WO2007120079A2

WO2007120079A2 - 4-aminomethyl-6-bromine-5-hydroxyindol-3-carboxilate derivatives, method for the production (variants) and the use thereof

Info

Publication number: WO2007120079A2
Application number: PCT/RU2007/000179
Authority: WO
Inventors: Rakhimdzhan Akhmetdzhanovich Roziev; Jury Grigorievich Verkhovsky; Fedor Alexandrovich Trofimov; Nina Gavrilovna Tsyshkova; Elena Sergeevna Shevchenko; Elena Ivanovna Burtseva; Anatoliy Fedorovich Tsyb
Original assignee: Obschestvo S Ogranichennoy Otvetstvennostju 'mbf'
Priority date: 2006-04-18
Filing date: 2007-04-13
Publication date: 2007-10-25
Also published as: RU2330018C2; RU2006112818A; WO2007120079A3

Abstract

The invention relates to medicine, in particular to antiviral prophylactic and therapeutic agents and to methods for the production thereof. The inventive agents are embodied in the form of 4-aminomethyl-6-bromine-5-hydroxyindol-3-carboxilate derivatives of general formula (I), wherein R is alkyl, aryl, cyclohexyl, cycloheptyl, R1-C1-C3-alkyl, CH2-X-C1-C5-alkyl, CH2-X-C1-C5-aryl, CH2-X-C1-C5-heterocycle, X is N, O, S, R2 is C1-C5-alkyl, R3 and R4 have equal CH3 or C1-C5-alkyl value, NR3R4 is a 5-10-membered heterocycle which can contain N, O, S in the form of a heteroatom. The methods for producing said derivatives and the use thereof and the salts thereof for preparing medicinal agents for treating influenza of type A or B are also disclosed. The technical result consists of the extended range of antiviral activity.

Description

Derivatives of 4-aminomethyl-6-bromo-5-hydroxy-indole-3-carboxylates, methods for their preparation (options) and application

The invention relates to medicine and relates to antiviral prophylactic and therapeutic agents and methods for their preparation.

Existing antiviral drugs are generally only active against certain viruses. And since more than a thousand varieties of viruses have already been discovered, and about half of them are dangerous to humans, the creation of new antiviral drugs is simply necessary. The mechanism of action of modern antiviral drugs is to block one of the stages of reproduction of viruses in the cells of the virus carrier (human), which includes the step of attaching the virus to the cell and penetrating inside it, embedding the nucleic acid of the virus in the genome of the host cell, synthesis of its own DNA and RNA, synthesis and assembly own proteins of the virus. Most of the available antiviral drugs are nucleoside analogues. They are effective, but after their use, a number of patients have relapses, a rebound phenomenon is possible, leading to an exacerbation of the disease. In addition, a number of antiviral drugs are characterized by the development of virus resistance to them. All of these factors are evidence that only the creation of new antiviral drugs can ensure progress in the treatment of viral diseases.

There are many publications describing derivatives of 6-halogen-5-hydroxyindo l-3-carboxylates.

WO05 / 87729 describes 5-hydroxyind o derivatives of l-3-carboxylates of the general formula M:

SUBSTITUTE SHEET (RULE 26)

where X is halogen, Y means a group NR ₃ R ₄ in which R ₃ and R ₄ can be hydrogen, C _1-10 alkyl, C3 _-7 cycloalkyl, C2-ioalkenyl or C _2-1 O alkynyl or R ₃ and R ₄ together with N form a 5-10 membered heterocycle, which may additionally contain N, 0 or S as a heteroatom,

R ₁ may be C _1-5 alkyl, C _3-7 cycloalkyl,

R ₂ may mean C _1-5 alkyl,

Z-CH ₂ -SR ₅ , CH ₂ -S (O) _n -R ₅ , m = 1, 2; CH ₂ -S (O) _m - (CH ₂ ) _{n (or p)} - (O) _q - Ar, where n, p mean 0-5, q = 0, or n, p and q = 0 or n, p = l-4, q = 0-1. These compounds can be used as medicines against hepatitis B virus (apt-HBV) and human immunodeficiency virus (apt-HI V). Methods for preparing compounds are also described.

WO04 / 0600873 describes compounds of the general formula N:

wherein X is halogen, Z -CH ₂ -SR _5, CH ₂ NR ₆ R _7, R ₁ may denote C _1-10 Alkyl, C _3- ₇ tsikloalkil,

R ₂ may be C _1-4 alkyl, R ₅ may be C ^ alkyl, R ₃ and R ₃ may be hydrogen, alkyl, etc., or R ₃ and R ₃ together with N form a ring. The compounds have a high inhibitory effect in influenza virus and acute respiratory

SUBSTITUTE SHEET (RULE 26) diseases and can be used as anti-influenza agents for the treatment and prevention of acute respiratory disease virus. Also described is a pharmaceutical composition and method for producing compounds.

In CN1482118 describes compounds of general formula N, wherein Z -H, CH2-S-R5 , _b SNgNR RSyoalkyu ^ Sg.ioalkenil or C _2-10 alkynyl which may be used as anti-influenza agents and for the treatment and prevention of acute virus with respiratory disease . Also described is a pharmaceutical composition and method for producing compounds.

JP63-188665 describes b-halogen-5-hydroxy-indole-3-carboxylates of the formula P:

where R ₁ and R _{2 are} hydrogen _; alkyl, aralkyl or together with a nitrogen atom form a heterocyclic group, Rz-alkyl, aralkyl, R ₄ -H, alkyl, cycloalkyl, aryl or aralkyl X-halogen, and their acid addition salts. In particular, methyl 1-cyclohexyl-4-piperidinomethyl-6-bromo-5-hydroxy-indole-3-carboxylate and methyl-1-benzyl-4-piperidinomethyl-6-bromo-5-hydroxyl are disclosed.

The compounds of formula P can be used to treat circulating diseases, such as blood diseases, possess anticoagulation effect, 5-lipogenase inhibitory properties, etc.

Synthesis Chemicals (English), 2004, 15 (9), 1039-1041 describe the synthesis and antiviral activity against influenza virus of ethyl 6-bromo-5-hydroxy-indole-3-carboxylic acid derivatives, in particular 6-bromo ethyl ester -l-cyclopropyl-4-dimethylaminomethyl-5-hydroxy-2 - [(phenylthio) methyl] -Sh-indole-3-carboxylic acid. Jurpaal IPdiam Chemical Company, 1994.71 (4), 175-8, describes the synthesis and antimicrobial activity of derivatives of 5-hydroxyindoles, in particular 6-bromo-5-hydroxy-2-methyl-l- (phenylmethyl) ethyl ester - (l-pyropolidinylmethyl) -Sh-indole-3-carboxylic acid and 6-bromo-5-hydroxy-2-methyl-l- (phenylmethyl) -4- (l-piperidinylmethyl) -Sh-indole-3 ethyl ester carboxylic acid.

WO90 / 08135, RU2033156, A61K 31/40, 1995; RU2033157, A61K 31/405, 1995 describes ethyl ester-6-bromo-5-hydroxy-4- ethyl hydrochloride monohydrate

SUBSTITUTE SHEET (RULE 26) dimethylaminomethyl-l-methyl-2-phenylthiomethylindinol-3-carboxylic acid (Arbidol), which has an antiviral, interferon-inducing and immunomodulating effect, its production method and pharmaceutical composition.

The drug "Apbidol" is not effective enough for some strains of viruses.

The problem solved by the invention is new compounds with a wide spectrum of antiviral activity, a method for their preparation, pharmaceutical composition and use of the compounds. None of the known documents disclose specific compounds of the general formula I indicated below, or the use of the compounds of the general formula I for the treatment or prophylaxis of influenza A and B.

According to the present invention, 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindinolone derivatives of the general formula I are provided:

R is alkyl, aryl, cyclohexyl, cycloheptyl, R ₁ is Ci-C3-alkyl, CH ₂ -X-Ci-C ₅ -alkyl, CH ₂ -X-Ci-C ₅ -apyl, CH ₂ -X-Ci- A C ₅ getqcycle, X is N, O or S, R ₂ is Ci-C ₅ alkyl, R ₃ , R ₄ have the same meaning and are selected from CH ₃ or Q-Cs alkyl, NR ₃ R ₄ - 5-10 member heterocycle, which may contain N, O, S. as a heteroatom

Derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindole of formula I are preferred, wherein R is cyclohexyl, benzyl.

Even more preferred are 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindole derivatives of formula I, wherein R is cyclohexyl, benzyl, R ₁ -methyl, CH ₂ S-phenyl.

