Pyrazinoisoquinoline compounds

Abstract

This invention relates to novel compounds that are pyrazinoisoquinoline derivatives, and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel pyrazinoisoquinoline derivatives that are derivatives of praziquantel. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering an antihelminthic agent, such as praziquantel.

1 - 12 . (canceled) 
     
     
         13 . A compound which is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein the isotopic enrichment for each designated deuterium atom is at least 90%. 
       
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 13  or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         15 . A method of disrupting cell permeability to calcium ions in a parasitic cell, comprising contacting a cell with a compound of  claim 13 , wherein the isotopic enrichment for each designated deuterium atom is at least 90%. 
     
     
         16 . A method of treating a disease or condition selected from  schistosoma  infections, infection due to  Clonorchis sinensis  or  Opisthorchis viverrini,  cysticercosis, neurocysticercosis, and malaria in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Z 1  is hydrogen or fluorine; 
 Z 2  is hydrogen, deuterium, or fluorine; 
 Z 3  is deuterium; 
 Z 4  is fluorine; 
 m is 2, 4, 6, 8, or 10; 
 n is 0 or 2; and wherein 
 
         the isotopic enrichment for each designated deuterium atom is at least is 90%; 
         provided that the sum of m and n does not exceed 10. 
       
     
     
         17 . The method of  claim 16  wherein 2, 4, 6, 8 or 10 geminal Z 3  are present. 
     
     
         18 . The method of  claim 17 , wherein Z 2  is hydrogen. 
     
     
         19 . The method of  claim 16 , wherein 2 geminal Z 4  are present. 
     
     
         20 . The method of  claim 19 , wherein Z 2  is hydrogen. 
     
     
         21 . The method of  claim 16 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The method of  claim 16 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . A method of treating a  schistosoma  infection in a patient in need thereof comprising the step of administering to said patient an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Z 1  is hydrogen or fluorine; 
 Z 2  is hydrogen, deuterium, or fluorine; 
 Z 3  is deuterium; 
 Z 4  is fluorine; 
 m is 2, 4, 6, 8, or 10; 
 n is 0 or 2; and wherein 
 
         the isotopic enrichment for each designated deuterium atom is at least is 90%; 
         provided that the sum of m and n does not exceed 10. 
       
     
     
         24 . The method of  claim 23 , wherein 2, 4, 6, 8 or 10 geminal Z 3  are present. 
     
     
         25 . The method of  claim 24 , wherein Z 2  is hydrogen. 
     
     
         26 . The method of  claim 23 , wherein 2 geminal Z 4  are present. 
     
     
         27 . The method of  claim 26 , wherein Z 2  is hydrogen. 
     
     
         28 . The method of  claim 23 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . The method of  claim 23 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The compound of  claim 13 , wherein the isotopic enrichment for each designated deuterium atom is at least 95%. 
     
     
         31 . The method of  claim 16 , wherein, for the compound of Formula I, the isotopic enrichment for each designated deuterium atom is at least 95%. 
     
     
         32 . The method of  claim 23 , wherein, for the compound of Formula I, the isotopic enrichment for each designated deuterium atom is at least 95%.