New diazabicyclic aryl derivatives, pharmaceutical compositions containing them and their use

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

 

The SCOPE of the INVENTION

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

PRIOR art

Endogenous cholinergic neurotransmitter acetylcholine implements biological action through cholinergic receptors of two types: muscarinic acetylcholine receptors (machr) and nicotinic acetylcholine receptors (Nahr).

It is well known that muscarinic acetylcholine receptors predominate on nicotinic acetylcholine receptors in brain regions important for memory and cognitive abilities, as th is Lennie research aims to develop agents for the treatment of disorders associated with memory have focused on the synthesis of modulators of acetylcholine receptors.

However, recently the interest in the development of modulators of Nahr. Some diseases associated with degeneration of the cholinergic system, such as senile dementia type, vascular dementia and deterioration of cognitive functions due to organic damage of the brain diseases that are directly related to alcoholism.

In WO 00/58311 described derivatives of 1,4-diazabicyclo[3.2.2]nonan-4-carboxylates and carboxamides which are useful as inhibitors of nicotinic receptors α7-subtype. Other derivatives of 1,4-diazabicyclo[3.2.2]nonan-4-methanone not described.

SUMMARY of the INVENTION

The present invention is devoted to the proposal of new modulators of nicotinic receptors, which are useful for treating diseases or disorders associated with cholinergic receptors, in particular with nicotinic acetylcholine receptors α7-subtype.

Compounds according to the invention may also be useful as diagnostic tools or agents for monitoring in various diagnostic methods, in particular for in vivo imaging of receptors (neuroimaging), and you can use them in labeled or Nemec the Noi form.

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

any of its enantiomers or any mixture of enantiomers, or their prodrugs, or pharmaceutically acceptable salt of accession, where

n is 1, 2 or 3 and

X and Y independently of one another represent CR2, CR3and/or N, where R2and R3independently of one another represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, aryl-alkyl, heteroaryl and/or heteroaromatic, and aryl, aryloxy, aryl-alkyl, heteroaryl, heteroaromatic may be substituted by one or two of halogen, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl;

R1represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl or heteroaryl, and aryl or heteroaryl may be substituted by one or two of alkyl, halogeno, halogenation, alkoxy, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, R SO2NH - or (R SO2)2N - where R' represents hydrogen, alkyl, cycloalkyl, halogenated, alkenyl, phenyl or benzyl; or a group of the formula aryl-alkyl-, aryl-Z-(alkyl)m-, aryl-S≡ -, heteroaryl-Z-(alkyl)mor heteroaryl-C≡C-, where m is 0 or 1, and Z represents O or S; and where the aryl and heteroaryl may be substituted by one or two of: alkyl, halogeno, halogenoalkane, hydroxy, alkoxy, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, R SO2NH - or (R SO2)2N-, where R' represents hydrogen or alkyl, or

R1and R2, R1and R3together with the carbon atoms to which they are attached, form benzododecinium aromatic carbocyclic ring, and benzododecinium aromatic carbocyclic ring may be substituted by one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, lanakila, halogeno, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl.

In the second aspect of the present invention proposed a pharmaceutical composition containing a therapeutically effective amount diazabicyclo aryl derivative of the invention or its pharmaceutically acceptable salts joining together with at least one pharmaceutically acceptable nose is Telem 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 of a mammal, including humans, and the disease, disorder or condition responsive to modulation of cholinergic receptors.

In another aspect of the invention, a method for treatment, prevention or relief of diseases, disorders or conditions of a living animal body, including a human, with a disorder, disease or condition responsive to modulation of cholinergic receptors, and this method includes a step of introducing such a living animal body in need, a therapeutically effective amount diazabicyclo aryl derivative of the invention.

Other objects of the invention will become obvious to a person skilled in the relevant field of technology from the following detailed description and examples.

DETAILED description of the INVENTION

Disabilitiesa aryl derivatives

In the first aspect of the present invention proposed diazabicyclo aryl derivative of the formula I

,

any of its enantiomers or any mixture of its enantiomers, or its prodrug, or pharmaceutically acceptable salt accession,

where n is 1, 2 or 3;

X and Y independently of one another represent CR2, CR3and/or N, where R2and R3independently of one another represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, aryl-alkyl, heteroaryl and/or heteroaromatic, and aryl, aryloxy, aryl-alkyl, heteroaryl, heteroaromatic may be substituted by one or two of halogen, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl;

R1represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl or heteroaryl, and aryl or heteroaryl may be substituted by one or two of alkyl, halogeno, halogenoalkane, alkoxy, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, R SO2NH - or (R SO2)2N-, where R' represents hydrogen, alkyl, cycloalkyl, halogenated, alkenyl, phenyl or benzyl; or a group of the formula aryl-alkyl-, aryl-Z-(al is silt) m-, aryl-C≡C-, heteroaryl-Z-(alkyl)mor heteroaryl-C≡C-, where m is 0 or 1; and Z represents O or S; and where the aryl and heteroaryl may be substituted by one or two of alkyl, halogeno, halogenoalkane, hydroxy, alkoxy, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, R SO2NH - or (R SO2)2N-, where R' represents hydrogen or alkyl, or

R1and R2, R1and R3together with the carbon atoms to which they are attached, form benzododecinium aromatic carbocyclic ring, and it benzododecinium aromatic carbocyclic ring may be substituted by one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, lanakila, halogeno, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl.

In the preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula I, where

X represents CR3or N, where R3represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkane, cianelli, halogen, CF3, OCF3, CN, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic;

R1and R2independently from each other, not only is jut a hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkane, cianelli, halogen, CF3, OCF3, CN, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic or

R1and R2together with the carbon atoms to which they are attached, form benzododecinium aromatic carbocyclic ring.

In another preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula I, where

X and Y independently of one another represent CR2or N, where R2represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic, and aryl, aryloxy, heteroaryl or heteroaromatic may be substituted by one or two of halogen, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl, and

R1represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic, and aryl, aryloxy, heteroaryl or heteroaromatic may be substituted by one or two of halogen, halogenoalkane, Galaga is alkoxy, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl, or

R1and R2together with the carbon atoms to which they are attached, form benzododecinium aromatic carbocyclic ring, and it benzododecinium aromatic carbocyclic ring may be substituted by one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkane, lanakila, halogeno, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl.

In a more preferred embodiment, the aryl is selected from the group consisting of phenyl, indenyl and naphthyl, and

heteroaryl represents an aromatic 5 - or 6-membered monocyclic heterocyclic group selected from the group consisting of furanyl, in particular furan-2 - or 3-yl; tanila, in particular Tien-2 - or 3-yl; pyrrolyl (azolyl), in particular pyrrol-2 - or 3-yl; oxazolyl, in particular oxazol-2-, 4 - or 5-yl; imidazolyl, in particular imidazol-2 - or 4-yl; pyrazolyl, in particular a pyrazole-1-, 3 - or 4-yl; isoxazolyl, in particular isoxazol-3-, 4 - or 5-yl; thiazolyl, in particular thiazol-2-, 4 - or 5-yl; thiadiazolyl, in particular 1,3,4-thiadiazole-2-yl; pyridyl, in particular of pyrid-2-, 3 - or 4-yl; pyridazinyl, in particular pyridazin-3 - or 4-yl; the feast is medinilla, in particular pyrimidine-2-, 4 - or 5-yl, and pyrazinyl, in particular pyrazin-2 - or 3-yl; or an aromatic bicyclic heterocyclic group selected from the group consisting of indolyl, in particular indol-2-, 3-, 5 - or 6-yl; benzo[b]furanyl, in particular benzofuran-2-, 5 - or 6-yl; benzo[b]teenie, in particular bestien-2-, 5 - or 6-yl; benzimidazolyl in particular, the benzimidazole-2-, 5 - or 6-yl; chinoline, in particular the quinoline-2-, 3-, 6 - or 7-yl; izochinolina, in particular isoquinoline-3-, 6 - or 7-silt and cinnoline, in particular cinnolin-6-or 7-Il.

