RU2367665C2 - Diazabicyclic aryl derivatives as ligands of nicotinic acetylcholine receptors - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I),

where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

Description

This invention relates to new diazabicyclic aryl derivatives, which are found to be cholinergic ligands for nicotinic acetylcholine receptors and modulators of monoamine receptors and transporters. Due to their pharmacological profile, the compounds of the invention may be useful in treating a variety of diseases or disorders such as diseases or disorders associated with the cholinergic system of the central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders associated with smooth muscle contraction endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and symptom cancellations due to cessation of abuse of chemicals.

BACKGROUND OF THE INVENTION

The endogenous cholinergic neurotransmitter acetylcholine exerts its biological effect through two types of cholinergic receptors, muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChR).

Since it has been firmly established that muscarinic acetylcholine receptors quantitatively exceed nicotinic acetylcholine receptors in areas of the brain that are important for memory and cognitive ability, many studies aimed at developing agents for the treatment of memory disorders have focused on the synthesis of modulators of muscarinic acetylcholine receptors.

Not so long ago, however, interest arose in the development of nAChR modulators. Some diseases are associated with degeneration of the cholinergic system, that is, senile dementia of the Alzheimer's type, vascular dementia and cognitive impairment due to organic brain damage directly associated with alcoholism.

WO 00/58311 describes 1,4-diaza-bicyclo [3.2.2] nonan-4-carboxylates and carboxamide derivatives useful as inhibitors of the α7 subtype nicotinic receptor. Other 1,4-diaza-bicyclo [3.2.2] nonan-4-methanone derivatives are not described.

SUMMARY OF THE INVENTION

The present invention provides novel nicotinic and / or monoamine receptor modulators useful for treating diseases or disorders associated with cholinergic receptors, and in particular, nicotinic acetylcholine receptor (nAChR), serotonin receptor (5-HTR), dopamine receptor (DAR) and norepinephrine receptor (NER), and biogenic amine transporters of serotonin (5-HT), dopamine (DA) and norepinephrine (NE).

Due to their pharmacological profile, the compounds of the invention may be useful in treating a variety of diseases or disorders such as diseases or disorders associated with the cholinergic system of the central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders associated with smooth muscle contraction endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and symptom cancellations due to cessation of abuse of chemicals.

The compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for imaging in vivo receptors (neuroimaging), and they can be used in labeled or unlabeled form.

In a first aspect, the invention provides diazabicyclic aryl derivatives of formula I

their N-oxides or pharmaceutically acceptable addition salts, where

n is 2;

A 'represents a furanyl group;

A "represents a phenyl group;

Is a

pyrrolyl or dihydropyrrolyl, optionally substituted with one or two hydroxy and / or oxo; or

a group of the formula -NR'-B ', -NR' - (C = V) -B 'or -NR' - (C = V) -NR "'- B', where

R 'represents hydrogen or a group of the formula - (C = V) -NR "- B',

R ″ represents hydrogen,

V represents O or S, and

B 'represents C _1-6 alkyl, phenyl, benzyl or pyridinyl, wherein phenyl, benzyl and pyridinyl are optionally substituted with one or two substituents selected from the group consisting of C _1-6 alkoxy, halo, trihalomethyl, nitro, amino C _1-6 alkyl-carbonyl-amino and N-C _1-6 -alkyl-amino-carbonyl-amino (NC _1-6 -alkyl-ureido); and

L is a single (covalent) bond.

In a second aspect, the invention provides pharmaceutical compositions for modulating cholinergic receptors comprising a therapeutically effective amount of a diazabicyclic aryl derivative of the invention or a pharmaceutically acceptable addition salt thereof together with at least one pharmaceutically acceptable carrier or diluent.

According to another aspect, the invention relates to the use of the diazabicyclic aryl derivative of the invention or a pharmaceutically acceptable addition salt thereof for the manufacture of pharmaceutical compositions / drugs for treating, preventing or alleviating a disease or disorder or condition in a mammal, including a human being, which is an anxiety, cognitive disorder, learning deficits, memory deficits or dysfunction, Alzheimer's disease, attention deficit disorder, hyperactivity disorder and deficiency and attention, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, Gilles de la Tourette’s disease, depression, manic syndrome, manic depression, schizophrenia, obsessive-compulsive disorder, panic disorder, eating disorder, anorexia nervosa, bulimia, obesity, narcolepsy nociception, AIDS dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, post-traumatic syndrome, social phobia, sleep disorder, pseudo-dementia , Ganser's syndrome, pre-menstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania or jet lag associated with the change of time zones.

Other objectives of the invention will become apparent to a person skilled in the art from the following detailed description and examples.

DETAILED DESCRIPTION OF THE INVENTION

Diazabicyclic aryl derivatives

In a first aspect, the present invention provides diazabicyclic aryl derivatives of formula I

their N-oxides or pharmaceutically acceptable addition salts, where

n is 2;

A 'represents a furanyl group;

A "represents a phenyl group;

Is a

pyrrolyl or dihydropyrrolyl, optionally substituted with one or two hydroxy and / or oxo; or

a group of the formula -NR'-B ', -NR' - (C = V) -B 'or -NR' - (C = V) -NR "'- B', where

R 'represents hydrogen or a group of the formula - (C = V) -NR "- B',

R ″ represents hydrogen,

V represents O or S, and

B 'represents C _1-6 alkyl, phenyl, benzyl or pyridinyl, wherein phenyl, benzyl and pyridinyl are optionally substituted with one or two substituents selected from the group consisting of C _1-6 alkoxy, halo, trihalomethyl, nitro, amino C _1-6 alkyl-carbonyl-amino and N-C _1-6 -alkyl-amino-carbonyl-amino (NC _1-6 -alkyl-ureido); and

L is a single (covalent) bond.

In a preferred embodiment, the diazabicyclic aryl derivative is a compound of formula I, wherein A ′ is furan-2,5-diyl.

In a preferred embodiment, the diazabicyclic aryl derivative is a compound of formula I, A ″ represents a phen-1,3-diyl or phen-1,4-diyl group.

In a most preferred embodiment, the diazabicyclic aryl derivative of the invention is:

5-hydroxy-1- {4- [5- (1-hydroxy-1,4-diaza-bicyclo [3.2.2] nonan-4-

carbonyl) -furan-2-yl] phenyl} -1,5-dihydro-pyrrol-2-one; or

(1,4-diaza-bicyclo [3.2.2] non-4-yl) - [5- (4-pyrrol-1-yl-phenyl) -furan-2-yl] -methanone;

or a pharmaceutically acceptable addition salt thereof.

In another embodiment, the diazabicyclic aryl derivative is a compound of formula II

or a pharmaceutically acceptable addition salt thereof, wherein n, A ′, A ″, L, R ′ and B ′ are as defined above.

In a more preferred embodiment, B ′ is pyridinyl, optionally substituted nitro.

In another preferred embodiment, B ′ is pyridin-2-yl, optionally substituted nitro.

In a most preferred embodiment, the diazabicyclic aryl derivative of the invention is:

(1,4-diaza-bicyclo [3.2.2] non-4-yl) - {5- [4- (3-nitro-pyridin-2-ylamino) phenyl] furan-2-yl} methanone;

or a pharmaceutically acceptable addition salt thereof.

In yet another embodiment, the diazabicyclic aryl derivative is a compound of formula III

or a pharmaceutically acceptable addition salt thereof, wherein n, A ′, A ″, L, R ′, V and B ′ are as defined above.

In a more preferred V is O; and B 'represents a C _1-6 alkyl, phenyl or pyridinyl group, wherein the phenyl and pyridinyl groups are optionally substituted with nitro or amino.

In a most preferred embodiment, the diazabicyclic aryl derivative of the invention is:

N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide;

N- {3- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide;

N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -2-nitro-benzamide;

N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -4-nitro-benzamide;

N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-nitro-benzamide;

4-amino-N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] -

phenyl} benzamide;

3-amino-N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] -

phenyl} benzamide; or

N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -

isonicotinamide;

or a pharmaceutically acceptable addition salt thereof.

In yet another embodiment, the diazabicyclic aryl derivative is a compound of formula IV

or a pharmaceutically acceptable addition salt thereof, wherein n, A ′, A ″, L, R ′, R ″, V and B ′ are as defined above.

In a more preferred embodiment, B ′ is C _1-6 alkyl phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with one or two substituents selected from the group consisting of C _1-6 alkoxy, halo, trifluoromethyl, nitro, amino , C _1-6 alkyl-carbonyl-amino, N-C _1-6 -alkyl-amino-carbonyl-amino (NC _1-6 -alkyl-ureido).

In a most preferred embodiment, the diazabicyclic aryl derivative of the invention is:

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-ethyl-urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-phenyl-urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-nitrophenyl) urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-acetylaminophenyl) urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-aminophenyl) urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (5-chloro-2-methoxy-phenyl ) urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -3-benzyl-urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -1'-benzylaminocarbonyl-3-benzyl-urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-chlorophenyl) urea;

1- {3- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-phenyl-urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-fluorophenyl) urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (3-fluorophenyl) urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-trifluoromethylphenyl) urea;

1- [2- (3- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -ureido) phenyl] - 3-ethyl urea;

1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (3-trifluoromethylphenyl) urea; or

1- {3- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-ethyl-urea;

or a pharmaceutically acceptable addition salt thereof.

It is believed that any combination of two or more embodiments set forth in this description of the invention is included in the scope of the present invention.

Determination of substituents

In the context of this invention, an alkyl group means a monovalent saturated straight or branched hydrocarbon chain. This hydrocarbon chain preferably contains from one to eighteen carbon atoms (C _1-18 alkyl), more preferably from one to six carbon atoms

(C _1-6 alkyl; lower alkyl) including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred embodiment, the alkyl is a C _1-4 alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of this invention, the alkyl is a C _1-3 alkyl group, which may, in particular, be methyl, ethyl, propyl or isopropyl.

In the context of this invention, an alkoxy group means an “alkyl-O-” group, wherein alkyl is as defined above. Examples of preferred alkoxy groups of the invention include methoxy and ethoxy.

In the context of this invention, a halogen is fluoro, chloro, bromo or iodo, and a haloalkyl group means an alkyl group as defined herein, wherein this alkyl group is substituted with one or more halogen groups. Thus, the trihalogenomethyl group is, for example, a trifluoromethyl group, a trichloromethyl group and similar trihalo-substituted methyl groups. Preferred haloalkyl groups of the invention include trihalogenomethyl, preferably —CF ₃ .

Pharmaceutically Acceptable Salts

The diazabicyclic aryl derivative of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts of a chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include addition salts of non-toxic inorganic and organic acids such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene para-sulfonate and the like, but are not limited to this. Such salts may be formed by techniques well known and described in the art.

The metal salts of the chemical compound of the invention include alkali metal salts, such as the sodium salt of the chemical compound of the invention containing a carboxy group.

In the context of this invention, "-onium salts" of N-containing compounds may also be considered as pharmaceutically acceptable salts. Preferred "-onium salts" include alkyl-onium salts, cycloalkyl-onium salts and cycloalkyl-alkyl-onium salts. Particularly preferred α-onium salts of the invention include salts formed at the N ′ position according to the following formula I ′

Spatial isomers

The chemical compounds of the present invention can exist in (+) - and (-) - forms, as well as in racemic forms. The racemates of these isomers and their individual isomers are within the scope of the present invention.

Racemic forms can be divided into optical antipodes by known methods and techniques. One method for separating diastereomeric salts is by using an optically active acid and releasing the optically active amino compound by treatment with a base. Another method for separating racemates into optical antipodes is based on the use of chromatography on an optically active matrix. Thus, the racemic compounds of the present invention can be resolved into their optical antipodes, for example, by fractional crystallization, for example, d- or l-salts (tartrates, mandelates or camphorsulfonates).

The chemical compounds of the present invention can also be separated by the formation of diastereomeric amides by reacting the chemical compounds of the present invention with an optically active activated carboxylic acid, such as an acid derived from (+) - or (-) - phenylalanine, (+) - or (-) - phenylglycine, (+) - or (-) - camphanic acid, or through the formation of diastereomeric carbamates as a result of the interaction of the chemical compound of the present invention with optically active chloroformate or the like.

Additional methods for resolving optical isomers are known in the art. Such methods include those described by Jaques J, Collet A & Wilen S in Enantiomers, Racemates. And Resolutions. John Wiley and Sons, New York (1981).

In addition, optically active compounds can be obtained from optically active starting materials.

Methods for the preparation of diazabicyclic aryl derivatives

The diazabicyclic aryl derivative according to the invention can be obtained by traditional methods of chemical synthesis, for example, by the methods described in the working examples. The starting materials for the methods described in this application are known or can be obtained by traditional methods from commercially available chemicals.

In addition, one compound of the invention can be converted to another compound of the invention using conventional methods.

The final products of the reactions described in this description of the invention can be distinguished by conventional methods, for example, extraction, crystallization, distillation, chromatography and so on.

Biological activity

The present invention provides new ligands and modulators of nicotinic receptors, while these ligands and modulators are useful for the treatment of diseases or disorders associated with cholinergic receptors and, in particular, with nicotinic acetylcholine receptor (nACDR). Preferred compounds of the invention exhibit distinct selectivity for the α7 subtype nicotinic acetylcholine receptor.

The compounds of the present invention can be, in particular, agonists, partial agonists, antagonists and / or allosteric modulators of the nicotinic acetylcholine receptor.

Due to their pharmacological profile, the compounds of the invention may be useful in treating a variety of diseases or disorders such as diseases or disorders associated with the cholinergic system of the central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders associated with smooth muscle contraction endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and symptom cancellations due to cessation of abuse of chemicals.

The compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for imaging in vivo receptors (neuroimaging), and they can be used in labeled or unlabeled form.

In a preferred embodiment, the compounds of the invention are used to treat diseases, disorders or conditions related to the central nervous system. Such diseases or disorders include anxiety, cognitive impairment, learning deficits, memory deficits or dysfunctions, Alzheimer's disease, attention deficit disorder, hyperactivity disorder and attention deficit disorder, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Gilles de la Tourette’s disease, depression, manic syndrome , manic depression, schizophrenia, obsessive-compulsive disorder, panic disorder, eating disorder, anorexia nervosa, bulimia, obesity, narcolepsy, nociception, SP ID dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, post-traumatic syndrome, social phobia, sleep disorder, pseudo-dementia, Ganser syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, fatigue syndrome or a biorhythm disorder associated with a change in time zones.

Preferably, diseases, disorders or conditions related to the central nervous system for which the compounds of the invention are used are cognitive disorders, psychosis, schizophrenia and / or depression.

Preferably, the compounds of the invention may be useful in the treatment of diseases, disorders or conditions associated with smooth muscle contraction, including convulsive disorders, angina pectoris, premature birth, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, problems with erection .

The compounds of the invention may be useful in the treatment of endocrine disorders such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

The compounds of the invention may be useful in the treatment of neurodegenerative disorders, including transient anoxia and induced neurodegeneration.

The compounds of the invention may be useful in the treatment of inflammatory diseases, disorders or conditions, including inflammatory skin disorders such as acne and rosacea, Crohn's disease, inflammatory bowel disease, ulcerative colitis and diarrhea.

