Deuterated n-ethyl-n-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, salts and uses thereof

Abstract

The subject invention provides deuterated N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, its salts and uses.

What is claimed is: 
     
         1 . A method of treating a human subject afflicted with an autoimmune disease comprising administering to the human subject 0.2 mg-2.0 mg per day of a deuterium-enriched compound having the structure: 
       
         
           
           
               
               
           
         
         wherein each of R1-R10 is independently H or D, and at least one of R1-R10 is D, or a pharmaceutically acceptable salt thereof, effective to treat the subject. 
       
     
     
         2 . The method of  claim 1 , wherein the deuterium-enriched compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 2 , wherein the deuterium-enriched compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of  claim 3 , wherein the deuterium-enriched compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the autoimmune disease is Multiple Sclerosis, Systemic Lupus Erythematosus, lupus nephritis, lupus arthritis, Crohn's Disease or Rheumatoid arthritis. 
     
     
         6 . The method of  claim 5 , wherein the autoimmune disease is Multiple Sclerosis. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein administration of the deuterium-enriched compound is more effective in treating the autoimmune disease than administration of an equivalent molar amount of non-deuterium-enriched laquinimod. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the level of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide formed in the human subject upon administration of the deuterium-enriched compound is reduced, compared to the level of 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide formed when an equivalent molar amount of non-deuterium-enriched laquinimod is administered to the human subject. 
     
     
         9 . The method of  claim 8 , wherein the level of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide is reduced by at least 50%. 
     
     
         10 . The method of  claim 9 , wherein the level of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide is reduced by at least 90%. 
     
     
         11 . A method of inducing reduced formation of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide in a human subject comprising administering to the human subject a therapeutically effective amount of a deuterium-enriched compound having the structure: 
       
         
           
           
               
               
           
         
         wherein each of R1-R10 is independently H or D, and at least one of R1-R10 is D, or a pharmaceutically acceptable salt thereof, 
         wherein the reduced formation is relative to formation of 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide upon administration of an equivalent molar amount of non-deuterium-enriched laquinimod. 
       
     
     
         12 . The method of  claim 11 , wherein the level of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide is reduced by at least 50%, compared to the level of 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide formed when an equivalent molar amount of non-deuterium-enriched laquinimod is administered to the human subject. 
     
     
         13 . The method of  claim 12 , wherein the level of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide is reduced by at least 90%. 
     
     
         14 . A mixture of at least two deuterium-enriched compounds, each compound having the structure: 
       
         
           
           
               
               
           
         
         wherein each of R1-R10 is independently H or D, and each of the at least two deuterium-enriched compounds contains D at a different R1-R10, 
       
       or pharmaceutically acceptable salts thereof. 
     
     
         15 . The mixture of  claim 14 , wherein one of the at least two deuterium-enriched compounds has the structure: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         16 . The mixture of  claim 14 , wherein one of the at least two deuterium-enriched compounds has the structure: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         17 . The mixture of  claim 14 , wherein one of the at least two deuterium-enriched compounds has the structure: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         18 . A pharmaceutical composition comprising the mixture of any one of  claims 14 - 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         19 . A pharmaceutical composition comprising a mixture of:
 a) deuterium-enriched laquinimod or a pharmaceutically acceptable salt thereof;   b) at least one pharmaceutically acceptable carrier; and   c) a compound having the structure:   
       
         
           
           
               
               
           
         
          present in an amount which is less than 0.1% based on the combined weight of the compound and deuterium-enriched laquinimod. 
       
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the compound is present in an amount less than 3 ppm based on the combined weight of the compound and deuterium-enriched laquinimod. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the compound is present in an amount less than 2 ppm based on the combined weight of the compound and deuterium-enriched laquinimod. 
     
     
         22 . The pharmaceutical composition of any one of  claims 19 - 21 , wherein the deuterium-enriched laquinimod has the structure: 
       
         
           
           
               
               
           
         
       
       wherein each of R1-R10 is independently H or D, and at least one of R1-R10 is D, 
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein in the deuterium-enriched laquinimod, each of R1-R5 is D and each of R6-R10 is H, or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein in the deuterium-enriched laquinimod, each of R1-R5 is H and each of R6-R10 is D, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein in the deuterium-enriched laquinimod, each of R1-R10 is D, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The pharmaceutical composition of any of  claims 18 - 25  in the form of a tablet. 
     
     
         27 . The pharmaceutical composition of any one of  claims 18 - 26 , which when ingested by a human subject, provides a reduced level of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide formed in the human subject, relative to the level of 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide formed when an equivalent molar amount of non-deuterium-enriched laquinimod is ingested by the human subject. 
     
     
         28 . A process for preparing the pharmaceutical composition of any one of  claims 18 - 27 , comprising:
 a) obtaining a batch of deuterium-enriched laquinimod or a pharmaceutically acceptable salt thereof;   b) determining by apparatus the total amount of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide present in the batch of deuterium-enriched laquinimod or a pharmaceutically acceptable salt thereof; and   c) preparing the pharmaceutical composition using the batch only if the batch is determined to have less than 0.1% by weight of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide.   
     
     
         29 . A process for producing a validated batch of the pharmaceutical composition of any one of  claims 18 - 27  for distribution comprising:
 a) obtaining a batch of the pharmaceutical composition; 
 b) determining by apparatus the total amount of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide in a sample of the batch; and 
 c) validating the batch for distribution only if the sample of the batch is determined to contain less than 0.1% by weight of optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide relative to the combined weight of laquinimod and optionally deuterated 5-chloro-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide. 
 
     
     
         30 . A deuterium-enriched compound having the structure: 
       
         
           
           
               
               
           
         
       
       wherein each of R1-R10 is independently H or D, and at least one of R1-R10 is D, or a pharmaceutically acceptable salt thereof, 
       for use in an amount of 0.2 mg-2 mg per day in treating an autoimmune disease in a human subject.