In an even more preferred embodiment the aryl represents phenyl; aryl-alkyl represents benzyl and heteroaryl is furanyl, in particular furan-2 - or 3-yl; imidazolyl, in particular imidazol-2 - or 4-yl; isoxazolyl, in particular isoxazol-3-, 4 - or 5-yl; thiazolyl, in particular thiazol-2-, 4 - or 5-yl; thiadiazolyl, in particular 1,3,4-thiadiazole-2-yl; pyridyl, in particular of pyrid-2-, 3- or 4-yl; or indolyl, in particular indol-2, 3-, 5 - or 6-yl.

In the third preferred embodiment of the invention proposed diazabicyclo aryl derivative of formula I, Ia, IB, II, or III, where n is 1, 2 or 3. In a more preferred embodiment diazabicyclo aryl according to the invention is diazabicyclo aryl derivative of formula I, Ia, IB, II, or III, where n is equal to 2.

In the fourth PR is doctitle embodiment of the invention proposed diazabicyclo aryl derivative of the formula I, where at least one of X and Y represents N and the other of X and Y represents CR2and n, R1and R2are as defined above.

In the fifth preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula la and 1B

;

where n and R1are as defined above.

In the sixth preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula IB or Iك

;

where R1is the same as defined above.

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-oxazolin-5-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(5-phenyl-oxazol-5-yl)-methanon or

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenyl-1,3,4-oxadiazol-2-yl-methanon,

its enantiomer or a mixture of its enantiomers or its pharmaceutically acceptable salt of the merger.

In the seventh preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula I where one or both of R2and R3independently of one another represent hydrogen and/or halogen and R1and the rest, and the R 2and R3independently of one another represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halogeno, CF3, OCF3, CN, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halogeno-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halogeno-phenyl 4 formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, N-3-phenyl-ndimethylacetamide, N-4-phenyl-ndimethylacetamide, N-4-phenyl-propionamide, N-4-phenyl-isobutyramide, N-4-phenyl-acrylamide, N-4-phenyl-benzamide, 4-(N,N-dimethyl-sulfonyl-amino)-phenyl, N-4-phenyl-2,2,2-Cryptor-ndimethylacetamide triperoxonane acid amide 4-phenyl-cyclopropanecarboxylic acid, 4-phenyloxy, 3,5-dihalogen-phenyloxy, phenyl-ethinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl and/or 5-trifluoromethyl-2-pyridyl-thiomethyl.

In the eighth preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula I, where one of R1and R2represents phenyl or naphthyl, and the other of R1and R2represents hydrogen.

In the ninth preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula I, where X and Y both represent CR2, CR3or N, where R2and Rsup> 3independently of one another represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, heteroaryl and/or heteroaromatic, and aryl, aryloxy, heteroaryl, heteroaromatic may be substituted by one or two of halogen, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl; or X represents N or CR2where R2represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic, and aryl, aryloxy, heteroaryl and/or heteroaromatic may be substituted by one or two of halogen, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl; and Y is N or CR3where R3together with R1and together with the carbon atoms to which they are attached, form benzododecinium aromatic carbocyclic ring, and it benzododecinium aromatic carbocyclic ring may be substituted by one or two of alkyl, cyclo is Lila, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, lanakila, halogeno, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl.

In the tenth preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula II

any of its enantiomers or any mixture of its enantiomers, or its prodrug, or pharmaceutically acceptable salt of accession, where

n is 1, 2 or 3;

X represents CR4or N, where R4represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic, and aryl, aryloxy, heteroaryl, heteroaromatic may be substituted by one or two of halogen, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl;

R1and R2independently of one another represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, phenyl, phenyloxy, heteroaryl and/or heteroaromatic, and phenyl, phenyloxy, heteroa the sludge and heteroaromatic may be substituted by one or two of alkyl, halogeno, halogenoalkane, halogenoalkane, cyano, amino, nitro, a group of the formula R CONH-, R SO2NH - and/or (R SO2)2N-, where R' represents hydrogen, alkyl, cycloalkyl, halogenated, alkenyl, phenyl or benzyl;

where R1represents hydrogen or alkyl, or

R1and R2together with the carbon atoms to which they are attached, form benzododecinium aromatic benzene ring, and this benzododecinium aromatic benzene ring can be substituted by one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, lanakila, halogeno, halogenoalkane, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic, and aryl, aryloxy, heteroaryl or heteroaromatic may be substituted by one or two of halogen, halogenoalkane, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, where R' represents hydrogen or alkyl.

In a more preferred embodiment of the invention diazabicyclo aryl derivative is diazabicyclo aryl derivative of the formula II, where

R1represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, halogeno, CF3, OCF3, CN, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halogeno-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halogeno-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, N-3-phenyl-ndimethylacetamide, N-4-phenyl-ndimethylacetamide, N-4-phenyl-propionamide, N-4-phenyl-isobutyramide, N-4-phenyl-acrylamide, N-4-phenyl-benzamide, 4-(N,N-dimethyl-sulfonyl-amino)-phenyl, N-4-phenyl-2,2,2-Cryptor-ndimethylacetamide triperoxonane acid amide 4-phenyl-cyclopropanecarboxylic acid, 4-phenyloxy, 3,5-dihalogen-phenyloxy, phenyl-ethinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl or 5-trifluoromethyl-2-pyridyl-thiomethyl;

R2represents hydrogen or halogen and

R4represents hydrogen, alkyl or halogeno.

In the eleventh preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula III

any of its enantiomers or any mixture of its enantiomers, or its prodrug, or pharmaceutically acceptable salt of accession, where

n is 1, 2 or 3;

X represents CR4or N, where R4represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, and is iloxi, heteroaryl or heteroaromatic;

R5and R6independently of one another represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkane, cianelli, halogeno, halogenated, halogenoalkane, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaromatic;

In a more preferred embodiment diazabicyclo aryl derivative of the invention is diazabicyclo aryl derivative of the formula III, where R4represents hydrogen or alkyl, R5represents hydrogen, alkyl or alkoxy and R6represents hydrogen, alkyl or alkoxy.

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-8-methoxy-benzofuran-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzofuran-2-yl-methanon or

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-benzofuran-2-yl-methanon;

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzoxazol-2-yl-methanon;

its enantiomer or a mixture of its enantiomers or its pharmaceutically acceptable salt of the merger.

In the twelfth preferred embodiment of the invention proposed diazabicyclo aryl derivative of formula I, Ia, IB or II, where

R1represents a group of formula -(alkyl)m-Z-Ari is, -(alkyl)m-Z-heteroaryl or≡s-aryl, where m is 0 or 1, Z represents O or S and where the aryl and heteroaryl may be substituted by one or two of alkyl, halogeno, halogenoalkane, alkoxy, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, R SO2NH - or (R SO2)2N-, where R' represents hydrogen or alkyl.

In the thirteenth embodiment of the invention proposed diazabicyclo aryl derivative of formula I, Ia, IB or II, where R1represents a group of formula-CH2-Z-phenyl, -CH2-Z-pyridyl or-C≡C-phenyl, where m is 0 or 1, Z represents O or S, and where phenyl and pyridyl may be substituted by one or two of alkyl, halogeno, halogenoalkane, alkoxy, halogenoalkane, cyano, amino, nitro and/or groups of the formula R CONH-, R SO2NH - or (R SO2)2N-, where R' represents hydrogen or alkyl.

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)-thiomethyl]-furan-2-yl-methanon or

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanon,

its enantiomer or a mixture of its enantiomers or its pharmaceutically acceptable salt, connected is inane.

In the fourteenth preferred embodiment of the invention proposed diazabicyclo aryl derivative of the formula I or II where R1represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, halogeno, CF3, OCF3, CN, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitrophenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halogeno-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 4-halogeno-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, N-3-phenyl-ndimethylacetamide, N-4-phenyl-ndimethylacetamide, N-4-phenyl-propionamide, N-4-phenyl-isobutyramide, N-4-phenyl-acrylamide, N-4-phenyl-benzamide, 4-(N,N-dimethyl-sulfonyl-amino)-phenyl, N-4-phenyl-2,2,2-Cryptor-ndimethylacetamide triperoxonane acid amide 4-phenyl-cyclopropanecarboxylic acid, 4-phenyloxy, 3,5-dihalogen-phenyloxy, phenyl-ethinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl and/or 5-trifluoromethyl-2-pyridyl-thiomethyl;

R2represents hydrogen, alkyl or halogeno and

R3represents hydrogen, alkyl or halogeno.

