DE10162442A1 - Medicaments, useful for improving attention, concentration, learning and/or memory performance, comprise new or known N-(hetero)aryl azabicycloalkane-carboxamides - Google Patents

Abstract

The use of N-(phenyl or monocyclic heteroaryl) azabicycloalkane-carboxamides (I) as medicaments for improving attention, concentration, learning and/or memory performance is new. The N-heteroaryl compounds (I) are new. The use of N-(hetero)aryl azabicycloalkane-carboxamides of formula (I) or their salts, solvates and solvated salts is claimed in the production of a medicament for improving attention, concentration, learning and/or memory performance. R1 = 7-11 membered 1-aza-bicyclo (m.n.p) alkyl; m, n = 2 or 3; p = 1-3; R2 = 5- or 6-membered heteroaryl or phenyl (both optionally substituted by one or more of halo, CHO, CONH2, CN, CF3, OCF3, NO2, 1-6C alkyl, 1-6C alkoxy or 1-6C alkylthio); and R3 = H or 1-6C alkyl. An Independent claim is included for new compounds of formula (I; 5- or 6-membered heteroaryl (optionally substituted as above)) (including their salts, solvates and solvated salts).

Description

The invention relates to the use of monocyclic N-arylamides for Manufacture of medicines to improve perception, Concentration, learning and / or memory as well as new monocyclic N-aryl amides.

Nicotinic acetylcholine receptors (nAChR) form a large family of Ion channels that are activated by the body's own messenger substance acetylcholine (Galzi and Changeux, Neuropharmacol. 1995, 34, 563-582). A functional one nAChR consists of five subunits that are different (certain Combinations of α1-9 and β1-4, γ, δ, ε subunits) or identical (α7-9) can. This leads to the formation of a variety of subtypes that are different Show distribution in muscles, nervous system and other organs (McGehee and Role, Annu. Rev. Physiol., 1995, 57, 521-546). Activation of nAChR leads to the influx of cations into the cell and the stimulation of Nerve or muscle cells. Selective activation of individual nAChR subtypes this stimulation is limited to the cell types that have the corresponding subtype own and can have undesirable side effects such. B. the stimulation of Avoid nAChR in the muscles. Clinical experiments with nicotine and Experiments in different animal models indicate a role of central nicotinic acetylcholine receptors in learning and memory processes (e.g. Rezvani and Levin, Biol. Psychiatry 2001, 49, 258-267). nicotinic Acetylcholine receptors of the alpha7 subtype (α7-nAChR) have a particularly high one Concentration in brain regions that are important for learning and memory, such as the Hippocampus and the cerebral cortex (Séguéla et al., J. Neurosci. 1993, 13, 596-604). The α7-nAChR has a particularly high permeability for calcium ions, increases glutamatergic neurotransmission, affects neurite and growth modulates neuronal plasticity in this way (Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).

Certain quinuclidinecarboxanilides are considered antiarrhythmic and Local anesthetics are described (see, for example, FR 1.566.045, GB 1 578 421 and Oppenheimer et al. Life Sci. 1991, 48, 977-985).

WO 01/60821 discloses biarylcarboxamides with affinity for the α7-nAChR for the treatment of learning and perception disorders.

The compounds used according to the invention show an unforeseeable, valuable spectrum of pharmacological effects. They stand out as ligands, especially agonists at the α7-nAChR.

The present invention therefore relates to the use of compounds of the general formula (I)


in which
R ^{1 represents} a 1-aza-bicyclo [mnp] alkyl radical with 7 to 11 ring atoms,
where m and n are independently 2 or 3,
where p is 1, 2 or 3,
and wherein the bicycloalkyl radical is optionally substituted by (C ₁ -C ₆ ) alkyl,
R ^{2 represents} 5- to 6-membered heteroaryl or phenyl, heteroaryl and phenyl optionally being selected from the group consisting of hydrogen, halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₆ ) -alkyl , (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio are substituted,
and
R ^{3 represents} hydrogen or (C ₁ -C ₆ ) alkyl,
for the manufacture of a medicament to improve perception, concentration, learning and / or memory

Compounds of the general formula (I) are preferably used,
in which
R ^{1 represents} 1-azabicyclo [2.2.2] octyl,
and R ² and R ^{3 have} the meaning given above.

Compounds of the general formula (I) are particularly preferably used,
in which
R ^{1 represents} 1-aza-bicyclo [2.2.2] oct-3-yl,
and R ² and R ^{3 have} the meaning given above.

Compounds of the general formula (I) are also preferably used,
in which
R ^{2 represents} thienyl, pyridyl or phenyl, the rings optionally being selected from 1 to 3 radicals from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio are substituted,
and R ¹ and R ^{3 have} the meaning given above.

Compounds of the general formula (I) are particularly preferably used,
in which
R ^{2 represents} phenyl, where phenyl is optionally selected from 1 to 3 radicals selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio is substituted,
and R ¹ and R ^{3 have} the meaning given above.

Compounds of the general formula (I) are also preferably used,
in which
R ^{3 represents} hydrogen or methyl,
and R ¹ and R ^{2 have} the meaning given above.

Compounds of the general formula (I) are particularly preferably used,
in which
R ^{3 represents} hydrogen,
and R ¹ and R ^{2 have} the meaning given above.

Combinations of two or are very particularly preferably used several of the preferred areas mentioned above.

Likewise, very particular preference is given to using compounds of the general formula (I)
in which
R ^{1 represents} 1-aza-bicyclo [2.2.2] oct-3-yl,
R ^{2 represents} phenyl, where phenyl is optionally selected from 1 to 3 radicals selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio is substituted,
and
R ^{3 represents} hydrogen.

The compounds of the general formula (I) are preferably used for the preparation a medicine for the treatment and / or prophylaxis of disorders of the Perception, concentration, learning and / or memory used.

In a further aspect, the invention relates to compounds of the general formula (Ia)


in which
R ^{1 represents} a 1-aza-bicyclo [mnp] alkyl radical with 7 to 11 ring atoms,
where m and n are independently 2 or 3,
where p is 1, 2 or 3,
and wherein the bicycloalkyl radical is optionally substituted by (C ₁ -C ₆ ) alkyl,
R ^{2a represents} 5- to 6-membered heteroaryl, where heteroaryl is optionally selected from the group consisting of hydrogen, halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio is substituted,
and
R ^{3 represents} hydrogen or (C ₁ -C ₆ ) alkyl.

Compounds of the general formula (Ia) are preferred
in which
R ^{1 represents} 1-azabicyclo [2.2.2] octyl,
and R ^2a and R ^{3 have} the meaning given above.

Compounds of the general formula (Ia) are particularly preferred
in which
R ^{1 represents} 1-aza-bicyclo [2.2.2] oct-3-yl,
and R ² and R ^{3 have} the meaning given above.

Also preferred are compounds of the general formula (Ia)
in which
R ^{2a represents} thienyl or pyridyl, the rings optionally being selected from 1 to 3 radicals from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, (C ₁ -C ₄ ) alkylthio are substituted,
and R ¹ and R ^{3 have} the meaning given above.

Also preferred are compounds of the general formula (Ia)
in which
R ^{3 represents} hydrogen or methyl,
and R ¹ and R ^{2a have} the meaning given above.

Compounds of the general formula (Ia) are particularly preferred
in which
R ^{3 represents} hydrogen,
and R ¹ and R ^{2a have} the meaning given above.

Combinations of two or more of the above are very particularly preferred mentioned preferred areas.

Compounds of the general formula (Ia) are also very particularly preferred,
in which
R ^{1 represents} 1-aza-bicyclo [2.2.2] oct-3-yl,
R ^{2a represents} phenyl, where phenyl is optionally selected from 1 to 3 radicals selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) alkylthio is substituted,
and
R ^{3 represents} hydrogen.

The compounds used according to the invention and according to the invention can in stereoisomeric forms, which are either like image and mirror image (enantiomers), or that do not behave like image and mirror image (diastereomers) exist. The The invention relates to both the enantiomers or diastereomers or their respective Mixtures. These mixtures of the enantiomers and diastereomers can be in separate in a known manner into the stereoisomerically uniform constituents.

