CZ20033112A3 - Naphtothiazine positive allosteric ampa receptor modulators (paarm) - Google Patents

Abstract

The present invention relates to new positive allosteric AMPA-receptor modulators of general formula (I), wherein R<1>, R<2>, R<3>, R<4> and R<5> may have the meanings given in the specification and claims, processes for preparing them and the use thereof as pharmaceutical compositions.

Description

BACKGROUND OF THE INVENTION

As compounds structurally similar to the compounds of the invention, WO 9967242 discloses carbapenem derivatives having antibacterial activity, wherein the compound naphtho [1,8-de] -2,3-dihydro-1,1-dioxide-1,2-thiazine is used as a component of synthesis.

SUMMARY OF THE INVENTION

The compounds of the invention are compounds of formula (I),

where

R 1 represents a group selected from hydrogen, C 1 -C ₆ -alkyl, optionally substituted with one or more hydrogen atoms, -SO ₂ H, -SO ₂ -C ₁ -C ₆ -alkyl, -SO

Ci-Ce-alkyl, -CO-CrCe-alkyl, -O, phenyl-C ₄ -alkyl, C _r C ₄ -alkyl-NR ⁶ R ⁷ and -CrC ^ alkyl ocicat alkyl and C ₃ - C 6 -cycloalkyl,

R ² , R ³ , which may be the same or different, represent a group selected from hydrogen, C 1 -C 6 -alkyl, optionally substituted by one or more halogen atoms, halogen, -NO 2, -SO 2 H, -SO 2 C 6 -C 6 -alkyl, -SO-C 1 -C 6 -alkyl, -CO-C 1 -C 6 -alkyl, -OH, -O-C 1 -C 6 -alkyl, -S-C 1 -C 6 -alkyl, -C 1 -C 4 -alkyl-NR ⁶ R ⁷ and -C 1 -C 4 alkyl-O-C 1 -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl, or. R ¹ and R ² together represent a C ₄ -C 6 -alkylene bridge;

R ⁶ , R ⁷ , which may be the same or different, represent hydrogen, C 1 -C ₄ -alkyl or -COC 1 -C ₄ -alkyl,

R ⁸ , R ⁹ , which may be the same or different, represent hydrogen or C 1 -C ₄ -alkyl,

R ⁴ , which may be the same or different, represents a group selected from C 1 -C 6 alkyl, optionally substituted with one or more halogen atoms, phenyl-C 1 -C 4 alkyl, halogen, -CN, -NO 2, -SO 2 H, -SO 3 H, -SO 2 - C 1 -C 6 -alkyl, -SO-C 1 -C 6 -alkyl, -SO 2 -NR ⁶ R ⁷ , -COOH, -CO-C 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, -CO-NR ⁶ R ⁷ , -OH, -O-C ₁ -C ₆ -alkyl, -S-C ₁ -C ₆ -alkyl,

-NR ⁶ R ⁷ and aryl, optionally mono or polysubstituted with halogen, -NO ₂ , -SO ₂ H or C 1 -C ₄ -alkyl,

R ⁵ , which may be the same or different, represents a group selected from C 1 -C 6 alkyl, optionally substituted with one or more halogen atoms, phenylC 1 -C 1 -alkyl, halogen, -CN, -NO 2, -SO 2 H, -SO 3 H, -SO 2 -C 1 -C 6 -alkyl, -SO-C 1 -C 6 alkyl, SO 2 -NR ⁶ R ⁷ , -COOH, -CO-C 1 -C 6 -alkyl, -O-CO-C 1 -C ₄ -alkyl, -CO-O-C 1 -C 4 alkyl, -O -CO-O-C _r C ₄ -alkyl, -CO-NR ⁶ R ^7, -OH, -O-C6-alkyl, -S-C 6 -alkyl, -NR ⁶ R ⁷ and aryl, optionally mono- or polysubstituted by halogen, -NO 2, -SO ₂ ^HTiebo'Ci-Cy álkyl7a n, m which may be identical or different, represent 0, 1, 2 or 3, ....... - s

with the proviso that the naphtho [1,8-de] -2,3-dihydro-1,1-dioxide-1,2thiazine compound, optionally in the form of its various enantiomers and diastereomers, and their pharmaceutically acceptable salts, is excluded.

Preferred compounds are those compounds of formula (I) wherein

R ¹ represents a group selected from hydrogen, C 1 -C 6 -alkyl optionally substituted by one or more hydrogen atoms, -SO 2 H, -SO 2 -C 1 -C 6 -alkyl, -SOC 1 -C 6 -alkyl, -CO-C 1 -C 6 -alkyl , -O, -C 1 -C 4 -alkyl-NR ⁷ R ⁸ and -C 1 -C ₄ -alkyl-O-C 1 -C ₄ -alkyl, benzyl,

R ² , R ³ , which may be the same or different, represent a group selected from hydrogen, C 1 -C 6 -alkyl optionally substituted by one or more halogen atoms, -NO 2, -SO ₂ H, -SO ₂ -C 1 -C 6 alkyl, _{-SO-Ci-C6-alkyl,} -CO-C 6 -alkyl, -OH, -OCiC ₆ -alkyl, -S-CrCe-alkyl, -C-C ₄ -alkyl-NR ₆ R 7 and - C 1 -C ₄ -alkyl-OC 1 -C ₄ -alkyl, or

R ¹ and R ² together represent a C ₄ -C ₆ -alkylene bridge,

R ⁶ , R ⁷ , which may be the same or different, represent hydrogen, C 1 -C ₄ -alkyl or -COC 1 -C ₂ -alkyl, and

R ⁴ , which may be the same or different, represents a group selected from C 1 -C 6 alkyl optionally substituted by one or more halogen atoms, halogen,

-CN, -NO 2, -SO ₂ H, -SO 3 H, -COOH, -CO-C ₁ -C ₆ -alkyl, -O-CO-C ₁ -C ₄ -alkyl, -COO-C ₁ -C ₄ alkyl, -O-CO-O -C 1 -C ₄ -alkyl, -CO-NR ⁶ R ⁷ , -OH, -O-C ₁ -C ⁶ -alkyl,

-S-C 1 -C ₆ -alkyl and -NR ⁶ R ⁷ ,

R ⁵ , which may be the same or different, represents a group selected from C 1-6 alkyl optionally substituted by one or more halogen atoms, halogen,

-CN, -NO 2, -SO ₂ H, -SO 3 H, -COOH, -CO-C 1 -C ₆ -alkyl, -O-CO-C 1 -C ₆ alkyl, -COO ₄ C 1 -C ₇ W 1 R 2 CO-OXFCFalkylT-CO-NR 4 OHr-Q-Gt-C 6 -alkyl ____

-S-C 1 -C ₆ -alkyl and -NR ₆ R 7, and _________________________, which may be the same or different, represent 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, and also as their pharmacologically acceptable salts .

·· ···· __

Particularly preferred are compounds of formula (I) wherein

R ¹ represents hydrogen, _Ci-C4 alkyl or benzyl;

R ² , R ³ , which may be the same or different, represent hydrogen or C 1 -C ₄ -alkyl or R ¹ and R ² together represent a butylene bridge and

R ⁴ , which may be the same or different, represents a group selected from C 6 -C 6 alkyl optionally substituted by one or more halogen atoms, halogen,

-CN, -NO 2, -COOH, -CO-O-C 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, -CO-NR ⁶ R ^7, -OH, -OC _r C ₆ -alkyl, -S-C ₆ alkyl and -NR ⁶ R ^7,

R ^5, which may be identical or different, represents a group selected from the group C _r C6 alkyl, optionally substituted by one or more halogen atoms, halogen,

-CN, -NO ₂ , -COOH, -CO-C 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, -CO-NR ⁶ R ^7, -OH, -O-CrCe-alkyl, -S-C ₆ -alkyl and R ^e NR ^7, n, m which may be identical or different, represent 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

Also particularly preferred are compounds of formula (I) wherein

R ¹ , R ² , R ³ , which may be the same or different, represent hydrogen or C 1 -C ₄ -alkyl,

R ^4, which may be identical or different, represents a group selected from the group Ο-ι-Οθalkyl optionally substituted jedmmTíe5dVíče toms ^ ~ ^ haíogenurhalogen -NO _{2, -O-CO-Ci-C4-alkyl,} -0-C0 , O-C 1 -C ₄ -alkyl, O-C ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ ,

R ⁶ , which may be the same or different, represents a group selected from C 1 -C ₆ alkyl, optionally substituted with one or more halogen atoms, halogen, -NO ₂ , -O-CO-C 1 -C ₄ -alkyl, -O-CO -O-C 1 -C ₆ alkyl, -O-C 1 -C ₆ -alkyl and -NR ⁶ R ⁷ , and n, m, which may be the same or different, are 0, 1 or 2;

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

Particularly important according to the invention are compounds of formula (I) wherein R 1 is methyl, ethyl, i-propyl, n-butyl; or benzyl, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

Particularly preferred are compounds of formula (I) wherein R ¹ is methyl, optionally in the form of their pharmacologically acceptable salts.

Also particularly preferred are compounds of formula (I) wherein

R ¹ represents methyl,

R ^2, R ³ represent hydrogen,

R ⁴ , R ⁵ , which may be the same or different, represent halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine, and

n, m, which may be the same or different, represent 0, 1 or 2, preferably 0 or 1, optionally in the form of their pharmaceutically acceptable salts.

The alkyl groups used, unless otherwise indicated, are straight or branched chain alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, propyl, butyl, pentyl and hexyl. The methyl, ethyl, propyl or butyl groups may optionally be abbreviated as Me, Et, Pr or Bu. Unless otherwise stated, the terms propyl, butyl, pentyl and hexyl may also include all possible isomeric forms of these groups. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl, etc.

In the above alkyl groups, one or more hydrogen atoms may be substituted by halogen, fluorine, chlorine, bromine or iodine atoms. Fluorine and chlorine substituents are preferred. Particularly preferred is a fluorine substituent. If desired, all hydrogen atoms of the alkyl group may be replaced.

The alkyl group mentioned in the phenyl-C 1 -C ₄ -alkyl group may be in a branched or unbranched form. Unless otherwise stated, preferred phenyl-C ₄ -C ₄ -alkyl groups are benzyl and phenylethyl. The benzyl group is particularly preferred.

Alkyl groups mentioned in the groups -SO ₂ -C ₁ -C ₆ -alkyl, -SO-C 1 -C 6 -alkyl, -CO-C 1 -C 6 -alkyl, -CO-C 1 -C ₄ -alkyl, -C 1 -C ₄ -alkyl- NR ⁶ R ⁷ , -C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl, -O-C 1 -C ₆ alkyl, -S-C ₁ -C ₆ -alkyl, -O-CO-C 1 -C ₄ -alkyl, -CO-O-C 1 -C ₄ -alkyl or -O-CO-OC- C 1 -C ₄ alkyl, may be in the form of a branched or straight chain of from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, particularly preferably from 1 to 4 carbon atoms. to 3 carbon atoms, most preferably 1 to 2 carbon atoms.

^; The C ₄ -C ₆ -alkylene bridge may be, unless otherwise indicated, branched or unbranched alkylene groups having 4 to 6 carbon atoms, for example n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, 1,2 dimethylethylene, etc. n-Butylene bridges are particularly preferred.

An aryl group is an aromatic ring system having 6 to 10 carbon atoms, preferably phenyl. For the above aryl groups, one or more hydrogen atoms may be optionally substituted by halogen atoms, -NO ₂ , -SO ₂ H or -CiC ₄ - alkyl, preferably fluoro, chloro, -NO ₂ , ethyl or methyl, most preferably fluoro or methyl.

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

The term halogen, unless otherwise indicated, means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, even more preferably fluorine and chlorine, and most preferably fluorine.

As mentioned above, the compounds of formula (I) or various enantiomers and diastereomers thereof may be converted into their salts, especially for pharmaceutical use, into their physiologically and pharmacologically acceptable salts. These salts, on the one hand, can form physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, compounds of formula (I), wherein R ¹ is hydrogen, can be converted into physiologically and pharmacologically acceptable salts by reaction with inorganic bases, such as counter ions, such as counter ions. Acid addition salts can be prepared using, for example, 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. It is also possible to use mixtures of the above acids. For the preparation of alkali metal and alkaline earth metal salts of compounds of formula (I) wherein R ¹ is hydrogen, it is preferred to use alkali metal and alkaline earth metal hydroxides and hydrides, alkali metal hydroxides and hydrides, especially sodium and potassium, wherein sodium and Potassium is particularly preferred.

The compounds of the invention may be prepared in a manner known per se. The following general synthesis methods 1 and 2, shown in diagrams 1 and 2 below, are intended to illustrate the invention in greater detail without limiting its scope.

·· ··

Method 1

(IV)

Starting from a compound of formula (II) and its sulfonation followed by chlorination, a compound of formula (II) is prepared. The compound of formula (IV), obtained after condensation with aminoacetic acid derivatives, is cyclized by the addition of polyphosphoric acid to give the final compound (I).

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

Sulfonation of naphthalene (II)

About 10 mmol of the naphthalene derivative (II) is absorbed in 2 - 100 ml, preferably 3 80 ml, most preferably about 4 ml of acetic anhydride and at a temperature of 0-50 ° C, preferably 5 - 20 ° C, particularly preferably about 18 ° C 10-100 mmol, preferably 11-9 mmol, particularly preferably 11 mmol of concentrated sulfuric acid are added. After 2-16 hours, preferably 5 hours, stirring at 20-100 ° C, preferably about 25 ° C, the mixture is poured into a saturated NaCl solution. The crystals formed are isolated.

Instead of acetic anhydride, methylene chloride, diisopropyl ether, ethyl acetate, trichloromethane, toluene, benzene or 1,4-dioxin can be used, while fuming sulfuric acid, sulfur trioxide, chlorosulphates or combinations thereof can be used as an alternative to concentrated sulfuric acid.

Synthesis of naphthalene-1-sulfonic acid chloride (III)

Approximately 10 mmol of naphthalene-1-sulfonic acid is successively combined with 10-500 mmol, preferably about 90 mmol, of phosphorus oxychloride and 8-50 mmol, preferably about 10 mmol, of phosphorus pentachloride and the mixture is heated for 2-16 hours, preferably about 5 mmol. hours, at a temperature of 20-100 ° C, preferably at reflux. Then the reaction mixture is evaporated and combined with water. After extraction with organic diluent, the organic extracts are dried and freed from solvent. The crude product obtained is used in the following steps without purification.

Thionyl chloride, phosphorus pentachloride, phosphoric acid / chlorine or phosgene may be used instead of phosphorus oxychloride / phosphorus pentachloride mixture. Alternatively, the reactions may be carried out in diluents such as ethyl acetate, water, acetonitrile, N, N-dimethylacetamide, sulfolane, DMF, hexane or dichloroethane.

Synthesis of naphthalene-1-sulfonylaminoacetic acid

About 10 mmol of chlorosulfonyl-naphthalene, 10-100 mmol, preferably 11-30 mmol, most preferably about 12 mmol, of aminoacetic acid and 10-100 mmol, preferably 11-30-mmol-most preferably-as-2-molar-hydroxide Sodium is dissolved in water and toluene. The reaction mixture is stirred for 2-16 hours at 0 - 110 ° C, preferably at about 65 ° C, then the phases are separated. The aqueous phase is acidified and extracted. The combined organic extracts were dried and evaporated. Purification can be performed by chromatography. Instead of sodium hydroxide, triethylamine, potassium carbonate, potassium bicarbonate or sodium hydride may be used, while instead of toluene, tetrahydrofuran, diethyl ether, dichloromethane, trichloromethane, dioxin, acetone, benzene, ethanol, methanol, ethyl acetate or acetonitrile may be used.

Cyclization of naphthalene-1-sulfonyl-amino-acetic acid (IV)

Approximately 10 mmol of naphthalene-1-sulfonylamino-acetic acid is combined with 10-200 g, preferably 40 g, of polyphosphoric acid and stirred for 2-16 hours, preferably about 5 hours, at 20-110 ° C, preferably 75-50 ° C. 95 ° C, most preferably at about 80 ° C. The reaction mixture was then poured into water and extracted. The combined organic extracts were dried and evaporated. The residue is purified.

Method 2

Diagram 2

Sat ₂ ci

(IN)

Compounds of formula (III) obtained as intermediates in method 1 are reacted with primary amines to give compounds of formula (V) and then cyclized by addition of a compound of formula R ² R ³ C = O in the presence of a strong acid to give final compounds (AND).

For the preparation of a compound of formula-CD- where R ¹ and R ² are hydrogen, paraformaldehyde, trioxane or formalin can be used and as strong acids, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid or polyphosphoric acid can be used.

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

·· ···· -1-1 ----

Synthesis of naphthalene-suiphonamide (V)

Approximately 10 mmol of chlorosulfonyl-naphthalene (III) is combined with an alcohol solution of the primary amine (10-1000 mmol in 5-200 mL, e.g. 200 mml in 50 mL ethanol) and then heated to 0-100 ° C for 2-16 hours , preferably about 5 hours, preferably at reflux. Then the reaction mixture is evaporated and purified.

Toluene, benzene, trichloromethane, dichloromethane, diethyl ether, tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone, pyridine, dimethylsulfoxide, dimethylformamide, dioxin or hexane can also be used instead of the alcohol solution.

Cyclization of naphthalene-1-sulfonamides (V) to give final compounds (I)

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

Instead of trioxane, paraformaldehyde or formalin can be used, while instead of trifluoroacetic acid it is possible to use boron trifluoride diethyl ether, acetic acid, polyphosphoric acid, phosphoric acid or sulfuric acid. Acetic anhydride or dichloromethane can be used as possible diluents.

The novel compounds of formula (I) can be synthesized analogously to the following synthesis examples. These examples further illustrate the invention without limiting its scope.