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-bromo-furan-2-yl-methanon,

(1,4-Diaz is-bicyclo[3.2.2]non-4-yl)-5-nitro-furan-2-yl-methanon,

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-triptoreline)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-chlorophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-nitrophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-acetylaminophenol)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-AMINOPHENYL)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-AMINOPHENYL)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-acetylaminophenol)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-acetylaminophenol)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-4,5-dibromo-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-chloro-5-triptoreline)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-were)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-amino-4-were)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-dimethylsulphamoyl)AMINOPHENYL]-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-formylamino)-furan-2-yl-meth is non,

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)thiomethyl]-furan-2-yl-methanon,

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-bromo-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanon,

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

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-diphenylacetylene)phenyl]-furan-2-yl-methanon,

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

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-2-yl-methanon,

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

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

their enantiomers, or a mixture of enantiomers, or pharmaceutically acceptable salt of the merger.

Any combination of two or more of the embodiments described in this description of the invention, included in this volume and the gain.

The definition of the substituents

In the context of this invention alkyl group means a monovalent saturated straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms (C1-18alkyl), more preferably from one to six carbon atoms (C1-6alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary of pentyl, hexyl and isohexyl. In the preferred embodiment, the alkyl is a1-4alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of this invention the alkyl represents a C1-3alkyl group, which, in particular, may be the stands, ethyl, propylene or isopropyl.

In the context of this invention cycloalkyl group means a cyclic alkyl group, preferably containing from three to seven carbon atoms (C3-7cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of this invention, cycloalkyl-alkyl group means cycloalkyl group, as defined above, and this cycloalkyl group substituted by an alkyl group, as defined above. Examples of preferred cycloalkyl-alkyl groups of the invention include the CEC shall propylether and cyclopropylethyl.

In the context of this invention alkoxygroup means the group "alkyl-O -, where alkyl is as defined above. Examples of preferred alkoxygroup according to the invention include methoxy, ethoxy.

In the context of this invention cycloalkanes means the group "cycloalkyl-O-"where cycloalkyl is the same as defined above.

In the context of this invention cyanoaniline group means an alkyl group substituted by CN, where cycloalkyl is the same as defined above.

In the context of this invention, halogen is a fluorescent, chloro, bromo or iodo, and halogenation group means an alkyl group as defined above, with an alkyl group substituted by one or more halogeno. Thus, trihalomethyl group represents, for example, triptorelin group, trichlorethylene group and similar trihalomethane methyl group. Preferred halogenoalkane group according to the invention include trihalomethyl, preferably CF3.

In the context of this invention halogenlampe means alkoxygroup, as defined here, and alkoxygroup substituted by one or more halogeno. Preferred halogenlampe according to the invention include trihalomethane, preferably CF3Oh.

In the context on the frame of the invention, the aryl group means a monocyclic or polycyclic aromatic hydrocarbon group. Examples of preferred aryl groups of the invention include phenyl, indenyl, naphthyl, azulene, fluorene and anthracene. The most preferred aryl group according to the invention is phenyl.

In the context of this invention alloctype means the group aryl-O -, where aryl is as defined above. The most preferred arroceros according to the invention is phenoxy.

In the context of this invention, the heteroaryl group means an aromatic mono - or polycyclic heterocyclic group, which contains one or more than one heteroatom in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S).

Preferred 5-6-membered heteroaryl groups of the invention include furanyl, in particular furan-2 - or 3-yl; thienyl, in particular Tien-2 - or 3-yl; selenophene, in particular selenophene-2 - or 3-yl; pyrrolyl (azolyl), in particular pyrrol-2 or 3-yl; oxazolyl in particular oxazol-2-, 4 - or 5-yl; thiazolyl, in particular thiazol-2-, 4 - or 5-yl; imidazolyl, in particular imidazol-2 - or 4-yl; pyrazolyl, in particular a pyrazole-3 - or 4-yl; isoxazolyl, in particular isoxazol-3-, 4 - or 5-yl; isothiazol, in particular isothiazol-3-, 4 - or 5-yl; oxadiazolyl, in particular 1,2,3-oxadiazol-4 - or 5-yl or 1,3,4-oxadiazol-2-yl; triazolyl, in particular 1,2,3-triazole-4-yl or 1,2,4-resol-3-yl; thiadiazolyl, in particular 1,2,3-thiadiazole-4 - or 5-yl, or 1,3,4-thiadiazole-2-yl; pyridyl, in particular of pyrid-2-, 3 - or 4-yl; pyridazinyl, in particular pyridazin-3 - or 4-yl; pyrimidinyl, in particular pyrimidine-2-, 4 - or 5-yl; pyrazinyl, in particular pyrazin-2 - or 3-yl, and triazinyl, in particular 1,2,4 - or 1,3,5-triazinyl.

Preferred 5-membered heteroaryl groups of the invention include furanyl, in particular furan-2 - or 3-yl; thienyl, in particular Tien-2 - or 3-yl; pyrrolyl (azolyl), in particular pyrrol-2 - or 3-yl; oxazolyl, in particular oxazol-2-, 4 - or 5-yl; thiazolyl, in particular thiazol-2-, 4 - or 5-yl; isoxazolyl, in particular isoxazol-3-, 4 - or 5-yl; isothiazolin, in particular isothiazol-3-, 4 - or 5-yl, and thiadiazolyl, in particular 1,2,3-thiadiazole-4 - or 5-yl or 1,3,4-thiadiazole-2-yl.

Preferred 5-membered heteroaryl groups of the invention include furanyl, in particular furan-2 - or 3-yl, and thienyl, in particular Tien-2 - or 3-yl.

The most preferred 6-membered heteroaryl groups of the invention include pyridyl, in particular of pyrid-2-, 3 - or 4-yl, and pyrazinyl, in particular pyrazin-2 - or 3-yl.

In the context of this invention an aromatic bicyclic heterocyclic group means a bicyclic heterocyclic group which contains one or more than one heteroatom in its ring structure. In the context of the present invention, the term "bicyclic heterocyclic group" includes benzododecinium five - and six-membered heterocyclic ring, containing one or more than one heteroatom. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S).

Preferred bicyclic heterocyclic groups of the invention include indolizinyl, in particular indolizine-2-, 5 - or 6-yl; indolyl, in particular indol-2-, 5 - or 6-yl; isoindolyl, in particular isoindole-2-, 5 - or 6-yl; benzo[b]furanyl, in particular benzofuran-2-, 5 - or 6-yl; benzo[b]thienyl in particular bestien-2-, 5 - or 6-yl; benzimidazolyl, in particular the benzimidazole-2-, 5 - or 6-yl; benzothiazolyl, in particular benzothiazole-5 - or 6-yl; purinol, in particular purine-2 - or 8-yl; chinoline, in particular the quinoline-2-, 3-, 6 - or 7-yl, ethenolysis, in particular isoquinoline-3-, 6 - or 7-yl; indolinyl, in particular cinnolin-6 - or 7-yl; phthalazines, in particular phthalazine-6 - or 7-yl; hintline, particular hinzelin-2-, 6 - or 7-yl; honokalani, in particular cinoxacin-2 - or 6-yl; 1,8-naphthyridines, in particular 1,8-naphthiridine-2-, 3-, 6 - or 7-yl, and pteridinyl, in particular pteridine-2-, 6 - or 7-yl.

Preferred bicyclic heterocyclic groups of the invention include indolyl, in particular indol-2-, 5 - or 6-yl; benzo[b]furanyl, in particular benzofuran-2-, 5 - or 6-yl; benzo[b]thienyl, in particular bestien-2-, 5 - or 6-yl; benzimidazolyl, in particular the benzimidazole-2-, 5 - or 6-yl, and honokalani, in particular cinoxacin-2 - or 6-yl.

Most FAV is citicoline bicyclic heterocyclic groups of the invention include indolyl, in particular indol-2-, 5 - or 6-yl; benzo[b]furanyl, in particular benzofuran-2-, 5 - or 6-yl; benzo[b]thienyl, in particular bestien-2-, 5 - or 6-yl.

In the context of this invention heteroanalogues means the group "heteroaryl-O-"where heteroaryl is the same as defined above.

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, and pre - or proletarienne form chemical compounds according to the invention.

Examples of pharmaceutically acceptable salts of the merger include, without limitation, non-toxic salt accession inorganic or organic acids, such as hydrochloride, derived from hydrochloric acid, hydrobromide, derived from Hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloro acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, formate derived from formic acid, acetate derived from acetic acid, aconitic derived from amanitowoc acid, the ascorbate derived from ascorbic acid, bansilalpet obtained from benzosulfimide acid, the benzoate derived of benzoic acid,cinnamic, derived from cinnamic acid, the citrate derived from citric acid, embonate derived from monowai acid, enanthate, derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from almond acid, methanesulfonate, obtained from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, the phthalate derived from phthalic acid, the salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, tartrate derived from tartaric acid, toluene-para-sulfonate obtained from pair-toluensulfonate acid and the like. Such salts can be formed using known and described in the relevant technical field methods.

Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in obtaining salts useful as intermediates in obtaining chemical compounds according to the invention and its pharmaceutically acceptable salts in which soedineniya acid.

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

Examples of pharmaceutically acceptable cationic salts chemical compounds according to the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, kalinovye, lysine and ammonium (and similar) salt chemical compounds according to the invention containing an anionic group. Such cationic salts can be well-known techniques described in the relevant field of technology

In the context of this invention "onevia salt" N-containing compounds are also considered as pharmaceutically acceptable salts (Aza-onieva salt). Preferred Aza-onieva salts include alkyl-onieva salts, in particular methyl and ethyl onevia salt, cycloalkyl-onieva salts, in particular cyclopropyl-onieva salt, and cycloalkenyl-onieva salts, in particular cyclopropyl-methyl-onieva salt.

Especially preferred onevia salt according to the invention include salts formed on the N'-position in accordance with the following formula I'

Spatial isomers

Chemical compounds of the present invention may exist in (+) and (-)-form is also in racemic forms. The racemates of these isomers and of themselves separate isomers are within the scope of the present invention.

The racemic forms can be divided into optical antipodes known methods and procedures. One of the methods of separation of the diastereomeric salts is the use of optically active acids and the release of the optically active amine compound in the processing of the base. Another method of separation of racemates on the optical coupling of the present invention is based on chromatography on optically active matrix. Thus, the racemic compounds of the present invention can be divided into their optical antipodes, for example, by fractional crystallization, for example, d - or I- (tartrate, mandelate or camphorsulfonate) salts.

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

Additional methods of separation of pricheski isomers are known in the relevant field. Such methods include the methods described Jaques J, Collet A, & Wilen S "Enantiomers. Racemates, and Resolutions". John Wiley and Sons, New York (1981).

Optically active compounds can also be obtained from optically active starting materials.

Methods of obtaining disabilitiesa aryl derivatives

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

Also one connection according to the invention can be converted into another compound of the invention by standard methods.

The final products of the reactions described here, can be separated by standard methods, such as extraction, crystallization, distillation, chromatography and the like.

Biological activity

The present invention relates to proposals of new ligands and modulators of nicotinic receptors, and these ligands and modulators are useful for treating diseases or disorders associated with cholinergic receptors, and in particular the nicotinic acetylcholine receptor (Nahr). Preferred compounds according to the invention are expressed by selectionist is against nicotinic acetylcholine receptors α 7-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 useful for the treatment of various diseases and disorders as diseases and disorders associated with cholinergic system of the Central nervous system (CNS), peripheral nervous system (PNS)diseases and disorders associated with contractions of the smooth muscle, endocrine diseases and disorders, diseases and disorders related to neurodegeneration, diseases and disorders associated with inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Compounds according to the invention may also be useful as diagnostic tools or agents for monitoring in various diagnostic methods, and in particular for in vivo imaging of receptors (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 associated with the Central nervous system. Such diseases or disorders on the anxious anxiety, cognitive disturbances and learning disorders and dysfunction of memory, Alzheimer's disease, attention deficit, attention deficit disorder with hyperactivity (ADHD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis syndrome Gilles de La Tourette, psychosis, depression, mania, manic depression, schizophrenia, obsessive-compulsive disorder (OCD), panic disorder, eating disorders such as nervous anorexia, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, late dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, social phobia, sleep disorders, pseudodementia syndrome Ganzera, pre-menstrual syndrome, late luteal phase, chronic fatigue syndrome, mutism, trichotillomania syndrome and jet lag.

In the preferred embodiment of diseases disorders and conditions associated with Central nervous system in which the use of the compounds according to the invention, are cognitive disorders, psychosis, schizophrenia and/or depression.

In another preferred embodiment of the compounds according to the invention can be useful for the treatment of diseases, disorders or conditions associated with contractions of smooth muscles, on the tea convulsive disorders, the angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, late dyskinesia, hyperkinesia, premature ejaculation and difficulty in erection.

In yet another preferred embodiment of the compounds according to the invention can be useful for the treatment of endocrine disorders such as hyperthyroidism, pheochromocytoma, hypertension and arrhythmia.

In yet another preferred embodiment of the compounds according to the invention may be useful for treatment of neurodegenerative disorders, including temporary anoxia and induced neurodegeneration.

In yet another preferred embodiment of the 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 diarrhea.

In yet another preferred embodiment of the compounds according to the invention can be useful for the treatment of mild, moderate and even severe pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, and phantom limb pain. In particular, the pain may be neuropathic pain, chronic headache, Central pain, pain related to diabetic neuropathy, postoperative never what LGIA or damage to a peripheral nerve.

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 benzodiazepinones drugs and alcohol. Cessation of addictive substances is in General a traumatic event characterized by anxiety and frustration, irritation, anxiety, difficulty concentrating, restlessness, reduced heart rate, increased appetite and weight gain.

In this context, "treatment" encompasses the treatment, prevention, prevention or relief of withdrawal symptoms and abstinence, and treatment, which is voluntary contraction of taking addictive substances.

In another aspect, compounds according to the invention are used as diagnostic agents, for example, for the identification and localization of nicotinic receptors in various tissues.

The pharmaceutical composition

In another aspect of the invention proposed new pharmaceutical compositions containing a therapeutically effective amount diazabicyclo aryl derivative of the invention.

<> Although the compounds according to the invention for use in therapy can be introduced in the form of the raw chemical, 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, carriers, buffers, diluents and/or other customary pharmaceutical auxiliaries.

In the preferred embodiment of the proposed invention 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 with other therapeutic and/or prophylactic ingredients, known and used in the relevant field of technology. The carrier(s) need(s) to be acceptable(and)" in the sense of compatibility with other ingredients of the drug and the lack of danger to the recipient.

The pharmaceutical compositions according to the invention can be entered in any traditional way, which corresponds to the desired therapy. Preferred routes of administration include oral administration, in particular, tablets, capsules, pills, powder or liquid form, and parenteral administration, in particular cutaneous, subcutaneous, vnutrimy acnee or intravenous. The pharmaceutical composition according to the invention can be made by any technician with use of standard methods and conventional procedures, appropriate to the desired preparation. At desire it is possible to apply a composition adapted to provide sustained release of the active ingredient.

Diazabicyclo aryl derivative of the invention can be introduced in the form of a wide range of oral and parenteral dosage forms. Specialists in the relevant field it is obvious that the following dosage forms may contain as an active ingredient or chemical compound according to the invention, or pharmaceutically acceptable salt of a chemical compound according to the invention.

At desire it is possible to apply a composition adapted to provide sustained release of the active ingredient.

The pharmaceutical preparations are preferably in the form of a standard dosage forms. In such form the preparation is divided into unit doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, where the package contains discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form may depict ablate a capsule, pill, capsule or pill by itself or it can represent a suitable amount of any of these in packaged form.

The preferred compositions are tablets or capsules for oral administration and fluids for intravenous injection, and continued infusion.

Further details of methods of preparation and administration of drugs can be found in the latest edition Remington''s Pharmaceutical Sciences (Maack Publishing Co, Easton, PA).

A therapeutically effective dose corresponds to that amount of active ingredient that relieves the symptoms or condition. Therapeutic efficacy and toxicity, such as ED50and LD50you can define a standard pharmacological methods in cell cultures or experimental animals. therapeutic index is the ratio of the doses of therapeutic and toxic effects, and can be expressed by the ratio LD50/ED50. Preferred are pharmaceutical compositions having high therapeutic indices.

