Sulfonamides as potassium channel blockers

Abstract

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels. More particularly, the invention provides sulfonamides, and compositions and methods utilizing sulfonamides that are useful in the treatment of diseases by blocking potassium channels associated with the onset or recurrence of the indicated conditions. Exemplary diseases treatable with the compounds, compositions and methods of the invention include sickle cell disease and glaucoma.

1 - 8 . (canceled)  
     
     
         9 . A method of inhibiting potassium flux of a cell, said method comprising contacting said cell with an effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
         wherein 
 ring system Z is a member selected from the group consisting of substituted or unsubstituted C 5 -C 7  carbocycle, substituted or unsubstituted aryl, substituted and unsubstituted membered heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;  
 A is a member selected from —NHS(O) 2 —, —S(O) 2 NH—, —C(R 4 R 5 )S(O) n —, —S(O) n C(R 4 R 5 )—, —C(R 4 R 5 )NHS(O) n —, —S(O) n NHC(R 4 R 5 )—, —C( 4 R 5 )S(O) n NH—, and —HNS(O) n C(R 4 R 5 )— 
 wherein 
 n is selected from the integers from 0 to 2; and  
 
 R′ is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C 5 -C 7 )carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl,  
 
         in an amount effective to inhibit said flux.  
       
     
     
         10 . The method according to  claim 9 , wherein said compound has a structure according to  FIG. 1 .  
     
     
         11 . A method for reducing intraocular pressure in a subject in need thereof by decreasing potassium ion flow through intermediate conductance potassium channels in a cell, the method comprising the step of administering to the subject a compound having the formula:  
       
         
           
           
               
               
           
         
         wherein 
 ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted C 5 -C 7  carbocycle, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;  
 A is a member selected from —NHS(O) 2 —, —S(O) 2 NH—, —C(R 4 R 5 )S(O) n —, —S(O) n C(R 4 R 5 )—, —C(R 4 R 5 )NHS(O) n —, —S(O) n NHC(R 4 R 5 )—, —C(R 4 R 5 )S(O) n NH—, and —HNS(O) n C(R 4 R 5 )— 
 wherein 
 n is selected from the integers from 0 to 2; and  
 
 R′ is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C 5 -C 7 )carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl,  
 
         in an amount sufficient to decrease potassium ion flow through intermediate conductance, calcium activated potassium channels, thereby reducing intraocular pressure.  
       
     
     
         12 . The method according to  claim 11 , wherein said compound has a structure according to  FIG. 1 .  
     
     
         13 . The method of  claim 11 , wherein the subject has glaucoma characterized by increased intraocular pressure.  
     
     
         14 . The method of  claim 11  wherein the method prevents glaucoma characterized by increased intraocular pressure.  
     
     
         15 . The method of  claim 14 , wherein additionally one or more agents selected from the group consisting of miotics, beta blockers, alpha-2 agonists, carbonic anhydrase inhibitors, beta adrenergic blockers, prostaglandins and docosanoid are administered to said subject.  
     
     
         16 . A method of preventing or retarding dehydration of erythrocytes comprising contacting said erythrocyte with a compound having the formula:  
       
         
           
           
               
               
           
         
         wherein 
 ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;  
 A is a member selected from —NHS(O) 2 —, —S(O) 2 NH—, —C(R 4 R 5 )S(O) n —, −S(O) n C(R 4 R 5 )—, —C(R 4 R 5 )NHS(O) n —, —S(O) n NHC(R 4 R 5 )—, —C( 4 R 5 )S(O) n NH—, and —HNS(O) n C(R 4 R 5 )— 
 wherein 
 n is selected from the integers from 0 to 2; and  
 
 R 1  is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C 5 -C 7 )carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl, in an amount effective to prevent or retard said dehydration.  
 
       
     
     
         17 . The method according to  claim 16 , wherein said compound has a structure according to  FIG. 1 .  
     
     
         18 . A method for treating or preventing sickle cell disease comprising administering to a subject suffering sickle cell disease a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
         wherein 
 ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted C 5 -C 7  carbocycle, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;  
 A is a member selected from —NHS(O) 2 —, —S(O) 2 NH—, —C(R 4 R 5 )S(O) n —, —S(O) n C(R 4 R 5 )—, —C(R 4 R 5 )NHS(O) n —, —S(O) n NHC(R 4 R 5 )—, —C(R 4 R 5 )S(O) n NH—, and —HNS(O) n C( 4 R 5 )— 
 wherein 
 n is selected from the integers from 0 to 2; and  
 
 R 1  is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C 5 -C 7 )carbocycle, and substituted or unsubstituted 5-7-membered heterocycloalkyl.  
 
       
     
     
         19 . The method according to  claim 18 , wherein said compound has a structure according to  FIG. 1 .  
     
     
         20 . A method of treating or preventing a disease state which is a member selected from inflammation and abnormal cell proliferation in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound having the formula:  
       
         
           
           
               
               
           
         
         wherein 
 ring system Z is a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted C 5 -C 7  carbocycle, substituted and unsubstituted heteroaryl and substituted and unsubstituted 5-7-membered heterocycloalkyl;  
 A is a member selected from —NHS(O) 2 —, —S(O) 2 NH—, —C(R 4 R 5 )S(O) n —, —S(O) n C( 4 R 5 )—, —C(R 4 R 5 )NHS(O) n —, —S(O) n NHC( 4 R 5 )—, —C(R 4 R 5 )S(O) n NH—, and —HNS(O) n C(R 4 R 5 )— 
 wherein 
 n is selected from the integers from 0 to 2; and  
 
 R 1  is a member selected from the group of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (C 5 -C 7 )carbocycle, and substituted or unsubstituted (C 5 -C 7 )heterocycloalkyl.  
 
       
     
     
         21 . The method according to  claim 20 , wherein said inflammation is respiratory inflammation.  
     
     
         22 . The method according to  claim 21 , wherein said respiratory inflammation is a member selected from acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma.