JP4711391B2 - Novel 1,4-diazabicycloalkane derivative and method for producing the same - Google Patents

Description

  The present invention relates to novel 1,4-diazabicycloalkane derivatives and methods for using them in the manufacture of pharmaceutical formulations. The compounds of the present invention have been found to be cholinergic ligands at the nicotinic acetylcholine receptor and modulators of monoamine receptors and transporters.

Because of the above pharmacological profile, the compounds of the present invention are not related to diseases or disorders related to cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine It can be said to be effective in the treatment of various diseases or disorders such as diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain , withdrawal symptoms resulting from withdrawal of chemical abuse.

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

  Muscarinic acetylcholine receptors are well documented to quantitatively dominate nicotinic acetylcholine receptors in brain regions that are important for memory and cognition, aiming to develop therapeutics for the treatment of memory-related disorders Much research has been focused on the synthesis of muscarinic acetylcholine receptor modulators.

Recently, however, interest in the development of nAChR modulators has increased. Some diseases are associated with cognitive impairment due to cholinergic degeneration, ie Alzheimer's type senile dementia, vascular dementia and alcoholic brain disorders directly related to alcoholism. Certainly some CNS disorders are cholinergic defects, dopaminergic
It is thought to be due to a defect or a serotonergic defect.

  Patent Document 1 describes a 1,4-diazabicyclo [3.2.2] nonane derivative having activity at a nicotine receptor. However, only 6-membered heteroaryl derivatives are described. The 5-membered heteroaryl derivatives of the present invention are not described.

  Patent Document 2 describes a 1,4-diazabicyclo [3.2.2] nonane derivative having activity at a nicotine receptor. However, only bicyclic heteroaryl derivatives are described. The monocyclic heteroaryl derivatives of the present invention are not described.

  Patent Document 3 describes a 1,4-diazabicyclo [3.2.2] nonane derivative having activity at a nicotine receptor. However, only phenyl-isoxazole derivatives are described. The thiadiazole derivatives of the present invention are not described.

  Patent Document 4 describes a 1,4-diazabicyclo [3.2.2] nonane derivative having activity at a nicotine receptor. However, only phenyl-thiazole derivatives are described. The thiadiazole derivatives of the present invention are not described.

Patent Document 5 describes a 1,4-diazabicyclo [3.2.2] nonane derivative having activity at a nicotine receptor. However, only bicyclic heteroaryl derivatives are described. The monocyclic heteroaryl derivatives of the present invention are not described.
International Patent Application (WO) No. 00/34279 (Sanofi-Synthelabo) International Patent Application (WO) No. 01/55150 (Sanofi-Synthelabo) International Patent Application (WO) No. 01/92259 (Sanofi-Synthelabo) International Patent Application (WO) No. 01/92260 (Sanofi-Synthelabo) European Patent No. 1219622 (Pfizer Ltd.)

SUMMARY OF THE INVENTION The present invention provides a biogenic amine transporter for cholinergic receptors and in particular nicotinic acetylcholine receptor (nAChR), serotonin receptor (5-HTR), DAR and NER, and 5-HT, DA and (NE). It relates to providing novel modulators of nicotinic and / or monoamine receptors that are effective in the treatment of related diseases or disorders.
Because of its pharmacological profile, the compounds of the present invention are suitable for diseases or disorders related to the cholinergic system of the central nervous system (CNS), peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine. It can be said that it is effective in treating various diseases or disorders such as diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain , withdrawal symptoms caused by withdrawal of chemical abuse.

  The compounds of the present invention are also useful in various diagnostic methods, particularly as diagnostic tools or monitoring agents for in vivo receptor imaging, and the compounds of the present invention are labeled And can be used in unlabeled form.

  In its first aspect, the present invention provides a compound of formula I

{Where,
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 may optionally be alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, alkoxy-alkyl, Substituents selected from the group consisting of alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halogen, CF ₃ , CN, NO ₂ , NH ₂ , carboxy, carbamoyl, amide, sulfamoyl, phenyl and benzyl May be substituted one or more times. }
The present invention provides a novel 1,4-diazabicycloalkane derivative represented by: or any enantiomer thereof or any mixture thereof, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof.

  In a second aspect, the present invention provides a therapeutically effective 1, 4-diazabicycloalkane derivative of the present invention or an enantiomer or a mixture of the enantiomers, or a pharmaceutically acceptable addition salt thereof. Provided is a pharmaceutical formulation comprising an amount together with at least one pharmaceutically acceptable carrier or diluent.

  Viewed from other aspects, the manufacture of a medicament for the treatment, prevention or alleviation of a disease or disorder or condition--the disease or disorder or condition responds to the modulation of cholinergic receptors and / or monoamine receptors-- And a method of using the 1,4-diazabicycloalkane derivative of the present invention, an enantiomer or a mixture of the enantiomers, or a pharmaceutically acceptable addition salt thereof.

  In yet another aspect, the present invention relates to diseases or disorders or pathologies of living animals including humans --------- the disorder, disease or condition is a modulation of cholinergic receptors and / or monoamine receptors. Is a method of treating, preventing or alleviating ------------, which is a 1,4-diazabicycloalkane derivative of the present invention, any of its enantiomers or its Administering a therapeutically effective amount of any mixture of enantiomers, or a pharmaceutically acceptable addition salt thereof, to an animal body, including a human being in need thereof, Provide prevention or mitigation methods.

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

Detailed Description of the Invention
In its first aspect, the invention provides a general formula I

{Where,
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 may optionally be alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, alkoxy-alkyl, Substituents selected from the group consisting of alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halogen, CF ₃ , CN, NO ₂ , NH ₂ , carboxy, carbamoyl, amide, sulfamoyl, phenyl and benzyl May be substituted one or more times. }
The present invention provides a novel 1,4-diazabicycloalkane derivative represented by: or any enantiomer thereof or any mixture thereof, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof.

In a more preferred embodiment, Ar represents a carbocyclic aromatic (aryl) group or a heterocyclic aromatic (heteroaryl) group, which may optionally be alkyl, alkoxy, halogen, CF ₃ , CN, NO ₂ , It may be substituted one or more times by a substituent selected from the group consisting of NH ₂ and phenyl.

