BG108324A - Napthothiazine positive allosteric ampa receptor modulators (paarm) - Google Patents

Abstract

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

Description

NAFTOTIAZINE POSITIVE ALLOSTERIC

AMRA-RECEPTOR MODULATORS

The present invention relates to novel positive allosteric modulators of the AMPA receptor, a process for their preparation and their use as pharmaceutical compositions.

WO 9967242 discloses carbapenem derivatives with antibacterial activity in which naphtho [1,8-de] -2,3-dihydro-1,1-dioxide-1,2-thiazine is used as a component in the synthesis, as compounds that are structurally similar of the compounds of the present invention.

The compounds of the present invention are compounds of general formula (I)

wherein

R ¹ denotes a group selected from hydrogen, a C 1 -C 6 -alkyl group 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- C1-Sbalkil, -O, phenyl-C1-C4-alkyl, -Ci-C4-alkyl-CC ⁶ R ⁷ and -SGS ₄ alkyl-O-C 1 -C ₄ -alkyl and C-Ce-cycloalkyl,

R ² , R ³ , which may be identical or different, denote a group selected from hydrogen, a C ₁ -C 6 -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -NO ₂ , -SO ₂ H, -COD-C 1 -C 6 -alkyl, -SO-C ₁ -C ₆ alkyl, CO-C ₂ -C 6 -alkyl, -OH, O-C 1 -C 6 -alkyl, S-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-R 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 denote a C ₄ -C ₆ -alkylene bridge,

R ⁶ , R ⁷ , which may be identical or different, denote hydrogen, C ₁ -C ₄ -alkyl or CO-C 1 -C ₄ -alkyl,

R ⁸ , R ⁹ , which may be identical or different, denote hydrogen, C ₁ -C ₄ -alkyl,

R ⁴ , which may be identical or different, means a group selected from a C 1 -C 6 alkyl group optionally substituted by one or more halogen atoms, a phenyl-C 1 -C 4 alkyl, halogen element, -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 ₂ -C ₄ -alkyl, -O-CO-O-C ₂ -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 an aryl group optionally mono- or polysubstituted by halogen atoms, -NO2, -SO ₂ H or C ₁ -C ₄ -alkyl,

R ⁵ , which may be identical or different, means a group selected from a C 1 -C 6 alkyl group optionally substituted by one or more halogen atoms, a phenyl-C 1 -C 4 alkyl, halogen element, -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 ₂ -C ₄ -alkyl, -O-CO-O-C ₂ -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 an aryl group, optionally mono- or polysubstituted by halogen atoms, -NO ₂ , -SO ₂ H or C 1 -C ₄ -alkyl, and n, m which may be identical or different are 0, 1,2 or 3, provided that naphtho [1,8-de] -2,3-dihydro-1,1-dioxy e-1,2thiazine is optionally excluded in the form of their various enantiomers and diastereomers and their pharmacologically acceptable salts.

Preferred compounds are the compounds of general formula (I), wherein R ¹ represents a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, -SO 2 H, -OR 2 -C 1 -C 6 -alkyl, -SO -C 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 identical or different, denote a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -NO 2, -SO 2 H, -8O 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 -anKHn-NR ⁶ R ⁷ and -C 1 -C 4 -alkyl-O-C 1 -C _4- alkyl or

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

R ⁶ , R ⁷ , which may be identical or different, denote hydrogen, C 1 -C ₄ -alkyl or -CO-C 1 -C ₄ -alkyl, and

R ⁴ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -CN, NO ₂ , -SO ₂ H, -SO ₃ H, -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 ,

- R ⁵ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -CN, NO ₂ , -SO ₂ H, -SO 3 H, -COOH , -CO-C 1 -C 6 -alkyl, O-CO-C 1 -C ₇ -alkyl, -CO-O-C 1 -C ₄ -alkyl, -O-CO-O-C ₂ -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 and n, 1, which may be identical or different, are 0, 1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts. p Particularly preferred are the compounds of general formula (I) in which R ¹ represents hydrogen, C ₁ -C ₄ -alkyl or benzyl, R ² , R ³ , which may be identical or different, represent hydrogen or C 1 -C ₄ - an alkyl group, or R ¹ and R ² together denote a butylene bridge, and R ⁴ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group, optionally substituted by one or more halogen atoms, a halogen element, - CN, NO2, -COOH, -CO-C1-C6-alkyl, O-CO-C ₂ -C ₄ -alkyl, -CO-C ₁ -C 8 C ₄ -alkyl, -O-CO-O-C ₂ 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 identical or different, means a group selected from a C 1 -C ₆ -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -CN, NO ₂ , -COOH, -CO-C _g 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, and -NR ⁶ R ⁷ and n, n, which may be identical or different, are 0, 1 or 2,

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

In addition, compounds of general formula (I) are particularly preferred in which

R ¹ , R ² , R ³ , which may be identical or different, denote hydrogen or C 1 -C ₄ -alkyl,

R ⁴ , which may be identical or different, means a group selected from a C ₁ -C ₆ -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -NO ₂ , O-CO-C 1 -C ₄ - alkyl, -O-CO-O-C ₂ -C ₄ -alkyl, -O-C ₂ -C ₆ -alkyl, and NR ⁶ R ⁷ ,

R ⁵ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -NO ₂ , O-CO-C ₂ -C ₄ -alkyl , -O-CO-O-C ₂ -C ₄ -alkyl, -O-C 1 -C ₆ -alkyl, and NR ⁶ R ⁷ and n, m, which may be identical or different, are 0, 1 or 2, respectively. desire in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts.

