RU2330018C2 - Derivative 4-aminomethyl-6-bromine-5-hydroxyindole-3-carboxylate, methods of their obtaining (versions) and their application - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivative 4-aminomethyl-5-hydroxyindole-3-carboxylate of the general formula I:

where; R indicates cyclohexyl, cycloheptyl; R₁ indicates C₁-C₃-alkyl, -CH₂-X-phenyl; X indicates NH, O, S; R₂ indicates C₁-C₅-alkyl, R₃, R₄ have identical value and are selected from C₁-C₃-alkyl, predominantly, CH₃, or R₃ and R₄ together with a nitrogen atom form -5-10- member heterocycle, which contains 1-2- heteroatom selected from N, O, S or their pharmaceutically acceptable salts, with the exception of 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-(piperidinomethyl)-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromine-5-hydroxy-4-dimethylaminomethyl-2-(pirrolidinemethyl)-1-cyclohexyl-3-ethoxycarbonylindole and methyl-1-cyclohexyl-4-piperidinomethyl-6-bromine-5-hydroxy-2-methyl-indole-3-carboxylate. The methods of obtaining compound I are described.

EFFECT: exhibit antiviral activity and can be used for treating influenza of the type A.

5 cl, 2 dwg, 2 tbl, 8 ex

Description

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, however, 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-hydroxyindole-3-carboxylates.

WO 05/87729 describes derivatives of 5-hydroxyindole-3-carboxylates of the general formula M:

,

,

where X is halogen,

Y means a group NR ₃ R ₄ in which R ₃ and R ₄ may be hydrogen, C _1-10 alkyl,

With _3-7 cycloalkyl, C _2-10 alkenyl or C _2-10 alkynyl or R ₃ and R ₄ together with N form a 5-10 membered heterocycle, which may additionally contain N, O or S as a heteroatom,

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

R ₂ may be C _1-5 alkyl,

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

WO 04/0600873 describes compounds of the general formula N:

where X is halogen, Z-CH ₂ -SR ₅ , CH ₂ NR ₆ R ₇ , R ₁ may mean C _1-10 alkyl, C _3-7 cycloalkyl, R ₂ may mean C _1-4 alkyl, R ₅ may mean C _1-4 alkyl, R ₃ and R ₃ may be hydrogen, alkyl, etc., or R ₃ and R ₃ together with N form a cycle. The compounds have a high inhibitory effect in influenza virus and acute respiratory disease and can be used as influenza agents for the treatment and prevention of acute respiratory disease virus. Also described is a pharmaceutical composition and method for producing compounds.

CN 1482118 describes compounds of general formula N, where Z — H, —CH ₂ —SR ₅ , —CH ₂ —NR ₆ R ₇ , C _1-10 alkyl, C _2-10 alkenyl, or C _2-10 alkynyl, which may be used as anti-influenza agents and for the treatment and prevention of acute respiratory disease virus. Also described is a pharmaceutical composition and method for producing compounds.

JP 63-188665 describes 6-halogen-5-hydroxyindole-3-carboxylates of the formula P:

where R ₁ and R ₂ are hydrogen, alkyl, aralkyl, or R ₁ and R ₂ together with a nitrogen atom form a heterocyclic group, R _{3 is} alkyl, aralkyl, R _{4 is} H, alkyl, cycloalkyl, aryl or aralkyl, X-halogen, and their acid addition salts. In particular, methyl 1-cyclohexyl-4-piperidinomethyl-6-bromo-5-hydroxyindole-3-carboxylate and methyl-1-benzyl-4-piperidinomethyl-6-bromo-5-hydroxyindole-3-carboxylate are disclosed. The compounds of formula P can be used to treat circulating diseases, such as blood diseases, and also have an anticoagulant effect, properties of a 5-lipogenase inhibitor, etc.

