SK14222003A3 - 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

Technical field

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

BACKGROUND OF THE INVENTION

As compounds structurally similar to the compounds of the present invention, WO 9967242 discloses carbapenem derivatives having antibacterial activity, using as naphtho [1,8-de] -2,3-dihydro-1,1-dioxide 1,2- tiazífi ". '

The essence of the invention

The present invention provides naphthothiazines of the formula I

(I) where

R ¹ is a group selected from hydrogen, C 1 -C 6 -alkyl unsubstituted or 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 , -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, are groups selected from hydrogen,

C 1 -C 6 -alkyl unsubstituted or substituted by one or more halogen atoms, halogen, -NO ₂ , -SO ₂ H, -SO ₂ -C 1 -C 6 -alkyl, -SO-2C 1 -C 6 alkyl, -CO-C 1 -C 6 -alkyl -C 8 -alkyl, -OH, -OC 1 -C 8 -alkyl, -SC 1 -C 8 -alkyl, -C 1 -C 4 -alkyl NR ⁶ R ⁷ , -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl and C 3 -C 8 -cycloalkyl, or R ¹ and R ² together are a C 4 -C 6 -alkylene bridge,

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

R ⁴ , which may be identical or different, are groups selected from C 1 -C 8 -alkyl, unsubstituted or 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, -C6-alkyl, -SO 2 NR ⁶ R ^7, -COOH, -CO-alkyl-CRCG, -0CO-C, -C4-alkyl, -CO O-C 1 -C ₄ -alkyl, -O-CO-OC ₁ -C ₄ -alkyl, -CO-NR ⁶ R ⁷ , -OH, -OC 1 -C 6 -alkyl, -S-C 1 -C 6 -alkyl, - NR ⁶ R ⁷ and an aryl group optionally mono- or polysubstituted with halogen atoms, -NO 2, -SO 2 H or C 1 -C 4 -alkyl,

R ⁵ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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, -C6-alkyl, -SO 2 NR ⁶ R ^7, -COOH, -CO--C ₆ -alkyl, -0CO-C ₄ -alkyl, -CO- OC ₁ -C ₄ -alkyl, -O-CO-OC ₁ -C ₄ -alkyl, -CO-NR ⁶ R ⁷ , -OH, -OC ₁ -C ₈ -alkyl, -S-C 1 -C 8 -alkyl, -NR ⁶ R ^7, and aryl groups 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 the naphtho [1,8-de] -2,3-dihydro-1,1-dioxide-1,2-thiazine is excluded, optionally in the form of their various enantiomers and diastereomers, and their pharmaceutically acceptable salts.

Preferred compounds are those compounds of formula I wherein R ¹ is a group selected from hydrogen, C 1 -C 6 -alkyl, unsubstituted or substituted with 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 8 -alkyl, -O, -C ₁ -C ₄ -alkyl-NR ⁷ R ⁸ , -C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl and benzyl,

R ² , R ³ , which may be identical or different, are selected from hydrogen, C 1 -C 6 alkyl, 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 -C 4 - alkyl, or

-3R ¹ and R ² together represent a C ₄ -C ₆ -alkylene bridge,

R ⁶ , R ⁷ , which may be identical or different, are groups selected from hydrogen, C 1 -C ₄ -alkyl or -CO-C 1 -C 2 -alkyl, and

R ⁴ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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, -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 _r C ₆ -alkyl and -NR ⁶ R ⁷ ,

R ⁵ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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, -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 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 pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I, wherein R ¹ is hydrogen, C ₄ alkyl or benzyl,

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

R ⁴ , which may be identical or different, are groups selected from C 1 -C ₆ -alkyl, unsubstituted or substituted by one or more halogen atoms, halogen, -CN, -NO 2, -COOH, -CO-C 1 -C 6 -alkyl , -O-CO-C _r C ₄ -alkyl, -CO-O-C-C ₄ -alkyl, -O-CO-O-C-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, are groups selected from C 1 -C 6 -alkyl, unsubstituted or substituted by one or more halogen atoms, halogen, -CN, -NO 2, -COOH, -CO-C 1 -C 6 -alkyl, -O-COCrC 1-6 alkyl, -CO-O-C 1 -C 6 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 , an, 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 pharmaceutically acceptable salts.

