RU2552422C2 - Indole-3-carboxylic acid derivatives having antiviral activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and particularly to aminoalkyl esters of 5-methoxyindole-3-carboxylic acid and pharmacologically acceptable salts thereof of general formula

(I), where R1 is cyclohexyl, C_1-3alkyl; R2 is phenylthio, phenyloxy, wherein the phenyl group can have 1-2 halogen substitutes or a C_1-4alkoxy group, or R2 is a 5-6-member heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen; n equals 1, 2, 3, 4; each R is independently selected from C_1-4alkyl; except compounds indicated in the claim. The invention also relates to a method of producing a compound of formula (I) and use thereof.

EFFECT: obtaining novel 5-methoxyindole-3-carboxylic acid derivatives, having antiviral activity.

4 cl, 2 tbl, 12 ex

Description

This invention relates to the field of meeting the vital needs of a person, namely to medicines that can find application in the pharmaceutical industry and medicine. More specifically, the invention relates to a class of compounds of dialkylaminoalkyl esters of indole-3-carboxylic acid derivatives.

Viral infections, despite the significant advances in modern virology and pharmacology, continue to remain uncontrolled infections (Kiselev OI, et al. Influenza pandemic 2009/2010: antiviral therapy and treatment tactics / St. Petersburg, 2010, 97 pp.). According to medical statistics, 60-65% of epidemic infections have a viral etiology. Moreover, the list of viral infections capable of epidemic spread is steadily expanding - over the past decades, at least 30 new pathogenic viruses have been discovered that are the causative agents of diseases dangerous to humans, such as AIDS, viral hepatitis, enterocolitis, pneumonia and hemorrhagic fevers (Sloots T.R. . et al. Emerging respiratory agents: new viruses for old diseases? // J. Clin. Virol. 2008. 42 (3), 233-243; Kahn JS Newly discovered respiratory viruses: significance and implications // Curr. Opin. Pharmacol 2007, 7 (5), 478-483). Some of them, such as bird flu, according to experts, currently pose a real threat to humanity and are of particular concern (Perdue ML, Swayne DE Public health risk from avian influenza viruses // Avian Dis. 49 (3), 317- 327; Liu JP Avian influenza - a pandemic waiting to happen? J. Microbiol. Immunol. Infect. 2006, 39 (1), 4-10; Malik Peiris JS Avian influenza viruses in humans // Rev. Sci. Tech. 2009, 28 (1), 161-173).

Currently, natural and synthetic compounds are used as prophylactics and treatment of diseases caused by viruses: vaccines, interferons and inducers of interferons, antiviral chemotherapeutic drugs that inhibit the reproduction of the virus and / or have a virucidal effect.

However, for the most part, current vaccines are highly specific. In this regard, the delay in their use and the emergence of resistant strains as a result of mutations of the original virus, as well as the mismatch of the vaccine with the strains circulating during epidemics, can drastically reduce the effect of vaccination (Katsunuma T. et al. Hospitalizations associated with pandemic influenza A (H1N1) 2009 in asthmatic children in Japan // Allergol. Int. 2012. 61 (1), 75-82; Blondel B. et al. Failure of the vaccination campaign against A (H1N1) influenza in pregnant women in France: results from a national survey // Vaccine. 2012.3 (38), 5661-5665; Nachtnebel M. et al. Lessons from a one-year hospital-based surveillance of acute respiratory infections in Berlin - comparing case definitions to monitor influenza // BMC Public Health. 2012, 12, 245).

Available antiviral chemotherapeutic drugs that suppress viral reproduction, including abnormal nucleosides, inhibitors of virus-specific proteins and enzymes, unlike vaccines, are usually effective against a wide range of pathogenic viruses.

However, during their use, side effects often develop and resistant strains of the virus are also formed, which leads to relapse and exacerbation of the disease (Kozal MJ Drug-resistant human immunodeflency virus // Clin. Microbiol. Infect. 2009, 15 (1), 69-73 ; Samson M. et al. Influenza virus resistance to neuraminidase inhibitors // Antiviral. Res. 2013, 98 (2), 174-185; Wyles DL Antiviral resistance and the future landscape of hepatitis C virus infection therapy // J. Infect. Dis. 2013, 207 (1), 33-39).

