HK1117503A - Novel oxadiazole derivatives and their medical use - Google Patents

Description

Novel oxadiazole derivatives and their pharmaceutical use

Technical Field

The present invention relates to novel oxadiazole derivatives, which are found to be modulators of the nicotinic acetylcholine receptors. The compounds of the present invention may be used for their pharmacological properties in the treatment of various diseases or disorders as follows: diseases or disorders 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 neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

Background

The endogenous cholinergic neurotransmitter acetylcholine exerts its biological effects through two types of cholinergic receptors, muscarinic acetylcholine receptors (machrs) and nicotinic acetylcholine receptors (nachrs).

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels and are widely distributed in the Central (CNS) and Peripheral (PNS) nervous systems. At least 12 subunit proteins, α 2- α 10 and β 2- β 4, have been identified in neural tissue. These subunits provide a large number of homomeric (homomeric) and heteromeric (heteromeric) combinations leading to various receptor subtypes. For example, the primary receptor involved in the high affinity of nicotine in brain tissue has the composition α 4 β 2, while another major receptor group consists of homomeric α 7.

The discovery that nAChRs play an important role in several CNS disorders has raised concerns about these membrane proteins and ligands capable of modulating their function. The presence of different subtypes at multiple levels has complicated the understanding of the physiological role of this receptor, but at the same time increased attempts to find selective compounds in order to improve the pharmacological characterization of this type of receptor and to make safer the possible therapeutic applications of its modulators.

Summary of The Invention

The present invention seeks to provide novel modulators of nicotinic receptors, which modulators are useful in the treatment of diseases or disorders associated with nicotinic acetylcholine receptors (nachrs).

The compounds of the present invention may be used for their pharmacological properties in the treatment of various diseases or disorders as follows: diseases or disorders 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 neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances, particularly nicotine.

The compounds of the invention may also be used as diagnostic tools or monitoring agents in various diagnostic methods and in particular in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.

In a first aspect thereof, the present invention provides oxadiazole derivatives of formula I:

any of its isomers or any mixture of isomers, its N-oxides, prodrugs or pharmaceutically acceptable addition salts thereof, wherein

n is 0, 1, 2 or 3;

Ar¹represents a monocyclic carbocyclic or heterocyclic group selected from cycloalkyl, phenyl, thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and is

Ar²Represents an aromatic monocyclic hetero ring selected from phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl(iii) cyclyl, which aromatic monocyclic heterocyclyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino.

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

Viewed from a further aspect the invention relates to the use of an oxadiazole derivative of the invention, or a pharmaceutically-acceptable addition salt thereof, in the manufacture of a pharmaceutical composition/medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of cholinergic receptors.

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 which method comprises the step of administering to such a living animal body in need thereof such an effective amount of an oxadiazole derivative of the invention.

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

Detailed disclosure of the invention

Oxadiazole derivatives

In a first aspect thereof, the present invention provides oxadiazole derivatives of formula I:

any of its isomers or any mixture of isomers, its N-oxides, prodrugs or pharmaceutically acceptable addition salts thereof, wherein

n is 0, 1, 2 or 3;

Ar¹represents a monocyclic carbocyclic or heterocyclic group selected from cycloalkyl, phenyl, thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and is

Ar²Represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl, which aromatic monocyclic heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino.

In a preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I,however, provided thatThe compound is not:

3- (5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl) -pyridine; or 3- (5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl) -pyridine.

In a preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein n is 0, 1, 2 or 3.

In a more preferred embodiment, n is 0 or 1.

In an even more preferred embodiment, n is 0.

In a more preferred embodiment, n is 1.

In another preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein:

Ar¹represents a group selected from cycloalkyl groups,Phenyl, thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic groups are optionally substituted one or more times by substituents selected from the group consisting of alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

In a more preferred embodiment, Ar¹Represents cycloalkyl, in particular cyclopropyl.

In a more preferred embodiment, Ar¹Represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In another preferred embodiment, Ar¹Represents an aromatic monocyclic carbocyclic or heterocyclic group selected from phenyl, thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

In a more preferred embodiment, Ar¹Represents an aromatic monocyclic carbocyclic group selected from phenyl and naphthyl, the aromatic monocyclic carbocyclic group being optionally substituted one or more times by substituents selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

In an even more preferred embodiment, Ar¹Represents phenyl optionally substituted once or twice by substituents selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

In a more preferred embodiment, Ar¹Represents phenyl optionally substituted by: halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; haloalkoxy, in particular trifluoromethoxy; nitro or cyano.

In a more preferred embodiment, Ar¹Represents phenyl optionally substituted by fluorine, chlorine or nitro.

In another more preferred embodiment, Ar¹Represents phenyl optionally substituted by chlorine.

In a third preferred embodiment, Ar¹Represents an aromatic monocyclic heterocyclic group selected from thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

In a more preferred embodiment, Ar¹Represents an aromatic monocyclic heterocyclic group selected from thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic heterocyclic group is optionally substituted once or twice by substituents selected from halogen, haloalkyl, haloalkoxy, nitro and cyano.

In an even more preferred embodiment, Ar¹Represents an aromatic monocyclic heterocyclic group selected from: thienyl, in particular thien-2-yl or thien-3-yl; furyl, in particular furan-2-yl or furan-3-yl; pyridyl, in particular pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; and pyrazinyl, especially pyrazin-2-yl.

In a third preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein Ar is²Represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl, which aromatic monocyclic heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino.

In a more preferred embodiment, Ar²Represents a group selected from phenyl, thienyl, furyl, pyrrolyl,An aromatic monocyclic heterocyclyl group of pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl, which aromatic monocyclic heterocyclyl group is optionally substituted one or more times by substituents selected from the group consisting of alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino.

In an even more preferred embodiment, Ar²Represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl, which aromatic monocyclic heterocyclic group is optionally substituted one or two times by substituents selected from alkyl, in particular methyl, ethyl or propyl; cycloalkyl, especially cyclopropyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano and amino.

In a more preferred embodiment, Ar²Represents an aromatic monocyclic heterocyclic group selected from thienyl, furyl, pyrrolyl and pyrazolyl, which aromatic monocyclic heterocyclic group is optionally substituted one or more times by a substituent selected from the group consisting of alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

In a more preferred embodiment, Ar²Represents an aromatic monocyclic heterocyclic group selected from the group consisting of furyl, pyrrolyl and pyrazolyl, which aromatic monocyclic heterocyclic group is optionally substituted once or twice by substituents selected from the group consisting of alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

In another more preferred embodiment, Ar²Represents an aromatic monocyclic heterocyclic group selected from the group consisting of furyl, pyrrolyl and pyrazolyl, which aromatic monocyclic heterocyclic group is optionally substituted by alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro or cyano.

In another more preferred embodiment, Ar²Is selected from furyl and pyrrolylAnd pyrazolyl optionally substituted by alkyl, especially methyl; or nitro substitution.

In another more preferred embodiment, Ar²Represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl, which aromatic monocyclic heterocyclic group is optionally substituted by: alkyl, in particular methyl, ethyl or propyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano or amino.

In another more preferred embodiment, Ar²Represents phenyl optionally substituted by: alkyl, in particular methyl, ethyl or propyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano or amino.

In another more preferred embodiment, Ar²Represents thienyl or furyl optionally substituted by: alkyl, in particular methyl, ethyl or propyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano or amino.

In another more preferred embodiment, Ar²Represents pyrrolyl or pyrazolyl optionally substituted by: alkyl, in particular methyl, ethyl or propyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano or amino.

In another more preferred embodiment, Ar²Represents thiazolyl or 1, 3, 4-thiadiazolyl optionally substituted by: alkyl, in particular methyl, ethyl or propyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano or amino.

In another more preferred embodiment, Ar²Represents a pyridyl group optionally substituted by: alkyl, in particular methyl, ethyl or propyl; halogen, especially fluorineOr chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano or amino.

In a fourth preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I,

n is 0 or 1;

Ar¹represents cycloalkyl, in particular cyclopropyl; and is

Ar²Represents thienyl, furyl, pyrrolyl or pyrazolyl, the aromatic monocyclic heterocyclyl being optionally substituted by: alkyl, in particular methyl: halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a hydroxyl group; alkoxy, in particular methoxy or ethoxy; haloalkoxy, in particular trifluoromethoxy; nitro or cyano.

In a fifth preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein

n is 0 or 1;

Ar¹is phenyl optionally substituted one or two times by substituents selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro or cyano; and is

Ar²Represents thienyl, furyl or pyridyl.

In a sixth preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein n is 0 or 1;

Ar¹represents thienyl or furyl; and is

Ar²Represents thienyl or furyl optionally substituted by alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano or amino.

In a seventh preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein n is 0 or 1;

Ar¹represents pyridyl or pyrazinyl optionally substituted by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro or cyano; and is

Ar²Represents phenyl, thienyl, furyl, pyrrolyl, pyrazolyl or thiazolyl optionally substituted by alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino.

In an eighth preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein

n is 0;

Ar¹represents cycloalkyl, in particular cyclopropyl; or

Ar¹Represents phenyl optionally substituted once or twice by substituents selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; or

Ar¹Represents an aromatic monocyclic heterocyclic group selected from thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or two times by substituents selected from halogen, haloalkyl, haloalkoxy, nitro and cyano; and is

Ar²Represents an aromatic monocyclic heterocyclic group selected from the group consisting of furyl, pyrrolyl and pyrazolyl, which aromatic monocyclic heterocyclic group is optionally substituted by: alkyl, especially methyl or ethyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a hydroxyl group; alkoxy, in particular methoxy or ethoxy; haloalkoxy, in particular trifluoromethoxy; nitro or cyano.

In a ninth preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein

n is 1;

Ar¹represents an aromatic monocyclic carbocyclic or heterocyclic group selected from phenyl, thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and is

Ar²Represents an aromatic monocyclic heterocyclic group selected from the group consisting of furyl, pyrrolyl and pyrazolyl, which aromatic monocyclic heterocyclic group is optionally substituted by: alkyl, especially methyl or ethyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a hydroxyl group; alkoxy, in particular methoxy or ethoxy; haloalkoxy, in particular trifluoromethoxy; nitro or cyano.

In a tenth preferred embodiment, the oxadiazole derivative of the invention is a compound of formula I, wherein

n is 1;

Ar¹represents phenyl optionally substituted once or twice by substituents selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and is

Ar²Represents an aromatic monocyclic heterocyclic group selected from the group consisting of furyl, pyrrolyl and pyrazolyl, which aromatic monocyclic heterocyclic group is optionally substituted by: alkyl, especially methyl or ethyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a hydroxyl group; alkoxy, in particular methoxy or ethoxy; haloalkoxy, in particular trifluoromethoxy; nitro or cyano.

