RU2448120C1 - Clathrate complexes of beta-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-h-indol-3-yl]carbonyl}-4-benzylpiperazine, having antiviral activity, synthesis and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a novel clathrate complex of β-cyclodextrin with 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine of formula

: with molar ratio 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine: β-cyclodextrin from 1:1 to 1:10, synthesis method and use thereof as an antiviral agent for treating influenza. The disclosed method involves mixing solutions of β-cyclodextrin and 1-{[6-bromo-1-methyl-5-methoxy-2-phehylthiomethyl-1-H-indol-3-yl]carbonyl}-4-benzylpiperazine in molar ratio from 1:1 to 1:10 while stirring and heating to temperature not higher than 70°C and then maintaining said conditions until a homogeneous solution is obtained and extraction of the obtained complex.

EFFECT: clathrate complex is a novel effective anti-influenza virus agent which is obtained using a novel efficient method.

13 cl, 2 ex, 3 tbl, 11 dwg

Description

The invention relates to new clathrate complexes of cyclodextrin with an antiviral agent that may find application in the pharmaceutical industry, and methods for their preparation. The invention also relates to compositions and drugs based on new clathrate cyclodextrin complexes.

Currently, complexes of active substances with cyclodextrins have found their application not only in pharmaceuticals, but also in cosmetology. For example, there are complexes of phytoamino acids included in the cyclodextrin capsule that are in demand. Similar complexes of cyclodextrin with monosaccharides, uronic acids are known.

Obtaining clathrate complexes in solving the problems of drug transport has a significant impact on almost every route of administration - from oral to injection. The development perspective of target delivery systems and transportation systems through mucous membranes is described (RF patent 2005115883, publ. 2006). The overall potential of drug transport systems based on inclusion complexes was also evaluated in RF patent 2121830, publ. in 1998

New forms and ways of transporting drugs can expand the therapeutic potential of the prescribed treatment, allowing you to deliver new types of drugs to previously unreachable areas in the human body. Complex-based drug transportation technologies can significantly change existing drugs, improving their bioavailability, and reducing the therapeutic dose. In the patent of the Russian Federation 2121830 above, a water-soluble drug composition and a method for its preparation are described for such known preparations as Sibazon, Azaleptin, Mezapam, Indomethacin. Pharmacological tests of the obtained complexes in laboratory animals showed a several-fold decrease in the therapeutic dose of drugs (drugs).

Molecules of cyclodextrins have a toroidal shape, and its internal cavity is hydrophobic. Water-soluble intermolecular complexes of lipophilic organic compounds are formed in solution due to the intercalation of their molecules in this cavity. Complexes of β-cyclodextrin with non-steroidal anti-inflammatory drugs (paracetamol, ibuprofen, ketoprofen, flufenamic and mefenamic acids, etc.), steroids, prostaglandins and prostacyclins, barbiturates, sulfonamides, cardiac glycosides and other drugs, for example, US Pat. 4727064, RF patent 2337710, published in 2008, Szejtii, "Industrial Applications of Cyclodextrins" Ch. 11 of Inclusion Compounds, v. 3, Atwood et al, ed. Acad. Pr., 1984. pp. 313-389 )

Known publications describing inclusion compounds (clathrate complexes) of α- or β-cyclodextrins with antiviral compounds, methods for their preparation and use (see, for example, RF application 2005114097, RF patents 2288921, RF 2377243, RF 2247576, DE 19814815 A1, DE 19814814 A1, US 4956351, US 5221669, applications US 2005/0209189, US 2005/0281872, US 2009/0286757, JP 10-045319, JP 58-092691, JP-2005-179329 JP-9-015632). In the patent of the Russian Federation 2128664, publ. 04/10/1999, the inclusion compound of 9- (2-hydroxyethoxymethylguanine (acyclovir) with β-cyclodextrin having anti-herpes activity is described. The same patent describes liquid-phase and solid-phase methods for producing the inclusion compound. or water-alcohol solutions when heated, followed by a concentration of the resulting product and the selection of the finished product.

The solid-phase method is the mechanical grinding of a mixture of crystalline acyclovir and β-cyclodextrin in a vibratory mill. In this case, the product remains crystalline and is a finely divided mobile powder. In RF patents 2242974, 2357968, 2377243, crystalline forms and nanoforms of cyclodextrin clathrates and anti-inflammatory drugs are described. According to the patent of the Russian Federation 2377243 describes a solid-phase method, which includes obtaining solid dispersions of the components, followed by optional grinding or grinding of this dispersion.

