N-aryl diazaspirocyclic compounds and methods of preparation and use thereof

Abstract

Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are N-aryl diazaspirocyclic compounds, bridged analogs of N-heteroaryl diazaspirocyclic compounds, or prodrugs or metabolites of these compounds. The aryl group can be a five- or six-membered heterocyclic ring (heteroaryl). The compounds and compositions can be used to treat and/or prevent a wide variety of conditions or disorders, particularly those disorders characterized by dysfunction of nicotinic cholinergic neurotransmission, including disorders involving neuromodulation of neurotransmitter release, such as dopamine release. CNS disorders, which are characterized by an alteration in normal neurotransmitter release, are another example of disorders that can be treated and/or prevented. The compounds and compositions can also be used to alleviate pain. The compounds can: (i) alter the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) when employed in effective amounts, not result in appreciable adverse side effects (e.g., side effects such as significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle).

1 . A method of treating a central nervous system disorder selected from the group consisting of mania, anxiety, dyslexia, schizophrenia, depression, obsessive-compulsive disorders and Tourette's syndrome, comprising administering an effective amount of 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane to treat the disorder. 
     
     
         2 . A method of treating a central nervous system disorder selected from the group consisting of pre-senile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Lewy Body dementia, HIV-dementia, multiple cerebral infarcts, Parkinsonism including Parkinson's disease, Pick's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, attention deficit disorder and mild cognitive impairment, comprising administering an effective amount of 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane to treat the disorder. 
     
     
         3 . A method of treating or preventing a CNS disorder associated with the release of neurotransmitters mediated by nicotinic receptors, comprising administering an effective amount of 7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane to a patient in need of treatment thereof. 
     
     
         4 . The method of  claim 3 , wherein the compound is administered at a dosage effective at treating or preventing the CNS disorder but at a dosage that does not result in appreciable amounts of side effects associated with stimulation of muscle or ganglionic receptors.