β-cyclodextrine clathrate complex with 5-hydroxy-4-aminomethyl-1 -cyclohexyl(or cycloheptyl)-3-alkoxycarbonylindole derivative, method for preparing it (versions), pharmaceutical composition and drug

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new β-cyclodextrine clathrate complex (an inclusion compound) with 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylindole derivative: β-cyclodextrine 1:1 to 1:5, preferentially at the relation of 1:1 to 1:3 of general formula (I): wherein X means - hydrogen, chlorine, iodine, n=1 or 2, R3-C1-C3 alkyl, ALK means C1-C6 alkyl group, R1, R2 are independently specified in C1-C4-alkyl, preferentially methyl, or R1 and R2 together with a nitrogen atom (i.e. group - NR1R2) means the groups described by formulas: wherein Bn is benzyl, a Ph is phenyl with the molar ratio of 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylindole derivative: β-cyclodextrine 1:1 to 1:5, preferentially 1:1 to 1:3, especially preferentially in the relation of 1:2. The clathrate complex may represent nanoparticles of size not less than 100 nm. There are preferential clathrate complexes wherein 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylindole derivative represents 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester. The new clathrate complexes possess antiviral action and exhibit high activity versus influenza viruses. The invention also involves a pharmaceutical composition and a drug based on the clathrate complexes. Besides, the invention refers to liquid-phase and solid-phase synthesis of the clathrate complexes.

EFFECT: preparing the compounds which possess antiviral action and exhibit high activity versus influenza viruses.

20 cl, 2 ex, 2 tbl, 8 dwg

 

The invention relates to a new clathrate complexes (connection connection) β-cyclodextrin derived from 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl possessing antiviral activity, and methods for their preparation. Clathrate complexes can find application in the pharmaceutical industry. The invention also relates to compositions and medicines on the basis of new clathrate complexes of cyclodextrin.

Currently active substances complexes with cyclodextrins have been applied not only in the pharmaceutical industry, but also in cosmetics. For example, there are demand complexes photoamination part cyclodextrines capsules. Similar complexes of cyclodextrin with monosaccharides, uronic acids.

Getting clathrate complexes in the solution of transport problems of drugs has a significant impact on virtually every route of administration from oral to injection. Describes the future development of systems targeted delivery and transportation systems through the mucous membranes (see RF patent 2005115883, publ. 2006). To evaluate the overall capacity of the transportation systems of medicines on the basis of the inclusion complexes described in the patent of the Russian Federation 2121830, publ. in 1998

New forms and ways of transportation is of medicines can expand therapeutic potential of prescribed treatment. Technology transportation of drugs on the basis of the complexes can significantly change the existing drugs, improving their bioavailability, reducing therapeutic dose. In the patent of the Russian Federation 2121830, publ. in 1998, described water-soluble drug composition and its preparation for such well-known drugs as Sibazon, Azaleptin, Medazepam, Indomethacin. Pharmacological tests of the obtained complexes in laboratory animals showed a decrease in therapeutic doses of the drug several times.

Molecules cyclodextrins have a toroidal shape, and its inner cavity is hydrophobic. Water-soluble intermolecular complexes of lipophilic organic compounds in solution due to the intercalation of these molecules in the cavity. Known complexes of β-cyclodextrin with nonsteroidal anti-inflammatory drugs (paracetamol, ibuprofen, Ketoprofen, floranova and mefenamovaya acid and others), steroids, prostaglandins and prostacyclins, barbiturates, sulfonamides, cardiac glycosides and other drugs (see for example, US patents 4524068, US 4727064, RF patent 2337710, published. in 2008, J.Szejtli, Industrial Applications of cyclodextrins. In Inclusion Compounds, v.3. ed. Atwood J.L., Davies J.E., Menicob D.D., Academic Press, N Y., 1984, p.331-390).

It is also known many publications about connections inclusion (clathrate complex is s) α - or β-cyclodextrin with antiviral compounds the methods of their production and use (see, for example, the RF application 2005114097, the patents of the Russian Federation 2288921, 2377243, 2247576, DE 19814815 A1, DE 19814814 A1, US 4956351, US 5221669, bids US 2005/0209189, US 2005/0281872, US 2009/0286757, JP 10-045319, JP 58-092691, JP-2005-179329 JP-9-015632). For example, in the patent of the Russian Federation 2128664, published. 10.04.1999 described compounds include 9-(2-oxetanemethanol(acyclovira) with β-cyclodextrin with Antiherpes activity, as well as liquid-phase and solid-phase methods for their preparation. Liquid-phase method is the gradual 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 release of the finished product. Solid-phase method is mechanical milling of a mixture of crystalline acyclovir and β-cyclodextrin in a vibrating mill. While the product remains crystalline in the form of fine rolling powder. In the patents of the Russian Federation 2242974, 2357968, 2377243 described crystalline forms and nanoform of cyclodextrin clathrates and anti-inflammatory drugs. In the patent of the Russian Federation 2377243 describes a solid-phase method, which includes the preparation of solid dispersions of components with subsequent optional grinding or rubbing the variance.