The compounds used according to the invention and according to the invention can also in the form of their salts, solvates or solvates of the salts.

In the context of the invention, salts which are physiologically acceptable are the salts Compounds of the invention preferred.

Physiologically acceptable salts of the and used according to the invention Compounds according to the invention can use acid addition salts of the compounds Mineral acids, carboxylic acids or sulfonic acids. Z are particularly preferred. B. 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.

However, salts with conventional bases can also be mentioned as salts, such as for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. Calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, Ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, 1-ephenamine or methyl piperidine.

Such forms of the compounds are considered as solvates in the context of the invention referred to, which in the solid or liquid state by coordination with Solvent molecules form a complex. Hydrates are a special form of solvate, where coordination takes place with water.

In the context of the present invention, the substituents generally have the following meaning:
(C ₁ -C ₆ ) and (C ₁ -C ₄ ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4, particularly preferably 1 to 3, carbon atoms is preferred. Examples and preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

(C ₁ -C ₆ ) and (C ₁ -C ₄ ) alkyl represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4, particularly preferably having 1 to 3, carbon atoms is preferred. For example and preferably, the following may be mentioned: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

(C ₁ -C ₆ ) Alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms. A straight-chain or branched alkylthio radical having 1 to 4, particularly preferably 1 to 3, carbon atoms is preferred. Examples and preferably mentioned are: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

The 1-aza-bicyclo [m.n.p] alkyl radical having 7 to 11 ring atoms is preferably and for example: 1-aza-bicyclo [3.2.1] octyl (isotropan), 1-aza-bicyclo [3.3.1] nonyl (Isogranatan), 1-aza-bicyclo [2.2.2] octyl (quinuclidine).

Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine and Bromine. Fluorine and chlorine are particularly preferred.

5- to 6-membered heteroaryl represents an aromatic radical with 5 to 6 Ring atoms and up to 4 heteroatoms from the series S, O and / or N. The heteroaryl radical can be attached via a carbon or hetero atom. For example and the following may preferably be mentioned: thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, Tetrazolyl, pyridyl, pyrimidinyl, and pyridazinyl.

If residues in the inventive and used Compounds optionally substituted, the radicals, unless otherwise specified, one or more times the same or different substituted. A Substitution with up to three identical or different substituents is preferred.

The compounds of formula (I) can be prepared by:
Compounds of the general formula (II),

R ¹ -CO-X (II)

in which R ^{1 has} the meaning given above, and
X represents hydroxy or a suitable leaving group,
with a compound of the general formula (III),

HNR ¹ R ² (III)

in which
R ² and R ^{3 have} the meaning given above,
in an inert solvent, if appropriate in the presence of a condensing agent and if appropriate in the presence of a base.

If X is a leaving group, chloro, mesyloxy and Isobutyloxycarbonyloxy, especially chloro preferred.

Inert solvents are, for example, halogenated hydrocarbons such as Methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, Dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or Petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, Dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, preference is given to tetrahydrofuran, dimethylformamide or chloroform.

Condensing agents are, for example, carbodiimides such as e.g. B. N, N'-diethyl-, N, N, '- Dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'- propyloxymethyl polystyrene (PS carbodiimide) or carbonyl compounds such as Carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2- oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or Acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or Propanephosphonic anhydride, or isobutyl chloroformate, or Bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or Benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-Oxo-1- (2H) pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl uronium hexafluorophosphate (HATU) or Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures of this.

It may be advantageous to use these condensing agents in the presence an auxiliary nucleophile such. B. 1-Hydroxybenztriazole (HOBt) to use.

Bases are, for example, alkali carbonates, such as. B. sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines z. B. triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or Diisopropylethylamine.

