EA006608B1

EA006608B1 - Naphtothiazine positive allosteric ampareceptor modulators (paarm)

Info

Publication number: EA006608B1
Application number: EA200301167A
Authority: EA
Inventors: Анджело Чечи; Клаус Клиндер; Томас Вайзер; Карин Винтер
Original assignee: Берингер Ингельхайм Фарма Гмбх Унд Ко. Кг
Priority date: 2001-05-17
Filing date: 2002-05-15
Publication date: 2006-02-24
Also published as: PL364053A1; NZ530154A; DE10123952A1; EA200301167A1; MXPA03010373A; NO20035088L; CA2449189A1; KR20040007572A; CO5550460A2; EP1404340A1; HUP0401273A3; UY27290A1; BG108324A; ECSP034852A; IL158642A0; WO2002100411A1; CN1533278A; NO20035088D0; CZ20033112A3; ZA200308466B

Abstract

The present invention relates to new positive allosteric AMPA-receptor modulators of general formula (I),wherein R1, R2, R3, R4 and R5 may have the meanings given in the specification and claims, processes for preparing them and the use thereof as pharmaceutical compositions.

Description

The present invention relates to new positive allosteric modulators of AMPAR receptors, to a method for their preparation, as well as to their use in the form of pharmaceutical compositions.

Compounds that are structurally similar to those proposed in the invention are described in application Ж9 99/67242, in which carbapenem derivatives are considered, which have an antibacterial effect and for the synthesis of which naphto [1,8-be] -2,3-dihydro 1,1-dioxide-1,2-thiazine.

Proposed in the invention compounds are compounds of General formula (I)

wherein

K ¹ is hydrogen, a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, -8O2H, -8O2-C1-C6 alkyl, -8O-C1-C6 alkyl, -CO-C1-C6 alkyl, -O, phenyl-C1-C4 alkyl , C1-C4 alkyl-PC ⁶ C ⁷ , -C1-C ₄ alkyl-O-C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl;

K ² , K ³ may have identical or different values and represent hydrogen, a C 1 C 6 alkyl group, optionally substituted by one or more halogen atoms, halogen, PO 2, -8 O 2 H, -8 O 2 -C 1 -C 6 alkyl, -8 O-C 1 -C 6 alkyl, -CO -C1-C6 alkyl, -OH, -O-C1-C6 alkyl, -8-C1-C6 alkyl, -C1 C4 alkyl-NK ⁶ K ⁷ , -C1-C ₄ alkyl-O-C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl either

K ¹ and K ² together denote the C4-C6 alkylene bridge,

K ⁶ , K ⁷ may have identical or different values and represent hydrogen, C ₁ -C ₄ alkyl or -CO-C ₁ -C ₄ alkyl,

K ⁸ , K ⁹ may have identical or different values and represent hydrogen or C 1 C 4 alkyl,

K ⁴ may have identical or different meanings and is a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, phenyl C1-C4 alkyl, halogen, -SP, -O2, -8O2H, 8O3H, -8O2-C1-C6 alkyl, -8O-C1-C6 alkyl, -8OL%, -COOH, -CO-C ^ alkyl, -O-CO-C ^ alkyl, -CO-O-C1-C4 alkyl, -O-CO-O-C1-C4 alkyl, -CO -YKk ^7, -OH, -O-C1-C ₆ alkyl, C ₁ _-8-C6 alkyl -YKya ⁷ or an aryl group optionally mono- or polysubstituted by halogen atoms, -ΝΘ group _2, group ₂ -8O N or C ₁ -C ₄ alkyl,

K ⁵ may have identical or different values and represents a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, phenyl C1-C4 alkyl, halogen, -SP, -PO2, -8О2Н, -8О3Н, -8О2-С1-С6 alkyl , -8О-СгС6 alkyl, -8О - GAC. -COOH, -CO-C ^ alkyl, -O-CO-C ^ alkyl, -CO-O-C 1 C 4 alkyl, -O-CO-O-C 1 -C 4 alkyl, -CO-P ^ Kt -OH, -O-C 1 -C6 alkyl, -8-C1-C6 alkyl, -ΝΙ < ⁶ Ι <or aryl group, optionally mono- or polysubstituted with halogen atoms, -PO2 group, -8O ₂ N group or C ₁ -C ₄ alkyl, and p, t can have identical or different values and represent 0, 1, 2 or 3, with the exception of naphtho [1,8-ba] -2,3-dihydro-1,1-dioxide-1,2-thiazine, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

Preferred compounds of the general formula (I) are compounds in which

K ¹ is hydrogen, a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, -8O2H, -8O2-C1-C6 alkyl, -8O-C1-C6 alkyl, -CO-C1-C6 alkyl, -O, -C1C4 alkyl-PC ⁷ K ⁸ , -C1-C ₄ alkyl-O-C ₁ -C ₄ alkyl or benzyl,

K ² , K ³ may have identical or different meanings and represent hydrogen, a C 1 C 6 alkyl group, optionally substituted by one or more halogen atoms, halogen, -PO 2, -8 O 2 H, -8 O 2 -C 1 -C 6 alkyl, -8 O-C 1 -C 6 alkyl, - CO S1S6alkil, -OH, -O-S1S6alkil -8-S1S6alkil, -C1-C4alkyl-PC ⁶ TO ⁷ or _-C1-C4 alkyl-O-C ₁ -C ₄ alkyl, or

K ¹ and K ² together designate a C4-C6 alkylene bridge, K ⁶ , K ⁷ can have identical or different values and represent hydrogen, C1-C ₄ alkyl or -CO-C ₁ -C ₂ alkyl,

K ⁴ can have identical or different values and represents a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, halogen, -SP, -PO2, -8О2Н, 8О3Н, -СООH, -О-С1-С6 alkyl, -О- CO-C1-C4 alkyl, -CO-O-C1-C4 alkyl, -O-CO-O-C1-C4 alkyl, -CO-PK ⁶ C ⁷ , -OH, -O-C1-C ₆ alkyl, -8-C ₁ -C ₆ alkyl or -PK ⁶ K ⁷ ,

K ⁵ may have identical or different values and represents a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, halogen, -SP, -PO2, -8О2Н, -8О3Н, -СООH, -С-С1-С6 alkyl, -О -CO-C1-C4 alkyl, -CO-O-C1-C4 alkyl, -O-CO-O-C1-C4 alkyl, -SOC ⁶ K ⁷ , -OH, -O-C1-C ₆ alkyl, -8-C ₁ —C ₆ alkyl or —PA ⁶ K ⁷ and n, t may have identical or different values and represent 0, 1 or 2,

-1006608 optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

More preferred are those compounds of general formula (I) in which

K ¹ denotes hydrogen, C1-C ₄ alkyl or benzyl,

I ² , K ³ can have identical or different values and represent hydrogen or C ₁ C ₄ alkyl or

I ¹ and I ² together designate the butylene bridge,

I ⁴ may have identical or different meanings and is a C ₁ -C ₆ alkyl group, optionally substituted by one or more halogen atoms, halogen, -ΟΝ, -ΝΟ ₂ , -COOH, -COS ₁ -C ₆ alkyl, -O- CO-C ₁ -C ₄ alkyl, -CO-O-C ₁ -C ₄ alkyl, -O-CO-O-C ₁ -C ₄ alkyl, -ίΌ-ΝΑΉ. -OH, -O-C ₁ C ₆ alkyl, -8-C ₁ -C ₆ alkyl or -ΝΚ ⁶ Κ ⁷ ,

I ⁵ can have identical or different meanings and is a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, halogen, -ίΝ, -ΝΌ2, -COOH, -COS1-C6 alkyl, -O-CO-C1-C4 alkyl, - CO-O-C1-C4alkyl, -O-CO-O-C1-C4alkyl, -CO-Xn ⁶ ⁷ I, -OH, -O-C1C ₆ alkyl, C ₁ _-8-C6 alkyl or -PYA ⁶ I ⁷ and n, t may have identical or different values and represent 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as in the form of their pharmacologically acceptable salts.

Particularly preferred are also those compounds of general formula (I) in which

I ¹ , I ² , I ³ can have identical or different values and represent hydrogen or C ₁ C ₄ alkyl,

I ⁴ may have identical or different meanings and is a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, halogen, -ΝΌ ₂ , -O-CO-C ₁ -C ₄ alkyl, -O-CO-O-C ₁ -C ₄ alkyl, -O-C ₁ -C ₆ alkyl or-NY ⁶ I ⁷ ,

I ⁵ may have identical or different meanings and is a C1-C6 alkyl group, optionally substituted by one or more halogen atoms, halogen, —IO ₂ , —O — CO — C ₁ -C ₄ alkyl, —O — CO — O — C ₁ -C ₄ alkyl, -O-C ₁ -C ₆ alkyl or- ^{6 6} ⁷ and n, t may have identical or different values and represent 0, 1 or 2, not necessarily in the form of their different enantiomers and diastereomers, and also in the form of their pharmacologically acceptable salts.

According to the invention, those compounds of general formula (I) in which I ¹ denotes methyl, ethyl, isopropyl, n-butyl or benzyl, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts, are of particular interest.

Most preferred are compounds of the general formula (I) in which I ¹ is methyl, optionally in the form of their pharmacologically acceptable salts.

Particularly preferred are also compounds of the general formula (I) in which

I ¹ denotes methyl,

I ² , I ³ denote hydrogen,

I ⁴ , I ⁵ may have identical or different values and denote halogen, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine, and n, t may have identical or different values and represent 0, 1 or 2, preferably 0 or 1, optionally in the form of their pharmacologically acceptable salts.

In the context of the present description, by alkyl groups is meant, unless otherwise indicated, branched and unbranched alkyl groups with 1-6 carbon atoms, preferably with 14 carbon atoms. By way of example, methyl, ethyl, propyl, butyl, pentyl and hexyl can be mentioned. In order to designate such groups as methyl, ethyl, propyl or butyl, in some cases the corresponding abbreviations Me, Εΐ, Pr or B, respectively, are also used. Unless otherwise indicated, the terms propyl, butyl, pentyl, and hexyl are also included to include all possible isomeric forms of each of these residues. So, for example, n-propyl and isopropyl are included in the concept of propyl, isobutyl, sec-butyl, tert-butyl, etc. are included in the concept of butyl.

In the above alkyl groups, one or more of their hydrogen atoms may optionally be substituted by halogen atoms, i.e. fluorine, chlorine, bromine or iodine. Preferred substituents are fluorine and chlorine. The most preferred substituent is fluorine. If necessary, all its hydrogen atoms can be replaced in the alkyl group.

An alkyl group that is a fragment of a phenyl-C ₁ -C ₄ alkyl group may be branched or unbranched. Unless otherwise indicated, preferred phenyl C1-C4 alkyl groups are benzyl and phenylethyl. The most preferred benzyl.

Alkyl groups, which are fragments of such groups as -8O ₂ -C ₁ -C ₆ alkyl, -8O-C ₁ -C ₆ alkyl, CO-C ₁ -C ₆ alkyl, -CO-C ₁ -C ₄ alkyl, - C ₁ -C ₄ alkyl-PN ⁶ I ⁷ , -C ₁ -C ₄ alkyl-O-C ₁ -C ₄ alkyl, -O-C ₁ -C ₆ alkyl, -8-C ₁ C ₆ alkyl, -O -CO-C ₁ -C ₄ alkyl, -CO-O-C ₁ -C ₄ alkyl or -O-CO-O-C ₁ -C ₄ alkyl, may be branched or unbranched and contain 1-6 carbon atoms, preferably 1-4 carbon atoms, more preferably 1-3 carbon atoms, most preferably 1 -2 carbon atoms.

Under C ₄ -C ₆ alkylene bridge in the context of the present invention means, unless otherwise specified, branched and unbranched alkylene groups with 4-6 carbon atoms, for example nbutylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, etc. The most preferred in this case, n-butylene bridges.

The aryl group is an aromatic ring system with 6-10 carbon atoms, preferably phenyl.

In the above aryl groups, one or more of their hydrogen atoms may optionally be substituted by halogen atoms, -ΝΟ group _2, group ₂ -§O H or _-C1-C4 alkyl, preferably fluorine, chlorine, -ΝΟ ₂ group, ethyl or methyl most preferably fluorine or methyl.

The term C ₃ -C ₆ cycloalkyl denotes saturated cyclic hydrocarbon groups with 36 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Halogen is, unless otherwise stated, fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine, most preferably fluorine.

The compounds of formula (I) or their various enantiomers and diastereomers can, as mentioned above, be converted into their salts, primarily physiologically and pharmacologically acceptable salts suitable for pharmaceutical use. Such salts can be, on the one hand, physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) formed with inorganic or organic acids. On the other hand, a compound of formula (I), in which K ¹ is hydrogen, can be converted by interaction with inorganic bases into physiologically and pharmacologically acceptable salts, in which the counter ions are alkali or alkaline earth metal cations. Acid addition salts can be prepared, for example, using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid. You can also use a mixture of such acids. For the formation of salts of the compounds of formula (I), in which K ¹ is hydrogen, alkali and alkaline earth metals are preferably hydroxides and hydrides of alkali and alkaline earth metals, with hydroxides and hydrides of alkali metals, especially sodium and potassium, being preferred. and most preferably sodium hydroxide and potassium hydroxide.

