RU2070554C1 - Water-soluble oligomer and method of its synthesis - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: water-soluble oligomer of the formula

where: X - -RO₃S-C₆H₄-SO₃R or 2--RO₃S-C₆H₄-C₆H₄-5-SO₃R; X¹ - unsubstituted phenyl or phenyl substituted with lower alkyl or 1-3 chlorine or bromine atoms; X² - unsubstituted phenylcarboxyl or phenylcarboxyl substituted with lower alkyl or 1-3 chlorine or bromine atoms; n = 6-9; R - hydrogen, or pharmaceutically acceptable cation. Reagent 1: corresponding diphenol. Reagent 2: substituted phenol and phosgene. Reaction conditions: in the presence of an aqueous base at pH = 7-8 and 0-40 C. Synthesized oligomers were used in medicine (virology) for AIDS treatment. EFFECT: improved method of synthesis. 7 cl, 19 tbl

Description

 The present invention relates to oligomers, their use, as well as to a method for their preparation. The oligomers of the present invention are anionic compounds and have significant activity against the human immunodeficiency virus, and therefore, these oligomers can be used to treat acquired immunodeficiency syndrome (AIDS).

 Currently, many scientific studies are aimed at the development of drugs for the treatment of viral diseases of humans and animals. Of particular interest to scientists is the AIDS and AIDS-associated complex (SAC) of humans, the prevalence of which 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 susceptible to serious disorders, suffer from various diseases caused by opportunistic microorganisms, for example, Kaposi’s sarcoma, pneumocytosis (Pneumocystis carninii pneumonia).

 An effective remedy for AIDS does not yet exist, and the available remedies are far from adequate for their practical use and cause many adverse side effects. People’s fear of AIDS leads to social stigma and discrimination against people with AIDS or those suspected of having the disease.

 Retroviruses belong to the class of viruses containing ribonucleic acid (RNA), which is replicated by reverse transcriptase, forming a strand of complementary DNA (cDNA), from which double-stranded proviral DNA is produced. This proviral DNA is then randomly introduced into the chromosomal DNA of the host cell, making it possible to replicate the virus genome by late translation of the viral RNA from the integrated viral genome.

 Many of the known retroviruses are oncogenic or cause tumor formation. In fact, the first two retroviruses found in humans, the so-called lymphocytic leukemia viruses I and II, or HTLV I and II, cause a rare form of human leukemia after infection with T-lymphocytes. The third virus found in humans, HTLV-III, currently caused by HIV, causes cell death after infection of T-lymphocytes and is identified as the causative agent of AIDS and SAK.

 The HIV envelope protein is a 160 kD glycoprotein. This protein is cleaved by a protease to form an external protein of 120 kD, other 120, and a transmembrane glycoprotein, other 41. Protein dr120 contains an amino acid sequence that recognizes the CD4 antigen on human T helper (T4) cells.

 Some studies have attempted to interfere with the binding of HIV to its target, human T4 cells. These T4 cells have a specific region, the CD4 antigen, which interacts with dr120. If this interaction is hindered, then the infection of the host cell can be inhibited.

 Interference by the formation of a viral envelope glycoprotein should prevent the initial interaction of the virus and the host cell, or subsequent fusion, or should prevent the duplication of the virus by preventing the formation of the intrinsic glycoprotein required to complete the viral membrane. In the work of N. A. Blongh et al. [Biochem. Biophys. Res.Comm. 141 (1), 33 38 (1986)] indicate that non-specific inhibitors of glycosylation of 2-deoxy-D-glucose and β-hydroxy-norvaline inhibit the expression of HIV glycoproteins and block the formation of synditia. Viral reproduction of HIV-infected cells treated with these agents is terminated, probably due to the lack of glycoprotein necessary for the formation of the viral membrane.

 In another work [W. Me Dowell et al. Biochemistry 24 (27), 8145 52 (1985)], the 2-deoxy-2-fluoro-1-mannose glycosylation inhibitor shows the inhibition of antiviral activity against the influenza virus of infected cells by preventing glycosylation of the viral protein membranes. The antiviral activity of 2-deoxyglucose and 2-deoxy-2-fluoroglucose was also investigated in this work, and as a result of these studies, it was found that each of these compounds inhibits the glycosylation of the viral protein by various mechanisms. However, other known glycosylation inhibitors did not show antiviral activity. Therefore, antiviral activity in general and activity against a specific glycosylation inhibitor virus is completely unpredictable.

 South African Patent 90/0094, issued October 31, 1990, states that the purified form of heparin, a sulfated polysaccharide, binds through interaction with a viral protein that is responsible for cell recognition and promotes limited inhibition of host cell infection. However, heparin has some side effects, for example, causes hemorrhage, and accelerates the formation of blood clots, and also causes thrombocytopenia. The use of heparin is contraindicated in patients with a tendency to bleed or in patients with hemophilia, purpura, thrombocytopenia, intracranial bleeding, septic endocarditis, active tuberculosis, increased capillary permeability, gastrointestinal ulcers, complicated by hypertension, threatening internal abortion or cancer. These contraindications are especially true for hemophiliacs, as they are especially prone to HIV-related illness.

 It has long been known that synthetic water-soluble polymers exhibit a wide range of biological activity (RMOtteubrite. Biological Activities of Polymers, Amer.Chem.Soc.Symp.Ser, N182, p. 205 220, ed. S.E. Carraher and GGGebeleni ( 1982)).

 The copolymer of divinyl ester and maleic anhydride has activity against a number of viruses, and the possibility of its use in anticancer chemotherapy has been studied for many years by Breslav D.S. [Pure and Applied 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 et al. Nature 186, 778 (1960)] Unfortunately, too high toxicity of these polymers does not allow their use in clinical conditions. In addition, these polymers have a common molecular weight and are not able to pass through the renal membranes.

 To solve the problems associated with the toxicity of polymers, attempts have been made to synthesize low molecular weight aliphatic polymers (1000 10000) [R. M. Ottenbrite. Biological Activities of Polymers, Amer Chem. Soc. Symp Ser. N182, p. 205 220, ed. S.E. Carraher and C. G. Gebeleni (1982)] It was found that these polymers are less toxic, but have lower antiviral activity. These low molecular weight aliphatic polymers can be classified as "statistical tangles."

 Such polymers have an unpredictable configuration due to the flexibility of the backbone bond groups. The configuration of a statistical coil in a solution can be generally characterized as globular. Although the mechanism of action of such water-soluble polymers is not yet known, however, as an assumption, it can be said that the polymer binds to the viral membrane, for example, the encephalomyocarditis virus, by means of interionic attraction, thereby giving the virus the inability to infect the host cell.

Another method using a synthetic polymer aims to supply ionic groups to the backbone of a polymer having a more specific geometry. There are many non-ionic synthetic polymers that have a more linear geometry in anhydrous solution than the aliphatic polymers described above [I. Macromolecular Sci-Rewiewsni Macromol. Chem. Phys. C.26 (4), 551 (1986)] Factors contributing to the formation of such structures of non-static tangles are complex and little studied. Basically, these polymers have either a very limited number of rotational bonds that are not parallel to the polymer axis, or in these structures there is hydrogen bonding or bipolar interactions that favor linear structures. These polymers are called "rigid chain polymers." A polyamide derived from terephthalic acid and n-diamonobenzola (known under the trademark Kevlar TM (Kevlar ^TM), available from DuPont), is a well-known example of such polymers.

 Rigid, synthetic, water-soluble polymers are generally less used, but very few such polymers having a large molecular weight are known (for example, see US Pat. Nos. 4,824,916 and 4,895,660). The structure of a non-statistical coil of polymers of this class leads to a high solution viscosity for a given molecular weight and concentration.

 Obviously, it would be desirable to find a treatment for AIDS and SAH that would not have side effects or have minimal side effects and would be significantly more effective than those polymers that have been used so far in pharmaceuticals.

