RU2338746C2 - New diazabicyclic aryl derivatives, pharmaceutical compositions containing them and their use - Google Patents

Abstract

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, C_1-6alkyl 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-(C_1-6alkyl)_m-, phenyl -C≡C- or pyridyl -Z-(C_1-6alkyl)_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

Description

FIELD OF THE INVENTION

This invention relates to new diazabicyclic aryl derivatives, which are found to be cholinergic ligands of nicotinic acetylcholine receptors. Due to their pharmacological profile, the compounds of the invention may be useful for treating various diseases or disorders such as diseases and disorders associated with the cholinergic system of the central nervous system (CNS), peripheral nervous system (PNS), diseases and disorders associated with smooth muscle contractions endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases and disorders associated with inflammation, pain and withdrawal symptoms, due lennye termination of abuse of chemical substances.

BACKGROUND OF THE INVENTION

The endogenous cholinergic neurotransmitter acetylcholine implements a biological effect through two types of cholinergic receptors: muscarinic acetylcholine receptors (mAHP) and nicotinic acetylcholine receptors (nAChR).

It is well known that muscarinic acetylcholine receptors quantitatively prevail over nicotinic acetylcholine receptors in the brain area important for memory and cognitive ability, and numerous studies aimed at developing agents for the treatment of memory disorders have focused on the synthesis of acetylcholine receptor modulators.

However, interest has recently appeared in the development of nAChR modulators. Some diseases are associated with degeneration of the cholinergic system, such as senile dementia of the Alzheimer's type, vascular dementia, and impaired cognitive function due to an organic brain-damaging disease directly associated with alcoholism.

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

SUMMARY OF THE INVENTION

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

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

In a first aspect of the invention, diazabicyclic aryl derivatives of formula I are provided.

any enantiomers thereof or any mixture of their enantiomers, or their prodrugs, or pharmaceutically acceptable addition salts, where

n is 1, 2 or 3 and

X and Y independently represent CR ² , CR ³ and / or N, where R ² and R ³ independently represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halogen , haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, aryl-alkyl, heteroaryl and / or heteroaryloxy, wherein aryl, aryloxy, aryl-alkyl, heteroaryl and heteroaryloxy may optionally be substituted with one or two of halo, haloalkyl, haloalkyl , cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'represents hydrogen or alkyl;

R ¹ represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl or heteroaryl, and aryl or heteroaryl may optionally be substituted with one or two of alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, R'SO ₂ NH- or (R'SO ₂ ) ₂ N-, where R 'is hydrogen, alkyl cycloalkyl, haloalkyl, alkenyl, phenyl or benzyl; or a group of the formula aryl-alkyl-, aryl-Z- (alkyl) _m -, aryl-C≡C-, heteroaryl-Z- (alkyl) _m - or heteroaryl-C≡C-, where m is 0 or 1, and Z represents O or S; and where aryl and heteroaryl may optionally be substituted with one or two of: alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, R'SO ₂ NH- or (R 'SO ₂ ) ₂ N-, where R' represents hydrogen or alkyl, or

R ¹ and R ² , R ¹ and R ^3, together with the carbon atoms to which they are attached, form a benzocondensed aromatic carbocyclic ring, wherein the benzocondensed aromatic carbocyclic ring may optionally be substituted with one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'represents hydrogen or alkyl.

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

According to another aspect, the invention relates to the use of a diazabicyclic aryl derivative according to the invention or a pharmaceutically acceptable addition salt thereof for the manufacture of pharmaceutical compositions / drugs for treating, preventing or alleviating a disease or disorder or condition of a mammal, including a human being, the disease, disorder or condition being sensitive to modulation of cholinergic receptors.

In yet another aspect of the invention, there is provided a method of treating, preventing or alleviating a disease, disorder or condition of a living animal organism, including a human being, the disorder, disease or condition being sensitive to modulation of cholinergic receptors, and this method comprises the step of administering to such a living animal organism in need of this, a therapeutically effective amount of a diazabicyclic aryl derivative according to the invention.

Other objects of the invention will become apparent to those skilled in the art from the following detailed description and examples.

DETAILED DESCRIPTION OF THE INVENTION

Diazabicyclic aryl derivatives

In a first aspect of the invention, there is provided a diazabicyclic aryl derivative of formula I

,

,

any enantiomers thereof or any mixture of its enantiomers, or prodrugs thereof, or pharmaceutically acceptable addition salts,

where n is 1, 2 or 3;

X and Y independently represent CR ² , CR ³ and / or N, where R ² and R ³ independently represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halogen , haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, aryl-alkyl, heteroaryl and / or heteroaryloxy, wherein aryl, aryloxy, aryl-alkyl, heteroaryl and heteroaryloxy may optionally be substituted with one or two of halo, haloalkyl, haloalkyl , cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'represents hydrogen or alkyl;

R ¹ represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl or heteroaryl, and aryl or heteroaryl may optionally be substituted with one or two of alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, R'SO ₂ NH- or (R'SO ₂ ) ₂ N-, where R 'is hydrogen, alkyl cycloalkyl, haloalkyl, alkenyl, phenyl or benzyl; or a group of the formula aryl-alkyl-, aryl-Z- (alkyl) _m -, aryl-C≡C-, heteroaryl-Z- (alkyl) _m - or heteroaryl-C≡C-, where m is 0 or 1; and Z represents O or S; and where aryl and heteroaryl may optionally be substituted with one or two of alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, R'SO ₂ NH- or (R ' SO ₂ ) ₂ N-, where R 'represents hydrogen or alkyl, or

R ¹ and R ² , R ¹ and R ³ together with the carbon atoms to which they are attached form a benzocondensed aromatic carbocyclic ring, and this benzocondensed aromatic carbocyclic ring may optionally be substituted with one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy , alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'represents hydrogen or alkyl.

In a preferred embodiment, the invention provides a diazabicyclic aryl derivative of formula I, wherein

X is CR ³ or N, where R ³ is hydrogen, alkyl, cycloalkyl, cycloalkyl alkyl, alkoxy, cycloalkoxy, cyanoalkyl, halogen, CF ₃ , OCF ₃ , CN, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy ;

R ¹ and R ² independently from each other are hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkoxy, cyanoalkyl, halogen, CF ₃ , OCF ₃ , CN, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy or

R ¹ and R ² together with the carbon atoms to which they are attached form a benzocondensed aromatic carbocyclic ring.