Currently, the number of antiviral drugs approved for clinical use is very limited - no more than 50 (Mashkovsky M.D. Medicines: in 2 volumes, 14th ed. / M.: New Wave, 2002; Brunton L., Chabner B., Knollman B. Goodman & Gilman’s The Pharmacological Basis of Therapeutics / 12th ed. NY: McGraw Hill Professional, 2010, 1808), which cannot satisfy modern needs for the prevention and treatment of viral diseases. Moreover, there are viral infections for the treatment of which there are no specific chemotherapeutic agents, such as herpes-6 viruses, severe acute respiratory syndrome (SARS), hemorrhagic fevers, smallpox, bird flu, adenoviruses (De Clerecq E. Recent highlights in the development of new antiviral drugs // Curr. Opin. Microbiol. 2005, 8 (5), 552-560).

As a prototype, one of the most successful and widely used antiviral drugs, similar in chemical structure to the compounds claimed in the present invention, is arbidol (international name Umifenovirum (WHO Drug Information // 2001, 25 (1), 91)). Arbidol is 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole monohydrate hydrochloride (see, for example, RU 2033156). It differs in its mechanism of action from many drugs used in the treatment of viral infections, such as amantadine, remantadine, zanamivir and oseltamivir. Arbidol has a specific antiviral effect, inhibiting the fusion of the viral envelope with cell membranes, which prevents the virus from entering the cells and impairs its reproduction (Leneva IA et al. Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol // Antiviral Res. 2009, 81 (2), 132-140). In addition, arbidol enhances the overall antiviral defense, stimulating the production of interferons and increasing the activity of cellular immunity (Glushkov R.G. et al. Mechanisms of the immunomodulating action of arbidol // Vestnik RAMS, 1999, 3, 36-40). Arbidol has been shown to be effective against influenza A and B viruses, including the H1N1, H2N2, H3N2 and H5N1 subtypes, as well as to a number of ARVI pathogens - adenovirus, respiratory syncytial virus, coronavirus, including the causative agent of SARS (Boriskin YS et al. Arbolol broad-spectrum antiviral compound that blocks viral fusion // Curr. Med. Chem. 2008, 15 (10), 997-1005; Fediakina IT et al. Susceptibility of pandemic influenza virus A 2009 H1N1 and highly pathogenic avian influenza virus A H5N1 to antiinfluenza agents in cell culture // Antibiot. Khimioter. 2011, 56 (3-4), 3-9; Brooks MJ et al. Antiviral activity of arbidol, a broad-spectrum drug for use against respiratory viruses, varies according to test conditions // J. Med. Virol. 2012, 84 (1), 170-181).

Disadvantages: the therapeutic effectiveness of arbidol, like most other drugs, is largely limited. A significant clinical effect of arbidol in influenza and acute respiratory viral infections is observed only when it is used in the early stages of the disease. In addition, arbidol has a weak antiviral effect against many common pathogenic viruses (for example, against herpes and hepatitis viruses), and in the treatment of diseases caused by such pathogens (for example, herpetic infection), arbidol is used in complex therapy, mostly as immunostimulatory, and not as an antiviral agent.

The limited antiviral activity of arbidol is largely due to its physico-chemical characteristics, namely the fact that this compound is not soluble in water. The low bioavailability and poor penetration of insoluble arbidol into the tissues affected by the virus can significantly weaken its therapeutic efficacy and breadth of applicability. At a minimum, this feature of arbidol requires high doses of the drug to achieve a significant effect, which is far from always permissible and safe.

