RU2633699C2 - Pyrimidyl-di(diazadispiroalkane)s with antiviral activity - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: compounds have a broad spectrum of antiviral activity and can be used for treatment and/or prevention of diseases caused by papillomavirus infection, infection caused by the immunodeficiency virus, cytomegalovirus or hepatitis B or C virus. In general formula I

, X = CH₂, Y = CH₂CH₂ or X = CH₂CH₂, Y = CH₂; A is pyrimidine-4,6-diyl or pyrimidine-2,4-diyl, which may contain, as substituents, H, NO₂, CHO, OH, OAlk, a halogen atom, NH(Alk), N(Alk) 2 group; wherein Alk is a linear or branched substituent having from 1 to 4 carbon atoms; Hal is a halogen atom, or X = Y = CH₂; A is pyrimidin-4,6-diyl or pyrimidine-2,4-diyl, which has Cl, Br, CH₃, HE atom as its substituent;Hal is a halogen, chlorine or bromine atom. Preference is given to compounds of formula (I) where X = CH₂CH₂, Y = CH₂ or X = CH₂, Y = CH₂CH₂, A = pyrimidine-4,6-diyl, which may have H, NO₂, Alk group, as substituents; Hal = chlorine or bromine and Alk = methyl.

EFFECT: increased composition application effeciency.

11 cl, 2 dwg, 2 tbl, 13 ex

Description

The invention relates to new biologically active compounds derived from pyrimidyl di (diazadispiroalkanes) of the general formula (I), their pharmaceutically acceptable salts, which are active against various viruses, the method for their preparation and their use as antiviral drugs.

The problem of finding new antiviral agents is due to the significant spread of viral infections in humans and animals. This is due to a decrease in the immune defense in the human population, as well as to the widespread development of virus resistance to commercially available drugs. The problem of the rapid development of resistance is due to the fact that basically many of the known antiviral drugs used are derivatives of the same class of compounds, as well as the lack of effectiveness and toxicity of the drugs.

A promising direction in the search for a new effective antiviral compound is the narrow specificity of the effect on the components of the virus life cycle. One of the unique mechanisms of influence on the process of invasion of the virus into the host cell is based on the process of adsorption of the virus to the target cell due to the specific blocking of heparan sulfate receptors (HS). After the discovery of the role of heparan sulfate receptors in cellular interactions, more and more scientific work has been devoted to the search for various ways to block this mechanism of viral adsorption due to competitive binding to host cell receptors. The possibility of applying this mechanism of action has been studied for a number of viruses: HSV-1, 2 (Shukla D., Spear PG Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. J Clin Invest. 2001, 108 (4), 503 -10) HPV (Selinka HC, Giroglou T, Sapp M. Analysis of the infectious entry pathway of human papillomavirus type 33 pseudovirions, Virology, 2002, 1, 279-287; Selinka HC, Giroglou T, Nowak T, Christensen ND, Sapp M. Further evidence that papillomavirus capsids exist in two distinct conformations, J Virol, 2003, 77, 12961-7), HCMV (Paeschke R., Woskobojnik I., Makarov V., Schmidtke M., Bogner E. DSTP-27 prevents entry of human cytomegalovirus. Antimicrob Agents Chemother. 2014, 58 (4): 1963-1971), no. HIV (Patel V, Ferguson M, Minor PD. Antigenic sites on type 2 poliovirus, Virology, 1993, 192, 361-4), RSV (Hallak LK, Spillmann D, Collins PL, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection, J Virol., 2000, 74, 10508-13; Donalisio M, Rusnati M, Cagno V, Civra A, Bugatti A, Giuliani A, Pirri G, Volante M, Papotti M, Landolfo S, Lembo D., Inhibition of human respiratory syncytial virus infectivity by a dendrimeric heparan sulfate-binding peptide, Antimicrob Agents Chemother., 2012, 56, 5278-88), HBV, HCV (Jiang YF, He B, Ma J, Li NP, Gong GZ, Cheng D. Comparison of the antiviral effects of entecavir and adefovir dipivoxil in chronic HBV infection: a randomized control trial, Acta Gastroenterol Belg., 2012, 75, 316-21), no. Enterovirus (Tan CW, Chan YF. Enterovirus 71 receptors: promising drug targets ?, Expert Rev Anti Infect Ther. 2013, 11, 547-9) and others. The mechanism of action of diazoniadispiroalkanes was studied using the derivative 3,12-diaz-6 as an example. 9-diazoniadispiro [5.2.5.2] hexadecane. It was proved that it is associated with the specific property of the compound to bind to heparan sulfate glucoconjugates, which leads to the inability to attach the virus to the host cell, the inability to continue its life cycle and ultimately decrease the titer of the virus. It has been shown that the addition of diazoniadispiroalkane is antagonized by heparin. The target for diazoniadispiroalkanes are two sulfate groups located in adjacent saccharide residues, for example, for GlcA2S-GlcNS3S, GlcA2S-GlcNS3S, IdoA2S-GlcNAc6S, IdoA2S-GlcNH23SS6S, IdoA3S and IIOAS sulfate groups and positively charged nitrogen atoms of diazoniadispiroalkanes. It was also shown that a similar kind of interaction can occur with the carboxyl group of the octasaccharide ΔUA-GlcNSIdoUA2S-GlcNAc-UA2S-GlcNS-IdoUA2S-GlcNH23S, which is one of the key sites of heparan sulfate glucoconjugates for the penetration of viruses into the host cell of O. R , Dahse N.-M., Stelzner A., Makarov V., Synthesis, Cytotoxicity and Antiviral Activity of N, N'-bis-5-nitropyrimidyl Derivatives of Dispirotripipeiperazine, Antiviral Research, 2002, 55, 117-127; Schmidtke, M., Wutzler, P., Makarov, V. Novel opportunities to study and block interactions between viruses and cell surface heparan sulfates, Lett. Drug Design Discov., 2004, 1, 35-44; Artemenko, AG, Muratov, EN, Kuz'min, VE, Kovdienko, NA, Hromov, AI, Makarov, VA, Riabova, OB, Wut zler, P., Schmidtke, M.,. Identification of individual structural fragments of N, N ’- (bis-5-nitropyrimidyl) dispirotripiperazine derivatives for cytotoxicity and antiherpetic activity allows the prediction of new highly active compounds. Journal of Antimicrobial Chemotherapy, 2007, 60, 68-77; Paeschke R., Woskobojnik I., Makarov V., Schmidtke M., Bogner E. DSTP-27 prevents entry of human cytomegalovirus. Antimicrob Agents Chemother. 2014, 58, 1963-1971). Medicines using this mechanism of action currently do not exist in the world.

