Bumetanide analgos, compositions, and methods of use

Abstract

The present invention provides bumetanide analogs and compositions comprising such analogs. The present invention also provides pharmaceutical compositions containing these bumetanide analogs and methods for their use. These analogs are believed useful for the treatment and/or prophylaxis of conditions that involve the Na + K + Cl − co-transporter or GABA A receptor.

1 - 107 . (canceled) 
     
     
         108 . A compound of formula X: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y is sulfur; 
         Z is nitrogen; 
         each of R 8  and R 9  independently is hydrogen, alkyl, alkenyl, alkylcyano, alkylhalo, alkaryl, alkylheteroaryl, alkylheterocycloalkyl, alkylaminoalkyl, or alkylaminodialkyl; 
         or 
         R 8  and R 9  together with the atom to which they are attached, form a heterocycloalkyl group; and 
         R 10  is hydrogen or alkyl. 
       
     
     
         109 - 191 . (canceled) 
     
     
         192 . The compound of  claim 108 , wherein R8 and R9 are the same. 
     
     
         193 . The compound of  claim 108 , wherein each of R8 and R9 are alkyl. 
     
     
         194 . The compound of  claim 193 , wherein each of R8 and R9 are ethyl. 
     
     
         195 . The compound of  claim 108 , wherein each of R8 and R9 are alkaryl. 
     
     
         196 . The compound of  claim 195 , wherein each of R8 and R9 are benzyl. 
     
     
         197 . The compound of  claim 108 , wherein R 8  and R 9  together with the atom to which they are attached, form a heterocycloalkyl group. 
     
     
         198 . A compound bumetanide diethylthioamide, or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         199 . A compound bumetanide dibenzylthioamide, or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         200 . A pharmaceutical composition comprising a compound of  claim 108  and one or more pharmaceutically acceptable carrier or excipient. 
     
     
         201 . A pharmaceutical composition comprising a compound of  claim 198  and one or more pharmaceutically acceptable carrier or excipient. 
     
     
         202 . A pharmaceutical composition comprising a compound of  claim 199  and one or more pharmaceutically acceptable carrier or excipient. 
     
     
         203 . A method of reducing seizure activity in subject in need thereof comprising administering an effective amount of a compound of  claim 108 . 
     
     
         204 . A method of reducing seizure activity in subject in need thereof comprising administering an effective amount of a compound of  claim 198 . 
     
     
         205 . A method of reducing seizure activity in subject in need thereof comprising administering an effective amount of a compound of  claim 199 . 
     
     
         206 . A method of treating idiopathic epilepsy, treating symptomatic epilepsy, treating cryptogenic epilepsy, treating status epilepticus, treating seizure disorders, reducing the rate of seizure occurrence, or reducing the severity of seizures in subject in need thereof comprising administering an effective amount of a compound of  claim 108 . 
     
     
         207 . A method of treating idiopathic epilepsy, treating symptomatic epilepsy, treating cryptogenic epilepsy, treating status epilepticus, treating seizure disorders, reducing the rate of seizure occurrence, or reducing the severity of seizures in subject in need thereof comprising administering an effective amount of a compound of  claim 198 . 
     
     
         208 . A method of treating idiopathic epilepsy, treating symptomatic epilepsy, treating cryptogenic epilepsy, treating status epilepticus, treating seizure disorders, reducing the rate of seizure occurrence, or reducing the severity of seizures in subject in need thereof comprising administering an effective amount of a compound of  claim 199 .