Of course, the input dose should be carefully chosen according to the age, weight and condition being treated with the individual, but also on the method of administration, dosage form and mode, as well as the desired result, and the exact dosage must, of course, determined by the change practitioner.

The actual dosage depends on the nature and severity of the disease that is treated is at the discretion of the physician and can be modified by dose titration in relation to particular cases in accordance with this invention to achieve the desired therapeutic effect. However, it is currently envisioned that a pharmaceutical composition containing from about 0.1 to about 500 mg of the active ingredient in a single dose, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg, are suitable for therapeutic treatment.

The active ingredient can be introduced in the form of one or more doses per day. In some circumstances, a satisfactory result can be obtained at such low dosages as 0.1 µg/kg I.V (intravenous) and 1 mg/kg P.O. (oral). Currently, the upper bound of the interval dosage is a dose of approximately 10 mg/kg I.V and 100 mg/kg P.O. Preferred intervals are the intervals from approximately 0.1 μg/kg to about 10 mg/kg per day .. and from about 1 μg/kg to about 100 mg/kg per day P.O.

The methods of treatment

Disabilitiesa aryl derivatives of the present invention are valuable modulators of nicotinic cocktail recipes. is s and therefore, useful for treating a range of ailments involving cholinergic dysfunction as well as a number of disorders sensitive to the action of modulators Nahr.

In another aspect of the invention, a method for treatment, prevention or relief of disease, disorder or condition of a living animal body, including a human, a disease, disorder or condition responsive to modulation of cholinergic receptors, and this method includes the introduction of such a living animal body in need, a therapeutically effective amount diazabicyclo aryl derivative of the invention.

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

Preferred indications, proposed according to the invention are the above statements.

Currently, it is assumed that suitable intervals dosage leave from 0.1 to 1000 milligrams per day, 10-500 milligrams daily, and especially 30-100 milligrams per day, usually depending on the exact way of introduction, forms of administration, indications, which is aimed at the introduction involved the individual and the masses of the bodies involved individual, and in addition preferences and experience of the responsible physician or veterinarian.

A satisfactory result can be, in some circumstances, obtained at such low dosages as 0.005 mg/kg I.V and 0.01 mg/kg P.O. Upper limit of dosage is about 10 mg/kg I.V and 100 mg/kg P.O. Preferred intervals range from approximately 0.001 to approximately 1 mg/kg I.V and from about 0.1 mg/kg to about 10 mg/kg P.O.

EXAMPLES

The invention is additionally illustrated by the following examples, it is assumed that they in no way limit the claimed scope of the invention.

Example 1

Preparatory example

All reactions using sensitive air reagents or intermediates were performed under nitrogen atmosphere or in anhydrous solvents.

1,4-Diazabicyclo[3.2.2]nonan-3-one (intermediate compound)

32,33 g (200 mmol) of the hydrochloride of 3-binucleation was dissolved in 75 ml of water and to the solution was added hydroxylamine hydrochloride (16.4 g, 236 mmol) and CH3CO2Na×3H2(80 g, 588 mmol). The mixture was stirred at 70°C for 1 hour. Then the mixture was dissolved NaCl (10 g) and the mixture was cooled to 0°C. the Separated crystals were filtered off and thoroughly dried. The crude oxime 3-hioliday (approximately 30 g) COI is litovali on the next stage of the synthesis without further purification.

Polyphosphoric acid (180 g) was heated to 100°and portions were added to the crude oxime 3-hinoklidina (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. The mass is thoroughly homogenized, the mixture was poured into ice (100 g). The mixture was podlachian (pH 12) by the addition of sodium hydroxide. Then the mixture was extracted with chloroform (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-diazabicyclo[3.2.2]nonan-3-one and 1,3-diazabicyclo[3.2.2]nonan-4-it was 19,02 g (68%). The mixture of isomers was led from 80 ml of dioxane to obtain 1,4-diazabicyclo[3.2.2]nonan-3-one (5,12 g, 18%). Drove the solvent from the filtrate, after flash chromatography of the residue (with acetone) was obtained 1,3-diazabicyclo[3.2.2]nonan-4-one (8,91 g, 32%).

1,4-Diazabicyclo[3.2.2]nonan [J. Med. Chem. 1993, 36, 2311-23201 (intermediate compound)

1,4-Diazabicyclo[3.2.2]nonan-3-one (5,12 g, 36 mmol) was dissolved in tetrahydrofuran (50 ml), the solution was added sociallyengaged (2.28 g, 60 mmol) and the reaction mixture was heated 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 was removed from the filtrate by evaporation on a rotary evaporator when s is low pressure. The resulting substance was distilled in the apparatus Cuellar (Kugelrohr) (0.5 mbar (50 PA), 70°). The output is specified in the header connection: 3.11 g (68%)

3-Bromo-2-francebuy acid (intermediate compound)

To a mixture of 3-bromofuran (51,0 g, 0,347 mol) and THF (tetrahydrofuran (THF) (250 ml) was added diisopropylamide lithium (191 ml, 0,382 mol; 2 M solution in a mixture of heptane BLTP/ethylbenzene) at -70°C. the Mixture was stirred for 1 hour at -70°C. was Added dry ice (100,3 g, 2.28 mol) and the mixture was stirred until stood out carbon dioxide. Was added water (50 ml), then aqueous solution of hydrochloric acid (380 ml, 2 M). The tetrahydrofuran evaporated. The mixture was extracted with diethyl ether (3×100 ml). The combined ethereal phase was extracted with aqueous sodium hydroxide solution (3×100 ml, 2 M). The aqueous phase was cooled on ice and acidified with an aqueous solution of hydrochloric acid (100 ml, 10 M). The mixture was extracted with ether (3×100 ml). The combined ethereal phase was evaporated. Yield 36 g (54%). TPL (melting point) 118,5°C.

Method And

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-furan-2-yl-methanone (Compound A1)

A mixture of 1,4-diaza-bicyclo[3.2.2]nonane (0.50 g, 4.0 mmol), 2-frailcare (0,52 mg, 4.0 mmol), diisopropylethylamine (1,02 g, 7.9 mmol) and 1,2-dimethoxyethane (25 ml) was stirred at room temperature overnight. The product was besieged in the form of hydrochloric acid Sol is, was filtered and washed with 1,2-dimethoxyethane (5 ml). Yield 0.84 g (82%). TPL 279-283 of the°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-bromo-furan-2-yl-methanone (Compound A2)

Specified in the title compound was obtained by method a from 5-bromo-2-frailcare (method B), without using diisopropylethylamine. Was added an aqueous solution of sodium hydroxide (10 ml, 1 M). The mixture was extracted with dichloromethane (3×10 ml). The result chromatography on silica gel with a mixture of dichloromethane, methanol and concentrated ammonia (89:10:1) has been specified in the header connection. The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. TPL 192,7-196,4°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-nitro-furan-2-yl-methanone (Compound A3)

Specified in the title compound was obtained by method a from 5-nitro-2-frailcare (method B), without using diisopropylethylamine. TPL 242,6-251,0°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanone (Compound A4)

Specified in the title compound was obtained by method a from 5-(4-nitrophenyl)-2-frailcare (method B), without using diisopropylethylamine. TPL 298,2°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-triptoreline)-furan-2-yl-methanone (Compound A5)

Specified in C is the cylinder compound was obtained by method a from 5-{3-triptoreline)-2-frailcare (method B), not using diisopropylethylamine. TPL EUR 236.9°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-chlorophenyl)-furan-2-yl-methanone (Compound A6)

Specified in the title compound was obtained by method a from 5-(4-chlorophenyl)-2-frailcare (method B), without using diisopropylethylamine. TPL 272,5-274,7°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methanone (Compound A7)

Specified in the title compound was obtained by method a from 5-(2-nitrophenyl)-2-frailcare (method B), without using diisopropylethylamine. TPL 216,3-219,9°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-{3-nitrophenyl)-furan-2-yl-methanone (Compound A8)

Specified in the title compound was obtained by method a from 5-(3-nitrophenyl)-2-frailcare (method B), without using diisopropylethylamine. TPL 224-230°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-8-methoxy-benzofuran-2-yl-methanone (Compound A9)

Specified in the title compound was obtained by method a from 8-methoxy-2-benzoperylene (method B), without using diisopropylethylamine. TPL 241-246°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-oxazolin-5-yl-methanone (Compound a10)

Specified in the title compound was obtained by method a from 5-oxytrichloride (method B), without using diisopropylethylamine. TPL >160°C (decomposition).

