Diazabicyclic aryl derivatives as ligands of nicotinic acetylcholine receptors

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

 

This invention relates to new disabilitiesin aryl derivatives, which, as found, are cholinergic ligands for nicotinic acetylcholine receptors and modulators monoamine receptors and transporters. Due to their pharmacological profile the compounds according to the invention can be useful for the treatment of various diseases or disorders as diseases or disorders related to the cholinergic system of the Central nervous system (CNS), peripheral nervous system (PNS)diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

PRIOR art

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

Since firmly established that muscarinic acetylcholine receptors quantitatively exceed nicotinic acetylcholine receptors in brain areas important is x for memory and cognitive abilities, many studies focused on the development of agents for the treatment of disorders associated with memory, focused on the synthesis of modulators of muscarinic acetylcholine receptors.

Not so long ago, however, he developed an interest in the development of nAChR-modulators. Some diseases associated with degeneration of the cholinergic system, i.e. senile dementia type, vascular dementia and cognitive failure due to organic lesions of the brain directly related to alcoholism.

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

The INVENTION

According to the present invention proposed new modulators of nicotinic and/or monoamine receptor useful for the treatment of diseases or disorders associated with cholinergic receptors and, in particular, with the nicotinic acetylcholine receptor (nAChR), serotonin receptor (5-HTR), dopamine receptor (DAR) and norepinephrine receptor (NER), and biogenic aminovymi conveyors serotonin (5-HT), dopamine (DA) and norepinephrine (NE).

Due to their pharmacological profile the compounds according to izopet the tion can be useful for the treatment of various diseases or disorders, as diseases or disorders related to the cholinergic system of the Central nervous system (CNS), peripheral nervous system (PNS)diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Compounds according to the invention can also be useful as diagnostic tools or the monitoring agents in various diagnostic methods, and in particular, to visualize in vivo receptor (neuroimaging), and they can be used in labeled or unlabeled form.

In the first aspect according to the invention proposed disabilitiesa aryl derivative of the formula I

their N-oxides or pharmaceutically acceptable salt of accession, where

n = 2;

A' represents fornillo group;

A" represents a phenyl group;

Represents a

pyrrolyl or dihydropyrrole, possibly substituted by 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" is predstavljaet a hydrogen

V represents O or S, and

In' represents a C1-6-alkyl, phenyl, benzyl, or pyridinyl, and phenyl, benzyl and pyridinyl possibly substituted by one or two substituents selected from the group consisting of C1-6-alkoxy, halogeno, trihalomethyl, nitro, amino, C1-6-alkyl-carbonyl-amino and N-C1-6-alkyl-amino-carbonyl-amino (N-C1-6-alkyl-ureido); and

L represents a single (covalent) bond.

In the second aspect according to the invention proposed pharmaceutical composition for modulation of cholinergic receptors containing a therapeutically effective amount diazabicyclo aryl derivative of the invention or its pharmaceutically acceptable salts joining together with at least one pharmaceutically acceptable carrier or diluent.

According to another aspect of the invention relates to the use of diazabicyclo aryl derivative of the invention or its pharmaceutically acceptable salt accession to the manufacture of pharmaceutical compositions/medicaments for the treatment, prevention or relief of a disease or disorder, or condition in a mammal, including man, which is an anxiety, a cognitive disorder, learning deficit, deficits or dysfunction of memory, the disease is of lzgamer, attention deficit, hyperactivity and attention deficit, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, disease, Gilles de La Tourette's, depression, manic syndrome, manic depression, schizophrenia, obsessive - compulsive disorder, panic disorder, eating disorder, nervous anorexia, bulimia, obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, late dyskinesia, hyperkinesia, epilepsy, post-traumatic syndrome, social phobia, sleep disorder, pseudodementia syndrome Ganzera, pre-menstrual syndrome, late luteal phase, chronic fatigue syndrome, mutism, trichotillomania or disruption of biological rhythms associated with the change of time zones.

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

DETAILED description of the INVENTION

Disabilitiesa aryl derivatives

In the first aspect according to the present invention proposed Disabilitiesa aryl derivative of the formula I

their N-oxides or pharmaceutically acceptable salt of accession, where

n = 2;

A' represents fornillo group;

A" is an F. niloy group;

Represents a

pyrrolyl or dihydropyrrole, possibly substituted by 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

In' represents a C1-6-alkyl, phenyl, benzyl, or pyridinyl, and phenyl, benzyl and pyridinyl possibly substituted by one or two substituents selected from the group consisting of C1-6-alkoxy, halogeno, trihalomethyl, nitro, amino, C1-6-alkyl-carbonyl-amino and N-C1-6-alkyl-amino-carbonyl-amino (N-C1-6-alkyl-ureido); and

L represents a single (covalent) bond.

In the preferred embodiment diazabicyclo aryl derivative is a compound of formula I, where A' represents furan-2,5-diyl.

In the preferred embodiment diazabicyclo aryl derivative is a compound of formula I, And represents the dryer-1,3-dialnow or Hairdryer-1,4-dialnow group.

In the preferred embodiment diazabicyclo 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-he; or

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

or its pharmaceutically acceptable salt of the merger.

In another embodiment diazabicyclo aryl derivative is a compound of formula II

or its pharmaceutically acceptable salt accession, where n, A', A", L, R' and' such as defined above.

In a more preferred embodiment of the In' represents pyridinyl, possibly substituted nitro.

In another preferred embodiment of the In' is a pyridine-2-yl, possibly substituted nitro.

In the preferred embodiment diazabicyclo aryl derivative of the invention is:

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

or its pharmaceutically acceptable salt of the merger.

In yet another embodiment diazabicyclo aryl derivative is a compound of formula III

or its pharmaceutically acceptable salt accession, where n, A', A", L, R', V' such as defined above.

In a more preferred V represents O; and a' represents a C1-6-alkyl, phenyl or pyridinyl group, with the phenyl and pyridinoline group possibly substituted by nitro or amino.

In the preferred embodiment diazabicyclo aryl PR is izvozna according to the invention represents:

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 its pharmaceutically acceptable salt of the merger.

In yet another embodiment diazabicyclo aryl derivative is a compound of formula IV

or its pharmaceutically acceptable salt accession, where n, A', A", L, R', R", V and' such as defined above.

In a more preferred embodiment of the In' represents a C1-6-alkyl phenyl or benzyl, and phenyl and benzyl groups possibly substituted by one or two substituents selected from the group consisting of C1-6-alkoxy, halogeno, trifloromethyl, nitro, amino, C1-6-alkyl-carbonyl-amino, N-C1-6-alkyl-amino-carbonyl-amino (N-C1-6-alkyl-ureido).

In the preferred embodiment diazabicyclo 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-acetylaminophenol)-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-forfinal)-urea;

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

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

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

or its pharmaceutically acceptable salt of the merger.

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

The definition of the substituents

In the context of this invention alkyl group means a monovalent saturated straight or branched hydrocarbon chain. This hydrocarbon chain preferably contains from one to eighteen carbon atoms (C1-18-alkyl), more preferably from one to six carbon atoms

(C1-6-alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary of pentyl, hexyl and isohexyl. In the preferred embodiment the alkyl represents a C1-4is an alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of this invention the alkyl represents a C1-3-alkyl group, which may, in particular, represent methyl, ethyl, propyl or isopropyl.

In the context of this invention, the alkoxy group means a group "alkyl-O -, where alkyl such as defined above. Examples of preferred the alkoxy groups of the invention include methoxy, ethoxy.

In the context of this invention, halogen is a fluorescent, chloro, bromo or iodo, and halogenoalkane group means an alkyl group that is defined in this description of the invention, and this alkyl group substituted by one or more groups of halogeno. Thus, trihalomethyl group represents, for example triptorelin group, trichlorethylene group and similar trihalogen-substituted methyl group. Preferred halogenoalkane group according to the invention include trihalomethyl, preferably-CF3.

Pharmaceutically acceptable salt

Diazabicyclo 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 chemical compounds according to the invention.

Examples of pharmaceutically acceptable salts of joining include salts of joining non-toxic inorganic and organic acids, such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconet, ascorbate, bansilalpet, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, with ccinet, tartrate, toluene-para-sulfonate and the like, but do not stop there. Such salts can be formed by methods well known and described in the field.

Metal salts chemical compounds according to the invention include alkali metal salts such as sodium salt chemical compounds according to the invention containing a carboxy group.

In the context of this invention "-onieva salt" N-containing compounds can also be considered as pharmaceutically acceptable salts. Preferred "-onieva salts include alkyl-onieva salt, cycloalkyl-onieva salt and cycloalkenyl-onieva salt. Especially preferred is onevia salt according to the invention include salts formed at the position N' according to the following formula I'

Spatial isomers

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

The racemic forms can be separated into the optical antipodes by known methods and techniques. One method of separation of the diastereomeric salts using an optically active acid and liberation of the optically active amino compounds in d is the query result processing base. Another method of separation of racemates on the optical antipodes is based on the use of chromatography on optically active matrix. Thus, racemic compounds of the present invention can be separated into their optical antipodes, for example, by fractional crystallization, for example, d - or l-salts (tartratami, mandelate or camphorsulfonate).