Also particularly preferred are compounds of formula I wherein R ¹ , R ² , R ³ , which may be identical or different, are hydrogen or C 1 -C 4 -alkyl,

R ⁴ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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 ,

R ⁵ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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 , an, 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 pharmaceutically acceptable salts thereof.

Of particular interest in the present invention are compounds of formula I wherein R ¹ is methyl, ethyl, n -propyl, n -butyl or benzyl, optionally in the form of their various enantiomers and diastereomers, as well as their pharmaceutically acceptable salts.

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

Also preferred compounds of formula I wherein R ¹ is methyl,

R ² , R ³ are hydrogen,

R ⁴ , R ⁵ , which may be identical or different, are halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine, and n, m, which may be identical or different, are 0, 1 or 2, optionally in the form of their pharmaceutically acceptable salts.

The alkyl groups used, unless otherwise indicated, are branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms.

-5 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl and hexyl. The methyl, ethyl, propyl or even butyl groups may optionally also be abbreviated as Me, Et, Pr or Bu. Unless otherwise indicated, the definitions of propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, secondary butyl and tert-butyl, and the like.

In the above alkyl groups, one or more hydrogen atoms may be unsubstituted or substituted by halogen atoms such as fluorine, chlorine, bromine or iodine. Fluorine and chlorine are preferred. A particularly preferred substituent is fluorine. 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 the branched or unbranched form. Unless otherwise stated, benzyl and phenylethyl are preferred phenyl-C 1 -C 4 -alkyl groups. Benzyl 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 ₄ -alkyl-C-O-C-C ₄ -alkyl, -O-dripped alkyl, -SO _r C ₆ -alkyl, -O-CO-C-alkyl, CO-OC _r C ₄ -alkyl or -O-COO-Ci-4 alkyl may be in branched or unbranched form with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, particularly preferably having 1 to 3 carbon atoms, most preferably the 1 to 2 carbon atoms.

The C4-C6-alkylene bridge may, unless otherwise indicated, be a branched and unbranched alkylene group having 4 to 6 carbon atoms, such as n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, 1,2 -dimethylethylene, etc. Particularly preferred are n-butylene bridges.

The aryl group is an aromatic ring system having 6 to 10 carbon atoms, preferably phenyl. In the above aryl groups, one or more hydrogen atoms may be unsubstituted or substituted by halogen atoms, -NO ₂ , -SO ₂ H or C 1 -C ₄ -alkyl, preferably fluorine, chlorine, -NO ₂ , ethyl or methyl, most preferably fluorine or methyl.

The term C ₃ -C ₆ -cycloalkyl refers to saturated cyclic hydrocarbon groups having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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

As mentioned above, the compounds of formula I or various enantiomers or diastereomers thereof may be converted into their salts, in particular 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 addition salts of the compounds of the formula I with inorganic and organic acids. On the other hand, the compounds of the formula I can be converted, by reaction with inorganic bases, into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as counterions. Acid addition salts may be prepared using, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric or maleic acids. Mixtures of the above acids can also be used. Alkali metal or alkaline earth metal hydroxides and hydrides may be used to prepare salts of compounds of formula I wherein R ¹ is hydrogen with alkali or alkaline earth metals, alkali metal hydroxides and hydrides, particularly sodium and potassium, are particularly preferred, while sodium and potassium hydroxide are particularly preferred.

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

Method 1 Scheme 1

(Π)

->

(III)

Starting from a compound of formula II, a compound of formula III was prepared via a sulfonation reaction followed by a chlorination reaction. The compound of formula IV obtained after condensation with aminoacetic acid derivatives is cyclized by adding polyphosphoric acid to the target compound of formula I.

The general preparation of compounds of the present invention in accordance with Scheme 1 is described in more detail below.