Specified in the title compound was obtained by method a from 2-benzoperylene (method B), without using diisopropylethylamine. TPL 264°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-furan-2-yl-methanone (Compound A12)

Specified in the title compound was obtained by method a from 3-methyl-2-frailcare (method B), without using diisopropylethylamine. TPL 225,8-227,2°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-4,5-dibromo-furan-2-yl-methanone (Compound A13)

Specified in the title compound was obtained by method a from 4,5-dibromo-2-frailcare (method B), without using diisopropylethylamine. TPL 250,9-254,3°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-chloro-5-triptoreline)-furan-2-yl-methanone (Compound A14)

Specified in the title compound was obtained by method a from 5-(2-chloro-5-triptoreline)-2-frailcare (method B), without using diisopropylethylamine. TPL 201°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-were)-furan-2-yl-methanone (Compound A15)

Specified in the title compound was obtained by method a from 5-(2-nitro-4-were)-2-frailcare (method B), without using diisopropylethylamine. TPL 199°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-benzofuran-2-yl-methanone (Compound A16)

Specified in the header of the floor connection is made by method a from Z-methyl-2-benzoperylene (method B), not using diisopropylethylamine. TPL 260-276°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenyl-1,3,4-oxadiazol-2-yl-methanone (Compound A17)

Specified in the title compound was obtained by method a from 5-methyl-1,3,4-oxadiazol-2-carbonyl-chloride chloride instead of using diisopropylethylamine. TPL 280-290°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-methanone (Compound A18)

Specified in the title compound was obtained by method a from 5-(3,5-dichlorophenoxy)-furan-2-carbonylchloride, not using diisopropylethylamine. TPL 124°C.

Hydrochloric acid salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)-thiomethyl]-furan-2-yl-methanone (Compound A19)

Specified in the title compound was obtained by method a from 5-[5-(trifluoromethyl-2-pyridyl)-thiomethyl]furan-2-carbonylchloride, not using diisopropylethylamine. TPL 176°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-bromo-furan-2-yl-methanone (Compound A20)

Specified in the title compound was obtained by method a from 3-bromo-2-frailcare (method B from 3-bromo-2-frankenboob acid), not using diisopropylethylamine. TPL 157,4-159,9°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanone (Compound A21)

Specified in the title compound was obtained by method a from harang drid 5-(2-phenylethenyl)-2-frankenboob acid. TPL 166,3-168,3°C.

Method B

3-Bromo-2-francebuy acid (intermediate compound)

To a mixture of 3-bromofuran (51,0 g, 0,347 mol) and THF (250 ml) was added diisopropylamide lithium (191 ml, 0,382 mol; 2 M solution in a mixture of heptane/THF/ethylbenzene) at -70°C. the Mixture was stirred for 1 hour at -70°C. was Added dry ice (100,3 g, 2.28 mol) and the mixture was stirred until stood out carbon dioxide. Was added water (50 ml), then aqueous solution of hydrochloric acid (380 ml, 2 M). The tetrahydrofuran evaporated. The mixture was extracted with diethyl ether (3×100 ml, 2 M). The combined ethereal phase was extracted with aqueous sodium hydroxide solution (3×100 ml, 2 M). The aqueous phase was cooled on ice and acidified with an aqueous solution of hydrochloric acid (100 ml, 10 M). The mixture was extracted with ether (3×100 ml). The combined ethereal phase was evaporated. Yield 36 g (54%). TPL 118,5°C.

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

Specified in the title compound was obtained by stirring a mixture of 5-(4-nitrophenyl)-2-frankenboob acid (1.0 g, 4.3 mmol) and thionyl chloride (10 ml) by boiling under reflux for 2 hours. The mixture was evaporated and then was evaporated with anhydrous toluene. The acid chloride was used without further purification.

Method In

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone (With the Association B1)

A mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanone (0,70 g, 1.9 mmol), palladium on coal (400 mg, 5%) and ethanol (30 ml) was stirred in hydrogen atmosphere for 24 hours. The mixture was filtered through celite and evaporated. The yield of 0.44 g (74%). The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. TPL 227,8°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-AMINOPHENYL)-furan-2-yl-methanone (Compound B2)

Specified in the title compound was obtained by the method of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methanone. TPL 201,1-207,3°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-AMINOPHENYL)-furan-2-yl-methanone (Compound B3)

Specified in the title compound was obtained by the method of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-nitrophenyl)-furan-2-yl-methanone. TPL 184,9-188,2°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-amino-4-were)-furan-2-yl-methanone (Compound B4)

Specified in the title compound was obtained by the method of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-were)-furan-2-yl-methanone. TPL 179°C.

Method D

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-acetylaminophenol)-furan-2-yl-methanon (Compound G1)

Acetic anhydride (133 mg, 1.3 mmol)dissolved in dichloromethane (2 ml)was added dropwise to a mixture of (1,diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone and dichloromethane (10 ml) at room temperature. The mixture was left to mix for 4 hours. Was added an aqueous solution of sodium hydroxide (20 ml, 1 M), then was extracted with dichloromethane (3×20 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane : methanol (4:1) and 2%methanol as eluent. The product was isolated as free base. TPL 113°C (decomposition).

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-acetylaminophenol)-furan-2-yl-methanone (Compound G2)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-AMINOPHENYL)-furan-2-yl-methanone. The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. TPL 178,9-to 185.0°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-acetylaminophenol)-furan-2-yl-methanone (Connection G3)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-AMINOPHENYL)-furan-2-yl-methanone. The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. TPL 216°C.

N-{4-{5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-propionamide, free base (Compound G4)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-m is tanona. TPL 264°C.

Triperoxonane salt of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-2.2.2-Cryptor-ndimethylacetamide (Connection G5)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone and triperoxonane anhydride. TPL 219°C.

Fumarola salt of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-isobutyramide (Connection G6)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone and anhydride somaclonal acid. TPL 223°C.

Method D

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-diphenylsulfone)AMINOPHENYL]-furan-2-yl-methanon, free base (Compound D1)

A mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone (0.5 g, 1.6 mmol) and dichloromethane (5 ml), methanesulfonamide (2,12 g, 18.4 mmol) and dichloromethane (5 ml) was stirred at room temperature for 15 hours. Was added an aqueous solution of sodium hydroxide (5 ml, 1 M), then was extracted with dichloromethane (3×5 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane : methanol (9:1) and 1%methanol as eluent. The product was isolated as free base. Yield 20 mg (3%). TPL 189°C.

Fumarola salt of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]n the NAS-4-carbonyl)-furan-2-yl]-phenyl}-acrylamide (Compound D2)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone and akriloilkhlorida (1.6 EQ.). TPL 220°C.

Fumarola salt of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-benzamide (Compound D3)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone, diisopropylethylamine (2 EQ.) and benzoyl chloride (1.5 EQ.). TPL 254°C.

Fumarola salt (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-dimethylbutylamine)phenyl]-furan-2-yl-methanone (Compound D4)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone, diisopropylethylamine (2 EQ.) and benzosulfimide (1.5 EQ.). TPL 201-203°C.

Fumarola salt cyclopropanecarboxylic acid {4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-amide (Compound D5)

Specified in the title compound was obtained by method D from (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone and cyclopropanecarbonitrile. TPL 254°C.

Method E

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(formylamino]-furan-2-yl-methanon (Compound E1)

A mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone (0.5 g, 1.6 mmol) and ethylformate (30 ml) was stirred p is boiled under reflux for 9 days. The mixture was evaporated. Was added an aqueous solution of sodium hydroxide (20 ml, 1 M), then the mixture was extracted with dichloromethane (3×20 ml). The crude mixture was purified by chromatography on silica gel using a mixture of dichloromethane : methanol (9:1) and 1%methanol as eluent. The product was isolated as free base. The output of 0.29 g (53%). TPL 236°C.

