HYDROXYALKYLAMINE- and HYDROXYCYCLOALKYLAMINE-SUBSTITUTED DIAMINE-ARYLSULFONAMIDE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS

Abstract

wherein R1, R2, and E are defined herein, which compounds have properties for inhibiting Nav 1.7 ion channels found in peripheral and sympathetic neurons. Also described are pharmaceutical formulations comprising the compounds of Formula A or their salts, and methods of treating pain disorders, cough, and itch using the same.

What is claimed is: 
     
         1 ) A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula A: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is: —Cl, —Br, or linear, branched or cyclic alkyl of up to 3 carbon atoms; 
 R 2  is:
 (a) a moiety of the formula: 
 
 
       
         
           
           
               
               
           
         
         
           wherein, one of R 3a  and R 3b  is —H and the other is —H, —F, CH 3 ; or 
           (b) a moiety of the formula: 
         
       
       
         
           
           
               
               
           
         
         E is:
 (I) a moiety of Formula E 1 : 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein: 
             R 6  is —H or a linear, branched or cyclic alkyl of up to 6 carbon atoms; and 
             B is: 
             (a) a moiety of the formula: 
           
         
       
       
         
           
           
               
               
           
         
         
           
              which moiety is bonded to nitrogen at one of R 7A , R 7B , or R 7C  via —CH 2 —, or is bonded to nitrogen directly at one of R 7C , and 
           
           wherein:
 m is 0, 1 or 2; 
 R 7A  and R 7B  are independently for each occurrence —H, or a linear, branched or cyclic alkyl of up to 3 carbon atoms when not selected to be bonded to the nitrogen via methylene; 
 R 7C  when not selected to be bonded to the nitrogen directly or via methylene is independently for each occurrence: (i) —H; (ii) linear, branched, or cyclic alkyl of up to three carbon; and 
 R 7D  is: (ai) —H; or (aii) a linear, branched or cyclic alkyl of up to 5 carbon atoms; or 
 
           (b) a moiety of the formula: 
         
       
       
         
           
           
               
               
           
         
         
           wherein:
 R 7h  is —H or a linear, branched or cyclic alkyl of up to 3 carbon atoms; and 
 R 7g  and R 7f  are selected as follows:
 (i) R 7 8 is a linear alkyl of at least 2, up to 4 carbon atoms, a branched alkyl of at least 3 up to 6 carbon atoms or cyclic alkyl of up to 6 carbon atoms and R 7f  is a linear alkyl of at least 2 carbon atoms up to 4 carbon atoms, or a branched or cyclic alkyl of up to 6 carbon atoms which is substituted with —OH on one carbon atom thereof that is bonded beta to, or further from, the nitrogen to which it is attached; or 
 (ii) R 7f  is —H or a linear, branched or cyclic alkyl of up 6 carbon atoms or and R 7g  is —(CH 2 ) 1-2 —(HC(OH))—(CH 2 ) 1-2 ; 
 
 
           (II) a moiety of Formula E 2 : 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein each R 8  is independently —H or linear, branched, or cyclic alkyl of up to 6 carbon atoms; or 
           
           (III) a moiety of Formula E 3 : 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein: 
             R 9A  is independently for each occurrence: (i) —H; (ii) —OH; or (iii) a linear, branched or cyclic alkyl of up to 6 carbon atoms which is optionally substituted on one carbon atom there of with an —OH; 
             R 10A  is independently for each occurrence: (i) —H; or (ii) linear, branched or cyclic alkyl of up to 6 carbon atoms which is optionally substituted on one carbon atom thereof with an —OH; 
             R 11A  is —H or an alkyl of 2 or 3 carbons which is optionally substituted on a beta or gamma carbon with an —OH, 
           
           with the proviso that only one —OH substituent is present among all of R 9A , R 10A , and R 11A . 
         
       
     
     
         2 ) A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is —Cl or —Br. 
     
     
         3 ) A compound of  claim 1  or  claim 2 , or a pharmaceutically acceptable salt thereof, wherein E has the structure: 
       
         
           
           
               
               
           
         
         wherein R 9A , R 10A , and R 11A  are as follows:
 R 10A  is —(CH 2 ) 1-2 —OH and R 9A  and R 11A  are all —H; or 
 R 11a  is —CH 2 CH 2 —OH and R 9A  and R 10A  are all —H; or 
 one of R 9A  is —OH, the other of R 9A  is lower alkyl, and R 10A  and R 11A  are all —H. 
 
