Water-soluble rigid-rod oligoether, the method of its production and composition based on it

 

(57) Abstract:

The invention relates to the oligoesters, method for their production and compositions on their basis, which possess significant activity against the virus of human immunodeficiency and is used for the treatment of acquired immunodeficiency syndrome (AIDS). Water-soluble rigid-rod oligoether get interaction diphenol with bifunctional electrophile containing the group-SO3R2in the presence of a solvent at 0 - 40oC, pH 7 - 8. The composition contains an effective amount of the active agent on the basis specified oligoether and a pharmaceutically acceptable carrier. 3 S. and 14 C.p. f-crystals, 11 PL.

The invention relates to the oligoesters, their use, and the way they are received. The oligomers according to the invention are anionic compounds and possess significant activity against virus, human immunodeficiency, and so the oligoesters can be used for the treatment of acquired immunodeficiency syndrome (AIDS).

Currently, much research is aimed at developing new drugs for the treatment of viral diseases of humans and animals. Sobotovich is increasing at an alarming rate. The life expectancy of AIDS patients is approximately 5 years, and patients with this disease, whose immune system is exposed to serious disorders, suffer from various diseases caused by opportunistic microorganisms, for example, Kaposi's sarcoma, pneumocytosis.

Effective remedies against AIDS does not exist yet, the available funds are not adequate for their practical use and cause many adverse side effects. Fear of AIDS in humans leads to social ostracism and discrimination against people with AIDS or suspected of this disease.

Retroviruses belong to the class of viruses that contain ribonucleic acid (RNA), which is replicated by using reverse transcriptase, forming a thread complementary DNA (cDNA), which is produced by double-strand proviral DNA. This proviral DNA is then the method of randomization is introduced into the chromosomal DNA of the host cell, making possible the replication of the viral genome by the late broadcast of viral RNA from the integrated viral genome.

Many of the known retroviruses are carcinogenic or cause OBRAZOVANIJA or HTLV-I and II cause a rare form of leukemia in humans after infection of T-lymphocytes. The third virus found in humans, HTLV-III, now called HIV causes cell death after infection of T-lymphocytes and identified as the causative agent of AIDS and NAO.

Envelope protein of the HIV virus is a glycoprotein 160 KD. This protein is cleaved by the protease with the formation of the outer protein of 120 KD, etc. 120, and the transmembrane glycoprotein, other 41. Protein other 120 contains an amino acid sequence that recognizes the CD4 antigen on T-helper (T4) in human cells.

Some studies were focused on the attempt to interfere with the binding of HIV to its target T-cells. These T4 cells have a specific area, CD4 antigen, which interacts with other 120. If you interfere with this interaction, the infection of the host cell can be ingibirovalo.

Interference through the formation of the viral envelope glycoprotein should prevent the initial interaction of the virus and the host cell or subsequent to the merger or is to prevent the duplication of the virus by preventing the formation of the native glycoprotein required for completion of the viral membrane. In the work of H. A. Beough, etc. /Biochem. Biophs. Res. comm. 141(1), 33 - 38 (1986)/ specifies that especificado and block the formation of entities. Viral replication of HIV-infected cells treated with the indicated agents stopped probably due to the absence of glycoprotein required for the formation of the viral membrane. In other work /W. Mc. Dowell, etc. Biochemistry 24 (27), 8145-52 (1985)/ the inhibitor glycosylamine 2-deoxy-2-fluorescent-D-mannose shows the inhibition of antiviral activity against influenza virus and infected cells by preventing glycosylamine protein in the viral membrane. In this work we investigated the antiviral activity of 2-deoxyglucose and 2-deoxy-2-fergusoni, as a result of these studies it was found that each of these compounds inhibits glycosylamine viral protein by different mechanisms. However, other known inhibitors glycosylamine did not show antiviral activity. Therefore, antiviral activity and activity against a particular virus inhibitors glycosylamine is totally unpredictable.

In South African patent 90/0094, issued October 31, 1990, indicated that the purified form of heparin, a sulfated polysaccharide, is bound by interacting with the viral protein, which is responsible what about the heparin has some side effects, for example, causes haemorrhage and accelerates the formation of blood clots, and also causes thrombocytopenia. The use of heparin is contraindicated in patients with a tendency to bleeding, or patients with hemophilia, purpura, thrombocytopenia, intracranial hemorrhage, septic endocarditis, active tuberculosis, increased capillary permeability, ulcers of the gastrointestinal tract, complicated hypertension, threatening abortion or cancer of the internal organs. These contraindications particularly related to hemophilia patients, as they are particularly prone to the disease caused by HIV.