The combination of N, N'-diisopropylcarbodiimide (IDC) and pentafluorophenol in DCM or DMF is particularly preferred. The use of resin-bound tetrafluorophenol and N, N'-diisopropylcarbodiimide (DC) is also particularly preferred (synthesis scheme 1). (The preparation of the tetrafluorophenol bound to resin and its use are preferably carried out according to Salvino et al. J. Comb. Chem. 2000, 6, 691-697. Synthesis scheme 1

The method according to the invention is preferably in a temperature range from room temperature to 50 ° C at normal pressure.

The compounds of the general formulas (II) and (III) are known or have not been used are synthesized from the corresponding starting materials by known processes (cf. z. B. "Comprehensive Heterocyclic Chemistry", Katritzki et al., Eds .; Elsevier, 1996).

For example, compounds of formula (II) can be prepared according to methods known from the literature.

3-Quinuclidine carboxylic acid hydrochloride: Orlek et al. J. Med. Chem. 1991, 34, 2726.

2-Quinuclidine carboxylic acid hydrochloride: Gassmann and Fox J. Org. Chem. 1967, 32, 480th

The compounds of the general formula (Ia) according to the invention are suitable for Use as a medicine for the treatment and / or prophylaxis of diseases in humans and / or animals.

The compounds used according to the invention and according to the invention can due to their pharmacological properties, alone or in combination with other medicines used to treat and / or prevent cognitive disorders Disorders, especially Alzheimer's disease. Because of their selective action as α7-nAChR agonists are suitable compounds according to the invention particularly for improving perception, Concentration performance, learning performance, or memory performance especially after cognitive Disorders such as occur in situations / diseases / syndromes such as "mild cognitive impairment", age-related learning and memory disorders, Age-related memory loss, vascular dementia, traumatic brain injury, Stroke, dementia that occurs after strokes ("post stroke dementia"), post-traumatic skull brain trauma, general concentration disorders, Impairment of concentration in children with learning and memory problems, attention Deficit Hyperactivity Disorder, Alzheimer's Disease, Vascular Dementia, Dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia, schizophrenia with dementia or Korsakoff's psychosis.

The compounds of the invention can be used alone or in combination with others Medicines are used for the prophylaxis and treatment of acute and / or chronic pain (for a classification see "Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms ", 2nd ed., Meskey and Begduk, eds .; IASP-Press, Seattle, 1994), especially for treatment of cancer-induced pain and chronic neuropathic pain, such as for example, in diabetic neuropathy, post-herpetic neuralgia, peripheral Nerve damage, central pain (e.g. as a result of cerebral Ischemia) and trigeminal neuralgia, and other chronic pain such as Example lumbago, low back pain or rheumatic pain. In addition, these substances are also suitable for the therapy of primarily acute Pain of any genesis and secondary resulting from it Painful conditions, as well as for the therapy of chronic, formerly acute painful conditions.

The in vitro activity of the compounds according to the invention can be seen in the following Assays are shown:

1. Determination of the Affinity of Test Substances for α7-nAChR by Inhibition of [ ³ H] Methyllycaconitine Binding on Rat Brain Membranes

The [ ³ H] -methyllycaconitine binding test is a modification of that described by Davies et al. (Neuropharmacol. 1999, 38, 679-690).

Rat brain tissue (hippocampus or whole brain) is in homogenization buffer (10% w / v) (0.32 M sucrose, 1 mM EDTA, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.01% (w / v) NaN ₃ , pH 7.4, 4 ° C) homogenized at 600 mm in a glass homogenizer. The homogenate is centrifuged (1000 × g, 4 ° C., 10 min) and the supernatant is removed. The pellet is resuspended (20% w / v) and centrifuged (1000 × g, 4 ° C, 10 min). The two supernatants are combined and centrifuged (15,000 × g, 4 ° C., 30 min). This pellet is called the P2 fraction.

The P2 pellet is washed twice with binding buffer (50 mM Tris-HCl, 1 mM MgCl ₂ , 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , pH 7.4) and centrifuged (15,000 × g, 4 ° C., 30 min ).

The P2 membranes are resuspended in binding buffer and incubated in a volume of 250 μl (membrane protein amount 0.1-0.5 mg) for 2.5 h at 21 ° C. in the presence of 1-5 nM [ ³ H] -methyllycaconitine, 0.1% (w / v ) BSA (bovine serum albumin) and various concentrations of the test substance. The non-specific binding is determined by incubation in the presence of 1 μM α-bungarotoxin or 100 μM nicotine or 10 μM MLA (methyllycaconitine).