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

Additional methods of separation of optical isomers are known in this field. Such methods include the methods described Jaques J, Collet And & Wilen S "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 of obtaining disabilitiesa aryl derivatives

Diazabicyclo the aryl derivative of the invention can be obtained by conventional methods of chemical synthesis, for example the methods described in the working examples. Starting materials for the methods described in this application are known or can be obtained by conventional methods from commercially available chemicals.

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

The final products of the reactions described in this description of the invention, it is possible to allocate conventional methods such as extraction, crystallization, distillation, chromatography and so on.

Biological activity

According to the present invention proposed new ligands and modulators of nicotinic receptors, and the data of the ligands and modulators are useful for treating diseases or disorders associated with cholinergic receptors and, in particular, with the nicotinic acetylcholine receptor (nACDR). Preferred compounds according to the invention show a pronounced selectivity for nicotinic acetylcholine receptor α7-subtype.

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

Due to their pharmacological profile the compounds according to the invention can be the ü useful for the treatment of various diseases or disorders, as diseases or disorders related to the cholinergic system of the Central nervous system (CNS), peripheral nervous system (PNS)diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Compounds according to the invention can also be useful as diagnostic tools or the monitoring agents in various diagnostic methods, and in particular, to visualize in vivo receptor (neuroimaging), and they can be used in labeled or unlabeled form.

In the preferred embodiment of the compounds according to the invention is used for the treatment of diseases, disorders or conditions related to the Central nervous system. Such diseases or disorders include anxiety, cognitive disorder, learning deficit, deficits or dysfunction of memory, Alzheimer's disease, attention deficit, hyperactivity and attention deficit, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, disease, Gilles de La Tourette's, depression, manic syndrome, manic depression, Shi is ofreneo, obsessive-compulsive disorder, panic disorder, eating disorder, nervous anorexia, bulimia, obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, late dyskinesia, hyperkinesia, epilepsy, post-traumatic syndrome, social phobia, sleep disorder, pseudodementia syndrome Ganzera, pre-menstrual syndrome, late luteal phase, chronic fatigue syndrome, mutism, trichotillomania or disruption of biological rhythms associated with the change of time zones.

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

Preferably, the compounds according to the invention can be useful for the treatment of diseases, disorders or conditions associated with smooth muscle contraction, including convulsive disorders, angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, late dyskinesia, hyperkinesia, premature ejaculation, erection problems.

Compounds according to the invention can be useful for the treatment of endocrine disorders such as hyperthyroidism, pheochromocytoma, hypertension, and arrhythmias.

Connect the ia according to the invention may be useful for treatment of neurodegenerative disorders including temporary anoxia and induced neurodegeneration.

Compounds according to the invention can be useful for 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 diarrhoea.

Compounds according to the invention can be useful for the treatment of mild, moderate or even severe pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, and phantom pain. The pain may be, in particular, neuropathic pain, chronic headache, Central pain, pain related to diabetic neuropathy, neuralgia after therapeutic treatment or damage to peripheral nerves.

Finally, the compounds according to the invention can be useful for the treatment of withdrawal symptoms caused by termination of use of addictive substances. Such addictive substances include nikotinsoderzhaschie products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and benzodiazepine-like drugs and alcohol. In the General case, the refusal of addictive substances is a traumatic experience, characterized by anxiety and frustration, wrath is om, anxiety, difficulty in concentrating, excited state, reduced heart rate and increased appetite and weight gain.

In this context, "treatment" encompasses the treatment, prevention, prevention and relief of withdrawal symptoms and abstinence, and treatment, leading to a voluntary reduction of reception of the calling addictive substances.

Compounds according to the invention can be used as diagnostic agents, for example for identification and localization of nicotinic receptors in various tissues.

The pharmaceutical composition

In another aspect according to the invention proposed new pharmaceutical compositions for the modulation of cholinergic receptors containing a therapeutically effective amount diazabicyclo aryl derivative of the invention or its pharmaceutically acceptable salts joining together with at least one pharmaceutically acceptable carrier or diluent.

Despite the fact that a chemical compound according to the invention for use in therapy can be introduced in the form of the raw chemical compound, it is preferable to introduce the active ingredient, possibly in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, wear the firs, buffers, diluents and/or other commercially available pharmaceutical auxiliary substances.