It has long been known that synthetic water-soluble polymers show a wide range of biological activity (R. M. Ottenbrite "Biological Activities of Polymers" Amer. Chem. Soc. Symp. Ser. N 182, pp. 205 - 220, ed. C. E. Carraher, and C. G. Gebeleni (1982)). Copolymer of polyvinyl ether and maleic anhydride has activity against a number of viruses and the possibility of its use in anti-cancer chemotherapy for many years he studied Breslow D-s [Pure and Apphied. chem 46, 103 (1976)/. Polyacrylic, polymethacrylic, and a number of other aliphatic water-soluble polymers also show a wide range of biological activity /W. Regelson, etc., Na what their conditions. In addition, these polymers have high molecular weight and is unable to pass through the kidney membrane.

To solve the problems associated with the toxicity of the polymers, attempts were made to synthesize low molecular weight aliphatic polymers (1000 - 10000) /R. M. Ottenbrite "Biological Activities Polymers". Amer Chem. Soc. Symp Ser N 182, pp. 205 - 220, ed. C. E. Carraher, and C. G. Gebeleni, 1982)/. It was found that these polymers are less toxic, but have a lower antiviral activity. These low molecular weight aliphatic polymers can be classified as "statistical balls." Such polymers are unpredictable configuration because of the flexibility of groups of connection of the main circuit. The configuration of the statistical coil in solution can be basically described as globular. Although the mechanism of action of such water-soluble polymers is unknown, but as assumptions, we can say that the polymer is associated with the viral membrane, for example, virus encephalomyocarditis through Legionowo attraction, thereby informing the virus unable to infect the host cell.

Another method using a synthetic polymer designed to postacetabular water-soluble complex oligoesters molecular weight < 6200 based on dicarboxylic acids and diatomic alcohols which are used as hot-melt adhesives (JP, application, 56-147822, class C 08 G 63/68, 1981).

Known oligoesters containing sulfopropyl, which impart water-solubility of oligoether used as a tool for hair styling (US patent 4150216, class C 08 G 63/68, 1976).

An object of the invention is to develop a pharmaceutical product on the basis of oligoether for the treatment of AIDS, which would not side effects and would be much more effective than those polymers that have been used to date in the pharmacy.

It was found that the anionic oligomers inhibit viral replication, without the side effects typical of heparin and well-known polymers. These oligomers have ordered mezanine distance and hard chain and are water soluble.

New oligomers according to the invention are anionic, carbonyl-containing compounds. Examples of these oligomers are polyesters having srednekamennogo mol. m Mn< 10,000 and ordered mezanine distance and which is rigid and water-soluble. Ol is the R funds.

Another application of the above anionic oligomers is their use as efficient thickeners in aqueous solutions, or as a mild ionic detergents. Mainly water-soluble polymers, including oligomers according to the invention, are widely used as thickeners, dispersants and flocculants. The oligomers according to the invention can be used in the oil industry, mining, paper industry, textile industry, in cosmetics and technology of food preparation. In addition, low molecular weight polymers according to the invention, i.e., the oligomers can be used as starting materials to obtain high molecular weight polymers and copolymers.

Thus, the invention relates to water-soluble rigid-rod to oligoether mol. m less than 10,000, containing repeating units linked through a carbonyl linking group, and specified the oligomer has anionic groups and predominantly linear geometry such that the distance between the anionic groups of the oligomer in the aquatic environment, are regular. Preferably, if repeated every link has at least two anionic groups.

New oligoesters according to the invention, which presents a complex polyesters have srednekamennogo mol. m Mn< 10000, structure with ordered mihaniona distance generally linear geometry in the aquatic environment and are rigid and water-soluble. These oligomers are preferably linear in its main chain, and may also be in the form of salts, especially preferred salt is a pharmaceutically acceptable salt.

