Novel enantiomeric compounds for treatment of cardiac arrhythmias and methods of use

Abstract

The subject invention pertains to novel enantiomerically pure compounds, and compositions comprising the compounds, for the treatment of cardiac arrhythmias. The subject invention further concerns a method of making and purifying the compounds. The enantiomerically purified compounds, and compositions of these compounds, exhibit unexpectedly distinct and advantageous characteristics, such as a markedly superior ability to reduce or inhibit ventricular premature beats, as compared to racemic mixtures of the compounds.

1 . (canceled)  
     
     
         2 . A method for preparing compounds of the formula  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, wherein 
 X 1  and X 2  may be the same or different and are selected from the group consisting of iodine, fluorine, bromine, and chlorine;  
 m is from 0-10; and  
 R 2  and R 3  may be the same or different and are each selected from the group consisting of C 1-20  alkyl, C 2-20  alkenyl, aryl, C 1-20  alkyl-aryl, C 2-20  alkenyl-aryl, heteroaryl, C 1-20  alkyl-heteroaryl, C 2-20  alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C 1-20  alkyl-heterocycloalkyl, and C 1-20  alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, CN, NO 2 , and sO 2 ,  
 the method comprising  
 a) reacting methyl benzofuran-2-acetate with  
                     
 in the presence of a Lewis acid to generate a compound of the formula 6:  
                     
 b) reacting the compound of formula 6 with a Lewis acid and tetrabutylammonium iodide to form a compound of formula 7:  
                     
 c) halogenating the compound of formula 7 to generate a compound of formula 8:  
                     
 d) reacting the compound of formula 8 with an alcohol to form a compound of formula 9:  
                     
 e) converting the compound of formula 9 into the final product.  
 
     
     
         2 . A method according to  claim 1 , wherein X 1  and X 2  are both iodo.  
     
     
         3 . A method according to  claim 1 , wherein 
 R 2  and R 3  may be the same or different and are each selected from the group consisting of C 1-2  alkyl, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, phenyl, naphthyl, C 1-2  alkyl-phenyl, C 1-2  alkyl-naphthyl, vinyl-phenyl, 1-propenyl-phenyl, 1- and 2-butenyl-phenyl, 2-methyl-2-propenyl-phenyl, C 1-2  alkyl-naphthyl, vinyl-naphthyl, 1-propenyl-naphthyl, 1- and 2-butenyl-naphthyl, 2-methyl-2-propenyl-naphthyl, furanyl, thienyl, pyridyl, indolyl, quinolyl, C 1-2  alkyl-furanyl, C 1-2  alkyl-thienyl, C 1-2  alkyl-pyridyl, C 1-2  alkyl-indolyl, C 1-2  alkyl-quinolyl, (vinyl, 1-propenyl, 1- and 2-butenyl, or 2-methyl-2-propenyl)-furanyl, (vinyl, 1-propenyl, 1- and 2-butenyl, or 2-methyl-2-propenyl)-thienyl, (vinyl, 1-propenyl, 1- and 2-butenyl, or 2-methyl-2-propenyl)-pyridyl, (vinyl, 1-propenyl,  1 - and 2-butenyl, or 2-methyl-2-propenyl)-indolyl, (vinyl, 1-propenyl, 1- and 2-butenyl, or 2-methyl-2-propenyl)-quinolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, tetrahydronaphthyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, indolinyl, tetrahydroquinolinyl, C 1-2  alkyl-azetidinyl, C 1-2  alkyl-pyrrolidinyl, C 1-2  alkyl-tetrahydrofuranyl, C 1-2  alkyl-piperidinyl, C 1-2  alkyl-indolinyl, C 1-2  alkyl-tetrahydroquinolinyl, and C 1-2  alkyl-cyclopropyl, C 1-2  alkyl-cyclobutyl, C 1-2  alkyl-cyclopentyl, C 1-2  alkyl-cyclohexyl, C 1-2  alkyl-indanyl, C 1-2  alkyl-tetrahydronaphthyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, CN, NO 2 , and SO 2 .    
     
     
         4 . A method according to  claim 1 , wherein m is 1.  
     
     
         5 . A method according to  claim 1 , wherein 
 X 1  and X 2  are both iodo;    R 2  and R 3  are both methyl; and    m is 1.    
     
     
         6 . A method according to  claim 1 , wherein the Lewis acid used in step a) is tin (IV) chloride.  
     
     
         7 . A method according to  claim 1 , wherein the Lewis acid used in step b) is aluminum iodide.  
     
     
         8 . A method according to  claim 1 , wherein the halogenation of step c) is performed with potassium carbonate and iodine.  
     
     
         9 . A method according to  claim 1 , wherein the alcohol used in the conversion of compound 8 to compound 9 is (R)-3-methyl-2-butanol.  
     
     
         10 . A method according to  claim 1 , wherein the alcohol used in the conversion of compound 8 to compound 9 is (S)-3-methyl-2-butanol.  
     
     
         11 . A method according to  claim 1 , wherein the alcohol used in the conversion of compound 8 to compound 9 is (R)-2-butanol.  
     
     
         12 . A method according to  claim 1 , wherein the alcohol used in the conversion of compound 8 to compound 9 is (S)-2-butanol.  
     
     
         13 . A method according to  claim 1 , wherein the conversion of the compound of formula 8 to a compound of formula 9 is accomplished in the presence of diethylaminoethyl chloride, diethylaminoethyl chloride hydrochloride, or a mixture thereof.  
     
     
         14 . A method according to  claim 1 , wherein 
 the Lewis acid used in step a) is tin (IV) chloride;    the Lewis acid used in step b) is aluminum iodide;    the halogenation of step c) is performed with potassium carbonate and iodine; and    the conversion of the compound of formula 8 to a compound of formula 9 is accomplished in the presence of diethylaminoethyl chloride, diethylaminoethyl chloride hydrochloride, or a mixture thereof.    
     
     
         15 . A method according to  claim 5 , wherein 
 the Lewis acid used in step a) is tin (IV) chloride;    the Lewis acid used in step b) is aluminum iodide;    the halogenation of step c) is performed with potassium carbonate and iodine; and    the conversion of the compound of formula 8 to a compound of formula 9 is accomplished in the presence of diethylaminoethyl chloride, diethylaminoethyl chloride hydrochloride, or a mixture thereof.    
     
     
         16 . A method according to  claim 1 , wherein the product is prepared in at least about 90% enantiomeric excess.  
     
     
         17 . A method according to  claim 14 , wherein the product is prepared in at least about 90% enantiomeric excess.  
     
     
         18 . A method according to  claim 15 , wherein the product is prepared in at least about 90% enantiomeric excess.