The compounds of the invention may be useful in treating mild, moderate, or even severe pain of an acute, chronic, or recurrent nature, as well as pain caused by migraine, postoperative pain, and phantom pain. The pain may be, in particular, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, with neuralgia after therapeutic treatment, or with damage to peripheral nerves.

Finally, the compounds of the invention may be useful in treating withdrawal symptoms caused by cessation of addictive substances. Such addictive substances include nicotine-containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and benzodiazepine-like drugs and alcohol. In the general case, giving up addictive substances is a traumatic experience characterized by anxiety and frustration, anger, anxiety, difficulty concentrating, an agitated state, a decreased heart rate, and increased appetite and weight gain.

In this context, “treatment” includes treatment, prevention, prevention and alleviation of withdrawal and withdrawal symptoms, as well as treatment resulting in a voluntary reduction in the use of an addictive substance.

The compounds of the invention can be used as diagnostic agents, for example, to identify and localize nicotinic receptors in various tissues.

Pharmaceutical Compositions

In another aspect, the invention provides novel pharmaceutical compositions for modulating cholinergic receptors comprising a therapeutically effective amount of a diazabicyclic aryl derivative of the invention or a pharmaceutically acceptable addition salt thereof together with at least one pharmaceutically acceptable carrier or diluent.

Although the chemical compound of the invention for use in therapy can be administered in the form of an untreated chemical compound, it is preferable to administer the active ingredient, possibly in the form of a physiologically acceptable salt, in the pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other commercially available pharmaceutical excipients.

Thus, pharmaceutical compositions are provided comprising the diazabicyclic aryl derivative of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers and possibly other therapeutic and / or prophylactic ingredients known and used in the art. The carrier (s) must be “acceptable” in the sense of being compatible with the other ingredients of the preparation and harmless to its recipient.

The pharmaceutical composition of the invention may be administered by any convenient route suitable for the desired therapy. Preferred routes of administration include oral administration, in particular in the form of a tablet, capsule, dragee, powder or in liquid form, and parenteral administration, in particular skin, subcutaneous, intramuscular or intravenous injection. The pharmaceutical composition of the invention may be prepared by one skilled in the art by using standard methods and conventional techniques appropriate for the desired preparation. If desired, compositions adapted to provide a sustained release of the active ingredient may be used.

Further details of drug preparation and administration procedures can be found in the most recent edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

The actual dosage depends on the nature and severity of the disease being treated, and is within the competence of the physician, and can be changed by determining the dosage for specific cases of this invention in order to obtain the desired therapeutic effect. However, it is currently believed that pharmaceutical compositions containing from about 0.1 to about 500 mg of active ingredient per individual dose, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10, are suitable for therapeutic treatments. 10 mg

The active ingredient can be administered in one or more doses per day. In some cases, a satisfactory result can be obtained in a dosage lower than 0.1 μg / kg intravenously and 1 μg / kg orally. The upper limit of the dosage range is currently considered to be approximately 10 μg / kg intravenously and 100 μg / kg orally. Preferred ranges are from about 0.1 μg / kg to about 10 μg / kg / day intravenously and from about 1 μg / kg to about 100 μg / kg / day orally.

Treatment methods

The diazabicyclic aryl derivatives of the present invention are valuable modulators of nicotinic and monoamine receptors and are therefore useful in treating a number of ailments, including cholinergic dysfunction, as well as a number of disorders sensitive to nAChR modulators.

In the context of this invention, the term “treatment” includes treatment, prevention, prophylaxis or relief, and the term “disease” covers diseases, diseases, disorders and conditions associated with the disease in question.

Preferred indications considered are those listed above.

It is now contemplated that suitable dosage ranges are from 0.1 to 1000 milligrams per day, 10-500 milligrams per day, and especially 30-100 milligrams per day, depending, as usual, on the exact route of administration, the form in which , the indications to which this introduction is directed, the subject involved and the body weight of the subject involved, and further the preferences and experience of the attending physician or veterinarian.

In some cases, a satisfactory result can be obtained in a dosage lower than 0.005 μg / kg intravenously and 0.01 μg / kg orally. The upper limit of the dosage range is currently approximately 10 μg / kg intravenously and 100 μg / kg orally. Preferred ranges are from about 0.001 to about 1 μg / kg intravenously and from about 0.1 to about 10 μg / kg orally.

EXAMPLES

The invention is further illustrated with reference to the following examples, which are not intended to limit in any way the scope of the invention as presented in the claims.

Example 1

Preparatory example

All reactions involving air-sensitive reagents or intermediates were carried out in a nitrogen atmosphere and in anhydrous solvents.

1,4-Diaza-bicyclo [3.2.2] nonan-3-one (Intermediate)

32.33 g (200 mmol) of 3-quinuclidinone hydrochloride was dissolved in 75 ml of water and added to a solution of hydroxylamine hydrochloride (16.4 g; 236 mmol) and CH ₃ CO ₂ Na · 3H ₂ O (80 g; 588 mmol). The mixture was stirred at 70 ° C. for 1 hour. Then NaCl (10 g) was dissolved in the mixture and cooled to 0 ° C. The separated crystals were filtered off and carefully dried. The 3-quinuclidinone oxime thus obtained (approximately 30 g) was used in the next synthesis step without further purification.