In another preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of formula I, wherein

X and Y independently are CR ² or N, where R ² is hydrogen, alkyl, cycloalkyl, cycloalkyl alkyl, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy , heteroaryl or heteroaryloxy, wherein aryl, aryloxy, heteroaryl or heteroaryloxy may optionally be substituted with one or two of halo, haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of formula R'CONH-, where R 'is hydrogen or alkyl , and

R ¹ represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy, and aryl, aryloxy, heteroaryl or heteroaryl be substituted by one or two of halo, haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'is hydrogen or alkyl, or

R ¹ and R ^2, together with the carbon atoms to which they are attached, form a benzocondensed aromatic carbocyclic ring, and this benzocondensed aromatic carbocyclic ring may possibly be substituted with one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cycloalkoxy, cyanoalkyl, halogen , haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'represents hydrogen or alkyl.

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

heteroaryl is an aromatic 5- or 6-membered monocyclic heterocyclic group selected from the group consisting of furanyl, in particular furan-2- or 3-yl; thienyl, in particular thien-2- or 3-yl; pyrrolyl (azolyl), in particular pyrrole-2- or 3-yl; oxazolyl, in particular oxazol-2-, 4- or 5-yl; imidazolyl, in particular imidazol-2- or 4-yl; pyrazolyl, in particular pyrazol-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-thiadiazol-2-yl; pyridyl, in particular pyrid-2-, 3- or 4-yl; pyridazinyl, in particular pyridazin-3- or 4-yl; pyrimidinyl, in particular pyrimidin-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] thienyl, in particular benzothien-2-, 5- or 6-yl; benzimidazolyl, in particular benzimidazol-2-, 5- or 6-yl; quinolinyl, in particular quinolin-2-, 3-, 6- or 7-yl; isoquinolinyl, in particular isoquinolin-3-, 6- or 7-yl; and cinnolinyl, in particular cinnolin-6-or 7-yl.

In an even more preferred embodiment, aryl is phenyl; aryl alkyl is 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-thiadiazol-2-yl; pyridyl, in particular pyrid-2-, 3- or 4-yl; or indolyl, in particular indol-2, 3-, 5- or 6-yl.

In a third preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of the formula I, Ia, Ib, II or III, where n is 1, 2 or 3. In a more preferred embodiment, the diazabicyclic aryl of the invention is a diazabicyclic aryl derivative of the formula I, Ia, Ib, II or III, where n is 2.

In a fourth preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of formula I, wherein at least one of X and Y is N and the other of X and Y is CR ² and n, R ¹ and R ² are as defined above.

In a fifth preferred embodiment of the invention, a diazabicyclic aryl derivative of the formulas la and 1b is provided

;

;

where n and R ¹ are as defined above.

In a sixth preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of formula IB or Ig

;

;

where R ¹ is as defined above.

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

(1,4-diaza-bicyclo [3.2.2] non-4-yl) -oxazolyl-5-yl-methanone,

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

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

its enantiomer or a mixture of its enantiomers, or its pharmaceutically acceptable addition salt.

In a seventh preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of formula I, wherein one or both of R ² and R ^{3 are} independently hydrogen and / or halogen and R ¹ and remaining from R ² and R ^{3 are} independently hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halogen, CF ₃ , OCF ₃ , CN, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino phenyl, N-3-phenyl-acetamide, N-4-phenyl-acetamide, 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-trifluoroacetamide trifluoroacetic acid, 4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy, 3,5- dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl and / or 5-trifluoromethyl-2-pyridyl-thiomethyl.

In an eighth preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of formula I, wherein one of R ¹ and R ² is phenyl or naphthyl, and the other of R ¹ and R ² is hydrogen.

In a ninth preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of formula I, wherein X and Y are both CR ² , CR ³ or N, where R ² and R ^{3 are} independently hydrogen, alkyl, cycloalkyl, cycloalkyl alkyl, hydroxy , alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl and / or heteroaryloxy, moreover, aryl, aryloxy, heteroaryl and heteroaryloxy may optionally be substituted with one or two of halo, halogen hydroxy, cyano, amino, nitro, and / or groups of formula R'CONH-, wherein R 'represents hydrogen or alkyl; or X represents N or CR ² , where R ² represents hydrogen, alkyl, cycloalkyl, cycloalkyl alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy, wherein aryl, aryloxy, heteroaryl and / or heteroaryloxy may optionally be substituted with one or two of halo, haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'is hydrogen or alkyl; and Y represents N or CR ³ , where R ³ together with R ¹ and together with the carbon atoms to which they are attached form a benzocondensed aromatic carbocyclic ring, and this benzocondensed aromatic carbocyclic ring may optionally be substituted with one or two of alkyl, cycloalkyl , cycloalkyl alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'is hydrogen or alkyl.

In a tenth preferred embodiment of the invention, a diazabicyclic aryl derivative of formula II is provided.

any enantiomers thereof, or any mixture of its enantiomers, or a prodrug thereof, or a pharmaceutically acceptable addition salt thereof, wherein

n is 1, 2 or 3;

X is CR ⁴ or N, where R ⁴ is hydrogen, alkyl, cycloalkyl, cycloalkyl alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy wherein aryl, aryloxy, heteroaryl and heteroaryloxy may optionally be substituted with one or two of halo, haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'is hydrogen or alkyl;

R ¹ and R ² independently are hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, phenyl, phenyloxy, heteroaryl and / or heteroaryloxy wherein phenyl, phenyloxy, heteroaryl and heteroaryloxy may optionally be substituted with one or two of alkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, a group of the formula R'CONH-, R'SO ₂ NH- and / or (R ' SO ₂ ) ₂ N-, where R 'represents hydrogen, alkyl, cycloalkyl, haloalkyl, alkenyl, phenyl or benzyl;

where R ¹ represents hydrogen or alkyl or

R ¹ and R ² together with the carbon atoms to which they are attached form a benzocondensed aromatic benzene ring, and this benzocondensed aromatic benzene ring may optionally be substituted with one or two of alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl , halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy, wherein aryl, aryloxy, heteroaryl or heteroaryloxy may optionally be substituted with one or two of halogen but haloalkyl, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, where R 'is hydrogen or alkyl.

In a more preferred embodiment of the invention, the diazabicyclic aryl derivative is a diazabicyclic aryl derivative of formula II, wherein

R ¹ represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, halogen, CF ₃ , OCF ₃ , CN, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro phenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, N- 3-phenyl-acetamide, N-4-phenyl-acetamide, 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-trifluoroacetamide trifluoroacetic acid, 4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy, 3,5-dihalo-phenyloxy, phenyl-ethynyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl or 5-trifluoromethyl-2-pyridyl-thiomethyl;

R ² represents hydrogen or halogen and

R ⁴ represents hydrogen, alkyl or halogen.