—_____

999

9 9

9 ·· ··

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of 2-methyl-2,3-dihydro-naphtho [1,8-deH 1,31thiazine-1,1-dioxide (Example 1)

2.21 g of N-methyl-1-naphthalenesulfonic acid amide was dissolved in 25 ml of methanesulfonic acid at 35 ° C and combined with a solution of 0.30 g of trioxane in 8 ml of trifluoroacetic acid. After stirring at room temperature for 2 hours, the reaction mixture was poured into 300 ml of ice water. The solid formed was collected 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

M.p .: 136 ° C

Synthesis of 6-chloro-2-methyl-2,3-dihydro-naphtho1,8-deH1,3-thiazine-1,1-dioxide (Example

0.45 g of 5-chloro-naphthalene-1-sulfonic acid N-methylamide is dissolved in 6.8 ml of methanesulfonic acid at 35 DEG C. and the solution is combined 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 combined organic extracts were dried over sodium sulfate, evaporated in vacuo and then purified by chromatography.

Yield: 0.41 g

Melting point: 150 ° C ·· ····

-134 4 ··

Synthesis of 2,3-dihydro-naphthalene-1,8-dimethyl-1,31-thiazine-1,1-dioxide (Example 3) Naphthalene-1-sulfonic acid tert-butylamide

8 ml of tert-butylamine are placed in 50 ml of chloroform, the solution is cooled to 0 DEG C. and a solution of 5.75 g of 1-naphthalenic acid chloride in 45 ml of chloroform is added dropwise. The mixture was then stirred at ambient temperature for 24 hours. After concentration by evaporation in vacuo, the residue obtained is dissolved in dichloromethane and washed with 2N hydrochloric acid. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo.

Yield: 5.48 g

^{2terc.-Butyl-1,1-dioxo-1,2-dihydro-1-A-6} -naftof1,8 de1f1,3jthiazin-3-one

4.36 g of naphthalene-1-sulfonic acid tert-butylamide are placed in 80 ml of tetrahydrofuran, the solution is cooled to -10 ° C and 29 ml of N-butyllithium (1.6 molar solution in hexane) is carefully added dropwise. The mixture was first stirred at -10 ° C for 0.5 hour, then at ambient temperature for 3 hours. The mixture was cooled to -5 ° C and dry ice CO 2 was introduced for 0.25 hours. The reaction mixture was stirred at ambient temperature for 2.5 hours, then combined with water. The solution was poured into 4N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and chromatographed after evaporation in vacuo.

Yield: 0.42 g

2-tert-Butyl-2,3-dihydro-naphthal-1,8-de] f 1,3-thiazine-1,1-dioxide

0.17 g of 2-tert-butyl-1,1-dioxo-1,2-dihydro-1X- ^6- naphtho [1,8-de] [1,3] thiazine-3- is suspended in 2 mol of tetrahydrofuran at room temperature. and then 1.17 ml of borane-tetrahydrofuran complex (1 molar solution) was added. Then the mixture was refluxed and stirred for 100 h and a total of 8.2 mL of a 1M borane-tetrahydrofuran complex solution was added in several portions. The reaction mixture was combined with 2 mL of 2N hydrochloric acid and 2 mL of methanol, then the mixture was refluxed for 12 hours and stirred. 2 ml of ammonia are added and the formed crystals are filtered. The filtrate was extracted with ethyl acetate, and the combined organic extracts were dried over sodium sulfate. After evaporation in vacuo, the residue is purified by chromatography.

Yield: 0.06 g

2,3-Dihydro-naphthof 1,8-delf 1,3] thiazine-1,1-dioxide

0.06 g of 2-tert-butyl-2,3-dihydro-naphtho [1,8de] [1,3] thiazine-1,1-dioxide is dissolved in 1 ml of dichloromethane and 0.02 ml of trifluoroacetic acid is added to the solution. . The mixture was then stirred for a total of 22 hours at reflux temperature and 96 hours at ambient temperature while a total of 0.07 ml of trifluoroacetic acid was added at this time. The reaction mixture was evaporated in vacuo and purified by chromatography.

Yield: 0.034 g

Mp .: 206-207 ° C

Synthesis of (2- ^{(1,1-dioxo-1H-3-n-6} -naftof1,8 delthiazin-2-yl) -ethvn-dimethylamine (Example 4) ·

0.028 g of sodium hydride is suspended in 0.5 ml of dimethylformamide and 0.073 g of 2,3-dihydro-naphtho [1,8-dej [1,3] thiazine-1,1-dioxide in 1 ml of dimethylformamide is added. Then 0.053 g of diethylaminoethyl chloride hydrochloride is added in portions. The reaction mixture was stirred at ambient temperature for 18 hours and then poured into ice water. The mixture was extracted with dichloromethane and the combined organic extracts were dried over sodium sulfate. After evaporation in vacuo, the residue is purified by chromatography.

Yield / -0 _T 035-g ___

Melting point: 97 - 98 ° C ee

- 15— ογι ιΐοζ-α

Μ / Ο / 1 ι ion ion · · ·· ··

-1,1-dioxo-2,3-dihydro-1H-1 \ ⁶ -n3fto [1,8-delf1,31th phthalazin-6-yl) · ee "·· · • • · ·

- acetamide (Example 5)

5-Acetylamino-naphthalene-1-sulfonyl chloride

1.40 g of 5-acetylamino-naphthalene-1-sulfonic acid and 2.23 g of phosphorus pentachloride were combined and stirred at 60 ° C for 4 hours. The solution was then poured into water and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo.

Yield. 1.10 g

N- (5-Methylsulfanoyl-naphthalen-1-yl) -acetamide

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

Yield: 0.50 g

N- (2-Methyl-1,1-dioxo-2,3-dihydro-1H-1X- ^6- naphtho [1,8-del [1,31-thiazin-6-yl) -acetamide

0.25 g of N- (5-methylsulfamoyl-naphthalen-1-yl) -acetamide was dissolved in 3.4 ml of methanesulfonic acid at 35 ° C and the solution was combined with a solution of 0.027 g of trioxane in 1 ml of trifluoroacetic acid. After stirring at 35 ° C for 6 hours, the reaction mixture was poured into ice water and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, evaporated in vacuo and purified by chromatography.

