Substituted Triazoles as Sodium Channel Blockers

Abstract

Substituted triazole compounds represented by Formula I, II or III, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, sodium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, migraine, headache pain, migraine headache, epilepsy, irritable bowel syndrome, diabetic neuropathy, multiple sclerosis, manic depression and bipolar disorder, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds. A method of administering local anesthesia comprises administering an effective amount of a compound of the instant invention, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier (I), (II), (III).

1 . A compound represented by Formula (I) or (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is 
 (a) H, 
 (b) C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, any of which is optionally substituted with one or more of the following substituents: NR a R b , COOH, CONR a R b , or 
 (c) —C(═O)R a , COOR a , CONR a R b —; 
 R a  is: 
 (a) H, 
 (b) C 1 -C 6 -alkyl, optionally substituted with one or more of halogen or CF 3 , or 
 (c) CF 3 ; 
 R b  is 
 (a) H, or 
 (b) C 1 -C 6 -alkyl, optionally substituted with one or more of halogen or CF 3 , or 
 (c) CF 3 ; 
 R 2  is H or C 1-4 alkyl; 
 R 3  and R 4  each independently is: 
 (a) H, 
 (b) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl or —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, 
 (c) halogen, or 
 (d) —C 1 -C 6  alkyl, optionally substituted with one or more of halogen or CF 3 ; and 
 R 5 , R 6  and R 7  each independently is: 
 (a) H, 
 (b) —O—C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkenyl, —O—C 1 -C 6 -alkynyl, any of which is optionally substituted with one or more of halogen or CF 3 , 
 (c) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, or —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, 
 (d) —O-phenyl, or —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted with 1-3 substituents selected from i) halogen, ii) —CN, iii) —NO 2 , iv) CF 3 , v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii)-(C 0-4 -alkyl) —CO—N(R a )(R b ), ix) and x) —C 1-10  alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a , C(O)—O—, or —N(R a )—C(O)—N(R a )—, or 
 (e) halogen, —OR a , or phenyl wherein phenyl is optionally substituted with 1-3 substituents selected from i) halogen, ii) —CN, iii) —NO 2 , iv) CF 3 , v) pyrazolyl, vi) —OR a , vii) —NR a R b , viii) —C 0-4 alkyl-CO—OR a , ix)-(C 0-4 alkyl) —CO—N(R a )(R b ), and x) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a , C(O)—O—, or —N(R a )—C(O)—N(R a )—. 
 
     
     
         2 . The compound of  claim 1  described by the chemical Formula (I), or a pharmaceutically acceptable salt thereof, wherein
 R 5  is other than H and is attached at the ortho position.   
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted —O—C 1 -C 6 -alkyl.   
     
     
         4 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted phenyl.   
     
     
         5 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.   
     
     
         6 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted —O—C 1 -C 6 -alkenyl.   
     
     
         7 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 6  is halogen.   
     
     
         8 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  is halogen.   
     
     
         9 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  and R 4  are halogen.   
     
     
         10 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 3 , R 4  and R 6  are halogen.   
     
     
         11 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  is —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl.   
     
     
         12 . The compound of  claim 1  described by the chemical Formula (II), or a pharmaceutically acceptable salt thereof, wherein
 R 5  is other than H and is attached at the ortho position.   
     
     
         13 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted —O—C 1 -C 6 -alkyl.   
     
     
         14 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted phenyl.   
     
     
         15 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.   
     
     
         16 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted —O—C 1 -C 6 -alkenyl.   
     
     
         17 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 6  is halogen.   
     
     
         18 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  is halogen.   
     
     
         19 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  and R 4  are halogen.   
     
     
         20 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 3 , R 4  and R 6  are halogen.   
     
     
         21 . The compound of  claim 12 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  is —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl.   
     
     
         22 . A compound represented by Formula (III) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 1 -R 7  each is as defined in  claim 1 . 
     