Chinese Chemical Letters (English), 2004, 15 (9), 1039-1041 describes the synthesis and antiviral activity against influenza virus of ethyl 6-bromo-5-hydroxyindole-3-carboxylate derivatives, in particular 6-bromo ethyl ester -1-cyclopropyl-4-dimethylaminomethyl-5-hydroxy-2 - [(phenylthio) methyl] -1H-indole-3-carboxylic acid. Journal of the Indian Chemical Society, 1994, 71 (4), 175-8, describes the synthesis and antimicrobial activity of 5-hydroxyindole derivatives, in particular 6-bromo-5-hydroxy-2-methyl-1- (phenylmethyl) -4 ethyl ester - (1-pyrrolidinylmethyl) -1H-indole-3-carboxylic acid and 6-bromo-5-hydroxy-2-methyl-1- (phenylmethyl) -4- (1-piperidinylmethyl) -1H-indole-3- ethyl ester carboxylic acid.

WO 90/08135, RU 2033156 publ. in 1995; RU 2033I57 publ. in 1995, ethyl 6-bromo-5-hydroxy-4-dimethylaminomethyl-1-methyl-2-phenylthiomethylindole-3-carboxylic acid hydrochloride monohydrate was described, having antiviral, interferon-inducing and immunomodulatory effects, as well as a method for its production and pharmaceutical composition.

The specified compound is the closest in structure and activity to the compounds of the present invention.

However, arbidol 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 the following specific compounds of general formula I or the use of compounds of general formula I for the treatment or prevention of influenza A and B.

The invention provides 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindole derivatives of the general formula I:

R is cyclohexyl, cycloheptyl,

R ₁ -C ₁ -C ₃ -alkyl, -CH ₂ -X-phenyl,

X-NH, O, S,

R ₂ -C ₁ -C ₅ -alkyl,

R ₃ , R ₄ have the same meaning and are selected from C ₁ -C ₃ alkyl, preferably CH ₃ , or

R ₃ and R ₄ together with a nitrogen atom form a 5-10 membered heterocycle that contains 1-2 heteroatoms selected from N, O, S,

or their pharmaceutically acceptable salts,

with the exception of

6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-1-cyclohexyl-3-ethoxycarbonylindole,

6-bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole and

6-bromo-5-hydroxy-4-dimethylaminomethyl-2- (1-piperidinomethyl) -1-cyclohexyl-3-ethoxycarbonylindole,

6-bromo-5-hydroxy-4-dimethylaminomethyl-2- (1-pyrrolidinomethyl) -1-cyclohexyl-3-ethoxycarbonylindole.

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.

The method of obtaining compounds of formula I, where R ₁ means C ₁ -C ₃ -alkyl includes the following stages:

a) the interaction of the corresponding alkyl-β-aminocrotonate with p-benzoquinone, with the receipt of alkyl-2-alkyl-5-hydroxyindole-3-carboxylate of the formula II

where R, R ₂ have the meanings indicated in claim 1, R ₁ -C ₁ -C ₃ -alkyl

b) the corresponding alkyl-2-alkyl-5-hydroxyindole-3-carboxylate of formula II:

subjected to bromination with a brominating agent in an acidic medium to obtain the corresponding alkyl-2-alkyl-6-bromo-5-hydroxyindole-3-carboxylate of the formula

where R ₁ , R ₂ , R have the above meanings,

c) the compound of formula III obtained in step b) is aminomethylated with an appropriate aminomethylating agent to obtain the corresponding compound of the invention of the general formula 1 above, wherein R ₁ is C ₁ -C ₃ alkyl

The method of obtaining compounds of formula I, where R ₁ means-CH ₂ -X-phenyl, in which X is selected from NH, O or S, includes the steps of:

a) the interaction of the corresponding alkyl-β-aminocrotonate with p-benzoquinone, with the receipt of alkyl-2-methyl-5-hydroxyindole-3-carboxylate of the formula II

where R, R ₂ have the meanings indicated in claim 1,

b) bromination of the corresponding alkyl-2-methyl-5-hydroxyindole-3-carboxylate of the formula II, to obtain the corresponding 6-bromo derivative of the formula III:

where R, R ₂ have the meanings indicated above.