The objective of the present invention is to find new pharmacologically active compounds against viral infections, including strains resistant to currently existing drugs, which would have low toxicity and would not cause side effects against warm-blooded living organisms, and according to the mechanism of action, they would affect the process of invasion of the virus into the host cell by blocking the heparan sulfate receptors of the target cell.

This problem was solved by the synthesis of pyrimidyl-di derivatives (diazadispiroalkanes), which include a central pyrimidine fragment associated with two diazadispiroalkane residues corresponding to the general structural formula I.

Where

X = Y = CH ₂ or X = CH ₂ , Y = CH ₂ CH ₂ or X = CH ₂ CH ₂ , Y = CH ₂ ;

A means pyrimidine-4,6-diyl or pyrimidine-2,4-diyl, which may have H, NO ₂ , CHO, OH, OAlk, halogen atom, NHAlk, NAlk _{2 as} substituents; where Alk means a linear or branched substituent having from 1 to 4 carbon atoms;

Hal means a halogen atom.

Preferred are the compounds of General formula (I), where

X = Y = CH ₂ or X = CH ₂ , Y = CH ₂ CH ₂ or X = CH ₂ CH ₂ , Y = CH ₂ ;

And means pyrimidine-4,6-diyl or pyrimidine-2,4-diyl, which has a substituent atom Cl, Br, CH ₃ , HE;

Hal means a halogen atom, chlorine or bromine.

Examples of such compounds are

the compound according to formula (I) where X = CH ₂ CH ₂ , Y = CH ₂ ; A = pyrimidin-4,6-diyl, which may have H, NO ₂ , Alk group as substituents; Hal = chlorine or bromine and Alk = methyl,

or a compound according to formula (I) where X = CH ₂ , Y = CH ₂ CH ₂ , A = pyrimidin-4,6-diyl, which may have H, NO ₂ , Alk as substituents; Hal = chlorine or bromine and Alk = methyl.

Compounds 3.3 '- (5-nitropyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane tetrachloride and and 3.3' - (2-methyl-5 -nitropyrimidine-4,6-diyl) bis-3,12-diaza-6,9-diazoniadispiro [5.2.5.2] - hexadecane tetrachloride obtained by us earlier and their insignificant antiherpetic activity is described (Schmidtke M., Riabova O., Dahse H .-M., Stelzner A., Makarov V., Synthesis, Cytotoxicity and Antiviral Activity of N, N'-bis-5-nitropyrimidyl Derivatives of Dispirotripiperazine, Antiviral Research, 2002, 55, 117-127; Artemenko AG, Muratov EN , Kuz'min VE, Kovdienko NA, Hromov AI, Makarov VA, Riabova OB, Wutzler P., Schmidtke M.,. Identification of individual structural fragments of N, N '- (bis-5-nitropyrimidyl) dispirotripiperazine derivatives for cytotoxicity and antiherpetic activity allows the prediction of new highly active compounds. Journal of Antimicrobial Chemotherapy, 2007, 60 (1), pp. 68-77).

The invention also relates to pharmaceutically acceptable acid salts of these compounds.

Compounds can be obtained and used in crystalline form.

The synthesized compounds of the general formula I and their pharmaceutically acceptable acid or base addition salts have been investigated for pathogenic viruses and can be used to obtain drugs based on them for the treatment or prevention of viral diseases, for example, caused by human immunodeficiency virus, cytomegalovirus, hepatitis virus C or B, herpes viruses of types 1 and 2, papillomatosis.

The term “pharmaceutically acceptable salts of a compound of formula (I)” means any salts of an inorganic or organic acid or base that possess the necessary pharmacological activity of the parent compound. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds of formula (I) or prepared specially.

Pharmaceutically acid addition salts are characterized in that they contain therapeutically active non-toxic acid salt addition forms which are capable of forming compounds of Formula I. These acid addition salts can be prepared by treating the compound as bases represented by general Formula I with suitable acids, for example, inorganic acids : hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric or phosphoric acid one; organic acids, for example: acetic acid, hydroxyacetic acid, protionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, maleic or fumaric acid, malic, tartaric or citric acid.

The invention also relates to the use of compounds of the general formula I and their pharmaceutically acceptable acid addition salts, possibly in crystalline form or a pharmaceutical composition based thereon for the preparation of drugs for the prevention and treatment of viral infections.

A subject of the invention is also a method for preventing or treating a viral infection, comprising administering or applying to a subject a compound of formula I, a pharmaceutically acceptable acid addition salt or pharmaceutical compositions based thereon in an effective amount. A method of treatment using the compounds of the invention, pharmaceutical compositions or drugs based on them is also effective against strains resistant to currently existing drugs.

In vitro experiments showed a high activity of representatives of pyrimidyl di (diazadispiroalkanes) against a group of strains of herpes viruses of types 1 and 2, papillomatosis, hepatitis C, cytomegalovirus.

The following are examples of the preparation of compounds of the invention.

A. Derivatives of 3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane dichloride

The synthesis of the starting 3,12-diaz-6,9-diazoniadispiro [5.2.5.2] hexadecane dichloride was carried out according to the scheme below.