A more correct solution seems to be the synthesis of water-soluble low molecular weight compounds with antiviral activity that are close in chemical structure to arbidol. Currently, a number of water-soluble compounds are known from chemical classes close to arbidol, for which activity against certain viruses is shown: substituted 2- (5-hydroxy-2-methyl-1H-indol-3-yl) acetic acids and their esters (RU 2397975 ) having activity against influenza virus and hepatitis C virus; substituted [4 (6) -bromo-5-hydroxy-1H-indol-3-yl] acetic acids and their esters (RU 2393149) having activity against the influenza virus; 4-amino-3-arylamino-6-arylpyrazolo [3,4-d] pyrimidine derivatives (RU 2456288) having activity against picornaviruses; substituted esters of 1,2,3,7-tetrahydropyrrolo [3,2-f] [1,3] benzoxazine-5-carboxylic acids (RU 2323221) having activity against hepatitis viruses and SARS.

The technical result of the invention consists in the synthesis of new low molecular weight compounds with high antiviral activity, which can be used to create effective drugs that can expand the treatment of viral diseases.

The essence of the invention is the synthesis and use as antiviral agents against viruses of encephalomyocarditis and herpes of aminoalkyl ethers of 5-methoxyindole-3-carboxylic acid of the General formula (I)

wherein:

R1 is cyclohexyl-C _1-3 alkyl, phenyl in which the substituents are selected from halogen atoms, C _1-4 alkyl, C _1-4 alkoxy groups, nitro, cyano;

R2 is phenylthio, phenyloxy in which the phenyl group may have halogen substituents, C _1-4 alkyl, C _1-4 alkoxy, or R2 is a 5-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen which may be substituted with C _1-4 alkyl;

n is 1, 2, 3, 4;

each R is independently selected from C _1-4 alkyl, or both R, together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen.

The invention also relates to pharmaceutically acceptable salts of the compounds of formula (I), such as monohydrochlorides, dihydrochlorides, hydrobromides, dihydrobromides, mesylates, acetates, salicylates, oxalates, which can be obtained by conventional methods, for example, by treating the compound of formula (I) with an appropriate acid.

The basis for the preparation of the 5-methoxyindole-3-carboxylic acid aminoalkyl esters of the formula (I) according to the invention is the process consisting in the fact that the acid chloride of general formula (II)

in which R1 and R2 are as defined above, is reacted with an aminoalkanol of the general formula HO (CH ₂ ) _n N (R) ₂ , in which R and n are as defined above.

Scheme 1 shows a process for preparing a compound of formula (I) with the value R1 is cyclohexyl, R2 is phenylthio.

According to this scheme, other compounds of formula (I) can also be prepared with the meanings R1, R2, R and n as defined above. The following examples describe in detail but do not limit the invention.

Intermediate 6-bromo-5-hydroxy-2-methyl-1-cyclohexyl-3-ethoxycarbonylinindole (compound IV) was obtained by brominating compound (III) with bromine in an acidic medium or bromosuccinimide in an organic solvent.

Example 1. 6-Bromo-2-methyl-5-methoxy-1-cyclohexyl-3-ethoxycarbonylindole (V)

To a solution of 4.23 g (0.011 mol) of 6-bromo-5-hydroxy-2-methyl-1-cyclohexyl-3-ethoxycarbonylinindole (IV) in 22 ml of dioxane was added 22 ml of a 10% sodium hydroxide solution, then dropwise at room temperature 3 ml of dimethyl sulfate with stirring. Stirring is continued at room temperature for 1 hour. The reaction mass is poured into water, cooled, the precipitate formed is filtered off, washed with water and recrystallized from ethanol. Yield 3.88 g, T _PL 142-143 ° C (from alcohol).

Example 2. 6-Bromo-2-bromomethyl-5-methoxy-1-cyclohexyl-3-ethoxycarbonylindole (VI)

A mixture of 1.78 g (0.01 mol) of bromosuccinimide, 0.1 g of benzoyl peroxide and 3.88 g (0.01 mol) of 6-bromo-2-methyl-5-methoxy-1-cyclohexyl-3-ethoxycarbonylindole ( compound V) in 25 ml of carbon tetrachloride under lighting boil for 5 hours. After separation of the succinimide in hot form and cooling, the precipitate is filtered off. Yield 4.18 g, T _PL 173 ° C. Use in the next stage without crystallization.