       
     
     
         4 ) A compound of  claim 1  or  claim 2 , or a pharmaceutically acceptable salt thereof, wherein E has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         5 ) A compound of  claim 1  or  claim 2 , or a pharmaceutically acceptable salt thereof, wherein E has the structure of Formula E 1 : 
       
         
           
           
               
               
           
         
         wherein: 
         R 6  is —H or a linear, branched or cyclic alkyl of up to 6 carbon atoms; and 
         B is: 
       
       
         
           
           
               
               
           
         
       
     
     
         6 ) A compound of  claim 1  or  claim 2 , or a pharmaceutically acceptable salt thereof, wherein E has the structure of Formula E 1a : 
       
         
           
           
               
               
           
         
         wherein B has the structure: 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           (a) R 7Cg  is —CH 2 —CH(OH)—CH 2 — and R 7Cf  is —H or lower alkyl or lower cyclic alkyl; or 
           (b) R 7Cg  is linear alkyl of at least 2 carbon atoms up to 4 carbon atoms, branched alkyl of from 3 up to 6 carbon atoms or cyclic alkyl of up to 6 carbon atoms and R 7Cf  is linear, branched, or cyclic alkyl of up to 6 carbon atoms that is substituted on one carbon thereof which is beta or further from the nitrogen with —OH. 
         
       
     
     
         7 ) A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula AI: 
       
         
           
           
               
               
           
         
         wherein:
 X is —N═ or —C(R C14c )═, wherein R C14c  is —H, —F, or —CH 3 ; 
 R 14  is —Cl or —Br; and 
 R 15  is a moiety of Formula AIb bonded to nitrogen via methylene through one of R 15b , R 15c , or R 15d , or bonded directly to nitrogen through R 15C  if present: 
 
       
       
         
           
           
               
               
           
         
         
           wherein:
 m is 0 or 1; 
 R 15c , when present and not selected to be bonded to nitrogen is, independently: (i) —H; or (ii) linear, branched or cyclic alkyl of up to 5 carbon atoms; and 
 R 15b  and R 15d , when not selected to be bonded to nitrogen are, independently: (i) —H; or (ii) linear, branched or cyclic alkyl of up to 5 carbon atoms. 
 
         
       
     
     
         8 ) A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula AI: 
       
         
           
           
               
               
           
         
         wherein:
 X is —N═ or —C(R C14c )═, wherein R C14c  is —H, —F, or —CH 3 ; 
 R 14  is —Cl or —Br; and 
 R 15  is H 2 N—CH 2 —CH(OH)—CH 2 —. 
 
       
     
     
         9 ) A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula AI: 
       
         
           
           
               
               
           
         
         wherein:
 X is —N═ or —C(R C14c )═, wherein R C14c  is —H, —F, or —CH 3 ; 
 R 14  is —Cl or —Br; and 
 R 15  is a moiety of the formula: 
 
       
       
         
           
           
               
               
           
         
       
     
     
         10 ) A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, having the structure: 
       
         
           
           
               
               
           
         
         wherein:
 X is —N═ or —C(R C14e )═, wherein R C14e  is —H, —F, or —CH 3 ; 
 R a14F  is —Cl, —Br or —CH 3 ; and 
 R 8F  is independently —H or linear, branched, or cyclic alkyl of up to 6 carbon atoms. 
 
       
     
     
         11 ) A compound of any of  claims 7  to  10 , or a pharmaceutically acceptable salt thereof, wherein X is ═N—. 
     
     
         12 ) A compound of any of  claims 7  to  10 , or or a pharmaceutically acceptable salt thereof, wherein X is ═CH—, ═C(CH 3 )—, or ═CF—. 
     