In the patent of the Russian Federation 2386616 describes derivatives of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxide is belindaloo, and their pharmaceutically acceptable salts, possessing antiviral activity.

The goal of this research is finding new clathrate complexes of β-cyclodextrin with an antiviral compound, representing a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl with improved solubility, improved bioavailability. Offer clathrate complexes can reduce the dosage of the medicinal product and, consequently, to reduce the toxicity of the drug. The present invention also is developing new ways to get clathrate complexes and their use in pharmaceutical compositions and medicines.

The present invention relates to a new clathrate complexes of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonyl-erindale corresponding to General formula (I), at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonyl:β-cyclodextrin is from 1:1 to 1:5.

where X means hydrogen, chlorine, iodine, n=1 or 2

R3-C1-C3alkyl,

ALK - means C1-C6alkyl group,

R1, R2independently selected from C1 -C4-alkyl, mainly methyl, or R1and R2together with the nitrogen atom (i.e., the group-NR1R2) means a group corresponding to the formula

where Bn is benzyl, and Ph is phenyl.

To pharmaceutically acceptable salts include, first of all, hydrogenogenic, such as hydrochloride, mesylates, oxalates, tozilaty, malonate, phosphates and other

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

It should be noted that in clathrate complex molar ratio of the derivatives of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl:β-cyclodextrin vary in the range from 1:1 to 1:5, allowing ions to transfer the connection in the clathrate complex, which significantly affects its bioavailability.

It was discovered that the clathrate complex as nanocomplex proposed according to the present invention, has an antiviral effect and can be used for most applications in medicine drug what s forms and routes of administration.

The invention also relates to a pharmaceutical composition having antiviral activity, comprising an effective amount of the aforementioned clathrate complex of β-cyclodextrin derivative 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) (possibly in the form of nanoparticles) at a molar ratio given above, and pharmaceutically acceptable excipients.

The invention also relates to a medicinal product in the form of capsules or tablets in pharmaceutically acceptable packing containing clathrate complex of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) at a molar ratio indicated above, or a pharmaceutical composition in an effective amount.

This clathrate complex can be used in the pharmaceutical composition or the medicinal agent in the form of nanoparticles with size less than 100 nm

The term "effective amount", as used in this application involves the use of the amount of compounds of formula (I), which, together with its indicators of activity and toxicity, as well as on the basis of knowledge of a specialist should be effective in a given pharmaceutical composition or dosage form.

When n is required, the pharmaceutical composition may contain auxiliary means, such as fillers, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, fragrances, flavors. Pharmaceutically acceptable additives can be selected, for example, from microcellulose, lactose, calcium stearate, starch. The choice and ratio of these components depends on the nature and mode of appointment and the dosages.

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, loosening agents, absorbents, fragrances, flavoring agents.

Specified in the pharmaceutical composition and the drug can be obtained by known pharmaceutical methods.

To obtain pharmaceutical compositions 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 and other Examples of liquid dosage forms for injection and parenteral administration are solutions, emulsions, suspensions, etc. the Receipt of these dosage forms is the traditional pharmaceutical methods is mixing the components, pelletizing, kapsulirovaniem etc.

Clathrate complexes, proposed according to the present invention, can be obtained in two ways:

1) liquid-phase method for the synthesis of

2) solid-phase method for the synthesis.

Liquid-phase method is that cook vodnoy solution of the original β-cyclodextrin and the corresponding alcohol derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl, which are then mixed with stirring and heated to a temperature not higher than 75°C, at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl or its pharmaceutically acceptable salt: β-cyclodextrin is from 1:1 to 1:5, followed by stirring at the same temperature to a homogeneous solution and the allocation obtained crystalline clathrate complex. According to the present method are non-covalent clathrate complexes stabilized by hydrogen bonds. Non-covalent complex - complex, which is formed between the molecules of the substances in a suitable solvent due to intermolecular van der Waals interactions non-covalent nature, namely hydrogen bonding.