An object of the present invention is to provide novel clathrate complexes of β-cyclodextrin with the antiviral compound 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine corresponding to formula (I), possibly in the form of nanoparticles, with improved solubility in water and bioavailability. These new compounds can reduce therapeutic doses of drugs based on them and, therefore, reduce the possible toxic effects of the drug. The present invention also is the development of new methods for their preparation and use in pharmaceutical compositions and medicines.

The present invention provides novel clathrate complexes of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine of the formula (I ) at a molar ratio of 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine: β-cyclodextrin from 1: 1 to 1 :10

It should be noted that the molar ratios of 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine corresponding to formula (I), and β-cyclodextrin ranges from 1: 1 to 1:10, preferably at a ratio of 1: 3 to 1: 7. These ratios make it possible to completely transfer the antiviral drug to the clathrate complex, which significantly affects its water solubility and bioavailability. So, for example, the solubility of the antiviral compound A corresponding to formula 1 in water is practically zero (5.7 · 10 ^-7 g / l), while the solubility in the 1: 5 complex is 0.02 g / ml, and in the complex 1 : 7 is almost 0.03 g / l.

The invention also relates to an antiviral pharmaceutical composition, which contains the above clathrate complex of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} - 4-benzylpiperazine of the general formula (I) at molar ratios of 1 - {[b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine: β- cyclodextrin in the range of 1: 1 to 1:10, preferably in a ratio of 1: 3 to 1: 7, in an effective amount and a pharmaceutically acceptable excipient.

The invention also relates to an antiviral drug in the form of capsules, tablets or injections in a pharmaceutically acceptable package containing the above clathrate complex of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H -indol-3-yl] carbonyl} -4-benzylpiperazine of the formula (I) with molar ratios of the derivative 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl ] carbonyl} -4-benzylpiperazine: β-cyclodextrin ranging from 1: 1 to 1:10, preferably in a ratio of 1: 3 to 1: 7, or a pharmaceutical composition as their basis in an effective amount.

It was found that clathrate complexes are suitable for most dosage forms and routes of administration.

The term "effective amount" used in this application means the use of that amount of a compound of formula 1, which, together with its activity and toxicity indicators, as well as on the basis of specialist knowledge, should be effective in this pharmaceutical composition or dosage form.

If necessary, the pharmaceutical composition may contain adjuvants, such as fillers, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, for example, such additives may be selected from microcellulose, lactose, calcium stearate, starch. The choice and ratio of these components depends on the nature and method of administration and dosage.

The content of the active ingredient is usually from 1 to 20 wt.%, In combination with one or more pharmaceutically acceptable auxiliary additives, such as diluents, binders, disintegrating agents, adsorbents, flavoring agents, flavoring agents.

Said pharmaceutical composition and drug can be prepared by methods known in the art of pharmacy.

To obtain a pharmaceutical composition, the active ingredient (compound of formula I) is mixed with a pharmaceutically acceptable carrier and, if necessary, with appropriate additives.

In this case, the drug may be in liquid or solid form.

Examples of solid dosage forms are, for example, tablets, pills, gelatin capsules, etc. Examples of liquid dosage forms for injection and parenteral administration are solutions, emulsions, suspensions, etc. The preparation of these dosage forms is carried out by methods traditional for the pharmaceutical industry — by mixing the components, tabletting, encapsulation etc.

Clathrate complexes can be obtained in two ways:

1) liquid-phase synthesis method and

2) solid-phase synthesis method.

According to the methods of the present invention receive non-covalent clathrate complexes stabilized by hydrogen bonds. A non-covalent complex is a complex that is formed between molecules of substances, for example, in a suitable solvent due to the intermolecular van der Waals interaction of a non-covalent nature, namely, hydrogen bonding, coordination-ionic.