In a more preferred embodiment, the oxadiazole derivative of the invention is:

3-cyclopropyl-5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3-phenyl- [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3- (4-fluoro) -phenyl- [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3-benzyl- [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3-thiophen-2-yl- [1, 2, 4] oxadiazole;

2- (5- (5-nitro-furan-3-yl) - [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5-furan-2-yl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5- (5-nitro-furan-3-yl) - [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5-furan-3-yl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- [5- (1H-pyrrol-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

4- (5-furan-2-yl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

2- [5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyrazine;

3- [5- (1-methyl-1H-pyrrol-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (1H-pyrazol-4-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (2-methyl-thiazol-4-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (4-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

2- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- (5-phenyl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -benzonitrile;

3- [5- (3-chloro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3-phenyl-5- (thiophen-3-yl) - [1, 2, 4] oxadiazole;

4- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (3-fluoro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

2- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyrazine;

3-phenyl-5- (thiophen-2-yl) - [1, 2, 4] oxadiazole;

3- [5- (2-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (3-trifluoromethyl-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [3- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-5-yl ] -pyridine;

6- (pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -pyridine-2-carbonitrile;

5- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -furan-2-carbonitrile;

5- (3-pyridin-3-yl- [1.2.4] oxadiazol-5-yl) -thiophene-2-carbonitrile; or

3- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -phenylamine;

any of its isomers or any mixture of isomers or a pharmaceutically acceptable addition salt thereof.

Any combination of two or more of the 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 represents a monovalent saturated, linear or branched hydrocarbon chain. The hydrocarbon chain preferably contains one to eighteen carbon atoms (C)_1-18-alkyl), more preferably one to six carbon atoms (C)_1-6-alkyl, lower alkyl) including pentyl, isopentyl, neopentyl, 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_1-3-an alkyl group, which may in particular be a methyl, ethyl, propyl or isopropyl group.

In the context of the present invention, cycloalkyl denotes cyclic alkyl, preferably containing from three to seven 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, which cycloalkyl is also substituted on alkyl as defined above. Examples of preferred cycloalkyl-alkyl groups of the present invention include cyclopropylmethyl and cyclopropylethyl.

In the context of the present invention, alkoxy represents alkyl-O-, wherein alkyl is as defined above. Examples of preferred alkoxy groups include methoxy and ethoxy.

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

In the context of the present invention cyano-alkyl denotes alkyl substituted by CN, wherein alkyl is as defined above.

In the context of the present invention, halogen denotes fluorine, chlorine, bromine or iodine, and haloalkyl denotes an alkyl group as defined herein, which alkyl group is substituted one or more times by halogen. Thus trihalomethyl represents: such as trifluoromethyl, trichloromethyl and similar trihalo-substituted methyl groups. Preferred in the inventionHaloalkyl includes trihalomethyl, preferably-CF₃。

In the context of the present invention, haloalkoxy denotes alkoxy as defined herein, which alkoxy is substituted one or more times by halogen. Preferred haloalkoxy groups of the present invention include trihalomethoxy, preferably-OCF₃。

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

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

Pharmaceutically acceptable salts

The oxadiazole derivatives of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts of the compounds of the invention as well as prodrug (predug) or prodrug (produg) forms.

Examples of pharmaceutically acceptable addition salts include, but are not limited to: non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconitate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, pamoate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate and the like. Such salts may be formed by methods well known and described in the art.

Metal salts of the compounds of the invention include alkali metal salts, such as the sodium salt of the compound of the invention containing a carboxyl group.

In the context of the present invention, an "onium salt" of an N-containing compound is also considered to be a pharmaceutically acceptable salt. Preferred "onium salts" include alkyl-, cycloalkyl-and cycloalkyl-alkyl-onium salts. Particularly preferred onium salts of the present invention include those formed at the N 'position of formula I':

isomers

One skilled in the art will appreciate that the compounds of the present invention may exist in different stereoisomeric forms, including enantiomers, diastereomers and geometric isomers (cis-trans isomers). The present invention includes all such isomers and mixtures thereof, including racemic mixtures.

Racemic forms can be resolved into the optical antipodes by well-known methods and techniques. One way of separating enantiomeric compounds (including enantiomeric intermediates) is by using optically active amines and by treatment with an acid to release diastereomeric resolved salts. Another method for resolving racemates into optical isomers is based on chromatography on optically active substrates. Thus, for example, racemic compounds of the present invention can be resolved into their optical isomers by fractional crystallization of, for example, D-or L- (tartrate, mandelate or camphorsulfonate) salts.

Other methods for resolving optical isomers are well known in the art. Such methods include those described by Jaques J, colelet a,&wilen S inEnantiomers.Racemates， And ResolutionsMethods described in John Wiley and Sons, New York (1981).

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

Process for producing oxadiazole derivatives

The oxadiazole derivatives of the invention can be prepared by conventional methods for chemical synthesis, such as those described in the preparation examples. The starting materials for the process described in the present invention are well known or readily prepared by conventional methods from commercially available chemicals.

In addition, conventional methods may be used to convert one compound of the invention to another compound of the invention.

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

Biological activity

The present invention seeks to provide novel nicotinic receptor modulators for the treatment of diseases or conditions associated with nicotinic acetylcholine receptors (nachrs). Preferred compounds of the invention exhibit positive allosteric modulation of the nicotinic acetylcholine receptor alpha 4 beta 2 receptor subtype.

The compounds of the present invention may be used for their pharmacological profile in the treatment of various diseases or disorders associated with: diseases or disorders 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 neurodegeneration, diseases or disorders associated with inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances, particularly nicotine.

In a preferred embodiment, the disease, disorder or condition is related to the central nervous system.

The compounds of the invention may also be used as diagnostic tools or monitoring agents in various diagnostic methods and in particular in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.

In another preferred embodiment, the disease, disorder or condition is a cognitive disorder, learning deficit, memory deficit and dysfunction, alzheimer's disease, Attention Deficit Hyperactivity Disorder (ADHD), tourette's syndrome, psychosis, depression, bipolar disorder, mania, manic depression, schizophrenia, cognitive or attention deficit associated with schizophrenia, Obsessive Compulsive Disorder (OCD), panic disorder; eating disorders such as anorexia nervosa, bulimia and obesity; narcolepsy; nociception; AIDS-dementia, senile dementia, autism; parkinson's disease, huntington's disease, Amyotrophic Lateral Sclerosis (ALS); anxiety, non-OCD anxiety disorders, convulsive disorders, convulsions, epilepsy, neurodegenerative disorders, transient hypoxia, induced neurodegeneration, neuropathy, diabetic neuropathy; periferalic dyslexia; tardive dyskinesia, hyperkinesia; pain, mild pain, moderate or severe pain, acute, chronic or recurrent pain, pain resulting from migraine, post-operative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, with post-therapeutic neuralgia, or with peripheral nerve injury; excessive appetite; post-traumatic syndrome; social phobia; sleep disorders; pseudodementia; ganser syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome; (ii) a medical condition of dumb; trichotillomania; jet lag syndrome; arrhythmia, smooth muscle contraction, angina; premature delivery; diarrhea; asthma; tardive dyskinesia, hyperkinesia; premature ejaculation and erectile difficulty; hypertension; inflammatory disorders, inflammatory skin diseases, acne, rosacea; crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea; or withdrawal symptoms resulting from termination of use of addictive substances, including nicotine-containing products such as tobacco, opioids such as heroin, cocaine, and morphine; benzodiazepines * and benzodiazepines * like drugs and alcohol.

In a more preferred embodiment, the compounds of the invention are used for the treatment, prevention or alleviation of pain, mild pain, moderate or severe pain, acute, chronic or recurrent pain, pain resulting from migraine, post-operative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, with post-therapeutic neuralgia, or with peripheral nerve injury.

In another more preferred embodiment, the compounds of the invention are useful for treating, preventing or ameliorating smooth muscle contractions, convulsive disorders, angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, or erectile difficulty.

In a third more preferred embodiment, the compounds of the invention are used for the treatment, prevention or alleviation of a neurodegenerative disorder, transient hypoxia or induced neurodegeneration.

In a fourth more preferred embodiment, the compounds of the invention are used for the treatment, prevention or alleviation of an inflammatory disorder, an inflammatory skin disease, acne, rosacea, crohn's disease, an inflammatory bowel disease, ulcerative colitis, or diarrhea.

In a fifth more preferred embodiment, the compounds of the present invention are used for the treatment, prevention or alleviation of diabetic neuropathy, schizophrenia, cognitive or attention deficits associated with schizophrenia or depression.

In a sixth more preferred embodiment, the compounds of the present invention are useful for the treatment, prevention or alleviation of pain, especially neuropathic pain, diabetic neuropathy, schizophrenia and cognitive or attention deficits associated with schizophrenia, depression, and to help achieve smoking cessation.

In a seventh more preferred embodiment, the compounds of the invention are useful for treating, preventing or alleviating withdrawal symptoms caused by the termination of use of addictive substances, including nicotine-containing products such as tobacco, opioids such as heroin, cocaine and morphine; benzodiazepines * and benzodiazepines * like drugs and alcohol.

In an eighth more preferred embodiment, the compounds of the present invention are useful for the treatment of anxiety, cognitive disorders, learning deficit, memory deficits and dysfunction, alzheimer's disease, Attention Deficit Hyperactivity Disorder (ADHD), parkinson's disease, huntington's chorea, amyotrophic lateral sclerosis, gilles de la tourette's syndrome, psychosis, 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 (periferaphy); autism disorder; dyslexia; tardive dyskinesia, hyperkinesia; epilepsy; excessive appetite; post-traumatic syndrome; social phobia; sleep disorders; pseudodementia; ganser syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome; (ii) a medical condition of dumb; trichotillomania; and jet lag syndrome.

In a ninth more preferred embodiment, the compounds of the present invention are used for the treatment of cognitive disorders, psychosis, schizophrenia and/or depression.

In a tenth more preferred embodiment, the compounds of the present invention are useful for treating diseases, disorders, or conditions associated with smooth muscle contraction, including convulsive disorders, angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile difficulty.

In an eleventh more preferred embodiment, the compounds of the invention are used for the treatment of endocrine disorders such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.

In a twelfth more preferred embodiment, the compounds of the invention are used for the treatment of neurodegenerative disorders, including transient hypoxia and induced neurodegeneration.

In a thirteenth more preferred embodiment, the compounds of the invention are used to treat inflammatory diseases, disorders or conditions, including inflammatory skin diseases such as acne and rosacea, crohn's disease, inflammatory bowel disease, ulcerative colitis, and diarrhea.

In a fourteenth more preferred embodiment, the compounds of the present invention are used for the treatment of pain, mild, moderate or severe pain, acute, chronic or recurrent pain, as well as pain caused by migraine and post-operative and phantom limb pain. The pain may in particular be neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, pain associated with post-therapeutic neuralgia or with peripheral nerve injury.