The technical object of the invention is solved by oligoethers General formula:

< / BR>
where

X - means:

< / BR>
n is an integer from 3 to 15;

R4is a hydrogen atom or HO-X, where X is defined above, phenyl or phenyl substituted from 1 to 2 - SO3R2groups

R2is a hydrogen atom or a pharmaceutically acceptable cation,

R5is:

< / BR>
where

R4defined above,

X3is:

< / BR>
The term "pharmaceutically acceptable cation" means a cation, which is acceptable for pharmaceutical use. The a cations, the a, in and of themselves do not possess significant pharmacological activity, also fall under the definition of "pharmaceutically acceptable cation". As an example, you can specify the alkali metal salts, such as sodium or potassium; alkaline earth metals such as potassium and magnesium; ammonium salts; salts of metals of group IIIA, for example, of aluminum; and organic primary, secondary and tertiary amines, such as trialkylamines, for example, triethylamine, procaine, dibenzylamine, N,N'-dibenziletilendiaminom, dehydroabietylamine, N - (C1-C4-alkylpiperidines and other suitable amines. Preferred are the sodium and potassium salts. The term "pharmaceutically acceptable" means acceptable to the introduction of warm-blooded animals and man, and as the pharmaceutically acceptable vehicle is non-toxic, it does no harm to warm-blooded animals, and can also be used for pharmaceutical purposes. Pharmaceutically acceptable cations oligomers according to the invention can be obtained by standard ion-exchange processing R1-acid corresponding basis.

If medicines obtained using the oligomers according to the invention, are intended for other item used additive salts of barium, zinc and titanium.

The oligomers according to the invention are low molecular weight, rigid and water-soluble polymers. In addition, these oligomers have a structure with ordered maganini distance. The term "ordered mezanine distance" or "regular spacing between anionic groups" means that these anionic groups (R1) present in the main chain of the polymer at a distance determined by the material used for the source reagent, and the location of these anionic groups are controlled in a predictable manner. Without pretending to any particular theory, it is possible only to indicate that the anionic groups of the oligomers according to the invention, in all probability, are the part that is associated with HIV and/or cell membrane, thus preventing the ability of the virus to replicate.

The term "predominantly linear geometry in the aquatic environment refers to the configuration of the solution of oligomer. To assess the configuration of polymer molecules in solution there is a known method based on the following formula, called the equation of Brand-Houwink:

[] = KM< / BR>
where is the characteristic viscosity; M - bulk moleculardynamics the viscosity of the polymer type of statistical tangle with 0.5 < < 0.9 , and for a linear polymer, it corresponds to 0.9 < a 1.8 . This formula expresses the relationship between viscosity and molecular mass "M". In the invention, the linear polymers are defined as polymers with a value of " greater than or equal to 0.9. For rod-like rigid polymers theoretical value (upper limit) is 1.8. For a given molecular weight, higher viscosity of the solution can be obtained using polymers with a linear configuration relative to the viscosity obtained using statistical tangle. In addition, it should be noted that the value depends on the used solvent. For example, "" for a given water-soluble polymer may vary at different salt concentrations.

The term "oligomer" as used in the description of the invention, includes oligomers with all possible values of n, for example n = 3-15. The main thing is that these oligomers had a fairly low molecular weight, such that on the one hand they passed through the renal excretory membrane, and on the other hand, that they had the ability to inhibition of the HIV virus. Brednikova molecular weight is governed by the stoichiometry of the reagents. Selino 1000-6000 mm..

It is preferable to oligoether, which is a poly { oxy/2,2'-disulfo(1,1'-diphenyl)-4,4'-diyl/oxy-carbonyl-1,4 - phenylenecarbonyl} General formula (I), where R4and R5are hydrogen, X3-phenylene, and X is

< / BR>
where

n = 3-15, preferably n = 4 (designation of oligoether : H B P DS/TPC. Other preferred oligoether is poly{-hydroxy(-2.5 disulfo-1,4-phenylene)oxycarbonyl-1,4-phenylenecarbonyl} General formula (I), where R4and R5are hydrogen, X3- phenylene, X is:

< / BR>
where

n = 3-15, preferably, n = 3, oligoether referred to as HBPDS/TPC.

The technical problem is also solved by a method of producing oligoether General formula (I), which is that carried out the interaction of diphenol formula HO-X-OH, where X is the above, with bifunctional electrophile of the formula:

< / BR>
where

Hal is a chlorine atom or bromine, and X3identified above. The process is carried out in the presence of a polar aprotic solvent at a molar ratio of diphenol to the bifunctional electrophile (0,9-1,2), 0-40oC and the pH of the medium 7-8. After adding the electrophile mixture was kept 15-120 minutes

Pre can be clicks the functional electrophile.

The technical problem is also solved by a composition having anti - HIV activity, which includes pharmaceutically acceptable carrier and an active agent, which contains an effective amount of a compound of the formula:

< / BR>
where

X - means:

< / BR>
n is from 3 to 15, R2means a hydrogen atom or a pharmaceutically acceptable cation; X3means:

< / BR>
preferably about 500 to about 10,000, and most preferably from about 1000 to about 6000.