Sulfonation of the naphthalenes II

Approximately 10 mmol of the naphthalene derivatives of formula II are dissolved in 2 to 100 ml, preferably 3 to 80 ml, most preferably in about 4 ml acetic anhydride and 10 to 100 ml, preferably 11 to 80 mmol, particularly preferably 11 mmol of concentrated sulfuric acid are added. at 0 to 50 ° C, preferably at 5 to 20 ° C, particularly preferably at about 18 ° C. After 2-16 hours, preferably about 5 hours, with stirring at 20 to 100 ° C, preferably at about 25 ° C, the mixture was poured into a saturated NaCl solution. The formed crystals were isolated.

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

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

Approximately 10 mmol of naphthalene-1-sulfonic acid is mixed sequentially with 10 to 500 mmol, preferably about 90 mmol of phosphorus oxytrichloride and with 8 to 50 mmol.

-8mmol, preferably with 10 mmol of phosphorus pentachloride, and the mixture is heated for 2 to 16 hours, preferably for about 5 hours at 20 to 100 ° C, preferably at reflux. Then, the reaction mixture was evaporated and mixed with water. After extraction with organic solvent, the organic extracts were dried and stripped of solvent. The crude product obtained is used in the next step without purification.

Thionyl chloride, phosphorus pentachloride, phosphoric acid / chlorine or phosgene may be used in place of the phosphorus oxytrichloride / phosphorus trichloride mixture. Alternatively, the reaction may be carried out in diluents such as ethyl acetate, water, acetonitrile, N, N -dimethylformamide, sulfolane, DMF, hexane or dichloroethane.

Synthesis of naphthaline-1-sulfonyl-amino-acetic acids

About 10 mmol of chlorosulfonyl-naphthalenes, 10 to 100 mmol, preferably 11 to 30 mmol, most preferably about 12 mmol of aminoacetic acid and 10 to 100 mmol, preferably 11 to 30 mmol, most preferably about 12 mmol of sodium hydroxide are dissolved in water and toluene. The reaction mixture was stirred for 2 to 16 hours at 0 to 110 ° C, preferably at about 65 ° C, then the phases were separated. The aqueous phase was acidified and extracted. The combined organic extracts were dried and evaporated. Purification can be accomplished by chromatography.

Instead of sodium hydroxide, triethylamine, potassium carbonate, sodium 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.

The cyclization of naphthalene-1-sulfonylamino-acetic acids of formula IV

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

Method 2

Scheme 2

(III)

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 target compounds of formula I .

To prepare a compound of formula I, wherein R ¹ and R ² are hydrogen may be used, paraformaldehyde, trioxane or formalin as a strong acid can be used, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

The general preparation of compounds of the present invention in accordance with Scheme 2 is described in more detail below.

Synthesis of Naphthalenesulfonamides of Formula V

Approximately 10 mmol of the chlorosulfonyl-naphthalenes of formula III are mixed with an alcoholic solution of a primary amine (10 to 1000 mmol in 5 to 200 mL, for example 200 mmol in 50 mL of ethanol) and then heated to 0 to 100 ° C over 2 to 16 hours, preferably within about 5 hours, preferably at reflux. Then the reaction mixture was evaporated and purified.

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

The cyclization of a naphthalene-1-sulfonamide of formula V to form the target compounds of formula I

About 10 mmol of naphthalene-1-sulfonamide was added to 0 to 100 ml, preferably to 20 to 80 ml, most preferably to about 40 ml of methanesulfonic acid and mixed.

With a solution of 3 to 50 mmol, preferably 4 to 30 mmol, most preferably 5 mmol of trioxane in 0 to 100 ml, preferably in about 12 ml of trifluoroacetic acid. The reaction mixture was stirred for 2-16 hours, preferably 5 hours at 20 to 100 ° C, preferably at 30 to 80 ° C, most preferably at 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 was purified.

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

The novel compounds of the formula I can be synthesized in analogy to the following synthesis examples. However, these examples are intended solely as examples of methods to further illustrate the invention without limiting it to the merits of these examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Synthesis of 2-methyl-2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide

N-methyl-1-naphthalenesulfonic acid amide (2.21 g) was dissolved in methanesulfonic acid (25 ml) at 35 ° C and a solution of trioxane (0.30 g) in trifluoroacetic acid (8 ml) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into 300 mL of ice water. The solid formed was separated by filtration, 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. M.p .: 136 ° C.

