Sodium Channel Inhibitors

Abstract

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-gated sodium channels. More particularly, the invention provides substituted aryl sulfonamides, compositions comprising these compounds, as well as methods of using these compounds or compositions in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrence of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a voltage-gated sodium channel.

1 . A compound according to Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently selected from H, halogen, C 1-8 haloalkyl, C 1-8 alkyl, aryl, heteroaryl or heterocycloalkyl, wherein two or more members selected from R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are optionally joined to form a 4-8-member carbocyclic or heterocyclic ring having from 1-3 heteroatoms as ring members selected from O, N or S; 
         R 7  is a member selected from C 1-8 alkyl, heterocycloalkyl, aryl and heteroaryl, with the proviso that R 7  is other than methyl, and R 7  is not bound to the S(O) 2  moiety of Formula (I) through a sulfur-nitrogen bond; 
         wherein the aliphatic portion of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  groups is optionally substituted with from 1-3 R a  substituents selected from the group consisting of —OR b , ═O, ═NR b , ═N—OR b , —NR b R b , —SR b , -halogen, —Si(R b ) 3 , —OC(O)R b , —C(O)R b , —CO 2 R b , —CON(R b ) 2 , —OC(O)N(R b ) 2 , —NR b C(O)R b , —NR b —C(O)N(R b ) 2 , —NR b C(O) 2 R b , —NR b —C(NR b R b )═NR b , —S(O)R b , —S(O) 2 R b , —S(O) 2 N(R b ) 2 , —NRSO 2 R b , C 1-8 alkyl, —R b , —CN and —NO 2 , wherein each R b  is independently H, C 1-8 alkyl, aryl or heteroaryl and two R b  groups when attached to the same nitrogen atom are optionally combined together with the nitrogen atom to which they are attached to form a 5-6 membered ring having from 0-2 additional heteroatoms as ring members selected from O, N or S; wherein R b  group is further optionally substituted with from 1-3 R c  substituents selected from —OR d , ═O, ═NR d , ═N—OR d , —NR d R d , —SR d , -halogen, —Si(R d ) 3 , —OC(O)R d , —C(O)R d , —CO 2 R d , —CON(R d ) 2 , —OC(O)N(R d ) 2 , —NR d C(O)R d , —NR d —C(O)N(R d ) 2 , —NR d C(O) 2 R d , —NR d —C(NR d R d )═NR d , —S(O)R d , —S(O) 2 R d , —S(O) 2 N(R d ) 2 , —NRSO 2 R d , C 1-8 alkyl, —CN and —NO 2 , wherein R d  is —H, C 1-8 alkyl or aryl and two R d  groups when attached to the same nitrogen atom are optionally combined together with the nitrogen atom to which they are attached to form a 5-6 membered ring having from 0-2 additional heteroatoms as ring members selected from O, N or S; the aryl or heteroaryl moiety of R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  groups are each optionally substituted with from 1-3 R e  substituents selected from halogen, —OR f , —NR f R f , —SR f , -halogen, —Si(R f ) 3 , —OC(O)R f , —C(O)R f , —CO 2 R f , —CON(R f ) 2 , —OC(O)N(R f ) 2 , —NR f C(O)R f , —NR f —C(O)N(R f ) 2 , —NR f C(O) 2 R f , —NR f —C(NR f R f )═NR f , —S(O)R f , —S(O) 2 R f , —S(O) 2 NR f R f , —NRSO 2 R f , C 1-8 alkyl, —CN and —NO 2 , C 1-8 alkyl, —N 3 , —CH(Ph) 2 , fluoroC 1-4 alkoxy, and fluoroC 1-4 alkyl, wherein R f  is —H, C 1-8 alkyl, aryl or heteroaryl and two R f  groups when attached to the same nitrogen atom are optionally combined together with the nitrogen atom to which they are attached to form a 5-6 membered ring having from 0-2 additional heteroatoms as ring members selected from O, N or S; wherein the aliphatic portion of R f  group is further optionally substituted with from 1-3 R a  substituents and the aromatic portion of the R f  group is further optionally substituted with from 1-3 R g  substituents selected from —OR h , —NR h R h , —SR h , -halogen, —Si(R h ) 3 , —OC(O)R h , —C(O)R h , —CO 2 R h , —CON(R h ) 2 , —OC(O)N(R h ) 2 , —NR h C(O)R h , —NR h —C(O)N(R h ) 2 , —NR h C(O) 2 R h , —NR h —C(NR h R h )═NR h , —S(O)R h , —S(O) 2 R h , —S(O) 2 NR h R h , —NRSO 2 R h , —CN and —NO 2 , C 1-8 alkyl, —N 3 , —CH(Ph) 2 , fluoroC 1-4 alkoxy, and fluoroC 1-4 alkyl, wherein R h  is —H or C 1-8 alkyl; wherein the two R h  groups when attached to the same nitrogen atom are optionally combined with the nitrogen atom to which they are attached to form a 5-6-membered ring having from 0-2 additional heteroatoms as ring members selected from O, N or S; 
         B is a member selected from C 3-7 cycloalkylene, arylene and heteroarylene, or B is optionally joined to R 7  to form a fused ring, wherein the cycloalkylene is optionally substituted with from 1-3 R b  substituents and the arylene or heteroarylene moiety is optionally substituted with from 1-3 R g  substituents; 
         Z is a five-membered heteroaryl having from 1-4 heteroatoms as ring members selected from O, N or S, wherein Z is optionally substituted with from 1-3 R e  substituents; 
         the subscripts m, n and p are each independently selected from the integers from 0 to 5; 
         with the proviso when p and m are 0, and n is not 0, then R 7  is other than aryl or heteroaryl; 
         the terms “alkyl”, “cycloalkyl” and “aryl” as recited herein mean the following: 
         “alkyl” by itself or as part of another substituent, is an unsubstituted, fully saturated, straight or branched chain hydrocarbon radical; 
         “cycloalkyl” by itself or as part of another substituent is an unsubstituted, fully saturated, cyclic hydrocarbon radical; 
         “aryl” by itself or as part or another substituent is a monovalent monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m and p are not both zero. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0. 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m and p are 0. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m and p are 0 and n is 1, 2, 3, 4 or 5. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m, p and n are 0. 
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is an arylene or a 6-membered heteroarylene having from 1-3 nitrogen heteroatoms as ring members, each of which is optionally substituted with 1-2 substituents selected from the group consisting of halogen, —OR h , C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 haloalkoxy and —CN. 
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein the arylene is substituted with halogen, —OR h , C 1-8 alkyl, —CN, CF 3  or —OF 3 . 
     