The composition of the invention can be produced in both solid and liquid form. These compositions can be made in the form of a set of dosage forms so that the two components are mixed for a certain time before the start of the reception. Either this drug or set mixed with the required pharmaceutically acceptable carrier or adjuvant.

Oligoesters according to the invention are soluble in water and in salt solutions, especially in solution with physiological pH. Thus, the oligoesters according to the invention can be easily prepared in a suitable standard dose in aqueous solution. After ingestion by oligoether according to the invention retains its R the Finance of entities in cells HIV-1-infected or other related viruses with surface protein gp 120. Anti-HIV anionic oligoesters can be used to treat AIDS and NAO and other diseases caused by the retrovirus HIV-1 or other related viruses with surface protein gp.120. Anionic oligoesters according to the invention can be used as pure compounds or as mixtures of such, in which the value of n corresponds to a specific definition of formulas I-IV, or mixtures of compounds belonging to different specified formulas, for example compounds of formula I and formula II, or as mixtures with other known agents used for the same purposes as the invention. However, for all the oligoesters n represents srednecenovogo the length of the redo allocation oligoesters all formulas.

The amount of anti-HIV anionic oligoesters necessary to prevent the formation of entities in HIV-infected cells can be any effective amount. It has been experimentally determined that the anti-HIV anionic oligoesters when used in the form of aqueous preparations at a concentration of 100 µg/ml showed a complete inhibition of the formation of entities, and way less than 300 mg/ml Amount of anti-HIV anionic oligoether introduced for the treatment of AIDS and Saka, caused by HIV infection can vary widely depending on specifically used a single form, treatment period, age and sex of the patient, the nature and extent of violations, and other factors well known to practitioners. In addition, anti-HIV anionic oligoesters can be used in combination with other known means used in the treatment of retroviral diseases, as well as common tools used for symptomatic treatment of complications and conditions caused by retroviruses.

According to the invention an anti-HIV effective amount of anti-HIV anionic oligoether introduced into the body, basically, is about 0.1 mg/kg to 500 mg/kg body weight of the patient and can be entered once or several times a day. Anti-HIV anionic oligoesters can be introduced in combination with pharmaceutical carriers which are generally used in the preparation of the standard one-forms for oral or parenteral administration.

For oral administration of anti-HIV anionic oligoesters can be used in the form of a solid or liquid Ave is si. Solid one-forms can be made in the form of capsules hard type and soft gelatin shell containing, for example, surfactants, oil and inert fillers such as lactose, saccharose, sorbitol, calcium phosphate, and corn starch. In another embodiment of the invention, anionic oligoesters can be made in the form of tablets using lactose, sucrose, and cornstarch in combination with binders, such as Arabian gum, corn starch, or gelatin; dezintegriruetsja agents to facilitate the decomposition and dissolution of the tablet after administration such as potato starch, alginic acid, corn starch, and hoerova gum; oil to improve the yield by granulation of tablets and prevent the adhesion of tablet material to the surfaces of the extrusion heads and molds, such as talc, stearic acid or magnesium stearate, calcium or zinc; dyes and promethazineodeine agents to improve the taste and appearance of the drugs used. Suitable excipients for oral liquid dosage forms include diluents, such as water, sleep is, or in combination with pharmaceutically acceptable surfactants, suspendresume agents, or emulsifying agents.

Anti-HIV anionic oligoesters according to the invention may be introduced parenterally, that is, subcutaneously, intravenously, intramuscularly or intraperitoneally, in the form of a single injectable forms containing anionic oligomers in a physiologically acceptable diluents in combination with pharmaceutical carriers, which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar; alcohols such as ethanol, isopropanol, or hexagonally alcohol; glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol; ethers, such as poly(ethylene glycol)400; oils; fatty acids; esters of fatty acids or glycerides, or acetylated glycerides of fatty acids, which can be used separately or in combination with pharmaceutically acceptable surface-active agents (surfactants), such as Soaps; detergents; suspendresume agents such as pectin, methylcellulose, hypromellose