Of particular importance according to the invention are the compounds of general formula (I) in which R ¹ is methyl, ethyl, i-propyl, n-butyl or benzyl, optionally in the form of various enantiomers or diastereomers, and pharmacologically acceptable salts.

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

R ¹ represents methyl, optionally in the form of pharmacologically acceptable salts.

Also particularly preferred are the compounds of general formula (I) in which

R ¹ stands for methyl,

R ² , R ³ denote hydrogen,

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

R ⁴ , R ⁵ , which may be identical or different, denote a halogen atom, preferably a fluorine, chlorine, bromine, especially preferably fluorine or chlorine, and n, m, which may be identical or different, are 0 , 1 or 2, preferably 0 or 1, optionally in the form of pharmacologically acceptable salts.

The alkyl groups used, unless specifically mentioned, are branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of these include: methyl, ethyl, propyl, butyl, pentyl, and xxyl. The methyl, ethyl, propyl or butane groups may optionally be referred to as Me, Et, Pr or Bo. Unless specifically mentioned, the definitions of propyl, butyl, pentyl and hexyl also include all possible isomeric forms of the forms in question. Thus, for example, propyl includes η-propyl and iso-propyl, butyl includes iso-butyl, secondary butyl and quaternary butyl, etc.

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

The alkyd groups mentioned in the groups -SO 1 C 1 -C 6 -alkyl, -SO-C 1 -C 6 alkyl, -CO-C 1 -C 6 -alkyl, -CO-C ₂ -C ₄ -alkyl, -C 1 -C ₄ -anKHn-NR ⁶ R ⁷ , and C 1 -C ₄ -alkyl-O-C 1 -C ₄ -alkyl, -O-C 1 -C 6 -alkyl, -S-C 1 -C 6 -alkyl, -O-COC 1 -C ₄ -alkyl, -CO -O-C ₂ -C ₄ -alkyl or -O-CO-O-C 1 -C ₄ -alkyl can be branched or unbranched with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, particularly preferably with 1 to 3 carbon atoms, in particular 1 to 2 carbon atoms.

C ₄ -C-alkyl bridge may comprise, unless otherwise specifically stated, branched or unbranched alkylene groups having 4 to 6 carbon atoms, for example n-butylene, 1-methylpropylene, 2metilpropilen, 1.1-dimethylethylene, 1.2-dimethylethylene, and etc. pButylene bridges are particularly preferred.

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

In the aforementioned aryl groups, one or more hydrogen atoms may be optionally substituted by halogen atoms, -NO ₂ , SO ₂ H or -C ₂ C ₄ -alkyl, preferably fluorine, chlorine, -NO ₂ , ethyl or methyl, preferably with a fluorine atom or methyl.

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

The term halogen atom, unless specifically indicated, refers to a fluorine atom, chlorine, bromine and iodine, preferably a fluorine, chlorine and bromine, most preferably a fluorine and chlorine, especially a fluorine atom.

As noted above, the compounds of formula (I) or the various enantiomers and diastereomers can be converted into their salts, especially for pharmaceutical use, into physiologically and pharmacologically acceptable salts. These salts may, on the one hand, take the form of physiologically and pharmacologically acceptable acid salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, the compound of formula (I) in which R ¹ is a hydrogen atom can be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with bases or with alkaline earth metal cations as partner ions. The salts obtained by the addition of acid 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. . It is also possible to use mixtures of the aforementioned acids. For the preparation of salts of the compound of formula (I) with alkali and alkaline earth metals, in which R ¹ represents a hydrogen atom, it is preferable to use alkali and alkaline earth metal hydroxides and hydrides, especially sodium and potassium, which are preferred while sodium and potassium bases are particularly preferred.

The compounds of the invention may be prepared in a manner known per se. The following basic methods for synthesizing 1 and 2 shown in diagrams 1 and 2 below are intended to illustrate the invention without limiting its content.

Method 1

Diagram 1

(IV) (I)

Starting with the compound of formula (II), the compound of formula (III) is prepared by sulfonation and subsequent chlorination. The compound of formula (IV), obtained after condensation with aminoacetic acid derivatives, is cyclized by the addition of polyphosphoric acid to the target compound (I).

The basic preparation of the compounds according to the invention according to Diagram 1 is described in detail hereinafter.