Proposed in the invention compounds can be obtained by methods that are known as such. It should be noted that the general methods 1 and 2 described below for the synthesis of the compounds proposed in the invention, presented in Schemes 1 and 2, only illustrate the present invention and do not limit its scope.

Method 1

Scheme 1

(Ii) (iii)

On the basis of the compound of formula (II), a compound of formula (III) is obtained by sulfonation and subsequent chlorination. Thereafter, a compound of formula (IV) is obtained by condensation with aminobutyric acid derivatives, which is cyclized by the addition of polyphosphoric acid, thereby obtaining the target compound of formula (I).

The general method for the preparation of compounds according to the invention according to Scheme 1 is described in more detail below.

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Naphthalene sulfonation (II)

About 10 mmol of the naphthalene derivative of formula (II) is dissolved in 2-100 ml, preferably 3-80 ml, most preferably in about 4 ml of acetic anhydride, then at a temperature of 0-50 ° C, preferably at 5-20 ° C, most preferably at about 18 ° C, 10-100 mmol, preferably 11-80 mmol, most preferably 11 mmol of concentrated sulfuric acid are added. Then the reaction mixture is stirred for 2-16 hours, preferably for about 5 hours, at a temperature of 20-100 ° C, preferably at a temperature of about 25 ° C, and then poured into a saturated solution of \ aC1. In conclusion, the resulting crystals emit.

In the above reaction, instead of acetic anhydride, methylene chloride, diisopropyl ether, ethyl acetate, trichloromethane, toluene, benzene or 1,4-dioxin can be used, and fuming sulfuric acid, sulfur trioxide, chlorine sulfates or combinations of these substances can be used instead of concentrated sulfuric acid.

Synthesis of naphthalene-1-sulfonic acid chlorides of formula (III)

About 10 mmol of naphthalene-1-sulfonic acids are successively mixed with 10-500 mmol, preferably about 90 mmol, phosphorus oxytrichloride and 8-50 mmol, preferably about 10 mmol, phosphorus pentachloride and then for 2-16 hours, preferably for about 5 hours, kept at a temperature of 20-100 ° C, preferably with heating under reflux. After that, the reaction mixture is evaporated and mixed with water. After extraction with an organic diluent, the combined organic extracts are dried and the solvent is separated. The crude product obtained in this way is used in the subsequent steps without purification.

In the above reaction, instead of a mixture of phosphorus oxytrichloride and phosphorus pentachloride, you can use thionyl chloride, phosphorus pentachloride, a mixture of phosphoric acid and chlorine, or phosgene. In another embodiment, the reaction can be carried out in solvents such as ethyl acetate, water, acetonitrile,,-dimethylacetamide, sulfolane, DMF, hexane or dichloroethane.

Synthesis of naphthalene-1-sulfonylaminoacetic acid

About 10 mmol of chlorosulfonylnaphthalenes, 10-100 mmol, preferably 11-30 mmol, most preferably about 12 mmol, aminoacetic acid and 10-100 mmol, preferably 11-30 mmol, most preferably about 12 mmol, sodium hydroxide are dissolved in water and toluene. After that, the reaction mixture is stirred for 2-16 hours at a temperature of 0110 ° C, preferably at a temperature of about 65 ° C, and then the phases are separated. The aqueous phase is acidified and extracted. The combined organic extracts are dried and evaporated. The product can be purified by chromatography.

Instead of sodium hydroxide, triethylamine, potassium carbonate, sodium bicarbonate or sodium hydride can be used, and instead of toluene, tetrahydrofuran, diethyl ether, dichloromethane, trichloromethane, dioxin, acetone, benzene, ethanol, methanol, ethyl acetate or acetonitrile can be used.

Cyclization of naphthalene-1-sulfonylaminoacetic acids of formula (IV)

About 10 mmol of naphthalene-1-sulfonylaminoacetic acids are mixed with 10-200 g, preferably about 40 g of polyphosphoric acid and stirred for 2-16 hours, preferably for about 5 hours, at a temperature of 20-110 ° C, preferably 75- 95 ° C, most preferably at about 80 ° C. After that, the reaction mixture is poured into water and extracted. The combined organic extracts are dried and evaporated. The residue is finally purified.

Method 2

Scheme 2

(111) (V)

The compounds of formula (III), obtained as intermediates in method 1, are reacted with primary amines to obtain compounds of formula (V), which are then subjected to cyclization in the presence of a strong acid by adding a compound of formula K ² K ³ C = O, resulting in target compounds of formula (I).

To obtain compounds of formula (I) in which K ¹ and K ² are hydrogen, paraformaldehyde, trioxane or formalin can be used, and methanesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid or polyphosphoric acid can be used as strong acids.

The general method for the preparation of compounds according to the invention according to Scheme 2 is described in more detail below.

-4006608

Synthesis of naphthalenesulfonamides of formula (V)

About 10 mmol of chlorosulfonylnaphthalenes of formula (III) are mixed with an alcoholic solution of a primary amine (10-1000 mmol in 5-200 ml, for example 200 mmol in 50 ml of ethanol) and then for 2-16 hours, preferably for about 5 hours at 0-100 ° C, preferably with heating under reflux. After that, the reaction mixture is evaporated and purified.

Toluene, benzene, trichloromethane, dichloromethane, diethyl ether, tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone, pyridine, dimethyl sulfoxide, dimethylformamide, dioxin or hexane can also be used instead of an alcohol solvent in the reaction described above.

Cyclization of naphthalene-1-sulfonamides of formula (V) with the formation of the target compounds of formula (I).

About 10 mmol of naphthalene-1-sulfonamides are added to 0-100 ml, preferably 20-80 ml, most preferably about 40 ml, of methanesulfonic acid and mixed with a solution of 3-50 mmol, preferably 4-30 mmol, most preferably 5 mmol, trioxane in 0-100 ml, preferably about 12 ml, of trifluoroacetic acid. Then the reaction mixture is stirred for 2-16 hours, preferably for 5 hours, at a temperature of 20-100 ° C, preferably 30-80 ° C, most preferably at a temperature of about 35 ° C and then poured into a mixture of water with ice. After extraction and drying of the combined organic extracts, the solution is evaporated. Finally, clean the raw product.