The liquid-phase method consists in preparing solutions of the starting β-cyclodextrin and 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine formulas (I), which are then mixed with stirring and heating to a temperature not exceeding 70 ° C, with a molar ratio of the derivative 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indole- 3-yl] carbonyl} -4-benzylpiperazine: β-cyclodextrin from 1: 1 to 1:10, followed by exposure under stirring at the indicated temperature until a homogeneous (true) solution is obtained and isolation is obtained Foot clathrate complex. In the preparation of the clathrate complex, molar ratios of 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine: β-cyclodextrin are predominantly in ranges from 1: 3 to 1: 7, especially with ratios of 1: 3, 1: 5 and 1: 7. If necessary, inclusion compounds (i.e., clathrate complexes) can be isolated in the form of nanoparticles with a size of less than 500 nm, preferably about 175 nm.

Obtaining a clathrate complex in the form of nanoparticles with the indicated size confirms the analysis carried out on a Zetasizer Nano ZS device (Figure 1). The measurement conditions are as follows: dispersion in water. Density 1,330, viscosity 0.8886 cP, temperature 25 ° C, attrition rate 210, diameter of the resulting particles 174.5 nm

The solid phase method is that β-cyclodextrin and 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine corresponding to the formula (I) subjected to grinding (grinding) at a speed of from 100 rpm to 500 rpm in the time interval from 10 to 60 minutes at a molar ratio of 1 - {[6-bromo-1-methyl-5-methoxy-2- phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine: β-cyclodextrin from 1: 1 to 1:10, mainly in the range from 1: 3 to 1: 7, especially at ratios of 1: 3, 1: 5 and 1: 7, at a temperature of 20 to 30 ° C. Optionally, inclusion compounds (i.e., clathrate complexes) can be isolated in the form of nanoparticles with a size of less than 500 nm, preferably about 175 nm, by further grinding the dispersion.

It is known from the theory of mechanosynthesis that plastic deformation of a solid usually leads not only to a change in the shape of the solid, but also to the accumulation of defects in it that alter the physicochemical properties, including reactivity. The accumulation of defects can be used in chemistry to accelerate reactions involving solids, reduce the temperature of processes, and other ways of intensifying chemical reactions in the solid phase.

A feature of the process of activation of a solid substance as a result of machining is that activation occurs when the particle size reaches a certain critical value as it is milled. During mechanical activation, the surface does not so much increase as defects accumulate in the entire crystal volume. This dramatically changes many of the physicochemical properties of solids, including reactivity.

The increase in reactivity as a result of mechanical activation can be considered as one of the methods for producing solids in a metastable, active form. Since chemical reactions involving solids, depending on the characteristics of their mechanism, are differently sensitive to various defects that are contained in the crystal, the task of mechanical activation is not only to accumulate defects in general, but also to obtain exactly the type of defects that necessary for this reaction. This goal can be achieved both by selecting the conditions of mechanical action on the crystal (exposure energy, duration, relationship between pressure and shear, processing temperature, composition of the surrounding atmosphere), and taking into account the structural features of the crystal, the nature of the chemical bond, its strength characteristics, etc. .

To obtain nanoparticles, a solid dispersion is usually first prepared, followed by optionally grinding or grinding the solid dispersion to an appropriate particle size. Fine grinding of particles can be carried out mechanically by applying a force to the particles, under the influence of which they are crushed. Such a force can be provided in the collision of particles, which are given a high speed, with each other. Fine grinding in order to obtain fine particles can be carried out, for example, by grinding, using an air-jet micron colloid mill, using a ball mill or using a pin mill. The size of the resulting nanoparticles can be determined by any means well known in the industry. The following methods can be used, for example: screening through sieves, sedimentation, microscopy. Preferred for use in the present invention are the particle size measurement methods most commonly used in the pharmaceutical industry, such as laser diffraction or sieve analysis.

In more detail, the invention is disclosed in the following examples, which, however, do not limit the claims of the applicant, but only illustrate the possibility of its implementation.

The resulting compounds have an improved therapeutic effect compared to the previously known, similar in structure and used in medical practice antiviral compound - Arbidol, which is unexpected and not obvious for this clathrate complex. Toxicological studies carried out at the Federal State Institution of Medical Science and Technology of the Russian Medical Technologies and the Medical Radiological Scientific Center of the Russian Academy of Medical Sciences indicate low toxicity of the claimed complex: LD ₅₀ for mice is 9800 and LD ₅₀ rats more than 6000 mg per 1 kg of body weight. It was obtained that the therapeutic index, which shows the breadth of the therapeutic effect of drugs and represents the ratio of the average lethal dose to the dose that causes a therapeutic effect in 50% of experimental animals, compounds A and the claimed complex do not differ and are approximately 80.