Sulfonation of Natal (II):

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

Methylene chloride, diisopropylene ether, ethyl acetate, trichloro-methane, toluene, benzene or 1,4-dioxin can be used instead of acetic anhydride, while sulfuric acid vapors, sulfur trioxide, chlorine sulphates or combinations thereof can be used as alternatives to concentrated sulfuric acid.

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

About 10 mmol of naphthalene-1-sulfonic acid is gradually mixed with 10-500 mmol, preferably about 90 mmol phosphorous oxytrichloride and 8-50 mmol, preferably about 10 mmol phosphorous pentachloride, and heated for 2 - 16 hours, preferably about 5 hours at 20-100 ° C, preferably by casting. The reaction mixture was then evaporated and mixed with water. After extraction with an organic solvent, the combined organic extracts are dried and freed from the solvent. The crude product thus obtained is used in the subsequent steps without purification.

Instead of phosphorus pentachloride, a mixture of phosphoric acid / chlorine or phosgene may be used. Alternatively, the reaction may be carried out in a solvent ethyl acetate, water, acetonitrile, N, N-dimethylacetamide, sulfolene, DMF, hexane or dichloroethane.

Synthesis of naphthalene-1-1 sulfonyl-amino acetic acid:

About 10 mmol of chlorosulfonyl-naphthalene, 10-100 mmol, preferably 11-30 mmol, preferably preferably about 12 mmol of aminoacetic acid and 10-100 mmol, preferably 11 30 mmol, more preferably about 12 mmol of sodium hydroxide 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 was acidified and extracted. The combined organic extracts were dried and evaporated. Purification can be carried out by chromatography. Triethylamine, potassium carbonate, sodium hydrogen carbonate, or sodium hydride may be used instead of sodium hydroxide, while tetrahydrofuran, diethyl ether, dichloromethane, trichloromethane, doxyn, acetone, benzene, ethanol, methanol, ethyl acetate or acetonitrile may be used.

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

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

Method 2

Diagram 2

SO ₂ CI

(V)

ίΐΊ R ⁴ -tt- 1 ^{4 are} , 1 2 ^m <7 AL Λ R ³ ^ (I) R ²

The compounds of formula (III), obtained as intermediates according to Method 1, are reacted with primary amines to afford the compounds of formula (V) and then cyclized by the addition of the compound of formula RR C = O in the presence of a strong acid to produce the target compounds (I).

To prepare the compounds of formula (I) in which R ¹ and R ² represent hydrogen, paraformaldehyde, trioxane or formalin may be used, and methanesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid or polyphosphoric acid may be used. used as strong acids. The basic preparation of the compounds according to the invention in accordance with Diagram 2 is described in detail hereinafter.

Synthesis of naphthalene-sulfonamides (V)

About 10 mmol of chlorosulfonyl-naphthalene (III) is mixed with an alcohol solution of primary amine (10-1000 mmol in 5 - 200 ml, for example 200 mmol in 50 ml, ethanol) and then heated to 0 100 ° C for 2 - 16 hours, preferably about 5 hours, preferably casting. The reaction mixture was then evaporated and purified.

Instead of the alcoholic solvent, it is possible to use toluene, benzene, trichloromethane, dichloromethane, diethyl ether, tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone, dimethylsulfoxide, dimethylformamide, doxin, or hexane.

Crystallization of naphthalene-1-sulfonamides (V) to form the target compounds! (I)

About 10 mmol of naphthalene-1-sulfonamides are added to 0-100 ml, preferably 20 to 80 ml, most preferably 40 ml of metasulfonic acid and added to 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. The reaction mixture is stirred for 2 16 hours, preferably for about 5 hours at 20-100 ° C, preferably 30-80 ° C, especially at about 35 ° C, and then poured onto ice water. After extraction and drying of the combined organic extracts, the solution was evaporated. The crude product is purified.

Paraformaldehyde or formalin may be used instead of trioxane, while boron trifluoride * diethyl ether, acetic acid, polyphosphoric acid, phosphoric acid or sulfuric acid may be used instead of trifluoroacetic acid. Acetic anhydride or dichloromethane can be used as possible solvents.

The new compounds of basic formula (I) can be synthesized in a similar manner to the Synthesis Examples. However, these Examples are given by way of example procedures only to illustrate the invention further, without limitation to the object of the invention.

Synthesis of 2-methyl-2,3-dihydro-naphtho [1,8-deS, 3] thiazine-1,1-dioxide (Example 1):

2.21 g of N-methyl-1-naphthalenesulfonic acid amide were dissolved in 25 ml of methanesulfonic acid at 35 ° C and mixed 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 onto 300 ml of ice water, the solid was filtered off, washed with 100 ml of water and dried overnight. After crystallization from methylcyclohexane, the product was isolated as a white solid. Yield: 2.20 g. Since 136 ° C.