Examples of oils that can be used in parenteral preparations of this invention are petroleum, animal, vegetable or synthetic oils, such as peanut oil, soybean oil, sesame oil, oil from cotton seeds, corn oil, olive oil, petroleum jelly and mineral oil. Suitable for use in the invention fatty acids are oleic acid, stearic acid and ezoterikova acid. Suitable esters of fatty acids are, for example, etiloleat and isopropylmyristate. Suitable Soaps are salts of fatty acids formed from alkali metals, ammonium, triethylamine, and suitable detergents are cationic detergents, for example, halide of dimethyldiallylammonium, halide alkylpyridine, acetates alkylamines followed; anionic detergents, for example, alkyl-, aryl - and the olefin sulfonates, alkyl sulphates, olefin sulfates, ether sulfates, and sulfates of monoglyceride and sulfosuccinates; nonionic detergents, for example, oxides of fatty acids, alkanolamine fatty acids, and copolymers of polyoxyethylene and polypropylene; and amphoteric detergents, for example, alkyl-beta-aminopropionic, and salts of 2-alkylimidazole-Chetverikova 25 wt.% anti-HIV anionic oligoether in solution. In addition, can be used preservatives and buffers. In order to minimize or eliminate irritation at the site of injection these compositions may contain a nonionic surfactant with a hydrophilic-diafilm balance (HLB) of from about 12 to about 17. The amount of surfactants in these compositions is from about 5 to about 15 wt.%. Surfactants may be the only component that has the specified HLB or may be a mixture of two or more components having the desired HLB. Examples of surfactants that can be used in parenteral compositions according to the invention are compounds belonging to the class of esters of fatty acids polyethylenimine, such as servicemanual.

Oligoesters according to the invention can also be used prophylactically, that is, in order to prevent transmission of the virus from infected to uninfected targets. The spread of the virus in proportion to the exchange of blood, but its transmission can be carried out also through the exchange of other physiological fluids. Thus, the oligomers according to the invention can be prepared using the detergent for use in cleaning, in particular for analyses in the clinical laboratory of the esters according to the invention, can be used for cleaning medical /surgical instruments and utensils, as well as treatment of hands and other skin areas of the laboratory assistants in the prevention. Oligoesters according to the invention can also be used in the form of powder and liquid compositions for external use by applying to the surface of contraception, such as condoms, either by the user or by the manufacturer of these contraceptives prior to their sale. Oligoesters according to the invention can be formulated into compositions in the form of vaginal douches for women use before sexual intercourse with an infected partner. Oligoesters according to the invention can also be produced in conjunction with oil in the form of spermatocytic jellies and lotions. And finally, oligoesters according to the invention can also be added in the form of compositions in hot tubs, vibratory tubs and swimming pools in order to inactivate potential viral activity.

The terms used in the description of the invention, have the following meanings:

n - Brednikova length of repeats in the distribution of the oligomer of all formulas.

RPMI cell culture medium.

TCIDSD - ed is 50% of the cells.

MTT - bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium.

MT4 cell line.

P24-test-Abbot-analysis of the viral core antigen using the test kit, Abbott delivered.

Analysis of HIV-CoulterTM- radioimmunoassay determination of viral antigen p24

SCD4recombinant soluble CD4containing 4 extracytoplasmic immunoglobulin similar variable (V) regions V1- V4.

T - 4-methyl aniline or toluidine except those cases, when using the term "T4-cells or T-helper cells."

P - phosgene.

C - p-cresol.

MBC - 4-methylbenzoate.

TPC - 1,4-benzylcarbamoyl or terephthaloylchloride.

TPCS - 2,5-bis chlorocarbonyl bansilalpet sodium, having the formula:

< / BR>
HBDS - dicale 2,5-dihydroxy-1,4-benzodiacepinas having the formula:

< / BR>
HBPDS - dicale 4,4'-dihydroxy(1,1'-biphenyl)-2,2'-disulfonate having the formula:

< / BR>
PDS - 2,5-diamino-1,4-benzolsulfonat acid having the formula:

< / BR>
BPDS - 4,4'-diamino-(1,1'-biphenyl)2,2'-disulfonate acid having the formula:

< / BR>
HBDS/TPC - poly{ oxy(2,5-disulfo-1,4-phenylene)oxy what is p-phenylene, X is:

< / BR>
where

R2defined in formula I.

HBPDS/TPC - poly {-hydroxy/2,2'-disulfo (1,1'-biphenyl)-4,4'-diyl/ oxycarbonyl-1,4-phenylenecarbonyl} and is represented by formula I, R4and R5are hydrogen, X3is p-phenylene and X is:

< / BR>
and R2defined above in formula I.

Oligoesters obtained by modification of the procedure of Kershner (US, patent, 4895660, CL 210/640, 1990) by the replacement of part of one of bifunctional monomers, monofunctional regulator of the molecular weight and the reaction in the absence of surfactant. Brednikova molecular weight (Vn) was regulated by the stoichiometry of the reactants.