Way W

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone chlormethine chloride (Compound W1)

Ethylisothiocyanate (182 mg, of 2.09 mmol)dissolved in dichloromethane (20 ml) was added dropwise to a mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanone and dichloromethane (10 ml) at 5°C. the Mixture was left to mix for 4 hours at 5°and for 11 hours at room temperature. The volume of solvent was reduced three times and the solid product was separated by filtration. TPL >300°C.

The method C

N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-acrylamide matilija iodide (Compound Z1)

A mixture of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl}-acrylamide (175 mg, 0,479 mmol) and dichloromethane (10 ml), was stirred at -70°C. was Added itmean (68 mg, 0,479 mmol)dissolved in dichloromethane (5 ml). The mixture was left to mix at -70°C for 1 hour. The mixture was left to warm to room temperature, evaporated and rubbed the place with diethyl ether. Yield 0.15 g (62%). TPL 230-246°C.

Method And

N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl)-acrylamide N-oxide (Compound I1)

A mixture of N-{4-[5-(1,4-diaza-bicyclo[3.2.2]nonan-4-carbonyl)-furan-2-yl]-phenyl)-acrylamide (175 g, 0,479 mmol), meta-chloroperoxybenzoic acid (165 mg, 0,958 mmol) and dichloromethane (5 ml) was stirred at room temperature for 15 hours. The raw mixture was evaporated. The result chromatography on silica gel with a mixture of dichloromethane, methanol and concentrated ammonia (89:10:1) has been specified in the header of the product. Yield 180 mg (99%). TPL 162°C.

Example 2

In vitro inhibition of binding3H-α-bungarotoxin in the rat brain

In this example, determine the affinity of the compounds according to the invention to bind to α7subtype of nicotinic receptors.

α-Bungarotoxin is a peptide selected from the Elapidae venom of the snake Bungarus multicinctus. It has a high affinity for neuronal and neuromuscular nicotinic receptors, where it acts as a strong antagonist,3H-α-bungarotoxin marks nicotinic acetylcholine receptors formed α7-isoform of the a subunit is found in the brain and α1-isoform in neuromuscular junctions.

Tissue preparation

Preparation was carried out at 0-4°C. the cerebral Cortex itself is s Wistar rats (150-250 g) are homogenized for 10 seconds in 15 ml of 20 mm HEPES 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. The tissue suspension is subjected to centrifugation at 27000×g for 10 minutes. The supernatant is drained off and the precipitate washed twice by centrifugation at 27000×g for 10 minutes in 20 ml of fresh buffer, the remaining residue is then resuspended in fresh buffer containing 0.01% BSA (35 ml per 1 g of original tissue)and used for analyses of the binding.

Analysis

500 μl aliquots of the homogenate is added to 25 μl of test solution and 25 μl of3H-α-bungarotoxin (2 nm final concentration), mixed and incubated for 2 hours at 37°C. non-specific binding determine using (-)-nicotine (1 mm, final concentration). After incubation in the sample add 5 ml of ice-cold HEPES buffer containing 0.05% PEI (polyethylenimine) and applied directly to fiberglass filters Whatman GF/C (pre-soaked in 0.1% PEI for at least 6 hours) with suction and immediately washed with 2×5 ml ice-cold buffer.

The amount of radioactivity on the filters define traditional liquid scintillation counting. Specific binding represents the total binding minus nonspecific binding.

The experimental value is expressed as IR50(the concentration of testere the CSOs substances, inhibiting specific binding3H-α-bungarotoxin 50%).

The results of the experiments are shown in table 1.

Table 1
Inhibition of binding3H-α-bungarotoxin
Connection # IR50(ΜM)
A10,54
A50,051
OT0,080
E10,017

Example 3

The pharmaceutical composition

Chemical compound according to the invention can be represented in the desired form of the composition and can be dosed in any desired quantity. This example describes the preparation in the form of a standard tablet, in which the active pharmaceutical ingredient (API) can be used any of the compounds according to the invention.

The composition of standard tablets

Tablets containing 1,585 mg API per tablet, is obtained using the composition shown in table 2.

1,585
Table 2
IngredientFunctionQuantity (mg/tablet
AFIThe active ingredient
Microcrystalline cellulose granulesThe filler /binder38,045
Microcrystalline celluloseThe filler /binder1,955
LactoseFiller56,715
Sodium salt croscarmelloseBaking powder0,500
Colloidal silicon dioxideImproved flowing properties0,200
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 granulate containing the active pharmaceutical ingredient, microcrystalline cellulose, lactose and sodium salt crosscarmelose weigh, sift in the mixer and mix. The resulting mixture is then pressed into tablets.

1. Diazabicyclo aryl derivative, represented by formula I

any e what about the enantiomers, or any mixture of its enantiomers or its pharmaceutically acceptable salt accession, where

n = 2 and

X and Y independently of one another represent CR2, CR3and N, where

R2represent hydrogen, C1-6alkyl or halogeno; and

R3represents hydrogen or halogeno; and

R1represents hydrogen, halogeno, trifluoromethyl, nitro or phenyl, whereby phenyl may be substituted by one or two substituents selected from: C1-6of alkyl, halogeno, trifloromethyl, amino, nitro and/or groups of the formula R CONH - or (R SO2)2N-, where R' represents hydrogen, C1-6alkyl, C3-7cycloalkyl, trifluoromethyl, vinyl, or phenyl; or

a group of formula phenyl-Z-(C1-6alkyl)m-, phenyl-S≡ - or pyridyl-Z-(C1-6alkyl)m-where

m is 0 or 1; and

Z represents O or S;

and where phenyl and pyridyl may be substituted by one or two substituents selected from: halogeno or trifloromethyl; or

R1and R3together with the carbon atoms to which they are attached, form benzododecinium aromatic carbocyclic ring which may be substituted With1-6the alkyl or C1-6alkoxy.

2. Diazabicyclo aryl derivative according to claim 1, where

at least one of X and Y represents N and the other of X and Y represents CR2.

3. Diazabicyclo aryl derivative according to claim 1, where

one or two of R2and R3independently of one another represent hydrogen and/or halogen; and

R1represents hydrogen, halogeno, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halogeno-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halogeno-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, 3-phenyl-ndimethylacetamide, 4-phenyl-ndimethylacetamide, 4-phenyl-propionamide, 4-phenyl-isobutyramide, 4-phenyl-acrylamide, 4-(N,N-dimethyl-sulfonyl-amino)-phenyl, 4-phenyl-2,2,2-Cryptor-ndimethylacetamide, amide 4-phenyl-cyclopropanecarboxylic acid, 4-phenyloxy, 3,5-dihalogen-phenyloxy, phenyl-ethinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl and/or 5-trifluoromethyl-2-pyridyl-thiomethyl.

4. Diazabicyclo aryl derivative according to claim 1, where X and Y both represent CR2, CR3or N.

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

,

any of its enantiomers or any mixture of its enantiomers, or supplied with the ski acceptable salt accession, where

n is 2; and

X represents CR4or N;

R1represents hydrogen, halogeno, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halogeno-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halogeno-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, 3-phenyl-ndimethylacetamide, 4-phenyl-ndimethylacetamide, 4-phenyl-propionamide, 4-phenyl-isobutyramide, 4-phenyl-acrylamide, 4-(N,N-dimethyl-sulfonyl-amino)-phenyl, 4-phenyl-2,2,2-Cryptor-ndimethylacetamide, amide 4-phenyl-cyclopropanecarboxylic acid, 4-phenyloxy, 3,5-dihalogen-phenyloxy, phenyl-ethinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl or 5-trifluoromethyl-2-pyridyl-thiomethyl;

R2represents hydrogen or halogeno; and

R4represents hydrogen, C1-6alkyl or halogeno.

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

any of its enantiomers or any mixture of its enantiomers or its pharmaceutically acceptable salt accession, where

n is 2; and

X represents CR4or N, where R4represents hydrogen or C1-6alkyl;

R5represents hydrogen, C1-6alkyl or C1-6alkoxy; and R6represents hydrogen, C1-6alkyl or C1-6alkoxy.

