NOVEL ANTI-ARRHYTHMIC AND HEART FAILURE DRUGS THAT TARGET THE LEAK IN THE RYANODINE RECEPTOR (RyR2)

Abstract

The present invention provides novel 1,4-benzothiazepine intermediates and derivatives, methods for synthesizing same, and methods for assaying same. The present invention also provides methods for using these novel compounds to limit or prevent a decrease in the level of RyR2-bound FKBP12.6 in a subject; to prevent exercise-induced sudden cardiac death in a subject; and to treat or prevent heart failure, atrial fibrillation, or exercise-induced cardiac arrhythmia in a subject. The present invention further provides methods for identifying an agent that enhances binding of RyR2 and FKBP12.6, and agents identified by these methods. Additionally, the present invention provides methods for identifying agents for use in treating or preventing heart failure, atrial fibrillation, or exercise-induced cardiac arrhythmia, and in preventing exercise-induced sudden cardiac death. Also provided are agents identified by such methods.

1 . A compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkenyl, —(CH 2 ) n NR′ 2 , or —(CH 2 ) n SR′, and n=0, 1, 2, or 3, and R 1 =alkyl or cycloalkyl. 
   
   
       2 . A compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkyl, —(CH 2 ) n NR′ 2 , or —(CH 2 ) n SR′, and n=0, 1, 2, or 3, and R′=alkyl or cycloalkyl. 
   
   
       3 . A compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=CO(CH 2 ) n XR′ 2 , SO 2 (CH 2 ) n XR′ 2 , or SO 2 NH(CH 2 ) n XR′ 2 , and X=N or S, and n 1, 2, or 3, and R′=alkyl or cycloalkyl; and wherein m=1 or 2. 
   
   
       4 . A compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkyl, —(CH 2 ) n NR′ 2 , —(CH 2 ) n SR′, and n=0, 1, 2, or 3, and R′=alkyl or cycloalkyl; and wherein X=NH or 0. 
   
   
       5 . A compound selected from the group consisting of S7, S-20, S-25, S-27, and S36. 
   
   
       6 . A method for the synthesis of a compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkenyl, alkyl, —(CH 2 ) n NR′ 2 , or —(CH 2 ) n SR′, and n=0, 1, 2, or 3, and R′=alkyl or cycloalkyl, comprising the steps of:
 (a) treating a compound having formula: 
 
     
       
         
         
             
             
         
       
     
     with a sulfonyl chloride compound and a base, to form a compound having the formula: 
     
       
         
         
             
             
         
       
       (b) optionally, treating the compound formed in step (a) with a primary or secondary amine, to form a compound having formula: 
     
     
       
         
         
             
             
         
       
     
     wherein R is as defined above. 
   
   
       7 . The method of  claim 6 , wherein the sulfonyl chloride compound in step (a) is selected from the group consisting of alkylsulfonyl chloride and arylsulfonyl chloride. 
   
   
       8 . The method of  claim 7 , wherein the base in step (a) is Et 3 N. 
   
   
       9 . The method of  claim 6 , wherein the primary or secondary amine in step (b) is 4-benzylpiperidine. 
   
   
       10 . The method of  claim 6 , further comprising the step of oxidizing the compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkenyl, alkyl, —(CH 2 ) n NR′ 2  or —(CH 2 ) n SR′, and n=0, 1, 2, or 3, and R′=alkyl or cycloalkyl, with an oxidizing agent, to form a compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R is as defined above, and wherein m=1 or 2. 
   
   
       11 . The method of  claim 10 , wherein the oxidizing agent is hydrogen peroxide. 
   
   
       12 . A method for the synthesis of a compound of having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkyl, —(CH 2 ) n NR′ 2 , or —(CH 2 ) n SR′ and n=0, 1, 2, or 3, and R′=alkyl or cycloalkyl, comprising the step of treating a compound having formula: 
     
       
         
         
             
             
         
       
     
     with a sulfuryl chloride and a primary or secondary amine, in the presence of a base, to form a compound having the formula: 
     
       
         
         
             
             
         
       
     
     wherein R is as defined above. 
   
   
       13 . The method of  claim 12 , wherein the base is Et 3 N. 
   
   
       14 . The method of  claim 12 , wherein the primary or secondary amine is 1-piperonylpiperazine. 
   
   
       15 . The method of  claim 12 , further comprising the step of oxidizing the compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkyl, —(CH 2 ) n NR′ 2 , or —(CH 2 ) n SR′, and n=0, 1, 2, or 3, and R′=alkyl or cycloalkyl, to form a compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R is as defined above, and wherein m=1 or 2. 
   
   
       16 . A method for the synthesis of a compound of having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=CO(CH 2 ) n XR′ 2 , SO 2 (CH 2 ) n XR′ 2 , or SO 2 NH(CH 2 ) n XR′ 2 , and X=N or S, and n=1, 2, or 3, and R′=alkyl or cycloalkyl; and wherein m=1 or 2, comprising the step of treating a compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R is as defined above, with an oxidizing agent, to form a compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R and m are as defined above. 
   
   
       17 . The method of  claim 16 , wherein the oxidizing agent is hydrogen peroxide. 
   
   
       18 . A method for the synthesis of a compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R=aryl, alkyl, —(CH 2 ) n NR′ 2 , or —(CH 2 ) n SR′, and n=0, 1, 2, or 3, and R′=alkyl or cycloalkyl; and wherein X=NH or O, comprising the step of treating a compound having formula: 
     
       
         
         
             
             
         
       
     
     with a carbonyl chloride compound, in the presence of a base, and with a primary or secondary amine or an alcohol, to form a compound having the formula: 
     
       
         
         
             
             
         
       
     
     wherein R and X are as defined above. 
   
   
       19 . The method of  claim 18 , wherein the carbonyl chloride compound is triphosgene. 
   
   
       20 . The method of  claim 18 , wherein the base is Et 3 N. 
   
   
       21 . The method of  claim 18 , wherein the primary or secondary amine is 4-benzylpiperidine. 
   
   
       22 . A method for the synthesis of 2,3,4,5-tetrahydro-1,4-benzothiazepine compounds having formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 =OR′, SR′, NR′, alkyl, or halide, at position 2, 3, 4, or 5 on the phenyl ring, and R′=alkyl, aryl, or H; wherein R 2 =H, alkyl, or aryl; and wherein R 3 =H, alkyl, or aryl, comprising the steps of:
 (a) treating a compound having formula: 
 
     
       
         
         
             
             
         
       
     
     wherein R 1  is as defined above, with a reducing agent, in the presence of an optional catalyst, to form a compound having formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is as defined above;
 (b) treating the compound formed in step (a) with a diazotizing agent and a disulfide, to form a compound having formula: 
 
     
       
         
         
             
             
         
       
     
     wherein R1 is as defined above;
 (c) treating the compound formed in step (b) with an activating agent and chloroethylamine, to form a compound having formula: 
 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , and R 3  are as defined above;
 (d) treating the compound formed in step (c) with a reducing agent and a base to form a compound having formula: 
 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , and R 3  are as defined above; and
 (e) treating the compound formed in step (d) with a reducing agent, to form a compound having formula: 
 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , and R 3  are as defined above.