Deuterium-enriched atorvastatin

Abstract

The present application describes deuterium-enriched atorvastatin, pharmaceutically acceptable salt forms thereof, and methods of treating using the same.

1 . A deuterium-enriched compound of formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 35  are independently selected from H and D; and the abundance of deuterium in R 1 -R 35  is at least 3%, provided that if R 22-26  are all D or R 27-31  are all D, then at least one other R is D. 
     
     
         2 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 1 -R 35  is selected from at least 3%, at least 9%, at least 14%, at least 20%, at least 26%, at least 31%, at least 37%, at least 43%, at least 49%, at least 54%, at least 60%, at least 66%, at least 71%, at least 77%, at least 83%, at least 89%, at least 94%, and 100%. 
     
     
         3 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 5 -R 6  is selected from at least 50% and 100%. 
     
     
         4 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 22 -R 35  is selected from at least 7%, at least 14%, at least 21%, at least 29%, at least 36%, at least 43%, at least 50%, at least 57%, at least 64%, at least 71%, at least 79%, at least 86%, at least 93%, and 100%. 
     
     
         5 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 7 -R 35  is selected from at least 3%, at least 7%, at least 14%, at least 21%, at least 28%, at least 34%, at least 41%, at least 48%, at least 55%, at least 62%, at least 69%, at least 76%, at least 83%, at least 90%, at least 97%, and 100%. 
     
     
         6 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 5 -R 6  and R 22 -R 35  is selected from at least 6%, at least 13%, at least 19%, at least 25%, at least 31%, at least 38%, at least 44%, at least 50%, at least 56%, at least 63%, at least 69%, at least 75%, at least 81%, at least 88%, at least 94%, and 100%. 
     
     
         7 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 5 -R 35  is selected from at least 3%, at least 6%, at least 13%, at least 19%, at least 26%, at least 32%, at least 39%, at least 45%, at least 52%, at least 58%, at least 65%, at least 71%, at least 77%, at least 84%, at least 90%, at least 97%, and 100%. 
     
     
         8 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 13 -R 14  is selected from at least 50% and 100%. 
     
     
         9 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 5 -R 6  and R 8 -R 9  is selected from at least 25%, at least 50%, at least 75%, and 100%. 
     
     
         10 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 32 -R 35  is selected from at least 25%, at least 50%, at least 75%, and 100%. 
     
     
         11 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 22 -R 26  is selected from at least 20%, at least 40%, at least 60%, at least 80%, and 100%. 
     
     
         12 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 15 -R 21  is selected from at least 7%, at least 14%, at least 29%, at least 43%, at least 57%, at least 71%, at least 86%, and 100%. 
     
     
         13 . A deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium in R 5 -R 14  is selected from at least 10%, at least 20%, at least 30%, at least 40%, and 50%, at least 60%, at least 70%, at least 80%, at least 90%, and 100%. 
     
     
         14 . A deuterium-enriched compound of  claim 1 , wherein the compound is selected from compounds 1-17 of Table 1. 
     
     
         15 . A deuterium-enriched compound of  claim 1 , wherein the compound is selected from compounds 18-34 of Table 2. 
     
     
         16 . An isolated deuterium-enriched compound of formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 35  are independently selected from H and D; and the abundance of deuterium in R 1 -R 35  is at least 3%, R 22-26  are all D or R 27-31  are all D, then at least one other R is D. 
     
     
         17 . A mixture of deuterium-enriched compounds of formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 35  are independently selected from H and D; and the abundance of deuterium in R 1 -R 35  is at least 3%, provided that if R 22-26  are all D or R 27-31  are all D, then at least one other R is D. 
     
     
         18 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt form thereof. 
     
     
         19 . A method for treating a disease selected from dyslipidaemia and/or combined hyperlipidemia comprising: administering, to a patient in need thereof, a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt form thereof.