The incubation is ended by adding 4 ml of PBS (20 mM Na ₂ HPO ₄ , 5 mM KH ₂ PO ₄ , 150 mM NaCl, pH 7.4, 4 ° C) and filtration through type A / E glass fiber filters (Gelman Sciences) which were previously soaked in 0.3% (v / v) polyethyleneimines (PEI) for 3 h. The filters are washed twice with 4 ml of PBS (4 ° C.) and the bound radioactivity is determined by scintillation measurement. All tests are carried out in triplicate. The dissociation constant of the test substance K _{i was} determined from the IC ₅₀ value of the compounds (concentration of the test substance at which 50% of the ligand bound to the receptor is displaced), the dissociation constant K _D and the concentration L of [ ³ H] methyllycaconitine (K _i = IC ₅₀ / (1 + L / K _D )).

Instead of [ ³ H] -methyllycaconitine, other α7-nAChR-selective radioligands such as e.g. B. [ ¹²⁵ I] -α-bungarotoxin or unselective nAChR radioligands can be used together with inhibitors of other nAChR.

The suitability of the compounds according to the invention for the treatment of cognitive Disorders can be shown in the following animal models:

2. Object recognition test

The object recognition test is a memory test. It measures the ability of Rats (and mice), between known and unknown objects too differ.

The test is carried out as described (Blokland et al. NeuroReport 1998, 9, 4205-4208; Ennaceur, A., Delacour, J.,. Behav. Brain Res. 1988, 31, 47-59; Ennaceur, A., Meliani, K.,. Psychopharmacology 1992, 109, 321-330; Prickaerts, et al. Eur. J. Pharmacol. 1997, 337, 125-136).

In a first pass, a raffe is made into an otherwise empty larger one Observation arena faced with two identical objects. The rat becomes both Examine objects extensively, d. H. sniff and touch. In a second Pass, after a waiting period of 24 hours, the rat is re-entered into the Observation arena set. Now one of the familiar objects is replaced by a new one unknown object replaced. If a rat recognizes the familiar object, she will mainly examine the unknown object. After 24 hours one has However, the rat usually forgot what object it was in the first Has examined continuity, and will therefore inspect both objects equally. The gift a substance with a learning and memory-improving effect will lead to the fact that a rat sees the object as seen 24 hours before, in the first round recognized. It makes the new, unknown object more detailed investigate as the already known. This memory performance is in one Discrimination index expressed. A zero discrimination index means that the rat both objects, the old and the new, examined at the same time; d. H. she has the old one Object not recognized and reacts to both objects as if they were unknown and new. A discrimination index greater than zero means that the rat is the new one Object inspected longer than the old one; d. H. the rat has the old object recognized.

3. Social recognition test

The social recognition test is a test to test the learning or memory-enhancing effects of test substances.

Adult rats that are kept in groups are given 30 minutes before Start of the test individually in test cages. The test animal is four minutes before the start of the test placed in an observation box. After this adaptation period, a juvenile becomes Animal to the test animal and measured the total time for 2 minutes adult animal examines the cub (Trial 1). All are clearly measured on that Juvenile-directed behaviors, d. H. ano-genital inspection; Track as well Grooming in which the old animal is at most 1 cm from the young animal Has. The juvenile is then removed and the adult in its test cage leave (with 24 hours retention the animal is in its home cage reset). Before or after the first test, the test animal is filled with substance treated. Depending on the time of the substance administration, learning or saving the information about the young animal influenced by the substance. After one The test is repeated for a specified period of time (retention) (Trial 2). The bigger the The difference between the investigation times determined in Trials 1 and 2, the better the adult animal remembered the young animal

The compounds of general formula (I) according to the invention are suitable for Use as a medicine for humans and animals.

The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and carriers or contain more compounds of the general formula (I), or those from one or more compounds of formula (I) exist, and methods for Manufacture of these preparations.

The compounds of formula (I) in these preparations are said to be in a Concentration of 0.1 to 99.5 wt .-%, preferably from 0.5 to 95 wt .-% of the Total mixture must be present.

In addition to the compounds of formula (I), the pharmaceutical Preparations also contain other active pharmaceutical ingredients.

The pharmaceutical preparations listed above can be used in a conventional manner are produced by known methods, for example with the auxiliary or carriers.

The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, coated tablets, pills, granules, aerosols, syrups, Emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. Here, the therapeutically active compound in a concentration of about 0.5 to 90% by weight of the total mixture is present, d. H. in amounts that are sufficient are in order to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the Active ingredients with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, z. B. in the case of use of water as a diluent, optionally organic solvents Auxiliary solvents can be used.

The application takes place in the usual way, preferably orally, transdermally or parenterally, especially perlingually or intravenously. You can also inhale over Mouth or nose, for example with the help of a spray, or topically on the Skin.

In general, it has been found advantageous to use amounts from about 0.001 to 10 mg / kg, preferably approximately 0.005 to 3 mg / kg body weight when administered orally to deliver 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 drug, 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 above upper limit 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 DMAP: 4-N, N-dimethylaminopyridine
DMF: N, N-dimethylformamide
DMSO: dimethyl sulfoxide
ESI: electrospray ionization (for MS)
HPLC: high pressure, high performance liquid chromatography
LC-MS: liquid chromatography-coupled mass spectroscopy
MS: mass spectroscopy
NMR: nuclear magnetic resonance spectroscopy
RT: room temperature
R _t : retention time (with HPLC) LC-MS method A device type MS:
Micromass Quattro LCZ
Ionization: ESI positive
Device type HPLC:
HP 1100
UV detector DAD: 208-400 nm
Oven temp .: 40 ° C
Pillar:
Symmetry C 18
50 mm x 2.1 mm; 3.5 µm

LC-MS method B device type MS:
Micromass Platform LCZ
Ionization: ESI positive
Device type HPLC:
HP 1100
UV detector DAD: 208-400 nm
Oven temp .: 40 ° C
Pillar:
Symmetry C 18
50 mm x 2.1 mm; 3.5 µm

starting compounds

3-Quinuclidine carboxylic acid hydrochloride was according to Orlek et al. J. Med. Chem. 1991, 34, 2726. Example 1A 3-quinuclidinecarboxylic acid chloride hydrochloride

500 mg (2.61 mmol) of 3-quinuclidinecarboxylic acid hydrochloride together with 1.9 ml (26.09 mmol) of thionyl chloride are heated under reflux for 2 h. The reaction mixture is freed from excess thionyl chloride under reduced pressure. It is mixed twice with 20 ml of toluene and concentrated to dryness in each case. The product obtained in this way is reacted directly without further purification. EXAMPLES Example 1 N- (3-pyridinyl) quinuclidine-3-carboxamide dihydrochloride

250 mg (2.57 mmol) of 3-quinuclidinecarboxylic acid chloride dihydrochloride are dissolved in 1 ml of dry DMF. 461 mg (3.57 mmol) of N, N-diisopropylethylamine, catalytic amounts of DMAP (approx. 1 mg) and 112 mg (1.19 mmol) of 3-aminopyridine are added. The mixture is stirred at room temperature for 3 days. For working up, the mixture is concentrated and taken up in dichloromethane. The crude product is chromatographed on silica gel 60 (mobile phase: dichloromethane, then dichloromethane / ethyl acetate 10: 1, then dichloromethane / methanol 10: 1, finally dichloromethane / methanol / triethylamine 80: 20: 2). The product is dissolved in a little methanol and an excess of 1N HCl in diethyl ether is added. The solvent is removed.
Yield: 117 mg (37% of theory) of the target compound
¹ H-NMR (200.1 MHz, DMSO-d ₆ ): δ = 11.42 (s, 1H), 10.17 (br. S, 1H), 9.12 (br. S, 1H), 8.53-8.41 (m, 2H), 7.87-7.63 (m, 2H), 3.62-3.53 (m, 1H), 3.40-3.10 (m, 7H), 2.00-1.80 (m, 2H), 1.80-1.60 (m, 2H)
MS (ESIpos): m / z = 232 (M + H) ⁺ (free base)
LC-MS (method A): R _t = 0.28 min., MS (ESIpos): m / z = 232 (M + H) ⁺ (free base). Example 2 N- (4-isopropylphenyl) quinuclidine-3-carboxamide hydrochloride