The most preferred compounds are derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindole selected from:

6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindole and

6-bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole and l-benzyl-6-bromo-5-hydroxy-2-methyl-4-piperidinomethyl-methoxy.

SUBSTITUTE SHEET (RULE 26) Salts can be prepared by conventional methods, for example, by treating a compound of formula I with an appropriate acid.

Salts include, for example, hydrochlorides, mesylates, oxalates, etc.

A process for preparing compounds of Formula I, Where R _ϊ-Indicates Q-Cs-alkyl comprising the steps of: a) obtained by the known reaction of derivatives of 2-C ₁ -Cz-Alkyl-5- gidpookciindol-3-kapbookcilata formula II:

where R, R ₁ , R ₂ have the above meanings, they are brominated with a brominating agent in an acidic medium to obtain the corresponding 2-alkyl-6-bromo-5-hydroxy-indole-3-carboxylates of the formula III:

where R ₁ , R ₂ , R have the above meanings, b) By reacting the compounds of formula III with the corresponding aminomethylating agent, 4-aminomethyl-6-bromo-5-hydroxy-indole-3-carboxylic acid derivatives of formula I are obtained

A method of obtaining compounds of formula I, where R ₁ means CH ₂ -X-Cj -C ₃ -alkyl, CH ₂ -XC _! -C ₃ -apyl, CH ₂ -X-Ci-C ₃ -heterocycle, X-N, O, S includes the steps of: a) bromination of derivatives of 2-methyl-5-hydroxy-indole-3-carboxylate of formula II:

SUBSTITUTE SHEET (RULE 26)

with the formation of 6-bomo derivatives of formula III:

where R, R ₂ have the meanings indicated above. b) the compounds of formula III are treated with acetic anhydride and receive derivatives of 5-acetoxyindole of the formula IV:

where R, R ₂ have the meanings indicated above c) the compounds of formula IV are brominated into a CH ₃ group and bromomethyl derivatives of the formula V are obtained:

where R, R ₂ have the meanings indicated above d) the compound of formula V is reacted with the corresponding thiol, phenol, primary and secondary amines in an organic solvent medium and after removal of the acetoxy group in an acidic medium, compounds of formula VI are obtained:

SUBSTITUTE SHEET (RULE 26)

where Ri is CH ₂ -XC i-Cz-alkyl, CHg-X-Ci-Cz-aryl, CH ₂ -XC iC ₃ -heterocycle, X -N ₅ O ₃ S. e) the compounds of stage VI obtained aminomethylate appropriate aminomethylating agents and get I.

The proposed antiviral compounds have been shown to be effective against various strains of the influenza virus. However, there are differences in the effectiveness of the proposed drugs and analogue (Arbidol) in relation to different strains. The inventive drugs were effective against other viruses. The claimed drugs are not analogues of nucleosides, which allows us to hope that they will replenish the list of drugs with another softer, not affecting the metabolic processes in cells mechanism of action. Thus, a technical result is achieved.

The invention is described in more detail below. Most preferred is l-benzyl-6-bromo-5-hydroxy-2-methyl-4-piperidinomethyl-3-ethoxycarbonylindole of formula A:

The synthesis method of this compound is carried out according to the following scheme: The available l-benzyl-5-hydroxy-2-methyl-3-ethoxycarbonylindinol used as a starting material is brominated with bromine in acetic acid at room temperature

SUBSTITUTE SHEET (RULE 26) temperature. The resulting product is subjected to aminomethylation with a mixture of piperidine with formalin in an organic solvent, for example, in dioxane. Synthesis Scheme:

CH ₃ COCH ₂ COOC ₂ H ₅ ⁺ H ₂ NCH ₂ Ph ->. CH ₃ CCHCOO

HNCH ₂ Ph

Example 1. l-benzyl-5-hydroxy-2-methyl-3-ethoxycarbonylindole (II). 26.0 (0.2 mol) of acetoacetate and 25.7 (0.24 mol) of benzylamine are dissolved in 50 ml of toluene. To the resulting solution, add 1 drop of concentrated hydrochloric acid and the water released as a result of the reaction is distilled off in the form of an azeotropic mixture with toluene with a Dean-Stark nozzle. After vacuum distillation of toluene and an excess of benzylamine, 50 ml of dichloroethane are added to N-benzyl-β-aminocrotone ether, then a solution of 19.6 (0.18 mol) of p-benzoquinone in 150 ml of dichloroethane is heated to boiling and distilled from the reaction solution 150 ml of an azeotropic mixture of dichloroethane with water. The contents of the flask are poured into a glass and left overnight. The precipitate formed is filtered off, washed with alcohol. Receive 16.0 g (28.7%) of II, so pl. ~ 190 ° (from acetone) Rf 0.43, in the benzene-acetone system (10: 1) on a Silufol UV 254 plate.