 The authors of this application, it was found that anionic oligomers inhibit the replication of the virus, without having the side effects characteristic of heparin and known polymers. These oligomers have an ordered interanion distance and a rigid chain and are water soluble.

 The new oligomers of the present invention are anionic, carbonyl-containing compounds. Examples of these oligomers are polyureas, polycarbonates, polyesters or polyamides having a number average molecular weight of Mn <10000 and an ordered interanion distance and which are rigidly chained and water soluble. Oligomers, as well as their salts, are pharmaceutically acceptable and can be used as medicaments.

 Another application of these anionic oligomers is their use as effective thickeners in aqueous solutions or as soft ionic detergents, mainly water-soluble polymers, including the oligomers of the present invention, are widely used as thickeners, dispersants and flocculant. The oligomers of the present invention can be used in the oil industry, mining, paper industry, textile industry, cosmetics and food processing technology. In addition, the low molecular weight polymers of the present invention, i.e. oligomers can be used as starting materials for the production of high molecular weight polymers and copolymers.

 Thus, the present invention relates to a water-soluble, rigid chain oligomer with a molecular weight of less than (<) 10,000, containing repeating units linked via carbonyl linking groups; wherein said oligomer has anionic groups, mainly linear geometry, such that the distances between the anionic groups of this oligomer in the aqueous medium are regular. Preferably, each repeating unit has at least two anionic groups.

 Any oligomer meeting the above criteria may be used in the present invention. Particularly preferred oligomers are polyureas, polycarbonates, polyesters or polyamides. These oligomers are believed to have linear geometry.

The new oligomers of the present invention, which can be represented by polyurea, polycarbonates, polyesters or polyamides, have a number average molecular weight M _n <10000, a structure with an ordered interanion distance, mainly linear geometry in an aqueous medium, and are rigid chain and water soluble. These oligomers are preferably linear in their main chain, and may also be in the form of a salt; especially preferred salts are pharmaceutically acceptable salts.

где X означает:
5

,

,

10

,

,

15

,

20

,

25

30
где N является целым числом от 3 до 50 и
где Х¹ является НО-Х-группой, где Х определен выше или С₁-C₄-алкильной группой, фенильной группой или фенильной группой, замещенной от 1 до 2R¹-частями и до 3 заместителями, независимо выбранными из атома хлора, атома брома, или С₁-С₄-алкильной группы: и
X² является атомом водорода, или -СО₂X¹, где X¹ определен выше;
R¹ означает SO₃R², -CO₂R², -PO₃(R²)₂, или -OPO₃R²,
R² означает атом водорода или фармацевтически приемлемый катион.Preferred oligomers of the present invention are compounds represented by the following formula:
polycarbonate formula:

where X means:
5

,

,

ten

,

,

fifteen

,

20

,

25

thirty
where N is an integer from 3 to 50 and
where X ¹ is a HO-X group, where X is as defined above or a C ₁ -C ₄ alkyl group, a phenyl group or a phenyl group substituted by 1 to 2R ¹ moieties and up to 3 substituents independently selected from a chlorine atom, an atom bromine, or a C ₁ -C ₄ alkyl group: and
X ² is a hydrogen atom, or —CO ₂ X ¹ , where X ^{1 is} defined above;
R ¹ is SO ₃ R ² , —CO ₂ R ² , —PO ₃ (R ² ) ₂ , or —OPO ₃ R ² ,
R ² means a hydrogen atom or a pharmaceutically acceptable cation.

The term "pharmaceutically acceptable cation" means a cation that is acceptable for pharmaceutical use. Those cations that are mainly non-toxic when administered in doses necessary to achieve the desired effect, and by themselves do not have significant pharmacological activity, also fall under the definition of “pharmaceutically acceptable cation”. Examples include alkali metal salts such as sodium or potassium; alkaline earth metals such as potassium and magnesium; ammonium salts; Group IIIA metal salts, for example aluminum; and organic primary, secondary, and tertiary amines, such as trialkylamine, for example triethylamine, procaine, dibenzylamine, N, N'-dibenzidethylenediamine, dihydroabiethylamine, N- (C ₁ -C ₄ ) -alkylpiperidine, and other suitable amines.

Sodium and potassium salts are preferred. The term “pharmaceutically acceptable” means acceptable for administration to warm-blooded animals and humans, and since the pharmaceutically acceptable agent is non-toxic, it does not harm warm-blooded animals and can also be used for pharmaceutical purposes. The pharmaceutically acceptable cations of the oligomers of the present invention can be obtained by standard ion exchange treatment or by treating the R ¹ acid with an appropriate base.

 If the drugs obtained using the oligomers of the present invention are intended for other uses, then pharmaceutically unacceptable salts may also be used. For example, addition salts of barium, zinc and titanium may be used.

The oligomers of the present invention are low molecular weight, rigid chain and water soluble polymers. In addition, these oligomers have a structure with an ordered interanion distance. The term “ordered interanion distance” or “regular distance between anionic groups” means that said anionic groups (R ¹ ) are present in the polymer backbone at a distance determined by the starting material used, and the location of said anionic groups is predictably controlled. Without claiming to be a specific theory, we can only indicate that the anionic groups of the oligomers of the present invention are most likely to be the part that binds to HIV and / or the cell membrane, thereby preventing the virus from replicating.

The term "predominantly linear geometry" in an aqueous medium refers to the configuration of an oligomer solution. To assess the configuration of polymer molecules in solution, there is a method known to those skilled in the art, based on the following formula, called the Mark-Houwink equation ["Introduction to Physical Polymer Science", ed. LHSperling Pub. John Wilay Sons (1985), pp. 81 - 83]
[η] = KM ^α
where η is the intrinsic viscosity; M weight average molecular weight; K constant, depending on the size of the bonds in the chain; and a constant determined by the configuration of the polymer. The intrinsic viscosity for a random coil polymer is 0.5 <a <0.9; and for a linear polymer, it corresponds to 0.9 ≅ a <1.8.

 This formula expresses the relationship between viscosity h and molecular weight M. In the present invention, linear polymers are defined as polymers with a value greater than or equal to 0.9. For rod-shaped rigid polymers, the theoretical value (upper limit) is 1.8. For a given molecular weight, a higher viscosity of the solution can be obtained using polymers with a linear configuration compared to viscosity obtained using a statistical coil. In addition, it should be noted that the value of a depends on the solvent used. For example, a for a given water-soluble polymer may vary at different salt concentrations. In the present invention, the salt concentration is taken in accordance with the levels of the presence of salts in the serum (about 80 g / l NaCl, 4 g / l KCl).

The term "oligomer" as used in the present description of the invention includes oligomers with all possible values of P, for example P 3 to 50. Preferred are linear oligomers with P equal to an integer from 3 to 50, and more preferably from 3 to 20, and even more preferably
from 3 to 15. It goes without saying that the quantity is directly related to the molecular weight of the oligomer. The main thing is that these oligomers have a sufficiently low molecular weight, such that on the one hand they pass through the renal excretory membrane, and on the other hand, so that they have the ability to inhibit the HIV virus. The number average molecular weight is controlled by stoichiometry of the reagents. The number average molecular weight (M _n ) is less than 10,000, preferably from about 500 to about 10,000, and most preferably from about 1000 to about 6000.

For the purposes of the present invention, the described oligomers and their physically acceptable salts are considered equivalent. The term "physiologically acceptable salts" refers to salts whose bases can form a salt with at least one acid group of the R ¹ group, and which do not adversely affect when they are introduced into the body. Suitable bases, for example, are alkali metal and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonate and bicarbonate, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate, magnesium carbonate and the like. as well as ammonia, primary, secondary and tertiary amines and the like.

Particularly preferred bases are alkali metal hydroxides, carbonates and bicarbonates. Physiologically acceptable salts can be obtained using standard ion exchange processes, or by treating the R ¹ acid with an appropriate base. Examples of additive salts will be given below.