Yield: 0.136 g

Melting point: 180 - 190 ° C • · ·

__o l Λ oyiiicZca z .- \ i

Ί '-Jiřwrv. I UHJAU

1H, 3H-1X6-naphtho [1,8-delfl, 31thiazin-2-yl] -Z

8-tert-Butylsulfamoyl-naphthalene-1-carboxylic acid

4.36 g of naphthalene-1-sulfonic acid tert-butylamide are placed in 80 ml of tetrahydrofuran, the solution is cooled to -10 ° C and 29 ml of N-butyllithium (1.6 molar solution in hexane) is carefully added dropwise. The mixture was stirred at -10 ° C for 0.5 hour, then at room temperature for 3 hours. It is then cooled to -5 [deg.] C. and CO ₂ obtained from dry ice is introduced for 0.25 hours. The reaction mixture was stirred at ambient temperature for 2.5 hours and then combined with water. The solution was poured into 4N hydrochloric acid solution and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and chromatographed after evaporation in vacuo.

Yield: 1.19 g of 1,1-Dioxo-1,1-dihydro-1X6-naphtho [1,8-deK1,31thiazin-3-one]

0.25 g of polyphosphoric acid is taken and 0.15 g of 8-tert-butylsulfamoyl-naphthalene-1-carboxylic acid is added. The mixture was stirred at 150 ° C for 4 hours. The reaction mixture was then poured into ice water and the aqueous weight was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo.

Yield: 0.07 g

2,3-dihydro-naphtho [1,8] -dichloro-1,3-thiazene-1,1-dioxide

0.07 g of 1,1-dioxo-1,1-dihydro-1X- ^6- naphtho [1,8de] [1,3] thiazin-3-one is dissolved in 2 ml of tetrahydrofuran and then carefully added dropwise 1 ml. 2 ml of a 1 molar solution of borane-tetrahydrofuran complex. The mixture was stirred at reflux temperature for 18 hours. The reaction mixture was combined with 1.5 mL of 2N hydrochloric acid and 2 mL of methanol, then stirred at reflux temperature for 2 hours. 2 ml of ammonia are added and the formed crystals are filtered. The filtrate was extracted with ethyl acetate, the combined organic extracts were dried over sodium sulfate and evaporated in vacuo.

__- 17- ____

- ··· - ·· _ ··

Yield: 0.06 g

2- (11-dioxo-1H, 3H-naphtho 1X ⁶ [1,8-de] [1,3] thiazin-2-yl) -acetamide

0.011 g of sodium hydride is suspended in 0.5 ml of dimethylformamide and a solution of 0.06 g of 2,3-dihydro-naphtho [1,8-di] -3-thiazine-1,1-dioxide in 1 ml of dimethylformamide is added. The mixture was stirred at ambient temperature for 1 hour and then 0.042 g of 2-bromoacetamide was added in portions. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and chromatographed after evaporation in vacuo.

Yield: 0.043 g

M.p .: 195-196 ° C

Synthesis of 7-hydroxy-2-methyl-2,3-dihydro-naphtho1,8-dia [1,3] thiazine-1,1-dioxide (Example

ZI

0.6 g of 7-methoxy-2-methyl-2,3-dihydronaphtho [1,8-de] [1,3] thiazine-1,1-dioxide is dissolved in 23 ml of dichloromethane and the solution is cooled to -78. Deň: 32 ° C. 2.3 ml of boron tribromide (1 molar in dichloromethane) were added dropwise. The mixture was then stirred at room temperature for 24 hours. After evaporation in vacuo, the residue is purified by chromatography.

Yield: 0.36 g

Melting point: 245-246 ° C

Synthesis of methyl 2-methyl-1,1-dioxo-2,3-dihydro-1H-1X-6-naphthal-1,8-de [1,3] thiazine-7-yl ester carboxylate (Example 8)

0.11 g of 7-hydroxy-2-methyl-2,3-dihydro-naphtho [1,8de] [1,3] thiazine-1,1-dioxide and 0.061 ml of triethylamine are placed in 2 ml of toluene and the solution is cooled. to 0 ° C. 0.037 ml of methyl chloroformate was added dropwise. The mixture was then stirred at ambient temperature for 5 hours. The suspension is then poured into ice water and extracted

ethyl acetate. The combined organic extracts were dried over sodium sulfate and chromatographed after evaporation in vacuo. Yield: 0.065 g

Melting point; 161-162 ° C

The following compounds of formula (IA) are obtained, inter alia, by analogous methods described above:

Table 1

Example R ¹ R ² R ³ R ⁴ . R ⁵ R ⁶ M.p. [° C] 9 CH ₃ H H H H Br 226-227 10 ch ₃ no ₂ H H H H 264-265 11 ch ₃ H H och ₃ H. H 174-175 12 ch ₃ H H F H H 129-130 -1-3-- -GH ₃ - -H H Br H H 163-164 14 --------------- CH ₃ H H CH ₃ H H 142-143 15 Dec ch ₃ H H J H H 192-193 16 ch ₃ H J H H H 160-161 17 ch ₃ H no ₂ H H H 169-170 18 ch ₃ H OH H H H 160-161

se · ·

Continuation of Table 1

19 Dec ch ₃ n / ch ₃ ) ₂ H H H t 1 Π 20 May ch ₃ H H H H N _{(CH3) 2} 21 ch ₃ i-Pr H H iso-Pr H 22nd ch ₃ H OCOMe H H H 23 ch ₃ H F H H H

The compounds of formula (I) have been found to exhibit a wide range of applications in the therapeutic field. Of particular importance are applications in which positive modulation of AMPA receptors plays a role.

The effect of the compounds of the invention as AMPA receptor modulators has been determined electrophysiologically on cells that express functional AMPA receptors. Investigations were performed to determine if test substances had a positive allosteric effect on agonist-induced current.

The test was performed at concentrations between 0.3 pmol and 300 pmol.

Table 2: agonist-induced current intensification (+ good, ++ very good activity)

The novel compounds can also be used for the treatment of diseases or conditions in which the functions of the neonone networks that need AMPA receptors for their function are suppressed or limited.