Synthesis of 6-chloro-2-methyl-2,3-dihydro-1H-11,8-de] N, 31 thiazine-1,1-dioxide (Example 2):

0.45 g of 5-chloro-naphthalene-1-sulfonic acid-1-methylamine are dissolved in 6.8 ml of methanesulfonic acid at 35 ° C and mixed with a solution of 0.07 g of trioxane in 2 ml of trifluoroacetic acid. The reaction mixture was poured onto 100 ml of ice water and the aqueous phase was extracted with ethyl acetate. The organic extracts which were collected were dried with sodium sulfate, evaporated in vacuo and then purified by chromatography. Yield: 0.41 g. Bp: 150 ° C.

Synthesis of 2,3-dihydro-naphtho 11,8-deH1,3] thiazine-1,1-dioxide (Example 3):

Naphthalene-1-sulfonic acid tert-butylamide:

ml of tert-butylamide naphthalene-1-sulfonic acid is placed in 50 ml of chloroform cooled to 0 ° C and 5.75 g of 1-naphthalene-1-sulfonic acid chloride in 45 ml of chloroform are added dropwise. The mixture was then stirred for 24 hours at room temperature. After concentration by evaporation in vacuo, the residue which was obtained was dissolved in dichloromethane and washed with 2N hydrochloric acid. The combined organic extracts were dried with sodium sulfate and evaporated in vacuo. Yield: 5.48 g.

2-tert-butyl-1,1-dioxo-1,2-dihydro-1X6-naphtho [1,8-de] [1,3] thiazine-

3- he:

4.36 g of tert-butylamide naphthalene-1-sulfonic acid are placed in 80 ml of tetrahydrofuran cooled to -10 ° C and 29 ml of N-butyl lithium (1.6 molar solution in hexane) is carefully added dropwise. The mixture was first stirred for 0.5 hours at -10 ° C, then for 3 hours at room temperature. The solution was poured into 4 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried with sodium sulfate and purified by chromatography after evaporation in vacuo. Yield: 0.42 g.

2-tert-butyl-2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide:

0.17 g of 2-tert-butyl-1,1-dioxo-1,2-dihydro-1 X ^6- naphtho [1,8-de] [1,3] thiazin-3-one are suspended in 2 ml of tetrahydrofuran per room temperature and 1.17 ml of borane-tetrahydrofuran complex (1 molar solution) were added. The mixture was then stirred for 100 hours with a total of an additional 8.2 ml of 1M borane-tetrahydrofuran complex solution added in several portions. The reaction mixture was mixed with 2 ml of 2 N hydrochloric acid and 2 ml of methanol, then allowed to drop for 12 hours with stirring. 2 ml of ammonia was added and all the crystals formed were filtered. The filtrate was extracted with ethyl acetate, the organic extracts were combined and dried with sodium sulfate. After evaporation in vacuo, the residue obtained is purified by chromatography. Yield: 0.06 g.

2,3-Dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide:

0.06 g of 2-tert-butyl-2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide are dissolved in 1 ml of dichloromethane and 0.02 ml of trifluoroacetic acid are added. The mixture was then stirred for a total of 22 hours at a drop in temperature and for 96 hours at room temperature, while a total of 0.07 ml of trifluoroacetic acid was added during this period. The reaction mixture was evaporated in vacuo and purified by chromatography. Yield: 0.034 g. M.p .: 206 207 ° C.

Synthesis of [2- (1,1-dioxo-1H-H-1? ⁶ naphtho [1,8-de] thiazin-2-yl) ethyl] dimethylamine (Example 4):

0.028 g of sodium hydride are suspended in 0.5 ml of dimethylformamide and 0.073 g of 2,3-dihydro-naphtho [1,8] [1,3] thiazine-1,1-dioxide in 1 ml of dimethylformamide are added. 0.053 g of diethylaminoethyl chloride hydrochloride chloroform are then added in portions. The reaction mixture was stirred for 18 hours at room temperature and then poured onto cold water. The mixture was extracted with dichloromethane and the combined organic extracts were dried with sodium sulfate. After evaporation in vacuo, the residue obtained is purified by chromatography. Yield: 0.035 g. Since 97-98 ° C.

Synthesis of a- (2-methyl-1E-dioxo-2,3-dihydro-1H-1? ⁶ naphtho [1,8de] thiazin-6-yl) -ethyl! -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 mixed and stirred for 4 hours at 60 ° C. The solution was then poured onto cold water and extracted with dichloromethane. The combined organic extracts were dried with sodium sulfate and evaporated in vacuo. Yield: 1.10 g.

N- (5-methylsulfamoyl-naphthalen-1-yl) -acetamide:

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

N - (2-methyl-1,1-dioxo-2,3-dihydro-1H-1H ^6- naphtho [1,8-de] [1,3] thiazin-6-yl) -acetamide:

0.25 g of N- (5-methylsulfamoyl-naphthalen-1-yl) -acetamide were dissolved in 3.4 ml of methanesulfonic acid at 35 ° C and mixed 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 onto ice water and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried with sodium phosphate, evaporated in vacuo and purified by chromatography. Yield: 0.136 g. Bp: 189 ° -190 ° C.