Example 3. 6-Bromo-5-methoxy-2-phenylthiomethyl-1-cyclohexyl-3-ethoxycarbonylindole (VII)

0.91 ml of thiophenol is added to a solution of 0.5 g of potassium hydroxide in 13 ml of alcohol, then, with stirring, a solution of 4.18 g (0.0085 mol) of 6-bromo-2-bromomethyl-5-methoxy-1-cyclohexyl-3 β-ethoxycarbonylindole (compound VI) in 35 ml of benzene and left overnight. Potassium bromide is filtered off. After distillation of benzene, alcohol is added, the precipitate is washed with water. Yield 4.3 g, T _PL 93-95 ° C.

Example 4. 6-Bromo-5-methoxy-2-phenylthiomethyl-1-cyclohexylindol-3-ylcarboxylic acid (VIII)

A solution of 2.01 g (0.004 mol) of 6-bromo-5-methoxy-2-phenylthiomethyl-1-cyclohexyl-3-ethoxycarbonylindole (VII), 2.0 g of sodium hydroxide, 1.2 ml of water and 12 ml of ethanol is boiled 1 hour. After cooling and acidification with concentrated HCl, the precipitate is filtered off, washed with water. Yield 1.82 g, T _PL 224 ° C.

Example 5. 6-Bromo-5-methoxy-2-fengsggiomethyl-1-cyclohexylindol-3-yl-carboxylic acid chloride (IX)

To a solution of 0.66 g (0.0014 mol) of 6-bromo-5-methoxy-2-phenylthiomethyl-1-cyclohexylindol-3-ylcarboxylic acid (VIII), 0.6 ml of thionyl chloride in 6 ml of dioxane, 1 drop of dimethylformamide is added and heated in a water bath until the original (VIII) disappears. After evaporation in vacuo, the product is used in the next step without purification.

Example 6. 6-Bromo-5-methoxy-2-phenylthiomethyl-1-cyclohexyl-3- (2′-dimethylaminoethoxy) carbonylindole (X)

To a solution of 0.0014 moles of 6-bromo-5-methoxy-2-phenylthiomethyl-1-cyclohexylindol-3-ylcarboxylic acid (IX) acid chloride in 5 ml of benzene was added 0.25 g (0.0028 mol) of 2-dimethylaminoethanol. The day after evaporation in vacuo add alcohol. The precipitate is filtered off, recrystallized from isopropyl alcohol. T _PL 132-134 ° C.

The hydrochloride of compound (X) is obtained by adding an ethereal HCl solution to a solution of the base in acetone, T _PL 198 ° C.

Similarly receive:

- 6-bromo-2-methyl-5-methoxy-1-cyclohexyl-3- (3′-diethylaminopropoxy) carbonylindole hydrochloride (XI), _TPL 190 ° C (from isopropyl alcohol);

- 6-bromo-5-methoxy-1-cyclohexyl-2-phenylthiomethyl-3- (3′-diethylaminopropoxy) carbonylindole hydrochloride (XII), T _PL 188-190 ° C.

Of the starting compounds 6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-3-ethoxycarbonylindole and 6-bromo-2-dialkylaminomethyl-1-methyl-5-methoxy-3-ethoxycarbonylindole (Trofimov F.A., Tsyshkova N.G., CGS, 1973, No. 3, 308-311.) After obtaining the corresponding acids and acid chlorides from them as intermediate products (similar to Projects 4 and 5), the following compounds were obtained.

Example 7. 6-Bromo-1-methyl-5-methoxy-2-phenylthiomethylindol-3-ylcarboxylic acid (XIII)

A solution of 5.0 g sodium hydroxide, 3.8 g (0.009 mol) of 6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-3-ethoxycarbonylindole, 3 ml of water and 100 ml of alcohol is boiled for 3 hours. After cooling and acidification with concentrated HCl, the precipitate is filtered off, washed with water. Yield 3.4 g (92%), T _PL 213 ° C (decomposed, from dioxane).