     
         11 . The compound of  claim 10 , or a pharmaceutically acceptable salt thereof, wherein the arylene is phyenylen. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl and Z is thiazolyl. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is thiazolyl, 2-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, isoxazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazol-4yl, 1,2,5-oxadiazol-4yl, 1,2,3,5-thiatriazol-4yl, 1,2,3,4-thiatriazol-5yl, 1,2,3,5-oxatriazol-4yl, 1,2,3,4-oxatriazol-5yl, benzimidazolyl, benzoxazolyl, benzthiazolyl, tetrahydrobenzothiazolyl or dihydrobenzothiazolone, each of which is optionally substituted with 1-2 members selected from the group consisting of C 1-8 haloalkyl, —CN, halogen, C 3-7 cycloalkyl, aryl, C 1-8 alkyl, aryl-NH—C 1-8 alkyl and C 1-8 alkoxy-C 1-4 alkyl. 
     
     
         14 . The compound of  claim 13 , or a pharmaceutically acceptable salt thereof, wherein Z is 2-thiazolyl, oxazolyl, isoxazoly, isothiazolyl or pyrazolyl, each of which is optionally substituted with 1-2 members from the group consisting of C 1-8 haloalkyl, —CN, halogen, C 3-7 cycloalkyl, aryl, C 1-8 alkyl, aryl-NH—C 1-6 alkyl and C 1-8 alkoxy-C 1-4 alkyl. 
     
     
         15 . The compound of  claim 14 , or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted with 1-2 members selected from the group consisting of 3-chloropropyl, phenylaminomethyl, —CH 3 , CH 2 CH 3 , —C1, —F, —CF 3 , —OCF 3 , —CF 2 H, CH 3 OCH 2 —, cyclopropyl, isopropyl and —CN. 
     
     
         16 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7  is aryl, aryl-C 1-8 alkyl or heteroaryl-C 1-8 alkyl, wherein the aryl or heteroaryl moiety is optionally substituted with from 1-3 R e  substituents. 
     
     
         17 . The compound of  claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 7  is aryl or aryl-C 1-8 alkyl, optionally the aryl moiety is substituted with from 1-3 R e  substituents. 
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 7  is aryl or aryl-C 1-8 alkyl, optionally the aryl moiety is substituted with from 1-3 members selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 haloalkoxy, —CN and —NO 2 . 
     
     
         19 . The compound of  claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 7  is aryl or aryl-C 1-8 alkyl, optionally the aryl moiety is substituted with from 1-3 members selected from the group consisting of —F, —C1, —CF 3  and CF 3 O—. 
     
     
         20 . The compound of  claim 19 , or pharmaceutically acceptable salt thereof, wherein R 7  is phenyl or phenyl-C 1-8 alkyl, optionally the phenyl moiety is substituted with from 1-3 members selected from the group consisting of —F, —C1, —CF 3  and CF 3 O—. 
     
     
         21 . The compound of  claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 7  is aryl-(CH 2 ) q — or heteroaryl —(CH 2 ) q —, wherein the aryl or heteroaryl moiety is optionally substituted with from 1-3 R e  substituents and the subscript q is each independently an integer of from 1-8. 
     
     
         22 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered arylene or heteroarylene, wherein B is optionally joined to R 7  to form a 5- or 6-membered fused carbocylic or heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S; and Z is a five member heteroaryl whose point of indirect attachment is para to that of R 7 . 
     
     
         23 - 32 . (canceled) 
     
     
         33 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         34 . A method of modulating activity of a sodium channel in a subject, said method comprising:
 administering to said subject in need thereof an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to modulate the activity of a sodium channel.   
     
     
         35 . A method for treating, preventing or ameliorating pain or seizures in a subject, said method comprising:
 administering to said subject a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to treat, prevent or ameliorate pain or seizures.   
     
     
         36 . The method of  claim 35 , or a pharmaceutically acceptable salt thereof, wherein said pain is selected from the group consisting of postoperative pain, osteoarthritis pain, pain associated with metastatic cancer, neuropathy secondary to metastatic inflammation, trigeminal neuralgia, glossopharangyl neuralgia, adiposis dolorosa, bum pain, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, bum pain, pain following stroke, thalamic lesions, radiculopathy, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.