N- (2-methyl-1,1-dioxo-2,3-dihydro-1H-1H ^6- naphtho [1,8-deS, 31 thiazin-2-yl) -acetamide: (Example 6):

8-tert-butylsulfamoyl-naphthalene-1-carboxylic acid:

4.36 g of naphthalene-1-sulfonic acid tert -butylamide were placed in 80 ml of tetrahydrofuran, cooled to -10 ° C and 29 ml of N-butyl lithium (1.6 molar solution in hexane) was added dropwise. The mixture was stirred first for 0.5 hours at -10 ° C, then for 3 hours at room temperature. Then cooled to -5 ° C and purged for a period of 0.25 hours with a CO ₂ obtained from dry ice. The reaction mixture was then stirred for 2.5 hours at room temperature and then mixed with water. The solution was poured onto 4 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried with sodium sulfate and purified by chromatography after evaporation in vacuo. Yield:

1.19 g.

1,1-Dioxo-1,1-dihydro-1? ^B naphtho [1,8-de] [1,3] thiazin-3-one:

0.15 g of 8-tertbutylsulfamoyl-naphthalene-1-carboxylic acid was added to 0.25 g of polyphosphoric acid. The mixture was stirred for 4 hours at 150 ° C. The reaction mixture was then poured onto ice water and the aqueous phase extracted with ethyl acetate. The organic extracts were dried with sodium sulfate and evaporated in vacuo. Yield: 0.07 g.

2,3-Dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide:

0.07 g of 1,1-dioxo-1,1-dihydro-1X ^6- naphtho [1,8-de] [1,3] thiazin-3-one are dissolved in 2 ml of THF and carefully added dropwise.

1.2 ml of 1 molar solution of borane-tetrahydrofuran complex. The mixture was stirred for 18 hours in 2 N hydrochloric acid and 2 ml of methanol, then stirred for 2 hours at falling temperature. 2 ml of ammonia was added and each crystal formed was filtered. The filtrate was extracted with ethyl acetate, and the organic extracts were combined, dried with sodium sulfate and evaporated in vacuo. Yield: 0.06 g.

2- (1,1-Dioxo-1H, 3H-1X ^6- naphtho [1,8-de] [1,31 thiazin-2-yl) acetamide:

0.011 g of sodium hydride are suspended in 0.5 ml of dimethylformamide and 0.06 g of 2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide in 1 ml of dimethylformamide are added. The mixture was stirred for 1 hour at room temperature and then 0.042 g of 2-bromoacetamide were added portionwise. The mixture was then poured onto ice water and extracted with dichloromethane. The organic extracts were combined and dried with sodium sulfate and purified by chromatography after evaporation in vacuo. Yield: 0.043 g. M.p .: 195 ° -196 ° C.

Synthesis of 7-hydroxy-2-methyl-2,3-dihydro-naphtho [1,8-deS, 31 thiazine-1,1-dioxide (Example 7):

0.6 g of 7-methoxy-2-methyl-2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1 dioxide are 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) were added dropwise. The mixture was then stirred for 24 hours at room temperature. After evaporation in vacuo, the residue was purified by chromatography. Yield: 0.36 g. M.p .: 245 ° -246 ° C.

Synthesis of methyl 2-methyl-1,1-dioxo-2,3-dihydro-1H-1X ^6- naphtho [1,8-d? N, 31 thiazin-7-yl ester carboxylate (Example 8);

0.11 g of 7-hydroxy-2-methyl-2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1 dioxide and 0.061 ml of triethylamine are placed in 2 ml of toluene and cooled to 0 ° C. . 0.037 ml of methyl fluoroformate are added dropwise. The mixture was then stirred for 5 hours at room temperature. The suspension was then poured onto ice water and extracted with ethyl acetate. The combined organic extracts were dried with sodium sulfate and, after evaporation in vacuo, purified by chromatography.

Yield: 0.065 g. Bp .: 161 ° - 162 ° C.

The following Formula IA formulations were prepared in a similar manner to the procedure described above:

(IA)

Table 1

An example R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ Since [° C] 9 CH ₃ N. N. Η N. Br 226-227 10 CH ₃ no ₂ N. N. N. N. 264-265 11 CH ₃ n N. OSN ₃ N. N. 174-175 12 CH ₃ n N. F N. N. 129-130 13 CH ₃ n N. Br N. N. 163-164 14 CH ₃ n N. CH ₃ N. N. 142-143 15 CH ₃ n N. I N. N. 192-193 16 CH ₃ n I N. N. N. 160-161 17 CH ₃ n no ₂ N. n N. 169-170 18 CH ₃ n he N. n N. 160-161 19 CH3 N (CH ₃ ) ₂ n N. n N. 20 CH ₃ n n N. n N (CH ₃ ) ₂ 21 CH3 i-Pr n N. Iso-Pr n 22 CH ₃ N. OSOME N. N. n 23 CH ₃ N. F N. N. n

The compounds of general formula (I) have been found to be characterized by their wide field of application in the field of therapy. Particular attention should be paid to those applications in which the positive modulator of AMPA receptors plays a role.