SUBSTITUTE SHEET (RULE 26) Example 2. l-benzyl-6-bromo-5-hydroxy-2-methyl-3-ethoxycarbonylindinol

(III). A suspension of 9.3 (0.03 mol) of l-benzyl-5-hydroxy-2-methyl-3-ethoxycarbonylindinolum (II) in 70 ml of acetic acid was added dropwise with stirring at room temperature, 4.8 g (0.03 mol) ) bromine in 10 ml of acetic acid for 30 minutes. After the addition of bromine, stirring was continued for 1 hour at room temperature. The precipitate formed is filtered off, washed with acetic acid, then with water. 10.2 g (87%) of III are obtained, m.p. 188-190 ⁰ C. (from alcohol with acetone). Found,%: C 59.05; H 4.84. C ₁₉ H ₁₈ BrNO ₃ . Calculated,%: C 58.78; H 4.68, identity confirmed by chromatography in a 10: 2 benzene-alcohol system.

Example 3. l-benzyl-6-bromo-5-hydroxy-2-methyl-4-piperidinomethyl-3-ethoxycarbonylindole (I). To 0.17 g (0.002 mol) of piperidine was added 0.4 ml of acetic acid, then 0.34 ml of a 40% formalin solution was cooled with ice water. To the resulting cold mixture, 0.78 g (0.002 mol) of 1-benzyl-6-bromo-5-hydroxy-2-methyl-3-ethoxycarbonylindinol (III) and 2 ml of dioxin are added. The mixture is heated until dissolved and left overnight. Water is added to the reaction mass, an ammonia solution until an alkaline reaction, the precipitate formed is filtered off, washed with water. Yield 0.7 g (72%), mp. ~ 170 ° C (from alcohol with acetone). Found,%: C 62.1; H 6.27; N, 5.71. C ₂₅ H ₂₉ BrN ₂ O ₃

Calculated,%: C 61.86; H 6.02; N 5.77

The individuality was confirmed chromatographically in a benzene-alcohol system (10: 2) on a Siluful UV 254 plate. The structure was confirmed by PMR spectrum.

6-Bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole corresponds to the formula B:

A method for synthesizing this new compound not described in the literature is provided below. 5-hydroxy-2-methyl-l-cyclohexyl-3-ethoxycarbonylindinol is brominated in

SUBSTITUTE SHEET (RULE 26) position 6 with bromine in acetic acid or N-bromosuccinimide in chloroform. The resulting 6-bromo-5 hydroxy-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole is subjected to aminomethylation with bis (dimethylamino) methane in an organic solvent, for example, dioxane. Synthesis Scheme:

CH ₃ COCH ₂ COOC ₂ H ₅ + / V-NH ₂ HCOOC

Example 4. Ethyl β-cyclohexyl aminocrotonic acid (II)

To 13 g (0.1 mol) of acetoacetate in 20 ml of toluene, 11.9 g (0.12 mol) of cyclohexylamine and 1 drop of concentrated HCl are added. Leave at room temperature for a day. Then, the released water is distilled off with a Dean-Stark nozzle.

The toluene is evaporated in vacuo, the residue is distilled. T. boiling point 130-134 ° / 1 mm • Front ²¹ 1.514.

Yield II 18.5 g (87%).

Example 5. 5-Hydroxy-2-methyl-l-cyclohexyl-3-ethoxycarbonylindole (III)

SUBSTITUTE SHEET (RULE 26) To a solution of 2.1 g (0.01 mol) II in 10 ml of glacial acetic acid, 1.08 g (0.01 mol) of 1,4-benzoxinone was added with stirring. The reaction mixture was left at room temperature for one day. The precipitate formed is filtered off, washed with cold acetic acid, crystallized and dried. Yield III 0.6 g (20%), mp. 237 ⁰ C (from acetic acid).

Found,%: C 71.14; H 7.87; N, 4.78. C ₁₈ H ₂₃ NO ₃ . Calculated,%: C 71.74; H 7.69; N 4.65.

