Putationally esters of oxidized type and method of production thereof
(57) Abstract:Usage: in medicine as substances that have hepatoprotective activity. The inventive disulfides L-glutamyl L - container.getinstance (lower) esters obtained by air oxidation, hydrogen peroxide, iodine in the aquatic environment salts-2-glutamyl - L containingelection (lower) esters. 2 S. p. f-crystals. The invention relates to new oxidized derivatives of glutathione, in particular oxidized putationally esters and method of production thereof.It is known that putationally esters (restored) than glutathione in terms of their ability to move in living organisms, for example in relation to getting them in the liver and kidneys, and that after this transfer, they undergo hydrolysis with the formation of glutathione.The inventors have conducted a search of the derivatives of glutathione, which was satisfactorily would be absorbed by the tissues, and would have sufficient stability. The result of this work it was found that by oxidation monoalkyl esters of glutathione carried out in a simple way, namely by using air, hydrogen peroxide or iodine, magiceskoe activity. These studies were further concentrated and ultimately led to the creation of inventions.The invention thus relates to oxidized putationally esters of the formula I
< / BR>(I) in which R is lower alkyl, to the way they are received.In the invention, the lower alkyl preferably denotes alkyl with 1-10 carbon atoms. This can be any of straight, branched or cyclic alkyl, selected from the specified preferred group, and the alkyl, representing a combination of the above Akilov.Examples of preferred lower Akilov are methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-ethylpropyl, isopentyl, benzyl, etc.The method of obtaining the claimed compounds is as follows.First of glutathione in alcoholic medium in the presence of acid transferred to an acidic salt of monoether glutathione formula II
(II) This salt is then neutralized with alkali and received in neutral aqueous solution to oxidize monoether glutathione injected air or add to it with vigorous stirring dropwise peroxide Woodard, sulfate or p-toluensulfonate, although the invention is not limited to these salts. These reactions can be easily implemented by simple methods, and the resulting reaction solution may be subjected to chromatography for purification or recrystallization to obtain the target compound.Compounds in accordance with the invention are able to suppress the increase of the level of aspartate aminotransferase, alamin aminotransferase etc. that They effectively prevent the beginning of acute and chronic liver diseases. Because of this they can be used for the prevention and treatment of acute and chronic hepatitis. In addition, they can be successfully used for the treatment of other liver diseases caused by drugs such as acetaminophen. Finally, it is very likely that they can be used to prevent progress and treatment of cataract.Compounds in accordance with the invention may be introduced into the body as oral and parenteral. Pharmaceutical compositions based on them can be prepared, for example, in the form of tablets, granules, powders or capsules, liquid preparations such as eye drops, or in any other form investigate usually used in such cases, components, such as binders, dispersing agents, thickening agents, disintegrators, agents that promote resorption, flavorings, buferiruemoi agents, surfactants, soljubilizatory, preservatives, emulsifiers, isotherwise supplements and additives to establish the desired pH. The dose of the active component can typically be in the range of, for example, about 1-1000 mg/day for adults for injection and approximately 10-2000 mg/dose (when taken several times a day) for adults in the case of oral administration, although it may vary depending on the nature and severity of the disease, age and weight of the patient, form of the drug, etc.Pharmaceutical compositions for the treatment of liver disease containing as an active ingredient the compound according to the invention can contain one, two or more of the inventive compounds in a proper combination. In addition, they can contain other components that have the same or different therapeutic activity, the choice of these components due to the fact that they did not suppress the activity of the claimed compounds.P R I m e R 1. The disulfide-L-glutamyl-L-container.getinstancepool ether (oxidized palaeontology e the GSH-isopropyl ester) are suspended in 200 ml of water. The resulting suspension is neutralized by gradually adding to it 3.0 g of calcium carbonate. In the GSH-isopropyl ester is released in the form of free and dissolved, and the calcium sulfate precipitates. The mixture was then filtered and to the filtrate upon cooling, is added dropwise 14 ml of 5% hydrogen peroxide. After stirring for 3 h, the reaction mixture was concentrated in vacuo at a temperature not exceeding 40aboutC. To the concentrate is added acetonitrile and drop the crystals are filtered, resulting in the 6 g of crude crystals.These crude crystals was subjected to purification using column chromatography (column: UMC ODS 120A S-50; eluent: a mixture of acetonitrile and water in the ratio 1: 4) and the solvent is distilled off in vacuum. The residue is crystallized from acetonitrile and then recrystallized from water and the combined acetonitrile mixture, resulting in the 2.5 g of colorless amorphous crystalline mass.Thin layer chromatography (silica gel): Rf0,26 (n-butanol/acetic acid/water 4/1/1). D20-82,7about(1, N2O).The results of elemental analysis calculated for the formula C26H44ABOUT12N6S2.2H2O
