Novel oxadiazole derivatives and their medical use

Abstract

This invention relates to novel oxadiazole derivatives, which are found to be modulators of the nicotinic acetylcholine receptors. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.

1 . An oxadiazole derivative represented by Formula I 
       
         
           
           
               
               
           
         
         any of its stereoisomers or any mixture of stereoisomers, an N-oxide, a prodrug, or a pharmaceutically acceptable addition salt thereof, wherein 
         n is 0, 1, 2 or 3; 
         Ar 1  represents an monocyclic carbocyclic or heterocyclic group selected from cycloalkyl, phenyl, thienyl, furanyl, pyridinyl, and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and 
         Ar 2  represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl and pyridinyl which aromatic monocyclic heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino. 
       
     
     
         2 . The oxadiazole derivative of  claim 1 , or a pharmaceutically acceptable addition salt thereof, wherein n is 0, 1, 2 or 3. 
     
     
         3 . The oxadiazole derivative of  claim 2 , or a pharmaceutically acceptable addition salt thereof, wherein n is 0 or 1. 
     
     
         4 . The oxadiazole derivative of  claim 1 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 1  represents an monocyclic carbocyclic or heterocyclic group selected from cycloalkyl, phenyl, thienyl, furanyl, pyridinyl, and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano. 
     
     
         5 . The oxadiazole derivative of  claim 4 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 1  represents cycloalkyl, in particular cyclopropyl. 
     
     
         6 . The oxadiazole derivative of  claim 4 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 1  represents an aromatic monocyclic carbocyclic or heterocyclic group selected from phenyl, thienyl, furanyl, pyridinyl, and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano. 
     
     
         7 . The oxadiazole derivative of  claim 6 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 1  represents phenyl, optionally substituted one or two times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano. 
     
     
         8 . The oxadiazole derivative of  claim 6 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 1  represents an aromatic monocyclic heterocyclic group selected from thienyl, furanyl, pyridinyl, and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano. 
     
     
         9 . The oxadiazole derivative of  claim 8 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 1  represents an aromatic monocyclic heterocyclic group selected from thienyl, furanyl, pyridinyl, and pyrazinyl, which monocyclic carbocyclic or heterocyclic group is optionally substituted one or two times with substituents selected from the group consisting of halo, haloalkyl, haloalkoxy, nitro and cyano. 
     
     
         10 . The oxadiazole derivative of  claim 1 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 2  represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl and pyridinyl, which aromatic monocyclic heterocyclic group is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano and amino. 
     
     
         11 . The oxadiazole derivative of  claim 10 , or a pharmaceutically acceptable addition salt thereof, wherein Ar 2  represents an aromatic monocyclic heterocyclic group selected from phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl and pyridinyl, which aromatic monocyclic heterocyclic group is optionally substituted with alkyl, in particular methyl, ethyl or propyl; halo, in particular fluoro or chloro; haloalkyl, in particular trifluoromethyl; nitro; cyano or amino. 
     
     
         12 . The oxadiazole derivative of  claim 1 , or a pharmaceutically acceptable addition salt thereof, wherein
 n is 0 or 1;   Ar 1  represents cycloalkyl, in particular cyclopropyl; and   Ar 2  represents thienyl, furanyl, pyrrolyl, or pyrazolyl, which aromatic monocyclic heterocyclic group is optionally substituted with alkyl, in particular methyl: halo, in particular fluoro or chloro; haloalkyl, in particular trifluoromethyl; hydroxyl; alkoxy, in particular methoxy or ethoxy; haloalkoxy, in particular trifluoromethoxy; nitro or cyano.   
     
     
         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 stereoisomers or any mixture of stereoisomers, or a pharmaceutically acceptable addition salt thereof.   
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of an oxadiazole derivative of  claim 1 , or a pharmaceutically acceptable addition salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. 
     
     
         15 . 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 the step of administering to such a living animal body in need thereof a therapeutically effective amount of an oxadiazole derivative of  claim 1 , or a pharmaceutically acceptable addition salt thereof. 
     
     
         16 . The method according to  claim 15 , wherein the disease, disorder or condition is a cognitive disorder, learning deficit, memory deficits and dysfunction, Alzheimer's disease, attention deficit, attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, psychosis, depression, bipolar disorder, mania, manic depression, schizophrenia, cognitive or attention deficits related to schizophrenia, obsessive compulsive disorders (OCD), panic disorders, 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 anoxia, induced neuro-degeneration, neuropathy, diabetic neuropathy, periferic dyslexia, tardive dyskinesia, hyperkinesia, pain, mild pain, moderate or severe pain, pain of acute, chronic or recurrent character, pain caused by migraine, postoperative pain, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, to post therapeutic neuralgia, or to peripheral nerve injury, bulimia, post-traumatic syndrome, social phobia, sleeping disorders, pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, mutism, trichotillomania, jet-lag, arrhythmias, smooth muscle contractions, angina pectoris, premature labour, diarrhoea, asthma, tardive dyskinesia, hyperkinesia, premature ejaculation, erectile difficulty, hypertension, inflammatory disorders, inflammatory skin disorders, acne, rosacea, Chron's disease, inflammatory bowel disease, ulcerative colitis, diarrhoea, or withdrawal symptoms caused by termination of use of addictive substances, including nicotine containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and benzodiazepine-like drugs, and alcohol.