Thus, the proposed pharmaceutical compositions containing diazabicyclo aryl derivative of the invention, or its pharmaceutically acceptable salt or a derivative thereof together with one or more pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic ingredients, known and used in the field. The carrier(s) must be "acceptable" in the sense of compatibility with other ingredients of the drug and harmless to its recipient.

The pharmaceutical composition according to the invention can be entered in any convenient way, suitable for the desired therapy. Preferred routes of administration include oral administration, in particular in the form of tablets, capsules, pills, powder or liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular or intravenous injection. The pharmaceutical composition according to the invention can be manufactured by a specialist by using standard methods and traditional techniques appropriate to the desired preparation. At desire it is possible to apply the composition, adapted for long-term release of the active ingredient.

Additional details of procedures in which otopleniya drugs and introduction can be found in the latest edition Remington''s Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

The actual dosage depends on the nature and severity of the disease, which is treatable and is the responsibility of the physician, and may be changed by determining dosages for specific cases according to this invention in order to obtain the desired therapeutic effect. However, currently it is assumed that suitable for therapeutic treatments are pharmaceutical compositions containing from about 0.1 to about 500 mg of the active ingredient on the individual dose, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg.

The active ingredient can be entered in one or more doses per day. In some cases, satisfactory results can be obtained at a dosage lower than 0.1 μg/kg I.V. and 1 mcg/kg orally. The upper limit of the range of dosing at the present time is equal to approximately 10 μg/kg I.V. and 100 mg/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.

Methods of treatment

Disabilitiesa aryl derivatives of the present invention are valuable modulators of nicotinic and Manoa inovah receptor and therefore are useful for the treatment of several ailments, including cholinergic dysfunction as well as a number of disorders sensitive to the action of nAChR-modulators.

In the context of this invention the term "treatment" includes treatment, prevention, prevention or relief, and the term "disease" includes diseases, diseases, disorders and conditions associated with this disease.

Preferred considering the indications are indications listed above.

Currently, it is assumed that appropriate dosing ranges are from 0.1 to 1000 milligrams per day, 10-500 milligrams daily, and especially 30-100 milligrams per day depending, as usual, the exact method of administration, form in which administered, the indication that directed this introduction involved subject and body mass of the affected entity, and further the preference and experience of the attending physician or veterinarian.

In some cases, satisfactory results can be obtained at a dosage lower than 0.005 mcg/kg intravenously and 0.01 µg/kg orally. The upper limit of the range of dosing at the present time is about 10 μg/kg I.V. and 100 mg/kg orally. Preferred ranges are from about 0.001 to about 1 mg/kg intravenously and from about 0.1 to about 10 mg/kg orally.

WHEN THE CAREER

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

Example 1

Preparatory example

All reactions involving sensitive to air reagents or intermediates were performed under nitrogen atmosphere and anhydrous solvents.

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

32,33 g (200 mmol) of 3-binucleation hydrochloride was dissolved in 75 ml of water and added to a solution of hydroxylamine hydrochloride (16.4 g; 236 mmol) and CH3CO2Na·3H2O (80 g, 588 mmol). The mixture was stirred at 70°C for 1 hour. Then, NaCl (10 g) was dissolved in a mixture and cooled to 0°C. the Separated crystals were filtered off and carefully dried. The resulting oxime 3-binucleation (approximately 30 g) was used in the next stage of the synthesis without further purification.

Polyphosphoric acid (180 g) was heated to 100°C and portions were added to the crude oxime 3-binucleation (30 g). The reaction mixture was heated at 130°C for 20 minutes. The mixture was cooled to room temperature and was added 50 ml of water. Mass gently homogenized, the mixture is poured into ice (100 g). The mixture was podlachian (pH 12)by adding sodium hydroxide. The mixture was extracted with chloroform, the m (2×400 ml). The extract was dried over sodium sulfate, and the solvent was removed under reduced pressure.

Yield a mixture of products of 1,4-diaza-bicyclo[3.2.2]nonan-3-one and 1,3-diaza-bicyclo[3.2.2]nonan-4-it was 19,02 g (68%). The mixture of isomers was led from 80 ml of dioxane, getting 1,4-diaza-bicyclo[3.2.2]nonan-3-one (5,12 g; 18%). The solvent from the filtrate drove, 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]nonan [J. Med. Chem. 1993, 36, 2311-23201 (Intermediate compound)

1,4-diaza-bicyclo[3.2.2]nonan-3-one (5,12 g; 36 mmol) was dissolved in tetrahydrofuran (50 ml), the solution was added alumoweld lithium (2.28 g; 60 mmol) and the reaction mixture is boiled under reflux for 36 hours. After cooling the reaction mixture to room temperature, was added dropwise water (2.3 ml) and the mixture was filtered. The solvent of the filtrate was removed with a rotary evaporator under reduced pressure. The resulting substance was subjected to distillation using Cuellar (Kugelrohr) (0.5 mbar (50 PA); 70°C). The output specified in the title compound was 3.11 g (68%).