In an eleventh preferred embodiment of the invention, a diazabicyclic aryl derivative of formula III is provided.

any enantiomers thereof, or any mixture of its enantiomers, or a prodrug thereof, or a pharmaceutically acceptable addition salt thereof, wherein

n is 1, 2 or 3;

X is CR ⁴ or N, where R ⁴ is hydrogen, alkyl, cycloalkyl, cycloalkyl alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy ;

R ⁵ and R ^{6 are} independently hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, cycloalkoxy, cyanoalkyl, halo, haloalkyl, haloalkoxy, cyano, amino, nitro, aryl, aryloxy, heteroaryl or heteroaryloxy;

In a more preferred embodiment, the diazabicyclic aryl derivative of the invention is a diazabicyclic aryl derivative of formula III, wherein R ⁴ is hydrogen or alkyl, R ⁵ is hydrogen, alkyl or alkoxy and R ⁶ is hydrogen, alkyl or alkoxy.

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

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

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

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

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

its enantiomer or a mixture of its enantiomers, or its pharmaceutically acceptable addition salt.

In a twelfth preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of the formula I, Ia, IB or II, wherein

R ¹ represents a group of the formula - (alkyl) _m -Z-aryl, - (alkyl) _m -Z-heteroaryl or -C≡C-aryl, where m is 0 or 1, Z is O or S and where aryl and heteroaryl may optionally be substituted with one or two of alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, R'SO ₂ NH- or (R'SO ₂ ) ₂ N- where R 'represents hydrogen or alkyl.

In a thirteenth embodiment of the invention, there is provided a diazabicyclic aryl derivative of the formula I, Ia, IB or II, wherein R ¹ is a group of the formula —CH ₂ —Z-phenyl, —CH ₂ —Z-pyridyl or —C≡C-phenyl, where m is 0 or 1, Z represents O or S and where the phenyl and pyridyl group may optionally be substituted with one or two of alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and / or groups of the formula R'CONH-, R 'SO ₂ NH- or (R'SO ₂ ) ₂ N-, where R' represents hydrogen or alkyl.

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

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

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

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

its enantiomer or a mixture of its enantiomers, or its pharmaceutically acceptable addition salt.

In a fourteenth preferred embodiment of the invention, there is provided a diazabicyclic aryl derivative of formula I or II, wherein R ¹ is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, halo, CF ₃ , OCF ₃ , CN, nitro, phenyl, 2-nitro-phenyl , 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitrophenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2 amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 4-halo-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl , N-3-phenyl-ac tamide, N-4-phenyl-acetamide, 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-trifluoroacetamide trifluoroacetic acid, 4-phenyl-cyclopropanecarboxylic acid amide, 4-phenyloxy, 3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl and / or 5-trifluoromethyl-2-pyridyl-thiomethyl;

R ² represents hydrogen, alkyl or halogen and

R ³ represents hydrogen, alkyl or halogen.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- [4- (N, N-dimethylsulfonyl) aminophenyl] furan-2-yl-methanone,

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

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-methanone,

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

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

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

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

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-diphenylsulfonylamino) phenyl] furan-2-yl-methanone,

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

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

(1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) -2-yl-methanone,

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 their enantiomers, or their pharmaceutically acceptable addition salts.

Any combination of two or more embodiments described herein is included within the scope of the present invention.

Determination of substituents

In the context of this invention, an alkyl group means a monovalent saturated straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms (C _1-18 alkyl), more preferably one to six carbon atoms (C _1-6 alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl . In a preferred embodiment, the alkyl is a C _1-4 alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of the present invention, the alkyl is a C _1-3 alkyl group, which in particular may be methyl, ethyl, propyl or isopropyl.

In the context of the present invention, a cycloalkyl group means a cyclic alkyl group, preferably containing from three to seven carbon atoms (C _3-7 cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the present invention, a cycloalkyl alkyl group means a cycloalkyl group as defined above, wherein this cycloalkyl group is substituted by an alkyl group as defined above. Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.

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

In the context of this invention, a cycloalkoxy group means a cycloalkyl-O- group, wherein cycloalkyl is as defined above.

In the context of the present invention, a cyanoalkyl group means an alkyl group substituted with CN, where cycloalkyl is as defined above.

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

In the context of the present invention, a haloalkoxy group means an alkoxy group as defined herein, wherein the alkoxy group is substituted with one or more halogen. Preferred haloalkoxy groups of the invention include trihalogenomethoxy, preferably CF ₃ O—.

In the context of this invention, an aryl group means a monocyclic or polycyclic aromatic hydrocarbon group. Examples of preferred aryl groups of the invention include phenyl, indenyl, naphthyl, azulenyl, fluorenyl and anthracenyl. The most preferred aryl group of the invention is phenyl.

In the context of the present invention, an aryloxy group means a group "aryl-O-", where aryl is as defined above. The most preferred aryloxy group of the invention is phenoxy.

In the context of the present invention, a heteroaryl group means an aromatic mono- or polycyclic heterocyclic group that contains one or more heteroatoms 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 thien-2- or 3-yl; selenophenyl, in particular selenophen-2- or 3-yl; pyrrolyl (azolyl), in particular pyrrole-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 pyrazol-3- or 4-yl; isoxazolyl, in particular isoxazol-3-, 4- or 5-yl; isothiazolyl, 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-triazol-4-yl or 1,2,4-triazol-3-yl; thiadiazolyl, in particular 1,2,3-thiadiazol-4- or 5-yl, or 1,3,4-thiadiazol-2-yl; pyridyl, in particular pyrid-2-, 3- or 4-yl; pyridazinyl, in particular pyridazin-3- or 4-yl; pyrimidinyl, in particular pyrimidin-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.

More preferred 5 membered heteroaryl groups of the invention include furanyl, in particular furan-2- or 3-yl; thienyl, in particular thien-2- or 3-yl; pyrrolyl (azolyl), in particular pyrrole-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; isothiazolyl, in particular isothiazol-3-, 4- or 5-yl; and thiadiazolyl, in particular 1,2,3-thiadiazol-4- or 5-yl or 1,3,4-thiadiazol-2-yl.