To a solution of 15.2 g (0.133 mol) of 1-formylpiperazine 3 in 267 ml of chloroform was added 12.26 g (0.146 mol) of sodium bicarbonate. The mixture was cooled with water to 10 ° C and a solution of 17 ml (0.146 mol) of benzoyl chloride in 27 ml of chloroform was added dropwise over 0.5 h. Stirred at room temperature for 16 hours (leave overnight). Then the reaction mixture is washed with water 2 times in 150 ml each, the organic layer is dried over sodium sulfate with stirring for 0.5 h. Chloroform is evaporated, 200 ml of hexane are added to the residue, stirred while cooling to 4 ° C, the hexane is decanted. The operation is repeated again. After adding a third portion of hexane, the mixture was stirred for 0.5 h. The precipitate formed was filtered off, washed with 20 ml of hexane and 20 ml of ether. Dried in the air. 22.4 g (77%) of 4-benzoylpiperazine-1-carbaldehyde are obtained, m.p. 87 ° C.

10.9 g (0.05 mol) of 4-benzoylpiperazine-1-carbaldehyde are dissolved in 60 ml of a mixture of MeOH and conc. HCl (ratio of HCl and MeOH 1:11) and stirred at room temperature for 24 hours. The precipitate was filtered off, washed with 2 × 5 ml of methanol and 2 × 10 ml of acetone. It is dried in an oven at 90 ° C. for 4 hours. 7.55 g (63%) of 1-benzoylpiperazine hydrochloride are obtained, mp. 315 ° C.

To a solution of 5.34 g (0.0954 mol) of KOH in 55 ml of ethanol was added 18 g (0.0795 mol) of benzoyl piperazine hydrochloride and stirred for 0.5 h at 20-22 ° C. Then, 13.3 ml (0.199 mol) of ethylene chlorohydrin was added and a solution of 11.6 g (0.207 mol) of KOH in 98 ml of ethanol (rectified) was added dropwise over 1 h, preventing the temperature increase in the mass above 20 ° C. After 20 hours, the resulting KCl is filtered off, washed with 25 ml of abs. ethanol. The filtrate was cooled to 10 ° C and 58 ml of 12% HCl / EtOH were slowly added (pH control 2-3), stirred for 1 h at 5 ° C, then left in the refrigerator overnight. The precipitate is filtered off, washed with 2 × 10 ml of absolute ethanol, dried either in air for 2 days, or in an oven at 50-55 ° C for 4-5 hours. 15.6 g (73%) of 1-benzoyl-4- hydrochloride are obtained ( β-hydroxyethyl) piperazine, mp 215 ° C.

To a suspension of 13.5 g (0.05 mol) of 1-benzoyl-4- (β-hydroxyethyl) piperazine hydrochloride in 96 ml of chloroform, 8 ml of SOCl _{2 are} added dropwise with stirring for 0.5 h, while the temperature of the reaction mixture is raised to 45 ° C by heating in oil bathhouse. It is kept at this temperature for 0.5 h, then heated to 55 ° C, kept for 0.5 h, then heated to 70 ° C and stirred for 3 hours. After this, the reaction mass is cooled to 20 ° C and left in the refrigerator for 16 hours. The precipitate is filtered off, washed 2 × 30 ml of chloroform and dried for 3 hours at 40-45 ° C in an oven. 11.7 g (81%) of 1-benzoyl-4- (β-chloroethyl) piperazine hydrochloride are obtained, m.p. 230 ° C.

To a suspension of 7.35 g (0.0254 mol) of 1-benzoyl-4- (β-chloroethyl) piperazine hydrochloride in 15 ml of ethanol (rectified), a solution of 1.12 g (0.028 mol) of NaOH in 19 ml of 96% ethanol is added and stirred at 20-25 ° C 1.5 h. Then NaCl is filtered off, washed with 2 × 5 ml of abs. ethanol. The filtrate is boiled with stirring for 1 h, and then evaporated on a rotary evaporator at 80 ° C in a bath to dryness. The residue was heated at 120 ° C for 16 hours. It was cooled, 15 ml of distilled water was added and stirred at boiling until complete dissolution. 0.7 g of activated carbon is added to the solution, boiled for 10 minutes. The coal is filtered off and washed with 2 × 5 ml of hot water. The mother liquor is cooled and left for 16 hours in the refrigerator. The precipitate formed is filtered off, washed with water (2 × 5 ml) and alcohol (2 × 5 ml). Dry for 2 hours at 100 ° C. Obtain 3.1 g (45%) of dichloride N, Nенз-dibenzoyl-N ’, Nʺ-dispirotripiperazinium in the form of a dihydrate, mp> 360 ° C (s. Decomp.).

A mixture of 3.1 g (0.0057 mol) of N, Nʺ-dibenzoyl-N 'dichloride, Nʺ-dispirotripiperazinium in the form of a dihydrate and 20 ml of 10% hydrochloric acid obtained by mixing 7 ml of concentrated hydrochloric acid and 13 ml of distilled water is boiled with stirring for 4 hours. The reaction mixture is cooled in an ice bath to 10-15 ° C, the precipitated benzoic acid is filtered off and washed with water. The filtrate was evaporated to dryness on a rotary evaporator. The solid residue is stirred with 10 ml of methanol, the precipitate is filtered off and washed with 5 ml of methanol. Dry for 2 hours at 100 ° C. 1.9 g (82%) of N ’, Nʺ-dispirotripiperazinium dihydrochloride dihydrate are obtained, mp> 330 ° C (decomp.).

To a solution of 1.9 g (0.0047 mol) of N ’, Nʺ-dispirotripiperazinium dihydrochloride dihydrate dichloride in 3.2 ml of water, 0.26 g (0.0108 mol) of LiOH are added in small portions with stirring and 20 ° C (pH 9). Then 0.17 g of activated carbon is added, stirred for 0.5 h, the carbon is filtered off and washed with 2 × 1 ml of water. The mother liquor is diluted with 30 ml of methanol and left for 16 hours at 5 ° C in the refrigerator. The precipitate formed is filtered off and washed on the filter with 5 ml of methanol. It is dried at 100 ° C for 2 hours. 1.1 g (79%) of 3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane dichloride are obtained, m.p. 350 ° C (decomp.)

Example 1

3,3 '- (5-Formylpyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazoniadi-spiro [5.2.5.2] hexadecane tetrachloride (Compound 1)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane dichloride (0.001 mol) in 3 ml of water was added a solution of 4,6-dichloro-5-formyl pyrimidine (0.0005 mol) in 4 ml of ethyl alcohol. The solution was boiled under stirring for 2 hours. Triethylamine (0.002 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. The solution was evaporated to dryness, 35 ml of methanol was added. The precipitate was filtered off, washed with methanol, acetone. Received 0.17 g of product. Dried at 100 ° C for 20 hours.

Yield: 46%. Yellow crystalline substance.

ESI-MS / MS - 663

Elemental analysis of C ₂₉ H ₅₂ Cl ₄ N ₁₀ O:

Calc: C, 49.86; H, 7.50; N, May 20

Found: C, 49.36; H, 7.84; N, 20.33

Example 2

3,3 '- (2-Phenyl-5-formylpyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane tetrachloride (Compound 2)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane dichloride (0.001 mol) in 2 ml of water was added a solution of 4,6-dichloro-2-phenyl-5-formyl-pyrimidine (0.0005 mol) in 6 ml of dioxane. The reaction mixture was boiled under stirring for 3.5 hours. Gradually, a new precipitate formed from the solution. Triethylamine (0.002 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. Added 20 ml of methanol, the precipitate was filtered off, washed with ethanol, acetone. Received 0.29 g of product. Dried at 100 ° C for 20 hours.

Yield: 37%. White crystalline substance.

ESI-MS / MS - 737.

Elemental analysis of C ₃₅ H ₅₆ Cl ₄ N ₁₀ O:

Calc: C, 54.26; H, 7.29; N, 18.08

Found: C, 53.57; H, 7.26; N, July 18

Example 3

3,3 '- (5-Formyl-6-hydroxypyrimidin-2,4-diyl) bis-3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane tetrachloride (Compound 3)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane dichloride (0.001 mol) in 2 ml of water was added a solution of 2-methylsulfanyl-5-formyl-4,6-dichloropyrimidine (0.0005 mol) in 7 ml dioxane. The solution was boiled with stirring for 4 hours. Oil was precipitated from the reaction mixture. Triethylamine (0.002 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. The solution was decanted, 20 ml of methanol and 5 ml of acetone were added to the remaining oil, the precipitate was filtered off, washed with methanol, tetrahydrofuran, acetone. Received 0.12 g of product. Dried at 100 ° C for 20 hours.

Yield: 17%. White crystalline substance.

ESI-MS / MS - 677.

Elemental analysis of C ₂₉ H ₅₂ Cl ₄ N ₁₀ O ₂ :

Calc: C, 48.74; H, 7.33; N, 19.60

Found: C, 49.07; H, 7.37; N, 19.62

B. Derivatives of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptodecane dibromide

The synthesis of the starting 3,12-diaz-6,9-diazoniadispiro [5.2.5.2] heptodecane dibromide was carried out according to the scheme below similar to the synthesis of 3,12-diaz-6,9-diazoniadispiro [5.2.5.2] hexadecane dichloride above.

1-Formylpiperazine 1 (0.1 mol) was dissolved in chloroform (200 ml) and sodium bicarbonate (0.11 mol) was added to the resulting solution, and a solution of benzoyl chloride (0.11 mol) in 20 ml of chloroform was slowly added dropwise. It is stirred at room temperature for 16 hours. Then it is extracted with water 2 times in 100 ml, dried over sodium sulfate. Chloroform was evaporated, hexane was added and cooled at 4 ° C. The precipitate formed is filtered off and washed with ether. The yield of 4-benzoylpiperazin-1-carbaldehyde is 71%.

4-Benzoylpiperazine-1-carbaldehyde 2 (0.005 mol) is dissolved in 10 ml of a solution prepared from 5.5 ml of concentrated hydrochloric acid and 60 ml of methanol and stirred at room temperature for 24 hours. The precipitate formed is filtered off and washed with methanol 3 times. The yield of 1-benzoyl piperazine hydrochloride is 60%.

1-Benzoyl piperazine hydrochloride 3 (0.014 mol) is suspended in 5 ml of ethanol and a solution of NaOH (0.017 mol) in 15 ml of ethanol is added. Stirred for 1 h. NaCl was filtered off, the mother liquor was evaporated, chloroform was added, NaCl was filtered off again and chloroform was evaporated. 1-benzoyl piperazine is obtained in the form of an oil, yield 95%.

A mixture of 1-benzoyl piperazine (0.035 mol) 4, 1,3-dibromopropane (0.0175 mol) and sodium bicarbonate (0.056 mol) is boiled in 60 ml of ethanol for 16 hours. The hot reaction mixture is filtered off with NaBr, evaporated to dryness, added chloroform, filtered off NaBr, again evaporated to dryness. Obtain 1,1'-propan-1,3-diylbis (4-benzoylpiperazine) as an oil, yield 60%.

A mixture of 1,1'-propane-1,3-diylbis (4-benzoylpiperazine) (0.005 mol) and 1,2-dibromoethane (0.05 mol) is heated at 110 ° C for 6 hours. Cool, the precipitate is filtered off, washed with ether. The yield of 3,12-dibenzoyl-3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide 69%.

3,12-Dibenzoyl-3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide (0.005 mol) is boiled with 18 ml of 10% hydrobromic acid for 4 hours. It is cooled, the benzoic acid is filtered off, the mother liquor is evaporated to a thick suspension. 40 ml of methanol and 10 ml of acetone are added, the precipitate formed is filtered off, washed with acetone. The yield of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide dibromohydrate is 70%.