Method And

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)

A 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 is; of 1.32 mmol), palladium on coal (0,60 g; 5%) and ethanol (50 ml) was stirred in hydrogen atmosphere. The crude mixture was filtered and purified by chromatography on silica gel using a mixture of dichloromethane/methanol (9:1) and 1% of methanol as eluent. Yield 0.50 g (85%). TPL 174°C.

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanon, salt fumaric acid (Intermediate compound)

Specified in the title compound was obtained according to Method a from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanone. TPL 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)

Specified in the title compound was obtained according to Method a of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-4-nitro-benzamide. TPL 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)

Specified in the title compound was obtained according to Method a of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-3-nitro-benzamide. TPL 249-252°C.

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanon, salt of hydrochloric acid (Intermediate compound)

A mixture of 5-(4-nitrophenyl)-2-frailcare (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) paramesh the Wali for 15 hours at room temperature. Specified in the title compound was filtered. Yield 1.4 g (93%). TPL 298,2°C.

5-(4-Nitrophenyl)-2-frailcare (Intermediate compound)

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

Method In

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-it (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 (0.24 g; 2.4 mmol) and dichloromethane (10 ml) was stirred for 4 hours at room temperature. The mixture was filtered, and the filter residue was dried to obtain specified in the title compound in the form of solids. The yield of 0.48 g (73%). TPL 191°C.

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

A 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; of 1.42 mmol) and dichloromethane (20 ml) was stirred for 4 hours. Was added aqueous sodium hydroxide (10 ml, 1M), then was extracted with dihl what Rotana (3×10 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane/methanol (9:1) and 1% of 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. TPL 159-169°C.

Way

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. Was added aqueous sodium hydroxide (10 ml, 1M), then was extracted with dichloromethane (3×10 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane/methanol (9:1) and 1% of methanol as eluent. Yield 0.16 g (23%). TPL 153-164°C.

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

Specified in the title compound was obtained according to the Method of 2-nitrophenylacetate. TPL 198-202°C.

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

Specified in the title compound was obtained according to the Method of utilizationof. TPL 167-171°C.

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

Specified in the title compound was obtained according to the Method of phenylisothiocyanate. TPL 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)

Specified in the title compound was obtained according to the Method of 5-chloro-2-methoxyphenylalanine. Allocated in the form of 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)

Specified in the title compound was obtained according to the Method of benzylisothiocyanate. Allocated in the form of 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)

Specified in the title compound was obtained according to the Method of benzylisothiocyanate. TPL 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)

Specified in the title compound was obtained according to the Method of 2-chlorophenylalanine. TPL 200-211°C (Razlog.).

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

Specified in the title compound was obtained according to the Method of (1,4-diaza-bicyclo[3.2.2]non-4-yl-5-(3-AMINOPHENYL)-furan-2-yl-methanone and phenylisocyanate. TPL 125-130°C.

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

Specified in the title compound was obtained according to the Method of 2-perteneciente. TPL 241°C (Razlog.).

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

Specified in the title compound was obtained according to the Method of the 3-perteneciente. TPL 230°C.

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

Specified in the title compound was obtained according to the Method of 2-triftormetilfullerenov. TPL 253°C (Razlog.).

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

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

Specified in the title compound was obtained according to the Method of 1-(2-amino-phenyl)-3-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-urea and utilizationof. TPL 162,5-165,5°C.

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

Specified in the title compound was obtained according to the Method of the 3-triftormetilfullerenov. TPL 171°C.

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

Specified in the title compound was obtained according to the Method of utilizationof. TPL 158-161°C.

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

isonicotinamide, salt fumaric acid (Compound C16)

Specified in the title compound was obtained according to the Method of [5-(4-amino-phenyl)-furan-2-yl]-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-methanone. TPL 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. was added benzoyl chloride (0,586 g; 4,18 mmol) and was stirred for 15 h at room temperature. Was added aqueous sodium hydroxide (10 ml, 1M), then was extracted with dichloromethane (3×10 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane/methanol (9:1) and 1% of methanol as eluent. Yield 0.50 g (75%). TPL 254°C.

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

Specified in the title compound was obtained according to Method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-AMINOPHENYL)-furan-2-yl-methanone. TPL 201-204°C.

