Charged ion channel blockers and methods for use

Abstract

The invention provides compounds, compositions, methods, and kits for the treatment of pain, itch, and neurogenic inflammation.

1 . A quaternary amine compound having formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1F  and R 1G  together complete a heterocyclic ring having at least one nitrogen atom; 
 each of R 1A  and R 1B  is independently selected from H, halogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OR 1I , NR 1J R 1K , NR 1L C(O)R 1M , S(O)R 1N , SO 2 R 1O R 1P , SO 2 NR 1Q R 1R , SO 3 R 1S , CO 2 R 1T , C(O)R 1U , and C(O)NR 1V R 1W ; 
 each of R 1I , R 1J , R 1K , R 1L , R 1M , R 1N , R 1O , R 1P , R 1Q , R 1R , R 1S , R 1T , R 1U , R 1V  and R 1W  is, independently selected from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 2-4  heteroalkyl; 
 R 1C  is H; 
 X 1  is —NH(C)O—; 
 each of R 1D  and R 1E  is independently selected from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 2-4  heteroalkyl, wherein R 1D  and R 1E  are independently optionally substituted with halogen, C 3-8  cycloalkyl, aryl, or heteroaryl; or R 1D  and R 1E  together form a 3-6-membered heterocyclic or heteroalkyl ring; 
 R 1H  is selected from C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 2-4  heteroalkyl, wherein R 1H  is substituted with halogen, C 3-8  cycloalkyl, aryl, or heteroaryl. 
 
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein each of R 1A  and R 1B  is independently selected from H, halogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, and NR 1J R 1K ; and each of R 1J  and R 1K  is independently selected from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 2-4  heteroalkyl. 
     
     
         4 . The compound of  claim 1 , wherein R 1D  is C 1-4  alkyl optionally substituted with halogen, C 3-8  cycloalkyl, aryl, or heteroaryl. 
     
     
         5 . The compound of  claim 1 , wherein R 1E  is H or C 1-4  alkyl optionally substituted with halogen, C 3-8  cycloalkyl, aryl, or heteroaryl. 
     
     
         6 . The compound of  claim 1 , wherein R 1H  is C 1-4  alkyl optionally substituted with halogen, C 3-8  cycloalkyl, aryl, or heteroaryl. 
     
     
         7 - 21 . (canceled) 
     
     
         22 . A composition comprising the quaternary amine compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         23 . The composition of claim  21 , wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration. 
     
     
         24 . A method for treating pain, itch, or a neurogenic inflammatory disorder in a patient, said method comprising administering to said patient a composition comprising the quaternary amine compound of  claim 1 , wherein said compound inhibits one or more voltage-gated ion channels present in nociceptors and/or pruriceptors when applied to the internal face of said channels but does not substantially inhibit said channels when applied to the external face of said channels, and wherein said compound is capable of entering nociceptors or pruriceptors through a channel-forming receptor when said receptor is activated and inhibiting said one or more voltage-gated ion channels present in said nociceptors. 
     
     
         25 . The method of  claim 24 , wherein said channel-forming receptor is a transient receptor potential ion channel (TRP channel-forming receptor) 
     
     
         26 . The method of  claim 25 , wherein said TRP channel-forming receptor is activated by an exogenous or endogenous agonist. 
     
     
         27 . The method of  claim 25 , wherein said TRP channel-forming receptor is TRPA1 or TRPV1. 
     
     
         28 . The method of  claim 27 , wherein said compound is capable of entering nociceptors or pruriceptors through said TRPA1 or TRPV1 receptor when said receptor is activated. 
     
     
         29 . The method of  claim 24 , wherein said compound inhibits voltage-gated sodium channels. 
     
     
         30 . The method of  claim 24 , wherein said pain is selected from the group consisting of neuropathic pain, inflammatory pain, nociceptive pain, pain due to infections, and procedural pain. 
     
     
         31 . The method of  claim 24 , wherein said neurogenic inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, a*-interstitial cystitis, and atopic dermatitis. 
     
     
         32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein R 1H  is C 1-4  alkyl optionally substituted with aryl. 
     
     
         34 . The compound of  claim 1 , wherein R 1H  is C 1-4  alkyl optionally substituted with heteroaryl. 
     
     
         35 . The compound of  claim 1 , wherein R 1D  is hydrogen. 
     
     
         36 . The compound of  claim 1 , wherein R 1E  is hydrogen. 
     
     
         37 . The compound of  claim 1 , wherein R 1A  is methyl and R 1B  is methyl.