3,12-Diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide dibromohydrate 7 (0.003 mol) is treated with a solution of LiOH (0.006 mol) in 3 ml of water. Then activated carbon is added, stirred for 20 minutes, the carbon is filtered off, 25 10 ml of acetone and 20 ml of methanol are added to the mother liquor. The precipitate formed is filtered off, washed with acetone. The yield of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide 88%. _Mp = 258 ° -262 ° C

Example 4

3.3 '- (5-nitropyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazonadi-spiro [5.2.5.3] heptadecane tetrabromide (Compound 4)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide (0.00075 mol) in 2 ml of water was added a solution of 4,6-dichloro-5-nitropyrimidine (0.000375 mol) in 4 ml of ethyl alcohol. The reaction mixture was boiled under stirring for 3 hours. Triethylamine (0.0015 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. 25 ml of methanol was added. Wiped, the precipitate was filtered off, washed with methanol, tetrahydrofuran, acetone. 0.13 g of product was obtained. Dried at 100 ° C for 20 hours.

Yield: 37%. Yellow crystalline substance.

ESI-MS / MS - 838.

Elemental analysis of C ₃₀ H ₅₅ Br ₄ N ₁₁ O ₂ :

Calc .: C, 39.10; H, 6.02; N, 18.91

Found: C, 39.08; H, 6.40; N, 18.91

Example 5

3.3 '- (2-methyl-5-nitropyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazonia-disiro [5.2.5.3] heptadecane tetrabromide (Compound 5)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide (0.001 mol) in 3 ml of water was added a solution of 2-methyl-4,6-dichloro-5-nitropyrimidine (0.0005 mol) in 4 ml ethyl alcohol. The reaction mixture was boiled with stirring for 3 hours. Gradually, oil fell out of the reaction mixture. Triethylamine (0.002 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. 30 ml of methanol was added. The solution was rubbed, the solution was decanted, 15 ml of methanol and 5 ml of acetone were added to the remaining oil, the precipitate was filtered off, washed with methanol, tetrahydrofuran, acetone. 0.36 g of product is obtained. Dried at 100 ° C for 20 hours.

Yield: 77%. Yellow crystalline substance.

ESI-MS / MS - 856.

Elemental analysis of C ₃₁ H ₅₇ Br ₄ N ₁₁ O ₂ :

Calc: C, 39.10; H, 6.14; N, 16.50

Found: C, 39.23; H, 6.19; N, 16.35

Example 6

3.3 '- (5-Formylpyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazonadi-spiro [5.2.5.3] heptadecane tetrabromide (Compound 6)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide (0.001 mol) in 3 ml of water was added a solution of 5-formyl-4,6-dichloropyrimidine (0.0005 mol) in 4 ml of ethyl alcohol. The solution was boiled under stirring for 2 hours. Triethylamine (0.002 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. The solution was evaporated to dryness, 30 ml of methanol was added. The precipitate was filtered off, washed with methanol, acetone. Received 0.23 g of product. Dried at 100 ° C for 20 hours.

Yield: 51%. Yellow crystalline substance.

ESI-MS / MS - 821

Elemental analysis of C ₃₁ H ₅₆ Br ₄ N ₁₀ O:

Calc: C, 41.17; H, 6.24; N, 15.49

Found: C, 41.69; H, 6.26; N, 15.37

Example 7

3,3 '- (6-Hydroxy-5-formylpyrimidin-2,4-diyl) bis-3,12-diaza-6,9-diazo-niadispiro [5.2.5.3] heptadecane tetrabromide (Compound 7)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide (0.00075 mol) in 2 ml of water was added a solution of 2-methylsulfanyl-5-formyl-4,6-dichloro-pyrimidine (0.000375 mol) in 6 ml of dioxane. The solution was boiled with stirring for 4.5 hours. Oil precipitated from the reaction mixture. Triethylamine (0.0015 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. The solution was decanted, 15 ml of methanol and 5 ml of acetone were added to the remaining oil, the precipitate was filtered off, washed with methanol, tetrahydrofuran, acetone. 0.16 g of product was obtained. Dried at 100 ° C for 20 hours.

Yield: 23%. White crystalline substance.

ESI-MS / MS - 835

Elemental analysis of C ₃₁ H ₅₆ Br ₄ N ₁₀ O ₂ :

Calc: C, 41.69; H, 6.29; N, 15.17

Found: C, 40.95; H, 6.13; N, 15.22

Example 8

3,3 '- (2-Phenyl-5-formylpyrimidin-2,4-diyl) bis-3,12-diaza-6,9-diazonia-disiro [5.2.5.3] heptadecane tetrabromide (Compound 8)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide (0.00075 mol) in 2 ml of water was added a solution of 2-phenyl-5-formyl-4,6-dichloropyrimidine (0.000375 mol) in 6 ml dioxane. The solution was boiled under stirring for 3 hours. Oil precipitated from the reaction mixture. Triethylamine (0.0015 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. The solution was decanted, 15 ml of methanol and 5 ml of acetone were added to the remaining oil, the precipitate was filtered off, washed with methanol, tetrahydrofuran, acetone. 0.15 g of product was obtained. Dried at 100 ° C for 20 hours.

Yield: 40%. Yellow crystalline substance.

ESI-MS / MS - 897.

Elemental analysis of C ₃₇ H ₆₀ Br ₄ N ₁₀ O:

Calc: C, 45.32; H, 6.17; N, 14.28

Found: C, 45.29; H, 6.67; N, 15.27

Example 9

3,3 '- (2-Chloropyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazonadi-spiro [5.2.5.3] heptadecane tetrabromide (Compound 9)

To a solution of 3,12-diaza-6,9-diazoniadispiro [5.2.5.3] heptadecane dibromide (0.0005 mol) in 2 ml of water was added a solution of 5-nitro-2,4,6-trichloropyrimidine (0.00025 mol) in 4 ml of methyl alcohol . The solution was boiled under stirring for 3 hours. Triethylamine (0.001 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. 25 ml of methanol was added. Wiped, the precipitate was filtered off, washed with methanol, tetrahydrofuran, acetone. Received 0.07 g of product. Dried at 100 ° C for 20 hours.

Yield: 30%. Light yellow crystalline substance

ESI-MS / MS - 875.

Elemental analysis of C ₃₀ H ₅₄ Br ₄ ClN ₁₁ O ₂ :

Calc: C, 37.69; H, 5.69; N, 16.12

Found: C, 37.58; H, 5.62; N, 16.17

B. Derivatives of 3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide

The synthesis of the starting 3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide was carried out according to the scheme below.