Finally, in the most preferred embodiment, the compounds of the present invention may be used to treat depression, cognition, dementia, obesity or conditions associated with withdrawal symptoms resulting from nicotine addiction.

In this context, "treatment" includes treatment, prevention, prophylactic and relief of withdrawal symptoms and contraindications as well as treatments that result in voluntary reduction of the intake of addictive substances.

In another aspect, the compounds of the invention are useful as diagnostic agents, e.g., for identifying nicotinic receptors and their localization in various tissues.

Pharmaceutical composition

In another aspect, the present invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of an oxadiazole derivative of the invention.

Although the compounds of the invention for use in therapy may be administered as the starting compound, it is preferred that the active ingredient, optionally in the form of a physiologically acceptable salt, is incorporated into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical adjuvants.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising an oxadiazole derivative of the invention, or a pharmaceutically acceptable salt or derivative thereof, in combination with one or more pharmaceutically acceptable carriers and optionally with other therapeutic and/or prophylactic components known and used in the art. The carrier 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 appropriate to the desired therapy. Preferred routes of administration include: oral administration, particularly in the form of tablets, capsules, lozenges, powders or liquid dosage forms; and parenteral administration, especially cutaneous, subcutaneous, intramuscular or intravenous injection. The pharmaceutical compositions of the present invention may be prepared by one skilled in the art using standard methods and conventional techniques appropriate for the desired formulation. If desired, compositions suitable for providing sustained release of the active ingredient may be used.

In a preferred embodiment, formulations such as gums, patches, sprays, inhalants, aerosols, and the like are contemplated when the pharmaceutical compositions of the present invention are intended for use in treating patients with withdrawal symptoms due to nicotine addiction.

More details on formulation and administration techniques can be found on the latest edition of Reminaton's Pharmaceutical Sciences (Maack publishing Co. Easton, Pa.).

The actual dosage depends on the nature and severity of the condition being treated and, within the judgment of the practitioner, may be varied in response to the dosage in accordance with the particular circumstances of the invention to produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing from about 0.1 to about 500mg of active ingredient per single dose, preferably from about 1 to about 100mg, more preferably from about 1 to about 10mg of active ingredient per single dose, are suitable for therapeutic treatment.

The active ingredient may be administered in one or several doses per day. In some cases satisfactory results can be obtained at doses as low as 0.1. mu.g/kg (intravenous) and 1. mu.g/kg (oral). The upper limit of the dosage range is currently considered to be about 10mg/kg (intravenous) and 100mg/kg (oral). Preferred ranges are from about 0.1 μ g/kg to about 10 mg/kg/day (intravenous) and from about 1 μ g/kg to about 100 mg/kg/day (oral).

Method of treatment

The oxadiazole derivatives of the invention are valuable nicotinic and monoamine receptor modulators and are therefore useful in a range of diseases including cholinergic dysfunction and a range of disorders 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 disease, disorder 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 an oxadiazole derivative of the invention.

In the context of the present invention, the term "treatment" encompasses treatment, prevention, prophylaxis or amelioration, and the term "disease" includes diseases, illnesses, disorders and conditions associated with said diseases.

Contemplated preferred indications of the invention are as described above.

It is presently contemplated that suitable dosage ranges are from 0.1 to 1000mg daily, from 10 to 500mg daily, and particularly from 30 to 100mg daily, depending generally on the exact mode of administration, form of administration, indication for which administration is being made, patient involved and the weight of the patient involved, and further, the preference and experience of the attending physician or veterinarian.

In some cases satisfactory results can be obtained at doses as low as 0.005mg/kg (intravenous) and 0.01mg/kg (oral). The upper limit of the dosage range is about 10mg/kg (intravenous) and 100mg/kg (oral). Preferred ranges are from about 0.001 to about 1 mg/kg/day (intravenous) and from about 0.1 to about 10 mg/kg/day (oral).

Examples

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

Examples

Preparation examples

Although 3- (5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl) -pyridine (compound 1) is available from Ambinter Screening Library, Ambinter, Paris, France, and 3- (5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl) -pyridine (compound 2) is available from Comcom X Gene Inc., Budapest, Hungary, the following examples describe the synthesis of a number of representative compounds of the invention.

All reactions involving air sensitive reagents or intermediates were carried out in nitrogen and anhydrous solvents.

Example 1

N-hydroxy-nicotinamidines (intermediate compounds)

Nicotinonitrile (1 g; 10mmol) and 1.3g hydroxylamine hydrochloride (19mmol) were dissolved in 15ml water. Sodium carbonate (2 g; 24mmol) in 10ml of water is added continuously, the resulting solution is stirred and heated at about 70 ℃ for 6 hours. Then no more starting material remained (checked by TLC), the reaction mixture was cooled to room temperature, sodium chloride was added to saturation and extracted 4 times with 50ml ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to a solid. Yield 1g (76%) as a white solid powder.

Prepared similarly (intermediate compounds):

n-hydroxy-benzamidine;

n-hydroxy-isonicotinamidine;

4-fluoro-N-hydroxy-benzamidine;

n-hydroxy-thiophene-2-carboxamidine;

n-hydroxy-cyclopropane-carboxamidine;

n-hydroxy-pyrazine-2-carboxamidine;

n-hydroxy-2-phenyl-acetamidine;

n-hydroxy-nicotinamidine;

n-hydroxy-pyridine-2-carboxamidine; and

n-hydroxy-3-nitro-benzamidine.

