Treatment of heart rhythm disturbances with N6-substituted-5'-(N-substituted) carboxamidoadenosines

Abstract

The present invention discloses a method for treating heart rhythm disturbances in a mammal in need thereof by the administration of N 6 -substituted-5′-(N-substituted)carboxamidoadenosines. More particularly, the invention is directed to a method for treatment of heart rhythm disturbances in a mammal that would benefit from the induction of negative dromotropic and/or negative chronotropic actions, comprising the administration to said mammal an effective amount of a compound of the Formula: or a pharmaceutically acceptable salt or ester thereof; wherein R 1 is C 3-7 secondary alkyl, or C 3-8 cycloalkyl; and R 2 is C 1-4 alkyl or C 3-5 cycloalkyl The invention is also directed to novel dosage forms comprising said compounds.

1 - 24 . (Cancelled)  
     
     
         25 . A pharmaceutical composition in a unit dosage form comprising one or more active compounds of the Formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof; wherein 
 R 1  is C 3-7  secondary alkyl, C 3-8  cycloalkyl, or C 7  bicycloalkyl; and  
 R 2  is C 1-4  alkyl, C 1-4  hydroxyalkyl or C 3-5  cycloalkyl,  
 in an amount effective to treat or prevent a heart rhythm disturbance in a human; and a pharmaceutically acceptable carrier:  
 
     
     
         26 . The composition of  claim 25 , wherein: 
 R 1  is 3-pentyl, cyclopentyl or norbomyl; and    R 2  is methyl, ethyl. isopropyl or cyclopropyl.    
     
     
         27 . The composition of  claim 25 , wherein said composition is in a parenteral dosage form.  
     
     
         28 . The composition of  claim 27 , wherein the concentration of said one or more active compounds is from about 0.1 μg/mL to about 500 μg/mL.  
     
     
         29 . The composition of  claim 28 , wherein the concentration of said one or more active compounds is from about 1 μg/mL to about 250 μg/mL.  
     
     
         30 . The composition of  claim 29 , wherein the concentration of said one or more active compounds is from about 5 μg/mL to about 50 μg/mL.  
     
     
         31 . The composition of  claim 27 , wherein said composition is in an intravenous dosage form.  
     
     
         32 . The composition of  claim 25 , wherein said composition is in an oral dosage form.  
     
     
         33 . The composition of  claim 25 , wherein R 2  is ethyl.  
     
     
         34 . The composition of  claim 25 , wherein R 2  is cyclopropyl.  
     
     
         35 . The composition of  claim 25 , wherein R 1  is 3-pentyl.  
     
     
         36 . The composition of  claim 25 , wherein R 1  is cyclopentyl.  
     
     
         37 . The composition of  claim 36 , wherein R 2  is ethyl.  
     
     
         38 . The composition of  claim 36 , wherein R 2  is cyclopropyl.  
     
     
         39 . The composition of  claim 31 , wherein said one or more active compounds are selected from the group consisting of: 
 N 6 -cyclopentyl-5′-(N-ethyl)carboxamidoadeno sine,    N 6 -cyclopentyl-5′-(N-cyclopropyl)carboxamidoadenosine,    N 6 -(3-pentyl)-5′-(N-ethyl)carboxamidoadenosine,    N 6 -cyclopentyl-5′-(N-methyl)carboxamidoadenosine, and    N 6 -cyclopentyl-5′-(N-t-butyl)carboxamidoadenosine,    as well as pharmaceutically acceptable salts and esters thereof.    
     
     
         40 . The composition of  claim 31 , wherein said one or more active compounds is N 6 -(3-pentyl)-5′-(N-ethyl)carboxamidoadenosine.  
     
     
         41 . The composition of  claim 27 , wherein said one or more active compounds is N 6 -cyclopentyl-5′-(N-ethyl)carboxamidoadenosine.  
     
     
         42 . The composition of  claim 27 , wherein said one or more active compounds is N 6 -cyclopentyl-5′-(N-cyclopropyl)carboxamidoadenosine.  
     
     
         43 . The composition of  claim 32 , wherein said one or more active compounds is N 6 -cyclopentyl-5′-(N-ethyl)carboxamidoadenosine.  
     
     
         44 . The composition of  claim 32 , wherein said one or more active compounds is N 6 -cyclopentyl-5′-(N-cyclopropyl)carboxamidoadenosine.  
     
     
         45 . The composition of  claim 25 , wherein said heart rhythm disturbance is a supraventricular tachyarrhythmia.  
     
     
         46 . The composition of  claim 25 , wherein said heart rhythm disturbance is paroxsymal supraventricular tachycardia.  
     
     
         47 . The composition of  claim 25 , wherein said heart rhythm disturbance is atrial fibrillation.  
     
     
         48 . The composition of  claim 25 , wherein said composition is in a transdermal dosage form.  
     
     
         49 . The composition of  claim 25 , wherein said composition is in a buccal dosage form.  
     
     
         50 . The composition of  claim 25 , wherein said heart rhythm disturbance is one that would benefit from the induction of negative dromotropic action, negative chronotropic action, or a combination of such actions.  
     
     
         51 . The composition  claim 25 , which is an orally administrable form, and said amount is from about 1 to about 50 μg/kg of body weight.  
     
     
         52 . The composition of  claim 25 , which is an intravenously infusible form, and said amount is from about 0.1 to about 10 μg/kg/min.  
     
     
         53 . The composition of  claim 27 , wherein said dosage form is for intravenous infusion and said amount is from about 0.001 μg/kg to about 100 μg/kg.  
     
     
         54 . The composition of  claim 53 , wherein said amount is from about 0.005 μg/kg to about 1 μg/kg.  
     
     
         55 . The composition of  claim 53 , wherein said amount is from about 0.01 μg/kg to about 0.5 μg/kg.  
     
     
         56 . The composition of  claim 32 , wherein said amount is from about 0.001 μg/kg to about 100 μg/kg.  
     
     
         57 . The composition of  claim 56 , wherein said amount is from about 0.01 μg/kg to about 10 μg/kg.  
     
     
         58 . The composition of  claim 57 , wherein said amount is from about 0.01 μg/kg to about 8 μg/kg.  
     
     
         59 . The composition of  claim 32 , wherein said amount is from about 1 to about 50 μg/kg.  
     
     
         60 . The composition of  claim 59 , wherein said dose is administered up to four times a day.