Halogenated derivatives of morphinans and uses thereof

Abstract

The present invention encompasses improved morphian compositions and methods of use of the improved compositions for modulating neuropathic pain, opioid-induced glial activation, or a combination thereof beyond what is currently known in the art. The methods involve administering the compound of Formula I to a subject.

1 . A compound of Formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
        wherein:
 R 1  is selected from the group consisting of hydroxyl, alkoxy, and aryloxy; 
 R 2  is selected from the group consisting of hydrogen, alkyl, alkynyl, alkenyl, alkoxy, alkylamide, alkylsulfamide, hydrocarbyl, substituted hydrocarbyl, cycloalkyl, alkylaryl, and substituted alkylaryl; 
 Y is selected from the group consisting of hydrogen and hydroxyl; 
 X is selected from the group consisting of fluorine, chlorine, bromine, and iodine; 
 Z is selected from the group consisting of hydrogen, fluorine; chlorine, bromine, and iodine; and 
 each bond between carbons 1 and 2, 3 and 4, 7 and 8, and 11 and 15 is selected from the group consisting of a single bond and a double bond, 
 provided that when R 1  is hydroxyl, R 2  is not cyclopropylmethyl. 
 
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
        or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
        or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound of  claim 1 , wherein X is fluorine, and Z is hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein X is fluorine, and Z is fluorine. 
     
     
         7 . The compound of  claim 1 , wherein X is fluorine, Z is hydrogen, and Y is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein X is fluorine, Z is fluorine, and Y is hydrogen. 
     
     
         9 . The compound of  claim 1 , wherein X is fluorine, Z is hydrogen, and Y is hydroxylhydroxy. 
     
     
         10 . The compound of  claim 1 , wherein X is fluorine, Z is fluorine, and Y is hydroxyl. 
     
     
         11 . The compound of  claim 1 , wherein R 1  is hydroxyl. 
     
     
         12 . The compound of  claim 1 , wherein R 1  is methoxy. 
     
     
         13 . The compound of  claim 1 , wherein R 2  is cyclopropylmethyl. 
     
     
         14 . The compound of  claim 1 , wherein R 2  is 2-propenyl. 
     
     
         15 . The compound of  claim 1 , where R 2  is phenethyl. 
     
     
         16 - 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
        and a pharmaceutically acceptable salts thereof. 
     
     
         21 . (canceled) 
     
     
         22 . A method for potentiating the analgesic effects of an opioid in a subject comprising administering to the subject an effective amount of the compound of  claim 1 . 
     
     
         23 - 29 . (canceled) 
     
     
         30 . A method for reducing the risk of developing an opioid dependency in a subject during opioid therapy, comprising the step of administering to the subject who is on opioid therapy an effective amount of the compound of  claim 1 . 
     
     
         31 - 37 . (canceled) 
     
     
         38 . A method for treating a subject with a clinical condition associated with Toll-like receptor (TLR) glial activation comprising the step of administering to the subject an effective amount of the compound of  claim 1 . 
     
     
         39 - 46 . (canceled) 
     
     
         47 . A method for treating a subject suffering from or susceptible to neuropathic pain, the method comprising administering to the subject an effective amount of the compound of  claim 1 . 
     
     
         48 - 51 . (canceled) 
     
     
         52 . A method for treating a subject suffering from or susceptible to nociceptive pain, the method comprising administering to the subject an effective amount of the compound of  claim 1 . 
     
     
         53 - 84 . (canceled)