Instead of trioxane, paraformaldehyde or formalin can be used in the reaction described above, and boron trifluoride etherate, acetic acid, polyphosphoric acid, phosphoric acid, or sulfuric acid can be used instead of trifluoroacetic acid. Anhydride or dichloromethane can be used as possible solvents.

New compounds of general formula (I) can be synthesized in the same way as the examples below. However, it should be noted that the methods discussed in these examples only additionally illustrate the present invention and do not limit its scope.

Synthesis of 2-methyl-2,3-dihydronaphto [1,8-4e] [1,3] thiazine-1,1-dioxide (Example 1)

2.21 g of amide N-methyl-1-naphthalenesulfonic acid at 35 ° C are dissolved in 25 ml of methanesulfonic acid and mixed with a solution of 0.30 g of trioxane in 8 ml of trifluoroacetic acid. After stirring for 2 hours at ambient temperature, the reaction mixture is poured into 300 ml of ice-water. The solid formed is separated by filtration, washed with 100 ml of water and dried overnight. After crystallization from methylcyclohexane, the product is isolated as a white solid. Yield: 2.20 g. 1 _mp : 136 ° C.

Synthesis of 6-chloro-2-methyl-2,3-dihydronaphto [1,8-4e] [1,3] thiazine-1,1-dioxide (Example 2)

0.45 g of α-methylamide 5-chloronaphthalene-1-sulfonic acid at 35 ° C is dissolved in 6.8 ml of methanesulfonic acid and mixed with a solution of 0.07 g of trioxane in 2 ml of trifluoroacetic acid. After stirring for 2 hours at 35 ° C., the reaction mixture is poured into 100 ml of ice-water and the aqueous phase is extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate, evaporated in vacuo and then purified by chromatography.

Yield: 0.41 g. 1 _mp : 150 ° C.

Synthesis of 2,3-dihydronaphto [1,8-4e] [1,3] thiazine-1,1-dioxide (example 3) tert-Butylamide naphthalene-1-sulfonic acid ml of tert-butylamine is added to 50 ml of chloroform, cooled to 0 ° C and 5.75 g of 1-naphthoic acid chloride in 45 ml of chloroform are added dropwise. After that, the mixture is stirred for 24 hours at ambient temperature. After concentration by evaporation in vacuo, the resulting residue is dissolved in dichloromethane and washed with 2N. hydrochloric acid. The collected organic extracts are dried over sodium sulfate and evaporated in vacuo. Yield: 5.48 g.

2-tert-Butyl-1,1-dioxo-1,2-dihydro-1X ^6- naphtho [1.8-4e] [1.3] thiazin-3-one

4.36 g of tert-butylamide naphthalene-1-sulfonic acid is added to 80 ml of tetrahydrofuran, cooled to -10 ° C and 29 ml of n-butyl lithium (1.6 molar solution in hexane) are carefully added dropwise. The mixture is first stirred for 0.5 hours at −10 ° C. and then for 3 hours at ambient temperature. After that, the mixture is cooled to -5 ° C and for 0.25 hours, CO ₂ , which is formed as a result of evaporation of dry ice, is fed into the mixture through a tube. The reaction mixture is stirred for 2.5 hours at ambient temperature and then mixed with water. The solution is poured into 4n. hydrochloric acid and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 0.42 g.

2-tert-Butyl-2,3-dihydronaphto [1,8-4e] [1,3] thiazin-1,1-dioxide

0.17 g of 2-tert-butyl-1,1-dioxo-1,2-dihydro-1X ^6- naphtho [1.8-4e] [1,3] thiazin-3-one is suspended in 2 ml of tetrahydrofuran at ambient temperature, then add 1.17 ml of the complex compound of borane with tetrahydrofuran (1-molar solution). After that, the mixture is heated under reflux for 100 hours with stirring, additionally adding a 1 molar solution of a complex compound of borane with tetrahydrofuran in a few portions with a total amount of 8.2 ml.

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Then the reaction mixture is mixed with 2 ml of 2n. hydrochloric acid and 2 ml of methanol, then with stirring, boil under reflux for 12 hours. Next, add 2 ml of ammonia and filter the resulting crystals. The filtrate is extracted with ethyl acetate and the collected organic extracts are dried over sodium sulfate. After evaporation in vacuo, the residue obtained is purified by chromatography. Output: 0.06 g.

2,3-Dihydronaphto [1,8-ba] [1,3] thiazin-1, -ioxide

0.06 g of 2-tert-butyl-2,3-dihydronaphto [1,8-be] [1,3] thiazine-1,1-dioxide is dissolved in 1 ml of dichloromethane and 0.02 ml of trifluoroacetic acid is added. The mixture is then stirred for 22 hours at reflux temperature and for 96 hours at ambient temperature, during which time trifluoroacetic acid is added, with a total amount of 0.07 ml. Finally, the reaction mixture is evaporated in vacuo and the residue is purified by chromatography. Yield: 0.034 g. 1 _mp : 206-207 ° C.

Synthesis of [2- (1,1-dioxo-1H-3H-1X ^6- naphtho [1,8-beta] thiazin-2-yl) ethyl] dimethylamine (Example 4)

0.028 g of sodium hydride is suspended in 0.5 ml of dimethylformamide and 0.073 g of 2,3-dihydronaphtho [1,8-ba] [1,3] thiazine-1,1-dioxide in 1 ml of dimethylformamide is added. Next, 0.053 g of chlorodiethylaminoethyl hydrochloride is added in portions. The reaction mixture is stirred for 18 hours at ambient temperature and then poured into ice-water. After that, the mixture is extracted with dichloromethane and the collected organic extracts are dried over sodium sulfate. After evaporation in vacuo, the residue obtained is purified by chromatography. Yield: 0.035 g. 1 _mp : 97-98 ° C.

Synthesis of N- (2-methyl-1,1-dioxo-2,3-dihydro-1H-1X ^6- naphtho [1,8-бе] [1,3] thiazin-6-yl) acetamide (Example 5)

5-Acetylamino-naphthalen-1-sulfonyl chloride

1.40 g of 5-acetylaminonaphthalene-1-sulfonic acid is mixed with 2.23 g of phosphorus pentachloride and stirred for 4 hours at 60 ° C. After that, the solution is poured into a mixture of ice water and extracted with dichloromethane. The collected organic extracts are dried over sodium sulfate and evaporated in vacuo. Yield: 1.10 g.