Rascheta get the same way as in the case of method A, using as starting material 10 g of sulfate GSH-isopropyl ester. To this solution is added dropwise two percent solution of iodine in methanol at room temperature until the color of the solution becomes pale yellow. The mixture is stirred for a further 2 hours at 40aboutAnd then neutralized with calcium carbonate. Precipitating the inorganic crystals are filtered off and the filtrate was concentrated in vacuo. To the concentrate is added acetonitrile and drop the crystals are filtered, resulting in the 5 g crude product. The crude crystals was subjected to purification using column chromatography in the same manner as in the case of method A, when receiving the result of 1.9 g of the pure product.Method C.A solution of GSH-isopropyl ester receive the same manner as in the case of method A, using as starting material 10 g of sulfate GS-isopropyl ether. Through the resulting solution at room temperature and vigorous stirring for 24 h breathable. The mixture is then treated in the same manner as in the case of the way And getting in the 2.3 g of the pure product.P R I m m e R 2. The disulfide-L-Glu is them the same way as in the case of method a in example 1, using as starting materials 10 g of the hydrochloride-L-glutamyl-L-container.getinstance ether and 3.0 g of calcium carbonate. The oxidation is carried out using 5% hydrogen peroxide. For cleaning use a similar column (UMC DDS 120A S-50) and eluent (acetonitrile/water 7/43). The obtained crystals are recrystallized from water and the combined acetonitrile mixture, resulting in the 1.5 g of colorless amorphous crystalline mass.Thin layer chromatography (silica gel): Rf0,16 (n-butanol/acetic acid/water 4/1/1); [ ]D20-89,7about(1, N2O).The results of elemental analysis calculated for the formula C24H40ABOUT12N6S2.2H2O
Calculated C 40,90; H 6,29; N 11,92
Found, 40,62; N 6,41; N OF 11.61
Pharmacological tests.Method.Male rats of Wistar breed weighing approximately 180 g were not fed for 24 h, after which he introduced them orally through the cannula, respectively 87-349 mg oxidized glutaronitrile ester (hereinafter also referred to as "GSSG-isopropyl, representing one of the compounds in accordance with the invention, 102 mg restored glutathioneperoxidase referred to as GSH-isopropyl) or 5% solution of gumarabic (for comparison). An hour later, the animals were injected intraperitoneally with 400 mg/kg acetaminophen, a compound that causes liver disease. After another 24 h, rats were anestesiologi pentobarbital, collected the blood from the abdominal aorta and determined the concentration of S-aspartate aminotransferase-and S-aluminiumindustrie for comparison overwhelming effect on the liver disease GSSG-isopropyl and GSH - isopropyl.The result was shown (see table), that the increase of blood S-aspartate aminotransferase-and S-aluminiumindustrie significantly suppressed (depending on dose) with the introduction of animal 87-349 mg/kg GSSG-isopropyl. It is also shown that the introduction of 102 mg/kg GSH-isopropylmalate significantly inhibits increase of blood S-aspartate aminotransferase-and S-aluminiumindustrie and that the introduction of 87 mg/kg GSSG-isopropyl this is almost equivalent to 102 mg/kg GSH-isopropylmalate.Effect of GSSG-isopropyl and GSH-isopropyl on caused by acetaminophen liver disease in rats is shown in table.In the following table all the values given are the average of the standard deviation (n 4-8). Figures in brackets represent molar dose (moglica compared with a 5% solution of gumarabic:x1: p < 0,05;x2: p < 0,01.Examples of compositions
P R I m e R 1. Tablets for oral administration, mg:
Oxidized, glutathiones - propyl ether 100 Lactose 80 Starch 17 Stearate 3
All of these components to get a tablet in the usual way. Such tablets may also contain sugar.P R I m m e R 2. Drug
Oxidized, glutathiones - propyl ether 1.0 sodium Chloride 0,7
Distilled water for injection 100 mlThese components are mixed and sterilized by filtration. 2 ml of the filtrate is filled under aseptic conditions into glass vials, which are then pressurized thermal method, receiving the drug for injection.P R I m e R 3. Eye drops, g: Oxidized, glutathiones - propyl ether and 1.0 Boric acid 0,7 Methyl-p-oxybenzoic 0.02 Chlorbutanol 0,3
10% aqueous solution At the right
sodium hydroxide quantity
to pH 6.0
Sterile purified water
water To 100 ml
Listed components are mixed to form a solution in the usual way. The resulting solution is sterilized by filtration and dispensed into sterile vials. 1. Glutathionylation esters of oxidized type formula 1
< / BR>where R is lower alkyl,
characterized in that putationally ether of the formula II
< / BR>where R is lower alkyl,
oxidized by air, hydrogen peroxide or iodine in water or in aqueous solution.
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
FIELD: veterinary science, pharmacy.