Example 6. 6-bromo-5-hydroxy-2-methyl-l-cyclohexyl-3-ethoxycarbonylindinol (IV)

A) To a suspension of 3.01 g (0.01 mol) III in 20 ml of acetic acid, a solution of 1.6 g (0.01 mol) of bromine in 2 ml of acetic acid is added dropwise with stirring at room temperature for 30 minutes. It is stirred for 2 hours at room temperature, water is added, the precipitate is filtered off, washed with water. Yield IV 2.6 g (68.4%), mp 218 ⁰ C (decomposition, from acetic acid). Found,%: 56.64; H 5.83; N 3.72. C ₁₈ H ₂₂ BrNO ₃ . Calculated,%: C 56.85; H 5.83; N 3.68

B) To a suspension of 6.03 g (0.02 mol) III in 100 ml of chloroform, 3.6 g of N-bromosuccinimide are added with stirring and left at room temperature overnight. Precipitate IV is filtered off. Chloroform is evaporated, alcohol and water are added, the precipitate is filtered off, the precipitates are combined and washed with alcohol. Yield 4.75 g (62.5%), mp. 218 C (from dioxane with a small amount of water). Identity was also confirmed by chromatography in the benzene-alcohol 10: 2 system on Silufol UV 254 plates.

Example 7. 6-bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-l-cyclohexyl-3-ethoxycarbonylindole (B).

A mixture of 0.76 g of IV (0.002 mol), 0.45 ml of bis (dimethylamino) methane in 10 ml of dioxane is boiled for 3 hours. After evaporation of the dioxane, a little alcohol and water are added. The aqueous layer is drained by decantation, alcohol is added, the precipitate is filtered off.

Yield 0.5 g (57.5%), mp ~ 143 ° C (from alcohol)

Found,%: C 57.66; H 6.62; N, 6.34

C ₂ IH ₂₉ BrN ₂ O ₃ . Calculated: C 57.66; H 6.69; N, 6.40

The individuality was confirmed by chromatography in the benzene-alcohol-triethylamine system (10: 2: 0.1) on a Silufol UV 254 plate. The structure was confirmed by PMR spectrum.

6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindole has the structure shown in the formula:

SUBSTITUTE SHEET (RULE 26)

Synthesis Scheme:

The synthesis is carried out by bromination of 5-hydroxy-2-methyl-l-cyclohexyl-3-ethoxycarbonylindole to the 6th position with bromine in acetic acid or N-bromosuccinimide in chloroform. The resulting 6-bromo-5-hydroxy-2-methyl-l-

SUBSTITUTE SHEET (RULE 26) cyclohexyl-3-ethoxycarbonylindinol after treatment with acetic anhydride is brominated into the side chain with N-bromosuccinimide, preferably in CCl ₄ medium, in the presence of a radical initiating catalyst (benzene peroxide) and lighting. Then, the resulting product is treated with potassium thiophenolate in an organic solvent medium and then hydrolyzed with a solution of mineral acid in an organic solvent. The resulting compound is subjected to aminomethylation with bis- (dimethylamino) methane in an organic solvent.

Example 8. Ethyl β-cyclohexylaminocrotonic acid (II).

Example 9. 5-hydroxy-2-methyl-l-cyclohexyl-3-ethoxycarbonylindinol (III).

Example 10. 6-bromo-5-hydroxy-2-methyl-l-cyclohexyl-3-ethoxycarbonylindinol (IV).

Example 11. 5-acetoxy-6-bromo-2-methyl-1-cyclorexyl-3-ethoxycarbonylindinol (V). A mixture of 2.3 g (0.006 mol) of IV, 0.61 ml of acetic anhydride and 0.7 ml of pyridine is boiled for 3 hours. The reaction mixture is cooled, water is added, the precipitate is filtered off, washed with water. Yield V 2.05 g (82%), mp. 170 ⁰ C (from alcohol). Found,% C 56.97; H 5.74; N, 3.40. C ₂₀ H ₂₄ BrNO ₄ . Calculated,%: C 56.88; H 5.73; N, 3.32.