Example 2

1H-pyrrole-2-carbonyl chloride (intermediate compound)

Oxalyl chloride (6.7 g; 53mmol) in a nitrogen atmosphere was cooled to 0-5 ℃ and 0.5g pyrrole-2-carboxylic acid (4mmol) was added. The reaction mixture was brought to room temperature and heated to 50 ℃ and stirred at this temperature until the reaction was terminated (controlled by TLC). The reaction mixture was cooled to room temperature and evaporated to an oil, the residue was washed with toluene and dried.

The product was used as such in the next reaction.

Prepared similarly (intermediate compounds):

1H-pyrazole-4-carbonyl chloride;

5-nitro-furan-2-carbonyl chloride;

2-methyl-thiazole-4-carbonyl chloride;

benzoyl chloride;

thiophene-2-carbonyl chloride;

3-fluoro-benzoyl chloride;

2-nitro-benzoyl chloride;

3-cyano-benzoyl chloride;

4-nitro-benzoyl chloride;

3-chloro-benzoyl chloride;

3-nitro-benzoyl chloride;

thiophene-2-carbonyl chloride;

5-bromo-thiophene-2-carbonyl chloride;

5-bromo-furan-2-carbonyl chloride; and

6-bromo-pyridine-2-carbonyl chloride.

Example 3

3- (5-Furan-2-yl- [1, 2, 4]]Oxadiazol-3-yl) -pyridine (Compound 3.1)

Furan-2-carboxylic acid (0.8 g; 7mmol) in 15ml dichloromethane was cooled to 0 ℃ and 0.76g1, 3-dicyclohexylcarbodiimide (4mmol) was added slowly. The reaction mixture was stirred at 0-5 ℃ for 2 hours and filtered. The filtrate was evaporated, the residue dissolved in 15ml pyridine and 0.43g N-hydroxy-nicotinamidine (3.2mmol) added. The reaction mixture was heated under reflux until the reaction was terminated (as determined by TLC), then cooled to room temperature and poured into 100ml of water. The precipitate was isolated by filtration and dried in vacuo. The product was isolated by column chromatography. Yield 0.23g (15%). Mp.110-114 ℃.

Similarly prepared were: 3- (5-furan-3-yl- [1, 2, 4] oxadiazol-3-yl) -pyridine (compound 3.2); mp.105-108 ℃.

Example 4

5- (5-Nitro-furan-2-yl) -3-phenyl- [1, 2, 4]Oxadiazole (Compound 4.1)

N-hydroxy-benzamidine (0.3 g; 2.1mmol) was dissolved in 10ml of dry pyridine and 0.5g 5-nitro-furan-2-carbonyl chloride (2.8mmol) was added. The reaction mixture was heated at reflux for 3 hours, cooled to room temperature and poured into 50ml of ice/water, and the product precipitated from solution and was isolated by filtration. Yield 0.3g (41%) as a yellow solid. Mp.164-166 ℃.

Similarly prepared were:

3- [5- (1H-pyrrol-2-yl) - [1, 2, 4] oxadiazol-3-yl-pyridine (compound 4.2); mp is 200-203 ℃;

3- (4-fluoro-phenyl) -5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazole (compound 4.3); mp.162-164 deg.C;

3-benzyl-5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazole (compound 4.4); mp.77-79 deg.C;

5- (5-Nitro-furan-2-yl) -3-thiophen-2-yl- [1, 2, 4] oxadiazole (Compound 4.5); mp.181-185 deg.C;

2- {5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl } -pyridine (compound 4.6); mp.190-191 ℃;

2- {5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl } -pyrazine (compound 4.7); mp.187-189 deg.C;

3-cyclopropyl-5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazole (compound 4.8); mp.67-70 deg.C;

4- {5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl } -pyridine (compound 4.9); mp.157-160 ℃;

3- {5- (1H-pyrazol-4-yl) - [1, 2, 4] oxadiazol-3-yl } -pyridine (compound 4.10); mp.219-221 ℃;

3- [5- (2-methyl-thiazol-4-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.11); mp.152-154 deg.C;

3- [5- (4-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.12); mp.179-181 deg.C;

2- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.13); 170 ℃ and 171 ℃;

3- (5-phenyl- [1, 2, 4] oxadiazol-3-yl) -pyridine (compound 4.14); mp.142-143 ℃;

3- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -benzonitrile (compound 4.15); mp.154-156 deg.C;

3- [5- (3-chloro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.16); mp.122-123 deg.C;

3-phenyl-5- (thiophen-3-yl) - [1, 2, 4] oxadiazole (compound 4.17); mp.mp.107-109 ℃;

4- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.18); mp.151-153 deg.C;

3- [5- (3-fluoro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.19); mp.112-113 ℃;

2- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyrazine (compound 4.20); mp.180-182 ℃;

3-phenyl-5- (thiophen-2-yl) - [1, 2, 4] oxadiazole (compound 4.21); mp.107-109 ℃;

3- [5- (2-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.22); mp.104-105 deg.C;

3- [5- (3-trifluoromethyl-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (compound 4.23); mp.78-83 deg.C;

3- [3- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-5-yl ] -pyridine (compound 4.24); mp.173-175 ℃;

n- [3- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -phenyl ] -acetamide (intermediate);

2-bromo-6- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -pyridine (intermediate);

3- [5- (5-bromo-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (intermediate); and

3- [5- (5-bromo-thiophen-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine (intermediate).