Polyphosphoric acid (180 g) was heated to 100 ° C. and crude 3-quinuclidinone oxime (30 g) was added portionwise. The reaction mixture was heated at 130 ° C for 20 minutes. The mixture was cooled to room temperature and 50 ml of water was added. The mass was carefully homogenized, the mixture was poured onto ice (100 g). The mixture was made basic (pH 12) by adding sodium hydroxide. The mixture was extracted with chloroform (2 × 400 ml). The extract was dried over sodium sulfate, and the solvent was removed under reduced pressure.

The yield of the product mixture of 1,4-diaz-bicyclo [3.2.2] nonan-3-one and 1,3-diaz-bicyclo [3.2.2] nonan-4-one was 19.02 g (68%). A mixture of isomers was crystallized from 80 ml of dioxane to give 1,4-diaza-bicyclo [3.2.2] nonan-3-one (5.12 g; 18%). The solvent from the filtrate was distilled off, flash chromatography (using acetone) of the residue gave 1,3-diaza-bicyclo [3.2.2] nonan-4-one (8.91 g; 32%).

1.4-Diaza-bicyclo [3.2.2] nonane [J. Med. Chem. 1993, 36, 2311-23201 (Intermediate)

1,4-Diaza-bicyclo [3.2.2] nonan-3-one (5.12 g; 36 mmol) was dissolved in tetrahydrofuran (50 ml), lithium aluminum hydride (2.28 g; 60 mmol) and the reaction were added to the solution the mixture was refluxed for 36 hours. After the reaction mixture was cooled to room temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent from the filtrate was removed using a rotary evaporator under reduced pressure. The resulting substance was subjected to distillation using Kugelrora (Kugelrohr) (0.5 mbar (50 PA); 70 ° C). The yield of the title compound was 3.11 g (68%).

Method A

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] -Phenyl} -3- (2-aminophenyl) -urea, free base (Compound A1)

Mixture of 1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-nitrophenyl) urea (0 , 63 g; 1.32 mmol), palladium on charcoal (0.60 g; 5%) and ethanol (50 ml) were stirred in a hydrogen atmosphere. The crude mixture was filtered and purified by silica gel chromatography using a mixture of dichloromethane / methanol (9: 1) and 1% methanol as eluent. Yield 0.50 g (85%). Mp 174 ° C.

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone, fumaric acid salt (Intermediate)

The title compound was prepared according to Method A from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-nitrophenyl) furan-2-yl-methanone. Mp 227.8 ° C.

4-amino-N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] -

phenyl} benzamide free base (Compound A2)

The title compound was prepared according to Method A from N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -4-nitro -benzamide. Mp 151 ° C.

3-amino-N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] -

phenyl} benzamide free base (Compound A3)

The title compound was prepared according to Method A from N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-nitro -benzamide. Mp 249-252 ° C.

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) -5- (4-nitrophenyl) furan-2-yl-methanone, hydrochloric acid salt (Intermediate)

A mixture of 5- (4-nitrophenyl) -2-furoyl chloride (1.0 g; 4.0 mmol), 1,4-diaza-bicyclo [3.2.2] nonane (0.50 g; 4.0 mmol) and 1 , 2-dimethoxyethane (20 ml) was stirred for 15 hours at room temperature. The title compound was filtered. Yield 1.4 g (93%). Mp 298.2 ° C.

5- (4-Nitrophenyl) -2-furoyl chloride (Intermediate)

Prepared by stirring a mixture of 5- (4-nitrophenyl) -2-furoic acid (1.0 g; 4.3 mmol) and thionyl chloride (10 ml) at reflux for 2 hours. The mixture was evaporated and co-evaporated with anhydrous toluene. The acid chloride was used without further purification.

Method B

5-Hydroxy-1- {4- [5- (1-hydroxy-1,4-diaza-bicyclo [3.2.2] nonane-4-carbonyl) -

furan-2-yl] phenyl} -1,5-dihydro-pyrrol-2-one (N-oxide) (Compound B1)

A mixture of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone (0.50 g; 1.6 mmol), maleic anhydride acids (0.24 g; 2.4 mmol) and dichloromethane (10 ml) were stirred for 4 hours at room temperature. The mixture was filtered, and the filter residue was dried to obtain the title compound as a solid. Yield 0.48 g (73%). Mp 191 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-acetylaminophenyl) urea, fumaric salt acids (Compound B2)

Mixture of 1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -3- (2-aminophenyl) urea (0 , 21 g; 0.47 mmol), acetic anhydride (144 mg; 1.42 mmol) and dichloromethane (20 ml) were stirred for 4 hours. Aqueous sodium hydroxide (10 ml; 1M) was added, then extracted with dichloromethane (3 × 10 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane / methanol (9: 1) and 1% methanol as eluent. Yield 174 mg (79%). The corresponding salt was obtained by adding a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Mp 159-169 ° C.