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

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

In the context of the present invention, an aromatic bicyclic heterocyclic group means a bicyclic heterocyclic group that contains one or more heteroatoms in its ring structure. In the context of this invention, the term "bicyclic heterocyclic group" includes benzocondensed five- and six-membered heterocyclic rings 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 indolisinyl, in particular indolysin-2-, 5- or 6-yl; indolyl, in particular indol-2-, 5- or 6-yl; isoindolyl, in particular isoindol-2-, 5- or 6-yl; benzo [b] furanyl, in particular benzofuran-2-, 5- or 6-yl; benzo [b] thienyl, in particular benzothien-2-, 5- or 6-yl; benzimidazolyl, in particular benzimidazol-2-, 5- or 6-yl; benzothiazolyl, in particular benzothiazol-5- or 6-yl; purinyl, in particular purin-2- or 8-yl; quinolinyl, in particular quinolin-2-, 3-, 6- or 7-yl, isoquinolinyl, in particular isoquinolin-3-, 6- or 7-yl; cinnolinyl, in particular cinnolin-6- or 7-yl; phthalazinyl, in particular phthalazin-6- or 7-yl; quinazolinyl, in particular quinazolin-2-, 6- or 7-yl; quinoxalinyl, in particular quinoxalin-2- or 6-yl; 1,8-naphthyridinyl, in particular 1,8-naphthyridin-2-, 3-, 6- or 7-yl, and pteridinyl, in particular pteridin-2-, 6- or 7-yl.

More 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 benzothien-2-, 5- or 6-yl; benzimidazolyl, in particular benzimidazol-2-, 5- or 6-yl, and quinoxalinyl, in particular quinoxalin-2- or 6-yl.

Most 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 benzothien-2-, 5- or 6-yl.

In the context of the present invention, a heteroaryloxy group means a heteroaryl-O- group, wherein heteroaryl is as defined above.

Pharmaceutically Acceptable Salts

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

Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic or organic acid addition salts such as hydrochloride derived from hydrochloric acid, hydrobromide obtained from hydrobromic acid, nitrate derived from nitric acid, perchlorate obtained from perchloric acid, phosphate, obtained from phosphoric acid, sulfate obtained from sulfuric acid, formate obtained from formic acid, acetate obtained from acetic acid, aconitate obtained from aconito acid, ascorbate derived from ascorbic acid, benzenesulfonate obtained from benzenesulfonic acid, benzoate obtained from benzoic acid, cinnamate obtained from cinnamic acid, citrate obtained from citric acid, embonate obtained from embonic acid, enanthate obtained from enanthic acid acids, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, lactate derived from lactic acid, maleate derived from maleic acid, little atm derived from malonic acid, mandelate obtained from mandelic acid, methanesulfonate obtained from methanesulfonic acid, naphthalene-2-sulfonate obtained from naphthalene-2-sulfonic acid, phthalate obtained from phthalic acid, salicylate obtained from salicylic acid, sorbate obtained from sorbic acid, stearate obtained from stearic acid, succinate obtained from succinic acid, tartrate obtained from tartaric acid, toluene-para-sulfonate obtained from para-toluenesulfonic acid and the like. Such salts can be formed using methods known and described in the relevant field of technology.

Other acids, for example oxalic acid, which cannot be considered pharmaceutically acceptable, may be useful in the preparation of salts suitable as intermediates in the preparation of the chemical compound of the invention and its pharmaceutically acceptable acid addition salt.

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

Examples of pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine and ammonium (and the like) salts of an anionic chemical compound of the invention. Such cationic salts can be obtained by well-known methods described in the relevant field of technology,

In the context of this invention, “onium salts” of N-containing compounds are also considered pharmaceutically acceptable salts (aza-onium salts). Preferred aza-onium salts include alkyl-onium salts, in particular methyl and ethyl-onium salts, cycloalkyl-onium salts, in particular cyclopropyl-onium salts, and cycloalkylalkyl-onium salts, in particular cyclopropyl methyl-onium salts.

Particularly preferred onium salts of the invention include salts formed at the N'-position in accordance with the following formula I '

Spatial isomers

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

Racemic forms can be divided into optical antipodes by known methods and procedures. One way to separate diastereomeric salts is to use an optically active acid and to release an optically active amine compound when treated with a base. Another method for separating racemates into optical compounds of the present invention is based on chromatography on an optically active matrix. Thus, the racemic compounds of the present invention can be divided into their optical antipodes, for example, fractional crystallization, for example, d- or I- (tartrate, mandelate or camphorsulfonate) salts.

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

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

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

Methods for the preparation of diazabicyclic aryl derivatives

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

Also, one compound of the invention can be converted into another compound of the invention by standard methods.

The final reaction products described herein can be separated by standard methods, for example, extraction, crystallization, distillation, chromatography and the like.

Biological activity

The present invention relates to the provision of new ligands and modulators of nicotinic receptors, these ligands and modulators "being useful for the treatment of diseases or disorders associated with cholinergic receptors, and in particular with the nicotinic acetylcholine receptor (nAChR). Preferred compounds of the invention exhibit pronounced selectivity for nicotinic acetylcholine receptors of the α7 subtype.

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

Due to their pharmacological profile, the compounds of the invention can be useful for treating various diseases and disorders such as diseases and disorders associated with the cholinergic system of the central nervous system (CNS), peripheral nervous system (PNS), diseases and disorders associated with smooth muscle contractions endocrine diseases and disorders, diseases and disorders associated with neurodegeneration, diseases and disorders associated with inflammation, pain and withdrawal symptoms caused by Reducing chemical abuse.

The compounds of 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 a preferred embodiment, the compounds of the invention are used to treat diseases, disorders or conditions associated with the central nervous system. Such diseases or disorders include anxiety, cognitive impairment, learning disabilities, memory impairment and dysfunction, Alzheimer's disease, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Gilles de la Tourette syndrome, psychosis , depression, mania, manic depression, schizophrenia, obsessive-compulsive disorder (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, but narcolepsy seizure, AIDS dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post-traumatic syndrome, sociophobia, sleep disorders, pseudo-dementia, Ganser syndrome, premenstrual syndrome, late lutein syndrome, phase syndrome, late lutein syndrome mutism, trichotillomania and time zone change syndrome.

In a preferred embodiment of the disease, the disorders and conditions associated with the central nervous system in which the compounds of the invention are used are cognitive disorders, psychosis, schizophrenia and / or depression.

In another preferred embodiment, the compounds of the invention may be useful in treating diseases, disorders or conditions associated with smooth muscle contractions, including convulsive disorders, angina pectoris, premature birth, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation and difficulty erections.

In yet another preferred embodiment, the compounds of the invention may be useful in treating endocrine disorders such as thyrotoxicosis, pheochromocytoma, hypertension, and arrhythmia.

In yet another preferred embodiment, the compounds of the invention may be useful in the treatment of neurodegenerative disorders, including transient anoxia and induced neurodegeneration.

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

In yet another preferred embodiment, the compounds of the invention may be useful for treating mild, moderate, and even severe pain of an acute, chronic, or intermittent nature, as well as pain caused by migraine, postoperative pain, and phantom limb pain. In particular, the pain may be neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, postoperative neuralgia, or with damage to the peripheral nerve.

Finally, the compounds of the invention may be useful in treating withdrawal symptoms caused by cessation of the use of addictive substances. Such addictive substances include nicotine-containing products such as tobacco; opioids such as heroin, cocaine and morphine; benzodiazepines and benzodiazepine-like drugs and spirits. Stopping addictive substances is generally a traumatic event characterized by anxiety and frustration, irritation, anxiety, difficulty concentrating, anxiety, decreased heart rate, increased appetite, and weight gain.

In this context, “treatment” includes treatment, prevention, prophylaxis or relief of withdrawal and withdrawal symptoms, as well as treatment resulting in voluntary reduction in the use of addictive substances.

In another aspect, the compounds of the invention are used as diagnostic agents, for example, for identifying and localizing nicotinic receptors in various tissues.

Pharmaceutical Compositions

In another aspect of the invention, novel pharmaceutical compositions are provided comprising a therapeutically effective amount of a diazabicyclic aryl derivative of the invention.

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

In a preferred embodiment of the invention, pharmaceutical compositions are provided comprising the diazabicyclic aryl derivative of the invention or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers and possibly other therapeutic and / or prophylactic ingredients known and used in the relevant field of technology. The carrier (s) must be (is) “acceptable (s)” in the sense of being compatible with other ingredients of the preparation and not endangering the recipient.

The pharmaceutical compositions of the invention can be administered by any conventional method that is appropriate for the desired therapy. Preferred routes of administration include oral administration, in particular in tablets, capsules, dragees, in powder or liquid form, and parenteral administration, in particular skin, subcutaneous, intramuscular or intravenous administration. The pharmaceutical composition according to the invention can be made by any specialist using standard methods and conventional procedures suitable for the desired preparation. If desired, compositions adapted to provide sustained release of the active ingredient may be used.

The diazabicyclic aryl derivative of the invention can be administered in a wide range of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain either the chemical compound of the invention or a pharmaceutically acceptable salt of the chemical compound of the invention as an active ingredient.

If desired, compositions adapted to provide sustained release of the active ingredient may be used.

The pharmaceutical preparations are preferably in unit dosage forms. In this form, the preparation is divided into unit doses containing suitable amounts of the active component. The unit dosage form can be a packaged preparation, where the package contains discrete quantities of preparation, such as packaged tablets, capsules, and powders in test tubes or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or pill per se, or it can be a suitable amount of any of the above in packaged form.

Preferred compositions are tablets or capsules for oral administration and intravenous fluids, as well as continuous infusion.

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

A therapeutically effective dose corresponds to an amount of the active ingredient that alleviates the symptoms or condition. Therapeutic efficacy and toxicity, for example, ED ₅₀ and LD ₅₀ , can be determined by standard pharmacological methods in cell cultures or experimental animals. The therapeutic index is the ratio of the doses of therapeutic and toxic effects and can be expressed by the ratio of LD ₅₀ / ED ₅₀ . Pharmaceutical compositions having high therapeutic indices are preferred.

Of course, the administered dose should be carefully selected according to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, as well as the desired result, and the exact dosage, of course, should be determined by the practitioner.

The actual dosage depends on the nature and severity of the disease being treated, is at the discretion of the doctor and can be changed by titration of the dose in relation to particular cases in accordance with this invention to achieve the desired therapeutic effect. However, it is currently contemplated that pharmaceutical compositions containing from about 0.1 to about 500 mg of the active ingredient per unit 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 may be administered in one or more doses per day. In some circumstances, a satisfactory result can be obtained at such low dosages as 0.1 μg / kg iv. (intravenously) and 1 mcg / kg bp (orally). Currently, a dose of approximately 10 mg / kg iv is considered to be the upper limit of the dosage range. and 100 mg / kg bp Preferred ranges are from about 0.1 μg / kg to about 10 mg / kg per day iv. and from about 1 μg / kg to about 100 mg / kg per day bp

Therapies

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

In yet another aspect of the invention, there is provided a method of treating, preventing or alleviating a disease, disorder or condition of a living animal organism, including a human being, the disease, disorder or condition being sensitive to modulation of cholinergic receptors, and this method comprises administering to such a living animal organism in need , a therapeutically effective amount of a diazabicyclic aryl derivative of the invention.

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

Preferred indications suggested by the invention are the above indications.

It is currently contemplated that suitable dosage ranges leave from 0.1 to 1000 milligrams per day, 10-500 milligrams per day, and in particular 30-100 milligrams per day, usually depending on the exact route of administration, form of administration, indication, which aims to introduce the individual involved and the body weight of the individual involved, and furthermore the preferences and experience of the responsible physician or veterinarian.

A satisfactory result may, in some circumstances, be obtained at such low dosages as 0.005 mg / kg iv. and 0.01 mg / kg bp The upper limit of the dosage range is approximately 10 mg / kg iv. and 100 mg / kg bp Preferred ranges are from about 0.001 to about 1 mg / kg iv. and from about 0.1 mg / kg to about 10 mg / kg bp

EXAMPLES

The invention is further 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 air-sensitive reagents or intermediates were performed in a nitrogen atmosphere or in anhydrous solvents.

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

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

Polyphosphoric acid (180 g) was heated to 100 ° C. and crude 3-quinuclidine oxime (30 g) was added portionwise. The reaction mixture was heated at 130 ° C for 20 minutes. The mixture was cooled to room temperature and 50 ml of water was added. The mass was thoroughly homogenized, the mixture was poured into ice (100 g). The mixture was made basic (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.

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

1,4-diazabicyclo [3.2.2] nonane [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), lithium aluminum hydride (2.28 g, 60 mmol) was added to the solution, and the reaction mixture was heated with reflux for 36 hours. After the reaction mixture was cooled to room temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent was removed from the filtrate by evaporation on a rotary evaporator under reduced pressure. The resulting substance was distilled in a Kugelrohr apparatus (Kugelrohr) (0.5 mbar (50 Pa), 70 ° C). Yield of the title compound: 3.11 g (68%)

3-Bromo-2-furancarboxylic acid (intermediate)

To a mixture of 3-bromofuran (51.0 g, 0.347 mol) and THF (tetrahydrofuran) (250 ml) was added lithium diisopropylamide (191 ml, 0.382 mol; 2 M solution in heptane LTF / ethylbenzene mixture) at -70 ° C. The mixture was stirred for 1 hour at -70 ° C. Dry ice (100.3 g, 2.28 mol) was added and the mixture was stirred until carbon dioxide was released. Water (50 ml) was added, followed by an aqueous hydrochloric acid solution (380 ml, 2 M). Tetrahydrofuran was evaporated. The mixture was extracted with diethyl ether (3 × 100 ml). The combined ether phase was extracted with an aqueous solution of sodium hydroxide (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 ether phase was evaporated. Yield 36 g (54%). Mp (melting point) 118.5 ° C.

Method A

Hydrochloric acid salt of (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-furoyl chloride (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 precipitated as hydrochloric acid, filtered and washed with 1,2-dimethoxyethane (5 ml). Yield 0.84 g (82%). Mp 279-283 ° C.

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

The title compound was prepared by Method A from 5-bromo-2-furoyl chloride (Method B) without using diisopropylethylamine. An aqueous solution of sodium hydroxide (10 ml, 1 M) was added. The mixture was extracted with dichloromethane (3 × 10 ml). Chromatography on silica gel with a mixture of dichloromethane, methanol and concentrated ammonia (89: 10: 1) gave the title compound. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Mp 192.7-196.4 ° C.

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

The title compound was prepared by Method A from 5-nitro-2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 242.6-251.0 ° C.

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

The title compound was prepared by Method A from 5- (4-nitrophenyl) -2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 298.2 ° C.

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

The title compound was prepared by Method A from 5- {3-trifluoromethylphenyl) -2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 236.9 ° C.

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

The title compound was prepared by Method A from 5- (4-chlorophenyl) -2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 272.5-274.7 ° C.

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

The title compound was prepared by Method A from 5- (2-nitrophenyl) -2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 216.3-219.9 ° C.

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

The title compound was prepared by Method A from 5- (3-nitrophenyl) -2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 224-230 ° C.

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

The title compound was prepared by Method A from 8-methoxy-2-benzofuroyl chloride (Method B) without using diisopropylethylamine. Mp 241-246 ° C.

Hydrochloric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -oxazolyl-5-yl-methanone (Compound A10)

The title compound was prepared by Method A from 5-oxazolyl chloride (Method B) without using diisopropylethylamine. Mp > 160 ° C (decomposition).

Hydrochloric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) benzofuran-2-yl-methanone (Compound A11)

The title compound was prepared by Method A from 2-benzofuroyl chloride (Method B) without using diisopropylethylamine. Mp 264 ° C.

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

The title compound was prepared by Method A from 3-methyl-2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 225.8-227.2 ° C.

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

The title compound was prepared by Method A from 4,5-dibromo-2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 250.9-254.3 ° C.

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

The title compound was prepared by Method A from 5- (2-chloro-5-trifluoromethylphenyl) -2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 201 ° C.

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

The title compound was prepared by Method A from 5- (2-nitro-4-methylphenyl) -2-furoyl chloride (Method B) without using diisopropylethylamine. Mp 199 ° C.

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

The title compound was prepared by Method A from 3-methyl-2-benzofuroyl chloride (Method B) without using diisopropylethylamine. Mp 260-276 ° C.

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

The title compound was prepared by Method A from 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride chloride without using diisopropylethylamine. Mp 280-290 ° C.

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

The title compound was prepared by Method A from 5- (3,5-dichlorophenoxy) -furan-2-carbonyl chloride without using diisopropylethylamine. Mp 124 ° C.

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

The title compound was prepared by Method A from 5- [5- (trifluoromethyl-2-pyridyl) thiomethyl] furan-2-carbonyl chloride without using diisopropylethylamine. Mp 176 ° C.

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

The title compound was prepared by Method A from 3-bromo-2-furoyl chloride (Method B from 3-bromo-2-furancarboxylic acid) without using diisopropylethylamine. Mp 157.4-159.9 ° C.

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

The title compound was prepared by Method A from 5- (2-phenylethynyl) -2-furancarboxylic acid chloride. Mp 166.3-168.3 ° C.

Method B

3-Bromo-2-furancarboxylic acid (intermediate)

To a mixture of 3-bromofuran (51.0 g, 0.347 mol) and THF (250 ml) was added lithium diisopropylamide (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. Dry ice (100.3 g, 2.28 mol) was added and the mixture was stirred until carbon dioxide was released. Water (50 ml) was added, followed by an aqueous hydrochloric acid solution (380 ml, 2 M). Tetrahydrofuran was evaporated. The mixture was extracted with diethyl ether (3 × 100 ml, 2 M). The combined ether phase was extracted with an aqueous solution of sodium hydroxide (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 ether phase was evaporated. Yield 36 g (54%). Mp 118.5 ° C.

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

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

Method B

Fumaric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone (Compound 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) were stirred in a hydrogen atmosphere for 24 hours. The mixture was filtered through celite and evaporated. Yield 0.44 g (74%). The corresponding salt was obtained by adding a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Mp 227.8 ° C.

Fumaric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-aminophenyl) furan-2-yl-methanone (Compound B2)

The title compound was prepared by Method B from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-nitrophenyl) furan-2-yl-methanone. Mp 201.1-207.3 ° C.

Fumaric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-aminophenyl) furan-2-yl-methanone (Compound B3)

The title compound was prepared by Method B from (1,4-diazabicyclo [3.2.2] non-4-yl) -5- (3-nitrophenyl) furan-2-yl-methanone. Mp 184.9-188.2 ° C.

Fumaric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-amino-4-methylphenyl) furan-2-yl-methanone (Compound B4)

The title compound was prepared by Method B from (1,4-diazabicyclo [3.2.2] non-4-yl) -5- (2-nitro-4-methylphenyl) furan-2-yl-methanone. Mp 179 ° C.

Method D

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) -5- (4-acetylaminophenyl) furan-2-yl-methanone (Compound G1)

Acetic anhydride (133 mg, 1.3 mmol) dissolved in dichloromethane (2 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 room temperature. The mixture was allowed to mix for 4 hours. An aqueous solution of sodium hydroxide (20 ml, 1 M) was added, then it was extracted with dichloromethane (3 × 20 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane: methanol (4: 1) and 2% methanol as eluent. The product was isolated as the free base. Mp 113 ° C (decomposition).

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

The title compound was prepared 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 adding a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Mp 178.9-185.0 ° C.