     
         23 . The compound of  claim 22 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is other than H and is attached at the ortho position.   
     
     
         24 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted —O—C 1 -C 6 -alkyl.   
     
     
         25 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted phenyl.   
     
     
         26 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.   
     
     
         27 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 5  is optionally substituted —O—C 1 -C 6 -alkenyl.   
     
     
         28 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 6  is halogen.   
     
     
         29 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  is halogen.   
     
     
         30 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  and R 4  are halogen.   
     
     
         31 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 3 , R 4  and R 6  are halogen.   
     
     
         32 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein
 R 3  is —O—CO—C 4 -alkyl-C 1 -C 4 -perfluoroalkyl.   
     
     
         33 . A compound represented by 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         34 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         35 . The pharmaceutical composition according to  claim 34 , further comprising a second therapeutic agent selected from the group consisting of: i) opiate agonists, ii) opiate antagonists, iii) calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT receptor antagonists vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2 selective inhibitors, x) NK1 antagonists, xi) non-steroidal anti-inflammatory drugs, xii) selective serotonin reuptake inhibitors, xiii) selective serotonin and norepinephrine reuptake inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate, and xviii) neurontin. 
     
     
         36 . A method of treatment or prevention of pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         37 . A method of treatment or prevention of chronic, visceral, inflammatory and/or neuropathic pain syndromes comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A method of treatment or prevention of pain resulting from, or associated with, traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and/or chemotherapy, comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         39 . A method of treatment or prevention of chronic lower back pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         40 . A method of treatment or prevention of phantom limb pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         41 . A method of treatment or prevention of HIV- and HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and/or related neuralgias comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         42 . A method of administering local anesthesia comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         43 . A method of treatment or prevention of irritable bowel syndrome and/or Crohn's disease comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         44 . A method of treatment or prevention of epilepsy and/or partial and generalized tonic seizures comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         45 . A method for neuroprotection under ischaemic conditions caused by stroke or neural trauma comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A method of treatment or prevention of multiple sclerosis comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         47 . A method of treatment or prevention of bipolar disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         48 . A method of treatment or prevention of tachy-arrhythmias comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A method of treatment or prevention of migraine, headache pain and/or migraine headache comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         50 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         51 . The pharmaceutical composition according to  claim 49 , further comprising a second therapeutic agent selected from the group consisting of: i) opiate agonists, ii) opiate antagonists, iii) calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT receptor antagonists vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2 selective inhibitors, x) NK1 antagonists, xi) non-steroidal anti-inflammatory drugs, xii) selective serotonin reuptake inhibitors, xiii) selective serotonin and norepinephrine reuptake inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate, and xviii) neurontin. 
     
     
         52 . A method of treatment or prevention of pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         53 . A method of treatment or prevention of chronic, visceral, inflammatory and/or neuropathic pain syndromes comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         54 . A method of treatment or prevention of pain resulting from traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and/or chemotherapy comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         55 . A method of treatment or prevention of chronic lower back pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         56 . A method of treatment or prevention of phantom limb pain comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         57 . A method of treatment or prevention of HIV- and HIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and/or related neuralgias comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         58 . A method of administering local anesthesia comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         59 . A method of treatment or prevention of irritable bowel syndrome and/or Crohn's disease comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         60 . A method of treatment or prevention of epilepsy and/or partial and generalized tonic seizures comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         61 . A method for neuroprotection under ischaemic conditions caused by stroke or neural trauma comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         62 . A method of treatment or prevention of multiple sclerosis comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         63 . A method of treatment or prevention of bipolar disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         64 . A method of treatment or prevention of tachy-arrhythmias comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof. 
     
     
         65 . A method of treatment or prevention of migraine, headache pain and/or migraine headache comprising the step of administering to a patient in need thereof a therapeutically effective amount, or a prophylactically effective amount, of a compound according to  claim 22 , or a pharmaceutically acceptable salt thereof.