The compounds of formula (I) may therefore be used in dementias, neurodegenerative or psychiatric disorders and in neurodegenerative disorders and cerebral ischemia of various origins, advantageous in schizophrenia or learning or memory disorders.

The following diseases can also include: epilepsy, hypoglycaemia, hypoxia, anoxia, cerebral trauma, brain swelling, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, sexual dysfunction, sensory and motor function disorders, memory formation, hyperkinetic behavioral changes (especially in children), hypotension, heart attack, cerebral pressure (increase in intracranial pressure), ischemic and haemorrhagic stroke, global cerebral ischemia in cardiac arrest, acute and chronic neuropathic pain, diabetic polyneuropathy, tinnitus (tinnitus), perinatal asphyxia, psychosis, Parkinson's disease and depression and similar anxiety states.

The novel compounds may also be administered in combination with other active agents, such as those used for the same indications, or, for example, neuroleptics, nootropics, psychostimulants, etc. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation. In addition, the compounds of formula (I) or salts thereof may also be combined with active ingredients of other species.

The compounds of formula (I) may be administered alone or in combination with other active agents of the invention and possibly also in combination with other pharmacologically active agents. Suitable formulations include, for example, tablets, capsules, suppositories, solutions, in particular injectable solutions (sc, iv, 17m.TA1nfGzeTeixirryremulsions or dispersion powders) The content of pharmaceutically active compounds should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50%. Suitable tablets may be obtained, for example, by mixing the active ingredient (s) with known excipients, for example, inert diluents, such as calcium carbonate, calcium phosphate, or the like. lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, _Λ '· · ·

----- · -— - - ......- - - - -—- --____— -........... ·. · __ · _ »

Λ. Lubricants such as magnesium stearate or talc and / or delayed-release agents such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also contain multiple layers.

Coated tablets may be made by coating cores, made analogously to tablets, with substances commonly used for coating tablets, for example, collidone or shellac, acacia, talc, titanium dioxide or sugar. To achieve delayed release or preventive incompatibility, the core may also consist of a plurality of layers. Similarly, the coating of a tablet may consist of a plurality of layers to achieve delayed release, preferably using the excipients listed above for tablets.

Syrups or elixirs containing the active ingredients or combinations thereof according to the invention may additionally contain a sweetening agent such as saccharin, cyclamate, glycerol or sugar and flavor enhancers, for example flavoring agents such as vanilla or orange extract. They may also contain suspension adjuvants or thickeners, such as sodium carboxymethylcellulose, wetting agents, such as the condensation products of fatty alcohols with ethylene oxide, or preservatives, such as phydroxybenzoates.

Injectable solutions and infusions are prepared in conventional manner, for example by the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and / or dispersants when water is used as a diluent, for example, organic solvents, can optionally be used as solvating agents or solubilizing agents, and is filled into vials or ampoules or infusion bottles.

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

Suitable suppositories may be prepared, for example, by mixing with carriers for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanuts or sesame oil), mono- or polyhydric alcohols (e.g. ethanol or glycerol), carriers such as natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly disperse silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, waste sulphite liquor) , methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The compositions are administered by conventional means, preferably by the oral or transdermal route, particularly orally. For oral administration, tablets may of course contain any of the above carriers, additives such as sodium citrate, calcium carbonate and calcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously with the tablets. In the case of aqueous suspensions, in addition to the excipients listed above, the active ingredients may additionally be combined with various flavor enhancers or colorants.

For parenteral use, solutions of the active compounds with suitable liquid carriers can be used.

The dosage for intravenous use is 1 to 1000 mg per hour, preferably 5 to 500 mg per hour.

However, it may sometimes be necessary to start from the amounts specified depending on body weight, route of administration, individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Therefore, in many cases less than the minimum dose mentioned above may be sufficient,

23- • ·· '0 0 · 0 * 0000 00 0 0 0 · · 0 0 · • · 0 ®000 • 0 0 9 0 0 0 6 '0 0 0 '' 0 '~ ”...... 0 '00 0

Then, in other cases, the upper limit may be exceeded. When large amounts are administered, it may be better to divide them into several smaller doses, spread out throughout the day.

The following formulation examples illustrate the present invention without limiting its scope.

Examples of pharmaceutical formulations

A) Tablets on tablet active substance 100 mg lactose 140 mg cornstarch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg The finely divided active ingredient, lactose and a portion of corn starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinyl pyrrolidone in water, knead, it is wet granulated and dried. Granules, remaining corn starch and magnesium stearate are stitch and mix together. V-eJJososL The mixture is compressed to form tablets of suitable shape and

AND

e ee · ee ee eeee »· ♦ ···· · · · • 9 9 9 -24-:. '':: T.: ΒΊ Tablets on tablet active substance 80 mg lactose 55 mg cornstarch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

Represented by:

Claims (16)