Example 2

Synthesis of 6-chloro-2-methyl-2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide

0.45 g of 5-chloronaphthalene-1-sulfonic acid N-methylamide was dissolved in 6.8

-11 ml of methanesulfonic acid at 35 ° C and the mixture was mixed with a solution of 0.07 g of trioxane in 2 ml of trifluoroacetic acid. After stirring at 35 ° C for 2 h, the reaction mixture was poured into 100 mL of ice water and the aqueous phase was extracted with ethyl acetate. The organic extracts were collected and dried over sodium sulfate, evaporated in vacuo and then purified by chromatography. Yield: 0.41 g. Melting point: 150 ° C.

Example 3

Synthesis of 2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide

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

2-tert-Butyl-1,1-dioxo-1,2-dihydro-1X- ^6- naphtho [1,8-de] [1,3] thiazin-3-one

4.36 g of naphthalene-1-sulfonic acid tert-butylamine were placed in 80 ml of tetrahydrofuran, cooled to -10 ° C and 29 ml of N-butyllithium (1.6 molar solution in hexane) was carefully added dropwise. The mixture was stirred at -10 ° C for 0.5 hour, then at room temperature for 3 hours. The mixture was then cooled to -5 ° C and CO2 obtained from dry ice was added to the mixture over 0.25 hours. The reaction mixture was stirred at room temperature for 2.5 hours and then treated with water. The solution was poured into 4N hydrochloric acid and extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 0.42 g.

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

-120.17 2 g of tert-butyl-1,1-dioxo-1,2-dihydro-1X ⁶ naphtho [1,8-de] [1,3] thiazine-3-one are suspended in 2 ml of tetrahydrofuran at room temperature, and then 1.17 ml of borane-tetrahydrofuran complex (1 molar solution) was added. The mixture was then refluxed with stirring for 100 hours, adding a total of 8.2 mL of a 1M borane-tetrahydrofuran complex solution in several portions. The reaction mixture was combined with 2 mL of 2N hydrochloric acid and 2 mL of methanol, then refluxed with stirring for 12 hours. 2 ml of ammonia were added and any crystals formed were filtered off. The filtrate was extracted with ethyl acetate, the collected organic extracts were dried over sodium sulfate. After evaporation in vacuo, the residue obtained was 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 was dissolved in 1 ml of dichloromethane and 0.02 ml of acid was added. TFA. The mixture was then stirred for a total of 22 hours at reflux temperature and 96 hours at room temperature, during which time a total of 0.07 ml of trifluoroacetic acid was added. The reaction mixture was evaporated in vacuo and purified by chromatography. Yield: 0.034 g. Mp .: 206-207 ° C.

Example 4

Synthesis of [2- (1,1-dioxo-1 / - / - 3 / - / - 1 and ⁶ naphtho [1,8-de] thiazin-2-yl) ethyl] dimetyfamínu

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

-13Example 5

Synthesis of N - (2-Methyl-1,1-dioxo-2,3-dihydro-1 H -n ⁶ -naphtho [1,8-de] [1,3] thiazin-6-yl) acetamide

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 at 60 ° C for 4 hours. Then the solution was poured into ice water and extracted with dichloromethane. The collected organic extracts were dried over 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 was dissolved in 8 ml of ethanol and 8 ml of a methylamine solution in ethanol was 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 was purified by chromatography. Yield: 0.50 g.

N- (2-Methyl-1,1-dioxo-2,3-dihydro-1H-1X- ^6- naphtho [1,8-de] [1,3] 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 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 into ice water and the aqueous phase was extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate, evaporated in vacuo and purified by chromatography. Yield: 0.136 g. Melting point: 189-190 ° C.

Example 6

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

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 carefully added dropwise.

29 ml of N-butyllithium was added. The mixture was stirred at -10 ° C for 0.5 hour and then at room temperature for 3 hours. The mixture was then cooled to -5 ° C and CO ₂ obtained from dry ice was added to the mixture over 0.25 hours. The reaction mixture was stirred at room temperature for 2.5 hours and then treated with water. The solution was poured into 4N hydrochloric acid and extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 1.19 g.

