DE10123952A1 - New naphtho-1,2-thiazine compounds, useful as neuroprotectants for treating e.g. epilepsy or Alzheimer's disease, are allosteric modulators of AMPA receptors - Google Patents

Abstract

The present invention relates to new, positive allosteric AMPA receptor modulators of the general formula (I) DOLLAR F1 in which R 1, R 2, R 3, R 4 and R 5 are those described in the specification and US may have the meanings indicated in the claims, process for their preparation and their use as medicaments.

Description

The present invention relates to new, positive allosteric AMPA receptor Modulators, processes for their preparation and their use as Drug.

As the compounds of the invention structurally similar compounds WO 9967242 describes carbapenem derivatives having antibacterial activity, in which Naphtho [1,8-de] -2,3-dihydro-1,1-dioxide-1,2-thiazine used as a synthesis block becomes.

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

wherein
R ¹ is a radical selected from the group consisting of hydrogen, an optionally by one or more halogen atoms substituted C ₁ -C ₆ - alkyl, -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-OC ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl,
R ² , R ^{3 are} identical or different and are selected from the group consisting of hydrogen, an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl C ₁ -C ₄ -alkyl-NR ⁶ R ⁷ and C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl, or
R ¹ and R ² together form a C ₄ -C ₆ -alkylene bridge,
R ⁶ , R ^{7 are} identical or different, are hydrogen, C ₁ -C ₄ -alkyl or -CO-C ₁ -C ₄ -alkyl,
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, phenyl-C ₁ -C ₄ alkyl, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -SO ₂ -C ₁ -C ₆ alkyl, -SO-C ₁ -C ₆ alkyl, -SO ₂ -NR ⁶ R ⁷ , -COOH, -CO-C C ₁ -C ₆ -alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl, -NR ⁶ R ⁷ and an optionally mono- or polysubstituted by halogen atoms, -NO ₂ , -SO ₂ H or C ₁ -C _4- alkyl substituted aryl radical,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, phenyl-C ₁ -C ₄ alkyl, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -SO ₂ -C ₁ -C ₆ alkyl, -SO-C ₁ -C ₆ alkyl, -SO ₂ -NR ⁶ R ⁷ , -COOH, -CO-C C ₁ -C ₆ -alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl, -NR ⁶ R ⁷ and an optionally mono- or polysubstituted by halogen atoms, -NO ₂ , -SO ₂ H or C ₁ -C _4- alkyl substituted aryl radical, and
n, m are the same or different 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 pharmacologically acceptable salts.

Preference is given to compounds of the general formula (I) in which
R ¹ is a radical selected from the group consisting of hydrogen, an optionally by one or more halogen atoms substituted C ₁ -C ₆ - alkyl, -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 and -C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl , Benzyl,
R ² , R ^{3 are} identical or different and are selected from the group consisting of hydrogen, an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl C ₁ -C ₄ -alkyl-NR ⁶ R ⁷ and C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl, or
R ¹ and R ² together form a C ₄ -C ₆ -alkylene bridge,
R ⁶ , R ^{7 are} identical or different, hydrogen, C ₁ -C ₄ -alkyl or -CO-C ₁ -C ₂ -alkyl, and
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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-OC ₁ -C ₄ -alkyl , -CO-NR ⁶ R ⁷ , -OH, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ ,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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-OC ₁ -C ₄ -alkyl , -CO-NR ⁶ R ⁷ , -OH, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ , and
n, m are the same or different 0, 1 or 2,
mean,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts.

Particular preference is given to compounds of the general formula (I) in which
R ^{1 is} hydrogen, C ₁ -C ₄ -alkyl or benzyl,
R ² , R ^{3 are} identical or different, hydrogen or C ₁ -C ₄ -alkyl, or
R ¹ and R ² together form a butylene bridge, and
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -CN, -NO ₂ , -COOH, -CO-C ₁ -C _6- alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ ,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -CN, -NO ₂ , -COOH, -CO-C ₁ -C _6- alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ , and
n, m are the same or different 0, 1 or 2,
mean,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts.