Example 12. 5-Acetoxy-6-bromo-2-bromomethyl-l-cyclohexyl-3-ethoxycarbonylindole (VI). A mixture of 1.9 g (0.0045 mol) V, 0.8 g (0.0045 mol) of N-bromosuccinimide, 0.04 g of benzoyl peroxide in 10 ml of carbon tetrachloride is boiled for 4 hours under a 300 W lamp. Succinimide was filtered off from the hot solution, washed with hot CCl _4. After evaporation of the solvent, 2 g of VI (88.8%) were isolated, mp. 140-141 ⁰ C (from heptane). Found,%: C 48.27; H 4.94; N, 3.14. C ₂₀ H ₂₃ Br ₂ NO _4. Calculated,%: C 47.93; H 4.63; N, 2.79.

Example 13. 6-bromo-5-hydroxy-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindole (VII). To a solution of 0.2 g (0.0035 mol) of potassium hydroxide in 6 ml of alcohol, 0.39 g (0.0035 mol) of thiophenol is added with stirring, and then a solution of 1.75 g of VI (0.0035 mol) in 10 ml benzene. After 4 hours, the precipitate of potassium bromide is filtered off. The mother liquor is evaporated in vacuo. To the residue add 10 ml of alcohol, 4 ml of concentrated hydrochloric acid and boil for 1 hour. After cooling and dilution

SUBSTITUTE SHEET (RULE 26) the precipitate is filtered off with water, washed with water. Yield VII 0.9 g (52.9%) mp. 185-186 ° (from alcohol). Found,%: C 58.88; H 5.38; N, 2.96. C ₂₄ H ₂₆ BrNO ₃ S. Calculated,%: C 59.01; H 5.37; N, 2.87.

Example 14. 6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindinol (C). A mixture of 0.74 g (0.0015 mol) of VII, 0.25 ml of bis- (dimethylamino) methane in 5 ml of dioxane is boiled for 4 hours. After evaporation of the dioxane, water is added, extracted with chloroform. The chloroform solution was washed with water, dried b / in Na ₂ SO ₄ , chloroform was evaporated in vacuo, hexane was added to the residue. The precipitate is filtered off. Yield C I 0.6 g (74%), mp. 155-156 ⁰ C (from alcohol). Found,%: C 59.49; H 6.01; N, 5.05. C ₂₇ H ₃₃ Br N ₂ O ₃ S. Calculated%: C 59.44; H 6.10; N, 5.13.

The cytotoxicity of the claimed compounds was studied by applying them in different concentrations (100; 50; 25; 12.5; 6.0; 3.0 and 1.5 μg / ml) on a monolayer of MDCK cell culture (transplantable dog kidney tissue culture cells) on 96-night panels. The number of viable cells was determined by comparing the intensity of staining the solution in the control and experimental wells with the addition of neutral red and incubation of the panels for 72 hours at 37, O ⁰ C.

Antiviral activity

A study of the effects of the compounds on influenza A and B viruses was carried out in an MDCK cell culture. The study was carried out according to the following scheme: a substance was added to a monolayer of a 96-well panel (previously dissolved in DMSO, then a nutrient medium) at various concentrations (12.5; 10.0; 7.5; 5.0 μg / ml), incubated 2 -3 hours at 37.0 ° C, and then virus dilutions were added (10 -1, 10-2, 10-3, 10-4). The panels were incubated for 24 hours at 37 ^° C, and then the reaction was completed by enzyme-linked immunosorbent assay, sequentially applying mouse monoclonal antibodies to influenza A or B viruses, conjugate (goat antibodies to monoclonal mouse antibodies labeled with horseradish peroxidase), substrate (orthophenylenediamine), The results were taken into account when comparing the optical density in the control, (virus) and experimental wells (virus + the claimed compound).

Tables 1, 2, and 3 show the results of suppressing the reproduction (%) of influenza A and B viruses in the presence of compounds of structure A, B, and C. It should be emphasized that the study included influenza viruses that had epidemic activity in the 2003-2004 and 2001 seasons. -2005, as well as the reference strain of influenza virus -

SUBSTITUTE SHEET (RULE 26) A / California / 7/04 (HZN2). The degree of sensitivity of viruses was determined by their strain.

The results obtained indicate a virus-specific activity of the claimed compounds, which was comparable with the activity of the drugs "Apbidol" and "Pantadin".

