التفاصيل البيبلوغرافية
| العنوان: |
NOVEL 1,4-DIAZA-BICYCLO[3.2.2]NONYL OXADIAZOLYL DERIVATIVES AND THEIR MEDICAL USE |
| Document Number: |
20100216780 |
| تاريخ النشر: |
August 26, 2010 |
| Appl. No: |
12/297333 |
| Application Filed: |
May 29, 2007 |
| مستخلص: |
This invention relates to novel 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivatives and their use in the manufacture of pharmaceutical compositions. The compounds of the invention are found to be cholinergic ligands at the nicotinic acetylcholine receptors and modulators of the monoamine receptors and transporters. 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. |
| Inventors: |
Peters, Dan (Malmo, SE); Olsen, Gunnar M. (Smorum, DK); Nielsen, Elsebet Østergaard (Kobenhavn k, DK); Timmermann, Daniel B. (Herlev, DK); Loechel, Steven Charles (Frederiksberg, DK); Mikkelsen, Jens Damsgaard (Lyngby, DK); Hansen, Henrik Björk (Kobenhavn N, DK); Redrobe, John Paul (Rodovre, DK); Christensen, Jeppe Kejser (Kobenhavn N, DK); Dyhring, Timo (Solrod, DK) |
| Claim: |
1-10. (canceled) |
| Claim: |
11. A 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative represented by Formula I [chemical expression included] or a pharmaceutically acceptable salt thereof; wherein Ar represents a phenyl, furanyl or thienyl group, which phenyl, furanyl and thienyl may optionally be substituted one or more times with substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, nitro, amino, N-alkyl-amino, N,N-dialkyl-amino, carboxy, alkyl-carbonyl, alkoxy-carbonyl, alkyl-carbonyl-oxy, carbamoyl, alkyl-sulfonyl, alkyl-sulfonyl-oxy, amido, sulfamoyl, methylenedioxy, ethylenedioxy, phenyl, benzyl, furanyl and thienyl; provided, however, that the 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative is not 4-(5-Benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane or 4-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane, or a pharmaceutically acceptable salt thereof. |
| Claim: |
12. The 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative of claim 11, or a pharmaceutically acceptable salt thereof; wherein Ar represents a phenyl, furanyl or thienyl group, which phenyl, furanyl and thienyl may optionally be substituted one or more times with substituents selected from hydroxy, alkoxy, halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, N,N-dialkyl-amino, alkyl-sulfonyl, alkyl-sulfonyl-oxy, amido, sulfamoyl, methylenedioxy, ethylenedioxy, phenyl, benzyl, furanyl and thienyl. |
| Claim: |
13. The 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative of claim 11 represented by Formula Ia [chemical expression included] or a pharmaceutically acceptable salt thereof; wherein R′, R″ and R′″, independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, nitro, amino, N-alkyl-amino, N,N-dialkyl-amino, carboxy, alkyl-carbonyl, alkoxy-carbonyl, alkyl-carbonyl-oxy, carbamoyl, alkyl-sulfonyl, alkyl-sulfonyl-oxy, amido, sulfamoyl, methylenedioxy, ethylenedioxy, phenyl, benzyl, furanyl or thienyl. |
| Claim: |
14. The 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative of claim 11 represented by Formula Ic [chemical expression included] or a pharmaceutically acceptable salt thereof; wherein R′ and R″, independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, nitro, amino, N-alkyl-amino, N,N-dialkyl-amino, carboxy, alkyl-carbonyl, alkoxy-carbonyl, alkyl-carbonyl-oxy, carbamoyl, alkyl-sulfonyl, alkyl-sulfonyl-oxy, amido, sulfamoyl, methylenedioxy, ethylenedioxy, phenyl, benzyl, furanyl and thienyl. |
| Claim: |
15. The 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative of claim 11 represented by Formula Id [chemical expression included] or a pharmaceutically acceptable salt thereof; wherein R′ and R″, independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, nitro, amino, N-alkyl-amino, N,N-dialkyl-amino, carboxy, alkyl-carbonyl, alkoxy-carbonyl, alkyl-carbonyl-oxy, carbamoyl, alkyl-sulfonyl, alkyl-sulfonyl-oxy, amido, sulfamoyl, methylenedioxy, ethylenedioxy, phenyl, benzyl, furanyl and thienyl. |
| Claim: |
16. The 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative of claim 11, which is 4-[5-(5-Bromo-furan-2-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; {4-[5-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-dimethyl-amine; 4-[5-(4-Bromo-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(5-Bromo-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(5-Chloro-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(3-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(4-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(2-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(3-Bromo-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(4-Nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(3,4-Dimethoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]-nonane; 4-[5-(3-Trifluoromethyl-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]-nonane; 4-[5-(3,4,5-Trimethoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]-nonane; 4-[5-(4-Trifluoromethyl-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]-nonane; 4-[5-(3,4-Difluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane; 4-[5-(2,4-Difluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diazabicyclo[3.2.2]nonane; 4-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(2-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(4-Iodo-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(4-Furan-2-yl-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane; 4-[5-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-[1,3,4]oxadiazol-2-yl]-phenol; Methanesulfonic acid 4-[5-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl ester; 4-[5-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-[1,3,4]oxadiazol-2-yl]-benzonitrile; or 4-[5-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine; or a pharmaceutically acceptable salt thereof. |
| Claim: |
17. A pharmaceutical composition comprising a therapeutically effective amount of the 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative of claim 11, or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent. |
| Claim: |
18. A method of treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disorder, disease or condition is responsive to modulation of cholinergic receptors and/or monoamine receptors, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of the 1,4-diaza-bicyclo[3.2.2]nonyl oxadiazolyl derivative of claim 11, or a pharmaceutically acceptable salt thereof. |
| Claim: |
19. The method according to claim 18, wherein the disease, disorder or condition is a cognitive disorder, learning deficit, memory deficits and dysfunction, Down's syndrome, 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, anxiety, non-OCD anxiety disorders, convulsive disorders, epilepsy, neurodegenerative disorders, transient anoxia, induced neuro-degeneration, neuropathy, diabetic neuropathy, periferic dyslexia, tardive dyskinesia, hyperkinesia, 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, fibromyalgia, 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. |
| Current U.S. Class: |
514/221 |
| Current International Class: |
61; 07; 61; 61; 61; 61; 61; 61; 61; 61; 61 |
| رقم الانضمام: |
edspap.20100216780 |
| قاعدة البيانات: |
USPTO Patent Applications |