Example 5

3- {5- (1-methyl-1H-pyrrol-2-yl) - [1, 2, 4]Oxadiazol-3-yl } -pyridine (Compound I) Thing 5.1)

To 3- {5- (1H-pyrrol-2-yl) - [1, 2, 4] oxadiazol-3-yl } -pyridine (1 g; 0.5mmol) in 15ml of dry THF at-70 ℃ was added 0.18g of sodium hexamethyldisilazide (1mmol), and the reaction mixture was stirred at-70 ℃ for 30 minutes and at 0 ℃ for 1 hour. The reaction mixture was cooled to-70 ℃ and 0.076g of methyl iodide (0.52mmol) was added. The reaction mixture was stirred for 1/2 hours at-70 ℃ and then at room temperature overnight. The product was isolated by column chromatography. Yield: 0.04g as a yellow solid (37%). Mp.108-109 ℃.

Example 6

6- (pyridin-3-yl- [1, 2, 4]]Oxadiazol-5-yl) -pyridine-2-carbonitrile (Compound 6.1)

2-bromo-6- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -pyridine (250mg, 0.83mmol) and 80mg potassium cyanide (1.24mmol) in 15ml acetonitrile were degassed three times (vacuum/nitrogen), 24. mu.l tributyltin chloride in heptane (1. mu. mol) were added, 2.3mg bis- (diphenylphosphino) ferrocene (4.1. mu. mol) and 4mg bis tris (dibenzylideneacetone) palladium (4.1. mu. mol) were added. The suspension was degassed three times and stirred at ambient temperature for 30 minutes. The mixture was degassed again and heated at 80 ℃ for 17 hours. The reaction mixture was concentrated, the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography using 20% ethyl acetate in petroleum ether, yield 80 mg. Mp201-203 ℃.

Similarly prepared were:

5- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -furan-2-carbonitrile (compound 6.2) mp.141-144 ℃; and

5- (3-pyridin-3-yl- [1.2.4] oxadiazol-5-yl) -thiophene-2-carbonitrile (Compound 6.3) mp.159-161 ℃.

Example 7

3- (3-pyridin-3-yl- [1, 2, 4]]Oxadiazol-5-yl) -phenylamine (Compound 7.1)

To a saturated solution of hydrogen chloride in ethanol (20ml) at 0 ℃ was added gradually 0.48g of N- [ 3-pyridin-3-yl [1, 2, 4] oxadiazol-5-yl ] -phenyl ] -acetamide (1.7mmol) after which the reaction mixture was brought to room temperature and heated at 50 ℃ for 15 h. The reaction mixture was evaporated to an oil and water was added. To the mixture was added saturated sodium bicarbonate (aq) and extracted with ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate and evaporated to an oil. The product was isolated by column chromatography. Yield 0.2g (48%). Mp.161-163 ℃.

Example 8

Characterization of h α 4 β 2 positive allosteric modulators using FLIPR

This experiment confirmed that a representative compound of the present invention (3- (5- (5-nitro-furan-2-yl) - [1, 2, 4]]Oxadiazol-3-yl) -pyridine; compound 1) Positive modulation by human HEK cells expressing human nicotinic acetylcholine receptor subtype α 4 β 2_20-30) The ability to induce a response. This capacity is measured in comparison to the maximum nicotinic response (typically 100 μ M). The activity was determined according to standard assays of fluorescence using a fluorescence image plate reader (FLIPR), as described in more detail below.

Generating full concentration/response curves and calculating EC based on peak values₅₀The value is obtained. EC (EC)₅₀The value (effective concentration) represents the concentration of the test substance at which the EC induced by nicotine is present_20-30The response was positively modulated such that the magnitude of the response was equal to 50% of the maximum nicotine control response. The maximum positively modulated response is determined in comparison to a reference (nicotine) response.

The results of this experiment are listed in table 1 below.

TABLE 1

FLIPR nAChR alpha 4 beta 2 positive allosteric modulator activity

Compound (I)	EC50Value (μ M)	Maximum response compared to nicotine (%)
			Compound 1	6.8	97

Claims (17)

1. An oxadiazole derivative represented by formula I:

any of its isomers or any mixture of isomers, an N-oxide, a prodrug or a pharmaceutically acceptable addition salt thereof, wherein:

n is 0, 1, 2 or 3;

Ar¹represents a group selected from cycloalkyl groups,Phenyl, thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic groups are optionally substituted one or more times by substituents selected from the group consisting of alkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and is

Ar²Represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl, which aromatic monocyclic heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino.

2. The oxadiazole derivative of claim 1, wherein n is 0, 1, 2, or 3.

3. The oxadiazole derivative of claim 2, wherein n is 0 or 1.

4. The oxadiazole derivative of any one of claims 1-3, wherein:

Ar¹represents a monocyclic carbocyclic or heterocyclic group selected from cycloalkyl, phenyl, thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

5. The oxadiazole derivative of claim 4, wherein Ar is¹Represents cycloalkyl, in particular cyclopropyl.

6. The oxadiazole derivative of claim 4, wherein:

Ar¹represents a group selected from phenyl, thienyl, furanAn aromatic monocyclic carbocyclic or heterocyclic group of the group, pyridyl, and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from the group consisting of alkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, and cyano.

7. The oxadiazole derivative of claim 6, wherein:

Ar¹represents phenyl optionally substituted once or twice by substituents selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

8. The oxadiazole derivative of claim 6, wherein:

Ar¹represents an aromatic monocyclic heterocyclic group selected from thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times by a substituent selected from alkyl, cycloalkyl-alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano.