  In a first preferred embodiment, the compounds of the invention have the formula II

(Wherein X and Ar are as defined above.)
1,4-diazabicyclo [3.2.2] nonane derivative represented by
In a more preferred embodiment, the compounds of the invention have the formula III

(Wherein Ar is as defined above.)
4-thiadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivative represented by
In another preferred embodiment, the compounds of the invention have the formula IV

(Wherein Ar is as defined above.)
4-oxadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivative represented by

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, carbocyclic aromatic group is phenyl, optionally alkyl, cycloalkyl, cycloalkyl - alkyl, alkoxy, cycloalkoxy, _{halogen, CF 3, CN, NO 2} , NH 2, carboxy, carbamoyl, Substituted once or twice by a substituent selected from the group consisting of amide, sulfamoyl, phenyl and benzyl.

In an even more preferred embodiment, the carbocyclic aromatic group is phenyl, optionally 1 or 2 depending on a substituent selected from the group consisting of alkyl, alkoxy, halogen, CF ₃ , CN, NO ₂ , NH ₂ and phenyl. Has been replaced twice.

In the 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 thereof or a mixture of enantiomers thereof, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof, and 4-oxadiazolyl-1 of the present invention , 4-Diazabicyclo [3.2.2] nonane derivatives are
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-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 the enantiomers, 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 bi- or poly-heterocyclic heterocyclic group. The heterocyclic groups are benzo-fused 5- and 6 having one or more heteroatoms selected from nitrogen (N), oxygen (O), sulfur (S) and / or selenium (Se). -Includes membered heterocyclic rings.

  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 furanyl, especially 2-furanyl or 3-furanyl; thienyl, especially 2-thienyl or 3-thienyl; selenophenyl, especially 2-selenophenyl Or 3-selenophenyl; pyrrolyl (azolyl), especially 2-pyrrolyl or 3-pyrrolyl; oxazolyl, especially oxazol-2-, 4- or 5-yl; thiazolyl, especially thiazol-2-, 4- or 5-yl; Imidazolyl, especially 2-imidazolyl or 4-imidazolyl; pyrazolyl, especially 3-pyrazolyl or 4-pyrazolyl; isoxazolyl, especially isoxazol 3-, 4- or 5-yl; isothiazolyl, especially isothiazol-3-, 4- or 5 -Yl; oxadiazolyl, especially 1,2,3-oxadiazol-4- or 5-yl, or 1,3,4-oxadiazol-2-yl; triazolyl, especially 1,2,3-tria 4-yl or 1,2,4-triazol-3-yl; thiadiazolyl, especially 1,2,3-thiadiazol-4- or 5-yl, or 1,3,4-thiadiazol-2-yl; Pyridinyl, especially 2-, 3- or 4-pyridinyl; pyridazinyl, especially 3- or 4-pyridazinyl; pyrimidinyl, especially 2-, 4- or 5-pyrimidinyl; pyrazinyl, especially 2- or 3-pyrazinyl; 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 the formula III, wherein Ar is selenophenyl, in particular 2-selenophenyl or 3-selenophenyl; imidazolyl, especially 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; pyrazolyl, especially 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl; thiazolyl, especially 2-thiazolyl or 5-thiazolyl; isothiazolyl, especially 3 -Isothiazolyl, 4-isothiazolyl or 5-isothiazolyl; oxadiazolyl, especially 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl or 1,3,4-oxadi Azol-2-yl; Frazanil, especially 3-Furazanyl; Triazolyl, especially 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazole-3- Il or 1,2,4-tria -5-yl; thiadiazolyl, especially 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; pyridazinyl, especially 3 Represents an optionally substituted aromatic monocyclic heterocyclic group selected from -pyridazinyl or 4-pyridazinyl; and triazinyl, in particular 1,3,5-triazin-2-yl.

In a more preferred embodiment, the aromatic 5- or 6-membered heterocyclic monocyclic group is optionally substituted selected from the group consisting of alkyl, alkoxy, halogen, CF ₃ , CN, NO ₂ , NH ₂ and phenyl It is substituted once or twice by the group.

In a most preferred embodiment, the 4-thiadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivative of the present invention is
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-oxadizol-4-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (1,2,3-oxadizol-5-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [1,3,4-oxadizol-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;
Or an enantiomer or a mixture of the enantiomers, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof.

  In another preferred embodiment, the compound of the invention is a 4-oxadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivative of the formula IV, wherein Ar is furyl, especially 2-furyl or 3 -Furyl; pyridyl, especially 2-pyridyl, 3-pyridyl or 4-pyridyl; thienyl, especially 2-thienyl or 3-thienyl; pyrrolyl, especially 2-pyrrolyl or 3-pyrrolyl; pyrimidinyl, especially 2-pyrimidinyl, 4-pyrimidinyl Or 5-pyrimidinyl; pyrazinyl; selenophenyl, especially 2-selenophenyl or 3-selenophenyl; oxazolyl, especially 2-oxazolyl, 4-oxazolyl or 5-oxazolyl; isoxazolyl, especially 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl Imidazolyl, especially 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; pyrazolyl, especially 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, especially 1,2,3-oxadiazole -4-yl, 1,2,3-oxadiazol-5-yl or 1,3,4-oxadiazol-2-yl; furazanyl, especially 3-furazanyl; triazolyl, especially 1,2,3-triazole -4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-5-yl; thiadiazolyl, especially 1,3,4- Thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl; pyridazinyl, especially 3-pyridazinyl or 4-pyridazinyl; and triazinyl, especially 1,3,5 -Represents an optionally substituted aromatic monocyclic heterocyclic group selected from -triazin-2-yl .

In a most preferred embodiment, the 4-oxadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivative of the present 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-oxadizol-4-yl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (1,2,3-oxadizol-5-yl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (1,3,4-oxadizol-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 or its enantiomer Or an enantiomer mixture thereof, or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof.

