Novel Compounds For Treatment of Cardiac Arrhythmia and Methods of Use

Abstract

The subject invention provides novel compounds for treatment of cardiac arrhythmia and methods of use.

1 .- 15 . (canceled) 
     
     
         16 . A method of treating cardiac arrhythmia comprising administering to a patient suffering from cardiac arrhythmia an effective amount of a composition comprising a compound of structural Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is H or C 1 -C 10  alkyl; 
 R 2  is H or optionally substituted C 1 -C 10  alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl; 
 n═O to 4; 
 p=0 or 1; 
 R 3  and R 4  are, independently, H or C 1 -C 4  alkyl; 
 
       and a pharmaceutically acceptable carrier, diluent or excipient; 
       and wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         17 . A method of treating cardiac arrhythmia according to  claim 16  wherein
 R 1  is H or ethyl;   R 2  is (S)-2-butyl, (R)-2-butyl, (S)-3-methyl-2-butyl or (R)-3-methyl-2-butyl;   n=0 or 1;   p=0; and   R 3  and R 4  are, independently, H or methyl.   
     
     
         18 . The method according to  claim 17  wherein R 1  is ethyl. 
     
     
         19 . The method according to  claim 17  wherein n is 1. 
     
     
         20 . The method according to  claim 17  wherein R 1  is ethyl and n is 1. 
     
     
         21 . The method according to  claim 16  wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method according to  claim 16  wherein the compound is selected from: 
       a) (S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       b) {3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid; 
       c) (S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       d) {3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid; 
       e) (R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       f) (R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid sec-butyl ester; 
       g) (S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; 
       h) (R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; 
       i) (S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; and 
       j) (R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodobenzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester. 
     
     
         23 . A method of treating cardiac arrhythmias comprising administering to a patient experiencing a cardiac arrhythmia an effective amount of a pharmaceutically acceptable salt of a compound of structural Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H or C 1 -C 10  alkyl; 
 R 2  is H or optionally substituted C 1 -C 10  alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl; 
 n=0 to 4; 
 p=0 or 1; 
 R 3  and R 4  are, independently, H or C 1 -C 4  alkyl, 
 
       and wherein the salt is selected from hydrochloride, hydrobromide, p-toluenesulfonate, phosphate, sulfate, perchlorate, acetate, trifluororacetate, propionate, citrate, malonate, succinate, lactate, oxalate, (L)-tartrate, (D)-tartrate, meso-tartrate, benzoate, alkali metal, morpholine, piperidine, dimethylamine, and diethylamine salts. 
     
     
         24 . A method of treating cardiac arrhythmias according to  claim 23 , wherein R 1  is H or ethyl;
 R 2  is (S)-2-butyl, (R)-2-butyl, (S)-3-methyl-2-butyl or (R)-3-methyl-2-butyl;   n=0 or 1;   p=0; and   R 3  and R 4  are, independently, H or methyl.   
     
     
         25 . A method of treating cardiac arrhythmias according to  claim 24 , wherein R 1  is ethyl. 
     
     
         26 . A method of treating cardiac arrhythmias according to  claim 24 , wherein n is 1. 
     
     
         27 . A method of treating cardiac arrhythmias according to  claim 24 , wherein R 1  is ethyl and n is 1. 
     
     
         28 . A method of treating cardiac arrhythmias according to  claim 23 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         29 . A method of treating cardiac arrhythmias according to  claim 23 , wherein the compound is selected from: 
       a) (S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       b) {3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid; 
       c) (S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       d) {3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid; 
       e) (R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       f) (R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid sec-butyl ester; 
       g) (S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; 
       h) (R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; 
       i) (S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; and 
       j) (R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodobenzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester. 
     
     
         30 . The method according to  claim 23  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         31 . The method according to  claim 24  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         32 . The method according to  claim 25  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         33 . The method according to  claim 26  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         34 . The method according to  claim 27  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or reentrant tachyarrhythmias of accessory pathways. 
     
     
         35 . The method according to  claim 28  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         36 . The method according to  claim 29  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         37 . A method of treating cardiac arrhythmias comprising administering to a patient experiencing a cardiac arrhythmia an effective amount of a composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of structural Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is E or C 1 -C 10  alkyl; 
 R 2  is H or optionally substituted C 1 -C 10  alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl; 
 n=0 to 4; 
 p=0 or 1; 
 R 3  and R 4  are, independently, H or C 1 -C 4  alkyl; 
 
       and wherein a compound contains less than 10% impurities on a weight basis. 
     
     
         38 . A method of treating cardiac arrhythmias according to  claim 37  wherein
 R 1  is H or ethyl;   R 2  is (S)-2-butyl, (R)-2-butyl, (S)-3-methyl-2-butyl or (R)-3-methyl-2-butyl;   n=0 or 1;   p=0; and   R 3  and R 4  are, independently, H or methyl.   
     
     
         39 . A method of treating cardiac arrhythmias according to  claim 38  wherein R 1  is ethyl. 
     
     
         40 . A method of treating cardiac arrhythmias according to  claim 38  wherein n is 1. 
     
     
         41 . A method of treating cardiac arrhythmias according to  claim 38  wherein R 1  is ethyl and n is 1. 
     
     
         42 . A method of treating cardiac arrhythmias according to  claim 37  wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         43 . A method of treating cardiac arrhythmias according to  claim 37  wherein the compound is selected from: 
       a) (S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       b) {3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid; 
       c) (S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       d) {3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid; 
       e) (R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid sec-butyl ester; 
       f) (R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid sec-butyl ester; 
       g) (S)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; 
       h) (R)-{3-[4-(2-Ethylamino-ethoxy)-3,5-diiodo-benzoyl]-benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; 
       i) (S)-{3-[4-(2-Amino-ethoxy)-3,5-diiodo-benzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; and 
       j) (R)-{3-[4-(2-Amino-ethoxy)-3,5-diiodobenzoyl]benzofuran-2-yl}-acetic acid 1,2-dimethyl-propyl ester; and wherein the compound contains less than 10% impurities. 
     
     
         44 . The method according to  claim 37  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         45 . The method according to  claim 38  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or reentrant tachyarrhythmias of accessory pathways. 
     
     
         46 . The method according to  claim 39  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         47 . The method according to  claim 40  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         48 . The method according to  claim 41  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         49 . The method according to  claim 42  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways. 
     
     
         50 . The method according to  claim 43  wherein the cardiac arrhythmia is selected from atrial fibrillation, flutter, paroxysmal supraventricular tachycardia, ventricular premature beats (VPB), sustained ventricular tachycardia (VT), non-sustained ventricular tachycardia (VT), ventricular fibrillation (VF), atrial narrow QRS tachycardia, intra-AV node narrow QRS tachycardia, para-AV node narrow QRS tachycardia, accessory pathway narrow QRS tachycardia, ventricular arrhythmias in cardiomyopathy, or re-entrant tachyarrhythmias of accessory pathways.