The following examples illustrate the invention.

1. The liquid phase method

The calculated sample of β-cyclodextrin was dissolved in 0.5 L of distilled water at a temperature of 65-70 ° C. A portion of compound A was dissolved in 0.5 L of ethanol at the same temperature as cyclodextrin. With stirring and heating, a solution of compound A corresponding to formula (1) was added to a cyclodextrin solution. After mixing, the temperature was maintained at 65-70 ° C until a true solution was obtained, after which the temperature was lowered to 55 ° C for 2 hours. Alcohol and part of the water from the solution were evaporated, the residue was sent to freeze drying.

2. Solid phase method

The tests were carried out on a ball planetary mill Pulverisette 7 with the material of grinding glasses made of zirconium oxide. The optimal regimes were 100 rpm 10 min, 200 rpm 10 min, 100 rpm 10 min, balls 3 mm to obtain the complex compound A: cyclodextrin, molar ratios also varied from 1: 1 to 1:10. Thanks to precisely these regimes, complexes were obtained with an optimal set of spectral data and solubility.

The formation of complexes was confirmed by UV and IR spectroscopy.

As a specific example, the UV spectrum data for compound A are shown: comparative UV spectra of pure compound A, complexes in a ratio of 1: 3, 1: 5 and 1: 7, as well as pure β-cyclodextrin, are presented. The results are shown in figures 2, 3, 4, 5 and 6, respectively.

Solvent: methanol: water = 1: 1 Dissolution is carried out by heating. Compound A 0.0250 g in 50 ml CD: Compound A = 3: 1 0,0500 g in 25 ml of solvent CD: Compound A = 5: 1 0.0750 g in 25 ml of solvent CD: Compound A = 7: 1 0.1000 g in 25 ml of solvent CD (cyclodextrin) 0.1750 g in 50 ml of solvent

To take the spectra, these solutions were diluted 21 times (0.2 ml + 4 ml of solvent).

Samples of the samples contained the same amount of compound A (0.025 g); therefore, a decrease in the absorption intensity can be attributed to the screening of the molecule of compound A by cyclodextrins, i.e. complex formation.

Moreover, the sample obtained at the ratio of CD: Compound A = 7: 1 contains more complex than the sample CD: Compound A = 5: 1, which is confirmed by the lower absorption intensity (complex formation), as well as the nature of the spectrum in the range 200-220 nm (lack of absorption characteristic of free cyclodextrin). Thus, it was found that the molar ratio of CD: Compound A = 7: 1 is optimal for complex formation.

In addition, a comparative analysis of the IR spectra of pure Compound A, complex preparations (ratios 1: 3, 1: 5 and 1: 7), as well as pure cyclodextrin was performed: Figures 7-11, respectively. Red indicates the IR spectrum of a pure antiviral drug (compound A).

It is clearly seen on these spectra that the signals of the characteristic groups of compound A overlap, especially the broadened absorption band in the region of 2200 cm ^-1 , associated with stretching vibrations of the CSC ₆ H ₅ group, as well as the absorption bands of 1585-1600 cm ^-1 and 1400-1500 cm ^-1 , corresponding to the stretching vibrations of the bonds C-C of the benzene ring. This fact suggests that the antiviral drug molecule is located in the cavity of the cyclodextrin molecule, due to which the signals overlap and the formation of clathrate complexes is unequivocally confirmed.

It should also be noted that, based on the set of physicochemical characteristics, the molar ratio of compound A: cyclodextrin is 1: 7.

PILLS

Clathrate complex Compound A and cyclodextrin with a molar ratio of 1: 7 100 mg

Possible additives: microcellulose, lactose, calcium stearate, starch.

Obtained by mixing the components in a Bectochem mixer and pressing on a Rimec tablet machine.

CAPSULES

Clathrate Nanocomplex Compounds A and cyclodextrin at a molar ratio of 1: 5 100 mg

Possible additives: microcellulose, lactose, starch.

Obtained by mixing the components in a Bectochem mixer and filling 3VC gelatin capsules.

