EA024643B1 - Clathrate complexes of beta-cyclodextrin and 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonyl indole derivative, which exhibit an anti-viral effect, and methods for producing the same - Google Patents

Abstract

The invention relates to a novel clathrate complex (inclusion compound) of β-cyclodextrin and 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonyl indole derivative, which has a molar ratio of 1:1 to 1:5. The clathrate complex may be in the form of nanoparticles of a size of less than 100 nm. Preferred are clathrate complexes, wherein 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonyl indole derivative is 1- cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester. Novel clathrate complexes exhibit an anti-viral effect and are highly active against influenza viruses. The invention also relates to a pharmaceutical composition and a drug based on the clathrate complexes. Furthermore, the invention relates to liquid-phase and solid-phase synthesis of the clathrate complexes.

Description

The invention relates to new clathrate complexes (inclusion compounds) of β-cyclodextrin with a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3 alkoxycarbonylindole having an antiviral effect, and methods for their preparation. Clathrate complexes may find application in the pharmaceutical industry. 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, phytoamino acid complexes exist and are in demand as part of a cyclodextrin capsule. 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 the mucous membranes is described (see RF patent 2005115883, published in 2006). Assessment of the overall potential of drug transport systems based on inclusion complexes is described in RF patent 2121830, publ. in 1998

New forms and ways of transporting drugs can expand the therapeutic potential of the prescribed treatment. 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, publ. in 1998, a water-soluble drug composition and a method for its preparation for such well-known preparations as Sibazon, Azaleptin, Mezapam, Indomethacin are described. Pharmacological tests of the obtained complexes in laboratory animals showed a several-fold decrease in the therapeutic dose of 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, 2 45, are known (2). I8 4727064, RF patent 2337710, publ. In 2008, 1. δζςίΐΐκ 1pbiChpa1 Arriesayoik sos1obekh1pp5. Ιη 1is1i8yup Soshroipbk, ν. 3. e. -Υ., 1984, p. 331-390).

There are also many publications on 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, 2377243, 2247576, ΌΕ19814815 A1, ΌΕ19814814 A1, υδ4956351, υδ5221669, applications υδ 2005/0209189, υδ2005 / 0281872, υδ2009 / 0286757, ТР10-045319, 1Р58-092691, 1Р-2005-179329 ТР-9-015632). For example, in the patent of the Russian Federation 2128664, publ. 04/10/1999, describes the inclusion compounds of 9-2-hydroxyethoxymethylguanine (acyclovir) with β-cyclodextrin having antiherpes activity, as well as liquid-phase and solid-phase methods for their preparation. The liquid-phase method consists in the phased dissolution of the components at a certain ratio in water or water-alcohol solutions when heated, followed by 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 in the form of a finely dispersed moving powder. In RF patents 2242974, 2357968, 2377243, crystalline forms and nanoforms of cyclodextrin clathrates and anti-inflammatory drugs are described. In 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.

In the patent of the Russian Federation 2386616 describes derivatives of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindoles, as well as their pharmaceutically acceptable salts having antiviral activity.

The objective of this study is to find new clathrate complexes of β-cyclodextrin with an antiviral compound, which is a derivative of 5-hydroxy-4aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole, which have increased solubility in water, improved bioavailability. The proposed clathrate complexes can reduce the dosage of the drug, and, therefore, reduce the toxicity of the drug. The present invention is also the development of new methods for producing clathrate complexes and their use in pharmaceutical compositions and drugs.

The present invention relates to novel clathrate complexes of β-cyclodextrin with a 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarboylindole derivative corresponding to the general formula (Ι) in a molar ratio of 5-hydroxy-4-aminomethyl-1 derivative - 1,024,643 cyclohexyl (or cycloheptyl) -3-alkoxycarboylindole: b-cyclodextrin from 1: 1 to 1: 5.

where X is hydrogen, chlorine, iodine; n is 1 or 2;

K ₃ represents a C1 to _C3 alkyl;

ABK means a C ₁ -C ₆ alkyl group;

Κι, K _{2 are} independently selected from C -C ₄ -alkyl, preferably methyl, or Кι and K ₂ together with a nitrogen atom (i.e., the group -ΝΚιΚ ₂ ) means groups corresponding to the formulas:

rp ι I

in which Bp means benzyl;

PH means phenyl.

Pharmaceutically acceptable salts include, first of all, hydrohalides, for example hydrochlorides, mesylates, oxalates, tosylates, malonates, phosphates, etc.

