HK1081954B

HK1081954B - Novel 1,4-diazabicycloalkane derivatives, their preparation and use

Info

Publication number: HK1081954B
Application number: HK06102123.0A
Authority: HK
Inventors: D‧彼得斯; G‧M‧奥尔森; E‧O‧尼尔森; T‧D‧约根森; P‧K‧阿林
Original assignee: 神经研究公司
Priority date: 2002-09-30
Filing date: 2003-09-29
Publication date: 2007-12-21

Description

Novel 1, 4-diazabicycloalkane derivatives, their preparation and use

Technical Field

The present invention relates to novel 1, 4-diazabicycloalkane derivatives and their use in the preparation of pharmaceutical compositions. The compounds of the present invention are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters.

The compounds of the present invention may be used for the treatment of various diseases or disorders which are associated with the cholinergic system of the Central Nervous System (CNS), the Peripheral Nervous System (PNS), diseases or disorders associated with smooth muscle contraction, endocrine diseases or disorders, diseases or disorders associated with neuro-degeneration, diseases or disorders associated with inflammation, pain, and withdrawal from termination of abuse of chemical substances, due to their pharmacological profile.

Background

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

Since muscarinic acetylcholine receptors are generally recognized as quantitatively superior to nicotinic acetylcholine receptors in brain regions important for memory and cognition, much research aimed at developing drugs for the treatment of memory-related disorders has focused on the synthesis of muscarinic acetylcholine receptor modulators.

However, in recent years there has been interest in the development of nAChR modulators. Some diseases are associated with degeneration of the cholinergic system, i.e. senile dementia of the alzheimer type, vascular dementia and cognitive impairment due to organic brain damage diseases directly related to alcoholism. In fact, there are several CNS disorders attributable to cholinergic, dopamine, adrenergic or 5-hydroxytryptamine deficiencies.

WO00/34279(Sanofi-Synthelabo) describes 1, 4-diazabicyclo [3.2.2] nonane derivatives having nicotinic receptor activity. Only six-membered heteroaryl derivatives are described. The five-membered heteroaryl derivatives of the present invention are not described.

WO01/55150(Sanofi-Synthelabo) describes 1, 4-diazabicyclo [3.2.2] nonane derivatives having nicotinic receptor activity. Only bicyclic heteroaryl derivatives are described. The monocyclic heteroaryl derivatives of the present invention are not described.

WO01/92259(Sanofi-Synthelabo) describes 1, 4-diazabicyclo [3.2.2] nonane derivatives having nicotinic receptor activity. Only phenyl-isoxazole derivatives are described. The thiadiazole derivatives of the present invention are not described.

WO01/92260(Sanofi-Synthelabo) describes 1, 4-diazabicyclo [3.2.2] nonane derivatives having nicotinic receptor activity. Only phenyl-thiazole derivatives are described. The thiadiazole derivatives of the present invention are not described.

EP 1219622(Pfizer Ltd.) describes 1, 4-diazabicyclo [3.2.2] nonane derivatives having nicotinic receptor activity. Only bicyclic heteroaryl derivatives are described. The monocyclic heteroaryl derivatives of the present invention are not described.

Summary of The Invention

The present invention seeks to provide novel modulators of nicotinic and/or monoamine receptors, which modulators are useful in the treatment of diseases or disorders associated with cholinergic receptors, particularly with the biogenic amine transporters of the nicotinic acetylcholine receptors (nAChR), monoamine receptors 5-HTR, DAR and NER, and 5-HT, DA and NE.

The compounds of the invention may also be used as diagnostic tools or monitoring agents in a variety of diagnostic methods, particularly in vivo receptor imaging (neuroimaging), and they may be used in labeled or unlabeled form.

In a first aspect the present invention provides novel 1, 4-diazabicycloalkane derivatives of formula I

Any enantiomer thereof or any mixture of enantiomers thereof or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof,

wherein N is 1, 2 or 3;

x represents O, S or Se; and

ar represents a carbocyclic aromatic (aryl) group or a heterocyclic aromatic (heteroaryl) group, which aromatic groups may optionally be substituted one or more times by substituents selected from: alkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halogen, CF₃、CN、NO₂、NH₂Carboxy, carbamoyl, amido, sulphamoyl, phenyl and benzyl.

In a second aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a1, 4-diazabicycloalkane derivative of the invention, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically-acceptable addition salt thereof, and at least one pharmaceutically-acceptable carrier or diluent.

Another aspect of the present invention relates to the use of a1, 4-diazabicycloalkane derivative of the invention, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically-acceptable addition salt thereof, for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition responsive to modulation of cholinergic receptors and/or monoamine receptors.

In another aspect the present invention provides a method for the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder or disease is responsive to modulation of cholinergic receptors and/or monoamine receptors, which method comprises administering to a living animal body, including a human, in need thereof a therapeutically effective amount of a1, 4-diazabicycloalkane derivative of the invention, any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically acceptable addition salt thereof.

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

Detailed Description

In a first aspect, the present invention provides novel 1, 4-diazabicycloalkane derivatives represented by the general formula I

wherein N is 1, 2 or 3;

x represents O, S or Se; and

ar represents a carbocyclic aromatic (aryl) group or a heterocyclic aromatic (heteroaryl) group, which aromatic group may be optionally substituted one or more times by a substituent selected from: alkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halogen, CF₃、CN、NO₂、NH₂Carboxy, carbamoyl, amido, sulphamoyl, phenyl and benzyl.

In a more preferred embodiment, Ar represents a carbocyclic aromatic (aryl) group or a heterocyclic aromatic (heteroaryl) group, which aromatic group may optionally be substituted one or more times by substituents selected from: alkyl, alkoxy, halogen, CF₃、CN、NO₂、NH₂And a phenyl group.

In a first preferred embodiment, the compounds of the invention are 1, 4-diazabicyclo [3.2.2] nonane derivatives represented by formula II,

wherein X and Ar are as defined above.

In a more preferred embodiment, the compounds of the present invention are 4-thiadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivatives represented by formula III

Wherein Ar is as defined above.

In another preferred embodiment, the compounds of the present invention are 4-oxadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivatives represented by formula IV

Wherein Ar is as defined above.

In a second preferred embodiment, the carbocyclic aromatic (aryl) group is an optionally substituted phenyl, indenyl, naphthyl, azulenyl, fluorenyl or anthracenyl group.

In a more preferred embodiment, the carbocyclic aromatic group is phenyl optionally substituted one or two times with substituents selected from: alkyl, cycloalkyl-alkyl, alkoxy, cycloalkoxy, halogen, CF₃、CN、NO₂、NH₂Carboxy, carbamoyl, amido, sulphamoyl, phenyl and benzyl.

In an even more preferred embodiment, the carbocyclic aromatic group is phenyl optionally substituted one or two times with substituents selected from: alkyl, alkoxy, halogen, CF₃、CN、NO₂、NH₂And a phenyl group.