Solid-phase method is that β-cyclodextrin and crystalline derivative of 5-hydroc and-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonyl-milindaa or its pharmaceutically acceptable salt at a temperature of 30-60°C, subjected to grinding with a speed of 400 rpm to 800 rpm in a period of time from 10 to 60 minutes, typically at a planetary ball mill, in the regimes of Shock-Shear to the Shock, when the molar ratio of the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl or its pharmaceutically acceptable salt:β-cyclodextrin is from 1:1 to 1:5 (for connection And are optimal ratio of 1:1 and 1:2), emitting the obtained crystalline clathrate complex, optionally in the form of nanoparticles with a particle size less than 100 nm.

From theory of mechanosynthesis known that plastic deformation of a solid body usually leads not only to a change in the shape of a solid body, but also to the accumulation in it of defects that alter the physico-chemical properties, including reactivity. The accumulation of defects can be used in chemistry to accelerate reactions involving solids, temperature reduction processes and other ways of intensification of chemical reactions in the solid phase.

A feature of the process of activation of solids in the mechanical processing is that the activation occurs when the size of the particles as grinding reaches a certain critical value. During mechanical activation is not so much increased surface, skolik the accumulated defects in the whole volume of the crystal. This dramatically changes to many physical and chemical properties of solids, including reactivity.

The increase in reactivity as a result of mechanical activation can be considered as one of the methods of obtaining solids in a metastable active form. Since chemical reactions involving solids, depending on their mechanism differently sensitive to different defects, which are contained in the crystal, the task of mechanical activation is not only to produce the accumulation of defects at all, but to get exactly the type of defects, which is needed for this reaction. This goal can be achieved by selection of the conditions of mechanical stress on the crystal (the energy of the impact, the duration, the ratio between pressure and shear, temperature treatment, the composition of the surrounding atmosphere), and taking into account the specific structure of the crystal, the nature of the chemical bond, its strength characteristics, etc.

For nanoparticles usually get a solid dispersion with subsequent optional grinding or kneading solid dispersion to obtain the appropriate particle size. Fine grinding particles can be carried out mechanically by applying to the particles a force, which PR is coming their chopping. Such a force may be provided by the collision of particles, which is given high speed, with each other. Pulverisation order to obtain fine particles can be carried out, for example, by grinding, using an air-jet micron colloidal mill, using a ball mill or a pin mill. The size of the resulting nanoparticles can be determined by any means known in the industry. Can be used, for example, the following methods: sieving through sieves, sedimentation, electrozone senseaware (using a counter of Coulter), microscopy, small-angle laser light scattering LALLS (an acronym for Low-Angle Laser Light-Scattering - angle laser light scattering). Preferred for use in the present invention are methods of measuring particle sizes, the most widely used in the pharmaceutical industry, such as laser diffraction or sieve analysis.

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, and increased activity that is unexpected and unobvious to this CL is tretego complex.

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

The following examples illustrate the invention.

1. Liquid-phase method. Calculated a portion of β-cyclodextrin was dissolved in 0.5 l of distilled water at t-re 65-70°C. a portion of the connection And was dissolved in 0.25 l of ethanol at the same t-re, and cyclodextrin. Under stirring and heating the solution of the hydrochloride of the ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid prilisaetsa to a solution of cyclodextrin. After mixing was continued to maintain the temperature at 65-70°C to obtain the true solution, then for 2 hours reduced the temperature to 55°C. the Alcohol from the solution was evaporated and the aqueous residue was sent lyophilic drying.

2. Solid-phase method. Tests were conducted in a planetary ball mill Activator 2s with the material of the grinding jar of aluminum oxide. Was optimal mode 400 rpm, 5 min, 600 rpm, 10 min, 400 rpm, 5 min, balls 10 mm (zirconium oxide) to obtain a complex compound a: β-cyclodextrin. Molar ratio of the components also varied from 1:1 to 1:3.

Thanks to these modes were obtained complexes with an optimal set range of the selected data and solubility. The resulting complex had a particle size less than 100 nm.

More getting clathrate complex (1:1) nanoparticles with the specified size confirms the analysis performed on the instrument Zetasizer Nano ZS (figure 1). Conditions of measurement are as follows: dispersion in water. Density 1330, viscosity 0,8886 Wed, 25°C, the rate of abrasion 210, the average diameter of the resulting particles 32.6 nm.