A preferred clathrate complex is the complex of β-cyclodextrin with 5-hydroxy-4-dimethylamino-2-methyl-1-cyclohexyl-1H indole-3-carboxylic acid ethyl ester (formula (II) and its hydrochloride (compound A):

It should be noted that in the clathrate complex the molar ratios of the derivatives of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: β-cyclodextrin vary in the range from 1: 1 to 1: 5, allowing the compound to be completely converted to clathrate complex, which significantly affects its bioavailability.

It was found that the clathrate complex, like the nanocomplex proposed according to the present invention, has an antiviral effect and can be used to obtain most of the dosage forms and routes of administration used in medicine.

The invention also relates to a pharmaceutical composition having an antiviral effect, comprising in an effective amount the above clathrate complex of β-cyclodextrin with 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3 alkoxycarbonylindole derivatives of the general formula (I) (possibly in the form of nanoparticles) in a molar ratio of the above and pharmaceutically acceptable excipients.

The invention also relates to a medicament in the form of capsules or tablets in a pharmaceutically acceptable package containing a clathrate complex of β-cyclodextrin with a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole of general formula (I) with the molar ratio of the above, or a pharmaceutical composition based on it in an effective amount.

In this case, the clathrate complex can be used in the pharmaceutical composition or in the drug in the form of nanoparticles with a size of less than 100 nm.

The concept of an effective amount used in this description means the use of that amount of a compound of formula (I), which, together with its indicators of activity and toxicity, as well as based on specialist knowledge, should be effective in this pharmaceutical

- 2 024643 composition or dosage form.

If necessary, the pharmaceutical composition may contain adjuvants, such as fillers, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors. Pharmaceutically acceptable additives may be selected, for example, 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 additives, such as diluents, binders, disintegrating agents, adsorbents, flavoring agents, flavoring agents.

The specified pharmaceutical composition and drug can be obtained by methods known in the pharmaceutical industry.

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.

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.

The clathrate complexes proposed according to the present invention can be obtained in two ways:

1) liquid-phase synthesis method;

2) solid-phase synthesis method.

The liquid-phase method consists in preparing an aqueous solution of the starting β-cyclodextrin and the alcohol corresponding derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole, which are then mixed with stirring and heating to a temperature not higher than 75 ° C, at a molar ratio of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole derivative or a pharmaceutically acceptable salt thereof: β-cyclodextrin from 1: 1 to 1: 5, followed by stirring at the indicated temperature to the floor eniya homogeneous solution and isolating the resulting crystalline clathrate complex. According to the present method, non-covalent clathrate complexes stabilized by hydrogen bonds are prepared. Non-covalent complex is a complex that is formed between the molecules of substances in a suitable solvent due to intermolecular van der Waals interactions of a non-covalent nature, namely, hydrogen bonding.

The solid-phase method consists in the fact that β-cyclodextrin and a crystalline derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole or a pharmaceutically acceptable salt thereof are subjected to grinding at a rate of 400 to 800 rpm in a period of time from 10 to 60 minutes, usually in a planetary ball mill, in modes from Impact-Shear to Impact, with a molar ratio of 5-hydroxy-4aminomethyl-1-cyclohexyl derivative (or cycloheptyl) - 3-alkoxycarbonylindole or its pharmaceutically riemlemaya salt: β-cyclodextrin from 1: 1 to 1: 5 (for compound A are optimal ratio of 1: 1 and 1: 2), with separation of the resulting crystalline clathrate complex, optionally in the form of nanoparticles with a particle size of less than 100 nm.

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 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 as a selection of the conditions of mechanical action on the crystal (exposure energy, duration, the ratio between

- 3 024643 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, electrozonal sensing (using a Coulter counter), microscopy, small-angle laser light scattering Llb (the abbreviation for Losu-Lpds Lakeg-Bsl-BaSpppd is small-angle laser light). 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.

The clathrate complex obtained according to the present invention, in comparison with the previously known similar in structure and used in industry antiviral compound - arbidol, has not only increased solubility and bioavailability, but also increased activity, which is unexpected and not obvious for this clathrate complex.

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

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 0.25 L of ethanol at the same temperature as cyclodextrin. With stirring and heating, a solution of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride is added to the 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. The alcohol from the solution was evaporated, and the aqueous residue was sent for freeze drying.

2. The solid-phase method. The tests were carried out on a ball planetary mill Activator 28 with the material of grinding cups of aluminum oxide. The optimal regime was 400 rpm for 5 min, 600 rpm for 10 min, 400 rpm for 5 min, balls of 10 mm (zirconium oxide) to obtain the compound A: b-cyclodextrin complex. The molar ratios of the components also ranged from 1: 1 to 1: 3.