1,1-Dioxo-1,1-dihydro-1 X ⁶ naphtho [1,8-de] [1,3] thiazine-3-one

0.25 g of polyphosphoric acid was collected and 0.15 g of Q-tert-butylsulfamoyl-naphthalene-1-carboxylic acid was added. The mixture was stirred at 150 ° C for 4 hours. Then the reaction mixture was poured into ice water and the aqueous phase was extracted with ethyl acetate. The collected organic extracts were dried over 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-1 and ^6, naphtho [1,8-de] [1,3] thiazine-3-one are dissolved in 2 ml of tetrahydrofuran, and then carefully added dropwise 1.2 ml of a 1 molar solution of borane-tetrahydrofuran complex was added. The mixture was stirred at reflux temperature for 18 hours. The reaction mixture was mixed 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 were added and any crystals formed were filtered off. The filtrate was extracted with ethyl acetate, the collected organic extracts were dried over sodium sulfate and evaporated in vacuo. Yield: 0.06 g.

2- (1,1-Dioxo-1 / 7-3 / - / - ^1-6- naphtho [1,8-de] [1,3] thiazin-2-yl) acetamide

0.011 g of sodium hydride was 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 was added. . The mixture was stirred at room 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 then poured into ice water and extracted

-15 with dichloromethane. The collected organic extracts were dried over sodium sulfate and evaporated in vacuo. Yield: 0.043 g. M.p .: 195-169 ° C.

Example 7

Synthesis of 7-hydroxy-2-methyl-2,3-dihydro-naphtho [1,8-de] [1,3] thiazine-1,1-dioxide

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

Example 8

Synthesis of methyl 2-methyl-1,1-dioxo-2,3-dihydro-1H-1X- ^6- naphtho [1,8-de] [1,3] thiazin-7-ylcarboxylate

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 were placed in 2 ml of toluene and the mixture The mixture was cooled to 0 ° C. 0.037 ml of methyl chloroformate was added dropwise. The mixture was stirred at room temperature for 5 hours. The suspension was then poured into ice water and extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 0.065 g. Melting point: 161-162 ° C.

The following compounds of formula IA were obtained, inter alia, in an analogous manner to that described above:

-16Table 1

Example R ¹ R ² R ³ R ⁴ R ⁵ R ^b temperature melting point [° C] 9 WHAT LL about H H H H br 226-227 10 ch ₃ no ₂ H H H H 264-265 11 WHAT LL about H H OCH ₃ H H 174-175 12 ch ₃ H H F H H 129-130 13 ch ₃ H H br H H 163-164 14 ch ₃ H H ch ₃ H H 142-143 15 ch ₃ H H I H H 192-193 16 ch ₃ H I 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 19 ch ₃ N _{(CH3) 2} H H H H 20 ch ₃ H H H H N _{(CH3) 2} 21 ch ₃ / Pr H H / Pr H 22 ch ₃ H OCOMe H H H 23 ch ₃ H F H H H

The compounds of formula I have been found to be characterized by a wide range of uses in the therapeutic field. Special mention should be made of those applications in which positive modulation of AMPA receptors plays a role.

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

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

Table 2

Agonist-induced current amplification (+ good, ++ very good effect)

Example effect 1 + 2 ++

The novel compounds can also be used to treat diseases or disorders in which neural networks requiring AMPA receptors are destroyed or restricted in their function.

Thus, the compounds of formula (I) may be used in dementia, neurodegenerative or psychotic disorders and in neurodegenerative disorders and cerebral ischemia of various origins, preferably schizophrenia, learning disabilities and memory disorders.

Also included are the following diseases: epilepsy, hypoglycemia, hypoxia, anoxia, brain injury, cerebral edema, amyotropic latent sclerosis, Huntington's disease, Alzheimer's disease, sexual dysfunction, sensory / motor function disorders, memory formation, hyperkinetic behavioral changes) , hypotension, heart attack, cerebral pressure (elevated intracranial pressure), ischemic and haemorrhagic seizure, total cerebral ischemia after cardiac arrest, acute and chronic neuropathic pain, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, Parkinson's disease and depression 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, nootropic agents, psychostimulants, etc. They can be administered topically, orally, transdermally, nasally, parenterally or by inhalation. In addition, the compounds of the formula I or their salts can also be combined with active substances of a different nature.