Fumaric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-acetylaminophenyl) furan-2-yl-methanone (Compound G3)

The title compound was prepared according to method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-aminophenyl) furan-2-yl-methanone. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol (9: 1) saturated with fumaric acid. Mp 216 ° C.

N- {4- {5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -propionamide, free base (Compound D4)

The title compound was prepared by Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone. Mp 264 ° C.

Trifluoroacetic acid salt of N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -2.2.2-trifluoroacetamide (Compound G5 )

The title compound was prepared by Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone and trifluoroacetic anhydride. Mp 219 ° C.

Fumaric acid salt of N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -isobutyramide (Compound D6)

The title compound was prepared by Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone and isobutyric acid anhydride. Mp 223 ° C.

Method D

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) -5- [4- (N, N-diphenylsulfonyl) aminophenyl] furan-2-yl-methanone, 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), methanesulfonyl chloride (2.12 g, 18.4 mmol) and dichloromethane (5 ml) were stirred at room temperature for 15 hours. An aqueous solution of sodium hydroxide (5 ml, 1 M) was added, then it was extracted with dichloromethane (3 × 5 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane: methanol (9: 1) and 1% methanol as eluent. The product was isolated as the free base. Yield 20 mg (3%). Mp 189 ° C.

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

The title compound was prepared by Method D from (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone and acryloyl chloride (1.6 eq. .). Mp 220 ° C.

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

The title compound was prepared by Method D from (1,4-diazabicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone, disopropylethylamine (2 equiv.) and benzoyl chloride (1.5 equiv.). Mp 254 ° C.

Fumaric acid salt of (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- [4- (N, N-dimethylsulfonylamino) phenyl] furan-2-yl-methanone (Compound D4)

The title compound was prepared by Method D from (1,4-diazabicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone, disopropylethylamine (2 equiv.) and benzenesulfonyl chloride (1.5 equiv.). Mp 201-203 ° C.

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

The title compound was prepared by Method D from (1,4-diazabicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone and cyclopropanecarbonyl chloride. Mp 254 ° C.

Method E

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) -5- (formylaminophenyl] furan-2-yl-methanone (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 ethyl formate ( 30 ml) was stirred at the boil under reflux for 9 days. The mixture was evaporated. An aqueous solution of sodium hydroxide (20 ml, 1 M) was added, then the mixture was extracted with dichloromethane (3 × 20 ml). The crude mixture was purified by silica gel chromatography using a mixture of dichloromethane: methanol (9: 1) and 1% methanol as eluent. The product was isolated as the free base. Yield 0.29 g (53%). Mp 236 ° C.

Method W

(1,4-Diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone chloromethyl chloride (Compound G1)

Ethyl isothiocyanate (182 mg, 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 allowed to stir for 4 hours at 5 ° C and for 11 hours at room temperature. The volume of solvent was reduced threefold and the solid product was separated by filtration. Mp > 300 ° C.

Method Z

N- {4- [5- (1,4-Diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} acrylamide methyl 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. Iodomethane (68 mg, 0.479 mmol) dissolved in dichloromethane (5 ml) was added. The mixture was allowed to stir at -70 ° C for 1 hour. The mixture was allowed to warm to room temperature, evaporated and triturated with diethyl ether. Yield 0.15 g (62%). Mp 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) were stirred at room temperature for 15 hours. The crude mixture was evaporated. Chromatography on silica gel with a mixture of dichloromethane, methanol and concentrated ammonia (89: 10: 1) gave the title product. Yield 180 mg (99%). Mp 162 ° C.

Example 2

In vitro inhibition of ³ H-α-bungarotoxin binding in rat brain

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

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

Tissue preparation

The preparations were carried out at 0-4 ° C. The cerebral cortex of male Wistar rats (150-250 g) is homogenized for 10 seconds in 15 ml of 20 mM HEPES buffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO ₄ and 2.5 mM CaCl ₂ ( pH 7.5) using an Ultra-Turrax homogenizer. The tissue suspension was centrifuged at 27,000 × g for 10 minutes. The supernatant was drained and the pellet was washed twice by centrifugation at 27,000 × g for 10 minutes in 20 ml of fresh buffer, the remaining pellet was then resuspended in fresh buffer containing 0.01% BSA (35 ml per 1 g of the original tissue) and used for binding assays .

Analysis

500 μl aliquots of the homogenate are added to 25 μl of the test solution and 25 μl of ³ H-α-bungarotoxin (2 nM, final concentration), mixed and incubated for 2 hours at 37 ° C. Nonspecific binding is determined using (-) - nicotine (1 mM, final concentration). After incubation, 5 ml of HEPES ice-cold buffer containing 0.05% PEI (polyethyleneimine) was added to the samples and applied directly to Whatman GF / C fiber glass filters (pre-soaked in 0.1% PEI for at least 6 hours) with suction and immediately washed with 2 × 5 ml of ice-cold buffer.

The amount of radioactivity on the filters is determined by traditional liquid scintillation counting. Specific binding is total binding minus non-specific binding.

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

The experimental results are shown in table 1.

Table 1 Inhibition of ³ H-α-Bungarotoxin Binding Compound No. IK ₅₀ (MKM) A1 0.54 A5 0.051 OT 0,080 E1 0.017

Example 3

Pharmaceutical Compositions

The chemical compound of the invention may be presented in the desired form of the composition and may be metered in any desired amount. This example describes the preparation of a preparation in the form of a standard tablet in which any of the compounds of the invention can be used as the active pharmaceutical ingredient (API).

Standard tablet composition

Tablets containing 1.585 mg of API per tablet are prepared using the composition shown in Table 2.

table 2 Ingredient Function Amount, mg / tablet API Active ingredient 1,585 Microcrystalline cellulose, granulate Filler / Binder 38,045 Microcrystalline cellulose Filler / Binder 1,955 Lactose Filler 56,715 Crosscarmellose sodium Baking powder 0,500 Colloidal silicon dioxide Fluid Improvement 0,200 Magnesium stearate Lubricant 1,000 Total tablet weight 100.0

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

Claims (11)