Thanks to precisely these regimes, complexes were obtained with an optimal set of spectral data and solubility. The resulting complex had a particle size of less than 100 nm.

In more detail, the preparation of the clathrate complex (1: 1) in the form of nanoparticles with the indicated size is confirmed by the analysis performed on the ΖοΚίδίζοΓ Ναηο Ζδ device (Fig. 1). The measurement conditions are as follows: dispersion in water. The density is 1.330, the viscosity is 0.8886 cP, the temperature is 25 ° C, the attrition rate is 210, and the average diameter of the particles obtained in this case is 32.6 nm.

According to the above procedure, a number of clathrate complexes of compounds of the general formula (I) with β-cyclodextrin were obtained for compound A:

5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cycloheptyl-3-ethoxycarbonylindole: cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5),

5-hydroxy-4-diethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole: β-cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5),

6-chloro-5-hydroxy-4-dimethylaminomethyl-2-ethyl-1-cyclohexyl-3-ethoxycarbonylindole: cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5),

6-iodine-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole: cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5),

5-hydroxy-4-morpholinomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole or its hydrochloride: β-cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5) ,

5-hydroxy-4 - ^ - methylpiperazino) methyl-2-ethyl-1-cyclohexyl-3-ethoxycarbonylindole, its hydrochloride or mesylate: b-cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5),

5-hydroxy-4 - ^ - benzylpiperazino) methyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole and its hydrochloride: β-cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5)

5-hydroxy-4 - ^ - phenylpiperazino) methyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole, its oxalate and hydrochloride: β-cyclodextrin (molar ratios from 1: 1, 1: 2, 1: 3, 1: 4, 1: 5).

The formation of clathrate complexes is confirmed by a set of spectral data.

For compound A.

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

- 4,024,643

As a specific example, comparative UV spectra of pure compound A, complexes in a ratio of 1: 2 and 1: 3, as well as pure β-cyclodextrin, are presented. The results are shown in FIG. 2-5 respectively.

Solvent: water.

Compound A: 0.0483 g in 25 ml of solvent.

CD: Compound A = 1: 1: 0.1862 g in 25 ml of solvent.

CD: Compound A = 2: 1: 0.3245 g in 25 ml of solvent.

TSC: (cyclodextrin): 0.1750 g in 50 ml of solvent.

To take the spectra, these solutions were diluted 100 times. Samples of the samples contained the same amount of compound A (0.0483 g); therefore, the decrease in the absorption intensity can be attributed to the screening of the molecule of compound A with β-cyclodextrin, i.e. complex formation.

In addition, a comparative analysis of the IR spectra of pure compound A and complex preparations (ratios 1: 1 and 1: 2) was carried out, FIG. 6-8 respectively.

It is clearly seen on these spectra that the signals of characteristic groups of compound A overlap: absorption bands in the region of 2700-2900 cm ^-1 associated with stretching vibrations of -CH and -CH2 groups of the cyclohexyl fragment, absorption bands in the region of 1750 cm ^-1 associated with valence vibrations of the ester group —COOC2H ₅ , absorption bands of 1400-1600 cm ⁻¹ , corresponding to stretching vibrations of CC bonds of the benzene ring, and also absorption bands of 1250 cm ^{−1 to the} corresponding phenyl —OH group. 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.

According to the set of physical and chemical characteristics, the molar ratio of the compound A ^ -cyclodextrin 1: 2 is optimal.

Tablets:

Clathrate complex 100 mg.

Compounds A and β-cyclodextrin in a 1: 2 molar ratio.

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

Obtained by mixing the components in a Vesoset mixer and pressing on a Rppes tableting machine.

Capsules:

Clathrate nanocomplex 100 mg.

Compounds A and β-cyclodextrin in a 1: 2 molar ratio.

Possible additives: microcellulose, lactose, starch.

Obtained by mixing the components in a Vesoset mixer and filling gelatin capsules

3US.

A comparative study of the antiviral activity of compound A and the complex form of the compound A compound with β-cyclodextrin in a ratio of 1: 2.

Antiviral activity of the obtained complex 1-cyclohexyl-4aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester with β-cyclodextrin in the form of nanoparticles at a ratio of 1: 2 and 1-cyclohexyl-4- native ethyl ester aminomethyl-5-hydroxy2-methyl-1H-indole-3-carboxylic acid was studied in experiments on the model of influenza pneumonia in mice. The effectiveness of the compounds was evaluated in terms of protection against mortality and life expectancy of virus-infected and treated animals.