 The compositions of the present invention can be made in both solid and liquid form. These compositions can be made in the form of a set of dosage forms in such a way that the two components are mixed for a certain time before the start of administration. Either the required pharmaceutically acceptable carrier or adjuvant is mixed with this preparation or kit.

 The oligomers of the present invention are soluble in water and in saline solutions, especially in a solution with physiological pH. Thus, the oligomers of the present invention can be easily prepared in a suitable unit dose in the form of an aqueous solution. Once introduced into the body, the oligomer of the present invention retains its solubility in vivo.

,

5

или

; и
10 X представляет собой:
15

,

,

,
20

,

,

,
25
30

5

или

;
10 при этом особо предпочтительно, если X представляет собой:

АНТИ-ВИЧ анионные олигомеры могут быть использованы для предупреждения образования синцитиев в клетках, инфицированных ВИЧ-1 или другими родственными вирусами, имеющими поверхностный белок gp 120. Анти-ВИЧ анионные олигомеры могут быть использованы для лечения СПИДа и САК и других заболеваний, вызванных ретровирусом ВИЧ-1 или другими родственными вирусами, имеющими поверхностный белок gp 120.Formula I of the oligomers described above has the following preferred definitions of the value of X:

,

5

or

; and
10 X represents:
fifteen

,

,

,
20

,

,

,
25
thirty

5

or

;
10, it is particularly preferred if X is:

ANTI-HIV anionic oligomers can be used to prevent the formation of syncytia in cells infected with HIV-1 or other related viruses having a surface protein of gp 120. Anti-HIV anionic oligomers can be used to treat AIDS and SAH and other diseases caused by HIV retrovirus -1 or other related viruses having a surface protein of gp 120.

 The anionic oligomers of the present invention can be used as pure compounds, or as a mixture, such in which the value II corresponds to the specific definition of formula I IV, or mixtures of compounds belonging to the different above formulas, for example, compounds of formula I and formula II, or in the form of mixtures with other known agents used for the same purposes as the present invention. However, for all the oligomers obtained, II represents the number-average length of the distribution repeats in the oligomers of all formulas.

 The amount of anti-HIV anionic oligomers needed to prevent the formation of syncytia in HIV-infected cells can be any effective amount. It was experimentally determined that anti-HIV anionic oligomers when used in the form of aqueous preparations at a concentration of 100 μg / ml showed complete inhibition of the formation of syncytia, and also helped to reduce the amount of gp 24 antigen present, which is an indicator of virus replication, to less than 300 pg / ml

 The amount of anti-HIV anionic oligomer administered to treat AIDS and ASA caused by HIV infection can vary widely depending on the specific form used, treatment period, age and gender of the patient, the nature and extent of the disorder, and other factors well known to practicing physicians. In addition, anti-HIV anionic oligomers can be used in combination with other known agents used in the treatment of retroviral diseases, as well as with known agents used for the symptomatic treatment of complications and conditions caused by retroviruses.

 According to the present invention, anti-HIV effective amount of the anti-HIV anionic oligomer introduced into the body is generally about 0.1 mg / kg to 500 mg / kg per patient body weight and can be administered once or several times a day. Anti-HIV anionic oligomers can be administered in combination with pharmaceutical carriers that are commonly used in unit dosage forms for oral or parenteral administration.

 For oral administration of anti-HIV anionic oligomers can be used in the form of solid or liquid preparations, for example, in the form of capsules, dragees, tablets, troches, melts, powders, solutions, suspensions or emulsions. Single solid forms can be made in the form of hard capsules and soft gelatin shells containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, sorbitol, calcium phosphate and corn starch.

 In another embodiment, anionic oligomers can be made into tablets using lactose, sucrose, corn starch in combination with binders such as gum arabic, corn starch or gelatin; disintegrating agents to facilitate decomposition and dissolution of the tablets after administration, such as potato starch, alginic acid, corn starch and huar gum; sizing agents to improve the fluidity during granulation of the tablets and to prevent adhesion of the tablet material to the surfaces of the extrusion heads and molds, for example, such as talc, stearic acid or magnesium, calcium or zinc stearate; dyes and flavoring agents to improve the taste and appearance of the preparations used.

 Suitable excipients for oral liquid dosage forms are diluents such as water, alcohols, for example ethanol, benzyl alcohol and polyethylene glycol, which can be used either alone or in combination with pharmaceutically acceptable surfactants, suspending agents or emulsifying agents .

 The anti-HIV anionic oligomers of the present invention can also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, intraperitoneally, in the form of injectable single forms containing anionic oligomers in physiologically acceptable diluents in combination with pharmaceutical carriers, which may be sterile liquids or mixtures liquids such as water, saline, aqueous solutions of dextrose and related sugars; alcohols such as ethanol, isopropanol or hexadecyl 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 or glycerides, or acetylated fatty acid glycerides, which may be used alone or in combination with pharmaceutically acceptable surfactants, such as soaps; detergents; suspending agents such as pectin, methyl cellulose, hydroxypropyl methyl cellulose or carboxymethyl cellulose; or emulsifying agents and other pharmaceutical adjuvants.

 Examples of oils that can be used in the parenteral preparations of the present invention are petroleum, animal, vegetable or synthetic oil, for example peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, liquid paraffin and mineral oil. Suitable fatty acids for use in the present invention are oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps are fatty acid salts derived from alkali metals, ammonium and triethylamine, and suitable detergents are cationic detergents, for example, dimethyldialkylammonium halides, alkyl pyridinium halides, alkyl amine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl sulfates, olefinic sulfates, ether sulfates and sulfates of monoglyceride and sulfosuccinates; nonionic detergents, for example, fatty acid oxides, fatty acid alkanolamides and copolymers of polyoxyethylene and polypropylene; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and salts of 2-alkyl-imidazoline-quaternary ammonium, as well as their salts.

 The parenteral compositions of the present invention generally comprise from about 0.5 to about 25 wt. anti-HIV anionic oligomer in solution. In addition, preservatives and buffers can be used. In order to minimize or eliminate irritation at the injection site, these compositions may contain nonionic surfactants with a hydrophilic-lyophilic balance (HLB) from about 12 to about 17. The amount of surfactant in these compositions is from about 5 to about 15 wt. A surfactant may be the only component having the above HLB, or it may be a mixture of two or more components having the desired HLB. Examples of surfactants that can be used in the parenteral compositions of the present invention are compounds belonging to the class of polyethylene sorbitan fatty acid esters, for example sorbitan monooleate.

 The oligomers of the present invention can also be used for prophylactic purposes, that is, in order to prevent transmission of the virus from an infected organism to an uninfected target. The spread of the virus is proportional to the exchange of blood, but its transmission can also be carried out by the exchange of other physiological fluids. Thus, the oligomers of the present invention can be formulated using detergents for use in purification, in particular in analyzes in clinical laboratories and hospitals where blood samples of infected patients are manually processed. Compositions containing the oligomers of the present invention can be used to clean medical / surgical instruments and utensils, as well as treat hands and other areas of the skin of laboratory assistants for prevention.

 The oligomers of the present invention can also be used in the form of liquid and powder compositions for external use by applying contraceptives to the surface, such as condoms, carried out either by the user or by the manufacturer of said contraceptives before they are sold. The oligomers of the present invention can be formulated as vaginal showers for use by women before intercourse with an infected partner. The oligomers of the present invention can also be made in combination with sizing agents in the form of spermatocidal jellies and lotions. Finally, the oligomers of the present invention can also be added as compositions to hot baths, vibratory baths and swimming pools in order to inactivate potential viral activity.

 Definitions.

The terms used in the description of the present invention have the following meanings:
II number-average length of repeats in the distribution of oligomers of all formulas.

 RPMI cell culture media.

 TC1D50 is a unit of tissue infectious culture, i.e. the amount of culture fluid effective to infect 50% of the cells.

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

 MT 4 cell line.