Example A. Obtaining HBPDS formula:

< / BR>
A 2-liter flask equipped with a funnel to add and core magnetic stirrer, was added 49,99 g (0,145 M) 4,4'-diamino (1,1'-biphenyl)-2,2'-disulfonic acid and 600 ml of water. The diamine was solubilizers by adding 30 ml (0.15 M) 5 M NaOH. To the resulting solution was added 20,56 g (0,298 M) sodium nitrate. Then the reaction mixture was cooled to 0oC and for 30 min was added concentrated H2SO4dissolved in 360 ml of water. In the formed yellow solid. Started. The yellow solid is dissolved in 800 ml of water were placed in a 1-liter flask and heated until then, until you are left with 50 ml of water. Nitrogen was emitted during the heating. To the concentrated solution was added 20,14 g (0,146 M) K2CO3then the solution was boiled. Then was added absolute ethanol (1.5 l) and the resulting brown solid was besieged. The precipitate was filtered and dried overnight in an oven at 50oC. the Product, HBPDS, was obtained with the yield 32,33 g (53%), and then analyzed using the N1NMR.

1H NMR 6,70 (DD, 1H), 7,05 (d, 1H), 7,14 (d, 1H).

Example B. Obtaining TPCS formula:

< / BR>
In a 500-ml flask equipped with a mechanical stirrer, thermometer and reflux condenser was loaded 40,49 g (0,143 M) monosodium salt 2-sulfoderivatives acid, 160 ml of chlorobenzene, 2,4 ml (0,031 M) of dimethylformamide, and 23 ml (0,315 M) of thionyl chloride. The solution was heated to 105oC and stirred for 2 h in nitrogen atmosphere. During this period witnessed the evolution of gas. The solution was cooled to room temperature and the solid was besieged. The precipitate was filtered and dried overnight in a vacuum oven at room temperature. As a result, we got a solid pale yellow product with the release of 20,56 St methyl ether.

A 25-ml flask equipped with magnetic stirrer rod and for nitrogen bubbler, was added 0,9509 g (3,12 mm) of the obtained product 0,6874 g (6,47 mm) Na2CO3and 10 ml of methanol. The reaction mixture is stirred over night at room temperature in a nitrogen atmosphere, after which the solid was filtered, dried in a vacuum oven for 6 h at room temperature and then determined that the resulting composite dimethyl ether product has the following data:

1H NMR ( ) to 3.34 (s, 6H), 7,39 (d, 1H), of 7.97 (d, 1H), compared to 8.26 (s, 1H).

13C NMR( ): 58,0; 136,0, 139,8, 140,9, 145,2, 146,8, 150,1, 183,5, 186,4.

Getting oligoether.

Example 1. Getting HBP/TPC formula:

< / BR>
Oligomer A(n=4)

In a 500-ml flask equipped with reflux condenser, a funnel for adding and mechanical stirrer, was loaded a 7.92 g (18,7 mm) HBPDS, and 3.16 g (37,6 mm) of sodium bicarbonate, 125 ml water, and 25 ml of methylene chloride. To the stirred reaction mixture was added 3.8 g (18,7 mm) TPC in 100 ml of methylene chloride for 1 h the resulting solution was stirred for 1.5 h at room temperature in a nitrogen atmosphere. Then the solution was transferred into a 2-liter flask was added 100 ml of water used for flushing the reaction vessel. For separation of the emulsion to relax the second looked like balls, filled with water. The solution was filtered, besieged 750 ml of acetone was again filtered and dried overnight in a vacuum oven at room temperature. The result has been 4,89 g of a brown solid product, characteristic viscosity which amounted to 0.16 DG/g in water, and Mn= 2100. Then the product was analyzed:

1H NMR : 2,2 (); 7,0 (Shir.C); 7,25 (Shir.s); 7.5 (a Shir.C); 8,0 (Shir.C).

Example 2. Getting HBDS/TPC formula:

< / BR>
Oligomer A(n=3)

Repeating the procedure of example 6, using the following amounts of reagents shown in table.1.