  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; benzoimidazolyl, especially 2-benzoimidazolyl; benzothiazolyl, especially 2-benzothiazolyl; quinolinyl, especially 2-quinolinyl, 3-quinolinyl or 4-quinolinyl; isoquinolinyl, especially 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl; cinnolinyl, especially 3-cinnolinyl or 4-cinnolinyl; phthalazinyl, especially 1- Phthalazinyl or 4-phthalazinyl; quinazolinyl, especially 2-quinazolinyl or 4-quinazolini Quinoxalinyl, especially 2-quinoxalinyl or 3-quinoxalinyl.

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

  In a further preferred embodiment, the compound of the invention is a 4-thiadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivative of the formula III, wherein the polycyclic aromatic heterocyclic group is quinolinyl, Especially 2-quinolinyl or 3-quinolinyl; isoquinolinyl, especially 3-isoquinolinyl; cinnolinyl, especially 3-cinnolinyl; indolizinyl, especially 2-indolidinyl; benzimidazolyl, especially 2-benzimidazolyl; benzothiazolyl, especially 2-benzothiazolyl; phthalazinyl, especially 7 -Phthalazinyl; quinazolinyl, especially 2-quinazolinyl; quinoxalinyl, especially 2-quinoxalinyl; naphthyridinyl, especially 1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl; and acridinyl, especially 2-acridinyl or 3- An optionally substituted bicyclic heteroaryl selected from acridinyl .

In an even more preferred embodiment, the bicyclic heteroaryl group is optionally substituted once or twice with a substituent selected from the group consisting of alkyl, alkoxy, halogen, CF ₃ , CN, NO ₂ , NH ₂ , and phenyl. Has been.

In a most preferred embodiment, the 4-thiadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivative of the present invention is
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-phthalazinolinyl) -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-naphthyridin-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 or an enantiomer thereof or a mixture of the enantiomers, or A pharmaceutically acceptable addition salt, or an N-oxide thereof.

  In a further preferred embodiment, the compounds according to the invention are 4-oxadiazolyl-1,4-diazabicyclo [3.2.2] nonane derivatives of the formula IV, wherein Ar is benzothienyl, in particular 2-benzothienyl, 3 -Benzothienyl, 5-benzothienyl or 6-benzothienyl; benzofuryl, especially 2-benzofuryl, 3-benzofuryl, 5-benzofuryl or 6-benzofuryl; quinolinyl, especially 2-quinolinyl or 3-quinolinyl; isoquinolinyl, especially 3-isoquinolinyl Cinnolinyl, especially 3-cinnolinyl; indolizinyl, especially 2-indolizinyl; indolyl, especially 2-indolyl; benzimidazolyl, especially 2-benzimidazolyl; benzothiazolyl, especially 2-benzothiazolyl; phthalazinyl, especially 7-phthalazinyl; quinazolinyl, especially 2- Quinazolinyl; quinoxalinyl, especially 2-quinoxalinyl; naphth Lydinyl, especially 1,8-naphthyridin-2-yl or 1,8-naphthyridin-3-yl; acridinyl, especially 2-acridinyl or 3-acridinyl; dibenzofuryl, especially 2-dibenzofuryl, or 3-dibenzofuryl; dibenzo Thienyl, especially 2-dibenzothienyl or 3-dibenzothienyl; phenoxazinyl, especially 2-phenoxazinyl or 3-phenoxazinyl, optionally substituted aromatic monocyclic heterocyclic group.

In a more preferred embodiment, the aromatic monocyclic heterocyclic group is optionally once or two depending on the substituent selected from the group consisting of alkyl, alkoxy, halogen, CF ₃ , CN, NO ₂ , NH ₂ , and phenyl. Has been replaced twice.

In the most preferred embodiment, the compounds of the 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-benzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (3-benzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (5-benzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (6-benzofuryl) -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-phthalazinolinyl) -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-dibenzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (3-dibenzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (2-dibenzothienyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
4- [5- (3-dibenzothienyl) -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 or an enantiomer thereof or a mixture of the enantiomers, Or a pharmaceutically acceptable addition salt thereof, or an N-oxide thereof.

  All combinations of two or more of the described embodiments herein are considered within the scope of the present invention.

Definition of Substituents Within the scope of the present invention, an alkyl group represents a monovalent saturated, linear or branched hydrocarbon chain. The hydrocarbon chain preferably has 1 to 18 carbon atoms (C _1-18 -alkyl), more preferably 1 to 6 carbon atoms (C _1-6 -alkyl: lower alkyl), Includes pentyl, isopentyl, neopentyl, t-pentyl, hexyl and isohexyl. In preferred embodiments, alkyl represents a C _1-4 -alkyl group, which includes butyl, isobutyl, s-butyl and t-butyl. In a preferred embodiment of the invention, alkyl represents a C _1-3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.

Within the scope of the present invention, a cycloalkyl group is a cyclic alkyl group, preferably a cycloalkyl group having 3 to 7 carbon atoms (C _3-7 -cycloalkyl), which is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. And cycloheptyl.

  In the scope of the present invention, a cycloalkyl-alkyl group denotes a cycloalkyl group as defined above, which cycloalkyl group is substituted with an alkyl group as defined above. Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.

Within the scope of the present invention, an alkenyl group designates a carbon chain having one or more double bonds, which includes dienes, trienes and polyenes. In a preferred embodiment the alkenyl group of the invention is from 2 to 8 carbon atoms containing at least one double bond (C _2-8 - alkenyl), more preferably 2 to 6 carbon atoms (C _2-6 - Alkenyl). In the most preferred embodiments, the alkenyl groups of the present invention are ethenyl; 1- or 2-propenyl (allyl); 1-, 2- or 3-butenyl, or 1,3-buthidienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1,3-hexidienyl, or 1,3,5-hexitrienyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octenyl, or 1,3- Octodienyl, or 1,3,5-octotrienyl, or 1,3,5,7-octatetraenyl.

Within the scope of the present invention, an alkynyl group refers to a carbon chain having one or more triple bonds, including diynes, triynes and polyynes. In a preferred embodiment, the alkynyl group of the present invention has 2 to 8 carbon atoms (C _2-8 -alkynyl), more preferably 2 to 6 carbon atoms (C _2-6 -alkynyl) containing at least one triple bond. ). In the most preferred embodiments, the alkynyl group of the present invention is ethynyl, 1- or 2-propynyl; 1-, 2-, 3- or 4-butynyl or 1,3-butodiinyl; 1-, 2-, 3-, 4 -Pentynyl, or 1,3-pentodiinyl; 1-, 2-, 3-, 4- or 5-henynyl, or 1,3-hexidiynyl, or 1,3,5-hextriinyl; 1-, 2-, 3- , 4-, 5- or 6-heptynyl, or 1,3-heptodiinyl, or 1,3,5-heptotriinyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, or 1,3-octodiinyl, or 1,3,5-octotriynyl, or 1,3,5,7-octetetriyl.

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

  Within the scope of the present invention, an alkoxy-alkyl group is an “alkyl-O-alkyl-” group, wherein alkyl is as defined above. Preferred alkoxy-alkyl groups of the present invention include methoxy-methyl, methoxy-ethyl, ethoxy-methyl and ethoxy-ethyl.

  Within the scope of the present invention an alkoxy-alkoxy group designates an “alkyl-O-alkyl-O—” group, wherein alkyl is as defined above. Preferred alkoxy-alkoxy groups of the present invention include methoxy-methoxy, methoxy-ethoxy, ethoxy-methoxy and ethoxy-ethoxy.

  Within the scope of the present invention, a cycloalkoxy group designates a “cycloalkyl-O—” group, wherein cycloalkyl is as defined above.

  Within the scope of the present invention, a cycloalkoxy-alkyl group designates a “cycloalkyl-O-alkyl” group, wherein cycloalkyl and alkyl are as defined above.

  Within the scope of the present invention, a cycloalkoxy-alkoxy group designates a “cycloalkyl-O-alkyl-O—” group, wherein cycloalkyl and alkyl are as defined above.

  In the scope of the present invention, halogen represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Thus, a trihalogenmethyl group represents, for example, a trifluoromethyl group, a trichloromethyl group and similar trihalogen-substituted methyl groups.

  Within the scope of the present invention, an acyl group denotes a carboxy group (—COOH) or an alkyl-carbonyl group (alkyl-CO—), wherein alkyl is as defined above. Examples of preferred acyl groups of the present invention include carboxy, acetyl and propionyl.

Pharmaceutically acceptable salts The 1,4-diazabicycloalkane derivatives of the present invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (ie physiologically) acceptable salts and pre- 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 hydrochlorides derived from hydrochloric acid, hydrobromic acids derived from hydrobromic acid Salt, 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, aconitine Derived from acid-derived aconitinate, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citric acid Citrate, embonic acid derived from embonic acid, enanthate derived from enanthic acid, fumarate derived from fumaric acid, glutamic acid Glutamate, glycolate derived from glycolic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonic acid Derived methanesulfonate, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, phthalate derived from phthalic acid, salicylic acid derived from salicylic acid, sorbate derived from sorbic acid, stearin It includes stearates derived from acids, succinates derived from succinic acid, tartrate derived from tartaric acid, and toluene-p-sulfonate derived from toluene-p-sulfonic acid. Such salts can be prepared by methods known in the art and described in the art.

Other acids, such as oxalic acid—which itself is not considered to be pharmaceutically acceptable—are the 1,4-diazabicycloalkane derivatives of the present invention and their pharmaceutically acceptable acid additions. It is suitable for the production of a salt useful as an intermediate compound in obtaining a salt.
The metal salts of 1,4-diazabicycloalkane derivatives of the present invention include alkali metal salts, such as the sodium salts of the compounds of the present invention containing a carboxy group.

  Within the scope of the present invention, “onium salts” of N-containing compounds are also considered as pharmaceutically acceptable salts (aza-onium salts). Preferred “onium salts” include alkyl-onium salts, especially methyl- and ethyl-onium salts; cycloalkyl-onium salts and cycloalkylalkyl-onium salts.

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

  Racemic forms can be resolved into optical antipodes by known methods and processes. One way to separate the diastereomeric salts is to use an optically active acid and then treat with a base to liberate the optically active amine compound. Another method for resolution of racemates into optical enantiomers is based on chromatographic methods on optically active matrices. The racemic compounds of the present invention can be resolved into their optical enantiomers by, for example, fractional crystals of d- or l- salts (tartrate, mandelate, or cyanosulfonate).

The 1,4-diazabicycloalkane derivatives of the present invention may also be optically activated carboxylic acids such as (+) or (−) phenylalanine, (+) or (−) with the compounds of the present invention. Reaction of a carboxylic acid derived from phenylglycine, (+) or (−) camphanic acid to form a diastereomeric amide, or by reacting the compound of the present invention with an optically active chloroformate or the like. Can be resolved by producing diastereomeric carbamates.
Other optical isomer resolution methods are well known in the art. Such a method is described in Jaques J. Collet A, and Wilen S, “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, New York (1981).
Optical active compounds can also be prepared from optical active starting compounds.

Production method The 1,4-diazabicycloalkane derivative of the present invention can be produced by a conventional method for chemical synthesis, for example, a method described in the following examples. The starting compounds of the process described in the present invention are known or can be prepared from commercially available compounds in a conventional manner.

Also, certain compounds of the present invention can be converted to other compounds of the present invention by conventional methods.
The reaction end products described herein can be isolated by conventional means such as extraction, crystallization, distillation, chromatography and the like.

Biological activity The present invention relates to novel 1,4-diazabicycloalkane derivatives, which are modulators of cholinergic ligands and monoamine receptors in the nicotinic acetylcholine receptor (nAChR), in particular biogenic amine transporters. It is known to be 5-HT, DA and NER. Furthermore, preferred compounds of the present invention exhibit selective α7 activity.

Within the scope of the present invention, the term “modulator” includes agonists, semi-agonists, antagonists and allosteric modulators of the receptor.
Because of the above pharmacological profile, the 1,4-diazabicycloalkane derivative of the present invention is effective in diseases or disorders related to cholinergic system of central nervous system (CNS) and peripheral nervous system (PNS), and smooth muscle contraction. Various diseases or disorders such as related diseases or disorders, endocrine diseases or disorders, diseases or disorders related to neurodegeneration, diseases or disorders related to inflammation, pain , withdrawal symptoms resulting from withdrawal of chemical abuse It can be said that it is useful for treatment.

In a preferred embodiment, the 1,4-diazabicycloalkane derivatives of the present invention are used for the treatment of diseases, disorders or conditions associated with the central nervous system. Such diseases, disorders or conditions include anxiety, cognitive impairment, learning impairment, memory impairment and dysfunction, Alzheimer's disease, attention deficit, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Huntington's disease, muscle atrophy Lateral sclerosis, Gilles de la Tourette syndrome, depression, mania, manic depression, schizophrenia, obsessive-compulsive disorder (OCD), panic disorder, eating disorders such as anorexia nervosa, bulimia and obesity, Sleep seizure, nociception, AIDS-dementia, senile dementia, neuropathy, autism, reading disorder, late-onset dyskinesia, hyperkinetic disorder, epilepsy, bulimia, post-traumatic syndrome, social hobia, sleep disorder , Including pseudodementia, Ganza syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, speechlessness, trichotiromania and jet lag.

  In another preferred embodiment, the 1,4-diazabicycloalkane derivative of the present invention is a convulsive disorder, angina, premature birth, convulsions, diarrhea, asthma, sputum, late-onset dyskinesia, hyperactivity, premature ejaculation And useful in the treatment of diseases, disorders or conditions associated with smooth muscle contraction, including erectile dysfunction.

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

  In yet another embodiment, the 1,4-diazabicycloalkane derivatives of the present invention are useful for the treatment of neurodegenerative diseases including transient anoxia and induced neurodegeneration.

  In yet another embodiment, the 1,4-diazabicycloalkane derivatives of the present invention include inflammatory skin disorders such as acne and rosacea, coulomb disease, inflammatory bowel disease, ulcerative ciliitis and diarrhea Useful for the treatment of inflammatory disorders.

In yet another embodiment, the 1,4-diazabicycloalkane derivatives of the present invention have acute, chronic or habitual mild, mild or severe pain and pain due to migraine, postoperative pain and fantasy Useful for the treatment of limb pain.

  Finally, the 1,4-diazabicycloalkane derivatives of the present invention are effective in treating withdrawal symptoms caused by the end of use of addictive substances. Such addictive substances include nicotine-containing substances such as tobacco, opioids such as heroin, cocaine or morphine, benzodiazepines or benzodiazepine-like drugs, or alcohols. Withdrawal symptoms from addictive substances are generally traumatic experiences characterized by anxiety and frustration, anger, anxiety, difficulty concentrating, restlessness, decreased heart rate and increased appetite and weight gain.

In the present invention, the term “therapy” includes treatment, prevention, prevention and alleviation of withdrawal symptoms and treatment that results in a spontaneously reduced intake of addictive substances.
In another aspect, the 1,4-diazabicycloalkane derivatives of the present invention are used as diagnostic agents, for example as diagnostic agents for identification and localization of nicotine receptors in various tissues.

Pharmaceutical formulations In another aspect, the present invention provides novel pharmaceutical formulations containing a therapeutically effective amount of the 1,4-diazabicycloalkane derivatives of the present invention.

  When the 1,4-diazabicycloalkane derivative of the present invention is used in therapy, it can be directly administered as a compound, but the active ingredient may optionally be in the form of a physiologically acceptable salt in one or more kinds. It is preferably provided in the form of a pharmaceutical formulation with agents, excipients, diluents, buffers, and / or other conventional pharmaceutical auxiliaries.

  In a preferred embodiment, the present invention further comprises a 1,4-diazabicycloalkane derivative of the present invention or a pharmaceutically acceptable salt or derivative thereof, one or more pharmaceutically acceptable carriers and optionally other treatments. And / or pharmaceutical formulations containing with prophylactic ingredients. This carrier must be “acceptable” in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient being administered thereto.

  The pharmaceutical formulations of the invention can be administered by any convenient means appropriate to the desired treatment. Preferred administration means are oral administration, especially in tablet form, capsule form, sugar-coated tablet form, powder form, or liquid form orally and parenterally, especially skin, subcutaneous, intramuscular or intravenous. Including internal injection. The pharmaceutical formulations can be prepared by one skilled in the art using standard and routine methods appropriate to the desired formulation. If desired, formulations adapted to produce a sustained release of the active ingredient can be used.

  A more detailed description of the formulation and method of administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

  The actual dosage will depend on the nature and severity of the disease being treated and the route of administration, and the amount will be at the discretion of the physician and will be used in the specific context of the present invention to produce the desired therapeutic effect. It can be varied by adapting the dosage. However, formulations containing from about 0.1 to about 500 mg, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg of active ingredient per unit dosage form are currently considered suitable for therapeutic treatment. .

  The active ingredient can be administered once or several times daily. Satisfactory results can be obtained in doses as low as 0.1 μg / kg (intravenous) and 1 μg / kg (intraperitoneal) in some cases. The upper limit of the dosage range is currently considered to be about 10 mg / kg (intravenous) and 100 mg / kg (intraperitoneal). Preferred ranges are about 0.1 μg / kg to about 10 mg / kg (intravenous) and about 1 μg / kg to about 100 mg / kg (intraperitoneal) per day.

Therapeutic Methods The 1,4-diazabicycloalkane derivatives of the present invention are important nicotine and monoamine receptor modulators and thus a series of treatments for cholinergic dysfunction and a series of responses to nAChR modulators. Useful for the treatment of disorders.

  In another aspect, the present invention relates to diseases or disorders or conditions in living organisms, including humans --- this disease, disorder or condition is responsive to modulation of cholinergic receptors and / or monoamine receptors --- A method for treating, preventing or alleviating ---, wherein said method comprises administering a therapeutically effective amount of a 1,4-diazabicycloalkane derivative of the present invention to an animal body including a human in need thereof The above treatment, prevention or alleviation method is provided.

In a preferred embodiment, the disease, disorder or condition is associated with the central nervous system.
In a preferred embodiment, the disease, disorder or condition is anxiety, cognitive impairment, learning impairment, memory impairment and dysfunction, Alzheimer's disease, attention deficit, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Huntington's disease, muscle Amyotrophic lateral sclerosis, Gilles de la Tourette syndrome, depression, mania, manic depression, schizophrenia, obsessive-compulsive disorder (OCD), panic disorder, eating disorders such as anorexia nervosa, overeating and Obesity, sleep seizures, nociception, AIDS-dementia, senile dementia, neuropathy, autism, reading disorder, late-onset dyskinesia, hyperactivity, epilepsy, bulimia, post-traumatic syndrome, social hobia, Sleep disorder, pseudodementia, Ganza syndrome, premenstrual syndrome, late luteal syndrome, chronic fatigue syndrome, speechlessness, trichotiromania and jet lag.

  In another preferred embodiment, the disease, disorder, or condition is smooth muscle, including convulsive disorders, angina, premature birth, convulsions, diarrhea, asthma, epilepsy, tardive dyskinesia, hyperactivity, premature ejaculation, and erectile dysfunction Related to contraction.

  In a third preferred embodiment, the disease, disorder or condition is an endocrine system such as thyroid poisoning, pheochromocytoma, hypertension and arrhythmia.

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

  In a fifth preferred embodiment, the disease, disorder or condition is an inflammatory skin disorder such as acne and rosacea, Coulomb disease, inflammatory bowel disease, ulcerative ciliitis and diarrhea.

In a sixth preferred embodiment, the disease, disorder or condition is acute, chronic or habitual, mild or severe pain and pain due to migraine, postoperative pain and phantom limb pain.

In a seventh preferred embodiment, the disease, disorder or condition results from withdrawal of addictive substances including nicotine-containing substances such as tobacco, opioids such as heroin, cocaine or morphine, benzodiazepine or benzodiazepine-like drugs, or alcohol Related to withdrawal symptoms.
Suitable dosage ranges are usually based on the exact mode of administration, the form to be administered, the symptoms to be administered, the subject involved and the patient's weight and also the preference or experience of the attending physician or veterinarian. It is currently considered to be 0.1-1000 mg of active substance, 10-500 mg per day, and especially 30-100 mg per day.

  Satisfactory results can be obtained at doses as low as 0.005 mg / kg (intravenous) and 0.01 mg / kg (intraperitoneal) in some cases. The upper limit of the dosage range is currently considered to be about 10 mg / kg (intravenous) and 100 mg / kg (intraperitoneal). Preferred ranges are about 0.001 to about 1 mg / kg (intravenous) and about 0.1 to about 10 mg / kg (intraperitoneal) per day.

  The following examples further illustrate the invention, but are not intended to limit the scope of the invention described in the claims.

Example 1
Preparation Examples All reactions involving air sensitive reagents or intermediates are carried out under nitrogen and in anhydrous solvents. Magnesium sulfate is used as a desiccant in the workup and the solvent is evaporated under reduced pressure.

1,4-diazabicyclo [3.2.2] nonane (intermediate compound) is prepared according to J. Med. Chem. 1993 36 2311-2320 and according to the following slightly modified method.
To a solution of 1,4-diazabicyclo [3.2.2] nonan-3-one (15.8 g, 113 mmol) in anhydrous dioxane (130 ml), LiAlH ₄ (4.9 g, 130 mmol) is added under argon. . The mixture is refluxed for 6 hours and then allowed to reach room temperature. Water (5 ml in 10 ml dioxane) is added dropwise to the reaction mixture, the mixture is stirred for 0.5 hours and then filtered through glass fibers. The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90 ^° C (0.1 mbar) to give 1,4-diazabicyclo [3.2.2] nonane (11.1 g, 78%) as a colorless hygroscopic compound. Let

1,4-diazabicyclo [3.2.2] nonan-3-one (intermediate compound)
To a solution of 3-quinuclidinone hydrochloride (45 g, 278 mmol) in 90 ml of water, add hydroxylamine hydrochloride (21 g, 302 mmol) and sodium acetate (CH ₃ COOHx3H ₂ O, 83 g, 610 mmol) The mixture is stirred at 70 ° C. for 1 hour and then cooled to 0 ° C. The separated crystalline compound is filtered (not washed!) And dried under reduced pressure to give 40.0 g of oxime.

Add 3-quinuclidinone oxime (40.0 g) in small portions to polyphosphoric acid * (190 g, prepared as described below *) for 2 hours and preheat to 120 ° C. The temperature of the solution is maintained at 130 ° C during the reaction. After all the oxime has been added, the solution is stirred for 20 minutes at the same temperature, then transferred to an enamel container and allowed to reach reaction temperature. The acidic mixture is neutralized with sodium carbonate solution (500 g in 300 ml water), transferred into a 2000 ml flask, diluted with 300 ml water, and then extracted with chloroform (3x600 ml). The combined organic extracts are dried using sodium sulfate, the solvent is evaporated and the solid residue is dried under reduced pressure to give 30.0 g (77%) of a lactam mixture.
Upon crystallization of a mixture obtained from 1,4-dioxane (220 ml), 15.8 g (40.5%) of 1,4-diazabicyclo [3.2.2] nonan-3-one was converted to Mp (melting point) 211-212 ° C. As large, colorless crystals.

  The filtrate is evaporated and the residue is chromatographed on a silica gel (Merck, 9385, 230-400 mesh) column using acetone as eluent. The solvent was evaporated and the residue was recrystallized from ethyl ethanolate to give 1,3-diazabicyclo [3.2.2] nonan-4-one (10.2 g, 26%) as colorless fine crystals (Mp 125-126 ° C ).