N- (5-Methylsulfamoylnaphthalen-1-yl) acetamide

1.10 g of 5-acetylaminonaphthalen-1-sulfonyl chloride is dissolved in 8 ml of ethanol and 8 ml of a solution of methylamine in ethanol is added dropwise. The resulting mixture is then stirred at reflux temperature for 3.5 hours and the solvent is distilled off in vacuo. The residue is purified by chromatography. Yield: 0.50 g.

No. (2-Methyl-1,1-dioxo-2,3-dihydro-1H-1X ^6- naphtho [1,8-be] [1,3] thiazin-6-yl) acetamide

0.25 g of the No. (5-methylsulfamoylnaphthalen-1-yl) acetamide at 35 ° C is dissolved in 3.4 ml of methanesulfonic acid and mixed with a solution of 0.027 g of trioxane in 1 ml of trifluoroacetic acid. After 6 hours of stirring at 35 ° C., the reaction mixture is poured into ice-water and the aqueous phase is extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate, evaporated in vacuo and purified by chromatography. Yield: 0.136 g. 1 _mp : 189-190 ° C.

Synthesis of 2- (1,1-dioxo-1H, 3H-1X ^6- naphtho [1,8-бе] [1,3] thiazin-2-yl) acetamide (Example 6) 8-tert-Butylsulfamoylnaphthalene-1-carboxylic acid

4.36 g of tert-butylamide naphthalene-1-sulfonic acid is added to 80 ml of tetrahydrofuran, cooled to -10 ° C and 29 ml of n-butyl lithium (1.6 molar solution in hexane) are carefully added dropwise. After that, the mixture is first stirred for 0.5 h at -10 ° C, and then for 3 h at ambient temperature. Next, the mixture is cooled to -5 ° C and for 0.25 hours, CO ₂ , which is formed as a result of evaporation of dry ice, is fed through the tube through the tube. Then the reaction mixture is stirred for 2.5 hours at ambient temperature, then mixed with water. Next, the solution is poured into 4n. hydrochloric acid and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 1.19 g.

1,1-dioxo-1,1-dihydro-1X ^6- naphtho [1,8-be] [1,3] thiazin-3-one

To 0.25 g of polyphosphoric acid, 0.15 g of 8-tert-butylsulfamoylnaphthalene-1-carboxylic acid is added. The mixture was stirred for 4 hours at 150 ° C. Then the reaction mixture is poured into a mixture of ice water and the aqueous phase is extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and evaporated in vacuo. Yield: 0.07 g

2,3-Dihydronaphto [1,8-be] [1,3] thiazin-1,1-dioxide

0.07 g of 1,1-dioxo-1,1-dihydro-1X ^6- naphtho [1,8-ba] [1,3] thiazin-3-one is dissolved in 2 ml of tetrahydrofuran, and then 1 is carefully added dropwise. , 2 ml of 1-molar solution of the complex compound of borane with tetrahydrofuran. After that, the mixture for 18 is stirred at the temperature of distillation. Then the reaction mixture is mixed with 1.5 ml of 2n. hydrochloric acid and 2 ml of methanol, then stirred for 2 hours at reflux temperature. Next, add 2 ml of ammonia and filter the resulting crystals. The filtrate is extracted with ethyl acetate, the collected organic extracts are dried over sodium sulfate and evaporated in vacuo. Output: 0.06 g.

2- (1,1-dioxo-1H, 3H-1X ^6- naphtho [1,8-be] [1,3] thiazin-2-yl) acetamide

0.011 g of sodium hydride is suspended in 0.5 ml of dimethylformamide and 0.06 g of 2,3-dihydronaphtho [1,8-ba] [1,3] thiazine-1,1-dioxide in 1 ml of dimethylformamide is added. Next, the mixture is stirred for

-6006608 h at ambient temperature, then 0.042 g of 2-bromoacetamide is added in portions. The mixture is then stirred for 18 hours at ambient temperature. After that, the reaction mixture is poured into a mixture of ice water and extracted with dichloromethane. The collected organic extracts are dried over sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 0.043 g. 1 _mp : 195196 ° C.

Synthesis of 7-hydroxy-2-methyl-2,3-dihydronaphtho [1,8-ba] [1,3] thiazine-1,1-dioxide (Example 7)

0.6 g of 7-methoxy-2-methyl-2,3-dihydronaphto [1,8-be] [1,3] thiazine-1,1-dioxide is dissolved in 23 ml of dichloromethane and the solution is cooled to -78 ° C. 2.3 ml of boron tribromide (1 molar solution in dichloromethane) are added dropwise. The mixture is then stirred for 24 hours at ambient temperature. After evaporation in vacuo, the residue is purified by chromatography. Yield: 0.36 g. 1 _mp : 245-246 ° C.

Synthesis of 2-methyl-1,1-dioxo-2,3-dihydro-1H-1 λ ^6- naphtho [1,8-бе] [1,3] thiazin-7-ylcarboxylic acid methyl ester (Example 8).

0.11 g of 7-hydroxy-2-methyl-2,3-dihydronaphto [1,8-ba] [1,3] thiazine-1,1-dioxide and 0.061 ml of triethylamine are added to 2 ml of toluene and cooled to 0 ° WITH. After this, 0.037 ml of methyl chloroformate is added dropwise. Next, the mixture is stirred for 5 hours at ambient temperature. Then the suspension is poured into a mixture of ice water and extracted with ethyl acetate. The collected organic extracts are dried over sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 0.065 g. 1 _mp : 161162 ° C.

The following compounds of the formula ΙΑ are prepared, in particular, in the same way as the methods described above.

Table 1

Example K. ¹ K ² to ³ 9 SNS n n ten SNS νο ₂ n eleven SNS n n 12 SNS n n 13 SNS n n 14 SNS n n 15 SNS n n sixteen CH ₃ n I 17 SNS n νο ₂ 18 SNS n he nineteen CH ₃ P (SNZ) ₂ n 20 SNS n n 21 SNS iso-Pr n 22 SNS H OSOM 23 CH ₃ H R

to ⁴ to ⁵ to ⁶ 1pl [° C] n n Vg 226-227 n n n 264-265 OSSN n n 174-175 R n n 129-130 Vg n n 163-164 SNS n n 142-143 I n n 192-193 n n n 160-161 n n n 169-170 n n n 160-161 n n n n n H (CH ₃ ) ₂ n iso-Pr n n n n n n n

The compounds of general formula (Ι) possess, as it was established, wide possibilities for therapeutic use, respectively, possess high therapeutic potential. Particularly noteworthy is the possibility of their use in cases where positive modulation of AMPA receptors is desired.

The effectiveness of the compounds according to the invention as AMRA receptor modulators was determined by electrophysiology methods in experiments on cells expressing functional AMPA receptors. The purpose of these experiments was to check whether the test substances had a positive allosteric effect on the current induced by the agonist.