To homopiperazine in an amount of 5.37 g (0.0537 mol), 25 ml of glacial acetic acid are added while cooling with ice water, while the temperature rises to 40-50 ° C. After the temperature drops to 20 ° C, the cooling is removed. The suspension is stirred until complete dissolution of homopiperazine (~ 2 hours). Then the solution is cooled to 5 ° C (ice bath) and 6.27 ml (0.0537 mol) of benzoyl chloride are added dropwise slowly (45 min) at such a rate that the temperature in the mass does not exceed 10 ° C. The solution was then stirred at room temperature for 3 hours. Acetic acid was distilled off on a rotary evaporator at 80 ° C. The distillation volume is approximately 15-16 ml, which corresponds to 2/3 of the volume of acetic acid taken into the reaction. To the residue, which is a thick oil, add 50 ml of water, cool in an ice bath to 15 ° C and, with stirring, make alkaline with a 40% NaOH solution (10 ml) to a pH of 8-8.5. The precipitated by-product of 1,4-dibenzoyldiazepine is filtered off and the mother liquor is extracted with 3 × 40 ml of chloroform. Check the pH of the aqueous layer. At pH <7, it is again alkalinized to pH 8-8.5 and extracted with chloroform 2 × 40 ml. The combined chloroform extracts are dried over Na ₂ SO ₄ . Chloroform was evaporated to give 7.13 g (65%) of 1-benzoyl-1,4-diazepine as an oil.

A mixture of 7.13 g (0.035 mol) of 1-benzoyl-1,4-diazepine, 60 ml of ethanol, 1.51 ml (0.0175 mol) of 1,2-dibromoethane and 4.7 g (0.056 mol) of sodium bicarbonate was stirred at reflux for 16 hours. the mass is cooled, the inorganic precipitate is filtered off, washed with 10 ml of alcohol. The mother liquor is evaporated to dryness, 100 ml of water are added and extracted with 3 × 70 ml of chloroform. Dried over Na ₂ SO ₄ with stirring for 0.5 hours. Chloroform was evaporated to dryness. 8 g (100%) of 1,1'-ethane-1,2-diylbis (4-benzoyl-1,4-diazepine) are obtained in the form of an oil.

A mixture of 8 g (0.0183 mol) of 1,1'-ethane-1,2-diylbis (4-benzoyl-1,4-diazepine) and 16 ml of 1,2-dibromoethane was stirred and heated at 120 ° C for 4 hours. The thick paste is cooled to 20 ° C, 50 ml of ether are added, stirred, the precipitate is filtered off, washed with 2 × 10 ml of ether. Then the paste on the filter is washed with stirring 3 × 50 ml of chloroform and 2 × 10 ml of ether. The paste is dried in air for 16 hours. 7.2 g (63.4%) of 3,13-dibenzoyl-3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide are obtained, mp ~ 320 ° C .

A mixture of 15.5 g (0.025 mol) of 3,13-dibenzoyl-3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide and 100 ml of 10% hydrobromic acid is stirred at reflux for 4 hours. Cool, the precipitated benzoic acid is filtered off. and washed with water. 1.5 g of activated carbon is added to the mother liquor, stirred for 20 minutes, filtered. The clarified solution is evaporated to dryness on a rotary evaporator. 210 ml of methanol and 60 ml of acetone are added to the residue. Stirred for 0.5 hours. The precipitate was filtered off, washed with acetone 2 × 50 ml. Dried in an oven at 100 ° C. 12.66 g (88%) of dihydrobromide 3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide are obtained, m.p. 310-315 ° C.

To a solution of 12.66 g (0.022 mol) of 3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecandibromide dihydrobromide in 22 ml of water was added 1.06 g (0.044 mol) of LiOH with stirring and 20 ° C (pH 10). Then 1.3 g of activated carbon is added, stirred for 20 minutes, the carbon is filtered off and washed with 3 ml of water. The mother liquor is diluted with 145 ml of acetone and 75 ml of methanol. The precipitated curd cake is filtered off under low vacuum and washed on the filter with stirring 2 × 30 ml of acetone and 1 more time without stirring. Dried in the air. Obtain 6.4 g (70%) of 3.13-Diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide, so pl. 280 ° C.

Example 10

3.3 '- (5-Nitropyrimidin-4,6-diyl) bis-3,13-diaza-7,10-diazonadi-spiro [6.2.6.2] octadecane tetrobromide (Compound 10)

To a solution of 3,13-diaz-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide (0.00072 mol) in 2 ml of water was added a solution of 5-nitro-4,6-dichloronitropyrimidine (0.00036 mol) in 5 ml of ethyl alcohol. The reaction mixture was boiled with stirring for 4 hours. Triethylamine (0.0014 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. 25 ml of methanol was added. Wiped, the precipitate was filtered off, washed with methanol, tetrahydrofuran, acetone. 0.1 g of product was obtained. Dried at 100 ° C for 20 hours.

Yield: 69%. Yellow crystalline substance.

ESI-MS / MS - 870.

Elemental analysis of C ₃₂ H ₅₉ Br ₄ N ₁₁ O ₂ :

Calc: C, 40.48; H, 6.26; N, 16.23

Found: C, 41.19; H, 6.28; N, 16.84

Example 11

3.3 '- (2-Methyl-5-nitropyrimidin-4,6-diyl) bis-3,13-diaza-7,10-diazonia-disiro [6.2.6.2] octadecane tetrabromide (Compound 11)

To a solution of 3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide (0.00072 mol) in 3 ml of water was added a solution of 2-methyl-5-nitro-4,6-dichloronitropyrimidine (0.00036 mol) in 4 ml ethyl alcohol. The reaction mixture was boiled under stirring for 3.5 hours. Gradually, oil precipitated from the reaction mixture. Triethylamine (0.0014 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. 30 ml of methanol was added. Rubbed, the precipitate was filtered off, washed with methanol, acetone. 0.13 g of product was obtained. Dried at 100 ° C for 20 hours.