Polyphosphoric acid *
85% orthophosphoric acid (500 g, 294 ml, 4.337 mol) is placed in a 2000 ml flask, then phosphorus pentoxide (750 g, 5.284 mol) is added at room temperature (acid-pentoxide ratio, 2: 3 ). The mixture is stirred at 200-220 ° C. for 2 hours to give 1250 g of polyphosphoric acid (containing 80% P ₂ O ₅ ).

2-Chloro-5-phenyl-1,3,4-thiadiazole (intermediate compound)
2-Amino-5-phenyl-1,3,4-thiadiazole sulfate (25.12 g, 142 mmol) is stirred in concentrated hydrochloric acid (300 ml) at 0 ° C. Sodium nitrite (12.7 g, 184 mmol) is added over 10 minutes. The reaction mixture is stirred at 50 ° C. for 15 hours. The hydrochloric acid is evaporated. Add aqueous sodium hydroxide (4 M, 250 ml) and filter the precipitate. Chromatographic separation on silica gel using ethyl acetate as solvent gives the pure product. Yield 15.5 g (56%).

Method A
4- (5-phenyl-1,3,4-thiadiazol-2-yl) -1,4-diazabicyclo [3.2.2] nonane fumarate (Compound A1);
1,4-diazabicyclo [3.2.2] nonane (1.28 g, 10.2 mmol), 2-chloro-5-phenyl-1,3,4-thiadiazole (2.00 g, 10.2 mmol), triethylamine (2.83 ml, 20.3 mmol) And a mixture of diquioxane (20 ml) is stirred at reflux for 70 hours. Aqueous sodium hydroxide (1 M, 25 ml) is added and the mixture is extracted twice with ethyl acetate (2 × 20 ml). Chromatographic separation on silica gel using dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gives the desired compound as an oil. The corresponding salt is obtained by addition of diethyl ether and methanol mixture (9: 1) saturated with fumaric acid. Yield 0.95 g, 23%. Mp 150.9 ° C.
The following compounds are prepared in a similar manner:
4- [5- (2-selenophenyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A2);
4- [5- (3-selenophenyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A3);
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-imidazolyl) -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 A7);
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 A9);
4- [5- (3-pyrazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A10);
4- [5- (4-pyrazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A11);
4- [5- (5-pyrazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A12);
4- [5- (1-Methyl-3-pyrazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A13);
4- [5- (1-methyl-4-pyrazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A14);
4- [5- (1-Methyl-5-pyrazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A15);
4- [5- (2-thiazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A16);
4- [5- (4-thiazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A17);
4- [5- (5-thiazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A18);
4- [5- (3-isothiazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A19);
4- [5- (4-Isothiazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A20);
4- [5- (5-isothiazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A21);
4- [5- (1,2,3-oxadizol-4-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A22);
4- [5- (1,2,3-oxadizol-5-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A23);
4- [1,3,4-oxadizol-2-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A24);
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 A26);
4- [5- (1,2,3-triazol-5-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A27);
4- [5- (1-Methyl-1,2,3-triazol-4-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A28 );
4- [5- (1-Methyl-1,2,3-triazol-5-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A29 );
4- [5- (1,2,4-triazol-3-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A30);
4- [5- (1,2,4-triazol-5-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A31);
4- [5- (1-Methyl-1,2,4-triazol-3-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A32 );
4- [5- (1-Methyl-1,2,4-triazol-5-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A33 );
4- [5- (1,3,4-thiadiazol-2-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A34);
4- [5- (1,2,4-thiadiazol-3-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A35);
4- [5- (1,2,4-thiadiazol-5-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A36);
4- [5- (3-pyridazinyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A37);
4- [5- (4-pyridazinyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A38);
4- [5- (1,3,5-triazin-2-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A39);
4- [5- (2-quinolinyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A40);
4- [5- (3-quinolinyl) -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 A42);
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 A45);
4- [5- (1-Methyl-2-indolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A46);
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 A48);
4- [5- (2-Benzothiazolyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A49);
4- [5- (7-phthalazinolinyl) -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 A51);
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 A53);
4- [5- (1,8-naphthyridin-3-yl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A54);
4- [5- (2-acridinyl) -1,3,4-thiadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound A55) 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 (16.8 ml, 141 mmol) was added to 5-phenyl-1,3,4-oxadiazole-2-thiol (commercially available) (25.2 g, 141 mmol), triethylamine ( Add to a mixture of 19.7 ml, 141 mmol) and ethanol (250 ml) at room temperature.
The mixture is stirred at room temperature for 3 hours. Aqueous sodium hydroxide (1 M, 250 ml) is added and the mixture is extracted twice with dichloromethane (2 × 200 ml). Chromatographic separation on silica gel using dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gives the desired compound as an oil. Yield 34.2 g (90%).

Method C
5- (2-Furyl) -1,3,4-oxadiazole-2-thiol (intermediate compound)
Carbon disulfide (16.5 g, 216 mmol) is added to a mixture of 2-fluoric hydrazide (13.6 g, 108 mmol), potassium hydroxide (6.68 g, 119 mmol) and methanol (125 ml) . The mixture is stirred at room temperature for 30 minutes and then refluxed for 8 hours. Methanol is evaporated. Acidify the aqueous phase with concentrated hydrochloric acid to pH = 4. The product is isolated by filtration. Yield 12.9 g (72%).
Method D
4- (5-Phenyl-1,3,4-oxadiazol-2-yl) -1,4-diazabicyclo [3.2.2] nonane fumarate (Compound D1)
2-mercaptobenzyl-5-phenyl-1,3,4-oxadiazole (Method B) (1.0 g, 3.7 mmol), 1,4-diazabicyclo [3.2.2] nonane (0.47 g, 3.7 mmol) and diisopropyl A mixture of ethylamine (1.3 ml, 7.4 mmol) is stirred at 100 ° C. for 4 days. Aqueous sodium hydroxide (1 M, 25 ml) is added, the mixture is added and the mixture is extracted twice with dichloromethane (2 × 20 ml). Chromatographic separation on silica gel using dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gives the desired compound as an oil. The corresponding salt is obtained by addition of diethyl ether and methanol mixture (9: 1) saturated with fumaric acid. Yield 0.47 g, 33%. Mp 176.6-178.8 ° C.