The experiments were carried out at a concentration of test substances from 0.3 μmol to 300 μmol.

-7006608

Table 2 Amplification induced by the agonist current (+ means high activity, ++ means very high activity)

Example Activity one + 2 ++

The novel compounds according to the invention can also be used to treat diseases and conditions associated with impairment or restriction of the function of the neural networks, for the functioning of which AMPA receptors are necessary.

In accordance with this, the compounds of general formula (I) can be used in dementia of various types, in neurodegenerative or psychotic diseases and in neurodegenerative disorders, as well as in cerebral ischemia of various origins, preferably in schizophrenia or in learning and memory disorders.

Epilepsy, hypoglycemia, hypoxia, anoxia, brain damage, brain edema, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, sexual dysfunction, and sensory disturbances motor function, impaired memory formation, changes in behavior due to hyperkinesis (especially in children), hypotension, myocardial infarction, cerebral pressure (increased intracher epic pressure), ischemic and hemorrhagic stroke, general (global) cerebral ischemia for cardiac arrest, acute and chronic neuropathic pain, diabetic polyneuropathy, a sensation of tinnitus, asphyxia during the perinatal period, psychosis, Parkinson's disease and depression, as well as related anxiety disorders.

The novel compounds according to the invention can also be used in combination with other active substances, such as active substances, the use of which is indicated for the same painful symptoms or in combination, for example, with neuroleptics, nootropic drugs, psychostimulants, etc. Proposed in the invention The compounds may be intended for topical, oral, transdermal, nasal, parenteral or inhalation use. In addition, the compounds of general formula I or their salts can also be used in combination with active substances of other types.

The compounds of general formula (I) can be used individually or in combination with other active substances of the invention, and, under certain conditions, in combination with other pharmacologically active active substances. Examples of acceptable dosage forms include tablets, capsules, suppositories, solutions, in particular solutions for injections (subcutaneous, intravenous, intramuscular) and infusions, mixtures, emulsions or dispersible powders. The proportion of pharmaceutically active compound (s) in such dosage forms should be in each case from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight, based on the total weight of the preparation, t. e. the content of the pharmaceutically active compound (s) in the dosage forms should correspond to the dosages, the intervals of which are indicated below.

Suitable tablets can be made, for example, by mixing the active ingredient or active ingredients with known auxiliary substances, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents to provide a depot effect, such as carboxymethylcellulose, cellulose acetate phthalate or polyvine latsetat. Tablets may also consist of several layers.

In a suitable manner, coated tablets or dragees can be made by coating the cores prepared similarly to tablets with materials commonly used for this purpose, for example kollidone or shellac, gum arabic, talcum powder, titanium dioxide or sugar. In order to provide a depoeffect or to avoid incompatibility, the dragee cores can also be made multi-layered. Likewise, the dragee shell may also consist of several layers to provide a depot effect, and the excipients mentioned above for the tablets can be used.

The composition of syrups or mixtures on the basis of the active ingredients proposed in the invention, or their combinations, may additionally also include a sweetener, such as saccharin, cyclamate, glycerin or sugar, as well as a flavor enhancer, such as a flavoring agent, such as vanillin or orange extract. In addition, syrups or mixtures may contain suspending auxiliaries or thickeners, such as sodium carboxymethylcellulose, wetting agents, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives (protective substances), such as p-hydroxybenzoates.

-8006608

Solutions for injections or infusions are prepared according to a known technology, for example, with the addition of isotonic agents, preservatives, such as η-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and, if necessary, using emulsifiers and / or dispersants, for example, when using water as a diluent, if necessary, you can use organic solvents as hydrotropic solubilizers or auxiliary solvents, and then azlivayut into bottles or vials for injection, respectively for infusion bottles.

Capsules containing one or more active ingredients, or combinations of active ingredients, can be made, for example, by mixing the active ingredients with inert carriers such as lactose or sorbitol, and packaging the resulting mixture into gelatin capsules.

Appropriate suppositories can be made, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol, or their derivatives.

As an example, excipients used in the preparation of dosage forms include water, pharmaceutically acceptable (harmless) organic solvents, such as paraffins (for example, mineral oil fractions), oils of vegetable origin (for example, peanut or sesame oil), mono- or polyfunctional alcohols (for example, ethanol or glycerin), carriers such as natural rock flour (for example, kaolin, alumina, talc, chalk), synthetic rock flour (for example, highly dispersed silica iic acid and silicates), sugars (for example, cane, milk and grape sugar), emulsifiers (for example, lignin, spent sulfite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example, magnesium stearate, talc, stearic acid and lauryl sulfate sodium ).

The preparations obtained on the basis of the respective active substances are administered into the body by conventional methods, preferably orally or transdermally, preferably orally. In the case of oral administration, the corresponding tablets can, as is obvious, in addition to the above carriers, also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various excipients such as starch, preferably potato starch, gelatin, etc. . In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used in the manufacture of tablets. In the case of aqueous suspensions, the active substances in addition to the above-described excipients can also be mixed with various flavor enhancers or colorants. For parenteral administration, solutions of the active ingredients with suitable liquid carriers can be used.

For intravenous administration, the dose administered to the body is from 1 to 1000 mg per hour, preferably from 5 to 500 mg per hour. However, in some cases, depending on the patient's body weight, the route of administration, the individual response to the drug, the type of pharmaceutical composition and its nature, and the period during which the drug is administered, the dose administered may differ from the indicated amounts. Thus, in particular, it may sometimes be sufficient to use the active ingredient or active ingredients in a dose less than the above lower limit, while in other cases it may be necessary to use the active ingredient or active ingredients in a dose exceeding the above upper limit. If necessary, the introduction of the active substance or active substances in large doses, it may be advisable to split them up into several smaller doses per several doses per day.

Below the invention is illustrated by examples in which the compositions of some dosage forms are presented and which do not limit its scope.

A) Tablets.

Component

Examples of pharmaceutical compositions

Content per tablet

Active substance

Lactose

Corn starch

Polyvinylpyrrolidone

Magnesium stearate

100 mg

140 mg

240 mg mg mg

500 mg

The finely divided active ingredient is mixed with lactose and part of the total amount of corn starch provided. The resulting mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, granulated in a wet state and dried. The resulting granules together with the remaining amount of corn starch and magnesium stearate are sieved and mixed together. From the mixture obtained, tablets of the required shape and size are pressed.

-9006608

B) Tablets.

