ZA200308466B

ZA200308466B - Naphtothiazine positive allosteric ampa receptor modulators (PAARM).

Info

Publication number: ZA200308466B
Application number: ZA200308466A
Authority: ZA
Inventors: Angelo Ceci; Klaus Klinder; Thomas Weiser; Karin Winter
Original assignee: Boehringer Ingelheim Pharma
Priority date: 2001-05-17
Filing date: 2003-10-30
Publication date: 2004-05-24
Also published as: EE200300566A; EA200301167A1; AR036332A1; BG108324A; NO20035088D0; CA2449189A1; CO5550460A2; PL364053A1; IL158642A0; EA006608B1; CZ20033112A3; WO2002100411A1; SK14222003A3; EP1404340A1; YU90403A; ECSP034852A; DE10123952A1; JP2004529980A; HUP0401273A2; KR20040007572A

Description

eT

I WO 02/100411 PCT/EP02/05338

NAPHTOTHIAZINE POSITIVE ALLOSTERIC AMPA RECEPTOR MODULATORS (PAARM)

The present invention relates to new positive allosteric AMPA receptor modulators, : processes for preparing them and their use as pharmaceutical compositions.

As compounds which are structurally similar to the compounds according to the invention, WO 9967242 describes carbapenem derivatives with an antibacterial activity, wherein naphtho[1,8-de}-2,3-dihydro-1,1-dioxide-1,2-thiazine is used as a synthesis component.

The compounds according to the invention are compounds of general formula (I) 5

Rw 0 0» Lo

R* iB (m) E | Neg 3 2

R™ R 0) wherein

R' denotes a group selected from among hydrogen, a C,-Ce-alkyl group optionally substituted by one or more halogen atoms, -SOzH, -S0,-C+-Cs-alkyl, -S0-C,-Ce-alkyl, -CO-Cy-Cg-alkyl, -O, phenyl-C4-C4—alkyl, -C-C4—alkyl-NR°R’ and -Cy-C4—alkyl-O- C;-C4-alkyl, and Cs-Cs-cycloalkyl, ow R? R®, which may be identical or different, denote a group selected from “ 25 among hydrogen, a C,-Cs-alkyl group optionally substituted by one or more ’ halogen atoms, halogen, -NO;, -SO;H, -S0,-C,-Ce-alky!, -SO-C,-C¢-alkyl, -CO-

C1-Ce-alkyl, -OH, -0-C4-Cs-alkyl, -S-C4-Cs-alkyl, -C4-C4—alkyl-NR°R’ and -C1-C4 —alkyl-0- C1-C4—alkyl and Cs-Ce-cycloalkyl, or

R' and R? together denote a C,-Ce-alkylene bridge,

oH .

Le WO 02/100411 PCT/EP02/05338

R® R”, which may be identical or different, denote hydrogen, C.-C4-alkyl or -CO-C4-Cq-alkyl , . R®, R®, which may be identical or different, denote hydrogen or C-C4-alkyl,

R* , which may be identical or different, denotes a group selected from among ° 5 a C1-Ce-alkyl group optionally substituted by one or more halogen atoms, phenyl-C1-C.—alkyl, halogen, -CN, NOs, -SOzH, -SOsH, -S0,-C-Cs-alkyl, -SO-

C,-Ce-alkyl, -SO,-NR°R’, -COOH, -CO-C;-Ce-alkyl, -0-CO-C4-C-alkyl, ~CO-O-

Ci-Ca-alkyl, -O-CO-0-C4-C,-alkyl, -CO-NR°R’, -OH, -O-C;-Ce-alkyl, -S-C4-Ce- alkyl, -NR®R” and an aryl group optionally mono or polysubstituted by halogen atoms, -NO,, -SO;H or C4-Cs-alkyl,

R®, which may be identical or different, denotes a group selected from among a

C,-Ce-alkyl group optionally substituted by one or more halogen atoms, phenyl-C,-C4—alkyl, halogen, -CN, -NO;, -SO.H, -SOsH, -S0,-C,-Ce-alkyl, -SO-

C4-Ce-alkyl, -SO.-NR°R’, -COOH, -CO-C;-Ce-alkyl, -0-CO-C,-C,-alkyl, -CO-O-

C+-Ca-alkyl, -O-CO-0-C4-C4-alkyl, -CO-NR°R’, -OH, -0-C;-Ce-alkyl, -S-C1-Ce- alkyl, -NR°R’ and an aryl group optionally mono or polysubstituted by halogen atoms, -NO,, -SO,H or C4-C,4-alkyl, and n, m which may be identical or different represent 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 the pharmacologically acceptable salts thereof.

Preferred compounds are the compounds of general formula (1), wherein

R' denotes a group selected from among hydrogen, a C;-Ce-alkyl group optionally substituted by one or more halogen atoms, -SOzH, -SO,-C;-Cg-alkyl, -S0-C,-Ce-alkyl, -CO-C4-Cg-alkyl, -O, -C4-C4—alkyl-NR'R® and -C;-C, ~alkyl-O- : i C,-C4—alkyl, benzyl,

R? R*, which may be identical or different, denote a group selected from among hydrogen, a C,-Ces-alky!l group optionally substituted by one or more halogen atoms, halogen, -NO,, -SOzH, -S0>-C4-Ce-alkyl, -SO-C,-Cg-alkyl, -CO-

C1-Ce-alkyl, -OH, -O-C4-Ce-alkyl, -S-C4-Ce-alkyl, -C4-C4—alkyl-NR°R’ and -C4-C4 —alkyl-O- C4-C4-alkyl, or . R'and R? together denote a C,-Cs-alkylene bridge,

R®, R’, which may be identical or different, denote hydrogen, C;-Cs-alkyl or ¥ 5 -CO-C;-Cz-alkyl, and

R*, which may be identical or different, denotes a group selected from among a

C+-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -CN, -NO,, -SO,H, -SO;H, -COOH, -CO-C;-Ce-alkyl, -O-CO-C4-C4- alkyl, -CO-0-C4-C4-alkyl, -0-CO-0-C4-C-alkyl, -CO-NR°R’, -OH, -0-C1-Cs- alkyl, -S-C4-Ce-alky! and -NR°R’,

R®, which may be identical or different, denotes a group selected from among a

C,-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -CN, -NO,, -SO;H, -SO;H, -COOH, -CO-C,-Cs-alkyl, -O-CO-C4-C,- alkyl, -CO-0-C,-C-alkyl, -0-CO-0-C4-Cs-alkyl, -CO-NR°R’, -OH, -0-C4-Ce- alkyl, -S-C+-Ce-alkyl and -NR°R’, and n, m which may be identical or different represent 0,1 or 2, optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.

Particularly preferred are compounds of general formula (1), wherein

R' denotes hydrogen, C4-Cs-alkyl or benzyl,

R?, R* which may be identical or different, denote hydrogen or C,-C,-alkyl, or

R'andR? together denote a butylene bridge, and

R*, which may be identical or different, denotes a group selected from among a

C,-Ce-alkyl group optionally substituted by one or more halogen atoms, ) halogen, -CN, -NO,, -COOH, -CO-C4-Cs-alkyl, -O-CO-C4-C,-alkyl, -CO-0O-C;- . C.-alkyl, -0-CO-0-C;-Cs-alkyl, -CO-NR®°R’, -OH, -0-C;-Ce-alkyl, -S-C,-Cq-alkyl and NR°R’,

R° which may be identical or different, denotes a group selected from among a

C4-Ce-alkyl group optionally substituted by one or more halogen atoms,

halogen, -CN, -NO,, -COOH, -CO-C+-Ce-alkyl, -O-CO-C;-C4-alkyl, -CO-O-C+-

Cs-alkyl, -0-CO-0-C4-C4-alkyl, -CO-NR®R’, -OH, -0-C;-Ce-alkyl, -S-C1-Ce-alky! - and -NR°R’, and n, m which may be identical or different represent 0,1 or 2, ) 5 optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.