The study of the antiviral activity of Compound A complex form of the drug with β-cyclodextrin in a ratio of 1: 7

Studies on the antiviral activity of the claimed complex in vivo were carried out at the Center for Chemistry of Medicinal Products (TsHLS-VNIHFI). The research results are shown in tables 2 and 3. The antiviral activity of the obtained complexes was studied in experiments on a model of influenza pneumonia in mice. The efficacy of the compounds was evaluated in terms of protection against mortality and life expectancy of virus-infected and treated animals.

In a preliminary experiment, a dose of virus containing 10 LD ₅₀ was determined.

For this, groups of 5-6 mice were infected with the whole allantoic virus and its successive 10-fold dilutions. Data for monitoring animals for 15 days are presented in Table 1.

From the presented data shows that 50% of the death of animals causes infection with the virus 10 ³ . All animals in the experiment were infected with this dose of the virus.

The data shown in Table 2 indicate that Tsytriver, applied at a dose of 60 mg / kg / day, is comparable in antiviral activity with Arbidol at the same dose and even slightly exceeded it, as evidenced by the mortality protection rates of 61% and 31 % respectively.

Table 3 presents data on the effectiveness of the claimed complex on a model of influenza infection in mice.

findings

As a result of studies, it was found that the claimed complex at doses of 20, 30, 60 and 90 mg / kg / day when infected with A / Aichi virus / 2/69 (H3N2) is effective in the treatment of mice and has a dose-dependent nature, increasing with increasing doses.

Oral administration of the claimed complex in doses of 20, 30, 60 and 90 mg / kg / day for 5 days reduces the mortality of mice from influenza pneumonia, increases the average life expectancy and reduces weight loss compared with the viral control.

Thus, based on the studies, we can conclude that the claimed complex is a promising anti-influenza drug.

Toxicological studies were carried out at the Federal State Institution RKNPK Rosmedtekhnologii and the Medical Radiological Scientific Center of RAMS. The data obtained indicate low toxicity of the claimed complex. The LD ₅₀ for mice is 9800 and the rat LD _{50 is} more than 6000 mg per 1 kg of body weight. It was obtained that therapeutic indices, which show the breadth of the therapeutic effect of drugs and represent the ratio of the average lethal dose to the dose that causes a therapeutic effect in 50% of experimental animals, substance A and the claimed complex do not differ and are approximately 80.

Table 1 Determination of LD ₅₀ in a mouse influenza pneumonia model Dilution of the Virus * The number of mice in the group Survivors / dead Mortality% 10 ^-1 5 0/5 one hundred 10 ^-2 5 0/5 one hundred 10 ^-3 6 3/6 fifty 10 ^-4 6 6/6 0 10 ^-5 5 5/5 0 * degree of dilution

table 2 The effectiveness of the compounds on the model of influenza infection in mice (virus A / Aichi / 2/69) Survival Mortality (%) Mortality reduction rate (%) Life expectancy (days) ** Arbidol Per os
(60 mg / kg / day) 5/10 fifty 31 9.3 (1 - 1 day, 1 - 4 day, 1 - 5 day, 2 - 9 day) The claimed Per os complex
(60 mg / kg / day) 8/10 twenty 61 13.1 (2 - 11 days) Viral control 8.1 (1 - 4 days, 2 - 5 days, 1 - 6 days, 2 - 7 days, (10 LD ₅₀ ) 3/16 81 2-8 days, 2-9 days, 3-11 days) * Treatment schedule: 24 and 1 hour before infection, then after 8, 24, 48, 72 and 96 hours after infection ** Average life expectancy was determined by the formula Σf (d-l) / n, where f is the number of mice that died on day d (surviving mice are included in f, and d in this case is 16), n is the number of mice in the group