SUBSTITUTE SHEET (RULE 26) Table 1

Comparative effectiveness of the action of compounds of structure A, Arbidol and

Remantadine for influenza A and B virus

SUBSTITUTE SHEET (RULE 26) table 2

Comparative effectiveness of the action of compounds of structure B, Arbidol and

Remantadine for influenza A and B virus

SUBSTITUTE SHEET (RULE 26) Table 3

Comparative effectiveness of the action of compounds of structure C, Arbidol and

Remantadine for influenza A and B virus

SUBSTITUTE SHEET (RULE 26)

Claims

Claim

1. Derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindinol of the general formula I:

R-alkyl, aryl, cyclohexyl, cycloheptyl, RrQ-Ce-alkyl, CH2-XC ₁ -C ₅ -alkyl, SS-X-Cr-Cr-aryl, SS-X-d-Cs-heterocycle, X - N, O, S, R ₂ - Ci-C ₅ -alkyl, R ₃ , R ₄ have the same meaning CH ₃ or Q-Cs-alkyl, NR ₃ R ₄ - 5-10 membered heterocycle, which may contain N, O, S. as a heteroatom.

2. Derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindole according to claim 1, wherein R is cyclohexyl and benzyl.

3. Derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindinol according to any one of paragraphs. 1 or 2, where R is cyclohexyl, R _{1 is} methyl, CH ₂ S is phenyl.

4. Derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindinol according to any one of paragraphs. 1,2 or 3 selected from:

6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-l-cyclohexyl-3-ethoxycarbonylindole;

6-bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole. l-benzyl-6-bromo-5-hydroxy-2-methyl-4-piperidinomethyl-3-ethoxycarbonylindinol

5. The method of obtaining compounds of formula I according to any one of claims 1 to 4, where Ri means Q-Q-alkyl comprising the steps of: a) reacting a β-aminocrotonic ester with p-benzoquinone to obtain 5-oxiindole II derivatives

SUBSTITUTE SHEET (RULE 26)

where R ₁ , R ₂ D have the above meanings, b) the compound of formula II is subjected to bromination with a brominating agent in an acidic medium to obtain the corresponding 6-substituted indole of formula III:

where R ₁ , R ₂ D have the above meanings, c) a compound of formula III is reacted with an appropriate aminomethylating agent to obtain a compound of formula I. b. The method of obtaining compounds of formula I according to any one of claims 1 to 4, where Ri-means CH ₂ -X-Ci-C ₅ -alkyl. CH ₂ -X-Ci-C ₅ -apyl, CH ₂ -XC iC ₅ -heterocycle, X - N, O or S, comprising the steps of: a) after the reaction of β-aminocrotonic ester with p-benzoquinone, 3-alkoxycarbonyl derivatives are obtained 2-methyl-5-hydroxyindole of the formula II:

where R, R ₂ have the above meanings, b) the compound of formula II is subjected to bromination with a brominating agent in an acidic medium to obtain the corresponding 1-substituted 6-bromo-5-hydroxy-2-methyl-3-alkoxycarbonylindole of the formula III:

SUBSTITUTE SHEET (RULE 26) c) the compound of formula III is treated with acetic anhydride to obtain the 5-acetoxyindole derivative of formula IV:

Where R, R ₂ have the meanings indicated above d) in the compound of formula IV, the methyl group is brominated in the second position to form a 2-bromomethyl derivative of the formula V:

where R, R ₂ have the meanings indicated above. d) the compound of formula V is reacted with the corresponding thiol, phenol, amine, and after removal of the acetoxy group in an acidic medium, a compound of formula VI is obtained

wherein R ₁ is CH ₂ -XC _ϊ -Ss alkyl, CH ₂ aryl -XC rSs-CIS-X-Ci-Cs-heterocycle, and X -N, O or S e) obtained in step d) compound aminometiliruyut.

7. The use of compounds of the general formula G:

SUBSTITUTE SHEET (RULE 26) where R is aryl, alkyl, cyclohexyl, cycloheptyl, Rj-CrQ3-alkyl, CH2-XC] -

C ₅ -alkyl, CH2-X-Ci-C ₅ -apyl, CH2-X-Ci-C ₅ -heterocycle, X - N, O, S, R ₂ - Ci-C ₅ -alkyl, R ₃ , R ₄ have the same meaning CH ₃ or CrC ₅ -alkyl, NR ₃ R ₄ - 5-10 membered heterocycle, which may contain N, O, S or their salts for the preparation of medicines for the treatment of influenza type A or B.

SUBSTITUTE SHEET (RULE 26)