Method C

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-phenyl-urea, free base (Compound C1)

A mixture of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone (0.50 g; 1.6 mmol), phenyl- isocyanate (498 mg; 4.18 mmol) and dichloromethane (50 ml) was stirred for 15 hours. Aqueous sodium hydroxide (10 ml; 1M) was added, then extracted with dichloromethane (3 × 10 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane / methanol (9: 1) and 1% methanol as eluent. Yield 0.16 g (23%). Mp 153-164 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-nitrophenyl) urea, fumaric salt acids (Compound C2)

The title compound was prepared according to Method C from 2-nitrophenyl isocyanate. Mp 198-202 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-ethyl-urea, fumaric acid salt (Compound C3 )

The title compound was prepared according to Method C from ethyl isocyanate. Mp 167-171 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-phenylthiourea, free base (Compound C4)

The title compound was prepared according to Method C from phenylisothiocyanate. Mp 171.4-174.7 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (5-chloro-2-methoxyphenyl) - urea, free base (Compound C5)

The title compound was prepared according to Method C from 5-chloro-2-methoxyphenyl isocyanate. Isolated as an oil.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-benzyl-urea, free base (Compound C6)

The title compound was prepared according to Method C from benzyl isocyanate. Isolated as an oil.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] -Phenyl} -1'-benzylaminocarbonyl-3-benzyl-urea, free base (Compound C7)

The title compound was prepared according to Method C from benzyl isothiocyanate. Mp 105-130 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-chlorophenyl) urea, free base (Compound C8)

The title compound was prepared according to Method C from 2-chlorophenyl isocyanate. Mp 200-211 ° C (decomp.).

1- {3- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -3-phenyl-urea, free base (Compound C9)

The title compound was prepared according to Method C from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-aminophenyl) furan-2-yl-methanone and phenylisocyanate. Mp 125-130 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-fluorophenyl) urea, free base (Compound C10)

The title compound was prepared according to Method C from 2-fluorophenyl isocyanate. Mp 241 ° C (decomp.).

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (3-fluorophenyl) urea, free base (Compound C11)

The title compound was prepared according to Method C from 3-fluorophenyl isocyanate. Mp 230 ° C.

1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-trifluoromethylphenyl) urea, free base (Compound C12)

The title compound was prepared according to Method C from 2-trifluoromethylphenyl isocyanate. Mp 253 ° C (decomp.).

1- [2- (3- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] -

phenyl} -ureido) phenyl] -3-ethyl-urea, fumaric acid salt (Compound C13)

The title compound was prepared according to Method C from 1- (2-amino-phenyl) -3- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2 -yl] -phenyl} -urea and ethyl isocyanate. Mp 162.5-165.5 ° C.

1- {4- [5- {1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (3-trifluoromethylphenyl) urea, free base (Compound C14)

The title compound was prepared according to Method C from 3-trifluoromethylphenyl isocyanate. Mp 171 ° C.

1- {3- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-ethyl-urea, fumaric acid salt (Compound C15 )

The title compound was prepared according to Method C from ethyl isocyanate. Mp 158-161 ° C.

N- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -

isonicotinamide, fumaric acid salt (Compound C16)

The title compound was prepared according to Method C from [5- (4-amino-phenyl) -furan-2-yl] - (1,4-diaza-bicyclo [3.2.2] non-4-yl) methanone. Mp 250-253.5 ° C.

Method D

N- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide, free base (Compound D1)

To a mixture of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone (0.50 g; 1.6 mmol), diisopropylamine (415 mg; 3.2 mmol) and dichloromethane (100 ml) at 0 ° C, benzoyl chloride (0.586 g; 4.18 mmol) was added and stirred for 15 h at room temperature. Aqueous sodium hydroxide (10 ml; 1M) was added, then extracted with dichloromethane (3 × 10 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane / methanol (9: 1) and 1% methanol as eluent. Yield 0.50 g (75%). Mp 254 ° C.

N- {3- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide, fumaric acid salt (Compound D2)

The title compound was prepared according to Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-aminophenyl) furan-2-yl-methanone. Mp 201-204 ° C.

N- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -2-nitro-benzamide, hydrochloric acid salt (Compound D3 )

The title compound was prepared according to Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone. Mp 283 ° C.

N- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -4-nitro-benzamide, hydrochloric acid salt (Compound D4 )

The title compound was prepared according to Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone. Mp 195-210 ° C.

N- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -3-nitro-benzamide, hydrochloric acid salt (Compound D5 )

The title compound was prepared according to Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone. Mp more than 300 ° C.

Method E

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) - [5- (4-pyrrol-1-yl-phenyl) -furan-2-yl] -methanone, fumaric acid salt (Compound E1 )

A mixture of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone (0.50 g; 1.6 mmol), 2, 5-dimethoxytetrahydrofuran (4.24 g; 64 mmol), acetic acid (0.5 ml) and dioxane (30 ml) were stirred at reflux for 20 hours. Aqueous sodium hydroxide (10 ml; 1M) was added, then extracted with dichloromethane (3 × 10 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane / methanol (9: 1) and 1% methanol as eluent. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Yield 0.33 g (43%). Mp 222 ° C.