c) the compound of formula III obtained in stage a) is treated with acetic anhydride and 5-acetoxyindole derivatives of formula IV are obtained:

where R, R ₂ have the meanings indicated above

d) in the resulting compound of formula IV, the CH ₃ group is brominated to give a bromomethyl compound of formula V:

where R, R ₂ have the meanings indicated above,

d) a compound of formula V is reacted with a compound selected from the corresponding thiophenol, phenol, primary or secondary amine in an organic solvent, and after removal of the protective acetoxy group in an acidic medium, a compound of formula VI is obtained:

where R, R ₂ have the meanings indicated above, and

R ₁ is —CH ₂ ; -X-phenyl in which X is selected from NH, O or S.

e) the compound VI obtained in step g) is aminomethylated with an appropriate aminomethylating agent to give a compound of general I, where R ₁ is —CH ₂ —X-phenyl.

The compound of general I obtained by any of the above methods is isolated or, if necessary, converted into the corresponding pharmaceutically acceptable salt.

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 the closest analogue (Arbidol) in relation to different strains. The inventive compounds were effective against other viruses and at the same time 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.

The following examples show the feasibility of the invention.

6-Bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-n-propoxycarbonylindole corresponding to the formula B:

A method for synthesizing this new compound not described in the literature is provided below. 3-hydroxy-2-methyl-1-cyclohexyl-3-n-propoxycarbonylindole is brominated at position 6 with bromine in acetic acid or N-bromosuccinimide in chloroform.

The resulting 6-bromo-5-hydroxy-2-methyl-1-cyclohexyl-3-n-propoxycarbonylindole is subjected to aminomethylation with bis (dimethylamino) methane in an organic solvent, for example, dioxane.

SYNTHESIS SCHEME of compound B.

Example 1. n-Propyl ester of β-cyclohexylaminocrotonic acid (II).

To 14.47 g (0.1 mol) of n-propylacetoacetic ester in 20 ml of toluene was added 11.9 g (0.12 mol) of cyclohexylamine and 1 drop of concentrated hydrochloric acid. Then the separated water is distilled off with a Dean-Stark nozzle. Toluene and excess cyclohexylamine are distilled off in vacuo, the residue is used without distillation. Yield 87%.

Example 2. 5-Hydroxy-2-methyl-1-cyclohexyl-3-n-propoxycarbonylindole (III).

To a solution of 2.24 g (0.01 mol) II in 10 ml of glacial acetic acid, 1.08 g (0.01 mol) of 1,4-benzoquinone is 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, water and alcohol. Yield (III) 0.64 g (20%), mp. 225 ° C (from dioxane).

Example 3. 6-Bromo-5-hydroxy-2-methyl-1-cyclohexyl-3-propoxycarbonylindole (IV)

A) A solution of 1.6 g (0.01 mol) of bromine in 2 ml of acetic acid is added dropwise to a suspension of 3.15 g (0.01 mol) III in 20 ml of acetic acid 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 2.7 g (68.4%). so pl. 215 ° C of acetic acid).

B) To a suspension of 6.3 g (0.02 mol) of 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 was evaporated in vacuo, alcohol and water were added. The precipitates formed are combined and washed with alcohol. Yield 4.92 (62.5%). Mp 215 ° C (from dioxane). The identity was also confirmed by chromatography in a benzene-alcohol 10: 2 system on Silufol UV 254 plates.

Example 4. 6-Bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-n-propoxycarbonylindole (B).

A mixture of 0.79 g (0.002 mol) of IV, 0.45 ml of bis (dimethylamino) methane in 10 ml of dioxane is boiled for 3 hours. After evaporation of the dioxane, alcohol and water are added, the alcohol-water layer is decanted, alcohol is added again, the precipitate is filtered off. Yield 0.52 g (57.5%) mp. 135 ° C (from alcohol).

The structure of the obtained compounds was confirmed by elemental analysis data, 1 H NMR spectra, individuality - chromatographically in a benzene-alcohol 10: 2 system and benzene-alcohol-triethylamine 10: 2: 0.1 on Silufol UV 254 plates.

6-Bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-1-cyclohexyl-3-n-propoxycarbonylindole has the structure corresponding to formula C:

Compound C was prepared according to the synthesis scheme below.