In a preliminary experiment, the dose of virus A / Aichi / 2/69 containing 10 TH ₅₀ was determined.

For this, groups of 5-6 mice were infected with the whole allantoic virus and its successive 10-fold dilutions. Data on the observation of animals for 15 days are presented in table. 1. Studies on the antiviral activity of the antivirus ίη νίνο were carried out at the Center for Chemistry of Medicinal Products (TsHLS-VNIHFI). The research results are given in table. 1 and 2.

Table 1

Determination of LH ₅₀ in a mouse influenza pneumonia model

The time of the introduction of the virus The number of mice in the group Survivors / dead Mortality% Whole virus 4 0/4 one hundred 10-1 5 0/5 one hundred 10-2 5 0/5 one hundred 10-3 5 3/6 fifty 10-4 6 6/0 0 10-5 5 5/0 0

From the data presented it is clear that 50% of the death of animals causes infection with the virus 10 ^-3 . All animals in the experiment were infected with a dose of the virus with a multiplicity of 10 TH ₅₀ .

- 5,024,643

table 2

Study of the effectiveness of the native form of an antiviral agent and its clathrate complex with cyclodextrin in a model of influenza infection in mice

Pre- parat 1 experience 2 experience Surviving the bridge Impressions tel sewn up s from death awn% Medium nanny longitudinal resident of nost of life (days) Surviving st Impressions tel Protection against death awn% Average continuous resident of- nost of life (days) ** alive / the general % death nosti alive / total her % mora tnos tee Native form thirty mg / kg / day 5/10 fifty 40 10.6 (1-5 d, 3-6 d., M3 d.) 4/10 60 40 9,4 (2-5 I, 3-7d „ 1-9 i) 60 mg / kg / day 5/10 fifty 40 10.3 (1-5 I, 1-6 I 2-7 d., 1-8 i) 3/10 70 thirty 9.5 (1-5 D 5-7 d., 2-9 d.) Clathrate form with cyclodextrin thirty mg / kg / day 7/10 thirty 60 13,4 (1st I, 2-11 d.) 7/10 thirty 70 14.1 (1-11 I, 2-10 d.) 60 mg / kg / day 6/10 40 fifty 12.6 1-3 i 1-6 I 2-8 d.) 6/10 40 60 13,2 (2-10 I, 4-7 d., 1-9 i) Viral control 1/10 10 90 6.2 (4-5d., 2-6d „ 1-7d., 1-8d 1-9d.) 0/10 one hundred 5.7 (3-5 I, 4-7d „ 3-8 d.)

* Treatment regimen: 24 and 1 hour before infection, then 8, 24, 48, 72, and 96 hours after infection.

** Average life expectancy was determined by the formula ΣΓ (6-1) / η, where G is the number of mice that died on day b (surviving mice are included in G and b in this case is 16), η is the number of mice in the group.

The data given in table. 2, indicate that the preparation of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester in the form of a clathrate complex with β-cyclodextrin at a ratio of 1: 2, used in doses of 30 and 60 mg / kg / day in antiviral activity exceeded the native ethyl ester of 1-cyclohexyl-4-aminomethyl-5hydroxy-2-methyl-1H-indole-3-carboxylic acid, as evidenced by the mortality protection indicators of 50-70 and 30-40% respectively.

Claims (24)