fV Patent claims Compounds of general formula (I), wherein: R ¹ represents a group selected from hydrogen, C 1 -C 6 -alkyl optionally substituted by one or more halogen atoms, -SO 2 H, -SO 2 -C 1 -C 6 -alkyl, -SO-C 1 -C 6 -alkyl, -CO-C 1 C6-alkyl, -O, phenyl-Cl-C4 alkyl, -C 4 alkyl-NR ⁶ R ⁷ and -C 4 alkyl-O-C _r C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl, R ² , R ³ , which may be the same or different, represent a group selected from hydrogen, C 1 -C 6 -alkyl, optionally substituted by one or more halogen atoms, halogen, -ΝΟ 2, -SO 2 H, -SO 2 -C 1 -C 6 -alkyl, -SO-C 1 -C 6 -alkyl, -CO-C 1 -C 6 -alkyl, -OH, -O-C 1 -C 6 -alkyl, -S-C 1 -C 6 -alkyl, -C 1 -C 4 -alkyl-NR ⁶ R ^7, and -C 1 -C ₆ alkyl-O-C 1 -C 4 alkyl and C 3 -C ₆ -cycloalkyl, or R ¹ and R ² together represent a C ₄ -C ₆ -alkylene bridge, R ⁶ , R ⁷ , which may be the same or different, represent hydrogen, C 1 -C ₄ -alkyl or -CO-C 1 -C ₄ -alkyl, R ⁴ , which may be the same or different, represents a group selected from C 1 -C 6 -alkyl, optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, -CN, -NO 2, -SO 2 H, -SO 3 H, - SO 2 -C 1 -C 6 -alkyl, -SO-C 1 -C 6 -alkyl, -SO 2 -NR ⁶ R ⁷ , -COOH, -CO-C ₁ -C ₆ -alkyl, -O-CO-C ₁ -C ₄ -alkyl, -CO-OC ₁ -C ₄ -alkyl, -O-CO-O-C 1 -C ⁶ alkyl, -CO-NR ⁶ R ⁷ , -OH, -O-C 1 -C 6 -alkyl, -S-C 1 -C 6 -alkyl, -NR ⁶ R ^7, and a group aryl, optionally mono- or polysubstituted with halogen atoms, -NO2, -SO2H or C1-C4-alkyl, R ⁵ , which may be the same or different, represents a group selected from C 1-6 -alkyl, optionally substituted with one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, -CN, -NO 2, -SO 2 H, -SO 3 H, -SO 2 C 1 -C 6 -alkyl, -SO-C 1 -C 6 -alkyl, -SO 2 -NR ⁵ R ⁷ , -COOH, -CO-C 1 -C 6 -alkyl, -O-CO-C 1 -C 4 -alkyl, -CO -O-C 1 -C ₄ -alkyl, -O-CO-O-C 1 -C ⁶ alkyl, -CO-NR ⁶ R ⁷ , -OH, -O-C 1 -C ⁶ -alkyl, -S-C 1 -C 6 -alkyl, -NR ⁶ R 7 ⁷ and aryl groups, optionally mono- or polysubstituted by halogen atoms, -NO 2, -SO 3 H or Ci-C4-alkyl, n, m which may be identical or different, represent 0, 1, 2 or 3, with the proviso that the compound naphtho [1,8-de] -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. Compounds of formula (I) according to claim 1, wherein R ¹ represents a group selected from hydrogen, C 1 -C 6 -alkyl optionally substituted by one or more halogen atoms, -SO 2 H, -SO 2 -C 1 -C 6 -alkyl, -SO-C 1 -C 6 -alkyl, -CO-C 1 lower alkyl, -O, -C -C 4 alkylNR ⁶ R @ ⁷ and CFC-a1kyl-O-CFCFalkyl7benzyl; --- R ^2, R ^3, which may be identical or different, represent a group selected from hydrogen, C 1 -C 6 -alkyl, optionally substituted by one or more halogen atoms, halogen, -NO ₂ , -SO ₂ H, -SO ₂ -C ₁ -C 6 -alkyl, -SO-C 1 -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl, -OH, -O-C 1 -C ₆ -alkyl, -S-C 1 -C ₆ -alkyl, -C 1 -C ₄ -alkyl-NR ⁶ R ⁷ and -C 1 -C ₄ -alkyl-O-C 1 -alkyl; -C ₄ -alkyl, or R ¹ and R ² together represent a C ₄ -C 6 -alkylene bridge, R ⁶ , R ⁷ , which may be the same or different, represent hydrogen, C ₁ -C ₄ -alkyl or -CO-C ₁ -C ₂ -alkyl, R ⁴ , which may be the same or different, represents a group selected from the group ad-substituted by one or more halogen atoms, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -COOH, -CO-C 1 -C ₆ -alkyl, -O-COC-C ₄ -alkyl, _{-CO-O-Ci-C4-alkyl,} -O-CO-O-C _r C ₄ -alkyl, -CO-NR ⁶ R ^7, OH , -O-C 1 -C ₆ -alkyl, -S-C 1 -C ₆ -alkyl and -NR ⁶ R ⁷ , R ⁵ , which may be the same or different, represents a group selected from C 1 -C ₆ -alkyl, optionally substituted by one or more halogen atoms, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -COOH, -CO-C 1 -C ₆ -alkyl, -O-COC 1 -C ₄ -alkyl, -CO-O-C 1 -C ₄ -alkyl, -O-CO-O-C 1 -C ₄ -alkyl, - CO-NR ⁶ R ⁷ , -OH, -O-C 1 -C 6 -alkyl, -SC 1 -C 6 -alkyl and -NR ⁶ R ⁷ , an, m, which may be the same or different, are 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts. Compounds of formula (I) according to claim 1 or 2, wherein R ¹ represents hydrogen, _Ci-C4 alkyl or benzyl; R ² , R ³ , which may be the same or different, represent hydrogen or C 1 -C ₄ -alkyl or "R ^J " and "R ² -protectively- ^H " A 3-butylene-a-R ^{4 group} , which may be the same or different, represents a group selected from the group consisting of. C 1 -C 6 -alkyl, optionally substituted with one or more halogen atoms, halogen, -CN, -NO 2, -COOH, -CO-C 1 -C 6 -alkyl, -O-CO-C 1 -C 4 -alkyl, -COO-C 1 -C 4 - alkyl, -O-CO-O-C 1 -C 4 -alkyl, -CO-NR ⁶ R ⁷ , -OH, -O-C 1 -C 6 -alkyl, -S-C 1 -C ⁶ -alkyl and -NR ⁶ R ⁷ , R ⁵ , which may be the same or different, represents a group selected from C 1 -C 6 -alkyl, optionally substituted by one or more halogen atoms, ..... _______... _ .... no • ·· ·· · · • · • ·· · · · · · · • · · · · · · · • · · · · - Zo - • · . 