Method F

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) - {5- [4- (3-nitro-pyridin-2-ylamino) -

phenyl] furan-2-yl} methanone, fumaric acid salt (Compound F1)

A mixture of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone (0.50 g; 1.6 mmol), 2- chlorine-3-nitropyridine (0.25 g; 1.6 mmol), cesium carbonate (0.78 g; 2.41 mmol) and NMP (N-methyl-2-pyrrolidone) (0.5 ml) were stirred at 80 ° C for 3 days. Aqueous sodium hydroxide (10 ml; 1M) was added, then extracted with dichloromethane (3 × 10 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane / methanol (9: 1) and 1% methanol as eluent. Yield 110 mg (16%). The corresponding salt was obtained by adding a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Mp 223 ° C.

Example 2

Inhibition of In Vitro ³ H-α-Bungarotoxin Binding in Rat Brain

In this Example, the affinity of the compounds of this invention for binding to the α ₇ subtype of nicotinic receptors was determined.

α-Bungarotoxin is a peptide isolated from snake venom Elapidae Bungarus multicinctus. It has high affinity for neuronal and neuromuscular nicotinic receptors, where it acts as a strong antagonist. ³ H-α-Bungarotoxin attaches to nicotinic acetylcholine receptors formed by the α ₇ subunit isoform found in the brain and the α ₁ isoform found in the neuromuscular synapse.

Tissue preparations

The preparations were prepared at 0-4 ° C. The cerebral cortex of male Wistar rats (150-250 g) was homogenized for 10 seconds in 15 ml of 20 mM Nerez buffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO ₄ and 2.5 mM CaCl ₂ (pH 7.5) using an Ultra-Turrax homogenizer. The tissue suspension was centrifuged at 27,000 × g for 10 minutes. The supernatant was discarded and the pellet was washed twice, centrifuged at 27,000 × g for 10 minutes in 20 ml of fresh buffer, and then the final pellet was resuspended in fresh buffer containing 0.01% BSA (35 ml per g of original tissue) and used for analysis binding.

Analysis

Aliquots of 500 μl of the homogenate were added to 25 μl of the test solution and 25 μl of ³ H-α-bungarotoxin (final concentration 2 nM), mixed and incubated for 2 hours at 37 ° C. Nonspecific binding was determined using (-) - nicotine (final concentration 1 mM). After incubation, 5 ml of ice-cold Hepes buffer containing 0.05% PEI (polyethyleneimine) was added to the samples and applied directly to GF / C glass fiber filters (Whatman) (pre-soaked in 0.1% PEI for at least 5 hours) with suction and immediately washed with 2 × 5 ml of ice-cold buffer.

The amount of radioactivity on the filters was determined using a traditional liquid scintillation counter. Specific binding is total binding minus non-specific binding.

The test value is given as IC ₅₀ (concentration of a test substance that inhibits specific binding of ³ H-α-bungarotoxin by 50%).

The results of these experiments are presented below in Table 1.

Table 1
Inhibition of ³ H-α-Bungarotoxin Binding Compound No. IC ₅₀ (μm) A1 0.0012 A2 0.12 A3 0,076 IN 1 0.30 IN 2 0.0016 C1 0.0015 C2 0.0017 C3 0,00056 C4 0.0068 D1 0.15 D2 0,061 D3 0,038 D4 0,090

Example 3

Pharmaceutical composition

The chemical compound of the invention may be presented in any desired form of composition and may be dosed in any desired amount. This example shows the preparation of a composition in the form of a standard tablet. The active pharmaceutical ingredient (API), Compound A1, i.e. 1- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-aminophenyl) urea from Example 1 .

Standard tablet composition

Tablets containing 1.585 mg of API per tablet are prepared using the following composition:

Ingredient Function Mg / tablet API Active ingredient 1,585 Microcrystalline Filler / Binder 38,045

cellulose granulate substance Microcrystalline cellulose Filler / Binder 1,955 Lactose Filler 56,715 Crosscarmelose Sodium Baking powder 0,500 Colloidal silicon dioxide Flow rate improvement 0,200 Magnesium stearate Lubricant 1,000 Total tablet weight 100.0

The active ingredient is dissolved in a granulation solvent, which consists of methyl cellulose and water, and then used to granulate microcrystalline cellulose. The resulting granulate is allowed to dry on a tray. The dried granulate containing the active pharmaceutical ingredient, lactose and sodium crosscarmellose are weighed, sieved into a mixer and mixed. Magnesium stearate is weighed and sieved into a mixer with the above mixture and mixed. The resulting mixture is compressed into tablets.