The resulting solution was stirred for 1.5 h at room temperature in the presence of nitrogen. Then the solution was transferred into a 1-liter flask was added 100 ml of water used for flushing the reaction vessel. To the flask was added 450 ml of acetone for separation of the emulsion. In the lower layer of water formed precipitate. Then the solution was transferred into a separating funnel and the lower layer was separated. Then the aqueous solution was treated with 500 ml of acetone. The resulting solid was filtered and dried off 2 days in a vacuum oven at room temperature. The result has been a product weight of 4.38 g and the characteristic viscosity of 0.05 DL/g Analysis using theis your source material, 2.0 g of the specified solid product was dissolved in 200 ml of water. The product was besieged by adding 700 ml of acetone, filtered and dried overnight in a vacuum oven at room temperature. The result has been 0,41 g of solid product, which had a characteristic viscosity of 0.11 DL/g in water and Mn=1300.

Biological data

Example 1. The ability of anti-HIV-oligomer to prevent the formation of entities and expression of antigen P24 viral core using JM-cells and viral strain GB8.

In order to show that the oligomer according to the invention blocks HIV infection, T-cells CD4+(JM) was subjected to a clinical isolate of HIV-1, GB8. First, the virus was incubated with oligomer for 15 min, and then added to cells. After a 2-hour adsorption, the virus inoculum was removed, and cells were washed three times to remove traces of the introduced virus. Antiviral activity was determined after 3-day incubation by building the graphical dependence of the average number of entities found in Quaternary cultures from log10- concentration of anionic polymer or other tested compounds. The ability of the oligomer was measured by analyzing the antigen in the in, textresult, SCD4 ATZ or ddC-data, which are given in table. 2-11.

Example 11. Infection with the virus JM-cells was carried out in the presence of different concentrations of the tested compounds. JM-cells (1 to 105) and 50-100 entityarray units of virus (GB3) was added in duplicate wells tablets for tissue cultures containing 1 ml volumes of medium for cultivation without drugs and with the content of the medicinal product. The plate were incubated for 2 days at 37oC, and then analyzed for the presence of entities. At the same time, cells were washed and the culture medium was replaced. Then incubated for two more days, the cell-free supernatant collected and analyzed for the concentration of antigen P24 viral core using the CoulterSo MHIV-antigen. The results of the analysis are given in table. 3-5. In table. 3-5. N D = not detected n A = not analyzed.

Example III. The ability of various anti-HIV-oligomers to prevent the death of the virus-induced cells using MT4 cells and strain RF.

Various oligomers was dissolved in RPMI medium and then analyzed for anti-HIV activity by double dilutions of solutions in 96-hole tablet for micro 7 days at 37oC. Then, to each well of MTT was added and the plates were incubated for another 2 h Blue crystals formazan was dissolved using acid isopropanol and measured the absorbance at 540 nm. The results given in table. 5.

Example IV. The ability to study the pre-treatment of cells with different oligomers and block HIV-1 using JM-cells and GB8-HIV-1 strain.

JM-cells were pre-treated overnight at 37oWith the different compounds at 20 μg/ml or left untreated. Cages were washed 3 times in RPMI medium and then infected with HIV-1 (GB8) for 2 h at room temperature. Then the cells were again washed 3 times in RPMI-medium, resuspendable in fresh medium for distribution in duplicate wells and incubated at 37oC. After 2 days, counted syncytia, and the cell-free supernatant collected and analyzed for the presence of viral antigen P24 core, using analysis of HIV-antigen . The results are presented in table. 6.

Example V. a Study of the ability of anti-HIV-1 oligomers to prevent entities and expression of antigen P24 viral core using different viral strains (GB8 and RF) and Ki of infection of 0.001. Cells were washed three times to remove residual virus, and then placed in fresh culture medium. Then the cells were treated with specified concentrations of the tested compounds after 24 and 48 h after investirovanie (p.i). After a specified number of days p.i was determined levels of entities and P24 of the methods. The results are presented in tables 7 - 9.

Results table. 7 show that virus-induced cytopathological changes, such as the formation of entities can be ingibirovany even if connections are introduced in already infected cells. These results also show that the anionic oligomers act on the mechanism of blocking the binding of the virus surface protein cell CD4.

Results table. 8 show that the oligomers according to the invention are effective against various viral strains and different types of cells, even if these oligomers is added by 24 h after virus infection.

After 48 h of p.i. in the control wells was observed approximately 50 syncytium/hole. At the same time, the wells were loaded with 5 μg/ml of the oligomer of example 1A and then incubated. Syncytia were counted on day 3 p.i. On the 4th day p.i. cells were washed in solo cells were washed in medium, not containing compound, and again incubated in parallel. At 6-1 day p.i. cell-free environment all samples were collected and determined the levels of virus antigen P24.

The results of these studies showed that the oligomers of example 1A cleanse culture from entities, stabilize against infection and reduce the levels of virus antigen in cells infected with the virus.