The effect of the compounds of the invention as AMPA receptor modulators was measured electrophysiologically on cells expressing functional AMPA receptors. Studies have been conducted to determine whether test substances have a positive allosteric effect on agonist-induced current.

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

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

An example Activity 1 + 2 ++

The new compounds can also be used to treat diseases or conditions in which neural networks that require AMPA receptors to function are damaged or restricted in their functions.

The compounds of general formula (I) can then be used in dementias, neurodegenerative or psychiatric disorders, and neurodegenerative disorders and cerebral ischemia of different origins, preferably in schizophrenia or disorders of study and memory functions.

The following also include: epilepsy, hypoglycemia, hypoxia, anoxia, cerebral trauma, cerebral edema, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, sexual dysfunction, impaired sensory / motor function, memory formation, hypertension especially in children), hypotension, heart attack, cerebral pressure (increased intracranial pressure), ischemic and hemorrhagic stroke, general cerebral ischemia in cardiac arrest, acute and chronic neuropathic pain, diabetic polyneurope th, tinnitus, prenatal asphyxia, psychosis, Parkinson's disease and depression, and related conditions of agitation.

The novel compounds may be administered in combination with other active substances, such as those used for the same indications, such as neuroleptics, nootropics, psychostimulants, etc. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation. Moreover, the compounds of general formula I or their salts may be combined with active ingredients of other types.

Compounds of general formula (I) may be administered alone or in combination with other active substances according to the invention, possibly also in combination with other pharmacologically active substances. Suitable formulations include, for example, tablets, capsules, suppositories, solutions, - especially injectable solutions (subcutaneous, intravenous, intramedullary) and transfusions - elixirs, emulsions or dispersion powders. The content of the pharmaceutically active compounds should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight of the composition as a whole, i.e. in quantities sufficient to reach the dosage range given below. Suitable tablets can be prepared, for example, by mixing active substances with known excipients, for example inert fillers such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginate, binders such as starch or gelatin or lubricants such as magnesium stearate or lubricants such as magnesium stearate. delayed release agents such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also be multilayered.

Coated tablets may be suitably prepared by coating a core produced in a manner analogous to the preparation of the tablets, with substances commonly used to coat the tablets, for example colidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or to prevent incompatibility, the core may also be multilayered. Similarly, the tablet cover may consist of a number of layers for sustained release, preferably using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may further comprise a sweetener such as saccharin, cyclamate, glycerol or sugar and an aroma enhancer, e.g. flavoring such as vanilla or orange extract. They may also contain auxiliary agents or sealants such as sodium carboxymethyl cellulose, moisturizing agents such as condensation products of fatty alcohols with ethylene oxide or preservatives such as p-hydroxybenzoates.

Injection and transfusion solutions are prepared in the usual manner, i. by adding isotonic agents, preservatives such as hydroxybenzoates or stabilizers such as alkali metal salts with ethylenediamine tetraacetate, optionally using emulsifiers and / or dispersants, whereas if water is used as a solvent, for example, as dissolving agents or dissolving agents, may desire dissolving agents use organic solvents and transfer to vials or ampoules for injection or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol or by packing them in gelatin capsules. Suitable suppositories may be prepared, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof. Fillers that may be used, for example water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), vegetable fats (eg peanut or sesame oil), monoculars polyfunctional alcohols (eg ethanol or glycerol), carriers such as e.g. natural mineral powders (eg kaolins, glue, talc, talc), synthetic mineral powders (eg highly dispersed silicic acid and silicates), sugars (eg cane sugar, lactose and glucose), emulsifiers (eg , waste sulfite liquids, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The formulations are administered by conventional methods, preferably by oral or transdermal administration, especially orally. For oral administration, the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives such as starch, preferably potato starch, gelatin and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used simultaneously in the tabletting process. In the case of aqueous suspensions, the active substances may be combined with different flavor enhancers or colorants in addition to the fillers mentioned above.

For parenteral use, solutions of the active ingredients in suitable liquid carriers may be used.

The dosage for intravenous administration is from 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to deviate from the indicated amounts depending on the body weight, route of administration, individual response of the drug, the nature of its composition and the time or interval during which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given, while in other cases the upper limit may be exceeded. When large quantities are administered, it may be desirable to divide these amounts into a series of smaller doses throughout the day.

The following examples of compositions illustrate the present invention without limiting its scope:

Examples of pharmacological compositions

Tablets for the Tablet Active substance 100 mg Lactose 140 mg Corn starch 240 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mg

500 mg

The finely divided active ingredients, lactose and part of the corn starch are mixed together. The mixture was screened, then moistened with a solution of polyvinylpyrrolidone in water, mixed, granulated in the wet and dried. The granules, remaining corn starch and magnesium stearate are sieved and mixed together. The mixture is compressed to form tablets of suitable shape and size.