1. Diazabicyclic aryl derivative represented by formula I

any enantiomers thereof, or any mixture of its enantiomers, or a pharmaceutically acceptable addition salt thereof, wherein n is 2 and X and Y independently from each other are CR ² , CR ³ and N, where R ² represent hydrogen, C _1-6 alkyl or halogen; and R ³ represents hydrogen or halogen; and R ¹ represents hydrogen, halogen, trifluoromethyl, nitro or phenyl, and phenyl may be substituted by one or two substituents selected from: C _1-6 alkyl, halo, trifluoromethyl, amino, nitro and / or groups of the formula R'CONH- or (R'SO ₂ ) ₂ N-, where R 'is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, trifluoromethyl, vinyl or phenyl; or a group of the formula phenyl-Z- (C _1-6 alkyl) _m -, phenyl-C≡C- or pyridyl-Z- (C _1-6 alkyl) _m -, where m is 0 or 1; and Z represents O or S; and where phenyl and pyridyl may be substituted with one or two substituents selected from: halogen or trifluoromethyl; or R ¹ and R ³ , together with the carbon atoms to which they are attached, form a benzofused aromatic carbocyclic ring which may be substituted with C _1-6 alkyl or C _1-6 alkoxy. 2. The diazabicyclic aryl derivative according to claim 1, where at least one of X and Y represents N, and the other of X and Y represents CR ² . 3. The diazabicyclic aryl derivative according to claim 1, where one or two of R ² and R ³ independently from each other represent hydrogen and / or halogen; and R ¹ represents hydrogen, halogen, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl- phenyl, 2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, 3-phenyl-acetamide, 4-phenyl-acetamide, 4-phenyl-propionamide, 4- phenyl-isobutyramide, 4-phenyl-acrylamide, 4- (N, N-dimethyl-sulfonyl-amino) -phenyl, 4-phenyl-2,2,2-trifluoroacetamide, 4-phenyl-cyclopamide opankarbonovoy acid, 4-phenyloxy, 3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl and / or 5-trifluoromethyl-2-pyridyl-thiomethyl. 4. The diazabicyclic aryl derivative according to claim 1, where X and Y are both CR ² , CR ³ or N. 5. The diazabicyclic aryl derivative according to claim 1, represented by formula II

, any enantiomers thereof, or any mixture of its enantiomers, or a pharmaceutically acceptable addition salt thereof, wherein n is 2; and X represents CR ⁴ or N; R ¹ represents hydrogen, halogen, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl- phenyl, 2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4-halo-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, 3-phenyl-acetamide, 4-phenyl-acetamide, 4-phenyl-propionamide, 4- phenyl-isobutyramide, 4-phenyl-acrylamide, 4- (N, N-dimethyl-sulfonyl-amino) -phenyl, 4-phenyl-2,2,2-trifluoroacetamide, 4-phenyl-cyclopamide opankarbonovoy acid, 4-phenyloxy, 3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl or 5-trifluoromethyl-2-pyridyl-thiomethyl; R ² represents hydrogen or halogen; and R ⁴ represents hydrogen, C _1-6 alkyl or halogen. 6. The diazabicyclic aryl derivative according to claim 1, represented by formula III

any enantiomers thereof, or any mixture of its enantiomers, or a pharmaceutically acceptable addition salt thereof, wherein n is 2; and X represents CR ⁴ or N, where R ⁴ represents hydrogen or C _1-6 alkyl; R ⁵ represents hydrogen, C _1-6 alkyl or C _1-6 alkoxy; and R ⁶ represents hydrogen, C _1-6 alkyl or C _1-6 alkoxy. 7. The diazabicyclic aryl derivative according to claim 1, where R ¹ represents a group of the formula —CH ₂ —Z-phenyl, —CH ₂ -Z-pyridyl or —C≡C-phenyl, where Z represents O or S; and where the phenyl and pyridyl groups may be 1-2 times substituted with trifluoromethyl. 8. The diazabicyclic aryl derivative according to claim 1, where R ¹ represents hydrogen, halogen, nitro, phenyl, 2-nitro-phenyl, 2-nitro-4-methyl-phenyl, 3-nitrophenyl, 4-nitro-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-halo-5-trifluoromethyl-phenyl, 2-amino-phenyl, 2-amino-4-methyl-phenyl, 3-amino-phenyl, 4-amino-phenyl, 2-amino-4-methyl-phenyl, 4- halogen-phenyl, 4-formylamino-phenyl, 2-acetylamino-phenyl, 3-acetylamino-phenyl, 4-acetylamino-phenyl, 3-phenyl-acetamide, 4-phenyl-acetamide, 4-phenyl-propionamide, 4-phenyl- isobutyramide, 4-phenyl-acrylamide, 4- (N, N-dimethyl-sulfonyl-amino) phenyl, 4-phenyl-2,2,2-trifluoroacetamide, 4-phenyl-cyclopr amide opanecarboxylic acid, 4-phenyloxy, 3,5-dihalo-phenyloxy, phenyl-ethynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-thiomethyl or 5-trifluoromethyl-2-pyridyl-thiomethyl; R ² represents hydrogen, C _1-6 alkyl or halogen; and R ³ represents hydrogen or halogen. 9. The diazabicyclic aryl derivative according to claim 1, which is: (1,4-diaza-bicyclo [3.2.2] non-4-yl) -oxazolyl-5-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- phenyl-1,3,4-oxadiazol-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -8-methoxy-benzofuran-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) benzofuran-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -3-methyl-benzofuran-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- [5- (trifluoromethyl-2-pyridyl) thiomethyl] furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5-phenylethinyl-furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5-bromo-furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5-nitro-furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-nitrophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-trifluoromethylphenyl) -furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-chlorophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-nitrophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-nitrophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-acetylaminophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-aminophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-aminophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-acetylaminophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (3-acetylaminophenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -3-methyl-furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -4,5-dibromo-furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-chloro-5-trifluoromethylphenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-nitro-4-methylphenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (2-amino-4-methylphenyl) furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- [4- (N, N-dimethylsulfonyl) aminophenyl] furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-formylaminophenyl) furan-2-yl-methanone, 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-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- [5- (trifluoromethyl-2-pyridyl) thiomethyl] furan-2-yl-methanone, N {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) furan-2-yl] phenyl} -2,2,2-trifluoroacetamide trifluoroacetic acid, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -3-bromo-furan-2-yl-methanone, (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5-phenylethinyl-furan-2-yl-methanone, 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-diphenylsulfonylamino) phenyl] furan-2-yl-methanone, N- {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -isobutyramide, Cyclopropanecarboxylic acid {4- [5- (1,4-diaza-bicyclo [3.2.2] nonan-4-carbonyl) -furan-2-yl] phenyl} -amide (1,4-diaza-bicyclo [3.2.2] non-4-yl) -5- (4-aminophenyl) furan-2-yl-methanone, 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 addition salt. 10. A pharmaceutical composition having modulating activity against nicotinic receptors, comprising a therapeutically effective amount of a diazabicyclic aryl derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. 11. The use of a diazabicyclic aryl derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a pharmaceutical composition / drug having (its) modulating activity against nicotinic receptors.