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

Specified in the title compound was obtained according to Method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone. TPL 283°C.

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

Specified in the title compound was obtained according to Method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone. TPL 195-210°C.

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

Specified in the title compound was obtained according to Method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone. TPL 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]-methanon, salt fumaric acid (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) was stirred at the temperature of reflux distilled for 20 hours was Added aqueous sodium hydroxide (10 ml, 1M), then was extracted with dichloromethane (3×10 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane/methanol (9:1) and 1% of methanol as eluent. The corresponding salt was obtained by adding to the ect diethyl ether and methanol (9:1), saturated with fumaric acid. Yield 0.33 g (43%). TPL 222°C.

Method F

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

phenyl]-furan-2-yl}-methanon, salt fumaric acid (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-chloro-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) was stirred at 80°C for 3 days. Was added aqueous sodium hydroxide (10 ml, 1M), then was extracted with dichloromethane (3×10 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane/methanol (9:1) and 1% of 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. TPL 223°C.

Example 2

Inhibition of binding in vitro3H-α-bungarotoxin in the rat brain

In this Example determined the affinity of the compounds according to this invention in relation to binding with α7subtype of nicotinic receptors.

α-Bungarotoxin is a peptide selected from the Elapidae venom of the snake Bungarus multicinctus. It has a high affinity against neural and neuromuscular nicotinic receptors, where it acts as a strong antagonist.3H-α-Bungarotoxin attached to the nicotinic acetylcholine re is EPERM, educated α7-subunit isoform, found in the brain, and α1-isoform, found in the neuromuscular synapse.

Preparations of tissues

The drugs were prepared at 0-4°C. the cerebral Cortex of male Wistar rats (150-250 g) are homogenized for 10 seconds in 15 ml of 20 mm Nerez-buffer containing 118 mm NaCl, 4.8 mm KCl, 1.2 mm MgSO4and 2.5 mm CaCl2(pH 7.5)using a homogenizer (Ultra-Turrax. Suspension tissue was centrifuged at 27000×g for 10 minutes. The supernatant was discarded and the precipitate was washed twice centrifuger at 27000×g for 10 minutes in 20 ml of fresh buffer, and then the final precipitate resuspendable in fresh buffer containing 0.01% BSA (35 ml per g of original tissue)and used for analyses of the binding.

Analysis

Aliquots of 500 μl of homogenate was added to 25 μl of test solution and 25 μl of3H-α-bungarotoxin (final concentration 2 nm)were mixed and incubated for 2 hours at 37°C. Nonspecific binding was determined using (-)-nicotine (final concentration 1 mm). After incubation, the samples were added to 5 ml chilled on ice Hepes buffer containing 0.05% PEI (polyethylenimine), and was applied directly onto glass fiber filters GF/C (Whatman) (pre-soaked in 0.1% PEI for at least 5 hours) with suction and immediately washed with 2×5 ml chilled on l the size of the buffer.

The amount of radioactivity on the filters was determined using a traditional liquid scintillation counter. Specific binding represents the total binding minus nonspecific binding.

The test value is given as IC50(the concentration of test substance which inhibits the specific binding3H-α-bungarotoxin 50%).

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

Table 1
Ingibirovanie binding3H-α-bungarotoxin
Connection # IC50(µm)
A10,0012
A20,12
A30,076
B10,30
B20,0016
C10,0015
C20,0017
C30,00056
C40,0068
D1/td> 0,15
D20,061
D30,038
D40,090

Example 3

The pharmaceutical composition

Chemical compound according to the invention can be provided in any desired form of the composition and can be dosed in any desired quantity. This example shows a composition in the form of a standard tablet. Used active pharmaceutical ingredient (API), the Connection A1, i.e. the 1-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-3-(2-AMINOPHENYL)-urea from Example 1.

The composition of standard tablets

Tablets containing 1,585 mg API per tablet, is obtained using the following composition:

IngredientFunctionAmount mg/tablet
AFIThe active ingredient1,585
MicrocrystallineFiller/binding38,045

substance
Microcrystalline celluloseThe filler/binder1,955
LactoseFiller56,715
The sodium crosscarmeloseBaking powder0,500
Colloidal silicon dioxideImproving yield0,200
Magnesium stearateGrease1,000
Total weight pills100,0

The active ingredient is dissolved in a solvent for granulation, which consists of methyl cellulose and water, and then used for the granulation of microcrystalline cellulose. The obtained granulate is allowed to dry on the pallet. The dried granules containing an active pharmaceutical ingredient, lactose and sodium crosscarmelose weigh sift into a blender and mix. Magnesium stearate are weighed and sieved in the mixer above the mixture and mix. The resulting mixture is pressed into tablets.