Component

Active substance

Lactose

Corn starch

Microcrystalline Cellulose Polyvinylpyrrolidone

Sodium Carboxymethyl Starch Magnesium Stearate

Content per mg mg tablet

190 mg mg mg mg mg

400 mg

The finely divided active ingredient is mixed with a portion of the total amount of corn starch provided, lactose, microcrystalline cellulose and polyvinylpyrrolidone, the mixture is sieved and, together with the rest of the corn starch and water, is processed into granules, which are dried and sieved. Next, sodium carboxymethyl starch and magnesium stearate are added, mixed and tablets of the required sizes are pressed from the resulting mixture.

B) Solution in ampoules.

Active ingredient 50 mg

Sodium chloride 50 mg

Water for injection 5 ml

The active substance at its own pH value or, if necessary, at a pH of from 5.5 to 6.5, is dissolved in water and mixed with sodium chloride as an agent that is isotonic. The resulting solution is filtered under pyrogen-free conditions and the filtrate is aseptically filled into ampoules, which are then sterilized and sealed. Such ampoules may contain 5 mg, 25 mg or 50 mg of active ingredient.

Claims

SUMMARY OF THE INVENTION in which

K ¹ is hydrogen, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, -8O2I, -8O2-C1-C6 alkyl, -8O-C1-C6 alkyl, -CO-C1-C6 alkyl, -O, phenyl-C1-C4 alkyl , -C1-C4 alkyl-IR ⁶ K ⁷ , -C1-C ₄ alkyl-O-C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl,

K ² , K ³ may have identical or different meanings and represent hydrogen, a C1C6 alkyl group, optionally substituted with one or more halogen atoms, halogen, -IO2, -8O2I, -8O2-C11-C6 alkyl, -8O-C1-C6 alkyl, - CO S1S6alkil, -OH, -O-S1S6alkil -8-S1S6alkil, -C1-C4alkyl-IC ⁶ TO ^7, _-C1-C4 alkyl-O-C ₁ -C ₄ alkyl or C ₃ - C ₆ cycloalkyl either

K ¹ and K ² together denote a C ₄ -C ₆ alkylene bridge,

K ⁶ , K ⁷ may have identical or different meanings and are hydrogen, C ₁ -C ₄ alkyl or -CO-C ₁ -C ₄ alkyl,

K ⁴ may have identical or different meanings and represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, phenyl-C1-C4 alkyl, halogen, -SI, -IO2, -8O2H, -8O3H, -8O2-C1-C6 alkyl , -8О-С1-С6 alkyl, -8О2-НК ⁶ К ⁷ , -COOH, -CO-С1С6 alkyl, -О-СО-С1-С4 alkyl, -CO-О-С ^ alkyl, -O-СО-О-С ^ alkyl, —CO — IR ⁶ K ⁷ , —OH, —O — Cl — C6 alkyl, —8 — Cl — C6 alkyl, —IC ⁶ K ^7, or an aryl group, optionally mono- or polysubstituted by halogen atoms, —IO2 group, —8O group ₂ H or C ₁ -C ₄ alkyl,

K ⁵ may have identical or different meanings and represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, phenyl-C1-C4 alkyl, halogen, -SI, -IO2, -8O2H, -8O3H, -8O2-C1-C6 alkyl , -8О-С1-С6 alkyl, -8О2-НК ⁶ К ⁷ , -COOH, -CO-С1С6 alkyl, -О-СО-С ₁ -С ₄ alkyl, -CO-О-С ₁ -С ₄ alkyl, -O -CO-O-C ₁ -C ₄ alkyl, -CO-IR ⁶ K ⁷ , -OH, -O-C1C6 alkyl, -8-C1-C6 alkyl, -IC ⁶ K ⁷ or an aryl group, optionally mono- or polysubstituted by atoms halogen -IO2 group, group ₂ -8O H or C ₁ -C ₄ alkyl and n and m may be identical or different and are represented yayut is 0, 1, 2 or 3, except naphtho [1,8-baa] -2,3-dihydro-1,1-dioxide-1,2-thiazine,

-10006608 optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

2. The compounds of General formula (I) according to claim 1, in which

K ¹ is hydrogen, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, -8O2H, -8O2-C1-C6 alkyl, -8O-C1-C6 alkyl, -CO-C1-C6 alkyl, -O, -C1C4 alkyl-LK ⁷ K ⁸ , -C 1 -C ₄ alkyl-O-C 1 -C ₄ alkyl or benzyl,

K ² , K ³ can have identical or different meanings and represent hydrogen, a C1C6 alkyl group, optionally substituted with one or more halogen atoms, halogen, -ΝΟ2, -8Ο2Η, -8О2-С1-С6 alkyl, -8О-С1-С6 alkyl, - CO S1S6alkil, -OH, -O-S1S6alkil -8-S1S6alkil, -C ^ ^^ Schalkil ⁷ K or _C1-C4 alkyl-O-C ₁ -C ₄ alkyl, or

K ¹ and K ² together denote a C4-C6 alkylene bridge,

K ⁶ , K ⁷ may have identical or different meanings and are hydrogen, C1-C4 alkyl or -CO-C1-C2 alkyl,

K ⁴ may have identical or different meanings and represents a C | -C6 alkyl group, optionally substituted with one or more halogen atoms, halogen, -ΟΝ, -ΝΟ2, -8О2Н, -8О3Н, -COOH, -CO-C1-C6 alkyl, - O-CO-S1S4alkil, -CO-O-S1S4alkil, -O-CO-O-S1S4alkil, -CO-ΝΚ ⁶ ^, -OH, -O-C1-C ₆ alkyl, C ₁ -8- -C ₆ alkyl or -ΝΚ ⁶ Κ ⁷ ,

K ⁵ may have identical or different meanings and represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, halogen, ΌΝ, -ΝΟ2, -8O2H, -8O3H, -COOH, -CO-C1-C6 alkyl, -O- CO-C1-C4 alkyl, -CO-O-C1-C4 alkyl, -O-CO-O-C1C4 alkyl, -CO ^ K ⁶ K ⁷ , -OH, -O-C1-C ₆ alkyl, -8-C ₁ - C ₆ alkyl or —YK ⁶ K ⁷ and p, t may have identical or different meanings and represent 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

3. The compounds of General formula (I) according to claim 1 or 2, in which

K ¹ is hydrogen, C ₁ -C ₄ alkyl or benzyl,

K ² , K ³ can have identical or different meanings and represent hydrogen or C1C4 alkyl or