In a most preferred embodiment, the 4-thiadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivative of the present invention is

4- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1, 4-diazabicyclo [3.2.2] nonane;

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof;

the 4-oxadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivative of the present invention is

4- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-methoxyphenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-methoxyphenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-chlorophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-phenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane; or 4- [5- (2-naphthyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically-acceptable addition salt thereof, or an N-oxide thereof.

In a third preferred embodiment, the heterocyclic aromatic (heteroaryl) group is an optionally substituted aromatic monocyclic heterocyclic group, or an optionally substituted aromatic di-or polyheterocyclic heterocyclic group comprising benzo-fused 5-and 6-membered heterocyclic rings containing one or more heteroatoms selected from nitrogen (N), oxygen (O), sulfur (S) and/or selenium (Se).

In a more preferred embodiment, the aromatic monocyclic heterocyclic group is an optionally substituted aromatic 5-or 6-membered heterocyclic monocyclic group.

In an even more preferred embodiment, the optionally substituted aromatic monocyclic heterocyclic group is furyl, in particular 2-furyl or 3-furyl; thienyl, in particular 2-thienyl or 3-thienyl; selenophenyl (selenophenyl), in particular 2-selenophenyl or 3-selenophenyl; pyrrolyl (azolyl), in particular 2-pyrrolyl or 3-pyrrolyl; oxazolyl, especially oxazol-2-, 4-or 5-yl; thiazolyl, especially thiazol-2-, 4-or 5-yl; imidazolyl, in particular 2-imidazolyl or 4-imidazolyl; pyrazolyl, in particular-3-pyrazolyl or 4-pyrazolyl; isoxazolyl, especially isoxazol-3-, 4-or 5-yl; isothiazolyl, especially 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, especially 2-, 3-or 4-pyridyl; a pyridazinyl group, in particular a 3-or 4-pyridazinyl group; pyrimidinyl, in particular 2-, 4-or 5-pyrimidinyl; a pyrazinyl group, in particular a 2-or 3-pyrazinyl group; and triazinyl, especially 1, 2, 4-or 1, 3, 5-triazinyl.

In another preferred embodiment, the compounds of the invention are 4-thiadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivatives of formula III, wherein Ar represents an optionally substituted aromatic monocyclic heterocyclic group selected from selenophenyl, in particular 2-selenophenyl or 3-selenophenyl; imidazolyl, in particular 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; pyrazolyl, in particular 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl; thiazolyl, especially 2-thiazolyl or 5-thiazolyl; isothiazolyl, especially 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl; oxadiazolyl, in particular 1, 2, 3-oxadiazol-4-yl, 1, 2, 3-oxadiazol-5-yl or 1, 3, 4-oxadiazol-2-yl; furazanyl, especially 3-furazanyl; triazolyl, in particular 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl or 1, 2, 4-triazol-5-yl; thiadiazolyl, in particular 1, 3, 4-thiadiazol-2-yl, 1, 2, 4-thiadiazol-3-yl or 1, 2, 4-thiadiazol-5-yl; a pyridazinyl group, in particular 3-pyridazinyl or 4-pyridazinyl; and triazinyl, especially 1, 3, 5-triazin-2-yl.

In a more preferred embodiment, the aromatic 5-or 6-membered heterocyclic monocyclic group is optionally substituted one or two times by a substituent selected from the group consisting of: alkyl, alkoxy, halogen, CF₃、CN、NO₂、NH₂And a phenyl group.

4- [5- (2-selenophenyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-selenophenyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-2-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-4-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-5-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-3-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-4-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-5-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-thiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-thiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-thiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-isothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-isothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-isothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-oxadiazol-4-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-oxadiazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [1, 3, 4-oxadiazol-2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-furazanyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-triazol-4-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 3-triazol-4-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 3-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-triazol-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 4-triazol-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 4-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 3, 4-thiadiazol-2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-thiadiazol-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-thiadiazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-pyridazinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-pyridazinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane; or

4- [5- (1, 3, 5-triazin-2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

In another preferred embodiment, the compounds of the invention are 4-oxadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivatives of formula IV, wherein Ar represents an optionally substituted aromatic monocyclic heterocyclic group selected from furanyl, in particular 2-furanyl or 3-furanyl; pyridyl, in particular 2-pyridyl, 3-pyridyl or 4-pyridyl; thienyl, in particular 2-thienyl or 3-thienyl; pyrrolyl, especially 2-pyrrolyl or 3-pyrrolyl; pyrimidinyl, in particular 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl; a pyrazinyl group; selenophenyl, especially 2-selenophenyl or 3-selenophenyl; oxazolyl, in particular 2-oxazolyl, 4-oxazolyl or 5-oxazolyl; isoxazolyl, in particular 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl; imidazolyl, in particular 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; pyrazolyl, in particular 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl; thiazolyl, especially 2-thiazolyl, 4-thiazolyl or 5-thiazolyl; isothiazolyl, especially 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl; oxadiazolyl, in particular 1, 2, 3-oxadiazol-4-yl, 1, 2, 3-oxadiazol-5-yl or 1, 3, 4-oxadiazol-2-yl; furazanyl, especially 3-furazanyl; triazolyl, in particular 1, 2, 3-triazol-4-yl, 1, 2, 3-triazol-5-yl, 1, 2, 4-triazol-3-yl or 1, 2, 4-triazol-5-yl; thiadiazolyl, in particular 1, 3, 4-thiadiazol-2-yl, 1, 2, 4-thiadiazol-3-yl or 1, 2, 4-thiadiazol-5-yl; a pyridazinyl group, in particular 3-pyridazinyl or 4-pyridazinyl; and triazinyl, especially 1, 3, 5-triazin-2-yl.

In one most preferred embodiment, the 4-oxadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivative of the invention is

4- [5- (2-furyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-furyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-pyridyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-pyridyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-pyridyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-thienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-thienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-2-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-3-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-pyrimidinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-pyrimidinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-pyrimidinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (pyrazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-selenophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-selenophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-oxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-oxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-oxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-isoxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-isoxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-isoxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-2-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-4-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-5-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-3-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-4-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-5-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-thiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-thiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-thiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-isothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-isothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-isothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-oxadiazol-4-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-oxadiazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 3, 4-oxadiazol-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-furazanyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-triazol-4-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 3-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 3-triazol-4-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 3-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-triazol-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 4-triazol-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-1, 2, 4-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 3, 4-thiadiazol-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-thiadiazol-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 2, 4-thiadiazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-pyridazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-pyridazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane; or

4- [5- (1, 3, 5-triazin-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

In a fourth preferred embodiment, the optionally substituted bicyclic aromatic heterocyclic group is indolyl, in particular 2-indolyl or 3-indolyl; isoindolyl, in particular 1-isoindolyl or 3-isoindolyl; benzo [ b ] furanyl, especially 2-benzo [ b ] furanyl or 3-benzo [ b ] furanyl; benzo [ b ] thienyl, especially 2-benzo [ b ] thienyl or 3-benzo [ b ] thienyl; benzimidazolyl, especially 2-benzimidazolyl; benzothiazolyl, especially 2-benzothiazolyl; quinolinyl, in particular 2-quinolinyl, 3-quinolinyl or 4-quinolinyl; isoquinolinyl, in particular 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl; cinnolinyl, in particular 3-cinnolinyl or 4-cinnolinyl; naphthyridinyl, in particular 1-naphthyridinyl or 4-naphthyridinyl; quinazolinyl, in particular 2-quinazolinyl or 4-quinazolinyl; quinoxalinyl, in particular 2-quinoxalinyl or 3-quinoxalinyl.