Scheme 1

Getting Connection A1

Scheme 2

The Connection A2

Scheme 3

Getting Connection A3

1. Diazabicyclo aryl derivative represented by the formula I

its N-oxide or pharmaceutically acceptable salt accession,
where n is 2;
A' represents fornillo group;
A" represents a phenyl group;
Represents a
pyrrolyl or dihydropyrrole, possibly substituted by 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
In' represents a C1-6alkyl, phenyl, benzyl, or pyridinyl, and phenyl, benzyl and pyridinyl possibly substituted by one or two substituents selected from the group consisting of C1-6-alkoxy, halogeno, trihalomethyl, nitro, amino, C1-6-alkyl-carbonyl-amino and N-C1-6-alkyl-amino-carbonyl-amino
(N-C1-6-alkyl-ureido); and
L represents a single (covalent) bond.

2. Diazabicyclo aryl derivative according to claim 1, where a' represents the FSD is n-2,5-diyl.

3. Diazabicyclo aryl derivative according to claim 1, where a represents a Hairdryer-1,3-dialnow or Hairdryer-1,4-dialnow group.

4. Diazabicyclo aryl derivative according to claim 1, which represents the
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-he or
(1,4-diaza-bicyclo[3.2.2]non-4-yl)-[5-(4-pyrrol-1-yl-phenyl)-furan-2-yl]-methanon,
or its pharmaceutically acceptable salt of the merger.

5. Diazabicyclo aryl derivative according to claim 1, represented by formula II

or its pharmaceutically acceptable salt accession, where n, A', A", L, R' and' such as defined in claim 1.

6. Diazabicyclo aryl derivative according to claim 5, where' represents pyridinyl, possibly substituted nitro.

7. Diazabicyclo aryl derivative according to claim 5, where' is a pyridine-2-yl, possibly substituted nitro.

8. Diazabicyclo aryl derivative according to claim 7, representing (1,4-diaza-bicyclo[3.2.2]non-4-yl)-{5-[4-(3-nitro-pyridine-2-ylamino)-phenyl]-furan-2-yl}-methanon or its pharmaceutically acceptable salt of the merger.

9. Diazabicyclo aryl derivative according to claim 1, represented by formula III

or its pharmaceutically acceptable salt accession, where n, A', A", L, R', V' such, as defined in the .1.

10. Diazabicyclo aryl derivative of claim 9, where
V represents O and
In' represents a C1-6-alkyl, phenyl or pyridinyl group, with the phenyl and pyridinoline group possibly substituted by nitro or amino.

11. Diazabicyclo aryl derivative of claim 10, including:
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 its pharmaceutically acceptable salt of the merger.

12. Diazabicyclo aryl derivative according to claim 1, represented by formula IV

or its pharmaceutically acceptable salt accession, where n, A', A", L, R', R", V and' such as defined in claim 1.

13. Diazabicyclo aryl derivative indicated in paragraph 12, where' is a
With1-6-alkyl, phenyl and and benzyl, moreover, the phenyl and benzyl groups possibly substituted by one or two substituents selected from the group consisting of C1-6-alkoxy, halogeno, trifloromethyl, nitro, amino, C1-6-alkyl-carbonyl-amino, N-C1-6-alkyl-amino-carbonyl-amino (N-C1-6-alkyl-ureido).

14. Diazabicyclo aryl derivative according to item 13, including:
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-acetylaminophenol)-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-forfinal)-urea;
1-{4-[5-(1,4-diaza-icicle[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-3-(3-forfinal)-urea;
1-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-3-(2-triptoreline)-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-triptoreline)-urea; or
1-{3-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-3-ethyl-urea,
or its pharmaceutically acceptable salt of the merger.

15. Pharmaceutical composition for modulation of cholinergic receptors containing a therapeutically effective amount diazabicyclo aryl derivative according to any one of claims 1 to 14 or its pharmaceutically acceptable salts joining together with at least one pharmaceutically acceptable carrier or diluent.