The compounds of the formula I can be administered as such or in combination with other active compounds according to the invention and optionally also in combination with other pharmacologically active compounds. Suitable formulations include, for example, tablets, capsules, suppositories, solutions - especially injectable solutions (s.c., i.v., i.m.) and infusions - elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound (s) should range from 0.1 to 90% by weight,

Preferably from about 18% to about 50% by weight of the total weight of the composition, i. in amounts sufficient to achieve the dosage range set forth below. Suitable tablets may be obtained, for example, by mixing the active ingredient (s) with known excipients, for example inert solvents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or slow release agents such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also include multiple layers.

Thus, coated tablets may be prepared by coating cores formed analogously to tablets with substances commonly used to coat tablets, such as collidone or shellac, acacia, talc, titanium dioxide or sugar. In order to achieve slow release or to avoid incompatibility, the core may also consist of multiple layers. Similarly, the coating of tablets may consist of a number of layers to achieve slow release, possibly using the excipients listed above for tablets.

Syrups or elixirs containing the active ingredients or combinations thereof according to the present invention may additionally contain a sweetening agent such as saccharin, cyclamate, glycerol or sugar and a flavoring agent, i. a flavoring agent such as a tannin or orange extract. They may also contain suspending adjuvants or thickeners, such as sodium carboxymethylcellulose, wetting agents, such as products of the condensation reaction of fatty alcohols with ethylene oxide, or preservatives, such as para-hydroxybenzoates.

Solutions for injection and infusion are prepared in a conventional manner, e.g. by adding isotonic agents, preservatives such as parahydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, while when water is used as a diluent, they may optionally be solvating or organic solvents, for example, as dissolution aids

The solvent is then transferred to 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 subsequent packaging into gelatin capsules.

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

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

The compositions are administered by conventional means, preferably by the oral or transdermal route, particularly orally. Of course, in addition to the above-mentioned carriers, tablets for oral administration may contain excipients such as sodium citrate, calcium carbonate and calcium phosphate, together with various excipients such as starch, preferably potato starch, gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used simultaneously in the tabletting process. In the case of aqueous suspensions, in addition to the excipients mentioned above, the active ingredients may be mixed with various flavorings or colorings.

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

The dose for intravenous use is from 1 to 1000 mg per hour, preferably between 5 and 500 mg per hour.

However, it may sometimes be necessary to deviate from the specified amounts depending on body weight, route of administration, individual response to the drug, the nature of the composition, and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose mentioned above, while in other cases the upper limit may be exceeded. In the case of administration of larger amounts, it may be appropriate to divide them into several smaller doses administered during the day.

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

Examples of pharmaceutical compositions

tablets On tablet active substance 100 mg lactose 140 mg maize starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

The finely milled active ingredient, lactose and some corn starch are together mixed. The mixture is checked, then moistened with a solution of polyvinylpyrrolidone in water, mixed, granulated for damp and dried. Granules, remaining corn starch and magnesium stearate are inspected and mixed together. The mixture is compressed, thereby to form tablets of suitable shape and size. B) Tablets On tablet active substance 80 mg lactose 55 mg maize starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg

-21 sodium starch magnesium carboxymethyl stearate mg 2 mg

400 mg

The finely milled active ingredient, a little corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is inspected and processed with the remaining corn starch and water to form granules which are dried and inspected. Carboxymethyl starch sodium and magnesium stearate are added and mixed and the mixture is compressed to form tablets of suitable shape and size.

C) Solution for ampoules Active substance 50 mg Sodium chloride 50 mg Water for injections ¹ 5 ml

The active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to form an isotonic solution. Pyrogens are filtered from the solution obtained and the filtrate is transferred under septic conditions into ampoules, which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 g of active ingredient.