In a more preferred embodiment, the optionally substituted polycyclic aromatic heterocyclic group is a tricyclic heteroaryl group, particularly 2-acridinyl, 3-acridinyl, 6-acridinyl or 7-acridinyl; carbazolyl, in particular 2-carbazolyl, 3-carbazolyl, 6-carbazolyl or 7-carbazolyl; a phenazine group, in particular a 2-phenazine group, a 3-phenazine group, a 7-phenazine group or an 8-phenazine group; phenothiazinyl, in particular 2-phenothiazinyl, 3-phenothiazinyl, 7-phenothiazinyl or 8-phenothiazinyl; and phenoxazinyl, in particular 2-phenoxazinyl, 3-phenoxazinyl, 7-phenoxazinyl or 8-phenoxazinyl.

In an even more preferred embodiment, the compounds of the invention are 4-thiadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivatives of formula III, wherein the polycyclic aromatic heterocyclic group is an optionally substituted bicyclic heteroaryl group selected from quinolinyl, in particular 2-quinolinyl or 3-quinolinyl; isoquinolinyl, especially 3-isoquinolinyl; cinnolinyl, especially 3-cinnolinyl; indolizinyl, in particular 2-indolizinyl; benzimidazolyl, especially 2-benzimidazolyl; benzothiazolyl, especially 2-benzothiazolyl; naphthyridinyl, especially 7-naphthyridinyl; quinazolinyl, especially 2-quinazolinyl, quinoxalinyl, especially 2-quinoxalinyl; naphthyridinyl, in particular 1, 8-naphthyridin-2-yl or 1, 8-naphthyridin-3-yl; and acridinyl, especially 2-acridinyl or 3-acridinyl.

In a more preferred embodiment, the bicyclic heteroaryl is optionally substituted one or two times with a substituent selected from the group consisting of: alkyl, alkoxy, halogen, CF₃、CN、NO₂、NH₂And a phenyl group.

4- [5- (2-quinolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-quinolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-isoquinolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-cinnolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-indolizinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-2-indolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-benzimidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-2-benzimidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-benzothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (7-naphthyridinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-quinazolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-quinoxalinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 8-naphthyridine) -2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 8-naphthyridin-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-acridinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane; or

4- [5- (3-acridinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

In another preferred embodiment, the compounds of the invention are 4-oxadiazolyl-1, 4-diazabicyclo [3.2.2] nonane derivatives of formula I V, wherein Ar represents an optionally substituted aromatic monocyclic heterocyclic group selected from benzothienyl, in particular 2-benzothienyl, 3-benzothienyl, 5-benzothienyl or 6-benzothienyl; benzofuranyl, in particular 2-benzofuranyl, 3-benzofuranyl, 5-benzofuranyl or 6-benzofuranyl; quinolinyl, in particular 2-quinolinyl or 3-quinolinyl; isoquinolinyl, especially 3-isoquinolinyl; cinnolinyl, especially 3-cinnolinyl; indolizinyl, in particular 2-indolizinyl; indolyl, especially 2-indolyl; benzimidazolyl, especially 2-benzimidazolyl; benzothiazolyl, especially 2-benzothiazolyl; naphthyridinyl, especially 7-naphthyridinyl; quinazolinyl, particularly 2-quinazolinyl; quinoxalinyl, especially 2-quinoxalinyl; naphthyridinyl, in particular 1, 8-naphthyridin-2-yl or 1, 8-naphthyridin-3-yl; acridinyl, especially 2-acridinyl or 3-acridinyl; a dibenzofuranyl group, in particular a 2-dibenzofuranyl or 3-dibenzofuranyl group; dibenzothienyl, in particular 2-dibenzothienyl or 3-dibenzothienyl; phenoxazinyl, in particular 2-phenoxazinyl or 3-phenoxazinyl.

In a more preferred embodiment, the aromatic monocyclic heterocyclic group is optionally substituted one or two times by a substituent selected from the group consisting of: alkyl, alkoxy, halogen, CF₃、CN、NO₂、NH₂And a phenyl group.

In a most preferred embodiment, the compounds of the present invention are

4- [5- (2-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (6-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (5-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (6-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-quinolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-quinolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-isoquinolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-cinnolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-indolizinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-indolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-2-indolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-benzimidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1-methyl-2-benzimidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-benzothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (7-naphthyridinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-quinazolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-quinoxalinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 8-naphthyridin-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (1, 8-naphthyridin-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-acridinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-acridinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-dibenzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-dibenzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-dibenzothiophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-dibenzothiophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-phenoxazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane; or

4- [5- (3-phenoxazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

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

Definition of substituents

In the context of the present invention, alkyl denotes 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 containing one to six carbon atoms (C)_1-6-an alkyl group; is low inA lower alkyl group) including pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. In a preferred embodiment, alkyl represents C_1-4Alkyl groups including butyl, isobutyl, sec-butyl and tert-butyl. In another preferred embodiment of the invention, alkyl represents C_1-3Alkyl groups, which may be in particular methyl, ethyl, propyl or isopropyl.

In the context of the present invention, cycloalkyl means a cyclic alkyl radical, preferably having 3 to 7 carbon atoms (C)_3-7Cycloalkyl) including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the present invention, cycloalkyl-alkyl denotes cycloalkyl as defined above, the cycloalkyl group being substituted on alkyl as defined above. Examples of preferred cycloalkyl-alkyl groups for the present invention include cyclopropylmethyl and cyclopropylhexyl.

In the context of the present invention, alkenyl denotes carbon chains containing one or more double bonds, including dienes, trienes and polyenes. In a preferred embodiment, the alkenyl groups of the present invention contain 2 to 8 carbon atoms (C)_2-8Alkenyl), more preferably 2 to 6 carbon atoms (C)_2-6Alkenyl) comprising at least one double bond. In a most preferred embodiment, the alkenyl groups of the present invention are vinyl groups; 1-or 2-propenyl (allyl); 1-, 2-or 3-butenyl, or 1, 3-butadienyl; 1-, 2-, 3-, 4-or 5-vinyl or 1, 3-hexadienyl, or 1, 3, 5-hexanetrienyl; 1-, 2, 3-, 4-, 5-, 6-, or 7-octenyl, or 1, 3-octadienyl, or 1, 3, 5-octatrienyl, or 1, 3, 5, 7-octatetraenyl.