     
         13 ) A compound, or a pharmaceutically acceptable salt thereof, which is:
 4-[(4-{[(2S)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   4-[(4-{[3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   4-({4-[3-(aminomethyl)-3-hydroxyazetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   4-({4-[3-(aminomethyl)-3-hydroxyazetidin-1-yl]butyl}amino)-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-5-methylbenzenesulfonamide;   5-bromo-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   4-[(4-{[(2R)-3-amino-2-hydroxypropyl]-amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;   4-[(4-{[(2S)-3-amino-2-hydroxypropyl]-amino}butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;   4-[(4-{[(2R)-3-amino-2-hydroxypropyl]-amino}-butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;   4-[(4-{[3-amino-2-hydroxypropyl]-amino}-butyl)amino]-5-bromo-2-fluoro-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-(4-methyl-1,3-thiazol-2-yl)-benzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-{[4-({3-[(2-hydroxyethyl)amino]propyl}amino)butyl]amino}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-{[4-({2-[(2-hydroxyethyl)amino]ethyl}amino)butyl]amino}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   4-({4-[(3-amino-2-hydroxypropyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3-hydroxyazetidin-3-yl)-methyl]amino}butyl)amino]benzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3S,4S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({2-[(2-hydroxy-1,1-dimethylethyl)-amino]-1,1-dimethylethyl}amino)butyl]amino}benzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({2-[(2-hydroxyethyl)amino]-ethyl}amino)butyl]amino}benzenesulfonamide;   4-({4-[(3-amino-2-hydroxypropyl)amino]butyl}amino)-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   5-chloro-2-fluoro-4-({4-[7-(hydroxymethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-({4-[2-(2-hydroxyethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-({4-[2-(hydroxymethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-{[4-(6-hydroxy-6-methyl-1,4-diazepan-1-yl)butyl]amino}-N-1,3-thiazol-2-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-({4-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]butyl}amino)-N-1,3-thiazol-2-ylbenzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-1{[(3 S,4S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]benzenesulfonamide;   4-[(4-1{[(2R)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   4-[(4-1{[(2 S)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   4-[(4-{[3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   5-chloro-2-fluoro-4-[(4-1{[(3R,4S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]benzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2S,4S)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;   5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{[4-({[(2R,4S)-4-hydroxypyrrolidin-2-yl]methyl}amino)butyl]amino}benzenesulfonamide;   5-bromo-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]benzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   4-({4-[(3-amino-2-hydroxypropyl)amino]butyl}amino)-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3-hydroxyazetidin-3-yl)methyl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[(2R)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[(2S)-3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[3-amino-2-hydroxypropyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[(1S)-3-amino-1-(hydroxymethyl)propyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[(1S)-3-amino-1-(hydroxymethyl)propyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   4-[(4-{[(1S)-3-amino-1-(hydroxymethyl)propyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   4-[(4-{[(1S)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[(1S)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   4-[(4-{[(1S)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;   5-chloro-2-fluoro-4-[(4-{[(3S,4S)-4-hydroxypyrrolidin-3-yl]amino}butyl)amino]-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[(1R)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide;   4-[(4-{[(1R)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide;   5-bromo-2-fluoro-4-((4-(6-hydroxy-1,4-diazepan-1-yl)butyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;   5-bromo-2-fluoro-4-((4-(((3S,4S)-4-hydroxypyrrolidin-3-yl)amino)butyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;   5-bromo-2-fluoro-4-((4-(((3R,4R)-4-hydroxypyrrolidin-3-yl)amino)butyl)amino)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;   4-((4-(3-(aminomethyl)-3-hydroxyazetidin-1-yl)butyl)amino)-5-bromo-2-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;   4-[(4-{[(1R)-2-amino-1-(hydroxymethyl)ethyl]amino}butyl)amino]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; or   5-chloro-2-fluoro-4-[(4-{[(4-hydroxy-4-methylpyrrolidin-2-yl)methyl]amino}butyl)-amino]-N-1,3-thiazol-2-ylbenzenesulfonamide.   
     
     
         14 ) A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any thereof. 
       
     
     
         15 ) A composition comprising at least one compound of any of  claims 1  to  14 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         16 ) A pharmaceutical composition of  claim 15  comprising additionally an effective amount of at least one other pharmaceutically active ingredient which is: (i) an opioid agonist or antagonist; (ii) a calcium channel antagonist; (iii) an NMDA receptor agonist or antagonist; (iv) a COX-2 selective inhibitor; (v) an NSAID (non-steroidal anti-inflammatory drug); or (vi) paracetamol (APAP, acetaminophen), and a pharmaceutically acceptable carrier. 
     
     
         17 ) A method of treating a pain disorder, or cough, or acute itch or chronic itch disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 15  or  claim 16 . 
     
     
         18 ) The composition of either  claim 15  or  claim 16  that provides an amount of said compound of any of  claims 1  to  14 , or a pharmaceutically acceptable salt thereof, which is sufficient to provide a therapeutic response in a subject in need of therapy for a pain disorder, cough, or acute itch or chronic itch disorder. 
     
     
         19 ) The method of  claim 17  wherein said disorder is an acute pain, inflammatory pain or neuropathic pain disorder. 
     
     
         20 ) A compound, or pharmaceutically acceptable salt thereof, according to any of  claim 1  to  14  for use in therapy. 
     
     
         21 ) A compound, or pharmaceutically acceptable salt thereof according to any of  claims 1  to  14  for treating a pain disorder.