Example VI. Protocol: C8166 cells were infected with HIV (strain RF) for 1 h at room temperature to obtain a multiplicity of infection of about 0.01 to detail.ed. on the cell. Then cells were washed three times resuspendable in fresh medium and were divided into duplicate wells containing various concentrations of the test compounds. After incubation for 2 days at 37oC, cells were examined for the presence of entities, and the supernatant was analyzed for antigen P24 viral core, using the method of analysis of HIV-antigen Coulter.

Example VII. JM-cells infected with HIV (strain GB8) and received approximately 200 syncytium/1105cells 3 days after infection; the virus infection was carried out for 1 h at room temperature. Then cells were washed and resuspendable in fresh medium, distributed settings. After 3 days cells were investigated, sincity calculated, and the supernatant was analyzed for antigen P24 viral core using the method of HIV-Ag - analysis Coulter.

1. Water-soluble rigid-rod oligoether mol.m. less than 10,000, containing the repeating unit, United carbonyl groups, anionic groups and linear geometry of General formula I

< / BR>
where X -

< / BR>
< / BR>
< / BR>
< / BR>
n is an integer of 3 to 15;

R4is a hydrogen atom or HO-X, where X has the values, phenyl or phenyl substituted 1 - 2 - SO3R2groups;

R2is a hydrogen atom, or a pharmaceutically acceptable cation;

R5-

< / BR>
where R4has the specified values;

X3-

< / BR>
< / BR>
< / BR>
2. Oligoether under item 1, in which the repeating element has two or more anionic groups.

3. Oligoether under item 1, which exists in the form of pharmaceutically acceptable salts.

4. Oligoether under item 1, Brednikova mol.m. which is equal to 500 - 10000.

5. Oligoether on p. 4, Brednikova mol.m. which is 1000 - 6000.

6. Oligoether under item 1, where R4and R5is hydrogen, X3-

< / BR>
< / BR>
X -

< / BR>
< / BR>
< / BR>
< / BR>
where R2has value is enyl)-4,4'-diyl] oxycarbonyl-1,4-phenylenecarbonyl} General formula I, where R4and R5is hydrogen, X3- p-phenylene, X -

< / BR>
R2and n have the meanings specified in paragraph 1.

8. Oligoether under item 7, where n = 4.

9. Oligoether under item 6, which is a poly-[-oxy(2,5-disulfo-1,4-phenylene) oxycarbonyl-1,4-FeNi lankarani] formula I, where R4and R5is hydrogen, X3- phenylene, X -

< / BR>
where R2and n have the specified values.

10. Oligoether under item 9, where n = 3.

11. The method of producing oligoether under item 1, namely, that spend the interaction of diphenol formula

HO - H - OH,

where X

< / BR>
< / BR>
< / BR>
< / BR>
with bifunctional electrophile of the formula

< / BR>
where Hal is a chlorine atom or bromine;

X3-

< / BR>
< / BR>
< / BR>
moreover, the process is carried out in the presence of a polar aprotic solvent or in a mixture of water and a water-soluble solvent, at a molar ratio of diphenol to the bifunctional electrophile (0,9 - 1,2) at 0 - 40oC and the pH of the medium 7 - 8.

12. The method according to p. 11, characterized in that after adding a bifunctional electrophile mixture was incubated for 15 to 120 minutes

13. The method according to p. 11, characterized in that conduct preliminary processing diphenol base with education is

14. The composition having anti - HIV activity, including an active agent and a pharmaceutically acceptable carrier, wherein the active agent it contains an effective amount of the compounds of formula II

< / BR>
where X -

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
n = 3 - 15;

R2is a hydrogen atom or a pharmaceutically acceptable cation;

X3-

< / BR>
< / BR>
< / BR>
15. The composition according to p. 14, characterized in that as the active agent contains a compound of the formula II, where n = 4 and X has the formula

< / BR>
where R2has the meanings given in paragraph 14.

16. The composition according to p. 14, characterized in that as the active agent contains the compound of formula II, where n = 3, X -

< / BR>
where R2has the meanings given in paragraph 14.

17. The composition according to p. 14, characterized in that it further comprises a detergent.

 

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The invention relates to the production of complex sobolifera used for finishing textile yarns filamentary fibers /filaments/ large length or yarn of the individual short fibers

FIELD: medicine.

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Transdermal plaster // 2445084

FIELD: medicine.

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where

,

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,

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1 tbl, 6 ex

FIELD: chemistry.

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