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

NH2-H2CH2CO-NH-NH-CH2-COOR

(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

injection g:

Oxidized, glutathiones - propyl ether 1.0 sodium Chloride 0,7

Distilled water for injection 100 ml

These 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.

 

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