Calculated%: C 53.21, H 3.96; C ₁₈ H ₁₆ BrNO ₃ S. Found%: C 53.37; H 3.94.

Example 8. 6-Bromo-1-methyl-5-methoxy-2-phenylthiomethyl-3- (2 ^1- dimethylaminoethoxy) -carbonylindole (XIV)

To a solution of 1.05 ml (0.0027 mol) of acid chloride (XI) in 10 ml of benzene was added 0.48 g (0.0054 mol) of 2-dimethylaminoethanol. The day after distillation of benzene, water is added. The precipitate is filtered off, washed with water. Yield 1.0 g (77.5%), T _PL 128 ° C (from alcohol).

Calculated%: C 55.34; H 5.28; C ₂₂ H ₂₅ BrN ₂ O ₃ S. Found%: C 55.24; H 5.31.

Similarly receive:

- 6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-3- (2 ^1- diethylaminoethoxy) carbonylindole hydrochloride (XV). T _PL 196-198 ° C (from absolute alcohol with ether). Calculated%: C 53.19; H 5.58; C ₂₄ H ₃₀ BrClN ₂ O ₃ S; Found%: C 53.09; H 5.63;

- 6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-3- (3 ^1- diethylaminopropoxy) carbonylindole (XVI). T _PL 75 ° C (from hexane). Calculated%: C 57.80; H 6.01; N, 5.39; C ₂₅ H ₃₁ BrN ₂ O ₃ S; Found%: C, 57.69; H 6.03; N, 5.39;

- 1-benzyl-6-bromo-5-methoxy-2-phenylthiomethyl-3- (2-dimethylaminoethoxy) carbonylindole hydrochloride (XVII). T _PL 185-187 ° C (from absolute alcohol);

- 1-benzyl-6-bromo-5-methoxy-2-phenylthiomethyl-3- (3 ^1- diethylaminopropoxy) carbonylindole hydrochloride (XVIII). T _PL 175-176 ° C (from absolute alcohol with ether);

- 6-bromo-1-methyl-5-methoxy-2- (2 ¹ , 4 ¹ -dibromophenyloxy) methyl-3- (2 ^1- dimethylaminoethoxy) carbonylindole hydrochloride (XIX). T _PL 215-217 ° C (from alcohol);

- 6-bromo-1-methyl-5-methoxy-2- (4 ¹ -methoxyphenyloxy) methyl-3- (2 ^1- diethylaminoethoxy) carbonylindole oxalate (XX). T _PL 132 ° C.

The synthesis of compounds of formula (I) having a dialkylaminomethyl radical in the 2nd position of the indole ring was carried out according to scheme 2.

Scheme 2

Example 9. 6-Bromo-1-methyl-5-methoxy-2- (1-piperidinomethyl) indole-3-carboxylic acid hydrochloride (XXI)

A solution of 6.0 g of sodium hydroxide, 4.1 g (0.01 mol) of 6-bromo-1-methyl-5-methoxy-2- (1-piperidinomethyl) -3-carbethoxyindole, 3 ml of water and 60 ml of ethyl alcohol boil for 3 hours. After cooling, add 10 ml of water, acidify with concentrated HCl, and the precipitate is filtered off. Yield 4.1 g (98%), T _PL 236-238 ° C (from aqueous alcohol).

In a similar manner, 6-bromo-1-methyl-2- (1-morpholinomethyl) indole-3-carboxylic acid hydrochloride (XXII) is obtained, T _PL 227-228 ° C.