SUBSTANCE: invention proposes a composition for antioxidant protection of cells, tissues and a whole body against hyperproduction of free radicals in acute inflammation, chemical thermal and radiation damages. The composition comprises peroxyredoxin Prx VI and, additionally, lipoic acid and pharmaceutically acceptable additives. The composition comprises peroxyredoxin Prx VI and dihydrolipoic acid taken in the effective amount in the ratio peroxyredoxin Prx VI to dihydrolipoic acid in the range (w/w) from 1:1 to 50:1 wherein peroxyredoxin Prx VI can represents human recombinant peroxyredoxin Prx VI. Also, invention relates to a method for enhancing antioxidant protection of mammals involving delivery of indicated pharmaceutical composition is carried out into intercellular space of tissue, organ or a whole body of mammal. The delivery can be carried out by passive or active diffusion in application or spraying, by parenteral or endolumbal administration by injection, by parenteral administration, infusion, inhalation, drainage, by sublingual, vaginal or rectal administration, by nasal or ophthalmic drops. Except for, the delivery can be carried out with using other therapeutic agent, in particular, interferon simultaneously. Invention provides prophylaxis of secondary alternative damages, recovery of epithelial tissue, protection of biomacromolecules against effect of irradiation.
EFFECT: valuable medicinal properties of composition.
6 cl, 9 tbl, 11 dwg, 45 ex
SUBSTANCE: invention relates to dipeptide mimetic selected from glutaminyl thiazolidine or glutaminyl pyrrolodine and salts thereof as well as to using of such compounds in treatment of abnormal glucose tolerance, glucoseuria, diabetes mellitus and other disordered as well as complications associated with diabetes mellitus in mammalians.
EFFECT: new effectors of dipeptidyl peptidase IV.
18 cl, 3 tbl, 2 ex
FIELD: medicine; pharmacology.
SUBSTANCE: invention relates to application of dipeptide with the general formula Nα-(γ-L-glutamyl)-L-lysine, for stimulation of function of the reproductive system by modulating the neuroendocrine status in aging and in hypogonadal condition. The pharmaceutical composition is invented, which contains Nα-(γ-L-glutamyl)-L-lysine, and the method of stimulation of function of reproductive system.
EFFECT: described compound efficiently stimulates function of reproductive system.
5 cl, 9 tbl, 8 ex
SUBSTANCE: invention refers to inhibitors of enzymes cleaving protein after proline, such as depeptidyl peptidase IV inhibitors, as well as to their pharmaceutical compositions, and methods of application of such inhibitors. Particularly, inhibitors under this invention are improved in comparison with those currently in use in the present art by selecting special classes of side chains in P1 and/or P2 positions of inhibitor which contains carboxylic acid grouping.
EFFECT: compounds of specified formulas I, II and III can have the improved therapeutic index, partially owing to reduced toxicity and improved specificity in relation to target protease.
15 cl, 2 dwg, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to compounds, which possess agonistic or antagonistic activity of NGF and BDNF neutrophins and represent monomer or dimmer substituted dipeptides, which are analogues of exposed outside parts of loops 1 and 4 of said neutrophins, close to beta-bends of said loops or coinciding with them. Effects in vivo are demonstrated by claimed compounds within dose interval 0.01-10 mg/kg in intraperitoneal introduction.
EFFECT: claimed compounds possess neuroprotective and differentiating activity on cell models, increase concentration of phosphorylated form of tyrosine kinase A and proteins of heat shock Hsp32 and Hsp70 in concentrations10-5-10-9 M, they also possess neuroprotective, antiparkinsonian, anti-stroke, antiischemic, antidepressant, antiamnestic activity on animal models and demonstrate activity on experimental models of Alzheimer's disease.
20 cl, 33 dwg, 23 tbl, 18 ex
SUBSTANCE: group of inventions refers to application of low molecular peptide mimetics of the nerve growth factor: hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine) - GC-2 compound; hexamethylenediamide bis-(N-acetyl-lysyl-glutamic acid) - GC-4 compound; amide N-aminocaproyl-glycyl-lysine - GC-5 compound; hexamethylenediamide bis-(N-aminocaproyl-glycyl-lysine) - GC-6 compound as compounds with angiogenic activity.
EFFECT: creation of new highly effective means to stimulate neoangiogenesis at different ischemic processes.
4 cl, 3 dwg, 2 tbl, 3 ex
SUBSTANCE: invention relates to compounds of formula I , as well as their enantiomers, diastereomers and salts, which can be used in the solid-phase synthesis of peptides. In formula I, R1 is C1-4-alkyl, R2 is hydrogen or C2-4-alkenyl, R3 is 9H-fluoren-9-ylmethoxycarbonyl (Fmoc) and R4 is C12-20-alkyl. The invention also relates to application of formula I compounds in the solid-phase synthesis of peptides that contain a block of glutamic acid (Glu)-fatty alkyl in the side chain attached to the lysine residue (Lys) of the peptide chain.
EFFECT: effective treatment.
9 cl, 5 ex