(1s,5s)-3-(5,6-dichloro-3-pyridinyl)-3,6- diazabicyclo[3.2.0]heptane

Abstract

The present invention discloses (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane, salts thereof, and its use to treat pain and other disorders associated with the nicotinic acetylcholine receptor.

1 . A method of treating a disorder associated with acetylcholine nicotinic receptors in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane. 
   
   
       2 . A method of treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof. 
   
   
       3 . A method of treating a cognitive deficit in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof. 
   
   
       4 . The method according to  claim 3  wherein the cognitive deficit in a patient, wherein the patient is suffering from Alzheimer's disease, Parkinson's disease, memory dysfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration, inflammation, neuroprotection, anxiety, depression, mania, schizophrenia, anorexia and other eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, substance abuse, smoking cessation or inflammatory bowel syndrome. 
   
   
       5 . The method according to  claim 4  wherein the cognitive deficit is in a patient suffering from Alzheimer's disease, Parkinson's disease, memory dysfunction, attention deficit hyperactivity disorder, or schizophrenia. 
   
   
       6 . A method of treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with a non-steroid anti-inflammatory agent. 
   
   
       7 . A method of treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with an opioid. 
   
   
       8 . A method of treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with a tricyclic antidepressant. 
   
   
       9 . A method of treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with an anticonvulsant. 
   
   
       10 . A pharmaceutical composition for treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with a non-steroid anti-inflammatory agent. 
   
   
       11 . A pharmaceutical composition for treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with an opioid. 
   
   
       12 . A pharmaceutical composition for treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with a tricyclic antidepressant. 
   
   
       13 . A pharmaceutical composition for treating pain in a mammal comprising administering to a mammal a therapeutically effective amount of (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane or a pharmaceutically acceptable salt or prodrug thereof, in combination with an anticonvulsant. 
   
   
       14 . A process for preparing a compound (5J) 
     
       
         
         
             
             
         
       
     
     comprising the steps of:
 a) treating compound (5H) 
 
     
       
         
         
             
             
         
       
     
     with Raney Nickel under a 40 PSI atmosphere of hydrogen in a solvent to obtain compound (5I), 
     
       
         
         
             
             
         
       
       b) treating compound (51) with N-methylpyrrolidinone in 1,2-dimethoxyethane at 50° C. with SOCl 2  for 3 hours; and 
       c) treating the mixture from step (b) with NaOH to obtain compound (5J).