Example 10. 6-Bromo-1-methyl-5-methoxy-2- (1-piperidinomethyl) -3- (2 ^1- dimethylaminoethoxy) carbonylindole dihydrochloride (XXIII)

A mixture of 1.25 g (0.003 mol) of 6-bromo-1-methyl-5-methoxy-2- (1-piperidinomethyl) indolyl-3-carboxylic acid hydrochloride, 2 ml of thionyl chloride, 1 drop of dimethylformamide in 20 ml of dioxane is heated on water bath for 3 hours. After evaporation in vacuo, the precipitate is washed with ether. To the resulting precipitate was added 15 ml of benzene and a mixture of 0.54 g (0.006 mol) of dimethylaminoethanol and 0.8 ml of triethalamine in 5 ml of benzene and heated in a water bath for 2 hours. The precipitate of triethalamine hydrochloride is filtered off, washed with hot benzene. After evaporating the benzene in vacuo, hexane was added. The precipitate is filtered off, washed with hexane. Yield 0.6 g (44.4%), T _PL 120-121 ° C (from hexane with alcohol). The dihydrochloride is prepared by adding ether saturated with HCl to a solution of the base in acetone, T _PL 248-250 ° C (with decomposition).

Similarly receive:

- 6-bromo-1-methyl-5-methoxy-2- (1-piperidinomethyl) -3- (3 ^1- diethylaminopropoxy) carbonylindole dihydrochloride (XXIV), T _PL 238-240 ° C;

- 6-bromo-1-methyl-5-methoxy-2- (1-piperidinomethyl) -3- (2 ^1- diethylaminoethoxy) carbonylindole dihydrochloride (XXV), T _PL 237-240 ° C;

- 6-bromo-1-methyl-5-methoxy-2- (1-morpholinomethyl) -3- (2 ^1- dimethylaminoethoxy) carbonylindole dihydrochloride (XXVI), T _PL 241-242 ° C;

- 6-bromo-1-methyl-5-methoxy-2- (1-pyrrolidinomethyl) -3- (2 ^1- diethylaminoethoxy) carbonylindole dihydrochloride (XXVII), T _PL 239-240 ° C (from absolute alcohol);

- 6-bromo-1-methyl-5-methoxy-2- (1-pyrrolidinomethyl) -3- (3 ^1- diethylaminopropoxy) carbonylindole dihydrochloride (XXVIII), T _PL 237-239 ° C (from absolute alcohol);

- 6-bromo-1-methyl-5-methoxy-2- (1-morpholinomethyl) -3- (3′-diethylaminopropoxy) carbonioindole dihydrochloride (XXIX), T _PL 235-237 ° C.

The structures of the obtained compounds were confirmed by the data of PMR spectra, elemental analysis, individuality by thin-layer chromatography on Silufol UV254 plates.

Another aspect of the invention is that the compounds of formula (I) have high antiviral activity, as confirmed by the results of experimental studies.

Example 11. The study of cytotoxic properties and antiviral activity against encephalomyocarditis virus (VEMK)

The study of the specific antiviral activity of the claimed compounds against VEMC mice (strain "Columbia SK-Col-SK") was carried out in vitro on a culture of transplantable bone marrow cells of a human patient with leukemia L-41 (clone J-96). L-41 cells at an initial concentration of 2 · 10 ⁵ cells / ml were sown in 0.2 ml in 96-well flat-bottomed culture plates in medium 199 with the addition of 10% fetal bovine serum (cattle), glutamine (300 μg / ml) and penicillin (100 U / ml) (complete culture medium - PPS). Cells were cultured for 24 hours at 37 ° C, 5% CO ₂ and 90% humidity until a cell monolayer was formed. Next, PPS was changed to a support medium (medium 199 with 2% fetal bovine serum, glutamine (300 μg / ml) and penicillin (100 U / ml) - PS), introducing 0.1 ml of PS into each well. Then, the test compound was introduced in a volume of 0.1 ml into the first well of the plate at the initial concentration (10 mg / ml) (1: 2 dilution). In the subsequent wells, the compound was added in various dilutions of the initial concentration (with a dilution step of 1: 2 - and from 1/2 to 1/4096). Titration of the compound was repeated 3 times. After 24 hours of culturing the cells with the test compound, its cytotoxic effect was studied at various concentrations. Then, VEMC with an initial titer of 10 ⁶ TCD ₅₀ / ML at a dilution of 10 ^{-4 was} added to each well. After 24 hours of incubation of cells with the virus, the cytopathogenic effect of the virus was studied in the presence of various concentrations of the test compound. The cytopathogenic effect of viruses and the cytotoxic effect of the compounds were studied visually under an inverted Leitz microscope (objective × 20, eyepiece × 10). Antiviral activity was evaluated by the average effective virus-inhibiting concentration (EC ₅₀ ) - the concentration of the compound that protects 50% of the cells from the cytopathogenic effect of the virus at a dose of 100 · TCD ₅₀ / ml. The cytotoxic effect was evaluated by the average toxic concentration (TK ₅₀ ) - the concentration of the compound that causes the death of 50% of the cells. As a criterion for the specific antiviral activity of the test compound, a chemotherapeutic index (CTI) equal to the ratio of TC ₅₀ / EC _{50 was used} .