The following compounds are 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) is prepared according to Method D To do. Mp 175 ° C.
4- [5- (4-Methoxyphenyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (compound D3) according to Method D To manufacture. Mp 190.1-191.2 ° C.
4- [5- (4-Pyridyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (compound D4) is prepared according to Method D To do. Mp 165.9-166.8 ° C.
4- [5- (2-Thienyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (compound D5) is prepared according to Method D To do. Mp 161.8-162.7 ° C.
4- [5- (3-Pyridyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (compound D6) is prepared according to Method D To do. Mp 176.8-177.5 ° C.
4- [5- (4-Chlorophenyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (compound D7) is prepared according to Method D To do. Mp 184.3-185.8 ° C.
4- [5- (3-methoxyphenyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (compound D8) according to Method D To manufacture. Mp 126-164 ° C.
4- [5- (4-Phenyl-phenyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (Compound D9) to Method D Therefore, manufacture. Mp 238-239 ° C.
4- [5- (2-Naphtyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane fumarate (Compound D10) is prepared according to Method D To do. Mp 194.6-195.7 ° C.

In a similar manner, the following compound is produced:
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-pyridyl) -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-imidazolyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D31);
4- [5- (5-imidazolyl) -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-oxadizol-4-yl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D48);
4- [5- (1,2,3-oxadizol-5-yl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D49);
4- [5- (1,3,4-oxadizol-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-benzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D70);
4- [5- (3-benzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D71);
4- [5- (5-benzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D72);
4- [5- (6-benzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D73);
4- [5- (2-quinolinyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D74);
4- [5- (3-quinolinyl) -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-phthalazinolinyl) -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-Dibenzofuryl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane (Compound D91);
4- [5- (3-Dibenzofuryl) -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-Dibenzothienyl) -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 inhibition of ³ H-α-bungarotoxin binding in rat brain In this example, the affinity of a compound of the invention that binds to the α ₇ -subtype of the nicotine receptor is measured.

  α-bungarotoxin is a peptide isolated from the venom of Elapidae snake Bungarus multicinctus. It has a high affinity for neuronal and neuromuscular nicotinic receptors, where it acts as a potent antagonist.

³ H-α-bungarotoxin labels the nicotinic acetylcholine receptor produced by the α ₇ -subunit isoform found in the brain and the α ₁ isoform found in the neuromuscular junction
Tissue preparation
Prepare at 0-4 ° C. The cerebral cortex obtained from male Worcester rats (150-250g) was converted to 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 Ultratalx homogenizer. Homogenize in 15 ml for 10 seconds. Centrifuge tissue suspension at 27.000 xg for 10 minutes. Discard the supernatant and wash the pellet twice in 20 ml of fresh buffer by centrifuging at 27.000 xg for 10 min and the final pellet with fresh buffer containing 0.01% BSA (35 ml / g of raw tissue). Resuspend in) and use for binding assay.

Assay An aliquot with 500 μl of homogenate is added to 25 μl of test solution and 25 μl of ³ H-α-bungarotoxin (final concentration 2 nM), mixed and incubated at 37 ° C. for 2 hours. Nonspecific binding is measured using (−)-nicotine (1 mM, final concentration). After incubation, the sample is added to 5 ml of ice-cold Hepes buffer containing 0.05% PEI and poured directly onto Whatman GF / C glass fiber filters (pre-soaked in 0.1% PEI for at least 6 hours) under aspiration, Immediately wash 2 x 5 ml of ice-cold buffer.
The amount of radioactivity on the filter is measured by a conventional liquid scintillation counter. Specific binding is the total binding minus non-specific binding.

The test 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 results are shown in Table 1 below.
table 1
³ Inhibition of H-α-bungarotoxin binding

Claims (6)

Formula IV

{Where,
Ar represents an aryl group selected from phenyl and naphthyl or a heteroaryl group selected from furanyl, thienyl and pyridinyl, and these aromatic groups are optionally alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, alkoxy - alkyl, alkoxy - alkoxy, cycloalkoxy, cycloalkoxy - selected from alkoxy, _{halogen, CF 3, CN, NO 2} , NH 2, carboxy, carbamoyl, amido, sulfamoyl, group consisting of phenyl and benzyl - alkyl, cycloalkoxy May be mono- or poly-substituted by substituents. }
A 1,4-diazabicycloalkane derivative represented by: or any enantiomer thereof, or any mixture thereof, or a pharmaceutically acceptable addition salt thereof. Ar is optionally alkyl, cycloalkyl, cycloalkyl - is selected from alkyl, alkoxy, cycloalkoxy, _{halogen, CF 3, CN, NO 2} , NH 2, carboxy, carbamoyl, amido, sulfamoyl, group consisting of phenyl and benzyl The 1,4-diazabicycloalkane derivative according to claim 1, which represents phenyl mono- or di-substituted by a substituent. Ar is 1 when the alkyl, alkoxy, _halogen, CF 3, _CN, where NO 2, NH illustrates a mono- or di-substituted phenyl by ₂ and substituents selected from the group consisting of phenyl, according to claim 2, 4-diazabicycloalkane derivatives. The Ar may optionally be mono- or poly-substituted with a substituent selected from the group consisting of C _1-6 alkyl, alkoxy, halogen, CF ₃ , CN, NO ₂ , NH ₂ , and phenyl. The 1,4-diazabicycloalkane derivative according to any one of -3. 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-phenyl) -1,3,4-oxadiazol-2-yl] -1,4-diazabicyclo [3.2.2] nonane;
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 a 1,4-diazabicycloalkane derivative according to claim 1, which is an enantiomer or a mixture of the enantiomers, or a pharmaceutically acceptable addition salt thereof. Therapeutic treatment of the 1,4-diazabicycloalkane derivative according to any one of claims 1-5 or any enantiomer thereof or any mixture thereof, or a pharmaceutically acceptable addition salt thereof. A pharmaceutical formulation comprising an effective amount together with at least one pharmaceutically acceptable carrier or diluent.