EP1242394A1

EP1242394A1 - Novel 3-oxo-2,1-benzisoxazol-1(3h)-carboxamides for treatment of cns diseases

Info

Publication number: EP1242394A1
Application number: EP00983231A
Authority: EP
Inventors: Toshiya Moriwaki; Chantal FÜRSTNER; Bernd Riedl; Jens-Kerim ERGÜDEN; Frank-Gerhard BÖSS; Bernard Schmidt; Franz-Josef Van Der Staay; Werner Schröder; Karl-Heinz Schlemmer; Nagahiro Yoshida
Original assignee: Bayer AG; Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 1999-12-17
Filing date: 2000-12-06
Publication date: 2002-09-25
Also published as: US6589949B1; AU2005501A; WO2001044211A1; DE19960917A1; JP2003516976A; CA2395167A1

Abstract

The invention relates to novel 3-oxo-2,1-benzisoxazol-1(3H)-carboxamides (I), where R<1>, R<2> are the same or different and independently = H, halogen, C1 C6 alkyl, C1 C6 alkoxy, C1 C3 perfluoroalkyl, or a group NR<5>R<6>; R<3>, R<4> are the same or different and independently = C1 C8 alkyl, whose carbon chain is optionally interrupted by an O, S or NR<7> and is optionally singly or severally substituted by C3 C6 cycloalkyl, C1 C4 alkoxy, OH, halogen or NR<8>R<9>; C3 C8 cycloalkyl whose carbon chain is optionally interrupted by an O, S or NR<10> and is optionally singly or severally substituted by C1 C4 alkoxy, OH, halogen or NR<11>R<12>; or R<3> and R<4> together with a nitrogen atom form a saturated or partially unsaturated 3- to 10-membered mono- or bi-cyclic heterocycle, which, optionally, contains up to two further heteroatoms, from N, O or S and is, optionally, substituted by C1 C4 alkyl, C1 C4 alkoxy, OH, halogen, COOR<13> or NR<14>R<15>and X = O or S. The invention further relates to methods for production thereof and use thereof in the production of medicaments for the prophylaxis and/or treatment of diseases of the central nervous system, in particular, cognitive disorders, such as Alzheimer's disease and other forms of dementia, cerebral infarct, skull and brain trauma and pain.

Description

New 3-oxo-2, l-benzisoxazole-l (3H) -carboxamides for the treatment of CNS diseases

The present invention relates to new 3-oxo-2, l-benzisoxazole-l (3H) -carboxamides,

Process for their preparation and their use for the production of medicaments for the prophylaxis and / or treatment of diseases of the central nervous system, in particular cognitive disorders such as Alzheimer's disease and other forms of dementia, cerebral infarction, traumatic brain injury and pain.

Acylpeptide hydrolase (ACPH) is a serine protease that cleaves N-acetylated amino acids from peptides. A function of ACPH is the breakdown of N-acetylated hormones and neuropeptides. ACPH is inhibited by low concentrations of diisopropyl fluorophosphate (DFP) (WO-A-99/52516). Studies in the so-called Morris test, an animal model for learning and memory, showed that DFP has a promoting effect on learning and memory processes (J Pharmacol. Exp. Ther. 1996, 278, 697-708). The use of ACPH inhibitors to treat Alzheimer's disease and to improve cognitive performance has been described previously (WO-A-99/52516).

WO-A-96/02537 discloses benzo-fused 5-membered heterocyclyl carboxamides for the treatment of diseases of the central nervous system.

The synthesis and the antimicrobial and antileukaemic effects of 1- (1-

Mono-alkylamino-carbonyl) -2, l-benzisoxazol-3 (1H) -ones have been described (J Med. Chem. 1984, 27, 1212-1215).

The present invention now relates to compounds of the general formula (I) in which

R and R are the same or different and independent of each other

represent hydrogen, halogen, (-CC ₆ ) -alkyl, (dC ₆ ) -alkoxy, (-C-C ₃ ) -perfluoroalkyl, (-CC) -perfluoroalkoxy or a radical -NR 5r R> 6,

wherein

R ⁵ and R ^{6 are the} same or different and represent hydrogen, (Cj-C) - alkyl, (Cι-C) acyl, (Cι-C) alkoxycarbonyl, carbamoyl, mono- or di- (C i -C ₄ ) - alkylaminocarbony 1,

R ³ and R ^{4 are the} same or different and independent of each other

stand for (Cj-C ₈ ) - alkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a residue NR ⁷ and which is optionally selected one or more times by residues from the group (C ₃ -C ₆ ) -cycloalkyl , (CC ₄ ) - alkoxy, hydroxy, halogen or NR ⁸ R ^{9 is} substituted,

stand for (C ₃ -C ₈ ) cycloalkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR ¹⁰ and which is optionally selected one or more times by radicals from the

1 1 1 9

Group (Cj-C ₄ ) - alkoxy, hydroxy, halogen or NR R is substituted, embedded image in which

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^u and R ^{12 are} identical or different and independently of one another have the meaning given for R ⁵ ,

or

R ³ and R ⁴ together with the nitrogen atom form a saturated or partially unsaturated 3 to 10-membered, mono- or bicyclic heterocycle which optionally contains up to two further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and if appropriate by radicals selected from the group (C ₁ -C ₄₎ alkyl, (Cι-C ₄₎ - alkoxy, hydroxy, halogen, COOR ¹³ or is substituted NR ¹⁴ R ^15,

wherein

R ^{13 is} hydrogen or (CC ₄ ) alkyl, and

R ¹⁴ and R ^{15 are} identical or different and independently of one another have the meaning given for R ⁵ ,

and

X represents oxygen or sulfur,

as well as their salts.

Halogen in the context of the invention generally represents fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred. In the context of the invention, (CrC ₆ ) -alkyl or (Cj-C) -alkyl stand for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. A straight-chain or branched is particularly preferred

Alkyl radical with 1 to 3 carbon atoms.

(-C-C ₆ ) - Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is particularly preferred.

In the context of the invention, (C i -C) -perfluoroalky 1 stands for a perfluorinated straight-chain or branched alkyl radical having 1 to 3 carbon atoms. Examples include: trifluoromethyl, pentafluoroethyl and heptafluoroisopropyl. Trifluoromethyl is preferred.

In the context of the invention, (C i -C) perfluoroalkoxy stands for a perfluorinated straight-chain or branched alkoxy radical having 1 to 3 carbon atoms. Examples include: trifluoromethoxy, pentafluoroethoxy and heptafluoroisopropoxy. Trifluoromethoxy is preferred.

(C _j -C ₄ ) acyl or (-C-C) acyl in the context of the invention represents a straight-chain or branched acyl radical having 1 to 4 or 1 to 3 carbon atoms. Examples include: formyl, acetyl, propionyl, n-butyryl and isobutyryl. Formyl, acetyl and propionyl are preferred.

(C 1 -C ₄ ) - Alkoxycarbonyl in the context of the invention represents a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. For example may be mentioned: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the invention, mono- or di- (C 1 -C) -alkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has one straight-chain or branched or two identical or different straight-chain or branched alkyl substituents each having 1 to 4 Has carbon atoms. Examples include: methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, n-propylaminocarbonyl, isopropylmethylaminocarbonyl, tert-butylaminocarbonyl and tert-butyl-methylaminocarbonyl. A mono- or dialkylaminocarbonyl radical is preferred, the straight-chain or branched alkyl radical or the same or different straight-chain or branched alkyl radicals having 1 to 3 carbon atoms.

In the context of the invention, (C ₃ -C ₈ ) cycloalkyl or (C -C) cycloalkyl represents a cycloalkyl radical having 3 to 8 or 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

(-C-C ₈ ) - alkyl, (CC ₆ ) - alkyl or (dC ₄ ) - alkyl, the carbon chain of which may be interrupted by an oxygen or sulfur atom or by a radical NR ⁷ , stands for a straight-chain or branched alkyl radical having 1 to 8, 1 to 6 or 1 to 4 carbon atoms, the carbon chain of which contains an oxygen or sulfur atom or a radical NR ⁷ as a further chain link. A straight-chain or branched alkyl radical having 1 to 6 carbon atoms is preferred, the carbon chain of which contains an oxygen or sulfur atom or a radical NR ⁷ as a further chain link. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms, the carbon chain of which contains an oxygen atom as a further chain link, is particularly preferred. In the context of the invention, (C ₃ -Cg) cycloalkyl or (C ₄ -C ₆ ) cycloalkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR, represents a cycloalkyl radical having 3 to 8 or 4 to 6 carbon atoms, the carbon chain of which contains an oxygen or sulfur atom or a radical NR ¹⁰ as a further ring member. A cycloalkyl radical having 4 to 6 carbon atoms is preferred, the carbon chain of which contains an oxygen or sulfur atom or a radical NR ¹⁰ as a further ring member. A cycloalkyl radical with 4 to 6 carbon atoms is particularly preferred, the carbon chain of which contains an acid

Substance atom or a radical NR, 10 contains as a further ring member.

Within the scope of the invention, the saturated or partially unsaturated 3 to 10-membered, mono- or bicyclic heterocycle stands for a monocyclic or bicyclic ring with 3 to 10 ring atoms, which is bonded to the adjacent carbonyl / thiocarbonyl group via a nitrogen atom and contains up to two further heteroatoms and optionally one or more double or triple bonds. In the case of the bicyclus, the two rings can be linked spirocyclically, or the bridgehead atoms of the two rings are directly adjacent or separated by one or more ring atoms. Examples include aziridin-1-yl, azidine-l-yl, pyrrolidin-1-yl, pyrrolin-1-yl, piperidin-1-yl, 1,2,5, 6-tetrahydropyridin-l-yl, morpholine -4-yl, thiomorpholin-4-yl, hexa-hydroazepin-1-yl, 2,3-dihydro- (lH) -indol-1-yl, octahydroindol-1-yl, 8-aza-bicyclo- [3.2. 1] octan-8-yl, 3-aza-bicyclo [3.2.1] octan-3-yl, 3-aza-bicyclo [3.2.0] heptan-3-yl, 3,8-diaza-l-oxa -bicyclo [4.3.0] - nonan-8-yl, azacyclodecen-1-yl. Azetidin-1-yl, pyrrolidin-1-yl, 3-aza-bicyclo [3.2.0] heptan-3-yl and morpholin-4-yl are preferred.

Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, Propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Depending on the substitution pattern, the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers and the diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

Compounds of the general formula (I) are preferred

in which

R and R are the same or different and independent of each other

represent hydrogen, fluorine, chlorine, bromine, (CC ₄ ) - alkyl, (-C-C ₄ ) - alkoxy, trifluoromethyl, trifluoromethoxy or a radical -NR 5r R> 6,

Wonn

R ⁵ and R are identical or different and represent hydrogen, (C ₁ -C ₃₎ - alkyl, _(Cι-C3) -acyl, _(Cj-C4) - alkoxycarbonyl, carbamoyl, mono- or di _(Cι. -C ₃ ) alkylaminocarbonyl,

R ³ and R ^{4 are the} same or different and independent of each other

stand for (-C-C ₆ ) - alkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR ⁷ and which is optionally selected one or more times by radicals from the Group (C ₃ -C ₆ ) cycloalkyl, (dC) - alkoxy, hydroxy, fluorine, chlorine or NR ⁸ R ^{9 is} substituted,

stand for (C -C ₆ ) cycloalkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR ¹⁰ and which is optionally selected one or more times by radicals selected from the group (C 1 -C ₄ ) alkoxy, Hydroxy, fluorine, chlorine or NR ⁿ R ^{12 is} substituted,

wherein

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are independently hydrogen, (C ₁ -C ₃ ) alkyl, (Cι-C ₃ ) acyl, (Cι-C) - Alkoxycarbonyl, carbamoyl, mono- or di- (-C-C ₃ ) alkylamino carbonyl,

or

R ³ and R ⁴ together with the nitrogen atom form a saturated or partially unsaturated 3- to 9-membered, mono- or bicyclic heterocycle, which may optionally have up to two further heteroatoms selected from the group

Contains nitrogen, oxygen or sulfur, and which is optionally substituted by radicals selected from the group (Cj-C ₃ ) - alkyl, (C ₁ -C ₃ ) - alkoxy, hydroxy, fluorine, COOR ¹³ or NR ¹⁴ R ¹⁵ ,

wherein

R ^{13 represents} hydrogen, methyl or ethyl, and

R ¹⁴ and R ^{15 are} identical or different and independently of one another are hydrogen, (dC ₃ ) -alkyl, (C, -C ₃ ) -acyl, (C, -C ₄ ) - alkoxycarbonyl,

Are carbamoyl, mono- or di- (-CC) alkylaminocarbonyl, and

X represents oxygen or sulfur,

as well as their salts.

Compounds of the general formula (I) are particularly preferred

in which

R and R are the same or different and independent of each other

represent hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or a radical -NR 5r R, 6,

embedded image in which

R and R are identical or different and represent hydrogen, methyl, formyl, acetyl or methoxycarbonyl,

R ³ and R ^{4 are the} same or different and independent of each other

stand for (Cj-C ₄ ) - alkyl, the carbon chain of which is optionally interrupted by an oxygen atom and which is optionally substituted one or more times by radicals selected from the group consisting of hydroxy, methoxy, fluorine, chlorine or NR ⁸ R ⁹ ,

stand for (C ₆ -C ₆ ) cycloalkyl, the carbon chain of which is optionally interrupted by an oxygen atom or by a residue NR ¹⁰ and which optionally substituted one or more times by radicals selected from the group consisting of hydroxy, methoxy, fluorine, chlorine or NR R,

wherein

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^{1 1} and R ^{12 are} identical or different and independently of one another are hydrogen, methyl, formyl, acetyl or methoxycarbonyl,

or

R and R together with the nitrogen atom form a saturated or partially unsaturated 4- to 9-membered, mono- or bicyclic heterocycle, which optionally contains up to two further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and optionally by

Radicals selected from the group consisting of methyl, methoxy, hydroxy, fluorine or NR ¹⁴ R ^{15 is} substituted,

embedded image in which

R and R are identical or different and independently of one another are hydrogen, methyl, formyl, acetyl or methoxycarbonyl,

and

X represents oxygen,

as well as their salts.

Compounds of the general formula (I) are very particularly preferred, in which

1 "?

R and R are the same or different and independent of each other

represent hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy or amino,

R ³ and R ^{4 are the} same or different and independent of each other

represent methyl or ethyl which is optionally substituted by chlorine,

or

R and R together with the nitrogen atom form an azetidin-1-yl, pyrrolidine-l-yl, morpholin-4-yl or 3-azabicyclo [3.2.0] heptan-3-yl radical, and

X represents oxygen,

as well as their salts.

In addition, processes for the preparation of compounds of the general formula (I) were found in that compounds of the general formula (II),

in which

R and R have the meaning given above and R 16 represents methyl or ethyl,

with a reducing agent, optionally in the presence of an acid and optionally in an inert solvent, to give compounds of the general formula (III)

implements,

in which

R ¹ and R ^{2 have} the meaning given above,

and

[A] then with a compound of the general formula (IV),

(Cl ₂ C = X) _q (IV),

in which

X represents oxygen or sulfur, and

1, 2 or 3 means optionally in the presence of an inert solvent and a base to give compounds of the general formula (V)

in which

R ¹ , R ² and X have the meaning given above,

implements,

which finally with a compound of general formula (VI)

in which

R ³ and R ^{4 have} the meaning given above,

optionally in the presence of an auxiliary base to give compounds of the general formula (I).

Alternatively, compounds of the general formula (I) can also be obtained by

[B] first a compound of the general formula (VI) optionally in the presence of an inert solvent and a base with a compound of the general formula (IV) to give compounds of the general formula (VII)

in which

R ³ , R ⁴ and X have the meaning given above,

implements,

which then optionally with a compound of general formula (III) in

In the presence of an auxiliary base to give compounds of the general formula (I).