The synthesis is carried out by bromination of 5-hydroxy-2-methyl-1-cyclohexyl-3-n-propoxycarbonylindole to the 6th position with bromine in acetic acid or N-bromosuccinimide (NBS) in chloroform. The resulting 6-bromo-5-hydroxy-2-methyl-1-cyclohexyl-3-n-propoxycarbonylindole, after treatment with acetic anhydride, is brominated into the side chain with N-bromosuccinimide, mainly in CCl ₄ medium, in the presence of a catalyst initiating a radical process (benzoyl peroxide ) under 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 an aminomethylating agent, such as bis- (dimethylamino) methane, in an organic solvent. It is also possible to use dimethylamine and formaldehyde as an aminomethylating agent.

SYNTHESIS SCHEME:

Example 5. 5-Acetoxy-6-bromo-2 methyl-1-cyclohexyl-3-n-propoxycarbonylindole (V).

A mixture of 2.36 g (0.006 mol) IV of 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 2.15 g (82%), mp. 165 ° C (from alcohol).

Example 6. 5-Acetoxy-6-bromo-2-bromomethyl-1-cyclohexyl-3-n-propoxycarbonylindole (VI).

A mixture of 1.96 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 is filtered off from the hot solution, washed with hot CCl ₄ . After evaporation of the solvent, VI is isolated. Yield 2.3 g (88.8%), mp. 130 ° C (from heptane).

Example 7. 6-Bromo-5-hydroxy-2-phenylthiomethyl-1-cyclohexyl-3-n-propoxycarbonylindole (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, then a solution of 1.76 g (0.0035 mol) of VI in 10 ml of 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 with water, the precipitate is filtered off, washed with water. Yield VII 0.93 g (52.9%) VII, mp. 180 ° C (from alcohol).

Example 8. 6-Bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-1-cyclohexyl-3-n-propoxycarbonylindole (C).

A mixture of 0.75 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 0.62 g (74%), mp. 145 (from alcohol).

In a similar manner to the preparation of compounds B and C, other compounds of the present invention can be prepared using the corresponding starting compounds.

6-Bromo-5-hydroxy-4-morpholinomethyl-2-phenylthiomethyl-1-cyclohexyl-3-n-ropoxycarbonylindole, T _pl. 153 ° C.

6-Bromo-5-hydroxy-4-pyrrolidinomethyl-2-phenylthiomethyl-1-cyclohexyl-3-n-propoxycarbonylindole, T _pl. 148 ° C.

6-Bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylaminomethyl-1-cyclohexyl-3-n-propoxycarbonylindole, T _pl. 175 ° C.

6-Bromo-5-hydroxy-4-dimethylaminomethyl-2-phenoxymethyl-1-cyclohexyl-3-n-propoxycarbonylindole, T _pl. 135 ° C.

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 introduced on 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-I. 10-2, 10-3, 10-4). The panels were incubated for 24 hours at 37.0 ° 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 (ortho-phenylenediamine ) 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 B and C. It should be emphasized that the study included influenza viruses that had epidemic activity in the 2003-2004 and 2001-2005 seasons. ., as well as the reference strain of influenza virus A / California / 7/04 (H3N2). The degree of sensitivity of viruses was determined by their strain.

Table 1
Comparative efficacy of compound B and arbidol on influenza A virus Flu virus Activity at 10 μg / ml.% Compound B Arbidol A / California / 07/04 (H3N2) 63 79.0

table 2
Comparative efficacy of compound C and arbidol on influenza A virus Flu virus Activity at 10 μg / ml,% Compound C Arbidol A / California / 07/04 (H3M2) 54 79.0

The results obtained indicate a virus-specific activity of the claimed compounds, which is comparable with the activity of the drugs "Arbidol" and "Remantadine".