In the context of the present invention, alkynyl denotes carbon chains containing one or more triple bonds, including diynes, triynes and polyacetylenes. In a preferred embodiment, alkynyl groups of the present invention contain 2 to 8 carbon atoms (C)_2-8Alkynyl), more preferably containing 2 to 6 carbon atoms (C)_2-6-alkynyl) including at least one triple bond. In its most preferred embodiment, the alkynyl group of the present invention is ethynyl; 1-or 2-propynyl; 1-, 2-or 3-butynyl, or 1, 3-butanediyl; 1-, 2-),3-or 4-pentynyl, or 1, 3-pentadecyl; 1-, 2-, 3-, 4-, or 5-hexynyl, or 1, 3-hexadiynyl, or 1, 3, 5-hexadiynyl; 1-, 2-, 3-, 4-, 5-, or 6-heptynyl, or 1, 3-heptyldiynyl, or 1, 3, 5-heptyltribuynyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octynyl, or 1, 3-octadiynyl, or 1, 3, 5-octatriynyl, or 1, 3, 5, 7-octatetraalkynyl.

In the context of the present invention, alkoxy means an "alkyl-O-" group, wherein alkyl is as defined above. Preferred examples of the alkoxy group of the present invention include methoxy and ethoxy groups.

In the context of the present invention, an alkoxy-alkyl group refers to an "alkyl-O-alkyl-" group, wherein alkyl is as defined above. Preferred examples of alkoxy-alkyl groups of the present invention include methoxy-methyl, methoxy-ethyl, ethoxy-methyl and ethoxy-ethyl.

In the context of the present invention, alkoxy-alkoxy groups refer to "alkyl-O-" groups, wherein alkyl is as defined above. Preferred examples of alkoxy-alkoxy groups of the present invention include methoxy-methoxy, methoxy-ethoxy, ethoxy-methoxy and ethoxy-ethoxy.

In the context of the present invention, cycloalkoxy groups refer to "cycloalkyl-O-" groups, wherein cycloalkyl is as defined above.

In the context of the present invention, cycloalkoxy-alkyl group refers to "cycloalkyl-O-alkyl", wherein cycloalkyl and alkyl are as defined above.

In the context of the present invention, cycloalkoxy-alkoxy groups refer to "cycloalkyl-O-alkyl-O-", wherein cycloalkyl and alkyl are as defined above.

In the context of the present invention, halogen represents a fluorine, chlorine, bromine or iodine atom. Thus, trihalomethyl represents, for example, trifluoromethyl, trichloromethyl and similar trihalomethyl groups.

In the context of the present invention, an acyl group refers to a carboxyl group (-COOH) or an alkyl-carbonyl group (alkyl-CO-), wherein alkyl is as defined above. Preferred examples of the acyl group of the present invention include a carboxyl group, an acetyl group and a propionyl group.

Pharmaceutically acceptable salts

The 1, 4-diazabicycloalkane derivatives of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salt and prodrug forms of the compounds of the invention.

Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts, such as hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, sulfate derived from sulfuric acid, formate derived from formic acid, acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, dihydronaphthoate derived from dihydronaphthoic acid, heptanoate derived from heptanoic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, lactate derived from lactic acid, maleic acid salts derived from maleic acid, malonic acid salts derived from malonic acid, mandelic acid salts derived from mandelic acid, methanesulfonic acid salts derived from methanesulfonic acid, naphthalene-2-sulfonic acid salts derived from naphthalene-2-sulfonic acid, phthalic acid salts derived from phthalic acid, salicylic acid salts derived from salicylic acid, sorbic acid salts derived from sorbic acid, stearic acid salts derived from stearic acid, succinic acid salts derived from succinic acid, tartaric acid salts derived from tartaric acid, p-toluenesulfonic acid salts derived from p-toluenesulfonic acid and the like. Such salts may be formed by methods known and described in the art.

Other acids, such as oxalic acid, may not be considered pharmaceutically acceptable, but may also be used to prepare salts which are useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

The metal salts of the compounds of the present invention include alkali metal salts, such as sodium salts of the compounds of the present invention containing carboxyl groups.

In the context of the present invention, the "onium salts" of nitrogen-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include alkyl-onium salts, particularly methyl-, cycloalkyl-onium salts, and cycloalkyl-alkyl-onium salts.

Stereoisomers

The 1, 4-diazabicycloalkane derivatives of the invention may exist in (+) and (-) forms as well as in racemic form (±). The racemates of these isomers and the individual isomers themselves are within the scope of the present invention.

The racemic forms can be resolved into the optical antipodes by known methods and techniques. One way to separate diastereomeric salts is by liberation of an optically active amine compound by treatment with an optically active acid and with a base. Another method for resolving racemates into the optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the invention can thus be resolved into their optical antipodes, for example by fractional crystallization of the d-or 1- (tartaric, mandelic or camphorsulfonic) salt.

The compounds of the present invention may also be resolved by reacting the 1, 4-diazabicycloalkane derivatives of the present invention with, for example, an optically active activated carboxylic acid derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphoric acid to form an diastereomeric amide, or reacting the compounds of the present invention with an optically active chloroformate or the like to form an diastereomeric carbamate.

Other methods of resolving optical isomers are well known in the art. These methods include methods described by Jaques J, colelet a,&wilen S inEnantionmers.Racemates，and Resolutions″，John Wiley and Sons，New York(1981) The method described in (1).

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

Preparation method

The 1, 4-diazabicycloalkane derivatives of the invention may be prepared by conventional methods of chemical synthesis, for example, by the methods described in the examples. The starting materials for the processes described herein are known or can be readily prepared from commercially available chemicals by conventional methods.

Furthermore, one compound of the present invention is converted to another compound of the present invention using conventional methods.

The final product of the reaction described herein may be isolated by conventional techniques such as extraction, crystallization, distillation, chromatography and the like.

Biological activity

The present invention relates to novel 1, 4-diazabicycloalkane derivatives, which are found to be cholinergic ligands at the nicotinic acetylcholine receptors (nAChR) and modulators of the monoamine receptors, particularly modulators of the 5-HT, DA and NE biogenic amine transporters. Preferred compounds of the invention also exhibit selective α 7 activity.

In the context of the present invention, the term "modulator" encompasses agonists, partial agonists, antagonists and allosteric modulators of receptors.

Due to their pharmacological profile the 1, 4-diazabicycloalkane derivatives of the present invention may be useful in the treatment of various diseases or disorders, such as CNS related diseases, PNS related diseases, diseases related to smooth muscle contraction, endocrine disorders, diseases related to neurodegeneration, diseases related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

In a preferred embodiment, the 1, 4-diazabicycloalkane derivatives of the invention are used to treat a disease, disorder or condition associated with the central nervous system. Such diseases or disorders include anxiety, cognitive disorders, learning deficit, memory deficits and dysfunctions, Alzheimer's disease, attention deficit hyperactivity disorder, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, Tourette's syndrome, depression, mania, manic depression, schizophrenia, Obsessive Compulsive Disorder (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post traumatic syndrome, social phobia, sleep disorders, pseudodementia, ganser's syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania, and jet lag.

In another preferred embodiment, the 1, 4-diazabicycloalkane derivatives of the invention are useful for treating diseases, disorders, or conditions associated with smooth muscle contraction, including spastic disorders, angina, premature labor, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile difficulty

In another preferred embodiment, the 1, 4-diazabicycloalkane derivatives of the present invention are useful for the treatment of endocrine disorders, such as thyrotoxicosis, pheochromocytoma, hypertension and cardiac arrhythmias.

In another preferred embodiment, the 1, 4-diazabicycloalkane derivatives of the invention are useful in the treatment of neurodegenerative diseases, including transient hypoxia and induced neurodegeneration.

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

In another preferred embodiment, the 1, 4-diazabicycloalkane derivatives of the invention are useful in the treatment of acute, chronic or recurrent mild, moderate or even severe pain, as well as migraine-induced pain, postoperative pain and prosthetic pain.

Finally, the 1, 4-diazabicycloalkane derivatives of the invention may be used to treat withdrawal disorders resulting from termination of use of addictive substances. These addictive substances include nicotine-containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines * and benzodiazepine * -like drugs and alcohol. In general, withdrawal from addictive substances is often a traumatic experience characterized by anxiety and frustration, anger, anxiety, impaired concentration, restlessness, reduced heart rate, and increased appetite and weight gain.

As used herein, "treatment" encompasses treatment, prevention and alleviation of withdrawal symptoms and withdrawal, as well as treatments capable of resulting in an active reduction in the intake of addictive substances.

In another aspect, the 1, 4-diazabicycloalkane derivatives of the invention are useful as diagnostic agents, e.g., for identifying and localizing nicotinic receptors in a variety of tissues.

Pharmaceutical composition

In another aspect, the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a1, 4-diazabicycloalkane derivative of the invention.

Although the 1, 4-diazabicycloalkane derivatives of the invention may be administered as raw compounds for therapeutic use, it is preferred that the pharmaceutical compositions be formulated together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical adjuvants, optionally in the form of physiologically acceptable salts, for the introduction of the active ingredient.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a1, 4-diazabicycloalkane derivative of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and/or prophylactic ingredients well known and used in the art. The carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions of the present invention may be administered by any convenient route, which is appropriate for the desired treatment. Preferred routes of administration include oral, in particular in the form of tablets, capsules, dragees, powders or liquids, and parenteral, in particular cutaneous, subcutaneous, intramuscular or intravenous injection. The pharmaceutical compositions of the present invention may be prepared by any person skilled in the art using standard methods and conventional techniques appropriate to the intended formulation. If desired, compositions suitable for sustained release of the active ingredient may be employed.

More details on formulation and administration techniques can be found in the latest editionRemington’s Pharmaceutical Sciences(Maack publishing company, Easton, Pa.).

The actual dosage will depend on the nature and severity of the condition being treated and is within the discretion of the physician and may be varied by titration of the dosage to achieve the desired therapeutic effect in accordance with the particular circumstances of the invention. However, it is presently contemplated that pharmaceutical compositions containing from about 0.1 to about 500mg, preferably from about 1 to about 100mg, most preferably from about 1 to about 10mg of active ingredient per single dose are suitable for treatment.

The active ingredient may be administered in one or more doses per day. In some cases satisfactory results are obtained at doses as low as 0.1. mu.g/kg i.v. and 1. mu.g/kg p.o.. The upper limit of the dosage range is currently believed to be about 10mg/kg i.v. and 100mg/kg p.o.. Preferred ranges are from about 0.1 μ g/kg to about 10 mg/kg/day i.v. and from about 1 μ g/kg to about 100 mg/kg/day p.o..

Method of treatment

The 1, 4-diazabicycloalkane derivatives of the invention are valuable nicotinic receptors and monoamine receptor modulators and are therefore useful in the treatment of a range of conditions involving cholinergic dysfunction and a range of conditions responsive to the action of nAChR modulators.

In another aspect the present invention provides a method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of cholinergic receptors and/or monoamine receptors, which method comprises administering to such a living animal body, including a human, in need thereof an effective amount of a compound of the present invention.

In a preferred embodiment, the disease, disorder or condition involves the central nervous system.

In a preferred embodiment, the disease, disorder or condition is anxiety, cognitive disorders, learning deficit, memory deficits and dysfunction, alzheimer's disease, attention deficit hyperactivity disorder, parkinson's disease, huntington's chorea, amyotrophic lateral sclerosis, tourette's syndrome, depression, mania, manic depression, schizophrenia, Obsessive Compulsive Disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post traumatic syndrome, social phobia, sleep disorders, pseudodementia, ganser's syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, Mutism, trichotillomania and jet lag.

In another preferred embodiment, the disease, disorder or condition is associated with smooth muscle contraction, including spastic disorders, angina, premature labor, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile difficulty.

In a third preferred embodiment, the disease, disorder or condition is related to the endocrine system, such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In a fourth preferred embodiment, the disease, disorder or condition is a neurodegenerative disease, including transient hypoxia and induced neurodegeneration.

In a fifth preferred embodiment, the disease, disorder or condition is a prodigious disease, including inflammatory skin diseases such as acne and rosacea, Chron's disease, inflammatory bowel disease, ulcerative colitis, and diarrhea.

In a sixth preferred embodiment, the disease, disorder or condition is mild, moderate or even severe pain, acute, chronic or recurrent, as well as pain caused by migraine, postoperative pain and pain in the prosthetic limb.

In a seventh preferred embodiment, the disease, disorder or condition is associated with withdrawal symptoms resulting from the termination of use of addictive substances, including nicotine-containing products, such as tobacco, opioids, such as heroin, cocaine and morphine, benzodiazepines * and benzodiazepine * -like drugs and alcohol.

It is now contemplated that suitable dosage ranges are from 0.1 to 1000mg per day, from 10 to 500mg per day, in particular from 30 to 100mg per day, depending generally on the exact mode of administration, the form of administration, the indication for which the administration is intended, the subject concerned and its body weight, and also on the preference and experience of the physician or veterinarian in charge.

In some cases satisfactory results are obtained at doses as low as 0.005mg/kg i.v. and 0.01mg/kg p.o.. The upper limit of the dosage range is about 10mg/kg i.v. and 100mg/kg p.o.. Preferred dosage ranges are from about 0.001 to about 1mg/kg i.v. and from 0.1 to about 10mg/kg p.o..

Examples

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

Example 1

Preparation examples

All reactions involving air sensitive reagents or intermediates were carried out under nitrogen atmosphere and in anhydrous solvents. Magnesium sulfate was used as a drying agent in the work-up step and the solvent was evaporated under reduced pressure.

1, 4-diazabicyclo [3.2.2]Nonane (intermediate compound)Prepared according to j.med.chem.1993362311-2320 and according to the following slightly modified procedure.

1, 4-diazabicyclo [3.2.2] in anhydrous dioxane (130ml) under argon]A solution of nonan-3-one (15.8g, 113mmol) was added LiAlH₄(4.9g, 130 mmol). The mixture was refluxed for 6 hours and then allowed to reach room temperature. Water (5ml in 10ml dioxane) was added dropwise to the reaction mixture, the mixture was stirred for 0.5 h and then filtered off through a glass filter. The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90 ℃ (0.1mbar) to give 1, 4-diazabicyclo [3.2.2]Nonane (11.1g, 78%) as a colorless hygroscopic substance.

1, 4-diazabicyclo [3.2.2]Nonane-3-ones (intermediate compounds)

To a solution of 3-quinuclidinone hydrochloride (45g, 278mmol) in 90ml of water was added hydroxylamine hydrochloride (21g, 302mmol) and sodium acetate (CH)₃COOH_x3H₂O, 83g, 610mmol), the mixture was stirred at 70 ℃ for 1 hour and then cooled to 0 ℃. The separated crystalline material was filtered off (without washing) and dried in vacuo to give 40.0g of oxime.

3-quinuclidinone oxime (40.0g) was added in small portions to polyphosphoric acid (190g, prepared as described below) over 2 hours and preheated to 120 ℃. The temperature of the solution during the reaction was maintained at 130 ℃. After all the oximes were added, the solution was stirred at the same temperature for 20 minutes and then transferred to an enameled vessel and allowed to reach room temperature. The acidic mixture was neutralized with a solution of potassium carbonate (500g in 300ml of water), transferred to a 2000ml flask, diluted with 300ml of water and extracted with chloroform (3X 600 ml). The combined organic extracts were dried over sodium sulfate, the solvent was evaporated and the solid residue was dried in vacuo to give 30.0g (77%) of a lactam mixture.

The resulting mixture was crystallized from 1, 4-dioxane (220ml) to give 15.8g (40.5%) of 1, 4-diazabicyclo [3.2.2] nonan-3-one as a colorless large crystal, mp211-212 ℃.

The filtrate was evaporated and the residue was chromatographed on silica gel (Merck, 9385, 230-. The solvent was evaporated and the residue was recrystallized from ethyl acetate to give 1, 3-diazabicyclo [3.2.2] nonan-4-one (10.2g, 26%) as colorless crystals, mp125-126 ℃.

Polyphosphoric acid

85% orthophosphoric acid (500g, 294ml, 4.337mol) was placed in a 2000ml flask, then phosphorus pentoxide (750g, 5.284mol) was added at room temperature (ratio: acid-pentoxide, 2: 3). The mixture was stirred at 200-220 ℃ for 2 hours to give 1250g of polyphosphoric acid containing 80% P₂O₅。

2-chloro-5-phenyl-1, 3, 4-thiadiazole (intermediate compound)

2-amino-5-phenyl-1, 3, 4-thiadiazole sulfate (25.12g, 142mmol) was stirred in concentrated hydrochloric acid (300ml) at 0 ℃. Sodium nitrite (12.7g, 184mmol) was added over 10 minutes. The reaction mixture was stirred at 50 ℃ for 15 hours. The hydrochloric acid is evaporated. Aqueous sodium hydroxide (4M, 250ml) was added and the precipitate was filtered. Chromatography on silica gel with ethyl acetate as solvent gave a pure product. Yield 15.5g (56%).

Method A

4- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1, 4-diazabicyclo [3.2.2]Nonane Fumarate salt (compound a 1):

a mixture of 1, 4-diazabicyclo [3.2.2] nonane (1.28g, 10.2mmol), 2-chloro-5-phenyl-1, 3, 4-thiadiazole (2.00g, 10.2mmol), triethylamine (2.83ml, 20.3mmol) and dioxane (20ml) was stirred at reflux for 70 h. Aqueous sodium hydroxide (1M, 25ml) was added and extracted twice with ethyl acetate (2X 20 ml). Chromatography on silica gel using dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as an oil. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol saturated with fumaric acid (9: 1). Yield 0.95g, 23%. Mp150.9 ℃.

The following compounds were prepared in a similar manner:

4- [5- (2-selenophenyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 2);

4- [5- (3-selenophenyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 3);

4- [5- (2-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A4);

4- [5- (4-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A5);

4- [5- (5-Imidazoyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (Compound A6);

4- [5- (1-methyl-2-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 7);

4- [5- (1-methyl-4-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A8);

4- [5- (1-methyl-5-imidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 9);

4- [5- (3-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 10);

4- [5- (4-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 11);

4- [5- (5-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 12);

4- [5- (1-methyl-3-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 13);

4- [5- (1-methyl-4-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 14);

4- [5- (1-methyl-5-pyrazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 15);

4- [5- (2-thiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 16);

4- [5- (4-thiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 17);

4- [5- (5-thiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 18);

4- [5- (3-isothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 19);

4- [5- (4-isothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 20);

4- [5- (5-isothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 21);

4- [5- (1, 2, 3-oxadiazol-4-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 22);

4- [5- (1, 2, 3-oxadiazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 23);

4- [1, 3, 4-oxadiazol-2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 24);

4- [5- (3-furazanyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A25);

4- [5- (1, 2, 3-triazol-4-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 26);

4- [5- (1, 2, 3-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 27);

4- [5- (1-methyl-1, 2, 3-triazol-4-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 28);

4- [5- (1-methyl-1, 2, 3-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 29);

4- [5- (1, 2, 4-triazol-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 30);

4- [5- (1, 2, 4-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 31);

4- [5- (1-methyl-1, 2, 4-triazol-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 32);

4- [5- (1-methyl-1, 2, 4-triazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 33);

4- [5- (1, 3, 4-thiadiazol-2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 34);

4- [5- (1, 2, 4-thiadiazol-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 35);

4- [5- (1, 2, 4-thiadiazol-5-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 36);

4- [5- (3-pyridazinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 37);

4- [5- (4-pyridazinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 38);

4- [5- (1, 3, 5-triazin-2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 39);

4- [5- (2-quinolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A40);

4- [5- (3-quinolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A41);

4- [5- (3-isoquinolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 42);

4- [5- (3-cinnolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A43);

4- [5- (2-indolizinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A44);

4- [5- (2-indolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 45);

4- [5- (1-methyl-2-indolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 46);

4- [5- (2-benzimidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A47);

4- [5- (1-methyl-2-benzimidazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 48);

4- [5- (2-benzothiazolyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 49);

4- [5- (7-naphthyridinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A50);

4- [5- (2-quinazolinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 51);

4- [5- (2-quinoxalinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A52);

4- [5- (1, 8-naphthyridin-2-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 53);

4- [5- (1, 8-naphthyridin-3-yl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 54);

4- [5- (2-acridinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound a 55); and

4- [5- (3-acridinyl) -1, 3, 4-thiadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound A56).

Method B

2-Mercaptobenzyl-5-phenyl-1, 3, 4-oxadiazole (intermediate compound)

Benzyl bromide (16.8ml, 141mmol) was added to a mixture of 5-phenyl-1, 3, 4-oxadiazole-2-thiol (commercially available) (25.2g, 141mmol), triethylamine (19.7ml, 141mmol) and ethanol (250ml) at room temperature over 10 min.

The mixture was stirred at room temperature for 3 hours. Aqueous sodium hydroxide (1M, 250ml) was added and extracted twice with dichloromethane (2X 200 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia gave the title compound as an oil. Yield 34.2g (90%).

Method C

5- (2-furyl) -1, 3, 4-oxadiazole-2-thiol (intermediate compound)

Carbon disulfide (16.5g, 216mmol) was added to a mixture of 2-furohydrazide (13.6g, 108mmol), potassium hydroxide (6.68g, 119mmol) and methanol (125 ml). The mixture was stirred at room temperature for 30 minutes and then refluxed for 18 hours. The methanol was evaporated. The aqueous phase was acidified with concentrated hydrochloric acid to pH 4. The product was isolated by filtration. Yield 12.9g (72%).

Method D

4- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -1, 4-diazabicyclo [3.2.2]Nonane Fumarate salt (Compound D1)

A mixture of 2-mercaptobenzyl-5-phenyl-1, 3, 4-oxadiazole (method B) (1.0g, 3.7mmol), 1, 4-diazabicyclo [3.2.2] nonane (0.47g, 3.7mmol) and diisopropylethylamine (1.3ml, 7.4mmol) was stirred at 100 ℃ for 4 days. Aqueous sodium hydroxide (1M, 25ml) was added and extracted twice with dichloromethane (2X 20 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia gave the title compound as an oil. The corresponding salt was obtained by adding a mixture of diethyl ether and methanol saturated with fumaric acid (9: 1). The yield was 0.47g, 33%. Mp176.6-178.8 ℃.

The following compounds were prepared in a similar manner:

4- [5- (2-furyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2] Nonane fumarate (Compound D2)

Prepared according to procedure D. Mp175 ℃.

4- [5- (4-methoxyphenyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2]Nonane fumarate (Compound D3)

Prepared according to procedure D. Mp190.1-191.2 ℃.

4- [5- (4-pyridinyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2] Nonane fumarate (Compound D4)

Prepared according to procedure D. Mp165.9-166.8 ℃.

4- [5- (2-thienyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2] Nonane fumarate (Compound D5)

Prepared according to method D, Mp161.8-162.7 ℃.

4- [5- (3-pyridinyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2] Nonane fumarate (Compound D6)

Prepared according to procedure D. Mp176.8-177.5 ℃.

4- [5- (4-chlorophenyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2] Nonane fumarate (Compound D7)

Prepared according to procedure D. Mp184.3-185.8 ℃.

4- [5- (3-methoxyphenyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2]Nonane fumarate (Compound D8)

Prepared according to procedure D. Mp126-164 ℃.

4- [5- (4-phenyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2]Nonane fumarate (Compound D9)

Prepared according to procedure D. Mp 238-.

4- [5- (2-naphthyl) -1, 3, 4-oxadiazol-2-yl]-1, 4-diazabicyclo [3.2.2] Nonane fumarate (Compound D10)

Prepared according to procedure D. Mp194.6-195.7 ℃.

The following compounds were prepared analogously:

4- [5- (3-furyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D11);

4- [5- (3-thienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D12);

4- [5- (2-pyridinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D13);

4- [5- (2-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D14);

4- [5- (3-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D15);

4- [5- (1-methyl-2-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D16);

4- [5- (1-methyl-3-pyrrolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D17);

4- [5- (2-pyrimidinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D18);

4- [5- (4-pyrimidinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D19);

4- [5- (5-pyrimidinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D20);

4- [5- (pyrazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D21);

4- [5- (2-selenophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D22);

4- [5- (3-selenophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D23);

4- [5- (2-oxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D24);

4- [5- (4-oxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D25);

4- [5- (5-oxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D26);

4- [5- (3-isoxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D27);

4- [5- (4-isoxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D28);

4- [5- (5-isoxazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound 29);

4- [5- (2-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D30);

4- [5- (4-Imidazoyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D31);

4- [5- (5-Imidazoyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D32);

4- [5- (1-methyl-2-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D33);

4- [5- (1-methyl-4-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D34);

4- [5- (1-methyl-5-imidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D35);

4- [5- (3-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D36);

4- [5- (4-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D37);

4- [5- (5-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D38);

4- [5- (1-methyl-3-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D39);

4- [5- (1-methyl-4-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D40);

4- [5- (1-methyl-5-pyrazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D41);

4- [5- (2-thiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D42);

4- [5- (4-thiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D43);

4- [5- (5-thiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D44);

4- [5- (3-isothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D45);

4- [5- (4-isothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D46);

4- [5- (5-isothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D47);

4- [5- (1, 2, 3-oxadiazol-4-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D48);

4- [5- (1, 2, 3-oxadiazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D49);

4- [5- (1, 3, 4-oxadiazol-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D50);

4- [5- (3-furazanyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D51);

4- [5- (1, 2, 3-triazol-4-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D52);

4- [5- (1, 2, 3-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D53);

4- [5- (1-methyl-1, 2, 3-triazol-4-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D54);

4- [5- (1-methyl-1, 2, 3-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D55);

4- [5- (1, 2, 4-triazol-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D56);

4- [5- (1, 2, 4-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D57);

4- [5- (1-methyl-1, 2, 4-triazol-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D58);

4- [5- (1-methyl-1, 2, 4-triazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D59);

4- [5- (1, 3, 4-thiadiazol-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D60);

4- [5- (1, 2, 4-thiadiazol-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D61);

4- [5- (1, 2, 4-thiadiazol-5-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D62);

4- [5- (3-pyridazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D63);

4- [5- (4-pyridazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D64);

4- [5- (1, 3, 5-triazin-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D65);

4- [5- (2-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D66);

4- [5- (3-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D67);

4- [5- (5-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D68);

4- [5- (6-benzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D69);

4- [5- (2-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D70);

4- [5- (3-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D71);

4- [5- (5-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D72);

4- [5- (6-benzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D73);

4- [5- (2-quinolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D74);

4- [5- (3-quinolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D75);

4- [5- (3-isoquinolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D76);

4- [5- (3-cinnolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D77);

4- [5- (2-indolizinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D78);

4- [5- (2-indolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D79);

4- [5- (1-methyl-2-indolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D80);

4- [5- (2-benzimidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D81);

4- [5- (1-methyl-2-benzimidazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D82);

4- [5- (2-benzothiazolyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D83);

4- [5- (7-naphthyridinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D84);

4- [5- (2-quinazolinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D85);

4- [5- (2-quinoxalinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D86);

4- [5- (1, 8-naphthyridin-2-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D87);

4- [5- (1, 8-naphthyridin-3-yl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D88);

4- [5- (2-acridinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D89);

4- [5- (3-acridinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D90);

4- [5- (2-dibenzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D91);

4- [5- (3-dibenzofuranyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D92);

4- [5- (2-Dibenzothienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D93);

4- [5- (3-dibenzothiophenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D94);

4- [5- (2-Phenoxazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D95); and

4- [5- (3-Phenoxazinyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane (compound D96).

Example 2

In vitro inhibition³Binding of H-alpha-bungarotoxin in rat brain

In this example, the binding of a compound of the invention to nicotinic receptor alpha was determined₇-affinity of the subtype.

Alpha-bungarotoxin is a peptide isolated from the venom of the elapidae bungarus multicinctus (bungarus multicinctus). The toxin has a high affinity for neuronal and neuromuscular nicotinic receptors, where it acts as a potent antagonist.

³H-alpha-bungarus multicinctusToxin labeling by alpha found in the brain₇Subunit isoforms and alpha in the neuromuscular junction₁Isoform forming nicotinic acetylcholine receptors.

Tissue preparation

The preparation is carried out at 0-4 ℃. Using an Ultra-Turrax homogenizer at a temperature of 118mM NaCl, 4.8mM KCl, 1.2mM MgSO₄And 2.5mM CaCl₂15ml of 20mM Hepes buffer (pH7.5) brain cortex from male Wistar rats (150-250g) was homogenized for 10 seconds. The tissue suspension was centrifuged at 27,000 Xg for 10 minutes. The supernatant was discarded and the pellet was washed 2 times by centrifugation at 27,000 Xg for 10 min in 20ml of fresh buffer, after which the final pellet was resuspended in fresh buffer containing 0.01% BSA (35 ml per gram of original tissue) and used for binding assays.

Measurement of

To 25. mu.l of test solution and 25. mu.l³To H- α -bungarotoxin (2nM, final concentration) was added an aliquot of 500 μ l homogenate, mixed and incubated at 37 ℃ for 2 hours. Non-specific binding was determined using (-) nicotine (1mM, final concentration). After incubation, 5ml of ice-cold Hepes buffer containing 0.05% PEI was added to the samples and poured directly onto Whatman GF/C glass fiber filters (pre-soaked in 0.1% PEI for at least 6 hours) under suction and immediately washed with 2 × 5ml ice-cold buffer.

The amount of radioactivity on the filter was determined by conventional liquid scintillation counting. Specific binding is equal to total binding minus non-specific binding.

Testing the value with IC₅₀(suppression of³Concentration of test substance that binds specifically to H- α -bungarotoxin by 50%).

The results of these experiments are shown in table 1 below.

TABLE 1

To pair³Inhibition of H-alpha-bungarotoxin binding

Compound numbering	IC₅₀(μM)
Compound numbering	IC₅₀(μM)	Compound A1	0.0067
Compound D1	0.0058	Compound A1	0.0067
Compound D1	0.0058	Compound D5	0.022

Claims

1.1, 4-diazabicycloalkane derivatives of formula I:

any enantiomer thereof or any mixture of enantiomers thereof, or a pharmaceutically-acceptable addition salt thereof,

wherein

X represents O or S; and

ar represents an aryl group selected from phenyl and naphthyl, or furanHeteroaryl groups of the group, thienyl and pyridyl; said phenyl, naphthyl, furyl, thienyl and pyridyl are optionally substituted one or more times by substituents selected from the group consisting of: c_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_1-6-alkoxy, C_1-6-alkoxy-C_1-6Alkyl radical, C_1-6-alkoxy-C_1-6-alkoxy, C_3-7Cycloalkoxy, C_3-7-cycloalkoxy-C_1-6Alkyl radical, C_3-7-cycloalkoxy-C_1-6Alkoxy, halogen, CF₃Phenyl and benzyl.

2. A compound according to claim 1, wherein Ar represents phenyl, optionally substituted once or twice with a substituent selected from: c_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_1-6-alkoxy, C_3-7Cycloalkoxy, halogen, CF₃Phenyl and benzyl.

3. A compound according to claim 2, wherein Ar represents phenyl, optionally substituted once or twice with a substituent selected from: c_1-6Alkyl radical, C_1-6Alkoxy, halogen, CF₃And a phenyl group.

4. A compound according to any one of claims 1 to 3, wherein Ar is optionally substituted one or more times with a substituent selected from: c_1-6Alkyl radical, C_1-6-alkoxy, halogen and phenyl.

5. The compound of claim 1 which is

4- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1, 4-diazabicyclo [3.2.2] nonane;

4- (5-phenyl-1, 3, 4-oxadiazol-2-yl) -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-phenyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane; or

4- [5- (2-naphthyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (2-furyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (3-pyridyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

4- [5- (4-pyridyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane; or

4- [5- (2-thienyl) -1, 3, 4-oxadiazol-2-yl ] -1, 4-diazabicyclo [3.2.2] nonane;

or an enantiomer or a mixture of enantiomers, or a pharmaceutically-acceptable addition salt thereof.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 5, any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.

7. Use of a compound according to any one of claims 1-5, any of its enantiomers or any mixture of its enantiomers, or a pharmaceutically acceptable addition salt thereof, for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition responsive to modulation of cholinergic receptors and/or monoamine receptors.

8. The use according to claim 7, wherein the disease, disorder or condition involves the central nervous system.

9. The use according to claim 7, wherein the disease, disorder or condition is anxiety, cognitive disorders, learning deficit, memory deficits and dysfunctions, Alzheimer's disease, attention deficit hyperactivity disorder, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, Tourette's syndrome, depression, mania, manic depression, schizophrenia, obsessive-compulsive disorders, panic disorders, eating disorders, narcolepsy, nociception, AIDS-dementia, senile dementia, peripheral neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post traumatic syndrome, social phobia, sleep disorders, pseudodementia, ganser's syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania, and jet lag.

10. Use according to claim 9, wherein the eating disorder is anorexia nervosa, bulimia or obesity.

11. The use according to claim 7, wherein the disease, disorder or condition is associated with smooth muscle contraction and is selected from the group consisting of spastic disorders, angina, premature labor, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile difficulty.

12. Use according to claim 7, wherein the disease, disorder or condition is related to the endocrine system and is selected from thyrotoxicosis, pheochromocytoma, hypertension and cardiac arrhythmias.

13. The use according to claim 7, wherein the disease, disorder or condition is a neurodegenerative disease selected from transient hypoxia and induced neurodegeneration.

14. The use of claim 7, wherein the disease, disorder or condition is an inflammatory disease selected from the group consisting of inflammatory skin diseases, Crohn's disease, inflammatory bowel disease, ulcerative colitis and diarrhea.

15. The use of claim 14, wherein the inflammatory skin disease is acne or rosacea.

16. The use according to claim 7, wherein the disease, disorder or condition is acute, chronic or recurrent mild, moderate or severe pain, or pain caused by migraine, postoperative pain or pain in the prosthetic limb.

17. Use according to claim 7, wherein the disease, disorder or condition is associated with withdrawal symptoms caused by termination of use of an addictive substance selected from the group consisting of nicotine-containing products, opioids, benzodiazepines * and benzodiazepines * -like drugs and alcohol.

18. The use according to claim 17, the nicotine-containing product being tobacco and the opioid being heroin, cocaine or morphine.