7. Diazabicyclo aryl derivative according to claim 1, where R1represents a group of formula-CH2-Z-phenyl, -CH2-Z-pyridyl or- ≡S-phenyl, where

Z represents O or S;

and where the group phenyl and pyridyl may be substituted 1-2 times by trifluoromethyl.

8. Diazabicyclo aryl derivative according to claim 1, where

R1represents hydrogen, halogeno, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitrophenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halogeno-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halogeno-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, 3-phenyl-ndimethylacetamide, 4-phenyl-ndimethylacetamide, 4-phenyl-propionamide, 4-phenyl-isobutyramide, 4-phenyl-acrylamide, 4-(N,N-dimethyl-sulfonyl-amino)-phenyl, 4-phenyl-2,2,2-Cryptor-ndimethylacetamide, amide 4-phenyl-cyclopropanecarboxylic acid, 4-phenyloxy, 3,5-dihalogen-phenyloxy, phenyl-ethinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl or 5-trifluoromethyl-2-pyridyl-thiomethyl;

R2represents hydrogen, C1-6alkyl or halogeno; and

R3 represents hydrogen or halogeno.

9. Diazabicyclo aryl derivative according to claim 1, which is:

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-oxazolin-5-yl-methanon, (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenyl-1,3,4-oxadiazol-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-8-methoxy-benzofuran-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzofuran-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-benzofuran-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)-thiomethyl]-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-bromo-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-nitro-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-triptoreline)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-chlorophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitrophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-nitrophenyl)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-acetylaminophenol)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-what AMINOPHENYL)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-AMINOPHENYL)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-acetylaminophenol)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3-acetylaminophenol)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-methyl-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-4,5-dibromo-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-chloro-5-triptoreline)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-nitro-4-were)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(2-amino-4-were)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-dimethylsulphamoyl)AMINOPHENYL]-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-formylamino)-furan-2-yl-methanon,

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(3,5-dichlorophenoxy)-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[5-(trifluoromethyl-2-pyridyl)-thiomethyl]-furan-2-yl-methanon,

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-3-bromo-furan-2-yl-methanon,

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-phenylethynyl-furan-2-yl-methanon,

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

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-[4-(N,N-diphenylacetylene)phenyl]-furan-2-yl-methanon,

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

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

(1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-AMINOPHENYL)-furan-2-yl-methanon,

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

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

its enantiomers, or a mixture of its enantiomers or its pharmaceutically acceptable salt of the merger.

10. Pharmaceutical composition having modulating activity against nicotinic receptors containing a therapeutically effective amount diazabicyclo aryl derivative according to any one of claims 1 to 9, or its pharmaceutically acceptable salts joining together with at least one pharmaceutically acceptable carrier or diluent.

11. Application diazabicyclo aryl derivative according to any one of claims 1 to 9, or its pharmaceutically acceptable salt accession to the manufacture of pharmaceutical compositions/medicaments with(his) modulating the activity is in respect of nicotinic receptors.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to novel individual compounds of series 2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates, namely, to isopropyl-12-aroyl-2-hydroxy-1,6-dioxo-4-(3-pyridinyl)-7-phenyl-1,3,6,7-tetrahydro-2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates of the formula (1) wherein Ar means phenyl or p-methoxyphenyl, and to a method for their synthesis. Method for synthesis of compound of the formula (1) involves interaction of 3-aroyl-5-phenylpyrrolo[1,2-a]-quinoxaline-1,2,4(5H)-triones with isopropyl-3-amino-3-(3-pyridinyl)-2-propenoate in an inert aprotonic solvent medium and the following isolation of end substances. The proposed method provides synthesis of novel compounds of the formula (1) possessing antibacterial effect with high yield and selectivity.

EFFECT: improved method of synthesis.

4 cl, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new individual compounds of azapentacycloeicosanes class. Invention describes 20-aroyl-12-hydroxy-17,17-dimethyl-3-phenyl3,10,13-triazapentacyclo[10.7.1.01,10.O4,9.O14,19]eicosa-4,6,14(19)-2,11,15-triones of the formula:

wherein R means hydrogen atom; Ar means phenyl; or R means benzyl and Ar means p-methoxyphenyl group. Also, the invention describes a method for preparing these compounds. Invention provides preparing new compounds that can be used as the parent substances for synthesis of new heterocyclic systems.

EFFECT: improved preparing method, valuable chemical properties of compounds.

4 cl, 1 tbl, 3 ex

The invention relates to a single-stage process for the preparation of new chemical compounds - cyclocarbonate

The invention relates to organic chemistry, specifically to a method for producing cyclic nitramines

The invention relates to new compounds which can be used as inhibitors of matrix metalloprotease, in particular interstitial collagenases, and which is effective for the treatment of painful condition caused by excessive activity of matrix metalloprotease
The invention relates to the selection of triethylenediamine, which is used as a catalyst in obtaining polyurethane foam and which is a hardener of epoxy resins and vulcanizer polyester oils

The invention relates to new compounds of General formula (I), where R1is hydrogen, alkyl with 1 to 4 carbon atoms, R2hydrogen, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl, residues of formula-CH=CH-COOR3CH2CH2COOR3, -CH2CH2CN, -CH2CH2COCH3, -CH2PINES3where R3means methyl or ethyl, or a residue of the General formula R4- NH-CHR5-CO-, where R4denotes hydrogen, alkyl with 1 to 3 atoms wereda R5denotes hydrogen, alkyl with 1 to 4 carbon atoms, or benzyl, the Invention also concerns a pharmaceutical composition having antibacterial activity, containing the compounds of formula (I)

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: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

8 cl, 11 tbl, 463 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel chemical compound, namely, to biologically active compound of the formula (I): possessing anti-arrhythmic activity and representing 5'-bromolappaconitine hydrobromide. Toxicity of this compound is by 4.8-fold less toxic as compared with analog used in medicinal practice and representing lappaconitine hydrobromide. Proposed compound possesses the expressed anti-arrhythmic activity in models with calcium chloride and adrenaline arrhythmia and provides the complete blocking both types of arrhythmia after administration of the dose that is 10-fold less of the therapeutic dose of lappaconitine hydrobromide.

EFFECT: improved and valuable medicinal properties of compound.

2 cl, 2 tbl, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a whitening composition comprising: (a) monomeric ligand or catalyst with transient metal of ligand of the formula (I): wherein R represents hydrogen atom; R1 and R2 are chosen independently from (C1-C4)-alkyl, pyridine-2-yl-methyl and (C2-C4)-alkylmethyl; X represents -C=O; R3 and R4 are similar and represent -(CH2)nC(O)O-(C1-C4)-alkyl; n = 0-4, and (b) equilibrating carriers and additional components. This composition is useful for catalytic whitening substrates with atmosphere oxygen. Also, invention describes a method for whitening the substrate involving applying step of the whitening composition on substrate in aqueous medium.

EFFECT: valuable properties of substances, improved whitening method.

11 cl, 2 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: compounds of formula I are disclosed, wherein R1, R2, R3, R4, R5, R6, R7, R41, R42, R43, R44, R45, R46, A, and B are as described in description.

EFFECT: new compounds with increased electrophysiological activity useful in treatment of cardiac arrhythmias.

132 cl, 1 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new substituted 2,3,4,5-tetrahydro-1N-pyrido[4,3-b]indoles with general formula 1.1, 1.2 or 1.3, their pharmaceutical salts and/or hydrates with antihistamine activity. In general formulae 1.1, 1.2 or 1.3 radicals assume values given below . In 1.1 compounds, R1 represents a substitute, chosen from hydrogen or unsubstituted C1-C5 alkyl; R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3; n=0 or 1-3; in 1.2 compounds R1 represents a substitute of an amino group, chosen from hydrogen or optionally substituted C1-C5 alkyl; R3 represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar1 represents an aryl or heterocyclyl, containing at least one carboxyl and/or alkoxycarboxyl substitute or R3i represents a carboxyl and/or alkyloxycarboxyl substitute, and Ar1 represents optionally substituted aryl or heterocyclyl; in 1.3 compounds, R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar2 represents optionally substituted aryl or heterocyclyl; k=0 or 1-4; m=1 or 2.

EFFECT: compounds can be used for making drug formulation for treating allergies, autoimmune diseases such as pollen allergy, urticaria, bronchial asthma etc.

17 cl, 10 dwg, 2 tbl,13 ex

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