Novel oxadiazole derivatives and their medical use

• US 20090312347A1
• Filed: 04/24/2006
• Published: 12/17/2009
• Est. Priority Date: 04/26/2005
• Status: Active Grant

• Current Assignee: Saniona APS
• Original Assignee: Neurosearch AS
• Inventors: Peters, Dan, Timmermann, Daniel B., Olsen, Gunnar M., Dahl, Bjarne H., Jørgensen, Susanne
• Granted Patent: US 8,017,631 B2
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

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.

Claims

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;

Ar¹ 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

Ar² 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

Ar¹ 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

Ar¹ represents cycloalkyl, in particular cyclopropyl.

6. The oxadiazole derivative of claim 4, or a pharmaceutically-acceptable addition salt thereof, wherein

Ar¹ 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

Ar¹ 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

Ar¹ 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

Ar¹ 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

Ar² 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

Ar² 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;

Ar¹ represents cycloalkyl, in particular cyclopropyl; and

Ar² 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 methods 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.

17. (canceled)