Compositions useful as inhibitors of voltage-gated ion channels

Abstract

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

1 - 135 . (canceled) 
     
     
         136 . A method of treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epileptic conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain, comprising the step of administering to said patient an effective amount of a compound according of formula III-B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2 , taken together with the nitrogen atom to which they are bound, form a ring selected from 
 
       
       
         
           
           
               
               
           
         
         
           x is 1-2; 
           z is 0-3; 
           each occurrence of R 4  is independently C 1-4  alkyl optionally substituted with hydroxy, C 1-4  alkoxy, halo, C 1-4  alkylcarbonyloxy or carbo(C 1-4 alkoxy); 
           each occurrence of R 5  is independently halo, oxo, hydroxy, trifluoromethyl, —O—C 1-4  alkyl, C 1-4  alkyl optionally substituted with hydroxy, amino, aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl 
           R 7  is selected from —OH, —OCH 3 , —OC(O)CH 3 , —OP(O)(ONa) 2 , or —OC(O)NHCH 3 ; 
           each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C 1-8  aliphatic, C 6-10  aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; and 
           each occurrence of R 6  is independently R′, —COR′, —CO 2 (C 1-6  aliphatic), —CON(R′) 2 , or —SO 2 R′. 
         
       
     
     
         137 . (canceled) 
     
     
         138 . The method according to  claim 136 , wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated sodium channels. 
     
     
         139 . The method according to  claim 136 , wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated calcium channels. 
     
     
         140 . The method according to  claim 139 , wherein the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain. 
     
     
         141 . The method according to  claim 136 , wherein the disease, condition, or disorder is radicular pain, sciatica, back pain, head pain, or neck pain. 
     
     
         142 . The method according to  claim 136 , wherein the disease, condition, or disorder is severe or intractable pain, acute pain, post-surgical pain, back pain, or cancer pain. 
     
     
         143 . A method of inhibiting one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in:
 (a) a patient; or   (b) a biological sample;   which method comprising administering to said patient, or contacting said biological sample with a compound of formula III-B:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2 , taken together with the nitrogen atom to which they are bound, form a ring selected from 
 
       
       
         
           
           
               
               
           
         
         
           x is 1-2; 
           z is 0-3; 
           each occurrence of R 4  is independently C 1-4 alkyl optionally substituted with hydroxy, C 1-4  alkoxy, halo, C 1-4  alkylcarbonyloxy or carbo(C 1-4 alkoxy); 
           each occurrence of R 5  is independently halo, oxo, hydroxy, trifluoromethyl, —O—C 1-4  alkyl, C 1-4  alkyl optionally substituted with hydroxy, amino, aminocarbonyl, di(C 1-4 alkyl)aminocarbonyl 
           R 7  is selected from —OH, —OCH 3 , —OC(O)CH 3 , —OP(O)(ONa) 2 , or —OC(O)NHCH 3 ; 
           each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C 1-8  aliphatic, C 6-10  aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms; and 
           each occurrence of R 6  is independently R′, —COR′, —CO 2 (C 1-6  aliphatic), —CON(R′) 2 , or —SO 2 R′. 
         
       
     
     
         144 . (canceled) 
     
     
         145 . The method according to  claim 136  or  143 , wherein said compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         146 . (canceled)