Similar complexes were obtained:

5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cycloheptyl-3-ethoxycarbonylethyl:β-cyclodextrin (molar ratio of from 1:1, 1:2, 1:3, 1:4, 1:5);

5-hydroxy-4-diethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl:β-cyclodextrin (molar ratio of from 1:1, 1:2, 1:3, 1:4, 1:5);

6-chloro-5-hydroxy-4-dimethylaminomethyl-2-ethyl-1-cyclohexyl-3-ethoxycarbonylethyl:β-cyclodextrin (molar ratio of from 1:1, 1:2, 1:3, 1:4, 1:5);

6-iodine-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl:β-cyclodextrin(molar ratio of from 1:1, 1:2, 1:3, 1:4, 1:5);

5-hydroxy-4-morpholinomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl or its hydrochloride:β-cyclodextrin (molar ratio of from 1:1, 1:2, 1:3, 1:4, 1:5);

5-hydroxy-4-(N-methylpiperazine)methyl-2-ethyl-1-cyclohexyl-3-ethoxycarbonylethyl, its hydrochloride or mesilate:β-cyclodextrin (molar ratio of from 1:1, 1:2, 1:3, 1:4, 1:5);

5-hydroxy-4-(N-benzylpiperazine the but)methyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl and its hydrochloride:β-cyclodextrin (molar ratio 1:1, 1:2, 1:3, 1:4, 1:5);

5-hydroxy-4-(N-phenylpiperazine)methyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl, its oxalate and hydrochloride:β-cyclodextrin (molar ratio of from 1:1, 1:2, 1:3, 1:4, 1:5).

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

To connect:

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

As a concrete example comparative UV spectra of pure compounds And complexes in the ratio 1:2 and 1:3, and the pure β-cyclodextrin. The results are shown in figures 2, 3, 4 and 5, respectively.

Solvent: water

Connection:0,0483 g in 25 ml of solvent
CD: Connection A=1:10,1862 g in 25 ml of solvent
CD: Connection A=2:10,3245 g in 25 ml of solvent
CD:(cyclodextrin)0,1750 g in 50 ml of solvent

For removal of the spectra of these solutions are diluted 100 times. Weighed samples contained the same number of connections And (0.0483 g), so the drop in intensity of the absorption can be attributed to the shielding molecule compounds And β-cyclodextrin, i.e. the education of the complex.

In addition, the comparative analysis of the IR spectra of pure Compounds And complex products (ratio 1:1 and 1:2), figures 6-8, respectively.

These spectra clearly shows that there is an overlap of the signals characteristic of the connection groups: the absorption bands in the area 2700-2900 cm-1associated with the stretching vibrations of-CH and-CH2groups tsiklogeksilnogo fragment, the absorption band in the region of 1750 cm-1associated with the stretching vibrations of the ester group-COOC2H5, absorption bands 1400-1600 cm-1corresponding to the stretching vibrations of relations With the benzene ring, as well as the absorption band 1250 cm-1corresponding phenyl-OH group. This fact suggests that the molecule antiviral drug is in the cavity of the cyclodextrin molecules, due to which there is overlap between the signals and unambiguously confirmed the formation of clathrate complexes.

On set of physico-chemical characteristics of the optimal is the molar ratio of the Compound a: β-cyclodextrin 1:2.

TABLETS

Clathrate complex 100 mg

The compounds a and β-cyclodextrin

when the molar ratio of 1:2.

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

Is produced by mixing the components in the mixer Bectochem and pressing on the letterwise car Rimec.

CAPSULES

Clathrate nanocomplex 100 mg

The compounds a and β-cyclodextrin

when the molar ratio of 1:2.

Possible additives: microcellulose, lactose, starch.

Is produced by mixing the components in the mixer Bectochem and filling gelatin capsules 3VC.

A comparative study of the antiviral activity of the Compound, and complex forms of the drug Compound And β-cyclodextrin at a ratio of 1:2.

Antiviral activity of the obtained complex ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid with β-cyclodextrin in the form of nanoparticles at a ratio of 1:2 and native ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-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 from mortality and life expectancy virus infected and treated animals.

In a preliminary experiment was determined dose of the virus A/Aichi/2/69 containing 10 LD50.

For this group, consisting of 5-6 mice were infected whole allantoin virus and serial 10-multiples of its dilutions. Data monitoring animals during the 15 days are shown in table 1. Studies on the antiviral activity of protivovirusny in vivo held in the center of the x is MIA medicines (CHLS-UNIFI). The research results are summarized in tables 1 and 2.

Table 1
Determination of LD 50 on the model of influenza pneumonia mice
the introduction of a VirusThe number of mice in groupSurvivors/victimsMortality, %
Whole virus40/4100
10-150/5100
10-250/5100
10-353/650
10-466/00
10-555/00

From the presented data shows that 50% causes the death of animals infected with a virus 10-3. All animals in the experiment were INF is s dose of the virus with multiplicity 10 LD 50.