Claims (15)

PATENT CLAIMS A compound of formula I wherein: R ¹ is a group selected from hydrogen, C 1 -C 6 -alkyl unsubstituted or 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 -alkylNR ⁶ R ⁷ , -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, are a group selected from hydrogen, C 1 -C 6 -alkyl unsubstituted or substituted by one or more halogen atoms, halogen, -NO 2, -SO 2 H, -SO 2 -C 1 -C 6 -alkyl , -SOC 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 , -C 1 -C 4 -alkyl-O-C 1 -C ₄ -alkyl and C 3 -C 6 -cycloalkyl; or R ¹ and R ² together are a C ₄ -C 6 -alkylene bridge, R ⁶ , R ⁷ , which may be identical or different, are hydrogen, C _1-4 alkyl or -COC _1-4 alkyl, R ⁴ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, -CN, -NO 2, -SO 2 H , -SO 3 H, -SOa-dripping-alkyl, -SO-C, -C6-alkyl, -SO 2 NR ⁶ R ^7, -COOH, -CO--C ₆ -alkyl, -OCO-C ₄ -alkyl, - CO-O-C _r C ₄ -alkyl, -O-CO-O-C-C ₄ -alkyl, -CO-NR ⁶ R ^7, OH, -C? C- | -C6-alkyl, -S-Ci-C6- alkyl, -NR ⁶ R ⁷ and aryl optionally mono- or polysubstituted by halogen atoms, -NO2, -SO2H, or C ₁ -C ₄ -alkyl, R ⁵ , which may be identical or different, are groups selected from C 1 -C ₆ -alkyl, unsubstituted or substituted by one or more halogen atoms, phenyl-C ₁ -C ₄ -alkyl, halogen, -CN, -NO 2, -SO 2 H, - SO 3 H, -23-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, -OCO-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 1 -C 6 -alkyl, -S-C 1 -C 6 -alkyl, -NR ⁶ R ⁷ and the 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 excluded, optionally in the form of their various enantiomers and diastereomers, and their pharmaceutically acceptable salts. A compound of formula I according to claim 1, wherein R ¹ is a group selected from hydrogen, C 1 -C 6 -alkyl, unsubstituted or 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, -C 1 -C 4 -alkyl-NR ⁷ R ⁸ , -C 1 -C ₄ -alkyl-OC- C ₁ -C ₄ -alkyl and benzyl, R ² , R ³ , which may be identical or different, are a group selected from hydrogen, C 1 -C 6 -alkyl, 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, -SC 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, 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, are a group selected from hydrogen, C 1 -C 4 -alkyl or -CO-C ₁ -C ₂ -alkyl, and R ⁴ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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, -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 _r C ₆ -alkyl, and -NR ⁶ R ^7, R ⁵ , which may be identical or different, are groups selected from C 1 -C ₆ -alkyl, unsubstituted or 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, -CO-OC 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 , an, 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 pharmaceutically acceptable salts. A compound of formula I according to claim 1 or 2, wherein R ¹ is hydrogen, C ₁ -C ₄ -alkyl or benzyl, R ² , R ³ , which may be identical or different, are hydrogen or C ₁ -C ₄ -alkyl, or R ¹ and R ² together represent a butylene bridge, and R ⁴ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or substituted by one or more halogen atoms, halogen, -CN, -NO 2, -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 _r C ₆ -alkyl, and -NR ⁶ R ^7, R ⁵ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or substituted by one or more halogen atoms, halogen, -CN, -NO 2, -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, _{-S-R 6} -alkyl and C ^{-NR6 R7,} n, m which may be identical or different, are 0,1 or 2, optionally in the form of the various enantiomers and diastereomers as well as their pharmaceutically acceptable salts. A compound of formula I as claimed in any one of claims 1 to 3, wherein: R ¹ , R ² , R ³ , which may be identical or different, are hydrogen or C 1 -C 4 alkyl, R ⁴ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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 , R ⁵ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or substituted by one or more halogen atoms, halogen, -NO ₂ , -O-CO-C 1 -C ₄ -alkyl, -O-CO -OC _r C ₄ -alkyl, -O-dripping-alkyl, and -NR ⁶ R ^7, and -25n, 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 pharmaceutically acceptable salts. Compounds of formula I according to any one of claims 1 to 4, wherein: R ¹ is methyl, ethyl, t -propyl, n -butyl or benzyl, optionally in the form of their various enantiomers and diastereomers, as well as their pharmaceutically acceptable salts. The naphthothiazines of formula I according to any one of claims 1 to 5, wherein R ¹ is methyl, optionally in the form of their pharmaceutically acceptable salts. A compound of formula I according to claim 1, wherein R ¹ is methyl, R ² , R ³ are hydrogen, R ⁴ , R ⁵ , which may be identical or different, are halogen, and n, m, which may be identical or different, are 0, 1 or 2, optionally in the form of their pharmaceutically acceptable salts. 8. A compound of formula I wherein -26R ¹ is selected from hydrogen, C 6 -C nesubstuovanej or the cycloalkyl group substituted by one or more halogen atoms, -SO2H, -SO2-Ci-6 alkyl, -SO-Ci-Ce-alkyl, CO-alkyl-dripped. -O, phenyl-C 1 -C 4 -alkyl, -C 1 -C 4 -alkylNR ⁶ R ⁷ , -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, are a group selected from hydrogen, C 1 -C 6 -alkyl unsubstituted or substituted by one or more halogen atoms, halogen, -NO 2, -SO 2 H, -SO 2 -C 1 -C 6 -alkyl , -SOC-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 , -C 1 -C ₄ -alkyl-OC 1 -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl, or R ¹ and R ² together are a C ₄ -C 6 -alkylene bridge, R ⁶ , R ⁷ , which may be identical or different, are hydrogen, C ₁ -C ₄ -alkyl or -COC 1 -C ₄ -alkyl, R ⁴ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or substituted by one or more halogen atoms, phenyl-C 1 -C 4 -alkyl, halogen, -CN, -NO 2, -SO 2 H, -SO 3 H, -SO2-Ci-C6-alkyl, -SO-C6-alkyl, -SO 2 NR ⁶ R ^7, -COOH, -CO-C6-alkyl, Ci--0CO -C ₄ -alkyl, -CO-O-C _r C ₄ -alkyl, -O-CO-O-C _r C ₄ -alkyl, -CO-NR ⁶ R ^7, OH, -OC-C6-alkyl, -S-C 6 -alkyl, -NR ⁶ R ⁷ and aryl groups optionally mono or polysubstituted with halogen atoms, -NO ₂ , -SO ₂ H or C 1 -C ₄ -alkyl, R ⁵ , which may be identical or different, are groups selected from C 1 -C 6 -alkyl, unsubstituted or 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 2 -C 1 -C 6 -alkyl, -SO 2 -NR ⁶ R ⁷ , -COOH, -CO-C ₁ -C ₆ -alkyl, -OCO-C ₁ -C ₄ -alkyl, -CO-OC _r C ₄ -alkyl, -O-CO-O-C _r C ₄ -alkyl, -CO-NR ⁶ R ^7, -OH, -C 6 alkyl, -SC-06-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 identical or different, are 0,1,2 or 3, optionally in the form of their various enantiomers, and diastereomers, and pharmaceutically acceptable salts thereof, for use as pharmaceutical compositions. -279. Compounds of formula I according to claim 8 for use as pharmaceutical compositions having a neuroprotective effect. Use of a compound of formula I according to one of Claims 1 to 7 for the manufacture of a pharmaceutical composition for the treatment and / or prevention of neurodegenerative diseases and / or cerebral ischemia of various origins. Use of a compound of formula I according to one of Claims 1 to 7 for the manufacture of a pharmaceutical composition for the treatment of schizophrenia. Use of a compound of the 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. Use of a compound of formula I according to one of Claims 1 to 7 for the manufacture of a medicament for the treatment of dementia. Use of a naphthothiazine according to any one of claims 1 to 7 for the manufacture of a medicament comprising an effective amount of a naphthothiazine of formula I for the treatment and / or prevention of deurodegenerative diseases and / or cerebral ischemia. Use of a naphthothiazine according to any one of claims 1 to 7 for the manufacture of a medicament comprising an effective amount of a naphthothiazine of the formula I for the treatment and / or prevention of memory and / or dementia disorders. Pharmaceutical composition, characterized in that it contains, as active ingredient, one or more compounds of the general formula I according to one of claims 1 to 7 or their physiologically acceptable salts, optionally in combination with conventional excipients and / or carriers.