 P 24-test Abbot analysis of viral nuclear antigen using the assay kit supplied by abbott.

Conlter ^™ HIV analysis A radioimmunoassay for the detection of the P 24 rs CDu viral antigen is a recombinant soluble CD ₄ containing 4 extracytoplasmic immunoglobulins similar to the variable (V) regions of V ₁ -V ₄ .

 T 4-methylaniline or toluidine, unless the term “T4 cells” or “T helper cells” is used.

 R phosgene.

 C p-cresol.

 MBS 4-methylbenzoyl chloride.

 TPC 1,4-benzenedicarbonyl chloride or terephthaloyl chloride.

НВDS дикалий 2,5-дигидрокси-1,4-бензолдисульфонат, имеющий формулу:

НВРDS дикалий 4,4'-дигидрокси(1,1'-бифенил)-2,2'-дисульфонат, имеющий формулу:

PDS-2,5-диамино-1,4-бензолдисульфоновая кислота, имеющая формулу:

БРDS-4,4'-диамино-(1,1'-бифенил)2,2'-дисульфоновая кислота, имеющая формулу:

St DS транс-2,2'-(1,2-этендиил)бис(5-аминобензолсульфоновая кислота), имеющая формулу:

БРDS (P/T - поли{амино[2,2'-дисульфо(1,1'-бифенил)-4,4'диил]иминокарбонил} альфа-{ [4-метилфенил)амино]карбонил}-омега-[(4-метилфенил)амино] и представлены формулой I (см. выше), где R является 4-метилфенилом, R² - водород, Х является:

где и определен выше в формуле I.TPCS 2,5-bis chlorocarbonyl benzenesulfonate sodium having the formula:

HBDS dipotassium 2,5-dihydroxy-1,4-benzenedisulfonate having the formula:

HBPDS dipotassium 4,4'-dihydroxy (1,1'-biphenyl) -2,2'-disulfonate having the formula:

PDS-2,5-diamino-1,4-benzenedisulfonic acid having the formula:

BRDS-4,4'-diamino (1,1'-biphenyl) 2,2'-disulfonic acid having the formula:

St DS trans-2,2 '- (1,2-ethenediyl) bis (5-aminobenzenesulfonic acid) having the formula:

BRDS (P / T - poly {amino [2,2'-disulfo (1,1'-biphenyl) -4,4'diyl] iminocarbonyl} alpha- {[4-methylphenyl) amino] carbonyl} -omega - [( 4-methylphenyl) amino] and are represented by formula I (see above), where R is 4-methylphenyl, R ² is hydrogen, X is:

where defined above in formula I.

где N определен в формуле I.St DS (P / T - poly [imino (3-sulfo-1,4-phenylene) -1,2-ethenediyl- (2-sulfo-1,4-phenylene) iminocarbonyl] alpha - {[(4-methyl- phenyl) amino] carbonyl} - omega - [(4-methylphenyl) amino] and is represented by formula I, if R is 4-methylphenyl, R ² is hydrogen, X is:

where N is defined in formula I.

и N определено выше в формуле I.PDS (P / T - poly [imino (2,5-disulfo-1,4-phenylene) iminocarbonyl] alpha - {(- methylphenyl) amino] carbonyl} -omega - [(4-methylphenyl) amino] and is represented by the formula I, where R is methylphenyl, R ² is hydrogen, X is

and N is as defined above in formula I.

, X² является

и N определено в формуле I.HBDS (P / C poly [hydroxy (2,5-disulfo-1,4-phenylene) hydroxycarbonyl] alpha - [(4-methylphenoxy) carbonyl] -omega- (4-methyl-phenoxy) and is represented by formula II (see above), where X ¹ is 4-methylphenyl, R ² is hydrogen, and X is:

X ² is

and N is defined in formula I.

, X² является

и N определен в формуле I.HBPDS (P / C-poly {oxy [2,2'-disulfo (1,1'-biphenyl) -4,4'-diyl] oxy-carbonyl} alpha - [(4-methylphenoxy) carbonyl] -omega- ( 4-methylphenoxy) and represented by formula II, where X ¹ is 4-methylphenyl, R ² is hydrogen, X is:

X ² is

and N is defined in formula I.

и N определен выше в формуле I.HBPDS (TPC-poly {hydroxy [2,2'-disulfo (1,1'-biphenyl) -4,4'-diyl] hydroxycarbonyl 1,4-phenylenecarbonyl} - and is represented by the formula III, R ⁴ and R ⁵ are hydrogen, X ³ is n-phenylene, and X is:

and N is as defined above in formula I.

где N определен в формуле I.HBDS (TPC - poly [hydroxy (2,5-disulfo-1,4-phenylene) hydroxycarbonyl-1,4-phenylenecarbonyl] and is represented by formula III, where R ⁴ and R ⁵ are hydrogen, X ³ is n-phenylene, X is an:

where N is defined in formula I.

где N определено формулой I.BPDS (TPC / MBC - poly {imino [(2,2'-disulfo (1,1'-biphenyl) -4,4'-diyl] iminocarbonyl-1,4-phenylenecarbonyl} alpha [(4-methylphenyl) amino] carbonyl} -omega - [(4-methylphenyl) amino] and is represented by formula IV, where R ⁶ is RC (O) -NH-X-NH, R is 4-methylenephenyl, R ² is hydrogen, R ⁷ is 4-methylbenzoyl X ³ is n-phenylene; X is:

where N is defined by formula I.

Oligomers were obtained by modifying the Kerschner procedure (US patent N4896660, the disclosure of which is introduced in the present description by reference) by replacing part of one of the bifunctional monomers with a monofunctional molecular weight regulator and carrying out the reaction in the absence of a surfactant. The number average molecular weight M _{n was} controlled by stoichiometry of the reagents.

 The oligomers of the present invention were obtained using various reactions described below.

 Polyureas and polyamides (formulas I and III).

 The following describes in detail the preferred method for producing polyurea and polyamide of the formula I and III, disclosed in US patent N4824916, and also describes various reagents and conditions for this method.

 Diamines: There is a wide variety of aliphatic and aromatic diamines. The hydrocarbylene bivalent radicals that make up the diamines can be methylene, ethylene, butylene, isopropylidene, phenylene, biphenylene, and other diradicals. A number of possible substituents is also quite wide and includes hydroxyl, alkenyl, lower alkyl groups, carboxylate, sulfonate and halogens. Substituents are not necessarily anionic at a neutral pH in water.

Bifunctional electrophiles are: phosgene (carbonyldichloride), carbonyldibromide, Cl ₃ COCOCl, Cl ₃ COCO ₂ CCl ₃ , primary acid halides of aliphatic and aromatic diacids, such as oxalic acid, maleic acid, succinic acid, glutaric acid, adicic acid , phthalic acid, isophthalic and 2,6-naphthalic acid.

 Acid Acceptors: Some bases have been used, such as sodium carbonate, sodium hydroxide and tributylamine.

 Various additives: various surfactants can be added. Suitable surfactants are nonionic surfactants such as sorbitan monolaurate, sorbitan monostearate, ethylene glycol distearate, polyethyleneoxy / polypropyleneoxy polymer. These surfactants are difficult to remove from the product, and therefore the use of surfactants is undesirable.

 Solvents: Only polar aprotic solvents such as N, N-dimethylacetamide and N, N-dimethylformamide were used as solvent. A problem is also the combination of water and a second solvent such as toluene, carbon tetrachloride, benzene, acetone, ethylene dichloride and the like. A typical ratio of organic to aqueous solvents is about 0.5 to 2.

In the methods described in the literature, primary acid halides are added to a mixed solution or suspension of other starting materials. In some cases, the base is added during the addition of carbonyldigalide. The temperature is maintained in the range from 0 ^° to 50 ^° C., and preferably from 20 ^° to 30 ^° C. The ratio of reactants (molar ratio of diamine to primary acid halide) is from about 0.9 to 1.2, and it is preferable to use equimolar amounts .