Yield: 37%). Yellow crystalline substance.

ESI-MS / MS - 880.

Elemental analysis of C ₃₃ H ₆₁ Br ₄ N ₁₁ O ₂ :

Calc: C, 41.44; H, 6.58; N, 15.99

Found: C, 40.52; H, 6.52; N, 16.08

Example 12

3.3 '- (5-Formylpyrimidin-4,6-diyl) bis-3,13-diaza-7,10-diazonium-disiro [6.2.6.2] octadecane tetrabromide (Compound 12)

To a solution of 3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide (0.00072 mol) in 2 ml of water was added a solution of 2-formyl-4,6-dichloropyrimidine (0.00036 mol) in 4 ml of ethyl alcohol. The solution was boiled with stirring for 2 hours. Triethylamine (0.0014 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. The solution was evaporated to dryness, 20 ml of methanol was added. The precipitate was filtered off, washed with methanol, acetone. Received 0.27 g of product. Dried at 100 ° C for 20 hours.

Yield: 40%. Beige crystalline substance.

ESI-MS / MS - 853.

Elemental analysis of C ₃₃ H ₆₀ Br ₄ N ₁₀ O:

Calc: C, 42.50; H, 6.46; N, 15.02

Found: C, 42.67; H, 6.43; N, 15.04

Example 13

3,3 '- (2-phenyl-5-formylpyrimidin-4,6-diyl) bis-3,13-diaza-7,10-diazo-niadispiro [6.2.6.2] octadecane tetrabromide (Compound 13).

To a solution of 3,13-diaza-7,10-diazoniadispiro [6.2.6.2] octadecane dibromide (0.00048 mol) in 1 ml of water was added a solution of 2-phenyl-5-formyl-4,6-dichloropyrimidine (0.00024 mol) in 5 ml dioxane. The reaction mixture was boiled with stirring for 4 hours. Gradually, oil precipitated from the solution. Triethylamine (0.00096 mol) was added. After 20 minutes, the heating was turned off. Cooled to room temperature. Evaporated to dryness. Added 20 ml of methanol, the precipitate was filtered off, washed with ethanol, acetone. Received 0.03 g of product. Dried at 100 ° C for 20 hours. Yield: 6%. Beige crystalline substance.

ESI-MS / MS - 929.

Elemental analysis of C ₃₉ H ₆₄ Br ₄ N ₁₁ O:

Calc: C, 46.44; H, 6.40; N, 13.89

Found: C, 46.48; H, 6.24; N, 13.32

Description of the cytotoxicity and antiviral activity of the compounds of the invention.

A study of the cytotoxicity of synthesized compounds of dispirotripiperazinium derivatives against GMK cells

2 × 10 ⁴ GMK cells were seeded into a well of 96-well flat-bottom microtiter plates (Falcon 3075). The cytotoxicity of the studied compositions was determined by the confluent monolayers of GMK cells formed in 60 wells (5% CO ₂ , 37 ° C). After extraction from the culture medium in nine twice diluted compositions, 100 L of culture medium was added and incubated for 72 hours at 37 ° C. in an atmosphere of 5% CO ₂ . Six-well cells without treatment were used for control. The Dynex immunoassay system (DIAS, Guernsey, UK), developed for the automated ELISA method, was used to carefully clean, stain, measure and evaluate the viability of cell monolayers in a cytotoxic preparation, as well as in an antiviral study. Staining to assess the cytotoxic activity of TNF-α was performed using crystalline violet, as described by Nain et al. (1990). First, the supernatant was aspirated and the cell monolayers were washed three times with 300 L of physiological saline solution to remove dead cells. Then the cells were fixed and washed once for 10 minutes using 50 l of a 0.03% solution of crystalline violet (w / v) in 20% methanol. After six subsequent washes with 100 L of water, the monolayers were treated with 100 L of lysis buffer (a solution of 0.8979 g of sodium citrate and 1.25 ml of 1 N HCl in 98.05 ml of 47.5% ethanol) for 20 minutes to elute crystalline purple. Next, the optical density of individual wells at 540/630 nm was determined spectrophotometrically and analyzed using DIAS. Cell viability was determined as a percentage of the average optical density according to the results of measuring six wells, which was taken as 100%. A cytotoxic concentration that reduces cell viability by 50% (CC ₅₀ ) was calculated from the dose-response curve from the average of two parallel samples in three studies.

The study of the antiviral activity of the synthesized compounds of pyrimidyl-di derivatives (diazadispiroalkanes) of the formula (I)

The study of antiviral activity was carried out according to the method described previously (M. Schmidtke, U. Schnittler, B. Jahn, N.-M. Dahse, A. Stelzner, A rapid assay for evaluation of antiviral activity against coxsackie virus B3, influenza virus A , and herpes simplex virus type 1, Journal of Virological Methods 95 (2001) 133-143). After extracting cells from the growth solution, confluent monolayers of cells formed in 6-well plates (FALCON 3046) were seeded with 1 ml of a suspension of the corresponding virus in nutrient medium on GMK cells containing approximately 100 plaque-forming units (PFU) in the absence and presence of cells during two days twice diluted test compositions. After adsorption for 1 hour at 37 ° C, the seed was aspirated and mixed with 2 ml of the appropriate growth solution containing 0.4% agar and with the appropriate concentration of the drug. Three untreated control samples of viruses and one uninfected untreated control cell were also examined. Component concentrations were determined by duplicate measurements. Samples were incubated at 37 ° C for 72 hours until platelets were detected, then fixed and washed with a solution of 0.4% crystal violet in a mixture of formalin (3% v / v) and ethanol (1.67% v / v) in water . The platelet count was calculated by means of a negatoscope after extraction from the agar application. The dependence of the average platelet count in two compared treated wells at each concentration on the platelet count in three untreated virus infected wells was plotted. The concentration at which the platelet count decreases by 50% (IC ₅₀ ) was calculated from the dose-response curve from the lowest values of the three platelet reduction trials.