Claims (5)

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

where R is cyclohexyl, cycloheptyl, R ₁ is C ₁ -C ₃ -alkyl, -CH ₂ -X-phenyl, X is NH, O, S, R ₂ - C ₁ -C ₅ -alkyl, R ₃ , R ₄ have the same meaning and are selected from C ₁ -C ₃ alkyl, predominantly CH ₃ , or R ₃ and R ₄ together with the nitrogen atom form a 5-10 membered heterocycle that contains 1-2 heteroatoms selected from N, O, S, or their pharmaceutically acceptable salts, with the exception of 6-bromo-5-hydroxy-4-dimethylaminomethyl-2-phenylthiomethyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromo-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylindole, 6-bromo-5-hydroxy-4-dimethylaminomethyl-2- (1-piperidinomethyl) -1-cyclohexyl-3-ethoxycarbonylindole, 6-bromo-5-hydroxy-4-dimethylaminomethyl-2- (1-pyrrolidinomethyl) -1-cyclohexyl-3-ethoxycarbonylindole and methyl 1-cyclohexyl-4-piperidinomethyl-6-bromo-5-hydroxy-2-methyl-indole-3-carboxylate. 2. Derivatives of 4-aminomethyl-5-hydroxy-6-bromo-3-alkoxycarbonylindole according to claim 1, where R is cyclohexyl. 3. The method of obtaining compounds of formula I according to any one of claims 1 and 2, where R ₁ means C ₁ -C ₃ alkyl, comprising the following stages: a) the interaction of the corresponding alkyl-β-aminocrotonate with p-benzoquinone to obtain alkyl-2-alkyl-5-hydroxyindole-3-carboxylate of the formula II

where R, R ₂ have the meanings indicated in claim 1, R ₁ - C ₁ -C ₃ -alkyl b) the corresponding alkyl-2-alkyl-5-hydroxyindole-3-carboxylate of formula II subjected to bromination with a brominating agent in an acidic medium to obtain the corresponding alkyl-2-alkyl-6-bromo-5-hydroxyindole-3-carboxylate of formula III

where R ₁ , R ₂ , R have the above meanings, c) the compound of formula III obtained in step b) is aminomethylated with an appropriate aminomethylating agent to obtain the corresponding compound of general formula I above, wherein R ₁ is C ₁ -C ₃ alkyl, which is isolated or converted into the corresponding pharmaceutically acceptable salts. 4. The method of obtaining compounds of formula I, where R ₁ means-CH ₂ -X-phenyl, in which X is selected from NH, O or S, includes the steps of: a) the interaction of the corresponding alkyl-β-aminocrotonate with p-benzoquinone to obtain alkyl-2-methyl-5-hydroxyindole-3-carboxylate of the formula II

where R, R ₂ have the meanings indicated in claim 1, b) the bromination of the corresponding alkyl 2-methyl-5-hydroxyindole-3-carboxylate of formula II in an acidic medium with the formation of a 6-bromo derivative of the formula III

where R, R ₂ have the meanings indicated above. c) the compound of formula III obtained in stage a) is treated with acetic anhydride and 5-acetoxyindole derivatives of formula IV are obtained

where R, R ₂ have the meanings indicated above g) in the resulting compound of formula IV, the CH ₃ group is brominated and a bromomethyl compound of formula V is obtained

where R, R ₂ have the meanings indicated above, d) the compound of formula V is reacted with the corresponding typhenol or phenol or NH ₂ phenyl in an organic solvent and after removal of the protective acetoxy group in an acidic medium, a compound of formula VI is obtained

where R, R ₂ have the meanings indicated above, and R ₁ means —CH ₂ —X-phenyl in which X is selected from NH, O or S. e) the compound VI obtained in step e) is aminomethylated with an appropriate aminomethylating agent to give a compound of general formula I as defined above. which is isolated or converted into appropriate pharmaceutically acceptable salts. 5. The use of compounds of General formula I

where R is cyclohexyl, cycloheptyl, R ₁ is C ₁ -C ₃ -alkyl, -CH ₂ -X-phenyl, X is NH, O, S, R ₂ - C ₁ -C ₅ -alkyl, R ₃ , R ₄ have the same meaning and are selected from C ₁ -C ₃ alkyl, preferably CH ₃ or R ₃ and R ₄ together with the nitrogen atom form a 5-10 membered heterocycle, which contains 1-2 heteroatoms selected from N, O, S, or their pharmaceutically acceptable salts for the preparation of drugs for the treatment of influenza type A.