C) Tablets for Tablets

Active substance 80 mg Lactose 55 mg Corn starch 190 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg Magnesium stearate 2 mg

400 mg

The finely divided active ingredients, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and treated with the remaining corn starch and water to form a granulate which is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added, mixed and the mixture is compressed to form tablets of the appropriate size.

C)

Ampoule solution

Active substance

Sodium chloride

Water for injection mg mg ml

The active substance is dissolved in water at its own pH, or more preferably at pH 5.5 to 6.5, and sodium chloride is added to make the solution isotonic. The resulting solution was filtered to release from pyrogens and the filtrate was transferred under sterile conditions into ampoules, which were then sterilized and soldered by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims (16)

Claims 1) Formulations of general formula (I) Characterized by the fact that in them u R ¹ means a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, -SO 2 H, -SO 2 Cl-C 6 -alkyl, -SO-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 ₂ C ₄ -alkyl and C ₃ -C ₆ cycloalkyl, R ² , R ³ , which may be identical or different, means a group selected from hydrogen, a C 1 -C 6 alkyl group 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, C 1 -C 6 -alkyl, -C 1 -C 4 -alkyl-K ^{6 b} K ⁷ and -C 1 - C4-alkyl-O-C 1 -C ₄ -alkyl, and C ₃ C cycloalkyl or R ¹ and R ² together denote a C ₄ -C ₆ -alkylene bridge, R ⁶ , R ⁷ , which may be identical or different, denote hydrogen, C ₁ -C ₄ -alkyl, or -CO-C ₂ -C ₄ -alkyl, R ⁴ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, a halogen element, -CN, -NO 2, - SO2H, -SO3H, -8O2-C1-Ce-alkyl, -SO-Ci-Ce-alkyl, -SO2NR ⁶ R ^7, -COOH, -CO-Ci-C6- alkyl, -O-CO-SrSd -alkyl, -COO-C 1 -C ₄ -alkyl, -O-CO-O-C ₂ -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 an aryl group, optionally mono- or polysubstituted by halogen atoms, -NO2, -SO ₂ H or C ₁ -C ₄ -alkyl, R ⁵ , which may be identical or different, means a group selected from a C1-C6-alkyl group optionally substituted complexes with one or more halogen atoms, phenyl-C1-C4-alkyl, halogen element, -CN, -NO2, -SO2H, -SO3H, -SOrCi-C6-alkyl, -SO-C1-C6-alkyl, -SO2NR ⁶ R ⁷ , -COOH, -CO-C 1 -C 6 -alkyl, O-CO-C ₂ -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, -C 1 -C ₆ -alkyl, -NR R and an aryl group, optionally mono- or polysubstituted by halogen atoms, -NO ₂ , -SO ₂ H or C 1 -C ₄ -alkyl, and n, m which may be identical or different, are 0, 1,2 or 3, with the proviso that naphtho [1,8-de] -2,3-dihydro- 1,1-dioxide-1,2-thiazine is optionally excluded in the form of their various enantiomers and diastereomers, and rmakologichno acceptable salts thereof. 2) Compounds of general formula (I) according to Claim 1, characterized in that R ¹ represents a group selected from hydrogen, a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, -SO 2 H, -SO 2 Cl-C 6 -alkyl, -SO-C 1 -C 6 -alkyl, CO-C] -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 identical or different, denote a group selected from hydrogen, a C 1 -C 6 alkyl group optionally substituted by one or more halogen atoms, halogen, -NO 2, -SO 2 H, -SO 2 -Cr C 6 -alkyl, -SO-C 1 -C 6 -alkyl, CO-C 1 -C 6 -alkyl, -OH, -O-C 1 -C 6 -alkyl, -C 1 -C 6 -alkyl, -C 1 -C 4 -alkyl-NR ⁶ R ⁷ and -C 1 -C 4 -alkyl-O-C ₂ -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 identical or different, denote hydrogen, C 1 -C ₄ -alkyl or -CO-C 1 -C ₄ -alkyl, and R ⁴ , which may be identical or different, means a group selected from a C 1 -C 6 alkyl group optionally substituted by one or more halogen atoms, a halogen element, -CN, -NO 2, -SO ₂ H, SO ₃ H, - 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, -SC 1 -C ⁶ -alkyl, -NR ⁶ R ⁷ , R ⁵ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group, optionally substituted by one or more halogen atoms, a halogen element, -CN, -NO2, -SO2H, SO3H, -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-C1-C6-alkyl, -SC [-C 6 -alkyl, and -NR ⁶ R ⁷ and n, m, which may be identical or different, are 0, 1 or 2, optionally in the form of their different enantiomers and diastereomers as well as their pharmacologically acceptable salts. 