The results of the experiments showed that almost all the studied compounds of formula (I) showed antiviral activity against VEMK (Table 1). Moreover, a significant part of the tested compounds (primarily water-soluble ones - XI, XIV, XIX, XXIV) had an effective virus-inhibiting effect at concentrations 1-2 orders of magnitude lower than arbidol. A comparison of antiviral activity and toxicity according to the chemotherapeutic index shows that in the range of the studied substances there are several compounds (HTI> 4), which, according to the current recommendations for the study of potential antiviral agents (Guidelines for preclinical studies of drugs. Part One / M: Grif and K., 2012, 944 pp.) Can be considered promising for further detailed studies in animal experiments.

Table 1 Indicators of toxicity and antiviral activity of the claimed compounds in relation to the virus EMC Compound Solubility TK ₅₀ , mcg / ml EC ₅₀ , μg / ml HTI Xi + 4.89 0.61 8 XIV + 9.77 2.44 four XVIII + > 10,000 2500 > 4 XIX + 39.06 9.77 four XXIII + 156.25 39.06 four XXIV + 39.06 4.88 8 XXV + 156.25 39.06 four XXVI + 156.25 39.06 four Xxvii + 78.13 19.53 four Arbidol - > 10,000 78.13 > 128

Example 12. The study of specific anti-herpes activity

Assessment of the specific antiviral activity of the claimed compounds in relation to the herpes simplex virus type 1 (strain VR3) was carried out on an inoculated cell culture of Vero green monkey kidney. Cells were plated at a concentration of 1.5 · 10 ⁵ cells / ml, 1 ml each in 24-well culture plates in a composition medium: 2/3 of medium MEM needle, 1/3 of DMEM medium, 10% fetal calf serum supplemented with gentamicin (15 IU / ml). Cells were cultured for 24 hours at 37 ° C, 5% CO ₂ and 90% humidity until a cell monolayer was formed. Then, 1 ml of type 1 herpes virus (VR3) was introduced into the wells in dilutions of 10 ^-3 -10 ^-7 (initial titer of 10 ⁷ TCD ₅₀ / ML). At the same time, the test compound in various concentrations was added to the test wells. Placebo solution was added to the same wells in the same volume. After 24 hours of incubation of the cells with the virus and the test compound, the number of symplasts in the control and experimental wells was counted. The specific anti-herpes activity of the compound was evaluated by suppressing the formation of symplasts, calculating the inhibition index (II):

where a and b are the number of symplasts in the control and experimental wells, respectively.

The experimental results showed that the compound suppresses symplastogenesis induced in cell culture by the herpes simplex virus type 1 (Table 2). Moreover, the effective anti-herpes activity of the studied compounds is observed at the same concentrations as the specific activity against VEMK (Table 1). This allows us to expect the presence of a wide spectrum of antiviral activity in the compounds of formula (I).

table 2 Indices of anti-herpes activity of the claimed compound Experience number Compound Concentration, mcg / ml The number of symplasts AI,% one XXV 100.0 Toxic - 5,0 42 59 2,5 88 fourteen 0.5 ≥100 - 0.25 ≥100 - The control - 102 - 2 XXV 10 29th 62 5 47 38 The control - 76 -