Table 2
Study of the effectiveness of the native form of the antiviral agent and its clathrate complex with cyclodextrin on the model of influenza infection in mice
Medication1 experience2 experience
SurvivalThe measure of protection from mortality %)Life expectancy (days)SurvivalThe measure of protection from mortality (%)Life expectancy (DAYS)∗∗
alive/total% mortalityalive/ total% mortality
The native form
30 mg/kg/day5/1050401,6 (1-5 days, 3-6 D., 1-13 days)4/1060409,4 (2-5 days, 3-7 days, 1-9 days)
60 mg/kg/day5/10504010,3 (1-5 l, 1-6 days, 2-7 days, 1-8 days)3/1070309,5 (1-5 days, 5-7 l, 2-9 days)
Clathrate form with cyclodextrin
30 mg/kg/day7/10306013,4 (1-10 days, 2-11 days)7/10307014,1 (1-11 D., 2-10 days)
60 mg/kg/day6/10405012,6 1-3 days, 1-6 l, 2-8 days)6/104060 13,2 (2-10 days, 4-7 days, 1-9 days)

Continuation of table 2
Virus control
1/1010906,2 (4-5 l, 2-6 days, 1-7 days, 1-8 D., D., 1-9 days)0/101005,7 (3-5 days, 4-7D., 3-8.)
Treatment: 24 and 1 h before infection, then after 8, 24, 48, 72 and 96 hours after infection
∗∗Life expectancy was determined by the formula Σf(d-1)/n, where f is the number of mice dead at day d (surviving mouse included in f and d in this case is 16), n is the number of mice in the group.

The data are shown in table 2, indicate that the drug ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid in the form of a clathrate complex with β-cyclodextrin at a ratio of 1:2, used at doses of 30 and 60 mg/kg/day, antiviral activity was superior to the native ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid, about what to eat the indicators demonstrate protection from mortality and 50-70 30-40%, respectively.

1. Clathrate complex of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I):

where X means hydrogen, chlorine, iodine, n=1 or 2
R3-C1-C3alkyl,
ALK - means C1-C6alkyl group,
R1, R2independently selected from C1-C4-alkyl, mainly methyl, or R1and R2together with the nitrogen atom (i.e., the group-NR1R2) means a group corresponding to the formula:
,
where Bn is benzyl, a Ph is phenyl, when the molar ratio of the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl: β-cyclodextrin is from 1:1 to 1:5.

2. Clathrate complex of claim 1, wherein the molar ratio of β-cyclodextrin and a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl is in the range from 1:1 to 1:3, preferably at a ratio of 1:2.

3. Clathrate complex according to claim 1 or 2, according to which it represents the nanoparticles with size less than 100 nm.

4. Clathrate complex of claim 1, wherein the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-is alkoxycarbonyl represents the ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid.

5. Clathrate complex according to claim 1, which has antiviral action.

6. Clathrate complex according to claim 5, with activity against influenza viruses A.

7. Liquid-phase method of obtaining a clathrate complex according to claim 1, which is that the mixed aqueous solution of β-cyclodextrin and corresponding alcohol derivative derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) or its pharmaceutically acceptable salt, at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl or its pharmaceutically acceptable salt: β-cyclodextrin in the range from 1:1 to 1:5 with stirring and heated to a temperature not higher than 75°C, then incubated with stirring at the same temperature to obtain a homogeneous solution, followed by separation of the obtained clathrate complex.

8. The method according to claim 7, characterized in that use the molar ratio of the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl: β-cyclodextrin in the range from 1:1 to 1:3, preferably 1:2.

9. The method according to claim 7, whereby as a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) used ethyl ester 1-cyclohe the power-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid.

10. Solid-phase method of obtaining a clathrate complex according to claim 1, characterized in that the β-cyclodextrin and the corresponding derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) or its pharmaceutically acceptable salt is subjected to grinding in a ball mill with a speed of 400 rpm to 800 rpm during the time from 10 to 60 minutes at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl or its pharmaceutically acceptable salt: β-cyclodextrin is from 1:1 to 1:5 at a temperature of from 30 to 60°C, to obtain the clathrate complex, which is optionally milled to obtain a product in the form of nanoparticles with size less than 100 nm.

11. The method according to claim 10, characterized in that the derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl: β-cyclodextrin is used in a molar ratio ranging from 1:1 to 1:3, especially at the ratios of 1:2.

12. The method according to claim 10, whereby as a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) use the ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid.

13. The method of paragraph 10, according to which it is obtained clathrate complex of the nanoparticles with size less than 100 nm.