Customary organic solvents which do not change under the reaction conditions are suitable as solvents for the processes. These include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichlorethylene or chlorobenzene , Dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. For the process (II) - »(III), water or a mixture of water with one of the organic solvents mentioned is also suitable. A mixture of diethyl ether and water is preferred for this process. Dichloromethane and trichloromethane are preferred for processes (III) - (V) and (V) -> (I). Dichloromethane is particularly preferred.

As reducing agents for the process (II) -> (III), for example zinc, hydrogen in the presence of a catalyst, or hydrazine in the presence of a Catalyst such as Raney nickel or palladium can be used. Suitable catalysts for the reduction with hydrogen are transition metals such as palladium, platinum or rhodium, preferably palladium. Zinc is preferred for process (II) → (III).

Suitable acids for the process (II) - (III) are, for example, acetic acid or ammonium chloride. Ammonium chloride is preferred.

In general, inorganic or organic bases can be used as bases for the processes according to the invention. These preferably include

Alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates such as sodium or potassium methanolate , Sodium or potassium ethanolate or potassium tert-butoxide, or organic

Amines _((Cι. _-C6) trialkyl amines) such as triethylamine, or heterocycles such as 1,4-

Diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU),

Pyridine, N, N-dimethylaminopyridine, methylpiperidine or morpholine. Preferred for process (V) - (I) is triethylamine.

In general, the base is used in an amount of 0.05 mol to 10 mol, preferably 1 mol to 3 mol, based on 1 mol of the compound of the formula (V).

The processes according to the invention are generally carried out in a temperature range from -20 ° C. to + 100 ° C., preferably from 0 ° C. to + 60 ° C.

The processes according to the invention are generally carried out at normal pressure. However, it is also possible to carry out the processes under positive pressure or under slight negative pressure (for example in a range from 0.5 to 5 bar). The compounds of the general formulas (II), (IV) and (VI) are known or can be prepared by customary methods.

Surprisingly, the new compounds show an unforeseeable, valuable spectrum of pharmacological activity.

They stand out as highly effective inhibitors of acyl peptide hydrolase (ACPH). They can be used alone or in combination with other drugs for the prophylaxis and / or treatment of diseases of the central nervous system. Examples include cognitive disorders such as Alzheimer's disease and other forms of dementia, as well as depression, schizophrenia and anxiety. They are also suitable for the prophylaxis and control of the consequences of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia. The compounds according to the invention can also be used for the treatment of traumatic brain injury and for combating pain conditions.

Their use is preferred for the treatment of cognitive disorders, in particular Alzheimer's disease or other forms of dementia.

Likewise preferred is their use for the treatment of cerebral infarction, craniocerebral trauma and pain.

In vitro determination of the inhibition of ACPH

In the standard experiment, rat brains are homogenized in 10-fold volume (w / v) 50 mM Tris HCl buffer, 1 mM EDTA, 100 mM NaCl, 0.1% BSA, 1 mM DDT, pH 7.2. The protein concentration of the homogenate is adjusted to about 5 mg / ml by dilution with buffer. The incubation batch (110 μl) contains 40 μl buffer, various test concentrations of the test substances to be tested in 10 μl buffer, 50 μl brain homogenate and 100 μM N-acetyl-methionyl-aminomethyl-coumarin as enzyme substrate. Before adding the substrate, the reaction mixture is preincubated for 30 min at room temperature. The enzyme reaction is started by adding substrate. The reaction time is 30 minutes. The samples are then excited in the fluorimeter at 390 nm and determined quantitatively at 460 nm. The Id _ö value is calculated from the enzyme activity in the presence of increasing concentrations of test substance in the test. To measure the ACPH activity, purified enzyme from the liver or other organs can also be used, as well as homogenates from other organs with ACPH activity, such as the liver or erythrocytes.

The results are shown as examples for some compounds in the following Table 1:

Table 1

The effectiveness of the substances identified in this way in the treatment and prevention of cognitive disorders is proven with the help of known standard animal models for learning and memory (see, for example, 'Alzheimer's Disease: Biology, Diagnosis and Therapeutics Iqbal et al, ed .; 1997, John Wiley, pp. 781-786). Suitable animal Models for this include, for example, passive or active avoidance behavior, classic or operant conditioning, spatial orientation tests, or object or subject recognition tests. The so-called Morris test, which is based on spatial memory, is recommended as a particularly suitable model (J. Neurosci. Methods 1984, 11, 47-60).