Particular preference is furthermore given to compounds of the general formula (I) in which
R ¹ , R ² , R ^{3 are} identical or different, hydrogen or C ₁ -C ₄ -alkyl,
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -NO ₂ , -O-CO-C ₁ -C ₄ alkyl, -O-CO-OC ₁ -C ₄ -alkyl, -OC ₁ -C ₆ -alkyl, and -NR ⁶ R ⁷ ,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -NO ₂ , -O-CO-C ₁ -C ₄ alkyl, -O-CO-OC ₁ -C ₄ -alkyl, -OC ₁ -C ₆ -alkyl, and -NR ⁶ R ⁷ , and
n, m are the same or different 0, 1 or 2,
mean,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts.

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

Particular preference is given to compounds of the general formula (I)
wherein
R ^{1 is} methyl,
optionally in the form of their pharmacologically acceptable salts.

Particular preference is furthermore given to compounds of the general formula (I)
wherein
R ^{1 is} methyl,
R ² , R ^{3 is} hydrogen,
R ⁴ , R ^{5 are} identical or different, preferably fluorine, chlorine, bromine, especially preferably fluorine or chlorine,
and
n, m, identically or differently, denote 0, 1 or 2, preferably 0 or 1,
optionally in the form of their pharmacologically acceptable salts.

As alkyl groups are, unless stated otherwise, branched and unbranched alkyl groups having 1 to 6 carbon atoms preferably 1 to 4 Called carbon atoms. For example: methyl, ethyl, Propyl, butyl, pentyl and hexyl. To designate the groups methyl, ethyl, propyl or butyl, if appropriate, the abbreviations Me, Et, Pr or Bu used. Unless otherwise stated, the definitions include propyl, Butyl, pentyl and hexyl all conceivable isomeric forms of the respective radicals. So includes, for example, propyl, n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl, etc.

In the above-mentioned alkyl groups, one or more may optionally be Hydrogen atoms substituted by the halogen atoms fluorine, chlorine, bromine or iodine his. Preferably, the substituents are fluorine and chlorine. Particularly preferred is the Substituent fluorine. Optionally, all hydrogen atoms of the Be replaced alkyl group.

The alkyl group listed in the group phenyl-C ₁ -C ₄ -alkyl may be in branched or unbranched form. Unless otherwise indicated, benzyl and phenylethyl are preferred phenyl-C ₁ -C ₄ alkyl groups. Particularly preferred is benzyl.

In the groups -SO ₂ -C ₁ -C ₆ -alkyl, -SO-C ₁ -C ₆ -alkyl, -CO-C ₁ -C ₆ -alkyl, -CO-C ₁ -C ₄ -alkyl, - C ₁ -C ₄ -alkyl-NR ⁶ R ⁷ , -C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl, -O -CO-C ₁ -C ₄ -alkyl, -CO-OC ₁ -C ₄ -alkyl or -O-CO-OC ₁ -C ₄ -alkyl, listed alkyl groups can be in branched or unbranched form having 1 to 6 carbon atoms, preferred having 1 to 4 carbon atoms, more preferably having 1 to 3 carbon atoms, more preferably having 1 to 2 carbon atoms.

Unless indicated otherwise, 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. are referred to as C ₄ -C ₆ -alkylene bridge. Particularly preferred are n-butylene bridges.

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

In the abovementioned aryl radicals, it is optionally possible to substitute one or more hydrogen atoms by halogen atoms, -NO ₂ , -SO ₂ H or C ₁ -C ₄ -alkyl, preferably fluorine, chlorine, -NO ₂ , ethyl or methyl, particularly preferably fluorine or methyl his.

C ₃ -C ₆ -cycloalkyl denotes saturated cyclic hydrocarbon radicals having 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The halogen is, unless stated otherwise, fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine, particularly preferably denotes fluorine.

As mentioned above, the compounds of the formula (I) or their different enantiomers and diastereomers, in their salts, in particular for the pharmaceutical application, can be converted into their physiologically and pharmacologically tolerable salts. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of the formula (I) with inorganic or organic acids. On the other hand, in the case of R ¹ , the compound of the formula (I) can also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as the counterion. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid are suitable for the preparation of the acid addition salts. Furthermore, mixtures of the abovementioned acids can be used. For the preparation of the alkali metal and alkaline earth metal salts of the compound of the formula (I) in which R ^{1 is} hydrogen, preference is given to the alkali metal and alkaline earth metal hydroxides and hydrides, the hydroxides and hydrides of the alkali metals, especially of sodium and potassium, preferably sodium and potassium hydroxide are particularly preferred.

The preparation of the compounds according to the invention can be known per se Done way. The following general scheme shown in Schemes 1 and 2 Synthesis methods 1 and 2 are to be understood as an explanation of the invention, without to limit it to its subject matter.  

Method 1

Scheme 1

Starting from a compound of formula (II) is a compound of formula (III) prepared by sulfonation and subsequent chlorination. The after obtained condensation with aminoacetic acid derivatives obtained compound of Formula (IV) is Prepared by Addition of Polyphosphoric Acid to the Target Compound (I) cycled.

The general preparation of the compounds according to the invention according to Scheme 1 will be described in more detail below.

Sulfonation of naphthalenes (II)

About 10 mmol of the naphthalene derivative (II) are dissolved in 2-100 ml, preferably 3-80 ml, more preferably about 4 ml, acetic anhydride added and at 0-50 ° C, preferably 5-20 ° C, more preferably about 18 ° C, 10-100 mmol, preferably 11-80 mmol, more preferably 11 mmol, conc. Sulfuric acid added. After 2-16 h, preferably about 5 h, stirring at 20-100 ° C, preferably about 25 C °, the mixture is added to a saturated NaCl solution cast. The resulting crystals are isolated.

As an alternative to acetic anhydride, methylene chloride, diisopropyl ether, Ethyl acetate, trichloromethane, toluene, benzene or 1,4-dioxane, alternatively to conc. Sulfuric acid can be oleum, sulfur trioxide, chlorosulfates or combinations from it, to be used.

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

About 10 mmol of the naphthalene-1-sulfonic acids are added sequentially with 10-500 mmol, preferably about 90 mmol, phosphoroxytrichloride and 8-50 mmol, preferably about 10 mmol phosphorus pentachloride and 2-16 h, preferably for about 5 hours, at 20-100 ° C, preferably heated under reflux. Then the reaction mixture is concentrated and treated with water. To Extraction with organic diluent become the combined organic Extracts dried and freed from solvent. The resulting crude product is used without purification in the subsequent stages.  

Alternatively to the phosphoroxytrichloride / phosphorus pentachloride mixture Thionyl chloride, phosphorus pentachloride, a phosphoric acid / chlorine mixture or Phosgene are used. The reaction may alternatively be in the diluents Ethyl acetate, water, acetonitrile, N, N-dimethylacetamide, sulfolane, DMF, hexane, or Dichloroethane be performed.

Synthesis of naphthalene-1-sulfonylaminoacetic acids

About 10 mmol of the chlorosulfonyl-naphthalenes, 10-100 mmol, preferably 11-30 mmol, more preferably about 12 mmol, the aminoacetic acid and 10-100 mmol, preferably 11-30 mmol, particularly preferably about 12 mmol, Sodium hydroxide are dissolved in water and toluene. The reaction mixture is 2-16 h at 0-110 ° C, preferably at about 65 ° C, stirred, then the Phases separated. The aqueous phase is acidified and extracted. The combined organic extracts are dried and concentrated. The cleaning can be done by chromatography.

As an alternative to sodium hydroxide, triethylamine, potassium carbonate, Sodium bicarbonate or sodium hydride, as an alternative to toluene Tetrahydrofuran, diethyl ether, dichloromethane, trichloromethane, dioxane, acetone, Benzene, ethanol, methanol, ethyl acetate or acetonitrile.

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

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

Method 2

Scheme 2

The compounds of the formula (III) prepared as intermediates in process 1 are reacted with primary amines to give the compounds of the formula (V) and then by adding a compound of the formula R ² R ³ C =O in the presence of strong acid to the target compounds ( I) cycled.

For the preparation of the compounds of formula (I) wherein R ¹ and R ^{2 are} hydrogen, paraformaldehyde, trioxane or formalin can be used and as strong acids methanesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid or polyphosphoric acid.

The general preparation of the compounds according to the invention according to Scheme 2 will be described in more detail below.

Synthesis of naphthalene sulfonamides (V)

About 10 mmol of the chlorosulfonyl-naphthalenes (III) are mixed with an alcoholic Solution of the primary amine (10-1000 mmol in 5-200 ml, for example 200 mmol in 50 ml of ethanol) and then for 2-16 h, preferably for about 5 h at 0-100 ° C, preferably under reflux, heated. Subsequently, the Concentrated and purified reaction mixture.

As an alternative to the alcoholic solvent, toluene, benzene, trichloromethane, Dichloromethane, diethyl ether, tetrahydrofuran, water, acetonitrile, Acetic anhydride, acetone, pyridine, dimethyl sulfoxide, dimethylformamide, dioxane or hexane.  

Cyclization of naphthalene-1-sulfonamides (V) to the target compounds (I)

About 10 mmol of the naphthalene-1-sulfonamides are dissolved in 0-100 ml, preferably 20-80 ml, more preferably about 40 ml of methanesulfonic acid and with a solution of 3-50 mmol, preferably 4-30 mmol, particularly preferably 5 mmol Trioxane in 0-100 ml, preferably about 12 ml, trifluoroacetic acid. The reaction mixture is 2-16 h, preferably 5 h, at 20-100 C °, preferably 30-80 ° C, particularly preferably stirred at about 35 ° C and then poured onto ice water. After extraction and drying of the combined organic extracts, the solution is concentrated. The crude product is cleaned.

As an alternative to trioxane, paraformaldehyde or formalin, as an alternative to Trifluoroacetic acid, boron trifluoride * diethyl ether, acetic acid, polyphosphoric acid, Phosphoric acid or sulfuric acid are used. As possible Diluents may be acetic anhydride or dichloromethane become.

The novel compounds of the general formula (I) can be prepared in analogy to be synthesized following synthesis examples. These examples are but only as a walkthrough for further explanation to understand the invention, without limiting selbige on the subject.

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-naphthalenesulfonic acid are dissolved in 25 ml of methanesulfonic acid at 35 ° C and treated with a solution of 0.30 g of trioxane in 8 ml of trifluoroacetic acid. After 2 h stirring at room temperature, the reaction mixture is poured onto 300 ml of ice water. The resulting solid is separated by filtration, washed with 100 ml of water and dried overnight. After crystallization from methylcyclohexane, the product is isolated as a white solid. Yield: 2.20 g.
Mp .: 136 ° C.

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

0.45 g of 5-chloronaphthalene-1-sulfonic acid N-methylamide are dissolved in 6.8 ml of methanesulfonic acid at 35 ° C and treated with a solution of 0.07 g of trioxane in 2 ml of trifluoroacetic acid. After 2 h stirring at 35 ° C, the reaction mixture is poured onto 100 ml of ice water and the aqueous phase is extracted with ethyl acetate. The collected organic extracts are dried with sodium sulfate, concentrated in vacuo and then purified by chromatography.
Yield: 0.41 g. Mp .: 150 ° C.

Analogous to the procedure described above, inter alia, the following compounds of the formula IA are obtained:

Table 1

As has been found, the compounds of general formula (I) are characterized through a variety of applications in the therapeutic field. To emphasize are such applications, for which the positive Modulation of AMPA receptors play a role.  

The effect of the compounds according to the invention as AMPA receptor Modulators were measured electrophysiologically on cells containing functional AMPA Express receptors. It was examined whether the test substances the Agonists induced current to influence allosterically positive.

The test was carried out at concentrations between 0.3 μmol and 300 μmol.

Table 2

Amplification of the agonist-induced current (+ good, ++ very good effect)

Also can be with the new compounds diseases or conditions treat in which neural networks responsible for their function AMPA receptors need to be damaged or impaired in their function.

The compounds of the general formula (I) can thus be used in dementia diseases, in neurodegenerative or psychotic disorders and in neurodegenerative disorders and brain ischemia of various origins, preferably used in schizophrenia or learning and memory disorders become.

Also included are: status epilepticus, hypoglycemia, hypoxia, anoxia, Brain trauma, brain edema, amyotrophic lateral sclerosis, Huntington's Disease, Alzheimer's disease, sexual dysfunction, sensory / motor disturbances Function, memory formation, hyperkinetic behavioral changes (in particular in children), hypotension, myocardial infarction, intracranial pressure (increased intracranial pressure), ischemic and hemorrhagic stroke, global cerebral ischemia Cardiac arrest, acute and chronic neuropathic pain, diabetic Polyneuropathy, tinnitus, perinatal asphyxia, psychosis, Parkinson's disease and Depression, and related anxiety.  

The new compounds can also be used in combination with other active ingredients such as those used for the same indications find, or z. With neuroleptics, nootropics, psychostimulants, etc. The Administration may be topical, oral, transdermal, nasal, parenteral or inhalative respectively. Furthermore, the compounds of general formula I or their Salts can also be combined with other active ingredients.

The compounds of general formula (I) may be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active agents, are used. suitable Forms of use are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (s.c., i.v., i.m.) and infusion - juices, emulsions or dispersible powders. Here, the proportion of pharmaceutically effective Compound (s) in each case in the range of 0.1-90% by weight, preferably 0.5-50% by weight the total composition, d. H. in amounts sufficient to the To reach below dosing range.

Corresponding tablets, for example, by mixing the or Active ingredients with known excipients, for example inert diluents, 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 agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate become. The tablets can also consist of several layers.

Coated tablets can be coated analogously to the tablets manufactured cores with commonly used in dragee coatings, For example Kollidon or shellac, gum arabic, talc, titanium dioxide or Sugar, to be produced. To achieve a depot effect or to avoid of incompatibilities, the core can also consist of several layers. Similarly, the dragee cover to achieve a depot effect from several layers are those mentioned above in the tablets Excipients can be used.  

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or Sugar as well as a taste-improving agent, e.g. B. flavorings, such as vanillin or orange extract. You can also use suspension aids or Thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example Condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection and infusion solutions are in the usual way, for. B. with the addition of Isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers, as alkali salts of ethylenediaminetetraacetic acid, optionally under Use of emulsifiers and / or dispersants, wherein, for example when using water as a diluent optionally organic Solvent can be used as a solubilizer or Hilflösemittel, prepared and filled into injection bottles or ampoules or infusion bottles.

The one or more active substances or combinations of active substances containing capsules can be prepared, for example, by the Ingredients with inert carriers, such as lactose or sorbitol, and mixes in Encapsulating gelatin capsules.

Suitable suppositories can be, for example, by mixing with it provided carriers, such as neutral fats or polyethylene glycol or its derivatives.

As auxiliaries, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (eg petroleum fractions), vegetable oils Origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg Ethanol or glycerol), excipients such. Natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg highly dispersed Silicic acid and silicates), sugars (eg, cane, milk and glucose) Emulsifiers (eg lignin, liquors, methylcellulose, starch and Polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).  

The application is carried out in a customary manner, preferably orally or transdermally, especially preferably orally. In case of oral administration, the tablets can Of course, in addition to the mentioned carriers also additives such. B. Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants, such as magnesium stearate, Sodium lauryl sulfate and talc are used for tableting. In the event of aqueous suspensions may be the active ingredients except those mentioned above Excipients with different flavor enhancers or dyes added become.

In the case of parenteral administration, solutions of the active ingredients may be added Use of suitable liquid carrier materials can be used.

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

Nevertheless, it may be necessary, if necessary, of the quantities mentioned derive, depending on the body weight or the type of Application route, from individual behavior to the drug, the Art its formulation and the time or interval at which the Administration takes place. So it may be sufficient in some cases, with less to get along as the aforementioned minimum, while in other cases the said upper limit must be exceeded. In case of application larger Quantities may be recommended, these in several single doses over the day to distribute.

The following formulation examples illustrate the present invention without However, to limit their scope:  

Pharmaceutical Formulation Examples A

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

The finely ground active ingredient, lactose and part of the corn starch will be mixed together. The mixture is sifted, followed by a solution of polyvinylpyrrolidone in water moistened, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture becomes tablets of suitable form and Size pressed.

B

tablets per tablet 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 ground active ingredient, part of the corn starch, lactose, microcrystalline Cellulose and polyvinyl pyrrolidone are mixed together, the mixture sieved and processed into granules with the remainder of the corn starch and water, which is dried and sieved. Add the sodium carboxymethyl starch and the magnesium stearate, mixes and compresses the mixture into tablets suitable size.

C

ampoule solution active substance 50 mg sodium chloride 50 mg Aqua pro inj. 5 ml

The active ingredient is at intrinsic pH or optionally at pH 5.5-6.5 in water dissolved and treated with sodium chloride as isotonic. The resulting solution is filtered pyrogen-free and the filtrate under aseptic conditions in ampoules bottled, which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg active substance.

Claims (16)

1. Compounds of the general formula (I)
wherein
R ¹ is a radical selected from the group consisting of hydrogen, an optionally by one or more halogen atoms substituted C ₁ -C ₆ - alkyl, -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-OC ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl,
R ² , R ^{3 are} identical or different and are selected from the group consisting of hydrogen, an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl C ₁ -C ₄ -alkyl-NR ⁶ R ⁷ and C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl, or
R ¹ and R ² together form a C ₄ -C ₆ -alkylene bridge,
R ⁶ , R ^{7 are} identical or different, are hydrogen, C ₁ -C ₄ -alkyl or -CO-C ₁ -C ₄ -alkyl,
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, phenyl-C ₁ -C ₄ alkyl, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -SO ₂ -C ₁ -C ₆ alkyl, -SO-C ₁ -C ₆ alkyl, -SO ₂ -NR ⁶ R ⁷ , -COOH, -CO-C C ₁ -C ₆ -alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl, -NR ⁶ R ⁷ and an optionally mono- or polysubstituted by halogen atoms, -NO ₂ , -SO ₂ H or C ₁ -C _4- alkyl substituted aryl radical,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, phenyl-C ₁ -C ₄ alkyl, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -SO ₂ -C ₁ -C ₆ alkyl, -SO-C ₁ -C ₆ alkyl, -SO ₂ -NR ⁶ R ⁷ , -COOH, -CO-C C ₁ -C ₆ -alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl, -NR ⁶ R ⁷ and an optionally mono- or polysubstituted by halogen atoms, -NO ₂ , -SO ₂ H or C ₁ -C _4- alkyl substituted aryl radical, and
n, m are the same or different 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 pharmacologically acceptable salts. 2. Compounds of general formula (I) according to claim 1, wherein
R ¹ is a radical selected from the group consisting of hydrogen, an optionally by one or more halogen atoms substituted C ₁ -C ₆ - alkyl, -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 and -C ₁ -C ₄ alkyl-OC ₁ -C ₄ alkyl , Benzyl,
R ² , R ^{3 are} identical or different and are selected from the group consisting of hydrogen, an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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-OC ₁ -C ₄ -alkyl, or
R ¹ and R ² together form a C ₄ -C ₆ -alkylene bridge,
R ⁶ , R ^{7 are} identical or different, hydrogen, C ₁ -C ₄ -alkyl or -CO-C ₁ -C ₂ -alkyl, and
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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-OC ₁ -C ₄ -alkyl , -CO-NR ⁶ R ⁷ , -OH, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ ,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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-OC ₁ -C ₄ -alkyl , -CO-NR ⁶ R ⁷ , -OH, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ , and
n, m are the same or different 0, 1 or 2,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts. 3. Compounds of general formula (I) according to claim 1 or 2, wherein
R ^{1 is} hydrogen, C ₁ -C ₄ -alkyl or benzyl,
R ² , R ^{3 are} identical or different, hydrogen or C ₁ -C ₄ -alkyl, or
R ¹ and R ² together represent a butylene bridge, and
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -CN, -NO ₂ , -COOH, -CO-C ₁ -C _6- alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ ,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -CN, -NO ₂ , -COOH, -CO-C ₁ -C _6- alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl and -NR ⁶ R ⁷ , and
n, m are the same or different 0, 1 or 2,
mean,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts. 4. Compounds of general formula (I) according to claim 1 to 3, wherein
R ¹ , R ² , R ^{3 are} identical or different, hydrogen or C ₁ -C ₄ -alkyl,
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -NO ₂ , -O-CO-C ₁ -C ₄ alkyl, -O-CO-OC ₁ -C ₄ -alkyl, -OC ₁ -C ₆ -alkyl, and -NR ⁶ R ⁷ ,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, halogen, -NO ₂ , -O-CO-C ₁ -C ₄ alkyl, -O-CO-OC ₁ -C ₄ -alkyl, -OC ₁ -C ₆ -alkyl, and -NR ⁶ R ⁷ , and
n, m are the same or different 0, 1 or 2,
mean,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts. 5. A compound of general formula (I) according to any one of claims 1 to 4, wherein
R ^{1 is} methyl, ethyl, i-propyl, n-butyl or benzyl,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts. 6. Compounds of general formula (I) according to any one of claims 1 to 5, wherein
R ^{1 is} methyl,
optionally in the form of their pharmacologically acceptable salts. 7. Compounds of general formula (I) according to claim 1, wherein
R ^{1 is} methyl,
R ² , R ^{3 is} hydrogen,
R ⁴ , R ^{5 are} identical or different halogen,
and
n, m are the same or different 0, 1 or 2,
optionally in the form of their pharmacologically acceptable salts. 8. Compounds of the general formula (I)
wherein
R ¹ is a radical selected from the group consisting of hydrogen, an optionally by one or more halogen atoms substituted C ₁ -C ₆ - alkyl, -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-OC ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl,
R ² , R ^{3 are} identical or different and are selected from the group consisting of hydrogen, an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, 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, -OC ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl C ₁ -C ₄ -alkyl-NR ⁶ R ⁷ and C ₁ -C ₄ -alkyl-OC ₁ -C ₄ -alkyl and C ₃ -C ₆ -cycloalkyl, or
R ¹ and R ² together form a C ₄ -C ₆ -alkylene bridge,
R ⁶ , R ^{7 are} identical or different and are hydrogen, C ₁ -C ₄ -alkyl or -CO-C ₁ -C ₄ -alkyl
R ^{4 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, phenyl-C ₁ -C ₄ alkyl, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -SO ₂ -C ₁ -C ₆ alkyl, -SO-C ₁ -C ₆ alkyl, -SO ₂ -NR ⁶ R ⁷ , -COOH, -CO-C C ₁ -C ₆ -alkyl, -O-CO-C ₁ -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 ₆ alkyl, -SC ₁ -C ₆ -alkyl, -NR ⁶ R ⁷ and an optionally monosubstituted or polysubstituted by halogen atoms, -NO _2, ^- SO ₂ H, or C ₁ -C _4- alkyl substituted aryl radical,
R ^{5 is} identical or different, a radical selected from the group consisting of an optionally substituted by one or more halogen atoms C ₁ -C ₆ alkyl group, phenyl-C ₁ -C ₄ alkyl, halogen, -CN, -NO ₂ , -SO ₂ H, -SO ₃ H, -SO ₂ -C ₁ -C ₆ alkyl, -SO-C ₁ -C ₆ alkyl, -SO ₂ -NR ⁶ R ⁷ , -COOH, -CO-C C ₁ -C ₆ -alkyl, -O-CO-C ₁ -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 ₆ -alkyl, -SC ₁ -C ₆ -alkyl, -NR ⁶ R ⁷ and an optionally mono- or polysubstituted by halogen atoms, -NO ₂ , -SO ₂ H or C ₁ -C _4- alkyl substituted aryl radical, and
n, m are the same or different 0, 1, 2 or 3,
optionally in the form of their various enantiomers and diastereomers, and their pharmacologically acceptable salts,
for use as a medicine. 9. A compound of general formula (I) according to claim 8 for use as Medicinal products with neuroprotective activity. 10. Use of a compound of general formula (I) according to one of Claims 1 to 7 for the preparation of a medicament for the treatment and / or Prevention of neurodegenerative diseases and / or brain ischemia different genesis. 11. Use of a compound of general formula (I) according to one of Claims 1 to 7 for the manufacture of a medicament for the treatment of Schizophrenia. 12. Use of a compound of general formula (I) according to one of Claims 1 to 7 for the preparation of a medicament for the treatment and / or Prevention of memory disorders. 13. Use of a compound of general formula (I) according to one of Claims 1 to 7 for the manufacture of a medicament for the treatment of Dementias.   14. Method for the treatment and / or prevention of neurodegenerative Diseases and / or cerebral ischemia, characterized in that an effective amount of a compound of formula I according to a patient Claims 1 to 7 administered. 15. Method for the treatment and / or prevention of memory disorders and / or dementia diseases, characterized in that one Patients an effective amount of a compound of formula I according to claim 1 administered until 7. 16. Pharmaceutical preparations containing 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 customary auxiliaries and / or carriers.