Also particularly preferred are compounds of general formula (1), wherein

R' R?, R® which may be identical or different, denote hydrogen or C,-C,-alkyl,

R*, which may be identical or different, denotes a group selected from among a

C:-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -NO,, -O-CO-C;-C.-alkyl, -O-CO-0-C4-C.s-alkyl, -O-C4-Ce-alkyl, and -NR°R’,

R®, which may be identical or different, denotes a group selected from among a

C.-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -NO,, -O-CO-C;-C4-alkyl, -0-CO-0-C4-Cg4-alkyl, -O-C4-Ce-alkyl, and -NR°R’, and n, m which may be identical or different represent 0,1 or 2, optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.

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

Particularly preferred are compounds of general formula (I) wherein

R' denotes methyl, optionally in the form of the pharmacologically acceptable salts thereof.

Also particularly preferred are compounds of general formula (I), wherein - R' denotes methyl,

R?, R® denote hydrogen, ® 5 R* R® which may be identical or different, denote halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine, . and n, m which may be identical or different represent 0,1 or 2, preferably 0 or 1, optionally in the form of the pharmacologically acceptable salts thereof.

The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl and hexyl. The groups methyl, ethyl, propyl or butyl may optionally also be referred to by the abbreviations Me, Et, Pr or

Bu. Unless otherwise stated, the definitions propyl, butyl, pentyl and hexyl also include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and tert.- butyl, etc.

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

The alkyl group mentioned in the group phenyl-C4-C4-alkyl may be in branched or . unbranched form. Unless otherwise stated benzyl and phenylethyl are preferred ) phenyl-C,-C4-alkyl groups. Benzyl is particularly preferred.

The alkyl groups mentioned in the groups -SO,-C4-Ce-alkyl, -SO-C,-Ce-alkyl, -CO-

C1-Ce-alkyl, -CO-C;-Ca-alkyl, -C4-C4-alkyl-NR°R’, -C4-C4—alkyl-O- C,-C4—alkyl, -O-

C,-Ce-alkyl, -S-C4-Cs-alkyl, -0-CO-C,-Cq-alkyl, -CO-0-Cy-Cs-alkyl or -O-CO-0-C;-C,-

alkyl may be in branched or unbranched form with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, particularly preferably with 1 to 3 carbon atoms, most . preferably with 1 to 2 carbon atoms. : 5 The C,-Ce-alkylene bridge may, unless otherwise stated, be branched and unbranched alkylene groups having 4 to 6 carbon atoms, for example n-butylene, 1- methylpropylene, 2-methylpropylene, 1.1-dimethylethylene, 1.2-dimethylethylene etc. n-Butylene bridges are particularly preferred.

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

In the abovementioned aryl groups, one or more hydrogen atoms may optionally be substituted by halogen atoms, -NO,, -SO,H or -C+-C,-alkyl, preferably fluorine, chlorine , -NO,, ethyl or methyl, most preferably fluorine or methyl.

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

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

As already mentioned, the compounds of formula (I) or the various enantiomers and diastereomers thereof may be converted into the salts thereof, particularly, for pharmaceutical use, into the physiologically and pharmacologically acceptable salts thereof. These salts may on the one hand take the form of physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (J) ) with inorganic or organic acids. On the other hand, the compound of formula ( )) : » where R' is hydrogen may be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ions. The acid addition salts may be prepared, for example, using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,

methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is also possible to use mixtures of the above - acids. For preparing the alkali and alkaline earth metal salts of the compound of formula (1) wherein R' denotes hydrogen, it is preferable to use the alkali and : 5 alkaline earth metal hydroxides and hydrides, the hydroxides and hydrides of the alkali metals, especially sodium and potassium, being preferred, while sodium and potassium hydroxide are particularly preferred.

The compounds according to the invention may be prepared in a manner known per 10 se. The following general methods of synthesis 1 and 2 shown in Diagrams 1 and 2 below are meant to illustrate the invention without restricting it to their content.

Method 1

Diagram 1 15

R® 5 (n) R )

RA SOH . _ SOC (m) —_— R (mj — (nm (hry 5

R ON R (nN

SO SO

Rm > i __. Ry

N N

RX R : R

I Rr R?

RZ COOH

(IV)

Starting from a compound of formula (Il) a compound of formula (Ill) is prepared by . sulphonation and subsequent chlorination. The compound of formula (IV) obtained after condensation with aminoacetic acid derivatives is cyclised by adding h 5 polyphosphoric acid to the target compound (1).

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

Sulphonation of the naphthalenes (lI):

About 10 mmol of the naphthalene derivative (ll) are taken up in 2 - 100 ml, preferably 3 - 80 ml, most preferably about 4 ml, of acetic anhydride and 10 - 100 mmol, preferably 11 - 80 mmol, particularly preferably 11 mmol or conc. sulphuric acid are added at 0 - 50°C, preferably 5 - 20°C, particularly preferably about 18 °C.

After 2 - 16 h, preferably about 5 h, stirring at 20 - 100°C, preferably about 25 C°, the mixture is poured onto a saturated NaCl solution. The crystals formed are isolated.

Methylene chloride, diisopropylether, ethyl acetate, trichloromethane, toluene, benzene or 1,4-dioxin may be used instead of acetic acid anhydride, while fuming sulphuric acid, sulphur trioxide, chlorine sulphates or combinations thereof may be used as an alternative to conc. sulphuric acid.

Synthesis of the naphthalene-1-sulphonic acid chlorides (iii):

About 10 mmol of the naphthalene-1-sulphonic acids are combined successively with 10 - 500 mmol, preferably about 90 mmol, of phosphorus oxytrichloride and 8 - 50 mmol, preferably about 10 mmol, of phosphorus pentachloride and heated for 2 - ] 16 h, preferably about 5 h, at 20 - 100°C, preferably by refluxing. Then the reaction mixture is evaporated down and combined with water. After extraction with organic : diluent the combined organic extracts are dried and freed from solvent. The crude product obtained is used in the subsequent steps without being purified.

Instead of the phosphorus oxytrichloride/phosphorus pentachloride mixture, thionyl chloride, phosphorus pentachloride, a phosphoric acid/chlorine mixture or phosgene may be used. The reaction may alternatively be carried out in the diluents ethyl acetate, water, acetonitrile, N,N-dimethylacetamide, sulpholane, DMF, hexane or : dichloroethane. ) 5 Synthesis of the naphthalene-1-sulphonyl-amino-acetic acids :

About 10 mmol of the chlorosulphonyl-naphthalenes, 10 - 100 mmol, preferably 11 - 30 mmol, most preferably about 12 mmol, of aminoacetic acid and 10 - 100 mmol, preferably 11 - 30 mmol, most preferably about 12 mmol, of sodium hydroxide are dissolved in water and toluene. The reaction mixture is stirred for2- 16 h at 0 - 110°C, preferably at about 65°C, then the phases are separated. The aqueous phase is acidified and extracted. The combined organic extracts are dried and evaporated down. Purification may be carried out by chromatography.

Triethylamine, potassium carbonate, sodium hydrogen carbonate or sodium hydride may be used instead of sodium hydroxide, while tetrahydrofuran, diethylether, dichloromethane, trichloromethane, dioxin, acetone, benzene, ethanol, methanol, ethyl acetate or acetonitrile may be used instead of toluene.

Cyclisation of the naphthalene-1-sulphonyl-amino-acetic acids (IV):

About 10 mmol of the naphthalene-1-sulphonyl-amino-acetic acids are combined with 10 - 200 g, preferably about 40 g, of polyphosphoric acid and stirred for 2 - 16 h, preferably about 5 h, at 20 - 110°C, preferably 75 - 95°C, most preferably at about 80°C . Then the reaction mixture is poured onto water and extracted. The combined organic extracts are dried and evaporated down. The residue is purified.

Method 2

Diagram 2

Ro) T= io

R 2 2 R (i) Vv) ®

The compounds of formula (Ill) obtained as intermediate compounds in Method 1 are reacted with primary amines to obtain the compounds of formula (V) and then cyclised by the addition of a compound of formula R?R?*C=0 in the presence of strong acid to obtain the target compounds (1).

In order to prepare the compounds of formula (I) wherein R' and R? represent hydrogen, paraformaldehyde, trioxane or formalin may be used and methanesulphonic acid, trifluoroacetic acid, sulphuric acid, phosphoric acid or polyphosphoric acid may be used as strong acids.

The general preparation of the compounds according to the invention in accordance with Diagram 2 is described in detail hereinafter.

Synthesis of the naphthalene-sulphonamides (V):

About 10 mmol of the chlorosulphonyl-naphthalenes (lil) are combined with an alcoholic solution of the 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 h, preferably " about 5 h, preferably by refluxing. Then the reaction mixture is evaporated down and purified. " Instead of the alcoholic solvent it is also possible to use toluene, benzene, trichloromethane, dichloromethane, diethylether, tetrahydrofuran, water, acetonitrile, acetic anhydride, acetone, pyridine, dimethylsulphoxide, dimethylformamide, dioxin or hexane.

Cyclisation of the naphthalene-1-sulphonamides (V) to form the target compounds - a)

About 10 mmol of the naphthalene-1-sulphonamides are added to 0 - 100 ml, ¢ 5 preferably 20 - 80 ml, most preferably about 40 m! of methanesulphonic acid and combined with a solution of 3 - 50 mmol, preferably 4 — 30 mmol, most preferably 5 mmol of trioxane in O - 100 ml, preferably about 12 ml, of trifluoroacetic acid. The reaction mixture is stirred for 2 - 16 h, preferably 5 h, at 20 - 100 C°, preferably 30 — 80 °C, most preferably about 35°C and then poured onto ice water. After extraction : 10 and drying of the combined organic extracts the solution is evaporated down. The crude product is purified.

Instead of trioxane it is possible to use paraformaldehyde or formalin, while instead of trifluoroacetic acid it is possible to use boron trifluoride*diethylether, acetic acid, polyphosphoric acid, phosphoric acid or sulphuric acid. Acetic anhydride or dichloromethane may be used as possible diluents.

The new compounds of general formula (I) may be synthesised analogously to the following Examples of synthesis. These Examples are, however, intended solely as examples of procedure to illustrate the invention further without restricting it to the subject matter thereof.

Synthesis of 2-methyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazine- 1,1-dioxide (Example 1): 2.21 g of N-methyl-1-naphthalenesulphonic acid amide are dissolved in 25 ml of methanesulphonic acid at 35°C and combined with a solution of 0.30 g of trioxane in 8 ml of trifluoroacetic acid. After 2 h stirring at ambient temperature The reaction . mixture is poured onto 300 ml of ice water. The solid formed is separated off by filtration, washed with 100 ml of water and dried overnight. After crystallisation from s methylcyclohexane the product is isolated as a white solid. Yield: 2.20 g. M.p.: 136°C.

Claims

v WO 02/100411 PCT/EP02/05338 Patent Claims 1) Compounds of general formula (1) . rR, Cg, Rm - N RY "R® (0 wherein R' denotes a group selected from among hydrogen, a C,-Ce-alkyl group optionally substituted by one or more halogen atoms, -SO,H, -SO,-C,-Cs-alky], -S0-C,-Cs-alkyl, -CO-C;-Cs-alkyl, -O, phenyl-C4-C4—-alkyl, -C1-C4—alkyl-NR°R’ and -C4-C,4—alkyl-O- C,4-C4—alkyl, and C3-Ce-cycloalkyl, R? R®, which may be identical or different, denote a group selected from among hydrogen, a C;-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -NO,, -SO.H, -S0.-C,-Ce-alkyl, -SO-C,-Cs-alkyl, -CO- C1-Ce-alkyl, -OH, -O-C,-Cs-alkyl, -S-C4-Cs-alkyl, -C1-C4~alkyl-NR°R’ and -C+-C. —alkyl-O- C,-C,—alkyl and C;-Ce-cycloalkyl, or R'and R? together denote a C,-Ce-alkylene bridge, R®, R”, which may be identical or different, denote hydrogen, C4-C,-alkyl or -CO-C4-Cys-alkyl , R*, which may be identical or different, denotes a group selected from among a

C.-Ce-alkyl group optionally substituted by one or more halogen atoms, phenyl-C,-C4—alkyl, halogen, -CN, -NG,, -SO;H, -SO3H, -S0.-C,-C¢-alkyl, -SO- C+-Cs-alkyl, -SO,-NR®R’, -COOH, -CO-C4-Cs-alkyl, -O-CO-C,-C-alkyl, -CO-O- : C1-Ca-alkyl, -0-CO-0-C;-Cq-alkyl, -CO-NR°R’, -OH, -O-C;-Ce-alkyl, -S-C;-Cs- alkyl, -NR®R’ and an aryl group optionally mono or polysubstituted by halogen } 25 atoms, -NO,, -SO,H or C;-Cs-alkyl, R® , which may be identical or different, denotes a group selected from among a C,-Ce-alkyl group optionally substituted by one or more halogen atoms, phenyl-C4-C4—alkyl, halogen, -CN, -NO, -SOzH, -SO3H, -S02-C,-C¢-alkyl, -SO-

C1-Cs-alkyl, -SO,-NR°R’, -COOH, -CO-C;-Ce-alkyl, -0-CO-C4-C,-alkyl, -CO-O- C1-Cq-alkyl, -0-CO-0-C;-C-alkyl, -CO-NR°R’, -OH, -O-C;-Ce-alky!, -S-C1-Ce- alkyl, -NR°R” and an aryl group optionally mono or polysubstituted by halogen atoms, -NO,, -SO2H or C,-C;-alkyl, and ’ 5 n, m which may be identical or different represent 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 the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
2) Compounds of general formula (Il) according to claim 1, wherein R' denotes a group selected from among hydrogen, a C4-Ce-alkyl group optionally substituted by one or more halogen atoms, -SO,H, -S0,-C;-Cs-alkyl, -S0-C4-Ce-alkyl, -CO-C;-Ce-alkyl, -O, -C4-C4—alkyl-NR'R® and -C,-C,—alkyl-O- C,-C4—alkyl, benzyl, R? R?, which may be identical or different, denote a group selected from among hydrogen, a C,-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -NO,, -SO.H, -S0,-C;-Cs-alkyl, -SO-C,-Cs-alkyl, -CO- C1-Ce-alkyl, -OH, -O-C;-Ce-alkyl, -S-C4-Ce-alkyl, -C4-C4—alkyl-NR°R’ and -C,-C, —alkyl-0- C4-C4-alkyl, or R'and R? together denote a C4-Ce-alkylene bridge, R® R’, which may be identical or different, denote hydrogen, C,-C,-alkyl or -CO-C4-Cz-alkyl, and R*, which may be identical or different, denotes a group selected from among a C+-Ce-alkyl group optionally substituted by one or more halogen atoms, : halogen, -CN, -NO,, -SO.H, -SO;H, -COOH, -CO-C,-Ce-alkyl, -O-CO-C,-C,- . alkyl, -CO-0-C;-Cq-alkyl, -0-CO-0-C;-Cs-alkyl, -CO-NR°R’, -OH, -0O-C,-Cs- alkyl, -S-C4-Ce-alkyl and -NR°R’, R®, which may be identical or different, denotes a group selected from among a Ci-Ce-alkyl group optionally substituted by one or more halogen atoms,

halogen, -CN, -NO,, -SO;H, -SO3H, -COOH, -CO-C;-Ce-alkyl, -O-CO-C,-C4- alkyl, -CO-0-C;-Cs-alkyl, -O-CO-0O-C;-C4-alkyl, -CO-NR°R’, -OH, -O-C;-Ce- : alkyl, -S-C4-Ce-alkyl and -NR°R’, and n, m which may be identical or different represent 0,1 or 2, ) 5 optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
3) Compounds of general formula (I) according to claim 1 or 2, wherein

R' denotes hydrogen, C:-C4-alkyl or benzyl,

R?, R® which may be identical or different, denote hydrogen or C,-C.-alkyl, or R'and R? together denote a butylene bridge, and

R*, which may be identical or different, denotes a group selected from among a C1-Cs-alkyl group optionally substituted by one or more halogen atoms,

halogen, -CN, -NO;, -COOH, -CO-C;-Ce-alkyl, -O-CO-C,-C,-alkyl, -CO-0-C;- Caalkyl, -0-CO-0-C4-C4-alkyl, -CO-NR®R’, -OH, -O-C4-Cs-alkyl, -S-C,-Ce-alkyl and -NR°R’,

R®, which may be identical or different, denotes a group selected from among a C4-Cs-alkyl group optionally substituted by one or more halogen atoms,

halogen, -CN, -NO,, -COOH, -CO-C,-C¢-alkyl, -O-CO-C,-C4-alkyl, -CO-0-C;- Ca-alkyl, -O-CO-0-C;-Ca-alkyl, -CO-NR°R’, -OH, -O-C;-Ce-alkyl, -S-C;-Cs-alky! and -NR°R’, and n, m which may be identical or different represent 0,1 or 2,

optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
4) Compounds of general formula (I) according to claims 1 to 3, wherein . R', R?, R®, which may be identical or different, denote hydrogen or C;-C,-alkyl,
R*, which may be identical or different, denotes a group selected from among a
C+-Ce-alkyl group optionally substituted by one or more halogen atoms,
halogen, -NO2, -0-CO-C,-C4-alkyl, -O-C0O-0-C4-C,-alkyl, -O-C;-Ce-alkyl, and -NR°R’, . R®, which may be identical or different, denotes a group selected from among a C+-Ce-alky! group optionally substituted by one or more halogen atoms, ¢ 5 halogen, -NO2, -0-CO-C,-C4-alkyl, -O-CO-0-C4-Cs-alkyl, -O-C,-Cs-alkyl, and -NR°R’, and n, m which may be identical or different represent 0,1 or 2, optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof. 5) Compound of general formula (I) according to one of claims 1 to 4, wherein R' denotes methyl, ethyl, i-propyl, n-butyl or benzyl, optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof. 6) Compounds of general formula (I) according to one of claims 1 to 5, wherein R' denotes methyl, optionally in the form of the pharmacologically acceptable salts thereof. 7) Compounds of general formula (I) according to claim 1, wherein R' denotes methyl, R?, R®*denote hydrogen, R* R® which may be identical or different denote halogen, and n, m which may be identical or different represent 0,1 or 2, optionally in the form of the pharmacologically acceptable salts thereof.
8) Compounds of general formula (1) Roo lg RY - 7=0 ~R' RR wherein R' denotes a group selected from among hydrogen, a C,4-Ce-alkyl group optionally substituted by one or more halogen atoms, -SO,H, -S0,-C,-Cs-alkyl, -80-C;-Ce-alkyl, -CO-C4-Ce-alkyl, -O, phenyl-C4-C,—alkyl, -C;-C4-alkyl-NR°R’ and -C4-C4—alkyl-O- C4-C4—alkyl, and C5-Ce-cycloalkyl, R? R®, which may be identical or different, denote a group selected from among hydrogen, a C4-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -NO,, -SO;H, -SO,-C+-Ce-alkyl, -SO-C;-Cs-alkyl, -CO- Ci-Ce-alkyl, -OH, -O-C,-Cs-alkyl, -S-C4-Cg-alkyl, -C4-C4—alkyl-NR®R” and -C;-C, —alkyl-O- C4-C4—alkyl and Cs-Cs-cycloalkyl, or R'and R? together denote a C,-Cs-alkylene bridge, RS R’ , which may be identical or different, denote hydrogen, C,-Cs-alky! or -CO-C4-Cs-alkyl , R* which may be identical or different, denotes a group selected from among a C4-Ce-alkyl group optionally substituted by one or more halogen atoms, phenyl-C4-C,4—alkyl, halogen, -CN, -NO2, -SOH, -SOsH, -S0,-C;-C¢-alkyl, -SO- Cs-Ce-alkyl, -SO,-NR°R’, -COOH, -CO-C;-Ce-alkyl, -0-CO-C,-C,-alkyl, -CO-O- C4-Ca-alkyl, -0-CO-0-Cy-C4-alkyl, -CO-NR°R’, -OH, -O-C,-Ce-alkyl, -S-C;-Ce- alkyl, -NR°R” and an aryl group optionally mono or polysubstituted by halogen atoms, -NO,, -SO,H or C;-Cs-alkyl, ” R®, which may be identical or different, denotes a group selected from among a } C+-Ce-alkyl group optionally substituted by one or more halogen atoms, phenyl-C,-C4—alkyl, halogen, -CN, -NO, -SO,H, -SO;H, -SO,-C,-C¢-alkyl, -SO- C4-Ce-alkyl, -SO,-NR°R’, -COOH, -CO-C;-Ce-alkyl, -0-CO-C4-C,-alkyl, -CO-O- C1-C4-alkyl, -O-CO-0-C,-C,-alkyl, -CO-NR°R’, -OH, -0-C4-Ce-alkyl, -S-C4-Cq-

} !

29 alkyl, -NR®R’ and an aryl group optionally mono or polysubstituted by halogen atoms, -NO, -SO2H or C4-Cs-alkyl, and n, m which may be identical or different represent 0, 1, 2 or 3, optionally in the form of their various enantiomers and diastereomers, and the pharmacologically acceptable salts thereof for use as pharmaceutical compositions.
9) Compound of general formula (I) according to claim 8 for use as pharmaceutical compositions with a neuroprotective effect.
10) Use of a compound of general formula (I) according to one of claims 1 to 7 for preparing a pharmaceutical composition for the treatment and/or prevention of neurodegenerative diseases and/or cerebral ischaemia of various origins.
11) Use of a compound of general formula (I) according to one of claims 1 to 7 for preparing a pharmaceutical composition for the treatment of schizophrenia.
12) Use of a compound of general formula (I) according to one of claims 1 to 7 for preparing a pharmaceutical composition for the treatment and/or prevention of memory disorders.
13) Use of a compound of general formula (1) according to one of claims 1 to 7 for preparing a pharmaceutical composition for the treatment of dementias.
14) A compound of formula | according to claims 1 to 7 for use in treating and/or preventing neurodegenerative disease and/or cerebral ischaemia.
15) A compound of formula | according to claims 1 to 7 for use in treating and/or preventing memory disorders and/or dementias.
16) Pharmaceutical preparations containing as active substance one or more compounds of general formula (I) according to one of claims 1 to 7 or the physiologically acceptable salts thereof optionally combined with conventional excipients and/or carriers.
17) Compounds according to claim 1 or claim 8, substantially as herein described and exemplified.
18) Use according to any one of claims 10 — 13, substantially as herein described and exemplified.
19) A compound according to claim 14 or claim 15, substantially as herein described and exemplified.
20) Pharmaceutical preparations according to claim 16, substantially as herein described and exemplified.