14. Pharmaceutical composition having antiviral action, which contains an effective amount of the clathrate complex of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl:β-cyclodextrin is from 1:1 to 1:5 according to claim 1 and a pharmaceutically acceptable filler.

15. The pharmaceutical composition according to 14, with activity against influenza a or influenza B, or influenza pneumonia, which contains a clathrate complex of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl:β-cyclodextrin is from 1:1 to 1:5 according to claim 1 in an effective amount and a pharmaceutically acceptable filler.

16. The pharmaceutical composition according to 14, which contains a clathrate complex of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl: β-cyclodextrin is between 1:1 to 1:3, especially at the ratios of 1:2.

17. The pharmaceutical composition according to 14, which contains a clathrate complex of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) according to claim 1 in the form of nanoparticles with size less than 100 nm.

18. The pharmaceutical composition according to 14, which contains a clathrate complex ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid as a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl.

19. The drug is in the form of capsules, tablets or injections in pharmaceutically acceptable packing, which contains a clathrate complex of β-cyclodextrin with the derived 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I) at a molar ratio derived 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I): β-cyclodextrin in the range from 1:1 to 1:5, preferably in the ratio from 1:1 to 1:3, according to claim 1, or a pharmaceutical composition based on 14 in an effective amount.

20. Drug in claim 19, characterized in that it contains clathrate complex of β-cyclodextrin and ethyl ester of 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indol-3-carbon is first acid as a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylmethyl.



 

Same patents:

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

FIELD: chemistry.

SUBSTANCE: method of intensifying antiaggregant activity in an experiment involves use of a chemical compound which is a conjugate of beta-cyclodextrin with acetylsalicylic acid.

EFFECT: wider range of agents for increasing antiaggregant activity.

1 tbl

FIELD: chemistry.

SUBSTANCE: method of obtaining complex with inclusion of cyclodextrin can include dry mixing of cyclodextrin and hydrocolloid for formation of dry mixture and mixing solvent and guest with dry mixture for formation of complex with inclusion of cyclodextrin. In some versions of realisation method of obtaining complex with inclusion of cyclodextrin can include mixing of cyclodextrin and hydrocolloid for formation of first mixture, mixing of first mixture with solvent for formation of second mixture and mixing of quest with second mixture for formation of third mixture.

EFFECT: elaboration of efficient method of obtaining complex with inclusion of cyclodextrin.

41 cl, 17 ex

FIELD: chemistry.

SUBSTANCE: molar ratio of cyclodextrin to the acid in the complex comprises 1:1. The complex is obtained by introduction of concentrated water cyclodextrin solution heated to boiling point to glacial acetic acid of room temperature, with further separation and drying of crystalline sediment. Complex of α- or β-cyclodextrin with acetic acid is stable in dry state, but in water solution it is decomposed into components. Obtained solution gains properties of dilated acetic acid, and therefore can be used as flavouring in food concentrates, as preservation agent, solution acidity regulator, and as buffer component in biochemistry and analytical chemistry.

EFFECT: enhanced efficiency of composition.

3 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to cyclodextrin-containing polymeric compounds, which are carriers for delivery of therapeutics, and pharmaceutical preparations based on them. Invention also relates to method of treating subjects with therapeutically effective quantity of said cyclodextrin-containing polymeric compound. Claimed cyclodextrin-containing polymers improve medication stability, increase its solubility and reduce toxicity of therapeutics when used in vivo. Furthermore, by selecting from a variety of linker groups and targeting ligands of said polymers it is possible to realise controlled delivery of therapeutic agents.

EFFECT: obtaining cyclodextrin-containing polymer compounds, improving medication stability, increasing its solubility and reducing toxicity of therapeutics when used in vivo.

56 cl, 13 dwg, 7 tbl, 46 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to the inclusion complex of cyclodextrins with elemental sulfur. Complex can be prepared using different homologues of cyclodextrins, for example, beta- and gamma-cyclodextrins and hydroxypropylated forms of gamma- and beta-cyclodextrins. Proposed complex can be used as a biologically active compound for medicinal, veterinary and agricultural designation. Invention provides the possibility for further preparing true solutions of elemental sulfur in water in the concentration up to 250-300 mg/l.

EFFECT: improved preparing method, valuable properties of complex.

7 cl, 7 ex

FIELD: chemical technology.

SUBSTANCE: invention describes a method for preparing immobilized β-cyclodextrin. Method involves pretreatment of organic and inorganic sorbents - polyvinyl alcohol and sorbitol based on silica with glutaraldehyde for incorporation of aldehyde group molecules into sorbents, washing out with water and dimethylsulfoxide on glass porous filter, drying on glass porous filter followed by addition of prepared sorbents to dimethylsulfoxide solution containing dissolved β-cyclodextrin in the ratio sorbent : β-cyclodextrin : dimethylsulfoxide = 1.0:(0.4- 2.0);10, respectively, stirring the prepared suspension at temperature 25-70°C for 30-180 min, washing out and drying. Method provides preparing an insoluble sorbent with immobilized β-cyclodextrin used for removing cholesterol or its derivatives.

EFFECT: improved preparing method.

5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a derivative of 6-mercaptocyclodextrin of the general formula (I):

wherein n = 0-7; n = 1-8 and m + n = 7 or 8; R represents (C1-C6)-alkylene substituted optionally with 1-3 OH-groups, or (CH2)o-phenylene-(CH2)p wherein o and p = 0-4 independently; X represents COOH, CONHR1, NHCOR2, SO2OH, PO(OH)2, O(CH2-CH2-O)q-H, OH or tetrazole-5-yl; R1 represents hydrogen atom (H) or (C1-C3)-alkyl; R2 represents carboxyphenyl; q = 1-3; or its pharmaceutically acceptable salt in mixture with pharmaceutically acceptable accessory substances. Also, invention describes a set and pharmaceutical composition for reversing drug-induced neuromuscular blocking comprising derivative of 6-mercaptocyclodextrin of the general formula (I), and a method for reversing drug-induced neuromuscular blockade in patient that involves parenteral administration to indicated patient the effective dose of 6-mercaptocyclodextrine derivative of the general formula (I) by cl. 1.

EFFECT: valuable medicinal properties of agents.

11 cl, 1 tbl, 20 ex

The invention relates to a linear cyclodextrin copolymers and oxidized cyclodextrin, which can be used as a carrier for the delivery of various therapeutic agents

FIELD: chemistry.

SUBSTANCE: invention relates to a novel α-crystalline form of ethyl ether of 6-bromo-5-hydroxy-4-dimethyl aminomethyl-1-methyl-2-phenylthiomethylindole-3-carboxylic acid hydrochloride monohydrate, which is characterised by the following X-ray diffraction parameters

The invention also relates to a method of producing said compound, involving bromination of ethyl ether of 5-acetoxy-1,2-dimethylindole-3-carboxylic acid to obtain ethyl-5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxyl, alkylation thereof with thiophenolate of an alkali metal at temperature 15-60°C for 1-2 hours, to obtain ethyl ether of 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethyl-indole-3-carboxylic acid, aminomethylation thereof with dimethylamine to obtain ethyl ether of 6-bromo-5-hydroxy-4-dimethyl aminomethyl-1-methyl-2-phenylthiomethylindole-3-carboxylic acid with subsequent conversion of the obtained compound to a hydrochloride monohydrate and recrystallisation from ethanol or a mixture of ethanol and acetone.

EFFECT: improved method.

7 cl, 3 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and pharmacology and deals with medication against influenza B virus, representing hydrochloride 1-{[6-bromine-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indole-3-yl]carbonyl}-4-benzylpiperazine.

EFFECT: medication possesses higher activity.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing perindopril of formula (I) or pharmaceutically acceptable salts thereof, protected compound

(I), (IV). The method involves removal of protective groups from a protected compound of formula (IV), where R1, R2 and R3 independently denote H, alkyl, aryl and Cl, via treatment thereof with palladium derivatives with aryl phosphines or biphosphines in protonic or aprotic solvents to obtain perindopril (I), which, if necessary, is treated with a base to obtain its pharmaceutically acceptable salt, followed by, if necessary, recrystallisation thereof from acetonitrile or a mixture of acetonitrile and ethanol.

EFFECT: high yield ratio.

23 cl, 3 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: agent is a 6-bromo-5-methoxy-indole-3-carboxylic acid derivative of general formula (I) , where B is a N(R)2 group, where both R groups together with the nitrogen atom to which they are bonded form a 5-6-member heterocyclic ring containing 1-2 heteroatoms selected from nitrogen, such as pyrrolidine, piperidine, piperazine or morpholine, where each of the said heterocyclic rings can be substituted with C1-4alkyl, phenyl, benzyl, phenethyl, carbonylamino, -COOC1-4alkyl group or -COOC1-4alkyl group and phenyl, which can also be substituted or have substitutes selected from halogen, C1-4alkyl, C1-4alkoxy, and alkyl in the said groups can be linear or branched; R1 is C1-4alkyl, phenyl, possibly substituted with C1-4alkyl or C1-4alkoxy, halogen atoms; R2 is -S-phenyl, -S-benzyl, -O-phenyl, where in each of the said groups, the phenyl ring is possibly substituted with C1-4alkyl, C1-4alkoxy, halogen atoms, or R2 denotes a -N(R)2 group, or pharmaceutically acceptable salts thereof.

EFFECT: agent has antiviral activity towards influenza A virus.

3 dwg, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of perindopril of formula I: . Also proposed are methods for synthesis of amorphous and crystalline perindopril using starting substance in form of stereospecific amino acid, N-[(S)-carbethoxy-1-butyl]-(S)-alanine, which is protected by a trimethylsilyl group and converted to reactive acid chloride using thionyl chloride or its complex with 1-H-benzotriazole (1:1), which reacts with (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid, having a protected carboxy group. The invention also relates to a pharmaceutical composition based on the said crystalline form of perindopril.

EFFECT: novel form of perindopril is obtained, which can be used in medicine for treating cardiovascular diseases.

8 cl, 4 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an agent which has antiviral activity towards influenza A virus, which is a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylindoles of general formula (I) , where X denotes - H; n=1, 2; R3 denotes C1-C5alkyl; Alk denotes C1-C6alkyl; R1 and R2 are independently selected from C1-C4-alkyl, mainly CH3, or its pharmaceutically acceptable salts.

EFFECT: obtaining an agent which has antiviral activity towards influenza A virus.

2 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline form of B (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone hydrochloride, as well as to synthesis method thereof by passing HCl gas through a solution of (3-cyano-1N-indol-7-yl)-[4-(4-fluorophenethyl)piperazin-1-yl] methanone, separating the formed residue from the reaction mixture and drying.

EFFECT: end product can be used in medicine as a medicinal agent which has antagonistic effect on 5-HT2A receptor.

4 cl, 4 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new 3-amino-1-arylpropylindoles of formula I: or to its pharmaceutically acceptable salts, where: p is equal to 1 or 2; Ar means: indolyl, 2,3-dihydroindolyl, indazolyl, benzimidazolyl, benzofuranyl, and each can be substituted; R1 means: phenyl, naphthyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isoxazolyl, pyrazolyl, quinolinyl, aryl-C1-6alkyl where each can be substituted; C3-6cycloalkyl; branched C1-6alkyl; R2 and R3 each independently stands for: H, C1-6alkyl; OH-C1-6alkyl; benzyl; or R2 and R3 together with nitrogen atom whereto attached can form optionally substituted tetra-heptamerous ring, optionally with additional heteroatom chosen from N, O; Ra means H, C1-6alkyl; Rb means H, C1-6alkyl; OH; Rc and Rd each independently means H, C1-6alkyl; Or one of R2 and R3 together with one of Ra and Rb and atoms whereto attached can form penta- or hexamerous ring, optionally with additional heteroatom chosen from O, N; or one of R2 and R3 together with one of Rc and Rd together with atoms whereto attached, can form tetra-hexamerous ring, optinally with additional heteroatom chosen from O, N; Rc means H, C1-6alkyl; provided when p =1, Ra, Rb, Rc and Rd mean H, Ar means indole-1-yl and R1 means C6H5, then R2 and R3 do not mean CH3 and do not form hexamerous ring, and when Ar means indole-3-yl, p =1, Ra, Rb, Rc and Rd means H and R1 means C6H5-, 3-OCH3C6H5- then R2 and R3 do not mean simultaneously H, and when p =1, Ra, Rb, Rc and Rd mean H, Ar means indolyl and R1 means thienyl, pyridinyl, quinolinyl, then one of R2 and R3 means H, and another means C1-6alkyl where possible substitutes are presented in cl.1 of.

EFFECT: compounds express activity of double inhibition serotonin reuptake, possibility to use thereof in making a pharmaceutical composition and a medical product.

32 cl, 7 tbl, 16 ex

FIELD: electricity.

SUBSTANCE: field transistor manufacturing method includes creation of source and drain contacts, active area identification, application of a dielectric film onto the contact layer surface, formation of a submicron chink in the dielectric film for the needs of subsequent operations of contact layer etching and application of gate metal through the resistance mask; immediately after the dielectric film application one performs lithography for opening windows in the dielectric at least one edge whereof coincides with the Schottky gates location in the transistor being manufactured; after the window opening a second dielectric layer is applied onto the whole of the surface with the resistance removed; then, by way of repeated lithography, windows in the resistance are created, surrounding the chinks formed between the two dielectrics; selective etching of the contact layer is performed with metal films sprayed on to form the gates.

EFFECT: simplification of formation of under-gate chinks sized below 100 nm in the dielectric.

6 dwg

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