3) Compounds of general formula (I) according to any one of Claims 1 or 2, characterized in that R ¹ represents hydrogen, a C ₁ -C ₄ -alkyl group or benzyl, R ² , R ³ , which may be identical or different, denote hydrogen or a C ₁ -C ₄ -alkyl group, or r ¹ h R ² together denote a butylene bridge, and R ⁴ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -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-C 0 -C 1 -C 4 -alkyl, -CO-NR ⁶ R ⁷ , -OH, -O-C 1 -C 6 -alkyl, -S-C1-C6-alkyl and -NR ⁶ R ⁷ , R ⁵ , which may be identical or different, means a group selected from a C 1 -C ₆ -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -CN, -NO 2, -COOH, -CO- C 1 -C ₆ -alkyl, O-C 0 -C 1 -C ₄ -alkyl, -CO-O-C] -C ₄ -alkyl, -O-CO-OC 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 and n, m, which may be identical or different, are 0,1 or 2, optionally below the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts. 4) Compounds of general formula (I) according to Claims 1 to 3, characterized in that in them: R ¹ , R ² , R ³ , which may be identical or different, denote hydrogen or C 1 -C ₄ -alkyl R ⁴ , which may be identical or different, means a group selected from a C 1 -C ₆ -alkyl group optionally substituted by one or more halogen atoms, a halogen element, -NO 2, -O-CO-C] -C ₄ alkyl, -O-CO-O-C _g C ₄ -alkyl, -O-C 1 -C 6 -alkyl, hNR ⁶ R ⁷ , R ⁵ , which may be identical or different, means a group selected from a C 1 -C 6 alkyl group optionally substituted by one or more halogen atoms, a halogen element, -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 n, m, which may be identical or different, are 0,1 or 2, optionally in the form of their various enantiomers and diastereomers, as well as their pharmacologically acceptable salts. The compounds of general formula (I) according to any one of Claims 1 to 4, characterized in that: R 1 represents methyl, ethyl, i-propyl, n-butyl or benzyl, optionally in the form of various enantiomers or diastereomers, and pharmacologically acceptable salts thereof. 6) The compounds of general formula (I) according to any one of Claims 1 to 5, characterized in that: R ¹ means methyl, optionally in the form of pharmacologically acceptable salts. 7. The compounds of general formula (I) according to claim 1, characterized in that: R ¹ stands for methyl, R ² , R ³ denote hydrogen, R ⁴ , R ⁵ , which may be identical or different, denote a halogen atom, and n, m, which may be identical or different, are 0, 1 or 2, optionally in the form of pharmacologically acceptable salts. 8) Formulations of general formula (I), characterized in that therein R ¹ represents a group selected from hydrogen, a C 1 -C 6 -alkyl group 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 -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 identical or different, denote a group selected from hydrogen, a C 1 -C 6 -alkyl group 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, C 1 -C 6 -alkyl, -C 1 -C 4 -anKH-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 denote a C ₄ -C ₆ -alkylene bridge, R ⁶ , R ⁷ , which may be identical or different, denote hydrogen, C ₁ -C ₄ -alkyl or -CO-C 1 -C ₄ -alkyl, R ⁴ , which may be identical or different, means a group selected from a C 1 -C 6 -alkyl group optionally substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, a halogen element, -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 _r C ₄ alkyl, -O-CO-O-C 1 -C ₄ -alkyl, -CO-NR ⁶ R ^7, -OH, -O-C1-C6-alkyl, -SCi-Ce-alkyl, -NR ⁶ R ⁷ and an aryl group, optionally mono- or polysubstituted by halogen atoms, -NO 2, -SO ₂ H or C 1 -C ₄ -alkyl, R ⁵ , which may be identical or different, means a group selected from a C 1 -C 6 alkyl group optionally substituted by one or more halogen atoms, a phenyl-C 1 -C 4 alkyl, halogen element, -CN, -NO 2, -SO2H, -SO3H, -8O2-C1-C6-alkyl, -SO-C1-C6-alkyl, -SO2NR 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] -C ₄ -alkyl, -CO-NR ⁶ R ⁷ , -OH, -O-C 1 -C 6 -alkyl, -SC 1 -C 6 -alk, -NR ⁶ R ⁷ and an aryl group, optionally mono- or polysubstituted by halogen atoms, -NO 2, -SO 2 H or C 1 -C 6 -alkyl, and n, m, which may be identical or different, are 0, 1,2 or 3 , optionally in the form of their various enanthates Omer and diastereomers, and the pharmacologically acceptable salts thereof for use as pharmaceutical compositions. 9) Composition of general formula (I) according to Claim 8 for use as pharmaceutical compositions with neuroprotective effect. 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 neurodegenerative diseases and / or cerebral ischemia of different origin. 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 of schizophrenia. 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 disorders. 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 of dementias. 14) A method of treating and / or preventing neurodegenerative diseases and / or cerebral ischemia, wherein the patient is administered an effective amount of a compound of formula I according to claims 1 to 7. < » 15) A method of treating and / or preventing memory and / or dementia disorders, characterized in that the patient is administered an effective amount of a compound of formula I according to claims 1 to 7. 16) Pharmaceutical preparations containing as active substance one or more compounds is the general formula (I) according to one of Claims 1 to 7, or the physiologically acceptable salts thereof, optionally mixed with conventional excipients and / or carriers.