Analogously to the procedure described in Example 1, 250 mg (2.57 mmol) of 3-quinuclidinecarboxylic acid chloride dihydrochloride, 461 mg (3.57 mmol) of N, N-diisopropylethylamine, catalytic amounts of DMAP (approx. 1 mg) and 161 mg (1.19 mmol) of 4-isopropylphenyl -amin implemented.
Yield: 100 mg (27% of theory) of the target compound
¹ H-NMR (200.1 MHz, DMSO-d ₆ ): δ = 10.18 (s, 1H), 9.86 (br. S, 1H), 7.51 (d, 2H), 7.18 (d, 2H), 3.60-3.50 ( m, 1H), 3.30-3.05 (m, 7H), 2.00-1.80 (m, 2H), 1.80-1.65 (m, 2H), 1.15 (d, 6H)
MS (ESIpos): m / z = 273 (M + H) ⁺ (free base)
LC-MS (method B): R _t = 2.56 min., MS (ESIpos): m / z = 273 (M + H) ⁺ (free base).

Claims (8)

1. Use of compounds of the general formula (I),


in which
R ^{1 represents} a 1-aza-bicyclo [mnp] alkyl radical with 7 to 11 ring atoms,
where m and n are independently 2 or 3,
where p is 1, 2 or 3,
and wherein the bicycloalkyl radical is optionally substituted by (C ₁ -C ₆ ) alkyl,
R ^{2 represents} 5- to 6-membered heteroaryl or phenyl, the rings optionally being selected from the group consisting of hydrogen, halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio are substituted,
and
R ^{3 represents} hydrogen or (C ₁ -C ₆ ) alkyl,
and their salts, solvates and solvates of the salts,
for the manufacture of a medicament to improve perception, concentration, learning and / or memory. 2. Use according to claim 1, wherein
R ^{1 represents} 1-aza-bicyclo [2.2.2] oct-3-yl,
and R ² and R ^{3 have} the meaning given in claim 1. 3. Use according to claim 1 or 2, wherein R ^{1 is} 1-aza-bicyclo [2.2.2] oct-3-yl, R ^{2 is} thienyl, pyridyl or phenyl, the rings optionally being selected by 1 to 3 radicals from the group hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₄ ) alkyl, (C ₁ - C ₄ ) alkoxy, (C ₁ -C ₄ ) alkylthio,
and
R ^{3 represents} hydrogen. 4. Compounds of the general formula (Ia),


in which
R ^{1 represents} a 1-aza-bicyclo [mnp] alkyl radical with 7 to 11 ring atoms,
where m and n are independently 2 or 3,
where p is 1, 2 or 3,
and wherein the bicycloalkyl radical is optionally substituted by (C ₁ -C ₆ ) alkyl,
R ^{2a represents} 5- to 6-membered heteroaryl, where heteroaryl is optionally selected from the group consisting of hydrogen, halogen, formyl, carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylthio is substituted,
and
R ^{3 represents} hydrogen or (C ₁ -C ₆ ) alkyl,
and their salts, solvates and solvates of the salts. 5. Compounds according to claim 4 for the treatment and / or prophylaxis of Diseases. 6. Medicament containing at least one of the compounds according to claim 4 in admixture with at least one pharmaceutically acceptable essentially non-toxic carriers or excipients. 7. Use of compounds according to one of claims 1 to 4 for Manufacture of a medicament for the treatment and / or prophylaxis of Disorders of perception, concentration, learning performance and / or Memory. 8. Medicament according to claim 6 for the treatment and / or prophylaxis of Disorders of perception, concentration, learning performance and / or Memory.