Table 3 The effectiveness of the proposed complex on a model of influenza infection in mice Data on the 7th day of observation Data on day 15 of observation Life expectancy, (days) ** Dose Survival Mortality Protection Rate (%) Survival Mortality Protection Rate (%) 20 mg / kg / day 1/9 eleven 1/9 eleven 6.1 (1 - 4 days, 2 - 5 days, 1 - 6 days, 4 - 7 days) 30 mg / kg / day 3/10 thirty 3/10 thirty 7.5 (2 - 4 days, 3 - 5 days, 2 - 7 days) 60 mg / kg / day 5/10 fifty 4/10 40 9.0 (1 - 3 days, 2 - 6 days, 2 - 7 days, 1-9 days) 90 mg / kg / day 6/10 60 5/10 fifty 9.5 (1 - 3 days, 3 - 5 days, 1 - 7 days) VIRAL CONTROL (10 LD ₅₀ ) 0/10 0/10 4.3 (3 - 4 days, 4 - 5 days, 3 - 7 days) * Treatment schedule: 24 and 1 hours before infection, then after 8, 24, 48, 72 and 96 hours after infection ** Average life expectancy was determined by the formula Σf (d-l) / n, where f is the number of mice that died on day d (surviving mice are included in f, and d in this case is 16), n is the number of mice in the group

Claims (13)

1. The clathrate complex of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine of the formula (I)

at a molar ratio, the derivatives 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine: β-cyclodextrin from 1: 1 to 1 :10. 2. The clathrate complex according to claim 1, in which the molar ratio of β-cyclodextrin and 1 - {[b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} - 4-benzylpiperazine ranges from 1: 1 to 1:10, preferably at ratios of 1: 3, 1: 5 and 1: 7. 3. The clathrate complex according to claim 1 or 2, according to which it is a nanoparticle with a size of about 175 nm. 4. The liquid phase method for producing the clathrate complex according to claim 1, which consists in mixing pre-prepared solutions of β-cyclodextrin and 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indole -3-yl] carbonyl} -4-benzylpiperazine of the formula (1) at a molar ratio in the range of 1: 1 to 1:10 with stirring and heating to a temperature of no higher than 70 ° C, then kept under stirring at the indicated temperature until a uniform solution with the allocation of the obtained clathrate complex. 5. The method according to claim 4, characterized in that the molar ratio of 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4- is used benzylpiperazine: β-cyclodextrin ranging from 1: 3 to 1: 7, especially a ratio of 1: 3, 1: 5 or 1: 7. 6. The method according to any one of claims 4 or 5, according to which receive a clathrate complex in the form of nanoparticles with a size of less than 500 nm, preferably about 175 nm. 7. The solid-phase method for producing the clathrate complex according to claim 1, characterized in that β-cyclodextrin and 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine of formula (I) is subjected to grinding at a speed of from 100 to 500 rpm for a time of 10 to 60 minutes at a molar ratio of 1 - {[6-bromo-1-methyl-5-methoxy-2- phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine: β-cyclodextrin from 1: 1 to 1:10 at a temperature of from 20 to 30 ° C. 8. The method according to claim 7, characterized in that 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine: β β-cyclodextrin is used in molar ratios ranging from 1: 3 to 1: 7, especially at ratios of 1: 3, 1: 5 and 1: 7. 9. The method according to any one of claims 7 or 8, according to which receive a clathrate complex in the form of nanoparticles with a size of less than 500 nm, preferably about 175 nm. 10. A pharmaceutical composition for the treatment of influenza infection which contains a clathrate complex of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} - 4-benzylpiperazine of formula (1) in a molar ratio ranging from 1: 1 to 1:10 according to claim 1 in an effective amount and a pharmaceutically acceptable excipient. 11. The pharmaceutical composition of claim 10, which contains a clathrate complex of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} - 4-benzylpiperazine of formula (1) in a molar ratio of 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl} -4-benzylpiperazine of formula (I) : β-cyclodextrin ranging from 1: 3 to 1: 7, especially at ratios of 1: 3, 1: 5 or 1: 7. 12. The pharmaceutical composition of claim 10 or 11, which contains a clathrate complex of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl } -4-benzylpiperazine of formula (1) according to claim 1 in the form of nanoparticles with a size of less than 500 nm, preferably about 175 nm. 13. A drug for the treatment of influenza infection in the form of capsules, tablets or injections in a pharmaceutically acceptable package that contains a clathrate complex of β-cyclodextrin with 1 - {[6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1- H-indol-3-yl] carbonyl} -4-benzylpiperazine of the formula (1) in a molar ratio of 1 - {[b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl ] carbonyl} -4-benzylpiperazine of formula (I): β-cyclodextrin in the range from 1: 1 to 1:10, preferably in a ratio of 1: 3 to 1: 7, according to claim 1 or 2, or a pharmaceutical composition for them the basis of claim 10 or 11, in an effective amount.

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