K ¹ and K ² together denote a butylene bridge,

K ⁴ may have identical or different meanings and represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, halogen, —CU —ΝΟ2, —COOH, —COC1 — C6 alkyl, —O — CO — C1 — C4 alkyl, —CO -O-C1-C4 alkyl, -O-CO-O-C1-C4 alkyl, -CO-IR ⁶ K ⁷ , -OH, -O-C1C ₆ alkyl, -8-C ₁ -C ₆ alkyl or -IR ⁶ K ⁷ ,

K ⁵ may have identical or different meanings and represents a C1-C6 alkyl group, optionally substituted with one or more halogen atoms, halogen, ΌΝ, -ΝΟ2, -COOH, -COC1-C6 alkyl, -O-CO-C1-C4 alkyl, -CO -O-C1-C4 alkyl, -O-CO-O-C1-C4 alkyl, -CO-IR ⁶ K ⁷ , -OH, -O-C1C ₆ alkyl, -8-C ₁ -C ₆ alkyl or -IR ⁶ K ⁷ and p, t may have identical or different meanings and represent 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

4. The compounds of General formula (I) according to any one of claims 1 to 3, in which

K ¹ , K ² , K ³ can have identical or different meanings and represent hydrogen or C ₁ C4 alkyl,

K ⁴ may have identical or different meanings and represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, halogen, -ΝΟ ₂ , -O-CO-C ₁ -C ₄ alkyl, -O-CO-O-C ₁ -C ₄ alkyl, -O-C ₁ -C ₆ alkyl, or -YK ⁶ K ⁷ ,

K ⁵ may have identical or different meanings and represents a C ₁ -C ₆ alkyl group optionally substituted with one or more halogen atoms, halogen, -ΝΟ ₂ , -O-CO-C ₁ -C ₄ alkyl, -O-CO- O — C ₁ -C ₄ alkyl, —O — C ₁ -C ₆ alkyl, or —YK ⁶ K ⁷ and n, t may have identical or different meanings and represent 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

5. The compound of general formula (I) according to any one of claims ¹ to ⁴ , in which K ¹ is methyl, ethyl, isopropyl, n-butyl or benzyl, optionally in the form of its various enantiomers and diastereomers, as well as in the form of its pharmacologically acceptable salts.

6. The compounds of general formula (I) according to any one of claims 1 to 5, in which K ¹ is methyl, optionally in the form of their pharmacologically acceptable salts.

7. The compounds of General formula (I) according to claim 1, in which

K ¹ is methyl,

K ² , K ³ denote hydrogen,

K ⁴ , K ⁵ can have identical or different values and denote halogen and n, t can have identical or different values and represent 0, 1 or 2,

-11006608 optionally in the form of their pharmacologically acceptable salts.

8. The use of compounds of General formula (I) in which

K ¹ is hydrogen, a C1-C6 alkyl group optionally substituted with one or more halogen atoms, -8O2H, -8O2-C1-C6 alkyl, -8O-C1-C6 alkyl, -CO-C1-C6 alkyl, -O, phenyl-C1-C4 alkyl , -C1-C4 alkyl-YK ⁶ K ⁷ , -C1-C ₄ alkyl-O-C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl,

K ² , K ³ may have identical or different meanings and represent hydrogen, a C1C6 alkyl group, optionally substituted with one or more halogen atoms, halogen, —YO2, -8O2H, -8O2-C1-C6 alkyl, -8O-C1-C6 alkyl, - СО-С1-С6 alkyl, -OH, -О-С1-С6 alkyl, -8-С1С6 alkyl, -С1-С4 alkyl-ЖК ⁶ К ⁷ , -С1-С ₄ alkyl-О-С ₁ -С ₄ alkyl or С ₃ - C ₆ cycloalkyl either

K ¹ and K ² together denote a C4-C6 alkylene bridge,

K ⁴ may have identical or different meanings and represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, phenyl-C1-C4 alkyl, halogen, -СЫ, -ЫО2, -8О2Н, -8О3Н, -8О2-С1-Салка , -8O-CrSbalkyl, -8O2-LK ⁶ K ⁷ , -COOH, -CO-C1Balkyl, -O-CO-C1-C4 alkyl, -CO-O-C ^ alkyl, -O-CO-O-C ^ alkyl , —CO — LYC ⁶ K ⁷ , —OH, —O — C1 — C6 alkyl, —8 — C ₁ –C ₆ alkyl, —YK ⁶ K ^7, or an aryl group, optionally mono- or polysubstituted with halogen atoms, —YO ₂ group, group -8O ₂ H or C ₁ -C ₄ alkyl,

K ⁵ may have identical or different meanings and represents a C1-C6 alkyl group optionally substituted with one or more halogen atoms, phenyl-C1-C4 alkyl, halogen, -СЫ, -ЫО2, -8О2Н, -8О3Н, -8О2-С1-С6 alkyl , -8O-C1-C6alkyl, -8O2-LK ⁶ K ⁷ , -COOH, -CO-C1Balkyl, -O-CO-C1-C4alkyl, -CO-O-CpCdalkyl, -O-CO-O-C ^ alkyl , —CO — LYC ⁶ K ⁷ , —OH, —O — C1 — C6 alkyl, —8 — C1 — C6 alkyl, —YK ⁶ K ^7, or an aryl group, optionally mono- or polysubstituted with halogen atoms, —YO2 group, —8O ₂ H group or C ₁ -C ₄ alkyl, and n, t may have identical or different meanings and represent oh 0, 1, 2 or 3, optionally in the form of their various enantiomers and diastereomers and their pharmacologically acceptable salts, as an active ingredient in pharmaceutical compositions.

9. The use of claim 8, as an active ingredient in pharmaceutical compositions having neuroprotective effects.

10. The use of the compounds of general formula (I) according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment and / or prevention of neurodegenerative diseases and / or cerebral ischemia of various origins.

11. The use of the compounds of general formula (I) according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment of schizophrenia.

12. The use of a compound of general formula (I) according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment and / or prevention of memory impairment.

13. The use of the compounds of general formula (I) according to any one of claims 1 to 7 for the preparation of a pharmaceutical composition for the treatment of various types of dementia.

14. A method of treating and / or preventing neurodegenerative diseases and / or cerebral ischemia, characterized in that the patient is administered an effective amount of a compound of formula (I) according to any one of claims 1 to 7.

15. A method for the treatment and / or prevention of memory disorders and / or dementia of various types, characterized in that the patient is administered an effective amount of a compound of formula (I) according to any one of claims 1 to 7.

16. Pharmaceutical preparations containing, as an active substance, one or more compounds of the general formula (I) according to any one of claims 1 to 7 or their physiologically acceptable salts, optionally in combination with conventional excipients and / or carriers.