Pharmaceutical Compositions and Methods for Relieving Pain and Treating Central Nervous System Disorders

Abstract

Patients susceptible to or suffering from disorders, such as central nervous system disorders, which are characterized by an alteration in normal neurotransmitter release, such as dopamine release (e.g., Parkinsonism, Parkinson's Disease, Tourette's Syndrome, attention deficient disorder, or schizophrenia), are treated by administering a compound of Formulas 1 or 2, as described herein. The compounds of Formulas 1 and 2 are also useful for treating pain, and treating drug addiction, nicotine addiction, and/or obesity. The compounds can exist as individual stereoisomers, racemic mixtures, diastereomers and the like.

1 . A method for the treatment or prevention of addiction comprising administration of a compound of Formulas 1 or 2: 
       
         
           
           
               
               
           
         
         wherein 
         k and p are each 1; 
         m and n are individually 0 or 1; 
         provided that if m is 1, then n is 0, and if n is 1, then m is 0; 
         Ar is pyridine, optionally substituted at any position with a substituent Z is selected from the group consisting of lower alkyl, lower alkenyl, cycloalkyl, phenyl, benzyl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C≡CR′, —SR′, and —SO 2 R′; 
         where R′ and R″ are individually hydrogen, lower alkyl, cycloalkyl, phenyl, or benzyl, 
         and 
         R is hydrogen, unsubstituted lower alkyl, unsubstituted arylalkyl, unsubstituted alkoxycarbonyl, or unsubstituted aryloxycarbonyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the compound is selected from: 
       6-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, and 
       7-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]nonane,
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . The method of  claim 1  wherein the addiction is associated with one or more stimulant, sedative, hypnotic, opiate, or opiod analgesic. 
     
     
         4 . The method of  claim 3  wherein the addiction is associated with amphetamine, methamphetamine, caffeine, cocaine, nicotine, alcohol, barbituates, benzodiazepines, methaqualone, quinazolinones, morphine, codeine, heroin, oxycodone, hydromorphone, fentanyl, meperidine, methadone, cannabis, or an analog thereof. 
     
     
         5 . The method of  claim 4 , wherein the addition is associated with nicotine. 
     
     
         6 . A method for the treatment or prevention of a substance use disorder comprising administration of a compound of Formulas 1 or 2: 
       
         
           
           
               
               
           
         
         wherein 
         k and p are each 1; 
         m and n are individually 0 or 1; 
         provided that if m is 1, then n is 0, and if n is 1, then m is 0; 
         Ar is pyridine, optionally substituted at any position with a substituent Z is selected from the group consisting of lower alkyl, lower alkenyl, cycloalkyl, phenyl, benzyl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C≡CR′, —SR′, and —SO 2 R′; 
         where R′ and R″ are individually hydrogen, lower alkyl, cycloalkyl, phenyl, or benzyl, 
         and 
         R is hydrogen, unsubstituted lower alkyl, unsubstituted arylalkyl, unsubstituted alkoxycarbonyl, or unsubstituted aryloxycarbonyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The method of  claim 6 , wherein the compound is selected from: 
       6-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, and 
       7-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]nonane,
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . The method of  claim 6  wherein the substance use disorder is substance abuse. 
     
     
         9 . The method of  claim 6  wherein the substance use disorder is substance dependence. 
     
     
         10 . The method of  claim 6  wherein the substance is nicotine. 
     
     
         11 . A method of aiding smoking cessation or nicotine replacement therapy comprising the administration of a compound of Formulas 1 or 2: 
       
         
           
           
               
               
           
         
         wherein 
         k and p are each 1; 
         m and n are individually 0 or 1; 
         provided that if m is 1, then n is 0, and if n is 1, then m is 0; 
         Ar is pyridine, optionally substituted at any position with a substituent Z is selected from the group consisting of lower alkyl, lower alkenyl, cycloalkyl, phenyl, benzyl, halo, —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C≡CR′, —SR′, and —SO 2 R′; 
         where R′ and R″ are individually hydrogen, lower alkyl, cycloalkyl, phenyl, or benzyl, 
         and 
         R is hydrogen, unsubstituted lower alkyl, unsubstituted arylalkyl, unsubstituted alkoxycarbonyl, or unsubstituted aryloxycarbonyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The method of  claim 11 , wherein the compound is selected from: 
       6-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(6-methoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-isopropoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-phenoxy-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       7-(5-phenyl-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, 
       6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       7-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene, 
       6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]nonane, and 
       7-(6-chloro-3-pyridinyl)-3-azabicyclo[3.3.1]nonane,
 or a pharmaceutically acceptable salt thereof.