9. The oxadiazole derivative of claim 8, wherein:

Ar¹represents an aromatic monocyclic heterocyclic group selected from thienyl, furyl, pyridyl and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted once or twice by substituents selected from halogen, haloalkyl, haloalkoxy, nitro and cyano.

10. The oxadiazole derivative of any one of claims 1-9, wherein:

Ar²represents an aromatic monocyclic heterocyclic group selected from the group consisting of phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridylThe heterocyclo group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano, and amino.

11. The oxadiazole derivative of claim 10, wherein:

Ar²represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1, 3, 4-thiadiazolyl and pyridyl, which aromatic monocyclic heterocyclic group is optionally substituted by: alkyl, in particular methyl, ethyl or propyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a nitro group; cyano or amino.

12. The oxadiazole derivative of claim 1, wherein:

n is 0 or 1;

Ar¹represents cycloalkyl, in particular cyclopropyl, and

Ar²represents thienyl, furyl, pyrrolyl or pyrazolyl, the aromatic monocyclic heterocyclyl being optionally substituted by: alkyl, especially methyl; halogen, in particular fluorine or chlorine; haloalkyl, especially trifluoromethyl; a hydroxyl group; alkoxy, in particular methoxy or ethoxy; haloalkoxy, in particular trifluoromethoxy; a nitro group; or a cyano group.

13. The oxadiazole derivative of claim 1 which is:

3-cyclopropyl-5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3-phenyl- [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3- (4-fluoro) -phenyl- [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3-benzyl- [1, 2, 4] oxadiazole;

5- (5-nitro-furan-2-yl) -3-thiophen-2-yl- [1, 2, 4] oxadiazole;

2- (5- (5-nitro-furan-3-yl) - [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5-furan-2-yl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5- (5-nitro-furan-3-yl) - [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (5-furan-3-yl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- [5- (1H-pyrrol-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

4- (5-furan-2-yl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

2- [5- (5-nitro-furan-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyrazine;

3- [5- (1-methyl-1H-pyrrol-2-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (1H-pyrazol-4-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (2-methyl-thiazol-4-yl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (4-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

2- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- (5-phenyl- [1, 2, 4] oxadiazol-3-yl) -pyridine;

3- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -benzonitrile;

3- [5- (3-chloro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3-phenyl-5- (thiophen-3-yl) - [1, 2, 4] oxadiazole;

4- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (3-fluoro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

2- [5- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyrazine;

3-phenyl-5- (thiophen-2-yl) - [1, 2, 4] oxadiazole;

3- [5- (2-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [5- (3-trifluoromethyl-phenyl) - [1, 2, 4] oxadiazol-3-yl ] -pyridine;

3- [3- (3-nitro-phenyl) - [1, 2, 4] oxadiazol-5-yl ] -pyridine;

6- (pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -pyridine-2-carbonitrile;

5- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -furan-2-carbonitrile;

5- (3-pyridin-3-yl- [1.2.4] oxadiazol-5-yl) -thiophene-2-carbonitrile; or

3- (3-pyridin-3-yl- [1, 2, 4] oxadiazol-5-yl) -phenylamine;

any of its isomers or any mixture of isomers or a pharmaceutically acceptable addition salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of an oxadiazole derivative of any one of claims 1-13, or a pharmaceutically-acceptable addition salt thereof, and at least one pharmaceutically-acceptable carrier or diluent.

15. Use of an oxadiazole derivative of any one of claims 1-13, or a pharmaceutically-acceptable addition salt thereof, in the manufacture of a pharmaceutical composition/medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition is responsive to modulation of cholinergic receptors.

16. The use of claim 15, wherein the disease, disorder or condition is a cognitive disorder, learning deficit, memory deficit and dysfunction, alzheimer's disease, Attention Deficit Hyperactivity Disorder (ADHD), tourette's syndrome, psychosis, depression, bipolar disorder, mania, manic depression, schizophrenia, cognitive or attention deficit associated with schizophrenia, Obsessive Compulsive Disorder (OCD), panic disorder; eating disorders such as anorexia nervosa, bulimia and obesity; narcolepsy; nociception; AIDS-dementia, senile dementia; autism disorder; parkinson's disease; huntington's chorea; amyotrophic Lateral Sclerosis (ALS); anxiety, non-OCD anxiety disorder, convulsive disorder, convulsion, epilepsy, degenerative disorder, transient anoxia, induced neurodegeneration, neuropathy, diabetic neuropathy, periferic dyslexia, tardive dyskinesia, hyperkinesia; pain, mild pain, moderate or severe pain, acute, chronic or recurrent pain, pain resulting from migraine, post-operative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, with post-therapeutic neuralgia, or with peripheral nerve injury; excessive appetite; post-traumatic syndrome; social phobia; sleep disorders; pseudodementia; ganser syndrome, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome; (ii) a medical condition of dumb; trichotillomania; jet lag syndrome; arrhythmia, smooth muscle contraction, angina; premature delivery; diarrhea; asthma; tardive dyskinesia, hyperkinesia; premature ejaculation and erectile difficulty; hypertension; inflammatory disorders, inflammatory skin diseases, acne, rosacea; crohn's disease, inflammatory bowel disease, ulcerative colitis, diarrhea; or withdrawal symptoms resulting from termination of use of addictive substances, including nicotine-containing products such as tobacco, opioids such as heroin, cocaine, and morphine; benzodiazepines * and benzodiazepines * like drugs and alcohol.

17. 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, which method comprises administering to such a living animal body in need thereof a therapeutically effective amount of an oxadiazole derivative of any one of claims 1-13.