9 ·. · · · · · halogen, -CN, -NO _2, -COOH, -CO-CrCe-alkyl, -O-CO-C _r C ₄ -alkyl, _{-COO-Ci-C4-alkyl,} -O-CO-O-C _r C ₄ -a1kyl, -CO-NR ⁶ R ^7, -OH, -OC _r C ₆ -alkyl, -S-CrCe-alkyl, and -NR ⁶ R ^7, n, m which may be identical or different, represent 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts. Compounds of formula (I) according to claims 1 to 3, wherein R ¹ , R ² , R ³ , which may be the same or different, represent hydrogen or C 1 -C ₄ alkyl, R ⁴ , which may be the same or different, represents a group selected from C 1 -C ₆ -alkyl, optionally substituted by one or more halogen atoms, halogen, -NO ₂ , -O-CO-C 1 -C ₄ -alkyl, - O-CO-O-C 1 -C ₄ -alkyl _and -O-C 1 -C ₆ -alkyl and-NR ^S R ⁷ , R ⁵ , which may be the same or different, represents a group selected from C 1 -C ₆ -alkyl, optionally substituted by one or more halogen atoms, halogen, -NO ₂ , -O-CO-C 1 -C ₄ -alkyl, - O-CO-O-C 1 -C ₄ -alkyl, -O-C 1 -C 6 -alkyl and-NR ⁶ R ⁷ and m, which may be the same or different, are 0, 1 or 2, optionally in the form of different enantiomers and diastereomers, as well as their pharmacologically acceptable salts; Compounds of formula (I) according to any one of claims 1 to 4, wherein R ¹ is methyl, ethyl, i-propyl), n-butyl or benzyl, optionally in the form of their various enantiomers and diastereomrů well as their pharmacologically acceptable salts. Compounds of formula (I) according to any one of claims 1 to 5, wherein R ¹ is methyl, optionally in the form of their pharmacologically acceptable salts. Compounds of formula (I) according to claim 1, wherein R ¹ is methyl, R ^2, R ³ represent hydrogen, R ⁴ , R ⁵ , which may be the same or different, represent halogen and n, m, which may be the same or different, represent 0, 1 or 2, optionally in the form of their pharmacologically acceptable salts. 8. Compounds of formula (I), (!) 'Β ^ββ ' - · - -β β · - · - 99 9 99 9 9 99 9 9 9 9 '·· Where R ¹ represents a group selected from hydrogen, C 1 -C 6 -alkyl optionally substituted by one or more halogen atoms, -SO 2 H, -SO 2 -C 1 -C 6 -alkyl, -Su-C 1 -C 6 -alkyl, -CO-C 1 -C 6 -alkyl, -O, phenyl-C 1 -C ₄ alkyl, -C ₁ -C ₄ -alkyl-NR ⁶ R ⁷ and -C ₁ -C ₄ -alkyl-O-C 1 -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl, R ² , R ³ , which may be the same or different, represent a group selected from hydrogen, C 1 -C 6 -alkyl optionally substituted by one or more halogen atoms, halogen, -NO 2 -SO 2 H, -SO 2 -C 1 -C 6 - alkyl, -SO-C 1 -C 6 -alkyl, -CO-C 1 -C 6 -alkyl, -OH, -O-C 1 -C 6 -alkyl, -S-C 1 -C 6 -alkyl, -C 1 -C 4 -alkyl-NR ⁶ R ⁷ and -C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl or R ¹ and R ² together represent a C ₄ -C ₆ -alkylene bridge, R ^6, R ^7, which may be identical or different, represent hydrogen, _Ci-C4-alkyl or -CO-C ₁ -C ₄ -alkyl, R ⁴ , which may be the same or different, represents a group selected from C 1 -C 6 -alkyl, optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, -CN, -NO 2, -SO 2 H, -SO 3 H, -SO 2 -C 6 -alkyl, -SO-C 6 -alkyl, -SO 2 NR ⁶ R ^7, -COOH, -CO-CrCe-alkyl, -O-CO-C1-C4alkyl, -CO-O-C C4-alkyl, _{-O-CO-O-Ci-C4-alkyl,} -CO-NR ⁷ R ^S, -OH, -O-CrCe-alkyl, -S-C 6 -alkyl, -NR ⁶ R ⁷ group aryl, optionally mono- or polysubstituted by halogen atoms, -NO2, _-SO2 H or C1-C4 alkyl, R 5 is also the same as the group up-C 1 -C ₆ -alkyl optionally substituted by one or more halogen atoms, phenyl-C 1 -C ₄ -alkyl, halogen, -CN, -NO ₂ , -SO ₂ H, - SO ₃ H, -SO ₂ C 1 -C ₆ -alkyl, -SO-C 1 -C ₆ -alkyl, -SO ₂ -NR ⁶ R ⁷ , -COOH, -CO-C 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, -CONR ⁶ R ⁷ , -OH, -O-C 1 -C ₆ -alkyl, -S-C 1 -C ₆ -alkyl, - NR ⁶ R ⁷ and aryl, optionally mono- or polysubstituted with halogen atoms, -NO ₂ , -SO ₂ H or C 1 -C ₄ -alkyl, and N, m, which may be the same or different, represent 0, 1, 2 or 3, optionally in the form of their various enantiomers and distereomers and their pharmacologically acceptable salts for use as pharmaceutical compositions. A compound of formula (I) according to claim 8 for use as a pharmaceutical composition having a neuroprotective effect. Use of a compound of formula (I) according to any one of claims 1 to 7 for the manufacture of a pharmaceutical composition for the treatment and / or prevention of neurodegenerative disorders and / or cerebral ischemia of various origins. AND Use of a compound of formula (I) according to any one of claims 1 to 7 for I. manufacture of a pharmaceutical composition for the treatment of schizophrenia. AND Use of a compound of formula (I) according to any one of claims 1 to 7 for The manufacture of a pharmaceutical composition for the treatment and / or prevention of memory disorders. I ’ Use of a compound of formula (I) according to any one of claims 1 to 7 for A pharmaceutical composition for the treatment of dementia is selected. 14. A method of treating and / or preventing neurodegenerative disorders and / or cerebral ischemia, comprising administering to a patient an effective amount of a compound of formula (I) according to claims 1 to 7. ··. 9 99 9 9 9 9 A method of treating and / or preventing memory disorders and / or dementias, comprising administering to a patient an effective amount of a compound of formula (I) according to claims 1 to 7. Pharmaceutical compositions, characterized in that they contain as active ingredient 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 customary auxiliaries and / or carriers. Represented by: