.1 mmol) of H-L-Glu(TA)OBzl was added 2.0 ml of methanol and 40 mg of 10% palladium on charcoal. Hydronaut in a stream of hydrogen for 1.5 hours. Pd/C was separated by filtration, the solvent of the filtrate is removed in vacuo. Get transparent pink crystals. Yield 22 mg ( 75% ), so pl. 82 90oC, Rf 0,39 (4). H1NMR-spectrum (CD3OD), d M. D. of 3.85 (t, 1H, a-CH), 2,12 (m, 2H, b-CH2), 2,43 (t, 2H, g-CH2), 2,96 (t, 2H+290,1. HPLC under the conditions (4): time out of individual peak of 22.0 minutesExample 6. g-L-glutamylcysteine (H-L-Glu(5-HT)-OH).6.1. Na-tert.-Butyloxycarbonyl- -benzyl - g-L-glutamyl(5-benzyloxycarbonyl) (Boc-L-Glu(5-OBzl-TA)-OBzl).Connection Boc-L-Glu(5-OBzl-TA)-OBzl synthesized similarly to compound Boc-L-Glu(TA)-OBzl (approx. 5.1. ), on the basis of 503 mg (1 mmol) of Boc-L-Glu(OPfp)-OBzl and 250 mg (1 mmol) 5-OBzlTA. Get a clear yellowish oil. Yield 350 mg ( 60% ). Rf 0,63 (7).6.2. a-Benzyl - g-glutamyl(5-benzyloxycarbonyl)(H-Glu(5-OBzl-TA)-OBzl).Connection H-L-Glu(5-OBzl-TA)-OBzl synthesized similarly to compound H-L-Glu(TA)-OBzl (approx. 6.2.), on the basis of 330 mg (0.6 mmol) of Boc-L-Glu(5-OBzl-TA)-OBzl. Get clear yellow oil. The output of 177 mg ( 61% ). Rf of 0.48 (8).6.3. g-L-glutamylcysteine (H-L-Glu(5-HT)-OH.Connection H-L-Glu(5-HT)-OH synthesized similarly to compound H-L-Glu(TA)-OH (approx. 6.3.), on the basis of 155 mg (0.32 mmol) of H-L-Glu(5-OBzl-TA)-OBzl. Get a pink oil, which was purified by preparative chromatography under the conditions (5). Get transparent colorless crystals. Yield 76 mg ( 80% ), So pl. 105 110oC, Rf Of 0.43 (4). H1NMR spectrum (CD3OD), d M. D. 3,62 (t,1H, a-CH2); 2,12 (m, 2H,-b,-CH2); at 2.45 (t, 2H, g-CH2); only 2.91 (t, 2H, a-CH2-TA); 3,51 (t, 2H, b-CH2-TA); 6,70 (doctor d, 1H, 6-CH-In); 6,97 is called7. N-Laurolactam.To a solution of 0.250 g (2.25 mmol) of histamine in 6 ml dry DMF with vigorous stirring was added at 0.31 ml (2.25 mmol) of triethylamine and then dropwise added 0.54 ml (2.48 mmol) of acid chloride of lauric acid. After 30 minutes, add 0.15 ml of triethylamine to pH 8. The solvent is removed in vacuum. Sediment washed from excess lauric acid on the porous filter 2 x 10 ml acetone and 2 x 15 ml water. Water washing is collected and lyophilized. Get a white crystalline substance. Output: 0,250 g ( 66,1% ), so pl. 121 125oC, Rf of 0.37 (9), IR spectrum, cm-1: 1569 (amide I); 1460 (amide II), H1NMR spectrum (CD3OD), d M. D. of 0.91 (t, 3H, w-CH3); 1,30 (sh.s, 16H, 8-CH2); and 1.56 (t, 2H, b-CY2); 2,17 (t, 2H, a-CY2); of 2.92 (t, 2H, a-CH2-HA); to 3.50 (t, 2H, b-CH2-HA); 7,30 (s, 1H, CH-4-Im); 8,80 (s, 1H, CH-2-Im). Found, C 69,67; H 10,57; N 14,29. C17H31N3O. Calculated, C 69,52; H 10,56; N 14,31.The impact of the proposed number of pseudopeptides on the process FLOOR shown on the model of the oxidation of fat (linoleic) acid in Fe2+-askarruttavista the accumulation of TBA-reactive products (malondialdehyde) using the techniques described in (6). Inhibition askarruttavista free radical oxidation of lipids in Dr>-6M Thus, the antioxidants of the proposed number of pseudopeptides operate at much lower concentrations than carnosine, and achieved a higher percentage of inhibition.These properties offer a number of compounds can be widely used, including in Oncology (antitumor activity), immunology (modulation of immune responses, radioprotective effect), cardiology (anti-ischemic and antihypoxic effect), ophthalmology (cataract treatment), to correct disorders of the Central nervous system, as well as antihypoxic drug under hyperbaric oxygenation.Thus, the proposed number of pseudopeptides N-acyl derivatives of biologically active amines modulators of the process of lipid peroxidation, which has, in comparison with the known analogue of carnosine, a lower effective concentrations (102103times) in similar conditions and higher levels of antioxidant activity (up to 60 -67% inhibition), with increased lipophilicity-affinity to membranes. Proposed a simple and effective way of getting all of the proposed compounds. 1. N-Alleniana from the group: -aminobutyric, programirovaniya, - alanine, L - or D-glutamic-carboxyla, lauric; NH-Y is a residue selected from the group of serotonin, tryptamine, histamine-modulators of lipid peroxidation.2. The method of obtaining the N-acyl derivatives of biogenic amines of General formula
where X is-CO - residue amino or fatty acids selected from the group: -aminobutyric, Pyroglutamate, - alanine, L - or D-glutamic-carboxyla, lauric; NH-Y is a residue selected from the group of serotonin, tryptamine, histamine,
characterized in that the amino group of histamine, or tryptamine, or O-benzylcyanide acelerou activated pentafluorophenyl esters of N- Vos - or Z-, -Bzl-substituted amino acids or acid chloride of the fatty acid in dimethylformamide 15 30oWith the removal of the products obtained from the N, protective groups in an acidic medium or by hydrogenolysis, followed by purification and isolation of target products in the form of free bases by column chromatography on unionamerica in the HE-form, or electrophoretic deposition, or re-extraction of water and an organic solvent.
< / BR>the way they are received and to farbkomposition based on them
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.
EFFECT: valuable properties of agents.
4 cl, 3 tbl, 78 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.
EFFECT: valuable biochemical and medicinal properties of peptides.
106 cl, 9 tbl, 61 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to compounds of the formula (I):
wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.
EFFECT: valuable medicinal properties of compounds and composition.
10 cl, 70 ex
FIELD: organic chemistry and drugs.
SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.
EFFECT: effective interleikyn-1beta converting enzyme inhibitors.
64 cl, 35 ex, 35 tbl, 21 dwg
FIELD: medicine, gastroenterology.
SUBSTANCE: traditional eradication therapy should be supplemented with licopid at the dosage of 10 mg per os once daily before breakfast for 10 d. The present innovation prevents transfer of microorganisms into inactive form, accelerates restoration of mucosal epithelial layer in gastroduodenal area, provides complete eradication of microorganisms, that in its turn, favors to prevent disease exacerbation and restoration of gastroduodenal functions.
EFFECT: higher efficiency of therapy.
3 dwg, 2 ex
FIELD: biotechnology, biochemistry.
SUBSTANCE: invention relates to producing the biologically active complex eliciting antioxidant and immunomodulating activity and used in medicine, cosmetics, veterinary science and food industry. The biologically active complex preparing by enzymatic hydrolysis of muscle tissue represents complex of biologically active compounds involving carnosine and anserine in the amount 85-97 wt.-% of the native content of these components in poultry muscle tissue, 1-7 weight parts of amino acids, 0.5-12 weight parts of oligopeptides of molecular mass 10 kDa, not above, and 0.1-15 weight parts of cyclic and polycyclic phenolic compounds as measured for 1 weight part of carnosine and anserine in the complex. This complex is prepared by enzymatic hydrolysis of milled and homogenized water muscle tissue in preferable dilution homogenate with water in the range 0.2-0.6 and with using proteolytic enzymes in the amount 2-5 wt.-% of the protein content and working at pH 4.5-8.5 and at enhanced temperature being preferably at 45-65°C. Product is isolated as extract or powder prepared in drying the extract. Invention provides enhancing effectiveness of the claimed complex.
EFFECT: improved method for preparing, valuable properties of complex.
7 cl, 6 tbl, 6 ex
FIELD: medicine, cardiology, gastroenterology.
SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.
EFFECT: improved method for treatment.
5 cl, 6 tbl, 2 ex
FIELD: organic chemistry, medicine, pharmacology.
SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)
method for their preparing, intermediate compounds used for their preparing of the formula (II)
and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
23 cl, 61 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.
EFFECT: improved and valuable properties of agent.
8 cl, 1 tbl, 5 ex