Morris test:

The Morris test records spatial orientation learning in rodents. The test is ideal for evaluating the learning and memory-enhancing effects of substances. In this test, rats or mice are trained to locate an invisible platform as the only way out of a water-filled swimming pool. A proven method is to train the animals four times a day over a period of 5 days. The test substances are tested on a daily basis at a defined time, e.g. 30 min before the first swimming attempt per day. Controls receive the corresponding

Vehicle. The learning performance of the animals is expressed in a training-related shortening of the swim distance between the starting position and the platform, and in a reduction in the swimming time until the platform is reached, i.e. the better the animal remembers the location of the platform, the shorter the distance covered and the faster the platform is reached. The test is performed on cognitively impaired animals, such as old animals or animals with experimentally induced brain damage.

Rats with an entorhinal cortex lesion are an animal model for Alzheimer's disease. The bilateral lesion of the entorhinal cortex is created by intracerebral injection of the excitotoxin ibotenic acid. It leads to a severe impairment of learning performance in the Morris test.

The new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.0001 to 90% by weight, preferably 0.0001 to 1.0% by weight, of the total mixture, ie in amounts which are sufficient to achieve the to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents, if appropriate

Auxiliary solvents can be used.

The application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously.

In general, it has proven to be advantageous to administer amounts of approximately 0.00001 to 10 mg / kg, preferably approximately 0.0001 to 1 mg / kg, of body weight in the case of intravenous administration in order to achieve effective results.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place , In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the upper limit mentioned must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day. Abbreviations:

EI electron impact ionization

DCI direct chemical ionization

LCMS liquid chromatography-coupled mass spectroscopy

starting compounds

Example I

60 g (331 mmol) of methyl 2-nitrobenzoate in 600 ml of diethyl ether and 840 ml of water are introduced with stirring. 35.97 g (672 mmol) of ammonium chloride are then added. Zinc (90.1 g, 1.378 mol) is then added to the 2-phase mixture thus obtained over 5 min. added. The mixture is stirred for 20 min. at room temperature, filters off the undissolved zinc and washes with ether. The aqueous phase is separated off and extracted twice with diethyl ether. The combined ether phases are extracted with 1 N NaOH solution until it remains colorless. The combined NaOH phases are adjusted to pH 6 with 1N HCl. An amorphous solid precipitates out. The solid is filtered off, taken up in methylene chloride, dried over sodium sulfate and concentrated. Yield: 46.7 g (77.8% of theory)

MS (DCI): 153 (M + NH ₄ ⁺ : 100%)

1H-NMR (DMSO, TMS): δ 11.85 (br, 1 H), 7.7 - 7.88 (m, 2 H), 7.2 - 7.4 (m, 2 H)

Analogously to the procedure of Example I, all of the compounds listed in Table 2 were synthesized.

Table 2

PREPARATION

example 1

A solution of 200 mg (1.18 mmol) of the compound from Example II and 457 mg

(3.54 mmol) of ethyldiisopropylamine in 2.5 ml of methylene chloride is initially introduced with stirring at RT and 165 mg (81.24 mmol) of 1-pyrrolidinecarbonyl chloride (J Am. Chem. Soc. 1951, 73, 1214) are added. After 16 hours at room temperature, the mixture is hydrolyzed with water, extracted with ether, washed with saturated NaCl solution, dried over sodium sulfate and concentrated. Chromatography on silica gel with

Petroleum ether to ethyl acetate 4: 1 provides the product. Yield: 227 mg (72% of theory) MS (DCI): 283 [M + NH ₄ ⁺ : 100%] NMR-NMR (DMSO, TMS): δ 7.95 (d, j = 8 Hz, 1H ), 7.78 (d, J = 2 Hz), 7.48 (dd, J = 8 Hz, J = 2 Hz, 1 H), 3.55 - 3.7 (m, 4 H), 1, 85-1.95 (m, 2H).

The example compounds listed in Table 3 were prepared in an analogous manner:

Table 3

Claims

claims:

1. Compounds of the general formula (I),

in which

R ¹ and R are the same or different and independent of each other

represent hydrogen, halogen, (d -C ₆ ) - alkyl, (-C-C ₆ ) - alkoxy, (C, -C ₃ ) - perfluoroalkyl, (Cι-C ₃ ) -perfluoroalkoxy or a radical -NR ⁵ R ⁶ .

wherein

R ⁵ and R ^{6 are the} same or different and are hydrogen, (C _t -C) - alkyl, (-C-C ₄ ) acyl, (-C-C) alkoxycarbonyl, carbamoyl, mono- or di- (-C-C ₄ ) -alkylaminocarbonyl,

R and R are the same or different and independent of each other

stand for (-CC) alkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR ⁷ and which is optionally selected one or more times by radicals selected from the group (C ₃ -C ₆ ) -cycloalkyl, (Cj-C ₄ ) -

Alkoxy, hydroxy, halogen or NR R is substituted, represent (C ₃ -C ₈ ) cycloalkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR ¹⁰ and which is optionally selected one or more times by radicals selected from the group (Cj-C) - alkoxy, Hydroxy, halogen or NR ¹ * R ^{12 is} substituted,

wherein

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} identical or different and, independently of one another, have the meaning given for R ⁵ ,

or

R ³ and R ⁴ together with the nitrogen atom are a saturated or partially unsaturated 3 to 10-membered, mono- or bicyclic

Form heterocycle, which optionally contains up to two further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and which is optionally selected from the group consisting of (C 1 -C ₄ ) -alkyl, (C, -C ₄ ) - alkoxy, hydroxy, Halogen, COOR ¹³ or NR ¹⁴ R ^{15 is} substituted,

embedded image in which

R ^{13 is} hydrogen or (-CC ₄ ) - alkyl, and

R ¹⁴ and R ^{15 are} identical or different and independently of one another have the meaning given for R, 5,

and

X represents oxygen or sulfur, as well as their salts.

2. Compounds according to claim 1,

in which

R and R are the same or different and independent of each other

for hydrogen, fluorine, chlorine, bromine, (dC ₄ ) - alkyl, (dC ₄ ) - alkoxy,

Trifluoromethyl, trifluoromethoxy or a radical -NR 5n R6,

embedded image in which

R ⁵ and R ^{6 are the} same or different and are hydrogen, (C ₁ -C ₃ ) -

Alkyl, (-C-C ₃ ) -acyl, (-C-C) - alkoxycarbonyl, carbamoyl, mono- or di- (-C-C ₃ ) -alkylaminocarbonyl,

R and R are the same or different and independent of each other

stand for (-C-C _ö ) alkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR ⁷ and which is optionally selected one or more times by radicals selected from the group (C ₃ -C ₆ ) -cycloalkyl , (Cj-C ₄ ) - alkoxy, hydroxy, fluorine, chlorine or NR ⁸ R ^{9 is} substituted,

stand for (C -C ₆ ) cycloalkyl, the carbon chain of which is optionally interrupted by an oxygen or sulfur atom or by a radical NR ¹⁰ and which is optionally selected one or more times by radicals selected from the group (-C-C) - alkoxy, hydroxy Fluorine

Chlorine or NR ^π R ^{12 is} substituted, wherein

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are the} same or different and are independently hydrogen, (Cj-C) - alkyl, (Cι-C ₃ ) -acyl, (Cι-C ₄ ) - Are alkoxycarbonyl, carbamoyl, mono- or di- (dC ₃ ) -alkylaminocarbonyl,

or

R ³ and R ⁴ together with the nitrogen atom form a saturated or partially unsaturated 3 to 9-membered, mono- or bicyclic heterocycle which optionally contains up to two further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and which may be selected from the group (Cj-

C ₃ ) alkyl, (CC ₃ ) alkoxy, hydroxy, fluorine, COOR ¹³ or NR ¹⁴ R ^{15 is} substituted.

embedded image in which

R ^{13 represents} hydrogen, methyl or ethyl, and

R and R are the same or different and independent of each other

, (Cι-C ₃₎ is hydrogen - alkyl, (C, -C ₃₎ mean acyl, (dC ₄₎ alkoxy- carbonyl, carbamoyl, mono- or di- (Cι-C ₃₎ alkylamino carbonyl,

and

X represents oxygen or sulfur, as well as their salts.

3. Compounds according to claim 1,

in which

1 7 •

R and R are the same or different and independent of each other

represent hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or a radical NR 5r R> 6,

wherein

R ⁵ and R ^{6 are} identical or different and represent hydrogen, methyl, formyl, acetyl or methoxycarbonyl,

R ³ and R ^{4 are the} same or different and independent of each other

represent (C) -C) alkyl, the carbon chain of which is optionally interrupted by an oxygen atom and which is optionally substituted one or more times by radicals selected from the group consisting of hydroxyl, methoxy, fluorine, chlorine or NR ⁸ R ⁹ ,

stand for (C -C ₆ ) cycloalkyl, the carbon chain of which is optionally interrupted by an oxygen atom or by a radical NR ¹⁰ and which is optionally selected one or more times by radicals from the group consisting of hydroxyl, methoxy, fluorine, chlorine or NR ^U R ¹² is substituted,

wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^{1 1} and R ^{12 are} identical or different and independently of one another are hydrogen, methyl, formyl, acetyl or methoxycarbonyl,

or

R and R together with the nitrogen atom form a saturated or partially unsaturated 4- to 9-membered, mono- or bicyclic heterocycle which optionally contains up to two further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and if appropriate by Radicals selected from the group consisting of methyl, methoxy, hydroxy, fluorine or NR ¹⁴ R ^{15 is} substituted,

embedded image in which

and

X represents oxygen,

as well as their salts.

4. Compounds according to claim 1,

in which

R ¹ and R ^{2 are the} same or different and independent of each other represent hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy or amino,

R ³ and R ^{4 are the} same or different and independent of each other

represent methyl or ethyl which is optionally substituted by chlorine,

or

R ³ and R ⁴ together with the nitrogen atom are an azetidin-1-yl, pyrrolidine-1-yl, morpholin-4-yl or 3-aza-bicyclo [3.2.0] heptan-3-yl radical form,

and

X stands for oxygen,

as well as their salts.

5. A process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that compounds of the general formula (II),

in which R and R have the meaning given in claim 1 and R ^{16 represents} methyl or ethyl,

implements.

in which

1 9

R and R have the meaning given in claim 1,

and

[A] then with a compound of the general formula (IV),

(Cl ₂ C = X) _q (IV),

in which

X represents oxygen or sulfur, and

1, 2 or 3 means

optionally in the presence of an inert solvent and a base to give compounds of the general formula (V)

in which

R, R and X have the meaning given in claim 1,

implements,

which finally with a compound of general formula (VI)

in which

R ³ and R ^{4 have} the meaning given in claim 1,

if appropriate in the presence of an auxiliary base to give compounds of the general formula (I),

or

[B] first a compound of the general formula (VI) optionally in the presence of an inert solvent and a base with a compound of the general formula (IV) to give compounds of the general formula (VII) in which

R ³ , R ⁴ and X have the meaning given in claim 1,

implements,

which are then reacted with a compound of the general formula (III), optionally in the presence of an auxiliary base, to give compounds of the general formula (I).

6. Use of compounds according to one of claims 1 to 4 for the manufacture of medicaments.

7. Medicament containing a compound according to claim 1 to 4.

8. Use of compounds according to one of claims 1 to 4 for the manufacture of medicaments for the prophylaxis and treatment of diseases of the central nervous system.

9. Use of compounds according to one of claims 1 to 4 for the manufacture of medicaments for the prophylaxis and / or treatment of cognitive disorders, in particular Alzheimer's disease or other forms of dementia.

10. Use of compounds according to one of claims 1 to 4 for the manufacture of medicaments for the prophylaxis and / or treatment of cerebral infarction, craniocerebral trauma and pain.