 The reaction is stirred at a rate sufficient to stir the reactants. The reaction rate partially depends on the interfacial boundary area, and therefore very intensive stirring is preferred. For this purpose, commercially available mixtures may be used.

 The method used to obtain the polyurea of the present invention is a modification of the method described above.

 Diamines: The diamines of the present invention are mainly aromatic compounds with the formulas described in the previous chapter. These diamines are substituted by at least one group that is charged at neutral pH, preferably a sulfonate. Monovalent aliphatic substituents are also acceptable. A small set of linking groups that bind together aromatic radicals, such as, for example, trans-substituted ethylene and acetylene, can be used. Preferred diamines are those diamines in which the carbon-nitrogen bonds are parallel, for example, such as PDS, PDS, SFDS and 2,5-diaminobenzenesulfonic acid.

Bifunctional electrophiles: phosgene (carbonyldichloride) and carbonyldibromide and other urea precursors such as carbonyldiimidazole, hexachloroacetone, Cl ₃ COCO ₂ CCl ₃ , CCl ₃ COCl and Cl ₃ OCOCl are used to produce polyureas. To obtain polyamides, aromatic dibasic acids, such as isophthalic and terephthalic acid (TPC), and 2,6-naphthalenedioic acid are used. Said dibasic acids can have neutral and charged substituents, such as a monovalent alkyl radical (methyl, ethyl, butyl) and / or charged groups, such as sulfonates, phosphates and the like. An example of such a charged bifunctional electrophile is sodium 2,5-bis chlorocarbonyl benzenesulfonate (TPCS).

 Acid Acceptors: A number of inorganic bases such as hydroxides, carbonates, bicarbonates and phosphates of alkali metals or divalent metals can be used as acid acceptors. Buffered acid acceptors are preferred if all bases are added before the addition of a bifunctional electrophile. Organic bases such as trialkylamines may also be used, however, these bases are not preferred.

 Monofunctional molecular weight regulator: a number of agents can be used to limit molecular weight. Such agents may be aliphatic or aromatic compounds that are regulated with diamines or bifunctional electrophiles. Examples of suitable monofunctional agents are amines such as aniline, methylaniline, methylamine, ethylamine, butylamine, diethylamine, ammonia, N-methylaniline, phenol and cresol. Examples of monofunctional aminoreactive agents are benzoyl chloride, acetyl chloride, biofinyl chloroformate. These molecular weight regulators may also contain charged substituents, for example potassium 2-sulfophenyl or potassium 4-sulfoaniline.

 Various additives: the addition of surfactants is optional or preferred and may complicate the isolation process.

 Solvents: one solvent, water, is preferred if the bifunctional electrophile is liquid at the reaction temperature. An example of such a bifunctional electrophile is phosgene. If said electrophile is solid, then water-insoluble reagents are used and it is preferable to use a small amount of a water-immiscible cosolvent. For example, if terephthaloyl chloride is used, a small amount of methylene chloride may be added to improve the reaction between the reactants. Examples of such water-immiscible solvents are chloroform, carbon tetrachloride, toluene and methyl chloride, mainly the ratio of organic solvents to aqueous solvents is 0 1, and preferably 0 0.1.

The process is carried out at a reaction temperature of generally from about 0 ^° C. to 100 ^° C. Preferably, the temperature is from 0 ^° to 25 ^° C. If low-boiling starting materials, for example phosgene (boiling point 6 ^° C.) are used, the reaction is preferably at boiling point or lower. Pressure is not a critical parameter for this method, and atmospheric pressure is mainly used. To optimize the process, the pH of the reaction should be carefully maintained. At low pH (<6), the reaction proceeds very slowly, and at high pH (> 10), the bifunctional electrophile becomes unstable under the influence of hydroxide or another base. At high pH, polyurea degradation may also occur. The preferred pH is in the range from 7 to 9.

If a molecular weight regulation agent is not used, then this control of molecular weight can be achieved by carefully adjusting the stoichiometry of the reagents. Both diamine and bifunctional electrophile can be used in excess, for example, in a molar excess of 1 to 100%
The specified stoichiometry should be calculated for any functional electrophile that is degraded by hydrolysis, before reacting with diamine. For example, if phosgene is used at high pH, then a large excess is necessary to compensate for the rapid reaction with the hydroxide that destroys it. Since the extent of this adverse reaction is difficult to control, it is preferable to use a monofunctional molecular weight regulator to control molecular weight. Although the above technique can be used to control the molecular weight, the products obtained are mixtures of polymers with several molecular weights characterized by a specific distribution.

 The order in which the reagents are added is not critical, but it is preferable to first add a bifunctional electrophile. If the acid acceptor used is not a buffer, for example hydroxides, it is most preferable to add part of it at the beginning to bring pH to the desired value, and add the remaining amount together with the bifunctional electrophile.

 Finally, these polymerizations are preferably carried out at high concentrations. This reduces the amount of solvent that must be removed in order to isolate the product. In addition, in some cases, the product is precipitated from the reaction solution shortly before completion of the reaction and isolated by simple decantation of the solvent. Most of the inorganic salt resulting from the reaction of the acid acceptor is removed during the process. The concentration is not critical and can range from 0.5 to 50 wt. by weight of diamine solvent. The preferred range is 5 to 20 wt.

 The product can be isolated by precipitating the reaction solution into a solvent which is a water-miscible but poor solvent for the product. An example of such solvents is acetone, methanol, ethanol and isopropanol. Polycarbonates and polyesters (formulas II and IV).

 The method described above was used to obtain polyurea and polyamides, with the following changes: diphenols were used instead of diamines, while the corresponding aromatic diphenols contained at least one substituent that is anionic at pH 7. These diphenols have structures identical to those of diamines, except that the amines are substituted hydroxyl groups. These diodes can be pretreated with 1M or 2M bases to form mono- or defenoxides. As specific examples, dipotassium 4,4'-dihydroxy (1,1'-biphenyl) -2,2'-disulfonate (HBPDS) and dipotassium 2,5-dihydroxy-1,4-benzenedisulfonate (HBDS) can be cited.

The conditions of the method are much more critical than in the previous case, due to the instability of the products in aqueous solutions. It is especially important to monitor pH. At pH below 7, the polymerization rate is very low, and at high pH (> 9), the carbonate or ester groups in the polymer undergo hydrolysis. The preferred pH range is 7-8, and it is advisable to use an automatic pH regulator to maintain it. The range of temperatures used at which the polymerization can be carried out is narrower and is 0 40 ^o C, and preferably 0 - 25 ^o C.

 After completion of the addition of the primary acid chloride, it is advisable to wait a while (usually 15 to 120 minutes) to verify that the conversion of the starting materials is complete. During this period, a certain amount of base may be added, but it must be strictly monitored so that pH does not rise above the established limit. The product is isolated in the form of the product composition described above.

 The present invention is more clearly described using the following examples.

 Description of the experiments.

 All solvents and reagents were obtained from commercial suppliers and used without further purification, except that BPDS was purified by recrystallization from dimethyl sulfoxide in a nitrogen atmosphere.

PDS was obtained by the method described in German patent N1393557 (the disclosure of which is incorporated into this description by reference), and the resulting product was recrystallized from 1% (v / v) H ₂ SO ₄ .

The intrinsic viscosity was measured at 0.5 g / dl in deionized water and Hank Balanced Salt Solution (HBSS) (supplied from Sigma Chemical) at 25 ^° C. unless otherwise noted.

 The water content in the purified diamines was determined by titration according to Karl Fischer.

Proton and C-nuclear magnetic resonance spectra were recorded on a VXP 300 or on a Varian ^TM Gemini 300 spectrometer. Samples were dissolved in D ₂ O, unless otherwise specified. Where possible, the number average molecular weights of the oligomers were confirmed by integrating the area of the resonances from the methyl groups of the end caps with respect to the aromatic resonances of the repeating units. In many cases, in particular for polyamides obtained from BPDS or St DS and TPC, the resonances had a too wide range of values.