1. The clathrate complex of β-cyclodextrin with a derivative of 5-hydroxy-4-aminomethyl-1cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole of the general formula (I) having antiviral activity: where X is hydrogen, chlorine, iodine; n is 1 or 2; K ₃ is C ₁ -C ₃ alkyl; ABK is a C ₁ -C ₆ alkyl group; K ₁ , K _{2 are} independently selected from C ₁ -C ₄ alkyl, which is methyl, or K ₁ and K ₂ together with a nitrogen atom form a group corresponding to the formulas: in which Bp means benzyl; Py means phenyl, in a molar ratio the 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: b-cyclodextrin derivative is from 1: 1 to 1: 5. 2. The clathrate complex according to claim 1, wherein the molar ratio of β-cyclodextrin and 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole derivative is from 1: 1 to 1: 3. 3. The clathrate complex according to claim 2, in which the molar ratio of β-cyclodextrin and derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole is 1: 2. 4. The clathrate complex according to any one of claims 1 to 3, according to which it is a nanoparticle with a size of less than 100 nm. 5. The clathrate complex according to claim 1, wherein the 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole derivative is 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H ethyl ester -indole-3-carboxylic acid. 6. The clathrate complex according to claim 5, having activity against influenza viruses A. 7. The liquid-phase method for producing the clathrate complex according to claim 1, which consists in mixing an aqueous solution of β-cyclodextrin and an alcohol solution of the corresponding 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole derivative of the general formula (I) or a pharmaceutically acceptable salt thereof, in a molar ratio, of a 5-hydroxy-4aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole derivative or a pharmaceutically acceptable salt thereof: β-cyclodextrin from 1: 1 to 1: 5 with stirring and heating to temperament rounds no higher than 75 ° C, then kept with stirring at the indicated temperature until a homogeneous solution is obtained, followed by isolation of the resulting clathrate complex. 8. The method according to claim 7, characterized in that a molar ratio of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: β-cyclodextrin from 1: 1 to 1: 3 is used. 9. The method according to claim 8, characterized in that a molar ratio of the derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: β-cyclodextrin equal to 1: 2 is used. 10. The method according to claim 7, according to which as the derivative of 5-hydroxy-4-aminomethyl-1cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole of the general formula (I) 1-cyclohexyl-4-aminomethyl-5-hydroxy- ethyl ester is used 2-methyl-1H-indole-3-carboxylic acid. 11. The solid-phase method for producing the clathrate complex according to claim 1, characterized in that β-cyclodextrin and the corresponding derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cyclo-7 024643 heptyl) -3-alkoxycarbonylindole of the general formula (I) or a pharmaceutically acceptable salt thereof, is subjected to grinding in a ball mill at a speed of 400 to 800 rpm for a time of 10 to 60 minutes at a molar ratio of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole derivative or its pharmaceutically acceptable salt: β-cyclode Stryneelva from 1: 1 to 1: 5 at a temperature of from 30 to 60 ° C to obtain a clathrate complex, which if necessary additionally milled to obtain a product in the form of nanoparticles of less than 100 nm. 12. The method according to claim 11, characterized in that the 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole derivative: β-cyclodextrin is used in a molar ratio of from 1: 1 to 1: 3. 13. The method according to p. 12, characterized in that the molar ratio of the derivative of 5-hydroxy-4aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: β-cyclodextrin is 1: 2. 14. The method according to claim 11, whereby 1-cyclohexyl-4-aminomethyl-5-hydroxy- ethyl ester is used as the derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole of the general formula (I) 2-methyl-1H-indole-3-carboxylic acid. 15. The method according to any one of claims 11 to 13, wherein the clathrate complex is obtained in the form of nanoparticles with a size of less than 100 nm. 16. A pharmaceutical composition having an antiviral effect, which contains an effective amount of a clathrate complex of β-cyclodextrin with a derivative of 5-hydroxy-4aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole of the general formula (I) according to claim 1 and a pharmaceutically acceptable filler. 17. The pharmaceutical composition according to clause 16, having activity against influenza A virus or influenza B virus or influenza pneumonia. 18. The pharmaceutical composition according to clause 16, which contains a clathrate complex of β-cyclodextrin with a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3alkoxycarbonylindole of the general formula (I) in a molar ratio of the derivative of 5-hydroxy-4aminomethyl- 1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: β-cyclodexΊrin from 1: 1 to 1: 3. 19. The pharmaceutical composition according to p. 18, in which the molar ratio of the derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: β-cyclodextrin is 1: 2. 20. The pharmaceutical composition according to clause 16, which contains a clathrate complex of β-cyclodextrin with a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3alkoxycarbonylindole of the general formula (I) according to claim 1 in the form of nanoparticles with a size of less than 100 nm 21. The pharmaceutical composition according to claim 16, which contains 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester in the clathrate complex as a derivative of 5-hydroxy-4-aminomethyl -1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole. 22. A dosage form having antiviral activity in the form of capsules, tablets or injections in a pharmaceutically acceptable package that contains a clathrate complex of β-cyclodextrin with a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3 alkoxycarbonylindole of the general formula ( I) according to claim 1 or a pharmaceutical composition based on it according to clause 16 in an effective amount. 23. The dosage form according to claim 22, wherein the molar ratio of the 5-hydroxy-4aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole: β-cyclodextrin derivative of the general formula (I) is from 1: 1 to 1: 3. 24. The dosage form according to claim 22, characterized in that it contains a β-cyclodextrin clathrate complex and 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester as a 5-hydroxy derivative -4-aminomethyl-1-cyclohexyl (or cycloheptyl) -3-alkoxycarbonylindole.