The results of the activity of the compounds against herpes virus are shown in table 1. The study of antiherpetic activity (HSV-1) showed that most of the studied compounds of formula (I) have high antiviral activity.

Derivatives of pyrimidyl di (diazadispiroalkanes) of the formula (I) have been shown to be highly active against the human immunodeficiency virus, while, as expected, all compounds are equally active in sensitive and resistant strains. The activity of the compounds against the respiratory syncytic virus is also shown. The results are shown in table 2, where:

EC50 - concentration of the compound, leading to 50% protection of cells from death,

CC50 - concentration leading to 50% cell death.

^a The concentration of the substance (μM) required to reduce the growth of mock-infected MT-4 cells by 50%, determined by the MTT method.

^b The concentration of the substance (μM) required to achieve 50% protection of MT-4 cells from death caused by HIV-1, as determined by the MTT method.

^c The concentration of the substance (μM) required to reduce the viability of mock-infected MDBK cells by 50%, as determined by the MTT method.

^d The concentration of the substance (μM) required to achieve 50% protection of MDBK cells from death caused by the BVDV virus, as determined by the MTT method.

^j The concentration of the substance (μM) required to reduce the viability of false infected Vero-76 cells by 50%, determined by the MTT method.

^m-p substance Concentration (.mu.M) required for 50% by preventing the formation of gaps in Vero-76 single cell layers infected CVB-5 ^(k), Sb-

The antiviral activity of pyrimidyl di (diazadispiroalkanes) of formula (I) against papillomavirus infection was tested using the Pseudovirus-based Neutralization Assay (PsV Assay) method with the HPV16-PsVs virus, which delivers a plasmid encoding Gaussia Luciferase to HeEM cells. This method is generally described in (Selinka et al., J Virol, 2007, 81 (20): 10970-80, Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus). Reading the results of the study was carried out on a luciferase 48 hpi instrument, configured to determine Relative Light Units (RLU). Based on the method described in the publication above, we treated the HeLaT cells with the HPV16-PsVs virus and directly treated them with two concentrations of pyrimidyl di (diazadispiroalkanes) of 0.5 μg / ml and 5 μg / ml. The test was carried out using 96 well plates not treated with the experimental compound (n = 4) and treated with the claimed compounds of the formula (I) cells (n = 3). Statistical analysis was performed using the Two-Way ANOVA Test. The results are shown in FIG. 1 and FIG. 2. In FIG. 1 shows the connection 3, in FIG. 2 depicts Compound 11, which were studied in a PsV experiment with HeLaT cells. Two concentrations of each compound were added simultaneously with the HPV16-PsVs virus and compared with untreated cells. Luciferase activity was measured at 48 hpi.

Both compounds tested significantly reduce luciferase activity, which characterizes PsV infection. They completely inhibit the penetration of the virus at a concentration of 5 μg / ml when the substances were added simultaneously with the virus (p <0.001). In the case of using compound 3 at a concentration of 0.5 μg / ml, the inhibition of the penetration of papilloma virus into the cell is more noticeable than for compound 11, but in any case, at a concentration of 0.5 μg / ml, both compounds significantly reduce the infection of cells with the virus compared to cells not treated with the drug (p <0.001).

Claims (26)

1. The compound corresponding to the General structural formula (I)

where X = CH ₂ , Y = CH ₂ CH ₂ or X = CH ₂ CH ₂ , Y = CH ₂ ; A means pyrimidine-4,6-diyl or pyrimidine-2,4-diyl, which may have substituents H, NO₂, CHO, OH, OAlk, halogen atom, NH (Alk), N (Alk)₂ a group; where Alk means a linear or branched substituent having from 1 to 4 carbon atoms; Hal means a halogen atom or its pharmaceutically acceptable salts. 2. The compound corresponding to the General structural formula (I)

where X = Y = CH ₂ ; And means pyrimidine-4,6-diyl or pyrimidine-2,4-diyl, which has a substituent atom Cl, Br, CH ₃ , HE; Hal means a halogen atom, chlorine or bromine, or its pharmaceutically acceptable salts. 3. The compound according to formula (I), where X = CH ₂ CH ₂ , Y = CH ₂ ; A = pyrimidin-4,6-diyl, which may have H, NO ₂ , Alk group as substituents; Hal = chlorine or bromine and Alk = methyl. 4. The compound according to formula (I), where X = CH ₂ , Y = CH ₂ CH ₂ , A = pyrimidin-4,6-diyl, which may have H, NO ₂ , Alk group as substituents; Hal = chlorine or bromine and Alk = methyl. 5. The use of compounds of formula (I) or their pharmaceutically acceptable salts

Where X = Y = CH ₂ or X = CH ₂ , Y = CH ₂ CH ₂ or X = CH ₂ CH ₂ , Y = CH ₂ ; A = pyrimidin-4,6-diyl or pyrimidin-2,4-diyl, which may have H, NO ₂ , CHO, OH, OAlk, Cl, NHAlk, NAlk _{2 as} substituents; Hal = chlorine or bromine; Alk = a linear or branched substituent having from 1 to 4 carbon atoms having antiviral activity for the prevention or treatment of diseases caused by viral infection; with the exception of compounds 3,3 '- (5-nitropyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane tetrachloride and 3.3' - (2-methyl- 5-nitropyrimidin-4,6-diyl) bis-3,12-diaza-6,9-diazoniadispiro [5.2.5.2] hexadecane tetrachloride and their pharmaceutically acceptable salts. 6. The use of compounds according to claims. 1-4 for the prevention and / or treatment of papillomavirus infection. 7. The use of compounds according to claims. 1-4 for the prevention and / or treatment of viral infection caused by the immunodeficiency virus. 8. The use of compounds according to claims. 1-4 for the prevention and / or treatment of viral infection caused by cytomegalovirus. 9. The use of compounds according to claims. 1-4 for the prevention and / or treatment of viral infection caused by hepatitis B or C. 10. The use of compounds according to claim 2, for the prevention and / or treatment of viral infection. 11. The use of compounds according to claim 5, for the prevention and / or treatment of human papillomavirus infection.

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