In the above examples of a sequential study of the antiviral efficacy of the test substances, 2 stages are presented: the first is the primary selection stage (Example 11), when the tested compounds are divided into active and inactive with simultaneous study of cytotoxicity in cell culture; and the second stage - when the substances that showed activity in the first stage are studied additionally in tests of specific activity (Example 12). The technical result is achieved by the fact that as a result of the studies, a group of water-soluble compounds of aminoalkyl esters of 5-methoxyindole-3-carboxylic acid of the general formula (I) with antiviral activity was selected. The low toxicity, water solubility and high bioavailability of such compounds in combination with a wide range of antiviral activity makes them promising for the development of drugs for the prevention and treatment of a wide range of viral diseases. At the same time, one of the studied compounds (XXV) has a high specific activity against viruses of the herpes group with an efficiency index of at least 60%.

Claims (4)

1. Aminoalkyl esters of 5-methoxyindole-3-carboxylic acid of the general formula (I) or pharmacologically acceptable salts thereof:

wherein:
R1 is cyclohexyl, C _1-3 alkyl;
R2 represents phenylthio, phenyloxy in which the phenyl group may have 1-2 halogen substituents, or a _C1-4 alkoxy group or R2 represents a 5-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen;
n is 1, 2, 3, 4;
each R is independently selected from C _1-4 alkyl;
with the exception of:
6-bromo-1-methyl-5-methoxy-2- (4 ¹ -methoxyphenyloxy) methyl-3- (2 ^1- diethylaminoethoxy) carbonylindole oxalate;
6-bromo-1-methyl-5-methoxy-2- (1-piperidinylmethyl) -3- (2 ^1- diethylaminopropoxy) carbonylindole;
6-bromo-5-methoxy-2-phenylthiomethyl-1-cyclohexyl-3- (2'-dimethylaminoethoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2-phenylthiomethyl-3- (2'-diisopropylethoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2- (1-piperidinylmethyl) -3- (2'-diethylethoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2 - ((4-methoxyphenoxy) methyl) -3- (2'-diethylethoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2 - ((4-morpholino) methyl) -3- (2'-dimethylethoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2- (1-piperidinylmethyl) -3- (2'-dimethylethoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2 - ((4-methoxyphenoxy) methyl) -3- (2'-diisopropylethoxy) carbonylindole;
6-Bromo-5-methoxy-1-methyl-2 - ((4-methoxyphenoxy) methyl) -3- (2'-diethylpropoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2-phenylthiomethyl-3- (2'-diethylethoxy) carbonylindole;
6-bromo-5-methoxy-1-methyl-2 - ((2,4-dibromophenoxy) methyl) -3- (2'-dimethylethoxy) carbonylindole;
6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-3- (3 ^1- diethylaminopropoxy) carbonylindole;
6-Bromo-1-methyl-6-methoxy-2-phenylthiomethyl-3- (2 ^1- dimethylaminoethoxy) carbonylindole. 2. The compounds according to claim 1 in the form of pharmacologically acceptable salts, such as monohydrochlorides, dihydrochlorides, hydrobromides, dihydrobromides, mesylates, acetates, salicylates, oxalates. 3. The method of obtaining the compounds of formula (I)

consisting in the interaction of the acid chloride of General formula (II)

with aminoalkanol of the general formula HO (CH2) _n N (R) ₂ , where R1 is cyclohexyl, C _1-3 alkyl;
R2 is phenylthio, phenyloxy in which the phenyl group may have 1-2 halogen substituents or a _C1-4 alkoxy group, or R2 is a 5-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen;
n is 1, 2, 3, 4;
each of R is independently selected from C _1-4 alkyl. 4. The use of the compounds of formula (I)

wherein
R1 represents cyclohexyl, C _1-3 alkyl;
R2 is phenylthio, phenyloxy in which the phenyl group may have 1-2 halogen substituents or a _C1-4 alkoxy group, or R2 is a 5-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen;
n is 1, 2, 3, 4;
each R is independently selected from C _1-4 alkyl as an active ingredient in pharmaceutical compositions for the prevention and treatment of viral diseases.