Scheme 1

Preparation of Compound A1

Scheme 2

Preparation of Compound A2

Scheme 3

Preparation of Compound A3

Claims (16)

1. Diazabicyclic aryl derivative represented by formula I

its N-oxide or a pharmaceutically acceptable addition salt,
where n is 2;
A 'represents a furanyl group;
A "represents a phenyl group;
Is a
pyrrolyl or dihydropyrrolyl, optionally substituted with one or two hydroxy and / or oxo; or
a group of the formula -NR'-B ', -NR' - (C = V) -B 'or -NR' - (C = V) -NR "'- B',
where R 'represents hydrogen or a group of the formula - (C = V) -NR''-B',
R ″ represents hydrogen,
V represents O or S and
B 'represents C _1-6 alkyl, phenyl, benzyl or pyridinyl, wherein phenyl, benzyl and pyridinyl are optionally substituted with one or two substituents selected from the group consisting of C _1-6 alkoxy, halo, trihalomethyl, nitro, amino, C _1-6 -alkyl-carbonyl-amino and NC _1-6 -alkyl-amino-carbonyl-amino
(NC _1-6 -alkyl-ureido); and
L is a single (covalent) bond. 2. The diazabicyclic aryl derivative according to claim 1, wherein A ′ is furan-2,5-diyl. 3. The diazabicyclic aryl derivative according to claim 1, wherein A ″ is a phen-1,3-diyl or phen-1,4-diyl group. 4. The diazabicyclic aryl derivative according to claim 1, which is
5-hydroxy-1- {4- [5- (1-hydroxy-1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -1.5- dihydro-pyrrole-2-one or
(1,4-diaza-bicyclo [3.2.2] non-4-yl) - [5- (4-pyrrol-1-yl-phenyl) -furan-2-yl] -methanone,
or a pharmaceutically acceptable addition salt thereof. 5. The diazabicyclic aryl derivative according to claim 1, represented by formula II

or a pharmaceutically acceptable addition salt thereof, wherein n, A ′, A ″, L, R ′, and B ′ are as defined in claim 1. 6. The diazabicyclic aryl derivative according to claim 5, wherein B ′ is pyridinyl, optionally substituted nitro. 7. The diazabicyclic aryl derivative according to claim 5, wherein B ′ is pyridin-2-yl, optionally substituted nitro. 8. The diazabicyclic aryl derivative according to claim 7, which is (1,4-diaza-bicyclo [3.2.2] non-4-yl) - {5- [4- (3-nitro-pyridin-2-ylamino) - phenyl] furan-2-yl} methanone or a pharmaceutically acceptable addition salt thereof. 9. The diazabicyclic aryl derivative according to claim 1, represented by formula III

or a pharmaceutically acceptable addition salt thereof, wherein n, A ′, A ″, L, R ′, V and B ′ are as defined in claim 1. 10. The diazabicyclic aryl derivative according to claim 9, where
V represents O and
B 'represents a C _1-6 alkyl, phenyl or pyridinyl group, wherein the phenyl and pyridinyl groups are optionally substituted with nitro or amino. 11. The diazabicyclic aryl derivative of claim 10, which is:
N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide;
N- {3- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide;
N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -2-nitro-benzamide;
N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -4-nitro-benzamide;
N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-nitro-benzamide;
4-amino-N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide;
3-amino-N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} benzamide; or
N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} isonicotinamide;
or a pharmaceutically acceptable addition salt thereof. 12. Diazabicyclic aryl derivative according to claim 1, represented by formula IV

or a pharmaceutically acceptable addition salt thereof, wherein n, A ′, A ″, L, R ′, R ″, V and B ′ are as defined in claim 1. 13. The diazabicyclic aryl derivative of claim 12, wherein B ′ is
C _1-6 alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with one or two substituents selected from the group consisting of C _1-6 alkoxy, halo, trifluoromethyl, nitro, amino, C _1-6 alkyl -carbonyl-amino; NC _1-6 -alkyl-amino-carbonyl-amino (NC _1-6 -alkyl-ureido). 14. The diazabicyclic aryl derivative according to item 13, which is:
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-ethyl-urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -3-phenyl-urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-nitrophenyl) urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-acetylaminophenyl) urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-aminophenyl) urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl) -3- (5-chloro-2-methoxy-phenyl ) urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3-benzyl-urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -1'-benzylaminocarbonyl-3-benzyl-urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-chlorophenyl) urea;
1- {3- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl) -3-phenyl-urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-fluorophenyl) urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (3-fluorophenyl) urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (2-trifluoromethylphenyl) urea;
1- [2- (3- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -ureido) phenyl] - 3-ethyl urea;
1- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -3- (3-trifluoromethylphenyl) urea; or
1- {3- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -3-ethyl-urea,
or a pharmaceutically acceptable addition salt thereof. 15. A pharmaceutical composition for modulating cholinergic receptors, comprising a therapeutically effective amount of a diazabicyclic aryl derivative according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. 16. The use of the diazabicyclic aryl derivative according to any one of claims 1 to 14, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition / medicament for treating, preventing or alleviating a disease or disorder or condition in a mammal, including a human being, which is anxiety, cognitive impairment, learning deficits, memory deficits or dysfunctions, Alzheimer's disease, attention deficit disorder, hyperactivity disorder and attention deficit disorder, Parkinson's disease, Gene disease ington, amyotrophic lateral sclerosis, Gilles de la Tourette’s disease, depression, manic syndrome, manic depression, schizophrenia, obsessive-compulsive disorder, panic disorder, eating disorder, anorexia nervosa, bulimia, obesity, narcolepsy, nociception, AIDS dementia dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, post-traumatic syndrome, social phobia, sleep disorder, pseudo-dementia, Ganser syndrome, premenstrual syndrome m, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania or biorhythm disturbance associated with a change in time zones.