16. Application diazabicyclo aryl derivative according to any one of claims 1 to 14 or its pharmaceutically acceptable salt accession to the manufacture of pharmaceutical compositions/medicaments for the treatment, prevention or relief of a disease or disorder, or condition in a mammal, including man, which is an anxiety, a cognitive disorder, learning deficit, deficits or dysfunction of memory, Alzheimer's disease, attention deficit, hyperactivity and attention deficit, Parkinson's disease G is ntington, amyotrophic lateral sclerosis, disease, Gilles de La Tourette's, depression, manic syndrome, manic depression, schizophrenia, obsessive-compulsive disorder, panic disorder, eating disorder, nervous anorexia, bulimia, obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, late dyskinesia, hyperkinesia, epilepsy, post-traumatic syndrome, social phobia, sleep disorder, pseudodementia syndrome Ganzera, pre-menstrual syndrome, late luteal phase, chronic fatigue syndrome, mutism, trichotillomania or disruption of biological rhythms associated with the change timezones.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to new crystalline form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, including 2 moles water to 1 mole (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, the form II content being equal 75% and more; the above form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3,3,1]non-4-yl)benzamide hydrochloride has one or more optional properties, as follows: a) form II infrared spectrum include characteristic peak at 835±1.5 cm-1; b) X-ray pattern obtained on the above form powder is essentially corresponds to image Fig. 21; and c) water content rates 8.3% to 9.8%. The invention relates also to the form II ofhydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride production methods, to the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, and the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride identification method, as well as to pharmaceutical composition and treatment method for gastrointestinal motility impairment related disorders.

EFFECT: composition has improved properties for medical applications.

22 cl, 1 ex, 11 tbl, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new N,N'-substituted 3,7-diazabicyclo[3.3.1]nonanes of the general formula 1: (HY), where HY is hereinafter a pharmacologically acceptable acid; E is , R1 is H, low-grade alkyl, C1-C10alkoxy; R2 is generally represented by the general formulae (1.1a) , (1.2a) , (1.3a) , (1.4a) , where L is CHR11, ; R11 is H, NH2; R15 is H, low-grade alkyl, C1-C10alkoxy; R19, R19', R20 and R20' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R24 and R25 can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R3 and R3' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R4 and R4' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; X is a group of the general formula: (CH2)m-Z, where m=0, while Z is acetyl, or X is a valence link. Compounds I are capable of AMPA receptor activity modulation and hence can be applied in pharmaceutical compositions.

EFFECT: obtaining compound capable of AMPA receptor activity modulation.

12 cl, 2 dgw, 2 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1,4-diazabicycloalkane of the formula (IV): or its pharmaceutically acceptable addition salt wherein Ar represents carbocyclic aromatic (aryl) group or heterocyclic aromatic (heteroaryl) group that represents 5-6-membered ring comprising one nitrogen, sulfur or oxygen atom as a heteroatom and wherein aromatic group can be substituted with one substitute chosen from group consisting of (C1-C6)-alkoxy, halogen atom, -CF3, phenyl and benzyl. Also, invention relates to a pharmaceutical composition possessing inhibitory effect on nicotine acetylcholine receptors and containing the effective amount of compound of the formula (IV) or its pharmaceutically acceptable addition salt in combination with at least one pharmaceutically acceptable carrier or diluting agent. Invention provides derivatives of 1,4-diazabicycloalkane possessing inhibitory activity with respect to nicotine acetylcholine receptors.

EFFECT: valuable medicinal and pharmacological properties of compounds.

10 cl, 3 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention covers new pyrrolopyrimidine and pyrrolotriazine derivatives substituted with carbamoyl group of formula [I], characterised as a CRF (corticotrophin release factor) receptor antagonist. The compounds can be effective as a therapeutic or preventive agent for such diseases, as depression, anxiety, Alzheimer's disease, Parkinson's disease, etc. in formula [I]: E means N or CR10; R1 means -OR4, -S(O)1R4 or-NR4R5; R2 means hydrogen, C1-6alkyl; R3 means hydrogen; R4 and R5 are identical or different, and independently mean hydrogen, C1-9alkyl, di(C3-7cycloalkyl)-C1-6alkyl, C1-6alkoxy-C1-6alkyl, di(C1-6alkoxy)-C1-6alkyl, hydroxy-C1-6alkyl, cyano-C1-6alkyl, carbamoyl-C1-6alkyl or di(C1-6alkyl)amino-C2-6alkyl, or R4 and R5 together form (CH2)m-A-(CH2)n where A means CHR9; R9 means hydrogen, hydroxy-C1-6alkyl, or cyano-C1-6alkyl; R10 means hydrogen; I means an integer 0, 1 and 2; m means an integer 1, 2, 3 and 4; n means an integer 0, 1, 2 and 3; Ar means phenyl, and specified phenyl is substituted by one or more substitutes being identical or different, and chosen from the group consisting of halogen, C1-6alkyl, trifluoromethyl; their individual isomers or pharmaceutically acceptable salts.

EFFECT: extended application.

9 cl, 2 dwg, 2 tbl, 2 ex

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