Analysis by high pressure liquid chromatography (HPLC) was carried out on an HP 1090 liquid chromatograph using a C-18 reverse phase column (200 mm x 2.1 mm). The column was eluted with a gradient of a solution, starting with 35% CH ₃ CN and 65% 5 mM tetra-n-butylammonium butyl sulfate and ending with 55% CH ₃ CN and 45% tetra-n-butylammonium sulfate.

The phosgenation reaction was carried out in a standard apparatus specially designed for this purpose, having a stainless steel phosgene tank connected to the phosgene tank by a nitrogen pipe and a supply pipe. The tank was mounted so that, if necessary, the supply could be carried out directly from the phosgene tank. The amount of phosgene supplied was determined as the difference in tank weight before and after the reaction. During the reaction, the nitrogen-containing flow rate was maintained at 0.3 ml / min, unless otherwise specified. Phosgene was injected at a rate of 0.9 ml / min (during the addition of phosgene the total gas flow was 1.2 ml / min). Phosgene was added mainly in triplicate to the reaction vessel. The stirring speed was 300 rpm, and the temperature of the solution was maintained within 10 15 ^o C.

The resulting products were dried in a standard way in a vacuum oven at 40-50 ^o C for 15 hours, at least. Source materials.

 Example A.

В 2-литровой колбе, снабженной воронкой для добавления и стержнем магнитной мешалки, добавляли 49,99 г (0,145 М) 4,4'-диамино(1,1'-бифенил)-2,2'-дисульфоновой кислоты и 600 мл воды. Диамин солюбилизировали путем добавления 30 мл (0,15 М) 5 М NaOH. К полученному раствору добавляли 20,56 г (0,298 М) нитрита натрия. Затем реакционную смесь охлаждали до 0^oС и в течение 30 минут добавляли концентрированную Н₂SO₄, растворенную в 360 мл воды. В результате образовывалось желтое твердое вещество. Затем к смеси добавляли 300 мл воды и смесь поддерживали при 0^oC в течение 1 часа. Затем реакционную смесь фильтровали. Желтое твердое вещество, растворенное в 300 мл воды, помещали в 1-литровую колбу и нагревали до тех пор, пока не останется 50 мл воды. Азот выделялся в течение нагревания. К концентрированному раствору добавляли 20,14 г (0,146 М) К₂CO₃, после чего раствор кипятили. Затем добавляли абсолютный этанол (1,5 л) и полученное коричневое твердое вещество осаждали. Осадок отфильтровывали и осушали в течение ночи в печи при 50^oC. Продукт, НВРDS, получали с выходом 32,33 г (53%), а затем анализировали с помощью Н¹ЯМР.Obtaining HBPDS formula:

In a 2 liter flask equipped with an addition funnel and a magnetic stir bar, 49.99 g (0.145 M) of 4,4'-diamino (1,1'-biphenyl) -2,2'-disulfonic acid and 600 ml of water were added. . The diamine was solubilized by adding 30 ml (0.15 M) of 5 M NaOH. To the resulting solution was added 20.56 g (0.298 M) of sodium nitrite. Then the reaction mixture was cooled to 0 ^{° C.} and concentrated H ₂ SO ₄ dissolved in 360 ml of water was added over 30 minutes. As a result, a yellow solid formed. Then, 300 ml of water was added to the mixture, and the mixture was maintained at 0 ^° C. for 1 hour. Then the reaction mixture was filtered. A yellow solid, dissolved in 300 ml of water, was placed in a 1 liter flask and heated until 50 ml of water remained. Nitrogen was released during heating. To the concentrated solution was added 20.14 g (0.146 M) K ₂ CO ₃ , after which the solution was boiled. Then absolute ethanol (1.5 L) was added and the resulting brown solid was precipitated. The precipitate was filtered off and dried overnight in an oven at 50 ^° C. The product, HBPDS, was obtained in 32.33 g (53%) yield and then analyzed by H ¹ NMR.

¹ NMR δ 6.70 (dd, 1H), 7.05 (d, 1H), 7.14 (d, 1H).

 Example B.

В 600-мл колбу, снабженную механической мешалкой, термометром и дефлегматором, загружали 40,49 (0,143 М) мононатриевой соли 2-сульфотерефталевой кислоты, 160 мл хлорбензола, 2,4 мл (0,031 М) диметилформамида и 23 мл (0,315 М) тионилхлорида. Раствор нагревали до 105^oС и размешивали в течение 2 часов в атмосфере азота. В течение этого периода отмечалось выделение газа. Раствор охлаждали до комнатной температуры и твердое вещество осаждали. Осадок фильтровали и осушали в течение ночи в вакуумной печи при комнатной температуре, в результате чего получали твердый бледно-желтый продукт с выходом 20,56 г (47%).Obtaining TPCS formula:

A 40-ml flask equipped with a mechanical stirrer, thermometer and reflux condenser was charged with 40.49 (0.143 M) of 2-sulfoterephthalic acid monosodium salt, 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 105 ^{° C.} and stirred for 2 hours under nitrogen. During this period, gas evolution was noted. The solution was cooled to room temperature and the solid precipitated. The precipitate was filtered and dried overnight in a vacuum oven at room temperature, resulting in a solid pale yellow product with a yield of 20.56 g (47%).

 To confirm the structure of the product, a certain amount of the product was converted into its methyl ester.

0.9509 g (3.12 mmol) of the product obtained above, 0.6874 g (6.47 mmol) of Na ₂ CO ₃ and 10 ml of methanol were added to a 25 ml flask equipped with a magnetic stir bar and a nitrogen bubbler. The reaction mixture was stirred overnight at room temperature in a nitrogen atmosphere, after which the solid was filtered off, dried in a vacuum oven for 6 hours at room temperature, and then it was determined that the resulting dimethyl ester product had the following data:
¹ H NMR (δ) 3.34 (s, 6H), 7.89 (d, 1H), 7.97 (d, 1H), 8.26 (s, 1H), ¹³ C NMR (d): 53 0; 136.0; 139.8; 140.9; 145.2; 146.8; 150.1; 183.5; 186.4.

 End products.

 Example 1

Олигомер А (n 6).Obtaining BRDS / P / T formula:

Oligomer A (n 6).

10.00 g (28.19 mmol) of BPDS was added to a 1-liter flask equipped with a syringe hole, a thermometer pocket, a pH electrode, a refrigerator with dry ice cooling, a phosgene gas inlet pipe and a mechanical stirrer; 1.35 g (9.40 mmol) of toluidine hydrochloride and 400 ml of water. The reaction mixture was stirred and cooled to 12 ^° C. The stirred suspension was reacted with 13 ml of 5M NaOH until all of the solid had dissolved. Then, 10.1 g (102 mmol) of phosgene was added to the reaction mixture over 27 minutes. During the addition of phosgene, 5 M NaOH was added via syringe, which was necessary to maintain the pH in the range from 7 to 8 to the extremes of pH 6 9. Then, all 31 ml of NaOH was added, the reaction mixture was continued to stir for another 30 minutes, and then pH was adjusted to 9.5 and the reaction mixture was stirred for another 30 minutes. After which the reaction mixture was transferred to a 2 liter flask and the crude product was precipitated by adding 1000 ml of acetone. The crude product was filtered, air dried, and 18.6 g of a whitish powder having M _n 2500 was obtained. The intrinsic viscosity was 0.39 dl / g in H ₂ O and 0.15 dl / g in HBSS.

Then the product was analyzed:
¹ H NMR (δ): 2.2 (br s); 6.7 7.4 (m); 7.9 8.3 (m). Oligomer B (n 9).

The procedure of Example 1A was repeated using the following amounts of reagents (see Table 1)
and the product (12 g) was obtained in the form of a whitish powder with M _n 3600. The intrinsic viscosity was 0.52 dl / g in H ₂ O and 0.21 dl / g in HBSS.

 Example 2

Олигомеры А (n 6).Obtaining St DS / P / T formula:

Oligomers A (n 6).

The procedure of Example 1A was repeated using the following amounts of reagents (see Table 2). and the product was obtained (7.4 g, M _n 2600) as a yellow solid. The intrinsic viscosity was 0.14 dl / g in H ₂ O. Product analysis showed:
¹ H NMR (δ): 2.1 (bs); 6.7 8.1 (wide m).

 Oligomer B (n 9).

 The procedure of Example 1A was repeated using the following amounts of reagents (see Table 3).

About half of the suspension obtained after the addition of acetone was filtered to prevent clogging of the sintered mixture. There was obtained 3.5 g (M _n 3800) of a yellow solid. The intrinsic viscosity was 0.18 dl / g in H ₂ O.

 Example 3

Олигомер А (n 9).Obtaining PDS / P / T formula:

Oligomer A (n 9).

The procedure of Example 1A was repeated using the following amounts of reagents (see Table 4)
and 2.95 g of product (M _n 2900) was obtained as a brown powder. The intrinsic viscosity was 0.12 dl / g in water and 0.07 dl / g in HBSS.

 Oligomer B (n 15).

The procedure of Example 1A was repeated using the following amounts of reagents (see Table 5)
and 3.83 g of product ( _n 4650) were obtained as a brown powder. The intrinsic viscosity was 0.12 dl / g in water and 0.14 dl / g in HBSS.

 Example 4

Олигомер А (n 6).Obtaining HBDS / P / C formula:

Oligomer A (n 6).

10.16 g (29.35 mmol) HBDS, 1.06 were added to a 1-liter flask equipped with a syringe hole, a thermometer pocket, a pHH electrode, a refrigerator for cooling with dry ice, a mechanical stirrer and a tube for the inlet of gaseous phosgene. g (0.81 mmol) of n-cresol and 400 ml of water. The reaction mixture was cooled to 10 ^° C. with nitrogen entering the flask through the phosgene inlet. The stirred reaction mixture was treated with 5M sodium hydroxide until the pH of the solution reached 8.0. Then, 10.5 g (106.0 mmol) of phosgene was added to the reaction mixture over 35 minutes along with 42 ml of 5M sodium hydroxide, since it was necessary to keep the pH of the solution within 7.0 to 7.5. After the completion of the phosgene addition, the solution was stirred for 20 minutes at 10 ^° C. Then the dry ice was removed from the refrigerator and the solution was stirred for another 30 minutes at 10 ^° C. to evaporate the excess phosgene. The aqueous solution was transferred to a 2 liter flask and 100 ml of water used to wash the reaction vessel was added. The product was precipitated by adding 1000 ml of acetone, filtered and dried overnight in a vacuum oven at room temperature. The product yield was 2.11 g, the intrinsic viscosity of the solid product was 0.30 dl / g in water, and M _n 2300.

 Example 5

Олигомер А (n 6).Obtaining HBPDS / P / C formula:

Oligomer A (n 6).

 The procedure of Example 4 was repeated using the following amounts of reagents (see Table 6).

The pH of the initial solution was 10.0, and then pH was adjusted to 6.1 with concentrated hydrochloric acid. Phosgene was added over 32 minutes along with 31 ml of 5M sodium hydroxide to maintain a pH between 7.5 and 8.0. After evaporation of the phosgene, the reaction mixture was transferred to a 2 liter flask and 100 ml of water used to wash the reaction vessel was added. The product was precipitated by adding 1400 ml of acetone, filtered and dried overnight in a vacuum oven at room temperature. The product yield was 1.89 g, the intrinsic viscosity of the solid product was 0.17 dl / g in water, and M _n 2700.

¹ H NMR: (δ) 2.4 (s); 7.0 (s); 7.2 (s); 7.5 (broad s).

 Example 6

Олигомер А (n 4).Obtaining HBPDS / TPC formula:

Oligomer A (n 4).

Into a 500 ml flask equipped with a reflux condenser, addition funnel and mechanical stirrer, 7.92 g (18.7 mmol) of HBPDS, 3.16 g (37.6 mmol) of sodium bicarbonate, 125 ml of water and 25 ml of methylene chloride were charged. 3.8 g (18.7 mmol) of TPC in 100 ml of methylene chloride were added to the placed reaction mixture over 1 hour. The resulting solution was stirred for 1.5 hours at room temperature in a nitrogen atmosphere. The solution was then transferred to a 2 liter flask and 100 ml of water used to wash the reaction vessel was added. Aceton in excess of 250 ml was added to separate the emulsion. After adding 1000 ml of acetone, a solid formed on the bottom of the flask, which looked like balls filled with water. The solution was filtered, precipitated with 750 ml of acetone, again filtered and dried overnight in a vacuum oven at room temperature. The result was 4.89 g of a brown solid powder, the characteristic viscosity of which was 0.16 dl / g in water, and M _n 2100. Then the product was analyzed:
¹ H NMR δ: 2.2 (s); 7.0 (br s); 7.25 (broad s); 7.5 (broad s); 8.0 (br s).

 Example 7

Олигомер А (n 3).Obtaining HBDS / TPC formula:

Oligomer A (n 3).

 The procedure of Example 6 was repeated using the following amounts of reagents (see Table 7).

The resulting solution was stirred for 1.5 hours at room temperature in the presence of nitrogen. The solution was then transferred to a 1 liter flask and 100 ml of water used to wash the reaction vessel was added. 450 ml of acetone was added to the flask to separate the emulsion. A precipitate formed in the lower layer of water. Then the solution was transferred to a separatory 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 for 2 days in a vacuum oven at room temperature. The result was a product weighing 4.38 g and with an intrinsic viscosity of 0.05 dl / g. Analysis by ¹ NMR and HPLC showed a significant amount of starting diphenol.

To remove unreacted starting material, 2.0 g of the above solid was dissolved in 200 ml of water. The product was precipitated by adding 700 ml of acetone, filtered and dried overnight in a vacuum oven at room temperature. The result was 0.41 g of a solid product which had an intrinsic viscosity of 0.11 dl / g in water and M _n 1300.

 Example 8

Олигомер А (n 6).Obtaining BPDS / TRS / MVS formulas:

Oligomer A (n 6).

 200 ml of deionized water and 2.65 g (25.0 mmol) of sodium carbonate were added to the Waring mixer and the mixture was stirred at low speed until the mixture was dissolved. 2.217 g (6.25 mmol) of BPDS was added to the reaction mixture through a funnel to add powder. The funnel was washed with 50 ml of water, which flowed into the mixture. The result was a clear, colorless sodium salt solution.

 Then a second solution was prepared containing 1.088 g (5.357 mmol) of TPC and 0.193 ml (236 mg, 1.786 mmol) of MBC in 200 ml of chloroform. This solution was immediately added to the sodium salt solution, while stirring vigorously. The resulting white suspension was stirred at low speed for 15 minutes.

After stirring for 15 minutes, the suspension was transferred to a 2 liter flask, and the mixer was washed with about 200 ml of water, which was added to the suspension. 200 ml of acetone was added to the suspension. The emulsion was stratified into two phases with an implicit sediment. The bottom layer was removed through a separatory funnel; the top layer was returned to the flask. Then 450 ml of acetone was added to the flask for precipitation. The precipitate was filtered through three layers of gauze. Residual solvents were removed from the white gelatinous product by vigorously pressing gauze. The crude product was dissolved in 600 ml of water and again precipitated by dilution to a total volume of 1000 ml of acetone. The precipitate was again collected, dissolved in 150 ml of water and precipitated by adding 850 ml of acetone. The precipitate was collected as described above, then dried in a vacuum oven overnight at 35–36 ^° C. and 0.8 g of a white fibrous product was obtained.

A second crop of the product was obtained from the initial mother liquor with a yield of 0.9 g. The combined solid fractions were dissolved by adding 500 ml of acetone, resulting in 1.26 g of an off-white solid, M 3450. The intrinsic viscosity was 3.85 dl / g in water. Product analysis showed:
¹ H NMR: δ 2.1 (s); 7.44 (s); 7.78 (s); 8.02 (br s).

 Oligomer B (n 3).

The procedure of Example 8A was repeated using the following amounts of reactants (see. Table. 8) to give 1.58 g (M _n 2000) of the product as an off-white powder. The intrinsic viscosity was 1.93 dl / g in water and 2.41 dl / g in HBSS.

 Oligomer C (n 9).

The procedure of Example 8A was repeated using the following amounts of reagents (see Table 9).
and obtained a white fibrous product with a yield of 1.42 g (M _n 4000), an intrinsic viscosity of 4.23 dl / g in water.

 Biological data.

 Example I.

 The ability of an anti-HIV oligomer to prevent the formation of syncytia and expression of the P24 virus core antigen using IM cells and the GB8 virus strain.

In order to show that the oligomer of the present invention blocks HIV infection, CD4 ⁺ T cells (IM) were exposed to HIV-1 clinical isolate, GB8. First, the virus was incubated with the oligomer for 15 minutes, and then the cells were added. After 2 hours of adsorption, the viral inoculum was removed and the cells were washed three times to remove traces of the introduced virus. Antiviral activity was determined after 3-day incubation by plotting the average number of syncytia found in Quaternary cultures on log ₁₀ concentration of anionic polymer or other test compounds. The ability of the oligomer was also measured by analysis of the antigen of the viral core (P24 test Abbott) in the supernatant. As a positive control used heparin, dextran sulfate, rsCD4, ATZ or ddC data, which are given in table. 10 19.

 Example II

Virus infection of IM cells was carried out in the presence of various concentrations of test compounds. IM cells (1 x 10 ⁵ ) and 50,100 syncytium-forming virus units (GB8) were added to duplicate wells for tissue culture plates containing 1 ml volumes of medium for growth without a drug and containing a drug. The plate was incubated for 2 days at 37 ^o C, and then analyzed for the presence of syncytia. At the same time, the cells were washed and the culture medium was replaced. Then, they incubated for another two days, cell-free supernatants were collected and analyzed for the concentration of P24 virus core antigen using the Coulter ^TM assay for HIV antigen. The results of the analysis are given in tables II IV. In these tables: N ₁ D was not detected and N ₁ A was not analyzed.

 Example III

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

Various oligomers were dissolved in RPMI medium and then assayed for anti-HIV activity by doubling dilutions of solutions on a 96-well microtiter plate. Then, 5 x 10 ⁴ cells and 100 TCID50 virus were added to each well and the plates were incubated for 7 days at 37 ^° C. Then MTT was added to each well and the plates were incubated for another 2 hours. Blue formazan crystals were dissolved using acidic isopropanol, and absorbance was measured at 540 nm. The results are presented in table 13.

 Example IV

 The study of the ability to pretreat cells with various oligomers and to block HIV-1 infection using IM cells and the GB8 strain of HIV-1.

IM cells were pretreated overnight at 37 ^° C. with various compounds at 20 μg / ml and left untreated. Cells were washed 3 times in RPMI medium and then infected with HIV-1 (GB8) for 2 hours at room temperature.

Then the cells were washed again 3 times in RPMI medium, resuspended in fresh medium for distribution in published wells and incubated at 37 ^° C. After 2 days, syncytia was counted and cell-free supernatants were collected and analyzed for the presence of the viral core antigen using an HIV test antigen Coulter ^TM . The results are presented in table 14.

 Example V.

 Investigation of the ability of anti-HIV-1 oligomers to prevent the formation of syncytia and expression of the P24 virus core antigen using various viral strains (GB8 and RF) and cells (IM and C8 166).

Cells were infected with a strain of RF or GB8 for 24 hours at 37 ^° C. with a multiplicity of infection of 0.001. Cells were washed three times to remove residual virus, and then again placed on fresh culture medium. Then the cells were treated with the indicated concentrations of the test compounds 24 and 48 hours after infection (pi). After the indicated number of days pi, the levels of syncytia and P24 were determined by the methods described above.

 The results are presented in tables 15 17.

 The results of table 15 show that virus-induced cytopathological changes, such as the formation of a syncytive, can be inhibited even if the compounds are introduced into already infected cells. These results also show that anionic oligomers act by a mechanism to block the binding of the virus to the surface protein of CD4 cells.

 The results of table 16 show that the oligomers of the present invention are effective against various viral strains and various types of cells, even if these oligomers are added 24 hours after virus initiation.

Note to table 17:
a) pi after infection;
b) after 48 hours pi, approximately 50 syncytium / well was observed in control wells. At the same time, the wells were loaded with 5 μg / ml of the oligomer of Example 1A and then incubated. Syncytia was counted on day 3 pi On day 4, pi cells were washed in water containing 5 μg / ml of the oligomer of Example 1A, and then incubated in 5 μg / ml of the oligomer of Example 1A. Virus control cells were washed in a medium containing no test compounds and again incubated in parallel. On day 6, pi cell free medium of all samples was collected and P24 virus antigen levels were determined.

 The results of these studies showed that the oligomers of Example 1A cleared cultures of syncytia, stabilized from infection, and reduced virus antigen levels in cells infected with the virus.

 Example VI

Protocol: C8166 cells were infected with HIV (RF strain) for 1 hour at room temperature until a multiplicity of infection of approximately 0.01 inf. units per cell. Then the cells were washed three times, resuspended in fresh medium and distributed in duplicated wells containing different concentrations of the test compound. After 2 days at 37 ^° C., the cells were examined for the presence of syncytia and the supernatant was analyzed for the P24 virus core antigen using the Coulter HIV antigen assay.

 Example VII

IM cells were infected with HIV (GBB strain) and received approximately 200 syncytia (1 x 10 ⁵ cells 3 days after infection; virus infection was carried out for 1 hour at room temperature. Then the cells were washed and resuspended in fresh medium, and plates were distributed over duplicated wells. tissue culture containing different concentrations of test compounds After 3 days, the cells were examined, syncytia was counted, and the supernatant was analyzed for P24 virus core antigen using the Coulter HIV-Ag analysis method.

 Despite the specific and illustrated specific embodiments of the present invention, it will be apparent to those skilled in the art that the present invention is not limited to the foregoing options and that various changes and modifications are possible without, however, departing from the spirit and scope of the following claims.

Claims (5)

1. A water-soluble rigid skeleton oligomer having a molecular weight of less than 10,000, containing anionic groups and repeating units joined to carbonyl linking moieties and having a predominantly linear geometry such that there is a regular distance between the anionic groups in an aqueous medium of the general formula I

where is X group

X ₁ unsubstituted or substituted with C ₁ C ₄ alkyl or 1 3 atoms of chlorine or bromine, phenyl;
X ₂ unsubstituted or substituted with C ₁ C ₄ alkyl, or 1 3 atoms of chlorine or bromine, phenylcarboxyl;
n 6 9;
R is hydrogen or a pharmaceutically acceptable cation.  2. The oligomer according to claim 1, characterized in that its average molecular weight of 2000 to 3000.  3. The oligomer according to claim 1, characterized in that n 6. 4. The oligomer according to claim 1, characterized in that it is represented by the formula

5. The oligomer according to claim 1, characterized in that it is represented by the formula

6. A method of obtaining a water-soluble oligomer of the general formula I according to claim 1, characterized in that the corresponding diphenol is reacted with substituted phenol and phosgene in the presence of an aqueous base at pH 7 8 and 0 40 ^o C.  7. The method according to claim 6, characterized in that after the addition of phosgene, the reaction mixture is maintained at pH 7 8 for 15 120 minutes